ICHG2016

MyAbstract
Program
The 13th International Congress of Human Genetics
ICHG2016 2
Sun.,April 03
Day 1
Day 1
Main Hall (1F)
[PrCS] Pre-Congress Symposium

Human Genetics on the Globe 16:00-18:30
Chair (Keynote)：Shoji Tsuji（Department of Neurology and Medical Genome Center, The University of Tokyo Hospital;
Medical Genomics Research Initiative, The University of Tokyo, Japan）
Chair ：Yoshimitsu Fukushima（Ex-President, The Japan Society of Human Genetics; Professor, Department of Medical
Genetics, Shinshu University School of Medicine, Japan）
Chair ：Han G. Brunner（Radboud UMC, Department of Human Genetics 855, Nijmegen; Maastricht University Medical
Center, Department of Clinical Genetics, Maastricht, The Netherlands）
Sun(1)-PrCS-1 (Keynote) DOCUMENTING AND PRESERVING THE HISTORY OF HUMAN GENETICS - WHAT HAVE
WE ACHIEVED? ···························································································································· 137
Peter S. Harper（Institute of Medical Genetics, Cardiff University, UK）
Sun(1)-PrCS-2 The mission of International Federation of Human Genetic Societies ·············································· 139
Helena Kääriäinen（Research Professor at National Institute for Health and Welfare, Helsinki; Clinical Geneticist,
Finland）
Sun(1)-PrCS-3 The American Society of Human Genetics and International Human Genetics ·································· 140
Nancy Cox（Vanderbilt University Medical Center, USA）
Sun(1)-PrCS-4 Human Genetics in Europe: Exciting history, present fact and future1challenges ······························ 141
Feliciano J. Ramos（President of European Society of Human Genetics (ESHG), Spain）
Sun(1)-PrCS-5 The Human Genetics Society of Australasia (HGSA) - Current challenges ······································· 142
Eric Haan（SA Pathology, Adelaide, Australia）
Sun(1)-PrCS-6 Asia Pacific Society of Human Genetics ······················································································ 144
Carmencita D. Padilla（Department of Pediatrics, College of Medicine, University of the Philippines Manila; Insti-
tute of Human Genetics, National Institutes of Health, University of the Philippines Manila; Philippine Genome
Center, University of the Philippines System, Philippines/Institute of Human Genetics, National Institutes of
Health, University of the Philippines Manila/Philippine Genome Center, University of the Philippines System）
Sun(1)-PrCS-7 Human Genetics in Latin America ······························································································ 145
Roberto Giugliani（Department of Genetics, Federal University of Rio Grande do Sul (UFRGS)l; Medical Ge-
netics Service, Hospital de Clinicas de Porto Alegre (HCPA); National Institute of Population Medical Genetics
(INAGEMP), Brazil/Medical Genetics Service, Hospital de Clinicas de Porto Alegre (HCPA), Brazil/National
Institute of Population Medical Genetics (INAGEMP), Brazil）
Sun(1)-PrCS-8 The African Society of Human Genetics ······················································································ 146
Charles N. Rotimi（Center for Research on Genomics and Global Health, National Human Genome Research
Institute, NIH, USA）
Sun(1)-PrCS-9 Medical Genetics Services in China ····························································································· 147
Xue Zhang（McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences & Peking Union
Medical College, China）
Sun(1)-PrCS-10 Human Genetics in Korea as a member of the EAUHGS ····························································· 148
Jin-Sung Lee（Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea）
Sun(1)-PrCS-11 Human Genetics in Japan ········································································································ 149
Yoichi Matsubara（National Center for Child Health and Development, Japan）
Garden and Banquet Hall Swan (1F)
Get-together 19:00-20:30
···················································································································································· 518
ICHG2016 3
Mon.,April 04
Day 2
Main Hall (1F)
Day 2
Opening Ceremony 10:00-10:30
···················································································································································· 515
[PL1] Plenary Lecture 1 10:30-12:00

Chair：Helena Kääriäinen（Research Professor at National Institute for Health and Welfare, Helsinki; Clinical Geneticist,
Finland）
Chair ：Shoji Tsuji（Department of Neurology and Medical Genome Center, The University of Tokyo Hospital; Medical
Genomics Research Initiative, The University of Tokyo, Japan）
Mon(2)-PL1-1 Recent Progress in iPS Cell Research and Application ··································································· 126
Shinya Yamanaka（Center for iPS Cell Research and Application (CiRA), Kyoto University, Japan）
Mon(2)-PL1-2 Secrets of the Human Genome: The 35-year journey of genomic medicine ······································· 128
Eric S. Lander（The Eli and Edythe L. Broad Institute; Department of Biology, Massachusetts Institute of
Technology, Cambridge, MA, USA）
Annex 1 (1F)
[LS1] Luncheon Seminar 1

The Value of Pedigree Analysis and Genetic Counseling for Fabry Disease Management 12:20-13:20
Chair：Norio Sakai（Professor, Division of Health Science, Osaka University Graduate School of Medicine）
Sumitomo Dainippon Pharma Co., Ltd.
The Value of Pedigree Analysis and Genetic Counseling for Fabry Disease Management ··························· 491
Paula Adriana Rozenfeld（IIFP (Institute for study of Immunology and Physiopathology) Facultad de Ciencias
Exactas, Universidad Nacional de La Plata and CONICET）
[CIS1] Concurrent Invited Session 1

Functional and Computational Genomics 13:30-15:30
Convener：Hiroyuki Aburatani（Research Center for Advanced Science and Technology, The University of Tokyo, Japan）
Convener ：Manolis Kellis（MIT Computational Biology, USA）
Mon(2)-CIS1-1 Dissecting the circuitry of FTO and adipocyte browning in human obesity ······································ 150
Melina Claussnitzer（BIDMC, Harvard Medical School, USA）
Mon(2)-CIS1-2 Histone Acetylome-wide Association Studies ··············································································· 151
Shyam Prabhakar（Computational and Systems Biology, Genome Institute of Singapore, Singapore）
Mon(2)-CIS1-3 A human variation panel of genetic influences on epigenomes and transcriptomes in three immune cells
······················································································································································ 152
Nicole Soranzo（Human Genetics, Wellcome Trust Sanger Institute, UK/Department of Hematology, University
of Cambridge）
Mon(2)-CIS1-4 Integrated genomic analysis of liver cancer progression ································································· 153
Hiroyuki Aburatani（Research Center for Advanced Science and Technology, The University of Tokyo, Japan）
ICHG2016 4

New Technology: Single Cell Sequencing 15:50-17:50
Convener：Sumio Sugano（Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University
of Tokyo, Japan）
Convener ：Stephen Quake（Departments of Applied Physics and Bioengineering, Stanford University and Howard Hughes
Medical Institute, USA）
Day 2
Mon(2)-CIS2-1 Highly accurate and precise single-cell sequencing facilitated by microfluidics ·································· 154
Yanyi Huang（Biodynamic Optical Imaging Center, Peking University, China）
Mon(2)-CIS2-2 Molecular Anatomy of the Brain by Large-Scale Single-Cell RNA-Seq ············································ 156
Sten Linnarsson（Medical Biochemistry and Biophysics, Karolinska Institutet, Sweden）
Mon(2)-CIS2-3 Immunology from the “Bottom-Up” with Single-Cell Genomics ·················································· 157
Alex K. Shalek（IMES & Chemistry, MIT, Ragon Institute & Broad Institute, USA）
Mon(2)-CIS2-4 Single Cell Genomics ················································································································ 158
Stephen Quake（Departments of Applied Physics and Bioengineering, Stanford University and Howard Hughes
[O1] Cancer Genetics 1 18:00-19:30

Chair：Stephen E. Lincoln（Scientific Affairs, Invitae, USA）
Chair ：Yoichi Furukawa（Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo,
Japan）
Mon(2)-O1-1 Monitoring Cancer Burden in Liquid Biopsies Utilizing Two Assays; Amplicon Sequencing and Global Methylation
Patterns to Characterize cfDNA ······································································································· 520
Matthew Hymes（Swift Biosciences, USA）
Mon(2)-O1-2 Evaluation of prediction models for Lynch Syndrome: Updating the PREMM1,2,6 model to identify PMS2
mutation carriers ····························································································································· 520
Anne Goverde（Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, the Nether-
lands/Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the
Netherlands）
Mon(2)-O1-3 Rapid and comprehensive routine diagnostic approach for prognostic genetic markers in multiple myeloma
······················································································································································ 521
Jacqueline Schoumans（Medical Genetics, Centre Hospitalier Universitaire Vaudois CHUV, Switzerland）
Mon(2)-O1-4 Clinical Validity and Actionability of Multigene NGS-Based Tests for Hereditary Cancers in a Large Multi-Center
Study ··········································································································································· 522
Stephen E Lincoln（Invitae, USA）
Mon(2)-O1-5 The Mitochondrial Mutational Landscape of Human Cancer and its Impact on Cancer Progression
······················································································································································ 522
Sneha Grandhi（Genetics and Genome Sciences, Case Western Reserve University, USA）
Mon(2)-O1-6 Withdrawn ································································································································ 523
Annex 2 (1F)

Korean Hereditary Breast Cancer (KOHBRA) Study: Review and Future Perspectives 12:20-13:20
Chair：Seigo Nakamura（Department of Breast Surgical Oncology, Showa University School of Medicine, Japan）
AstraZeneca
Korean Hereditary Breast Cancer (KOHBRA) Study: Review and Future Perspectives ····························· 492
Sung-Won Kim（Department of Surgery, Breast Care Center, Daerim St. Mary’s Hospital, Korea）
ICHG2016 5

Implementation of Genome Information for Health Care and Drug Discovery 13:30-15:30
Convener：Robyn Ward（The University of Queensland, Australia）
Convener ：Geoffrey Ginsburg（Duke University, School of Medicine; Pratt School of Engineering, USA）
Mon(2)-CIS3-1 Assessing the value of genomics ································································································ 159
Day 2
Robyn Ward（The University of Queensland, Australia）
Mon(2)-CIS3-2 Implementation of Genome Information for Health Care and Drug Discovery ··································· 161
Geoffrey Ginsburg（Duke University, School of Medicine; Pratt School of Engineering, USA）
Mon(2)-CIS3-3 The New Era of Drug Discovery: Human Genetics, Data Science & New Modalities ························ 162
Andrew S. Plump（Chief Medical & Scientific Officer, Takeda Pharmaceutical Co., Ltd., USA）
Mon(2)-CIS3-4 Making Discoveries on the 23andMe Platform ············································································· 163
Anne Wojcicki（23andMe., USA）

Regenerative Medicine 15:50-17:50
Convener：Haruhisa Inoue（Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application
(CiRA), Kyoto University, Japan）
Convener ：John D. Sinden（ReNeuron Limited, UK）
Mon(2)-CIS4-1 Stem cell therapies in Europe: Taking the CTX human neural stem cell product to clinical trials in disabled
stroke patients ································································································································ 164
John D. Sinden（ReNeuron Limited, UK）
Mon(2)-CIS4-2 Engineering the Morphogenesis of Pluripotent Stem Cells ····························································· 165
Todd C. McDevitt（Gladstone Institutes of Cardiovascular Diseases; Bioengineering and Therapeutics at the
University of California, San Francisco, USA）
Mon(2)-CIS4-3 Retinal stem cells from bench to clinic ······················································································· 171
Petr Baranov（Schepens Eye Research Institute, Mssachusetts Eye & Ear; Department of Ophthalmology, Harvard
Medical School, Boston MA, USA）
Mon(2)-CIS4-4 Possible future of regenerative medicine using cell sheet engineering and iPS cell technology ············· 172
Katsuhisa Matsuura（Tokyo Women’s Medical University, Japan）
[O2] Genetics/Genomics Education 18:00-19:30

Chair：Brenda J. Wilson（School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Canada）
Chair ：Takahito Wada（Department of Medical Ethics and Medical Genetics, Kyoto University Graduate School of Medicine,
Japan）
Mon(2)-O2-1 Genomics and personalized medicine in primary care: a professional engagement study using theory-informed
approaches ···································································································································· 524
Brenda J Wilson（School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Canada）
Mon(2)-O2-2 Supporting the workforce to deliver the 100,000 Genomes Project: the work of Health Education England’s
Genomics Education Programme ······································································································ 525
Michelle Bishop（Genomics Education Programme, Health Education England, UK）
Mon(2)-O2-3 Human Genetics: Medical and Societal Implications. A high school course on a medical school campus
······················································································································································ 525
Maurice Godfrey（Munroe Meyer Institute, University of Nebraska Medical Center, USA）
Mon(2)-O2-4 Impact of educational messages for parents about newborn screening: a randomized factorial survey
······················································································································································ 526
Beth K Potter（University of Ottawa, Canada）
Mon(2)-O2-5 A psycho-educational intervention for people with a family history of depression for use in general practice.
Results from pilot testing ················································································································ 527
Kristine K Barlow-Stewart（Sydney Medical School Northern, University of Sydney, Australia）
Mon(2)-O2-6 Exploring Australian public knowledge and understanding of DNA, genes and genetic testing in the era of
personal genomics ·························································································································· 527
Bronwyn N Terrill（Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Australia）
ICHG2016 6
Room A (2F)

Precision Oncology with IBM Watson 12:20-13:20
Chair：Yoichi Furukawa（Institute of Medical Science, University of Tokyo, Japan）
Day 2
IBM Japan
Precision Oncology with IBM Watson ································································································ 493

Takahiko Koyama（IBM T. J. Watson Research Center, USA）

Advances in Cancer Genomics 13:30-15:30
Convener：Tatsuhiro Shibata（Laboratory of Molecular Medicine & Laboratory of Genome Technology of Human Genome
Center, Institute of Medical Science, The University of Tokyo, Japan）
Convener ：David A. Wheeler（Human Genome Sequencing Center/ Baylor College of Medicine, USA）
Mon(2)-CIS5-1 Genomic Profiling of a T-cell Leukemia ······················································································ 174

David A. Wheeler（Human Genome Sequencing Center/ Baylor College of Medicine, USA）
Mon(2)-CIS5-2 Genetic and transcriptomic landscape of biliary tract cancer ·························································· 176
Tatsuhiro Shibata（Laboratory of Molecular Medicine, The Institute of Medical Science, The University of Tokyo;
Division of Cancer Genomics, National Cancer Center, Japan/Division of Cancer Genomics, National Cancer
Center）
Mon(2)-CIS5-3 ASIAN CANCER GENOMICS AND ITS CLINICAL IMPLICATIONS ············································· 177
Bin Tean Teh（National Cancer Centre Singapore, Singapore）
Mon(2)-CIS5-4 The evolutionary history of prostate cancer from pre-malignant lesion to lethal metastasis ················ 178
David Wedge（Cancer Genome Project, Wellcome Trust Sanger Institute, UK）

Cancer Genomics: HBOC 15:50-17:50
Convener：Seigo Nakamura（Department of Breast Surgical Oncology, Showa University School of Medicine, Japan）
Convener ：Sung-Won Kim（Daerim St. Mary’s Hospital, Korea）
Mon(2)-CIS6-1 The current approach for hereditary breast cancer from the aspect of precision medicine in the U.S.
······················································································································································ 180
Banu Arun（University of Texas MD Anderson Cancer Center, USA）
Mon(2)-CIS6-2 Current Status and Future of Hereditary Breast Cancer in Asia ····················································· 181
Ava Kwong（Division of Breast Surgery, Department of Surgery, The University of Hong Kong, Hong Kong,
China/The University of Hong Kong Shen Zhen Hospital, China/The Hong Kong Hereditary Breast Cancer
Family Registry/Hong Kong Sanatorium and Hospital, Hong Kong）
Mon(2)-CIS6-3 The current approach for hereditary breast cancer from the aspect of basic science ·························· 182
Soo H. Teo（Cancer Research Malaysia; University Malaya Medical Center, Malaysia/University Malaya Medical
Centre）
Mon(2)-CIS6-4 Updates of the Korean Hereditary Breast Cancer (KOHBRA) Study ·············································· 183
Sung-Won Kim（Surgery, Daerim St. Mary’s Hospital, Korea）
[O3] Prenatal, Perinatal and Reproductive Genetics 1 18:00-19:30

Chair：Lingqian Wu（State Key Laboratory of Medical Genetics, Central South University, China）
Chair ：Michiko Yamanaka（Dept. Clinical Genetics, St.Luke’s International Hospital, Japan）
Mon(2)-O3-1 Noninvasive Prenatal Testing and its Relevance to Clinical Practice: Update on Clinical Outcome Metrics on
Over 85,000 Cases ························································································································· 529
Sucheta Bhatt（Illumina, Redwood City, CA, USA）
Mon(2)-O3-2 Non-invasive prenatal diagnosis for single gene disorders ································································ 529
Lingqian Wu（State Key Laboratory of Medical Genetics, Central South University, China/Hunan Jiahui Genetics
Hospital, Changsha, China）
ICHG2016 7
Mon(2)-O3-3 Indication and detective rate of amniocentesis changed by the adoption of non-invasive prenatal genetic testing
···················································································································································· 530
Rie Oi（Obstetrics, Aiiku Hospital, Japan/Graduate School of Tokyo Medical and Dental University）
Mon(2)-O3-4 Development and validation of a novel whole genome sequencing pipeline for non-invasive prenatal detection of
fetal submicroscopic chromosome anomalies ······················································································ 531
Desheng Liang（State Key Laboratory of Medical Genetics, Central South University, China/Hunan Jiahui Ge-
Day 2
netics Hospital, Changsha, China）
Mon(2)-O3-5 Informed Choice in Prenatal Genetic Testing: the Choice Between Non-invasive and Invasive Prenatal Testing
······················································································································································ 531
Karin E.M. Diderich（Clinical Genetics, Erasmus MC, Netherlands）
Mon(2)-O3-6 Differences in the background factors and awareness of noninvasive prenatal testing between pregnancies
achieved with assisted reproductive technology and spontaneous pregnancy in Japan ······························ 532
Akimune Fukushima（Clnical Genetics, School of Medicine, Iwate Medical University, Japan）
Room E (1F)

MaterniT™ GENOME” 12:20-13:20
Chair：Akihiko Sekizawa（Professor and Chairman, Department of Obstetrics and Gynecology, Showa University School of
Medicine, Japan）
GeneTech Inc.
MaterniT™ GENOME” ·················································································································· 494

Mathias Ehrich（Senior Vice President, Research & Development, Sequenom, Inc., USA）

Human Evolution: Archaic and Modern Humans 13:30-15:30
Convener：Naruya Saitou（Division of Population Genetics, National Institute of Genetics, Japan）
Convener ：Mark Stoneking（Max Planck Institute for Evolutionary Anthropology, Germany）
Mon(2)-CIS7-1 Population genetic analysis of Negrito populations in Southeast Asia ············································· 185
Timothy A. Jinam（Division of Population Genetics, National Institute of Genetics, Japan）
Mon(2)-CIS7-2 Ancient DNA of early modern humans ······················································································· 186
Qiaomei Fu（Institute of Vertebrate Paleontology and Paleoanthropology, Chinese Academy of Sciences, China）
Mon(2)-CIS7-3 A Genomic Perspective on the Colonization of the Pacific ···························································· 187
Mark Stoneking（Max Planck Institute for Evolutionary Anthropology, Germany）
Mon(2)-CIS7-4 Formation of Japonesian from viewpoint of modern human dispersal in East Eurasia ······················· 188
Naruya Saitou（Division of Population Genetics, National Institute of Genetics; Department of Genetics, SOK-
ENDAI; Department of Biological Sciences, Graduate School of Science, University of Tokyo, Japan/Department
of Genetics, SOKENDAI/Department of Biological Sciences, Graduate School of Science, University of Tokyo）

Genetics of Recurrent Pregnancy Loss 15:50-17:50
Convener：Mayumi Sugiura-Ogasawara（Obstetrics and Gynecology, Nagoya City University, Graduate School of Medical
Sciences; Center for Recurrent Pregnancy Loss, Japan）
Convener ：Mary D. Stephenson（Department of Obstetrics and Gynecology, University of Illinois at Chicago, USA）
Mon(2)-CIS8-1 Miscarriage chromosome testing: Conventional cytogenetic analysis vs. molecular ··························· 189
Evica Rajcan-Separovic（Department of Pathology, University of British Columbia, Canada）
Mon(2)-CIS8-2 Recurrent Pregnancy Loss: Miscarriage and Parental Chromosome Testing ····································· 191
Mary D. Stephenson（Department of Obstetrics and Gynecology, University of Illinois at Chicago, USA）
Mon(2)-CIS8-3 Can PGS/PGD improve live birth rate in RPL? ··········································································· 192
Ruth B. Lathi（Department of Reproductive Rndocrinology and Infertility, Stanford University, USA）
ICHG2016 8
Mon(2)-CIS8-4 Candidate genes associated with recurrent pregnancy loss ····························································· 193
Mayumi Sugiura-Ogasawara（Obstetrics and Gynecology, Nagoya City University, Graduate School of Medical
Sciences; Center for Recurrent Pregnancy Loss, Japan/Center for Recurrent Pregnancy Loss）
[O4] Bioinformatics and Genomic Technology 1 18:00-19:30
Day 2
Chair：Altuna Akalin（BIMSB, Max Delbrueck Center, Germany）
Chair ：Masao Nagasaki（Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University,
Japan）
Mon(2)-O4-1 A shared system for collating, storing, analysing and reporting clinical genomic data across ten independent
organisations: a demonstration evaluation ························································································· 533
Clara L. Gaff（Melbourne Genomics Health Alliance, Australia）
Mon(2)-O4-2 A systematic computational pipeline for mining high-confidence candidate mirSNPs in Hypertension-implicated
genes ············································································································································ 534
Linda Koshy Vaidyan（Inter-University Centre for Genomics and Gene Technology, Department of Biotechnology,
Kerala University, India）
Mon(2)-O4-3 The BioOntological Relationship Graph (BORG) Database - a Novel Concept for Prioritizing Candidates from
High Throughput Genomics Studies ································································································· 534
Junaid Gamieldien（South African National Bioinformatics Institute, University of the Western Cape, South
Africa）
Mon(2)-O4-4 An automatic pipeline for analyzing sequencing data in families for disease studies ···························· 535
Ren-Hua Chung（Institute of Population Health Sciences, National Health Research Institutes, Taiwan）
Mon(2)-O4-5 coalescentSTR: a statistical method that estimates repeat numbers for multiple samples from high-throughput
sequencing data by considering coalescent theory ··············································································· 535
Kaname Kojima（Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Japan）
Mon(2)-O4-6 A Statistical Exploration of How Multiple Enhancers Affect Traits Jointly ········································ 536
Yutaka Yasui（St. Jude Children’s Research Hospital, USA）
Room B-1 (2F)

Using Single Cell Genomics to Deconvolute Dynamic Biological Processes 12:20-13:20
Chair：Naoya Hosono（Application Specialist, Fluidigm K.K.）
Fluidigm Corporation
Using Single Cell Genomics to Deconvolute Dynamic Biological Processes ·············································· 495
Charles Gawad（Oncology Department, St. Jude Children’s Research Hospital）

Clinical Genetics and Dysmorphology 13:30-15:30
Convener：Hiroshi Kawame（Department of Education and Training, Tohoku University, Japan）
Convener ：Louanne Hudgins（Pediatrics/Medical Genetics, Stanford University School of Medicine, USA）
Mon(2)-CIS9-1 Prenatal Presentation of Genetic Disorders ················································································· 195

Louanne Hudgins（Pediatrics/Medical Genetics, Stanford University School of Medicine, USA）
Mon(2)-CIS9-2 Next Generation Sequencing demands Next Generation Phenotyping ·············································· 197
Raoul C. Hennekam（Department of Paediatrics, Academic Medical Center, University of Amsterdam, The Nether-
lands）
Mon(2)-CIS9-3 Primary microcephalies and primordial microcephalic dwarfisms ····················································· 198
Alain Verloes（Dept of Genetics, Robert DEBRE Univerity Hospital, Sorbonne Paris-Cité University Denis Diderot
Medical School and INSERM UM1141, Paris, France）
Mon(2)-CIS9-4 From dysmorphology to human biology: A lesson from the discovery of Ehlers-Danlos syndrome caused by
CHST14/D4ST1 deficiency ·············································································································· 199
Tomoki Kosho（Medical Genetics, Shinshu University School of Medicine, Japan）
ICHG2016 9

Human Genomics in Infectious Diseases 15:50-17:50
Convener：Katsushi Tokunaga（Department of Human Genetics, The University of Tokyo Graduate School of Medicine,
Japan）
Convener：Adrian V.S. Hill（Director of Jenner Institute & Wellcome Trust Centre for Human Genetics, University of Oxford,
UK）
Day 2
Mon(2)-CIS10-1 Genetic Susceptibility to some Common Bacterial Diseases of Humans ········································· 200
Adrian V.S. Hill（Wellcome Trust Centre for Human Genetics, Oxford University, UK）
Mon(2)-CIS10-2 Immunogenetic Factors that Impact the Course of HIV infection ·················································· 201
Mary Carrington（Cancer and Inflammation Program, Leidos Biomedical Research Inc., Frederick National Lab-
oratory for Cancer Research, USA）
Mon(2)-CIS10-3 Genetic Study of Leprosy in Chinese Population: Susceptibility and Treatment Response ················ 202
Jianjun Liu（Human Genetics, Genome Institute of Singapore, Singapore）
Mon(2)-CIS10-4 Genomic approaches to hepatitis B virus related diseases ···························································· 203
Katsushi Tokunaga（Department of Human Genetics, The University of Tokyo Graduate School of Medicine,
Japan）
[O5] Clinical Genetics and Dysmorphology 1 18:00-19:30

Chair：Pornswan Wasant（Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Siriraj Hospital,
Mahidol University, Thailand）
Chair ：Kayoko Saito（Institute of Medical Genetics, Tokyo Women’s Medical University, Japan）
Mon(2)-O5-1 Heterozygous mutation of alpha 3 chain of collagen type IV (COL4A3 ) in a large Japanese pedigree with
autosomal dominant Alport syndrome showing a typical ultrastructural change in the glomerular basement membrane
(GBM) of the kidney ······················································································································· 537
Hiroyuki Morita（Division of Endocrinology and Metabolism, Department of Internal Medicine, Aichi Medical
University School of Medicine, Japan）
Mon(2)-O5-2 Identification of a 21.7kb deletion of SLC25A13 gene causing untranscription of the affected allele: Definite
diagnosis of an infant with citrin deficiency by using a diversity of molecular tools ·································· 538
Qi-Qi Zheng（Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China）
Mon(2)-O5-3 Unique biochemical alterations in patients with neonatal intrahepatic cholestasis caused by citrin deficiency: A
comparison with congenital biliary atresia and idiopathic infantile cholestasis ········································· 538
Wei-Xia Lin（Department of Pediatrics, the First Affiliated Hospital, Jinan University, Guangzhou, China）
Mon(2)-O5-4 The Common and Rare Variants of UGT1A1 in Neonatal Hyperbilirubinemia in Indonesian Population
······················································································································································ 539
Dewi A Wisnumurti（Neonatology Subdivision, Departement of Pediatric, Arifin Achmad General Hospital, Pekan-
baru, Indonesia）
Mon(2)-O5-5 Molecular Diagnosis of Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency by Analyzing SLC25A13
Gene and Its Transcripts in Peripheral Blood Mononuclear Cells ··························································· 540
Yuan-Zong Song（Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, Guang-
dong, China）
Mon(2)-O5-6 GATA binding protein 2 (GATA2) mutation identified in a Japanese patient with adult-onset pulmonary alveolar
proteinosis ····································································································································· 540
Ryushi Tazawa（Niigata University Medical and Dental Hospital, Japan）
Room B-2 (2F)
[O6] Complex Traits and Polygenic Disorders 1 18:00-19:30

Chair：Margaret Pericak-Vance（John P. Hussman Institute for Human Genomics, University of Miami Miller School of
Medicine, USA）
Chair ：Lin He（Human Neuropsychiatric Genetics Group of Shanghai Jiao Tong University & China Academy of Sciences,
China）
Mon(2)-O6-1 A novel regulatory variant of FADS1 determines binding of PATZ1 and is associated with metabolic and
inflammatory diseases ····················································································································· 542
Claes Wadelius（Immunology, Genetics and Pathology, Uppsala University, Sweden）
ICHG2016 10
Mon(2)-O6-2 A meta-analysis of genome-wide association studies for diabetic nephropathy in Japanese patients with type 2
diabetes ········································································································································· 542
Makiko Taira（Laboratory for Endocrinology, Metabolism and Kidney Diseases, Center for Integrative Medical
Sciences, RIKEN, Yokohama, Japan）
Mon(2)-O6-3 HETEROZYGOUS CONNEXIN50 MUTATION LOWERS BLOOD LIPIDS AND AFFECTS TRANSCRIPTOME
IN HEART AND KIDNEY IN A RAT MODEL ·················································································· 543
Day 2
Ondrej Seda（Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University in Prague,
Czech Republic）
Mon(2)-O6-4 Gaining mechanistic insights at type 2 diabetes and glycemic trait association loci by integration with human
pancreatic islet transcriptome and regulatory information ···································································· 544
Martijn van de Bunt（Wellcome Trust Centre for Human Genetics, University of Oxford, UK/Oxford Centre for
Diabetes, Endocrinology & Metabolism, University of Oxford）
Mon(2)-O6-5 Large scale exome array meta-analyses identify numerous novel common, low-frequency, and rare coding variants
associated with glycaemic traits ······································································································· 544
Hidetoshi Kitajima（Wellcome Trust Centre for Human Genetics, University of Oxford, UK）
Mon(2)-O6-6 Large-scale exome chip association analysis identifies novel type 2 diabetes susceptibility loci and highlights
candidate effector genes ·················································································································· 545
Anubha Mahajan（WTCHG, University of Oxford, UK）
Room C-1 (1F)
[O7] Molecular Basis of Mendelian Disorders 1 18:00-19:30

Chair：John Christodoulou（Neurodevelopmental Genomics Research Unit, Murdoch Childrens Research Institute, Australia）
Chair ：Mariko Taniguchi-Ikeda（Department of Pediatrics, Kobe University Graduate School of Medicine, Japan）
Mon(2)-O7-1 A Homozygous loss-of-function mutation in DNAJA3 causes Hereditary Motor and Sensory Neuropathy with
Spastic Paraplegia (HMSN type V) ·································································································· 546
Toshitaka Kawarai（Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate
School, Japan）
Mon(2)-O7-2 Genetic profile for suspected dysferlinopathy identified by targeted next generation sequencing ············· 547
Naoki Suzuki（Neurology, Tohoku University, Japan）
Mon(2)-O7-3 Plastin 3, a human protective modifier is highly upregulated in iPSC-derived motoneurons in asymptomatic
SMN1-deteted individuals and rescues spinal muscular atrophy in mice ················································· 547
Brunhilde Wirth（Institute of Human Genetics, Institute of Genetics and Center for Molecular Medicine Cologne,
University of Cologne, Cologne, Germany）
Mon(2)-O7-4 Evaluating biomarkers and natural history of Fukuyama Congenital Muscular Dystrophy ···················· 548
Mariko Taniguchi-Ikeda（Department of Pediatrics, Kobe University Graduate School of Medicine,
Japan/Department of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine）
Mon(2)-O7-5 Mutation in hnRNPA1 causes isolated inclusion body myopathy in two families with multisystem proteinopathy
···················································································································································· 549
Rumiko Izumi（the Department of Neurology, Tohoku University Graduate School of Medicine, Japan/the De-
partments of Medical Genetics, Tohoku University Graduate School of Medicine）
Mon(2)-O7-6 Biophysical characteristics of GJB1 mutations and the correlation with clinical phenotypes of Charcot-Marie-
Tooth disease type X1 ···················································································································· 549
Yo-Tsen Liu（Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Tai-
wan/Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan）
Room C-2 (1F)
[O8] Metabolic Disorders 1 18:00-19:30

Chair：David Thorburn（Genetics Theme, Murdoch Childrens Research Institute, Australia）
Chair ：Akira Ohtake（Pediatrics, Saitama Medical University, Japan）
Mon(2)-O8-1 A mitochondrial tRNA modopathy due to QRSL1 mutations causes infantile mitochondrial disease
······················································································································································ 551
Nana Akiyama（Clinical Genetics, Chiba Childrens Hospital, Japan）
ICHG2016 11
Mon(2)-O8-2 CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutropenia,
Epilepsy, and Methylglutaconic Aciduria ···························································································· 551
Elsebet Ostergaard（Clinical Genetics, Copenhagen University Hospital, Denmark）
Mon(2)-O8-3 A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex
deficiencies ···································································································································· 552
Masakazu Kohda（Research Center for Genomic Medicine, Saitama Medical University, Japan）
Day 2
Mon(2)-O8-4 Clinical, Molecular basis and Genetics of Hepatocerebral Mitochondrial DNA Depletion Syndrome in Japan
······················································································································································ 552
Masaru Shimura（Department of Metabolism, Chiba Children’s Hospital, Japan）
Mon(2)-O8-5 Modulation of Mitochondrial Bioenergetics in Fibroblasts Derived From Patients With A3243G Mitochondrial
DNA Mutation ······························································································································ 553
Dar-Shong Lin（Pediatric Genetics, Mackay Memorial Hospital, Taipei, Taiwan/Pediatric Neurology, Mackay
Memorial Hospital, Taipei, Taiwan）
Mon(2)-O8-6 Whole exome analysis of mitochondrial respiratory chain disorders: Prenatal genetic diagnosis ············· 554
Taro Yamazaki（Pediatrics, Saitama Medical University, Japan）
Room D (1F)

Addressing Unmet Medical Needs in Rare Hematological Diseases 12:20-13:20
Chair：Yoshikatsu Eto（Director, Advanced Clinical Research Center, Institute of Neurological Disorders / Tokyo Jikei
University School of Medicine, Tokyo, Japan）
Genzyme Japan K.K.
Addressing Unmet Medical Needs in Rare Hematological Diseases ························································· 496

Ana Cristina Scheidt Puga（Medical Director, Clinical Development Rare Diseases Sanofi Genzyme, USA）
[ED1] Educational Program 1

Career Development Sessions: How to Write a Good Manuscript 14:00-15:30
Moderator：Eiji Nanba（Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University,
Japan）
Moderator：Naomichi Matsumoto（Department of Human Genetics, Yokohama City University Graduate School of Medicine,
Japan）
Mon(2)-ED1-1 How to Write a Scientific Paper ································································································· 452

Maximilian Muenke（Chief, Medical Genetics Branch, National Human Genome Research Institute (NHGRI),
National Institutes of Health (NIH), and Director, NIH Medical Genetics and Genomic Medicine Residency and
Fellowship Programs, Bethesda, MD, USA）
Mon(2)-ED1-2 How to write a scientific paper and a good piece of literary prose ·················································· 454
Giovanni Neri（Institute of Medical Genetics, Università Cattolica del S. Cuore, Rome, Italy）

Career Development Sessions: How to Develop an Academic Career 15:50-16:50
Moderator：Kenjiro Kosaki（Center for Medical Genetics, Keio University School of Medicine, Japan）
Moderator ：Shinji Saitoh（Department of Pediatrics and Neonatology, Nagoya City University, Japan）
Mon(2)-ED2-1 Career Development Sessions: How to Develop Academic Career ··················································· 455
Judith G. Hall（Professor Emerita of Pediatrics and Medical Genetics, University of British Columbia, Canada）
ICHG2016 12
Room I (2F)
[O9] Psychiatric Genetics, Neurogenetics and Neurodegeneration 1 18:00-19:30

Chair：Bing-Wen Soong（Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan）
Chair ：Hiroyuki Takashima（Department of Neurology and Geriatrick, Kagoshima University, Japan）
Day 2
Mon(2)-O9-1 Target genes of transcriptional regulation by Dentatorubral-Pallidoluysian Atrophy protein (DRPLAp) that acts
as a transcriptional co-regulator ········································································································ 555
Keiko Hatano（Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan）
Mon(2)-O9-2 Sigmar1 receptor: Genetics, clinical/subclinical investigations and animal and cell models characterisation to
dissect the mechanisms of cell death leading to motor neuron disease ···················································· 556
Hamid Azzedine（Institute of Neuropathology, Germany）
Mon(2)-O9-3 Identification of Long non-coding RNA as a Novel Susceptibility Gene for Non-Familial Hypokalemic Periodic
Paralysis by GWAS ························································································································· 556
I-Wen Song（Institute of Biomedical Sciences, Academia Sinica, Taiwan）
Mon(2)-O9-4 Features of dysferlin mutations in Japan ······················································································ 557
Toshiaki Takahashi（Department of Neurology and Division of Clinical Research, National Hospital Organization
Sendai-Nishitaga National Hospital, Japan）
Mon(2)-O9-5 Mutations in CAPN1 Cause Autosomal Recessive Hereditary Spastic Paraplegia ······························· 557
Ziv Gan-Or（McGill University, Canada）
Mon(2)-O9-6 Exome sequencing of singletons from individual families revealed a novel causative gene for autosomal recessive
hereditary spastic paraplegia ············································································································ 558
Hiroyuki Ishiura（Department of Neurology, The University of Tokyo, Japan）
Room J (2F)
[O10] Development 18:00-19:30

Chair：Andrew McCallion（McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine,
USA）
Chair ：Tadashi Kaname（Genome Medicine, National Center for Child Health and Developmen, Japan）
Mon(2)-O10-1 Fast and effective genome editing to study dominant de novo mutations: the Wdr45 mouse model for BPAN
···················································································································································· 560
Caroline A. Biagosch（Institute of Human Genetics, Technische Universitaet Muenchen, Germany/Institute of
Human Genetics, Helmholtz Zentrum Muenchen, Neuherberg, Germany）
Mon(2)-O10-2 Placental phenotypes of Chst14 -/- fetal mice: a model for vascular manifestations in Ehlers-Danlos syndrome
caused by CHST14/D4ST1 deficiency ······························································································ 560
Takahiro Yoshizawa（Division of Laboratory Animal Research, Research Center for Human and Environmental
Sciences, Shinshu University, Japan）
Mon(2)-O10-3 Critical roles of Rdh10 in craniofacial development ······································································ 561
Hiroshi Kurosaka（Osaka University Graduate School of Dentistry, Japan/Stowers Institute for Medical Research）
Mon(2)-O10-4 Mutations in components of the endothelin 1-endothelin receptor type A signaling pathway cause homeotic
transformations of the first pharyngeal arch in humans ······································································· 562
Jeanne Amiel（Institut Imagine, France）
Mon(2)-O10-5 Cell culture model for X-linked disorder: craniofrontonasal dysplasia and severe phenotype in female
······················································································································································ 562
Masanori Sugimoto（Division of Molecular Genetics, ICMS, Fujita Health University, Japan）
Mon(2)-O10-6 MicroRNA in human induced pluripotent stem cells lineage specification ········································ 563
Lu Li（The Chinese University of Hong Kong - Chinese Academy of Sciences Guangzhou Institute of Biomedicine
and Health Joint Laboratory on Stem Cell and Regenerative Medicine, School of Biomedical Sciences, Faculty of
Medicine, The Chinese University of Hong Kong, China）
ICHG2016 13
Room K (2F)
[O11] Cytogenetics 18:00-19:30

Chair：Ina E. Amarillo（Cytogenomics and Molecular Path Lab, Division of Lab and Genomic Medicine, Dept. of Pathology
and Immunology, Washington University in St. Louis School of Medicine, USA）
Day 2
Chair ：Keiko Wakui（Medical Genetics, Shinshu University School of Medicine, Japan）
Mon(2)-O11-1 Finding Small Copy Number Variations (CNVs) and Regions of Homozygosity (ROH) Beneath the Surface: A
Retrospective Chromosome Microarray Analysis (CMA) and Genomic-Epigenomic Integration in Disorders of Sex
Development (DSD) ······················································································································· 564
Ina E Amarillo（Pathology and Immunology, Washington University in St Louis School of Medicine,
USA/Cytogenomics and Molecular Pathology Lab）
Mon(2)-O11-2 Assessing copy number variants involving the ACMGG secondary finding genes in a clinical pediatric population
···················································································································································· 564
Jinbo Fan（The Department of Pathology and Laboratory Medicine, The Childrens Hospital of Philadelphia,
USA）
Mon(2)-O11-3 Mechanistic Insight into Formation of Chromosomal Insertions ····················································· 565
Shen Gu（Molecular and Human Genetics, Baylor College of Medicine, USA）
Mon(2)-O11-4 Cytogenetic study of Ovotesticular Disorder of Sex Development (OT- DSD) among Egyptian DSD patients
······················································································································································ 566
Mona K. Mekkawy（Human Cytogenetics department, National Research Centre, Egypt）
Mon(2)-O11-5 Contribution of genomic copy number variations in prenatal oral clefts: a multi-center cohort study
······················································································································································ 566
Ye CAO（Department of Obstetrics and Gynecology, The Chinese University of Hong Kong, Hong Kong/Shenzhen
Research Institute, The Chinese University of Hong Kong, Shenzhen, China）
Mon(2)-O11-6 Blood SNP-array can replace bone marrow SNP-array in Myelodysplastic Syndrome (MDS) and may be used
in place of Karyotype in some patients ······························································································ 567
Sarah Moore（Genetics and Molecular Pathology, SA Pathology, Australia）
Room H (1F)
[O12] Statistical Genetics and Genetic Epidemiology 1 18:00-19:30

Chair：Suzanne M. Leal（Department of Molecular and Human Genetics, Baylor College of Medicine, USA）
Chair ：Taesung Park（Statistics, Seoul National University, Korea, South）
Mon(2)-O12-1 Collapsed Methylation Quantitative Trait Loci analysis for Low Frequency and Rare variants ············· 568
Tom G Richardson（MRC Integrative Epidemiology Unit, University of Bristol, UK）
Mon(2)-O12-2 A statistical approach for testing cross-phenotype effects of rare variants ······································· 568
Michael P Epstein（Human Genetics, Emory University, USA）
Mon(2)-O12-3 Pitfalls in the development of statistical methods for rare variant association studies ······················· 569
Suzanne M Leal（Molecular and Human Genetics, Baylor College of Medicine, USA）
Mon(2)-O12-4 Pathway-based association tests for rare variants using hierarchical structures ································· 570
Sungkyoung Choi（Interdisciplinary Program in bioinformatics, Seoul National University, Korea, South）
Mon(2)-O12-5 Increased power for detection of parent-of-origin effects via the use of haplotype estimation ············· 570
Richard A. J. Howey（Institute of Genetic Medicine, Newcastle University, UK）
Mon(2)-O12-6 FINEMAP: Ultrafast high-resolution fine-mapping using summary data from genome-wide association studies
···················································································································································· 571
Christian Benner（Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Fin-
land/Department of Public Health, University of Helsinki, Helsinki, Finland）
ICHG2016 14
Event Hall (1F)
Poster Session
Cancer Genetics 1 19:40-20:40
Day 2
Mon(2)-P-1 TP53 gene status in patients with Diffuse large B-cells lymphoma ····················································· 772
Elena Voropaeva（Institute of Therapy and Preventive Medicine, Russia）
Mon(2)-P-2 Withdrawn ·································································································································· 772
Mon(2)-P-3 Germline mutation and IHC result of MLH1 and MSH2 in young-onset nonpolyposis colorectal cancer in Thai
families: Two novel germline mutations of MLH1 in two siblings and a novel mutation of MSH2 ············· 773
Atchara Tunteeratum（Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand）
Mon(2)-P-4 Low grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma: studies on impact of gene fusions on
gene expression profile and tumor development ··················································································· 774
Elsa Arbajian（Clinical Genetics, Lund University, Sweden）
Mon(2)-P-5 Pediatric individualized dosing of Cyclophosphamide using Pharmacogenetics of CYP2B6 as a response-biomarker
in Rhabdomyosarcoma Egyptian Patients ··························································································· 774
Rania M Labib（Research, Children’s Cancer Hospital, Egypt/Clinical Pharmacy, Faculty of Pharmacy, Beni Suef
University, Beni Suef, Egypt）
Mon(2)-P-7 The ESR1 Gene rs1801132 variation and Breast Cancer risk in Iran ··················································· 775
Sakineh Abbasi（Tehran University of Medical Sciences, Tehran, Iran）
Mon(2)-P-8 To Investigate the Mechanism and Function of Nucleobindin-2 in Human Hepatoma Cells ···················· 775
Jui-Hsiang Hung（Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan, Tai-
wan/Drug Discovery and Development Center, Chia Nan University of Pharmacy and Science, Tainan, Taiwan）
Mon(2)-P-9 Drug Metabolizing Enzymes Polymorphisms May Determine Response and Toxicity of Chemotherapy based
Treatment in Breast Cancer Patients: a North Indian Study ································································· 776
Sonam Tulsyan（Genetics, SGPGIMS, India）
Mon(2)-P-10 Integrated miRNA and mRNA expression profiling to identify biomarkers for response to treatment in rectal
cancer ··········································································································································· 777
Marta Cuadros（Department of Biochemistry and Molecular Biology III e Immunology, Medicine College, Uni-
versity of Granada, Spain）
Mon(2)-P-12 Modification of association between polymorphism in genes UGT1A6 and PAFAH1B2 with colorectal cancer
risk by aspirin use ···························································································································· 777
Harsh Sheth（Institute of Genetic Medicine, Newcastle University, UK）
Mon(2)-P-13 A germline RAD51C duplication in breast and ovarian cancer ·························································· 778
Liisa M. Pelttari（Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University
Hospital, Helsinki, Finland）
Mon(2)-P-14 Cytogenetic and molecular assessment of oral cancer risk in smokeless tobacco users and their association with
socio economic strategies ················································································································· 778
Ramachandran Chandirasekar（Department of Zoology, Bharathiar University, India/PG and Research Depart-
ment of Zoology Sri Vasavi College Erode, India）
Mon(2)-P-15 The association of patatin-like phospholipase domain-containing protein 3 polymorphism with the development
and prognosis of hepatocellular carcinoma in Thai population ······························································· 779
Pisit Tangkijvanich（Research Unit of Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of
Medicine, Chulalongkorn University, Thailand）
Mon(2)-P-16 Circulating MicroRNAs as Potential Biomarkers in Hepatocellular Carcinoma ····································· 780
Yu Jin（National Cancer Centre Singapore, Singapore）
Mon(2)-P-17 FANCM c.5101C>T mutation and breast cancer survival ································································ 780
Johanna I. Kiiski（Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University
Hospital, Finland）
Mon(2)-P-18 Fine mapping of nasopharyngeal carcinoma susceptible region discovered by genome-wide association study
······················································································································································ 781
Wen-Hui Su（Dept. of Biomedical Sciences, Chang Gung University, Taiwan）
ICHG2016 15
Mon(2)-P-19 Polymorphism in chromosome 5 is associated with survival specifically among breast cancer patients treated
with endocrine therapy ····················································································································· 781
Sofia Khan（Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital,
Helsinki, Finland）
Mon(2)-P-20 Gene expression and relapse of superficial cell carcinoma. A microarray analysis ································· 782
Jaroslav Mares（Inst. Biol. Med. Genet., 2nd Faculty of Medicine, Charles University, Czech Republic）
Day 2
Mon(2)-P-21 Effect of Paclitaxel on miRNA expression in prostate cancer ···························································· 782
Murat Samli（Department of Urology, Acibadem University, Turkey）
Mon(2)-P-22 Analysis of cytogenetic alterations and polymorphism in MTHFR gene of Colorectal Cancer patients in Indian
population ······································································································································ 783
Vellingiri Balachandar（Human Genetics and Molecular Biology, Bharathiar University, India）
Mon(2)-P-23 Identification of Genetics alterations in Colorectal Cancer Patients in Coimbatore Population, South India
······················································································································································ 784
Dhivya Venkatesan（Department of Human Genetics and Molecular Biology, Bharathiar University, India）
Mon(2)-P-24 Detection of BRCA1 gene polymorphism in Breast Cancer Patients in South Indian population ············· 784
Balasubramanian Venkatesh（Department of Human Genetics and Molecular Biology, Bharathiar University,
Coimbatore, Tamil Nadu, India/Department of Microbial biotechnology, Bharathiar University, Coimbatore, In-
dia）
Mon(2)-P-25 Association of MYCN status with certain prognosis factors of neuroblastomas ··································· 785
Quang Dinh Vu（Human Genetics Department, National Hospital of Pediatrics, Vietnam）
Mon(2)-P-26 CYTOGENETIC INVESTIGATION, BIOCHEMICAL ALTERATIONS AND METHYLENETETRAHYDROFO-
LATE REDUCTASE (MTHFR) GENE POLYMORPHISM IN BREAST CANCER PATIENTS IN TAMIL NADU
POPULATION ································································································································ 786
Shantkriti S（Department of Biotechnology, National College, Tamilnadu, India）
Mon(2)-P-27 ANO7 is associated with aggressive prostate cancer ········································································ 787
Elina Kaikkonen（Medical Biochemistry and Genetics, University of Turku, Turku, Finland）
Mon(2)-P-28 Three microRNAs are associated with poor prognosis in squamous cell carcinoma of the lung ·············· 787
Sana Yokoi（Cancer Genome Center, Chiba Cancer Center Research Institute, Japan/Division of Gene Diagnostics,
Chiba Cancer Center）
Mon(2)-P-29 Clinical Significance of MLH1 Methylation and CpG Island Methylator Phenotype as Prognostic Markers in
Patients with Gastric Cancer ············································································································ 788
Yoshiko Mori（Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and
Pharmaceutical Sciences, Japan/Clinical Genomic Medicine, Okayama University Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences）
Mon(2)-P-31 Discovery of a gene alteration that causes clear cell carcinoma of the ovary ······································· 788
Yusuke Shibuya（Department of Obstetrics and Gynecology, Tohoku University Hospital, Japan）
Mon(2)-P-32 Identification of transcriptomic signatures in multiple myeloma using single cell RNA-sequencing ············· 789
Da-eun Ryu（Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences
and Technology, Sungkyunkwan University, Korea, South/Samsung Genome Institute）
Mon(2)-P-33 FRY Pancreas-Specific Methylation and Clinical Application ··························································· 789
Nakarin Kitkumthorn（Oral Biology, Faculty of Dentistry, Mahidol University, Thailand）
Mon(2)-P-34 Chromosome 3p rearrangement and BAP1 mutations in renal cell carcinomas and malignant mesotheliomas
······················································································································································ 790
Tomoko Hashimoto-Tamaoki（Department of Genetics, Hyogo College of Medicine, Japan/Department of Clinical
Genetics, Hyogo College of Medicine, Hyogo, Japan）
Mon(2)-P-35 Functional Characterization of Coexistent KRAS/PIK3CA and NRAS/PIK3CA Mutations in Colorectal Cancer
······················································································································································ 791
Joshua Reginald P. Malapit（Disease Molecular Biology and Epigenetics Laboratory, National Institute of Molec-
ular Biology and Biotechnology, University of the Philippines - Diliman, Philippines）
Mon(2)-P-36 Thyrotropin-releasing hormone (TRH) methylation in squamous cell carcinoma ·································· 791
Kanwalat Chalertpet（Biomedical Sciences, Chulalongkorn University, Thailand）
Mon(2)-P-37 Characterization of UROC3 as a novel prognostic biomarker and therapeutic target for oral cancer
······················································································································································ 792
Thang Manh Phung（Center for Antibody and Vaccine Therapy, Research Hospital, The Institute of Medical
Science, The University of Tokyo, Japan/Department of Medical Oncology and Cancer Center, Shiga University
of Medical Science）
ICHG2016 16
Mon(2)-P-38 Not HOXB13 p.G84E, but p.R217C appears to be associated with increased breast cancer risk in the Dutch
population ······································································································································ 792
Margriet Collee（Department of Clinical Genetics, Erasmus MC Cancer Institute, Rotterdam, The Netherlands）
Mon(2)-P-39 Leukemia Inhibitory Factor (LIF) plays a role in Chordoma Progression ············································· 793
Ozlem Silan Coskun（Biotechnology, Yeditepe University, Turkey）
Day 2
Mon(2)-P-40 Microsatellite instability, hMLH1 methylation and BRAF V600E mutation in sporadic colorectal cancer
······················································································································································ 793
Loraine Kay D Cabral（Research and Biotechnology, St. Luke’s Medical Center, Philippines）
Mon(2)-P-41 A Cancer-SNP-Panel-based case-control study of genetic susceptibility to cancer in Thai individuals
······················································································································································ 794
Jakris Eu-ahsunthornwattana（Div of Medical Genetics, Dept of Internal Medicine, Ramathibodi Hospital, Mahidol
University, Thailand）
Mon(2)-P-42 Functional Sequelae of the Novel NRAS Mutation E132K ······························································· 794
Ryan Timothy D. Yu（National Institute of Molecular Biology and Biotechnology, University of the Philippines
Diliman, Philippines）
Mon(2)-P-43 POLYMORPHISMS IN FOLATE METABOLIZING GENES AMONG CANCER PATIENTS FROM WEST
UKRAINE ······································································································································ 795
Iryna Dmytruk（SI Institute of hereditary pathology NAMS of Ukraine, Ukraine）
Mon(2)-P-44 Investigations on the effects of miRSNPs on the tumor suppressive capacity of PTEN ························ 795
Mia Helena B Reisland（Disease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular
Biology and Biotechnology, Philippines）
Mon(2)-P-45 Functional Characterization of the Rare BRAF Mutations R462G and T440A ···································· 796
Kevin Kent Vincent C Canlas（National Institute of Molecular Biology and Biotechnology, Disease Molecular
Biology and Epigenetics Laboratory, Philippines）
Mon(2)-P-46 Phenotypic Characterization of the Putative KRAS mutant E31D ···················································· 796
Jonathan P Chan（National Institute of Molecular Biology and Biotechnology, University of the Philippines
Mon(2)-P-47 Phenotypic Characterization of the Putative Oncogenic PIK3CA Mutants Q661K and C901R ·············· 797
Arman A Ghodsinia（National Institute of Molecular Biology and Biotechnology, University of the Philippines-
Mon(2)-P-48 Evaluation of genome-wide association study-identified SNPs at 4q12, 17q12, and 6p21.32 with cervical cancer
susceptibility in a Japanese population ······························································································· 797
Kiyonori Miura（Obstetrics and Gynecology, Nagasaki University, Japan）
Mon(2)-P-49 Genome-wide association study identified three copy number polymorphisms associated with sporadic colorectal
cancer risk in Singapore Chinese ······································································································· 798
LaiFun Thean（Singapore General Hospital, Singapore）
Mon(2)-P-50 Withdrawn ································································································································ 798
Mon(2)-P-51 Sensitive Mutation Detection by Sequencing Circulating Cell-Free DNA ············································ 799
Nan Fang（QIAGEN GmbH, Germany）
Mon(2)-P-52 Germline mutations in DNA mismatch repair genes in breast cancer patients ····································· 799
Ann S.G. Lee（Division of Medical Sciences, National Cancer Centre, Singapore/Department of Physiology, Yong
Loo Lin School of Medicine, National University of Singapore, Singapore/Office of Clinical & Academic Faculty
Affairs, Duke-NUS Graduate Medical School, Singapore）
Mon(2)-P-53 Up-regulation of non-coding RNAs in adult and pediatric liver cancers ·············································· 800
Kosuke Hashimoto（RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama,
Kanagawa, Japan）
Poster Session
Complex Traits and Polygenic Disorders 1 19:40-20:40
Mon(2)-P-54 Rs738409 Polymorphism in PNPLA3 gene is associated with lower insulin resistance in Korean MenRs738409
Polymorphism in PNPLA3 gene is associated with lower insulin resistance in Korean Men ························ 801
Jin Ho Park（Family Medicine, Seoul National University Hospital, Korea, South）
ICHG2016 17
Mon(2)-P-55 Candidate genes for strabismus (esotropia and exotropia) susceptibility chromosomal loci ···················· 802
Toshihiko Matsuo（Ophthalmology, Okayama University Graduate School of Medicine, Dentistry, and Pharma-
ceutical Sciences, Japan）
Mon(2)-P-56 Deep Resequencing of SULF2-PREX1 intergenic region in Nephrotic Syndrome ································· 802
Khun Z Latt（Department of Human Genetics, School of International Health, The University of Tokyo, Japan）
Mon(2)-P-57 Contribution of variants in the FGD6 gene with endometriosis risk ··················································· 803
Day 2
Hien T. T Luong（Pediatric department, Hanoi Medical University, Vietnam/Department of Genetics and Com-
putational Biology, QIMR Berghofer Medical Research Institue, Brisbane, Australia）
Mon(2)-P-58 Genome-wide association study of clinically-ascertained gout identifies multiple risk loci and its association with
clinical subtypes ······························································································································ 803
Airi Akashi（Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College,
Japan）
Mon(2)-P-59 Variant c.2262A>C in DOCK9 leads to exon skipping in keratoconus family ····································· 804
Marzena Gajecka（Institute of Human Genetics, Polish Academy of Sciences, Poland/Department of Genetics and
Pharmaceutical Microbiology, Poznan University of Medical Sciences）
Mon(2)-P-60 Whole-exome sequencing reveals a novel gene as a cause of aggressive periodontitis in Japanese families
······················································································································································ 805
Takeaki Sudo（Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical
and Dental University, Tokyo, Japan/Department of Human Genetics and Disease Diversity, Graduate School of
Medical and Dental Sciences, Tokyo Medical and Dental University）
Mon(2)-P-61 Association of HLA-DPB1 with ANCA-associated vasculitis in a Japanese population ························· 805
Aya Kawasaki（Molecular and Genetic Epidemiology Laboratory, University of Tsukuba, Japan）
Mon(2)-P-62 Variants discovery by amplicon-based exome sequencing for adult population of Yamagata Cohort Study in
Japan ············································································································································ 806
Hidenori Sato（Genome Informatics Unit, Yamagata University, Faculty of Medicine, Japan）
Mon(2)-P-63 The B Lymphoid Tyrosine Kinase (BLK ) gene polymorphisms and susceptibility to Kawasaki diseases
······················································································································································ 807
Chia-Jung Chang（Institute of Biomedical Sciences, Academia Sinica, Taiwan/Graduate Institute of Microbiology,
College of Medicine, National Taiwan University）
Mon(2)-P-64 IkBL regulates susceptibility to HIV-1 infection ·············································································· 807
Akinori Kimura（Medical Research Institute, Tokyo Medical and Dental University, Japan）
Mon(2)-P-65 APOBEC3H polymorphisms are associated with susceptibility to HIV-1 infection and development of AIDS in
Asian populations ···························································································································· 808
Taeko K. Naruse（Medical Research Institute, Tokyo Medical and Dental University, Japan）
Mon(2)-P-66 Delay discounting, genetic sensitivity, and leukocyte telomere length ················································· 809
Richard P. Ebstein（Psychology, National University of Singapore, Singapore）
Mon(2)-P-67 Identification of novel susceptibility region for Tuberculosis on Chromosome 5q31.1 ···························· 809
Jing Hao Wong（Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo,
Japan）
Mon(2)-P-68 Association study of OPRD1 gene variants with susceptibility to opioid addiction in a northern Iranian population;
a candidate gene approach for methadone maintenance treatment ························································· 810
Alireza Sharafshah（Cellular and Molecullar research center, Faculty of medicine, Guilan University of Medical
Science, Iran）
Mon(2)-P-69 A polymorphism in CCR1 /CCR3 is associated with narcolepsy ························································ 810
Hiromi Toyoda（Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Japan）
Mon(2)-P-70 Association of the I264T variant in the sulfide quinone reductase-like (SQRDL) gene with osteoporosis in Korean
postmenopausal women ··················································································································· 811
Jeonghyun Kim（Department of Medical Genetics, Ajou University School of Medicine, Suwon, Korea,
South/Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of
Korea）
Mon(2)-P-71 Association of genes polymorphisms from various functional classes with type 1 diabetes complications and their
combination ··································································································································· 812
Nataliya Tarasenko（Federal State Budgetary Scientific Institution The Research Institute for Medical Genetics,
Russia）
Mon(2)-P-72 Whole exome sequencing of twins for Biliary Atresia ······································································· 812
Ohsuke Migita（St. Marianna University School of Medicine, Japan/National Research Institute for Child Health
and Development）
ICHG2016 18
Mon(2)-P-73 Whole Genome Sequencing Approach to Discover Susceptibility Genomic Variants in a Multiplex Nuclear Family
of Schizophrenia ····························································································································· 813
Shun-Chun Yu（Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taiwan）
Mon(2)-P-74 Association of a variant in interleukine 13 (IL13) with food allergy in the Japanese population ············· 813
Tomomitsu Hirota（RIKEN Yokohama Institute, Japan）
Day 2
Mon(2)-P-75 CYP27A1 rs19969157 is the rare variant associated with atopic dermatitis with high serum IgE levels
······················································································································································ 814
Hisato Suzuki（Department of Child Health, Graduate School of Comprehensive Human Sciences, University of
Tsukuba, Japan）
Mon(2)-P-76 miRNA modulation of extracellular matrix gene-gene interactions and susceptibility to ACL rupture
······················································································································································ 815
Kyle Willard（Division of Exercise Science and Sports Medicine, Department of Human Biology, University of
Cape Town, Cape town, South Africa）
Mon(2)-P-77 Genetic and functional assessment of rare alleles of NAFLD susceptibility loci in Japanese ··················· 815
Supichaya Boonvisut（Division of Human Genetics, Center for Molecular Medicine, Jichi Medical Uni versity,
Japan）
Mon(2)-P-78 Decoding Musculoskeletal Soft Tissue Injuries ················································································ 816
Alison V September（Human Biology, University of Cape Town, Division of Exercise Science and Sports Medicine,
South Africa）
Mon(2)-P-79 Analyses of TGF-β stimulated gene expression levels of BGN in a susceptibility model for musculoskeletal soft
tissue injuries: A pilot ex vivo study ·································································································· 817
Mary-jessica N. Laguette（Human Biology, University of Cape Town, South Africa）
Mon(2)-P-80 The associate network approach identified of novel genes of tuberculosis susceptibility ························ 817
Elena Bragina（Institut of Medical Genetics, Russia）
Mon(2)-P-81 Search for genetic variations responsible for giant coronary aneurysms in Kawasaki disease patients by whole
exome sequencing ··························································································································· 818
Yoshihiro Onouchi（Department of Public Health, Chiba University Graduate School of Medicine, Japan）
Mon(2)-P-82 Fine-mapping of CDKN2B-AS1 in African Americans with primary open-angle glaucoma from a biorepository
linked to de-identified electronic medical records ················································································· 818
Nicole A Restrepo（Epidemiology & Biostatistics, Case Western Reserve University, USA）
Mon(2)-P-83 Whole exome sequencing in Thrombotic Storm patients identified rare variants in genes affecting efficiency of
the negative feedback system blocking thrombin formation ··································································· 819
Karen Nuytemans（John P. Hussman Institute for Human Genomics, University of Miami Miller School of
Medicine, USA）
Mon(2)-P-84 Identification of Putative Autism Spectrum Disease [ASD] Predisposing Genes by Whole Genome Next Gen-
eration Sequencing [WGNGS] & Complex Comparative Genome Analyses in an Extended Family with ASD
······················································································································································ 820
Marios Kambouris（Pathology-Genetics, Sidra Medical & Research Center, Qatar/Genetics, Yale University School
of Medicine, New Haven, CT, USA）
Mon(2)-P-85 Putative Relation Between Autism Spectrum Disease [ASD] and Hereditary Multiple Exostosis [HME] Investi-
gated by Whole Genome Next Generation Sequencing [WGNGS] & Comparative Genome Analyses in a Family with
ASD and HME with EXT-1 Mutations ······························································································ 821
Marios Kambouris（Pathology-Genetics, Sidra Medical & Research Center, Qatar/Genetics, Yale University School
of Medicine, New Haven, CT, USA）
Mon(2)-P-86 Identifying candidate genes under linkage peaks for metabolic syndrome traits in a Japanese American (JA)
family ············································································································································ 822
Karen L Edwards（Epidemiology, University of California, Irvine, USA）
Mon(2)-P-88 Polymorphisms of genes involved in extracellular matrix homeostasis of ligaments and the risk of anterior cruciate
ligament injury ································································································································ 822
Mariana F Leal（Morfologia e Genetica, Universidade Federal de Sao Paulo, Brazil/Ortopedia e Traumatologia,
Universidade Federal de Sao Paulo）
Mon(2)-P-89 Effect of HLA polymorphisms on the survival in the patient with AIDS ············································· 823
Michio Yasunami（Institute of Tropical Medicine, Nagasaki University, Japan）
Mon(2)-P-90 Association of SNPs of TLR pathway regulating innate immune responses with pediatric respiratory infectious
diseases in Vietnamese ····················································································································· 823
Reiko Miyahara（Institute of Tropical Medicine, Nagasaki University, Japan）
ICHG2016 19
Mon(2)-P-91 Association of ADAMDEC1 polymorphism with common human diseases ·········································· 824
Irina Goncharova（The Research Institute for Medical Genetics, Russia/Research Institute for Complex Issues of
Cardiovascular Diseases）
Mon(2)-P-92 Whole genome rare variant association study identifies a non-genic region near TFAM associated with severe
emphysema ···································································································································· 825
Josiah Radder（University of Pittsburgh, USA）
Day 2
Mon(2)-P-93 Trio-based exome sequencing case study in identifying the underlying genetic factors associated with progressive
flail arm syndrome, motor neuron disorder ·························································································· 825
Mahjoubeh Jalali Sefid Dashti（South African National Bioinformatics Institute, South African National Bioin-
formatics Institute, South Africa）
Poster Session
Bioinformatics and Genomic Technology 19:40-20:40
Mon(2)-P-94 New features of the UCSC Genome Browser - tools for research and the clinic ··································· 827
Robert M Kuhn（UC Santa Cruz Genomics Institute, University of California Santa Cruz, USA）
Mon(2)-P-95 f-tree: a novel and improved automated questionnaire-based pedigree chart creation software for use in large-
scale genome cohort studies ············································································································· 827
Tomoharu Tokutomi（Department of Clinical Genetics, School of Medicine, Iwate Medical University, Japan）
Mon(2)-P-96 A computational platform for human genome analysis and interpretation in Argentina ······················· 828
Patricio Yankilevich（Instituto de Investigacion en Biomedicina de Buenos Aires. CONICET - Partner Institute
of the Max Planck Society, Argentina）
Mon(2)-P-98 PhaSTESt (v1.2), a user friendly tool for power calculations in pharmacogenomic studies with "time to event"
outcomes ······································································································································· 829
Hamzah Syed（Biostatistics, University of Liverpool, UK）
Mon(2)-P-99 NGS-SWIFT: A Cloud-Based Variant Analysis Framework Using Control-Accessed Sequencing Data from db-
GaP/SRA ······································································································································· 829
Chunlin Xiao（NIH, USA）
Mon(2)-P-100 EIGEN: A spectral approach for the integration of functional genomics annotations for both coding and non-
coding sequence variants ·················································································································· 830
Iuliana Ionita-Laza（Biostatistics, Columbia University, USA）
Mon(2)-P-101 An Evaluation of Methods for HLA Allele Imputation from SNP Genotypes ····································· 830
Allan J. Motyer（Statistical Genetics, Murdoch Childrens Research Institute, Australia/Centre for Systems Ge-
nomics, The University of Melbourne, Australia）
Mon(2)-P-102 Effect of various minor groove binding compounds on DNA-triplex containing (GAA)5 repeat: A comparative
study to screen potential drug candidate for Friedrich’s ataxia therapeutics ············································ 831
Himanshu N Singh（Biochemistry, All India Institute of Medical Sciences, India）
Mon(2)-P-103 Systematic analysis of mutation distribution in three dimensional protein structures identifies mutational
hotspot in Mendelian disease genes ··································································································· 832
Akihiro Fujimoto（RIKEN, Japan）
Mon(2)-P-104 In-silico Prediction of Causal Coronary Artery Disease Genes ·························································· 832
Benedikt Reiz（Institute for Integrative and Experimental Genomics, University of Luebeck, Germany/DZHK
(German Research Centre for Cardiovascular Research), partner site Hamburg/Luebeck/Kiel, Luebeck）
Mon(2)-P-105 UnderCover : A Next Generation Sequencing Coverage Analysis tool for Whole genome, exome and custom
targeted panel sequencing ················································································································ 833
Pavlos Antoniou（Nuffield Division of Clinical Laboratory Sciences, University of Oxford, UK/Oxford Molecular
Diagnostic Centre, Molecular Haematology, Level 4, John Radcliffe Hospital, Oxford, UK）
Mon(2)-P-106 Accurate detection of mutations from RNA-seq in lung adenocarcinoma for clinical translation of precision
medicine ········································································································································ 833
Zhifu Sun（Health Sciences Research, Mayo Clinic, USA）
Mon(2)-P-107 Genomic Signal Processing algorithm for conserved and variable sequence search ······························ 834
Ernesto Borrayo（Gene Research Center, University of Tsukuba, Japan）
Mon(2)-P-108 Towards HLA imputation network: A network of HLA genotype imputation reference from multiple populations
······················································································································································ 835
Seik-Soon Khor（Graduate School of Medicine, Department of Human Genetics, The University of Tokyo, Japan）
ICHG2016 20
Mon(2)-P-109 Bio-Virtuoso: A package of Docker containers for multiple source data retrieval, RDF conversion, and triplestore
deployment in a simplified manner ····································································································· 835
Hiroyuki Mishima（Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences,
Japan）
Mon(2)-P-110 Comprehensive Genetic Exploration of Skeletal Dysplasia Using Targeted Exome Sequencing ············· 836
Jun-Seok Bae（Samsung Genome Institute, SungKyunKwan University, Korea, South）
Day 2
Mon(2)-P-111 Performance comparison of four commercial human whole-exome capture platforms ························· 836
Daichi Shigemizu（Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and
Dental University, Japan/Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical
Sciences）
Mon(2)-P-112 A Statistical Model for the Refinement and Ranking of Variant Calls ·············································· 837
Tony Kuo（BRD, National Institute of Advance Industrial Science and Technology, AIST, Tokyo, Japan）
Mon(2)-P-113 Identifying sequence differences among copy number variants from sequencing data ·························· 837
Takahiro Mimori（Tohoku University, Japan）
Mon(2)-P-114 Next Generation Sequencing Strategies to reconstruct Ancient African Mitochondrial Genomes ············· 838
Tasneem Salie（Division of Human Genetics, University of Cape Town, South Africa）
Mon(2)-P-115 Comparison of the clinical sequence using two platforms of hereditary disease panels and exome sequencing
······················································································································································ 838
Naoko Sato（Neurology, Graduate School of Medicine, The University of Tokyo, Japan）
Mon(2)-P-116 A combination of targeted enrichment methodologies for whole-exome sequencing reveals novel pathogenic
mutations ······································································································································· 839
Fuyuki Miya（Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental
University, Japan/Laboratory for Medical Science Mathematics, Center for Integrative Medical Sciences, RIKEN）
Mon(2)-P-117 Happy families - the benefits and bioinformatics of using extended pedigrees for next-generation sequencing
······················································································································································ 840
Nicholas B. Blackburn（South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley,
USA/Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia）
Mon(2)-P-118 Inferring the sequence and timing of admixture events in populations with complex admixture history using
genome-wide SNP-chip data ············································································································· 841
Irina Pugach（Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Germany）
Mon(2)-P-119 LAMPLINK: Additional functions for PLINK to detect SNP combination statistically significantly associated
with a trait ····································································································································· 841
Aika Terada（The University of Tokyo, Japan/National Institute of Advanced Industrial Science and Technology）
Mon(2)-P-120 An integrated Chromosomal omics approach to decipher molecular mechanism of CGG repeat expansion in
Fragile X syndrome ························································································································· 842
Yuji Nakayama（Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori Uni-
versity, Japan）
Mon(2)-P-121 High Efficiency Automated DNA Extraction Methods for Degraded Old Skeletal Samples ·················· 842
Seung-Bum Hong（Division of DNA Analysis, Scientific Investigation Laboratory, Criminal Investigation Com-
mand, Korea, South）
Mon(2)-P-122 Sparse modeling of genetic variants using summary statistics from genome-wide association studies
······················································································································································ 843
Zheng Ning（Medical Epidemeology and Biostatistics, Karolinska Institutet, Sweden）
Mon(2)-P-123 Universal system for analysis most type of mutation ······································································ 843
Oksana P Ryzhkova（Research Centre of Medical Genetics, Russia）
Mon(2)-P-124 The intolerance to functional genetic variation of protein domains predicts the localization of pathogenic
mutations within genes ···················································································································· 844
Ayal B Gussow（Columbia University, USA/Duke University）
Mon(2)-P-125 The Qatar Genome Reference: A Population-Specific Tool for Precision Medicine in the Middle East
······················································································································································ 844
Juan L Rodriguez-Flores（Department of Genetic Medicine, Weill Cornell Medical College, USA）
Mon(2)-P-126 CNVs assessment by whole exome sequencing in patients with multiple congenital malformations and develop-
mental delay ·································································································································· 845
Leslie D Kulikowski（Pathology, University of São Paulo, Brazil/Cytogenomics Laboratory - LIM 03, Universidade
de Sao Paulo-HC-FMUSP, Sao Paulo, Brazil）
ICHG2016 21
Mon(2)-P-127 Analysis of the human subtelomeric regions to elucidate the real structure and pathogenesis of the related
diseases ········································································································································· 845
Yoko Kuroki（Department of Genome Medicine, National Research Institute for Child Health and Development,
Japan）
Mon(2)-P-128 Application of High Throughput Chemical Genomics Screening Using Yeast Deletion Set for Taiwanofungus
Camphoratus ·································································································································· 846
Day 2
Edward Tsui（La Sierra University, USA）
Mon(2)-P-129 PAFFT: A new homology search algorithm for third-generation sequencers ······································ 847
Kazuharu Misawa（Tohoku Medical Megabank Organization, Tohoku University, Japan/Graduate School of
Medicine, Tohoku University）
Mon(2)-P-130 Iterative pruning method of unsupervised clustering for categorical data ·········································· 847
Kridsadakorn Chaichoompu（Montefiore Institute, University of Liege, Belgium/GIGA-R, University of Liege,
Belgium）
Mon(2)-P-131 HLA-HD, a high performance HLA typing algorithm using next generation sequencing results to create a reliable
catalog of HLA alleles ······················································································································ 848
Shuji Kawaguchi（Center for Genomic Medicine, Graduate School of Medicine Kyoto University, Japan）
Mon(2)-P-132 Functional Analysis of Human Methyl-CpG Binding Protein 2 by RNA Silencing and Expression Profiling
······················································································································································ 849
Injoo Kim（Supercomputing center, Pusan National University, Korea, South/Research Center for Anti-Aging
Technology Development, Pusan National University/Department of Medical Informatics, School of Medicine,
Pusan National University）
Mon(2)-P-133 MultiDCoX: Algorithm for Multivariate Differential Co-expression Analysis ······································· 849
Herty Liany（Genome Institute of Singapore, Singapore）
Mon(2)-P-134 Network biology to identify druggable targets for Parkinson’s disease ·············································· 850
Jhumur Pani（Cytogenetics, MTA Infotech, India）
Mon(2)-P-135 Differentially Expressed Genes-At-Risk in Affected Alzheimer’s Brain as Potential Biomarkers ············· 850
Vishnu Swarup（Neurology, All India Institute of Medical Sciences, New Delhi, India）
Mon(2)-P-136 Publically available bioinformatics resources point to novel functions and epigenetic regulation of BMP8A: a
potential role in air quality-related peripheral arterial disease pathogenesis ·············································· 851
Cavin K Ward-Caviness（Helmholtz Institute Munich, Germany/Duke Molecular Physiology Institute, Duke Uni-
versity Medical Center）
Mon(2)-P-137 Kinship-assisted variant filtering for exome sequencing analysis of extended pedigrees ······················· 851
Evangelos Bellos（Genomics of Common Disease, Imperial College London, UK）
Mon(2)-P-138 NGS Library Prep Methods to Achieve Comprehensive Coverage for WGS and Targeted Sequencing at Low
DNA Input Quantities, Including FFPE Samples ················································································· 852
Matthew Hymes（Swift Biosciences, USA）
Poster Session
Clinical Genetics and Dysmorphology 1 19:40-20:40
Mon(2)-P-139 Comprehensive Genetic Screening of GJB2 , GJB6 and SLC26A4 among Non- Syndromic Hearing Loss Patients
in Eastern part of India ···················································································································· 853
Bidisha Adhikary（Zoology, University of Calcutta, India）
Mon(2)-P-140 Clinical and genetic study of cleft lip with or without cleft palate and its association with Interferon regulatory
factor 6 polymorphism in Egypt ········································································································ 853
Amira M. Nabil（Human Genetics, Medical Research Institute, Egypt）
Mon(2)-P-141 Syndromic DSD; A study of 30 Egyptian cases using cytogenetic techniques ···································· 854
Mona A El Gammal（Clinical Genetics, National Research Centre, Egypt）
Mon(2)-P-142 Clinical and Cytogenetic Studies of Patients with Sex Chromosome Disorders of Sex Development (DSD)
······················································································································································ 854
Aya AB. Elaidy（Clinical Genetics, National Research Centre, Egypt）
Mon(2)-P-143 A PLK4 mutation causing azoospermia in a man with Sertoli cell-only syndrome ····························· 855
Toshinobu Miyamoto（Obstetrics and Gynecology, Asahikawa Medical University, Japan）
ICHG2016 22
Mon(2)-P-144 Two cases of monosomy of 3q with cerebral MRI findings ······························································ 855
Yuri Dowa（Department of Neurology, Gunma Children’s Medical center, Japan）
Mon(2)-P-145 De novo 4q31.21 delection and 9q34.2 duplication in the same patient. A case report ······················· 856
Matías Pérez（Unidad de Genética. Servicio de Análisis Clínicos., Hospital Virgen de las Nieves. Servicio Andaluz
de Salud, Spain/Instituto Biosanitario de Granada. Granada. Spain）
Mon(2)-P-146 A case of 45,X male ··················································································································
Day 2
857
Shinsuke Ninomiya（Department of Clinical Genetics, Kurashiki Central Hospital, Japan）
Mon(2)-P-147 Dosage changes of NIPBL cause various types of neurodevelopmental disability ································ 858
Chihiro Hatano（Division of Medical Genetics, Kanagawa Children’s Medical Center, Japan）
Mon(2)-P-148 Clinical and neuroimaging findings of an incomplete form of Moebius syndrome ······························· 858
Mitsuo Masuno（Genetic Counseling Program, Graduate School of Health and Welfare, Kawasaki University of
Medical Welfare, Japan）
Mon(2)-P-149 Simpson-Golabi-Behmel syndrome: A prenatal diagnosis in a fetus with GPC3 and GPC4 gene microduplica-
tions ·············································································································································· 859
Nadja Kokalj Vokac（Laboratory of Medical Genetics, University Medical Centre Maribor, Slovenia/Medical
Faculty, University Maribor, Slovenia）
Mon(2)-P-150 A lethal outcome of Costello syndrome due to a novel pathogenic variant in the HRAS gene - a case report
······················································································································································ 860
Magdalena Pelc（Department of Medical Genetics, The Children’s Memorial Health Institute, Poland）
Mon(2)-P-151 Distinct skeletal phenotypes in a Korean boy with SOFT syndrome caused by compound heterozygous mutations
in POC1A ······································································································································ 860
Jung Min Ko（Pediatrics, Seoul National University Hospital, Korea, South/Research Coordination Center for
Rare Diseases, Seoul National University Hospital）
Mon(2)-P-152 Cerebellar vermis hypoplasia in CHARGE syndrome: clinical and molecular characterization of 18 unrelated
Korean patients ······························································································································· 861
Jung Min Ko（Pediatrics, Seoul National University Hospital, Korea, South）
Mon(2)-P-153 Similarities of the Ectodermal dysplasia, hypohidrotic, with hypothyroidism and agenesis of the corpus callosum
(OMIM 225040) and cardio-facio-cutaneous syndrome (OMIM 115150) ················································· 861
Masaharu Moroto（Department of Pediatrics, Fukuchiyama City Hospital, Japan）
Mon(2)-P-154 A musical pathway to improve some cognitive functions in Williams syndrome ································· 862
Lilian M J Albano（Pediatrics, Instituto da Crianca, Brazil）
Mon(2)-P-155 Systemic and craniomaxillofacial characteristics of patients with Williams syndrome ·························· 862
Rina Hikita（Maxillofacial Orthognathics, Tokyo Medical and Dental University, Japan）
Mon(2)-P-156 Two cases of AIS (androgen insufficiency syndrome) pursued different courses ·································· 863
Yoichiro Fujiwara（Department of Obstetrics and Gynecology, Kyoto City Hospital, Japan）
Mon(2)-P-157 A rare case of mosaic trisomy 7 in a 5 year old child ····································································· 864
Danielle K Bourque（Dept. of Medical Genetics, Children’s Hospital of Eastern Ontario, Canada）
Mon(2)-P-158 CMA Analysis Identifies Homozygous Deletion of MCPH1 in 2 Brothers with Primary Microcephaly-1
······················································································································································ 864
Morteza Hemmat（Cytogenetics, Quest Diagnostics Inc., USA）
Mon(2)-P-159 Two cases with mosaic trisomy 8 and 9 fortuitously detected by conventional G-banding chromosome analy-
sisImportance of conventional chromosome analysis to diagnose mosaicism with low frequency ················· 865
Satoshi Ishikiriyama（Division of Cytogenetics and Clinical Genetics, Shizuoka Children’s Hospital, Japan）
Mon(2)-P-160 Structural brain abnormalities associated with deletion at chromosome 2p16.1 ································· 865
Hiroko Shimbo（Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama, Japan）
Mon(2)-P-161 A study of Williams syndrome in children at Siriraj hospital, Bangkok, Thailand ······························· 866
Achara Sathienkijkanchai（Pediatrics, Faculty of Medicine Siriraj hospital, Mahidol University, Thailand）
Mon(2)-P-162 Chromosomal abnormalities in 1354 Japanese patients with azoospermia due to spermatogenic dysfunction
······················································································································································ 867
Yasuhiro Kido（Genetic Counseling Center, Dokkyo Medical Universitiy Koshigaya Hospital, Japan）
Mon(2)-P-163 Maxillofacial morphological characteristics of two Japanese patients with chromosome 18p deletion syndrome
······················································································································································ 867
Michiko Tsuji（Maxillofacial Ortthognathics, Tokyo Medical and Dental University, Japan）
Mon(2)-P-164 Cytogenetics in the Centre of Excellence for Human Genetics ························································ 868
Alaa K. Kamel（Human Cyrogenetics, National Research Centre, Egypt）
ICHG2016 23
Mon(2)-P-165 FGFRL1 is a possible candidate for the severe renal phenotype in a case of Wolf-Hirschhorn syndrome
······················································································································································ 869
Yuko Tezuka（Department of Pediatrics, Ehime University Graduate School of Medicine, Japan）
Mon(2)-P-166 8q13 microdeletion detected in a Japanese case with mesomelia-synostoses syndrome ······················· 869
Issei Imoto（Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate
School, Japan）
Day 2
Mon(2)-P-167 Complete 46,XY female of 14 cases and review of the literature ····················································· 870
So Yeon Park（Laboratoy of Medical Genetics, Cheil General Hospital and Women’s Healthcare Center, Korea,
South）
Mon(2)-P-168 A familial case of brain malformation with marker chromosome ······················································ 870
Mika Nakajima（Pediatrics, Hakodate Chuo General Hospital, Japan）
Mon(2)-P-169 Inhibition of overactivated PIK3/AKT/mTOR signalling pathway as a therapeutic strategy for PIK3CA-related
overgrowth spectrum (PROS) ··········································································································· 871
Yasuyo Suzuki（Department of Genetics, Institute for Developmental Research, Aichi Human Service Center,
Japan）
Mon(2)-P-170 Molecular analysis of partial duplication of the chromosome 21 in two patients presenting Down syndrome
phenotype ······································································································································ 872
Hidefumi Tonoki（Pediatrics, Tenshi Hosipital, Japan/Pediatrics, Hokkaido University Graduate School of
Medicine）
Mon(2)-P-171 Ring chromosome 9 with a 9p24.3-p24.1 deletion and 9p24.1-p21.1 duplication in a girl with developmental
delay and sex reversal ······················································································································ 872
Yukako Muramatsu（Pediatrics, Nagoya university graduate school of medicine, Japan/Pediatrics, Japanese Red
Cross Nagoya Daiichi Hospital）
Mon(2)-P-172 Possible disruption of cis and trans regulation due to 22q11.2 deletion ············································ 873
Anelisa G. Dantas（Genetics, Universidade Federal de Sao Paulo, Brazil）
Mon(2)-P-173 Chromosomal microarray (CMA) in Brazilian patients with phenotypic alterations and normal G-banding kary-
otypes ··········································································································································· 873
Maria I Melaragno（Genetics Department, Universidade Federal de Sao Paulo, Brazil）
Mon(2)-P-174 Novel mutations in PDE4D and molecular pathology of acrodysostosis without hormone resistance
······················································································································································ 874
Tadashi Kaname（Department of Genome Medicine, National Center for Child Health and Development,
Japan/National Research Institute for Child Health and Development）
Mon(2)-P-175 Subtelomeric rearrangements’ detection and characterization by combined use of MLPA kits in intellectual
disability patients ···························································································································· 875
Cristina Rusu（Medical Genetics, University of Medecine and Pharmacy, Romania）
Mon(2)-P-176 Withdrawn ······························································································································· 875
Mon(2)-P-177 Haploinsufficiency of HDAC4 and de novo nonsense mutation ofHDAC8 confirmed by whole exome sequencing
······················································································································································ 875
Jeesuk Yu（Pediatrics, Dankook University Hospital, Korea, South）
Mon(2)-P-178 ELECTRONIC DATABASE OF OROFACIAL CLEFTS - APPROACH AND ADVANTAGES IN HEALTH POLI-
CIES ············································································································································ 876
Elaine L Mendes（Genetics Departament, State University of Campinas, UNICAMP, Brazil）
Mon(2)-P-179 a web-based application for validation of A cost-effective INVESTIGATION OF 22q11.2 Deletion syndrome
······················································································································································ 877
Mon(2)-P-180 MICROFORM OF HOLOPROSENCEPHALY AND TYPICAL ORAL CLEFT IN INDIVIDUAL WITH PARTIAL
18Q TRISOMY AND 18P MONOSOMY RESULTING FROM MATERNAL PERICENTRIC INVERSION
······················································································································································ 877
Mon(2)-P-181 Partial 1q duplication and associated phenotype ··········································································· 878
Jose E. Baroneza（Genetics and Morphology Departmant, Universidade de Brasilia, Brazil/Universidade Federal
do Parana/Universidade Positivo）
Mon(2)-P-182 De novo NSD1 intragenic microduplication in a Patient with clinical presentation of Sotos syndrome
······················································································································································ 878
Eriko Nishi（Division of Medical Genetics, Nagano Children’s Hospital, Japan/Department of Medical Genetics,
Shinshu University School of Medicine/Life Science Research Center, Nagano Children’s Hospital）
ICHG2016 24
Mon(2)-P-183 Identification of Microduplitations on Chromosome 6q22 in A Sporadic Case with Congenital Generalized
Hypertrichosis ································································································································· 879
Yingzhi Huang（McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences - Peking
Union Medical College, China）
Mon(2)-P-184 Mosaic ring chromosome 21 and monosomy 21 in a patient with anterior ectopic anus and perineal lipoma
······················································································································································ 879
Day 2
Takako Sasaki（Department of Pediatrics and Child Health, Kurume University School of Medicine, Japan）
Mon(2)-P-185 Chromosome 8p abnormalities associated with severe global developmental delay: report of two cases
······················································································································································ 880
Ina O Focsa（V.Babes Nathional Institute of Pathology, Romania）
Mon(2)-P-186 Whole genomic analysis of Mayer- Rokitansky- Küster- Hauser syndrome ········································ 881
Kazumi Takahashi（Department of Obstetrics and Gynecology, Tokai University School of Medicine,
Japan/Department of Clinical Genetics, Tokai University Hospital）
Mon(2)-P-187 A rare case of Happle-Tinschert syndrome ··················································································· 881
Mehmet Seven（Cerrahpasa Medical School of Istanbul University, Turkey）
Mon(2)-P-188 Ehlers-Danlos syndrome and 22q11.21 microduplication in one patient ············································ 882
Soghra Jougheh Doust（Pediatrics, Genetics Program, Peterborough Regional Health Centre, Canada）
Poster Session
Clinical Genetic Testing 19:40-20:40
Mon(2)-P-189 Title Prevalence of the JAK2 V617F mutation in Srinagarind hospital between June 2013 - June 2014
······················································································································································ 883
Kanokon Chaicom（Department of Medicine, Medicine Faculty, Department of Medicine, Medicine Faculty
KhonKaen University, Thailand）
Mon(2)-P-190 A case of chromosome 9 trisomy mosaicism not detected by conventional karyotyping or standard aCGH
analysis method ······························································································································ 883
Tomonari Awaya（Department of Pediatrics, Kyoto University Hospital, Japan）
Mon(2)-P-191 Genetic heterogeneity in 26 infants with a hypomyelinating leukodystrophy ······································ 884
Natsuko Arai-Ichinoi（Pediatrics, Tohoku University School of Medicine, Japan）
Mon(2)-P-192 Genome Sequencing Carrier Testing in Preconception Women: Lessons Learned from the First Two Years of
the NextGen Study ·························································································································· 884
J A Reiss（Center for Health Research, Kaiser Permanente Northwest, USA）
Mon(2)-P-193 Identification of Novel mutations in SLC20A2 and PDGFB responsible for primary familial brain calcification
······················································································································································ 885
Shingo Koyama（Yamagata University, Japan）
Mon(2)-P-194 Mutational spectrum and genotype-phenotype association in a cohort of Croatian, Serbian and Slovenian
patients with hereditary angioedema due to C1 inhibitor deficiency ························································ 886
Mira Silar（Laboratory for Clinical Immunology and Molecular Genetics, University Clinic for Respiratory and
Allergic Diseases Golnik, Slovenia）
Mon(2)-P-195 Universal Lynch Syndrome Screening in an Integrated Health Care System: Results of a 5-Year Study
······················································································································································ 887
Jacob A Reiss（Center for Health Research, Kaiser Permanente Northwest, USA）
Mon(2)-P-196 From Sanger sequencing to NGS approaches for molecular diagnosis for primary immunodeficiency diseases
(PID) ············································································································································ 887
Jing Yang（The University of Hong Kong, Hong Kong）
Mon(2)-P-197 Application of array-based comparative genomic hybridization to pediatric neurologic diseases ············· 888
Amal M Alhashem（Pediatrics, Prince Sultan Military Medical City, Saudi Arabia）
Mon(2)-P-198 Diagnostic Utility of Regions of Homozygosity Detected by Chromosome Microarray in Two Cases of Inborn
Errors of Metabolism ······················································································································· 889
Roya M Mostafavi（Le Bonheur Children’s Hospital, USA）
Mon(2)-P-199 Functional Analysis of Three Novel TSC2 Variants Identified in Taiwanese TSC Patients ·················· 889
Da-Chang Chu（Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Tai-
wan/Graduate Institute of Biomedical Sciences, Chang Gung University, Tao-Yuan, Taiwan）
ICHG2016 25
Mon(2)-P-200 Identification of a Factor VIII Exon 14 novel frame shift mutation c. 2138 delA, p.(N713Tfs*9) in Saudi
Arabian patient: Genotype-Phenotype Correlation ··············································································· 890
Faisal A. Allaf（Medical Genetics, Umm-Al-Qura University, Makkah, KSA, Saudi Arabia/Science and Technology
Unit, Umm Al-Qura University, Makkah/Department of Laboratory Medicine and Blood Bank, King Abdullah
Medical City, Makkah）
Mon(2)-P-201 Development of a melting curved-based allele-specific PCR of apoliooprotein E (APOE) genotyping method
Day 2
for genomic DNA, Guthrie blood spot and whole blood ········································································ 890
Chia-Hsiang Chen（Chang Gung University, Taiwan/Chang Gung Memorial Hospital-Linkou）
Mon(2)-P-202 Next generation sequencing-based panel analysis for hereditary connective tissue disorders through the ion
PGM™ system ······························································································································· 891
Tomomi Yamaguchi（Division of Clinical and Molecular Genetics, Shinshu University Hospital, Japan）
Mon(2)-P-203 Indications for first erythrocyte transfusion in patients with upper gastrointestinal bleedings considering the
genetic constitution ························································································································· 891
Sergiy Kharchenko（Department of Surgery, Radiology and Phthisiology, Medical Institute of Sumy State Uni-
versity, Ukraine）
Mon(2)-P-204 From synaptic architecture to epileptic encephalopathy ································································· 892
Gholamreza Shariati（Narges laboratory, Iran）
Mon(2)-P-205 Next Generation Sequencing based detection of NRXN1 gene mutation in an autistic individual from Southwest
Iran ··············································································································································· 893
Hamid Galehdari（Narges laboratory, Iran）
Mon(2)-P-206 Identification of a rare form of autosomal recessive ataxia by Next Generation Sequencing ················· 893
Alireza Sedaghat（Jundishapur University, Iran）
Mon(2)-P-207 Comparison of three different methods for heteroplasmy detection of the Mitochondrial DNA 1555A>G mu-
tation ············································································································································ 894
Shayan Wang（Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, China）
Mon(2)-P-208 Mosaic Ratio Quantification of Isochromosome 12p in Pallister-Killian syndrome using Droplet Digital PCR
······················································································································································ 894
Kosuke Izumi（Laboratory of Genome Structure and Fuction, The University of Tokyo, Institute of Molecular
and Cellular Biosciences, Japan）
Mon(2)-P-209 A Collaborated Study of Fragile X syndrome and Fragile-X-Associated Tremor/ataxia Syndrome (FXTAS) for
promoting clinical research in Japan ·································································································· 895
Kaori Adachi（Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University,
Japan）
Mon(2)-P-210 Evaluation of Digital PCR for Monitoring of Acute Rejection in Kidney Transplantation ···················· 895
Hyeseon Lee（1Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea, South）
Mon(2)-P-211 HER-2/neu status in paraffin-embedded tissue from breast cancer patients by immunohistochemistry (IHC)
and fluorescence in situ hybridization (FISH) assays ············································································ 896
Pitichai Phornsarayuth（Pathology, Ramathibodi Hospital Faculty of Medicine, Thailand）
Mon(2)-P-212 Optimal cutoff value for diagnosis G-6-PD-deficient heterozygous female neonates based on molecular identi-
fication of G-6-PD mutations ············································································································ 896
Suttiphan Kitcharoen（Clinical Microscopy, Faculty of Associated Medical Sciences, Khon Kaen University, Thai-
land）
Mon(2)-P-213 A novel COL11A1 mutation affecting splicing in a Japanese patient with Stickler syndrome ·············· 897
Takuya Naruto（Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate
School, Japan）
Mon(2)-P-214 Filaggrin mutations in early- and late-onset atopic dermatitis ························································· 898
Peter Korosec（Laboratory for Clinical Immunology & Molecular Genetics, University Clinic of Respiratory and
Allergic Diseases Golnik, Slovenia）
Mon(2)-P-215 SUNMAC: A Project for Population Based Screening of Thalassemia and its Mutations in Pakistan
······················································································································································ 898
Muhammad Imran Qadeer（Department of Microbiology and Molecular Genetics, University of the Punjab, Pak-
istan/Sundas Foundation Molecular Analysis Center, Lahore）
Mon(2)-P-216 Relationship between G6PD deficiency and UGT1A1 mutation in neonates with hyperbilirubinemia
······················································································································································ 899
Noppmats Khemtonglang（Graduate School, Khon Kaen University, Thailand）
ICHG2016 26
Mon(2)-P-217 An investigation of definite diagnosis rate for monogenic diseases in the order receiving system of genetic
testing ·········································································································································· 900
Tomohiro Nakayama（Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon Uni-
versity School of Medicine, Japan/Division of Companion Diagnostics, Department of Pathology of Microbiology,
Nihon University School of Medicine）
Mon(2)-P-218 Implementation of Genomic Medicine in Sri Lanka ········································································ 900
Day 2
Vajira H.W. Dissanayake（Human Genetics Unit, Faculty of Medicine, University of Colombo, Sri Lanka）
Mon(2)-P-219 Next-generation sequencing approach in skeletal dysplasias with prenatal onset: experience of a tertiary center
in Brazil ········································································································································· 901
Guilherme L Yamamoto（Genetica Medica - departamento de Pediatria, Instituto da Crianca do Hospital das
Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Brazil/Genetica e biologia evolutiva, Instituto
de Biociencias da Universidade de Sao Paulo）
Mon(2)-P-220 Rapid and accurate genetic testing for CHARGE syndrome based on long-range PCR and Next-Gen high-
throughput sequencer ······················································································································ 901
Kumiko Yanagi（Genome Medicine, Center for National Research Institute for child health and development,
Japan）
Mon(2)-P-221 Toward Objective Interpretation of Sequence Variants ··································································· 902
James L. Weber（PreventionGenetics, USA）
Mon(2)-P-222 Identification of genetic alterations in the APC gene by the use of NGS for patients with polyposis of the colon
······················································································································································ 902
Yoichi Furukawa（The Institute of Medical Science, The University of Tokyo, Japan）
Mon(2)-P-223 Genomics and precision in variant filtering strategies and phenotypic characterisation for accurate genetic
diagnosis in the retinal dystrophies ···································································································· 903
Benjamin M Nash（Sydney Genome Diagnostics, The Children’s Hospital at Westmead, Cnr Hawkesbury Rd and
Hainsworth St, Westmead NSW, Australia/Eye Genetics Research Group, Children’s Medical Research Institute,
The Children’s Hospital at Westmead, Westmead, Australia/Save Sight Institute, Sydney, Australia/Discipline of
Paediatrics and Child Health, Sydney Medical School, University of Sydney, Sydney, Australia）
Mon(2)-P-224 Triaging Patients for Genomic Tests in South Australia: a Multi-disciplinary Team Approach ············· 903
Janice M Fletcher（Genetics & Molecular Pathology, SA Pathology, Australia）
Mon(2)-P-225 Alport Syndrome - Interesting Cases and Findings ········································································ 904
Evelyn Douglas（Molecular Genetics, Genetics and Molecular Pathology, SA Pathology, Australia）
Mon(2)-P-226 Experience of introducing chromosome microarray analysis as a diagnostic tool in a clinical genetics service in
Brasilia, Brazil ································································································································ 905
Juliana F Mazzeu（Faculty of Medicine, Universidade de Brasilia, Brazil/Hospital Universitario de Brasilia,
Brasilia, Brazil）
Mon(2)-P-227 The Medical Genome Reference Bank - Whole genome sequencing of 4,000 healthy elderly individuals
······················································································································································ 905
Marcel E Dinger（Kinghorn Centre for Clinical Genomics, Garvan Institute for Medical Research, Australia/St
Vincents Clinical School, Faculty of Medicine, UNSW）
Mon(2)-P-228 Targeted next-generation sequencing panel assay in a patient with bilateral hands postaxial polydactyly: Iden-
tification of one novel and one reported CENPJ mutations ··································································· 906
Chia-Cheng Hung（Sofiva Genomics Co., Ltd., Taiwan/Phoebus Genetics Co., Ltd.）
Mon(2)-P-229 Retrospective evaluation of rare benign CNVs detected by chromosomal microarray ·························· 906
Keiko Wakui（Medical Genetics, Shinshu University School of Medicine, Japan/Clinical and Molecular Genetics,
Shinshu University Hospital）
Mon(2)-P-230 Identification of copy number aberration in hereditary cancer susceptibility genes using data from next gener-
ation sequencing ····························································································································· 907
Ja-Hyun Jang（Green Cross Laboratories, Korea, South）
Mon(2)-P-231 Molecular Diagnostics using Genomics: Our Experiences & Success Stories in Inherited Disorders from Over a
Hundred Cases in India ···················································································································· 908
Nandita Mullapudi（Dhiti Omics Technologies Private Limited, India）
Mon(2)-P-232 Fragile X premutation screening in Korean women ········································································ 908
Kyung Min Kang（Genetics Laboratory of Fertility Center, CHA University School of Medicine, Korea, South）
Mon(2)-P-233 The clinical utility of whole exome sequencing in clinical practice: detecting mosaic post-zygotic mutations in
neonates ········································································································································ 909
John M Taylor（Oxford Medical Genetics Laboratory, Oxford University Hospitals NHS Trust, UK）
ICHG2016 27
Mon(2)-P-234 Whole Exome Sequencing as a diagnostic Tool to Identify Novel Mutations in 3M syndrome ············· 909
Asuman Koparir（Istanbul University, Turkey）
Mon(2)-P-235 Utilisation of Non-invasive prenatal testing to exclude an unbalanced karyotype in a translocation carrier’s
pregnancy: A case study ·················································································································· 910
Alison Yeung（Vicorian Clinical Genetics Services）
Mon(2)-P-236 Diagnostic Application of Targeted Exome Sequencing for Skeletal Dysplasia ···································
Day 2
911
Eun Kyung Cho（Department of Pediatrics, Samsung Medical Center, Korea, South）
Mon(2)-P-237 Prenatal clinical and molecular (epi-) genetic diagnosis of Beckwith-Wiedemann syndrome: time to shift gears?
······················································································································································ 911
Maria Paola R. Lombardi（Department of Clinical Genetics, University of Amsterdam, Netherlands）
Mon(2)-P-238 A method for large scale screening of sex chromosome aneuploidies at birth ···································· 912
Marisol Ibarra-Ramirez（Genetics, Medicine School Of Universidad Autonoma de Nuevo Leon, Mexico）
Poster Session
Cardiovascular Genetics 19:40-20:40
Mon(2)-P-240 Molecular genetic risk scale of coronary artery disease (CELERA, USA) and sudden cardiac death: a case-
control study ·································································································································· 913
Anastasiya A. Ivanova（Federal State Budgetary of Scientific Institution Institution of Internal and Preventive
Medicine, Russia）
Mon(2)-P-241 Detection and Putative Functional Effect of Variants in Congenital Heart Defects -Related Genes
······················································································································································ 914
Alaaeldin G Fayez（Molecular Genetics and Enzymology, National Research Centre, Egypt）
Mon(2)-P-242 Genetics and Environment: Impact of Ethnicity, Age and Sex on Heritability of Cardiometabolic and Inflam-
matory Risk Traits ··························································································································· 914
Enkhmaa Byambaa（Internal Medicine, University of California - Davis, USA）
Mon(2)-P-243 The First Genetic Epidemiological Study of North Cyprus: Genetic Mapping of Cardiovascular Diseases and
Using Those Variants as a Biomarker ································································································· 915
Mahmut Cerkez Ergoren（Medical Genetics, Near East University, Cyprus/Medical Genetic Laboratory, Near
East University Hospital）
Mon(2)-P-244 Incidence of homozygous familial hypercholesterolaemia (hoFH) in New Zealand ······························ 915
Andrew D Laurie（Molecular Pathology, Canterbury Health Laboratories, New Zealand）
Mon(2)-P-245 Analysis of genotype-phenotype correlations for desmoplakin mutations ··········································· 916
Wanling Yang（The University of Hong Kong, Hong Kong）
Mon(2)-P-246 Investigation of Pathogenic Genes in Chinese sporadic Hypertrophic Cardiomyopathy Patients by Whole Exome
Sequencing ····································································································································· 916
Jing Xu（Insititute of Life Science, Southeast University, Nanjing, China）
Mon(2)-P-247 Interaction of maternal age and MTHFR C677T polymorphism increases the risk of co-occurrence of Down
syndrome and congenital heart disease ······························································································· 917
S. Justin Carlus（Cardiogenetics team- Pediatric Cardiology, College of Medicine, Taibah University, India）
Mon(2)-P-248 IL10 promoter polymorphisms are associated with rheumatic heart disease in Saudi Arabian patients
······················································································································································ 917
Khalid M Al Harbi（Cardiogenetics Team- Department of Pediatrics, College of Medicine, Taibah University,
Saudi Arabia）
Mon(2)-P-250 Targeted Resequencing of 174 Genes in Patients with Inherited Cardiovascular Diseases for Future Clinical
Utility ············································································································································ 918
Akiyoshi Ogimoto（Ehime University Graduate School of Medicine, Japan）
Mon(2)-P-251 Tight junction gene CLDN8 were associated with plasma chemokine IP-10 level in methadone maintenance
patients ········································································································································· 918
Sheng-Wen Liu（Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan）
Mon(2)-P-252 Among RyR2 carriers, sinus bradycardia is more frequent in CPVT than other types of phenotype
······················································································································································ 919
Seiko Ohno（Shiga University of Medical Science, Japan）
ICHG2016 28
Mon(2)-P-253 Analysis of Moyamoya disease associated genetic variant RNF213 c.14576G>A in various cerebrovascular
diseases ········································································································································· 919
Satoru Miyawaki（Department of Neurosurgery, The University of Tokyo, Japan）
Mon(2)-P-254 A novel de novo mutation in Lamin A/C gene in Emery Dreifuss Muscular Dystrophy: The first clinical and
molecular report of an Indonesian patient ··························································································· 920
Almira Zada（Biochemistry and Molecular Biology, Faculty of Medicine Universitas Padjadjaran, Indonesia）
Day 2
Mon(2)-P-255 Hypertrophic Cardiomyopathy - Retrospective Analysis 18 Months On ············································ 921
Kathy R Cox（Molecular Genetics, Genetics and Molecular Pathology, SA Pathology at the Women’s and Chil-
dren’s Hospital, Adelaide, Australia）
Mon(2)-P-256 DNA copy number and copy-neutral changes in patients with both coronary artery disease and metabolic
comorbidity ···································································································································· 921
Aleksei Sleptcov（Laboratory of Population Genetics, Research Institute of Medical Genetics, Russia/Tomsk State
University）
Mon(2)-P-257 Mutations in the BMPR2 Gene in Patients with Heritable Pulmonary Arterial Hypertension ··············· 922
Yuki Aimi（Division of Cardiology, Second Department of Internal Medicine, Kyorin University School of Medicine,
Japan/Department of Molecular Biology, Kyorin University School of Health Sciences）
Mon(2)-P-258 Polygenic risk score of 45 coronary artery disease risk variants is associated with the progression of coronary
artery calcification - Results of the Heinz Nixdorf Recall Study ······························································ 922
Sonali Pechlivanis（Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen,
University Duisburg-Essen, Germany）
Mon(2)-P-259 Genome wide array analysis of patients with conotruncal heart defects in the Kingdom of Bahrain
······················································································································································ 923
Cristina Skrypnyk（Al Jawhara Center for Molecular Medicine, Kingdom of Bahrain, Arabian Gulf University,
College of Medical Sciences, Bahrain）
Mon(2)-P-260 Exome sequencing in 111 Czech families with inherited cardiovascular diseases ································· 924
Hana Hartmannova（Institute of Inherited Metabolic Disorders, Charles University of Prague, First Faculty of
Medicine, Czech Republic）
Mon(2)-P-261 Uncoupling associations of the Apolipoprotein B locus alleles with lipids, myocardial infarction, and survival
······················································································································································ 925
Alexander Kulminski（Duke University, USA）
Mon(2)-P-262 Genetic Analysis using next-generation sequencing in Brugada Syndrome ········································· 925
Yoshinori Katsumata（Department of Cardiology, Keio University, Japan）
Mon(2)-P-263 A PDE3A mutation in familial hypertension and brachydactyly syndrome ········································ 926
Hidehito Inagaki（ICMS, Division of Molecular Genetics, Fujita Health University, Japan）
Mon(2)-P-264 Functional Characterization of mir-1297 and mir-3179 in ABCA1 and Apo-A1 genes involved in Reverse Choles-
terol Transport (RCT) and Cholesterol Efflux (CE) ·············································································· 927
Sarah Peñafrancia L Coralde（National Institute of Molecular Biology and Biotechnology, University of the
Philippines-Diliman, Philippines）
Mon(2)-P-265 20-HETE Regulates the Expression of Nedd4-2 in Kidney via Neddylation ······································· 927
Yanyan Zhao（Department of Clinical Genetics, Shengjing Hospital of China Medical University, China）
Mon(2)-P-266 Apolipoprotein E is Associated with Coronary Artery Disease in Asian-Filipinos ································ 928
Arielle Kae L Sulit（Research and Biotechnology Group, St. Luke’s Medical Center, Philippines）
Mon(2)-P-267 Associations of the polymorphisms wihtin the CRP and IL1ß genes with acute cardiovascular events in patients
with multivessel coronary artery disease ····························································································· 928
Anastasiia V. Ponasenko（Russian Academy of Sciences, Research Institute for Complex Issues of Cardiovascular
Diseases, Russia）
Mon(2)-P-268 Mutations in an actin filament nucleation gene predispose individuals to thoracic aortic aneurysms and dissec-
tions ·············································································································································· 929
Alex Y.B Wan（Cardiovascular and Cell Sciences Research Institute, St. George’s Hospital, University of London,
United Kingdom, St George’s University of London, UK）
Poster Session
Metabolic Disorders 19:40-20:40
ICHG2016 29
Mon(2)-P-269 Neuronal ceroid lipofucinosis type CLN2: Clinical presentation, Enzyme analysisand Genotype study in 7 cases
from India ······································································································································ 930
Jayesh J Sheth（Dr. Kalam’s centre of excellence for rare disease study, Foundation for Research in Genetics and
Endocrinology (FRIGE) and Institute of Human Genetics, India）
Mon(2)-P-270 Extended newborn screening program in Chile (NESPC) ································································ 930
Silvia Castillo Taucher（Seccion Genetica, Hospital Clinico Universidad de Chile, Chile/Seccion Citogenetica,
Laboratorio Clinica Alemana de Santiago, Vitacura, Santiago, Chile）
Day 2
Mon(2)-P-271 9 YEARS OLD GIRL SUFFERING FROM WILSON DISEASE HAS ONLY ONE HETEROZYGOTE
LYS1010THR MUTATION IN ATP7B GENE ····················································································· 931
Nguyen T.M Huong（Human Genetics Department, National Hospital of Pediatrics, Vietnam）
Mon(2)-P-272 Screening of MCAD deficiency in Japan: 15 years’ experience of enzymatic and genetic evaluation
······················································································································································ 931
Go Tajima（Department of Pediatrics, Graduate School of Biomedical & Health Sciences, Hiroshima University,
Japan）
Mon(2)-P-273 An intergraded tandem mass spectrometry method for the quantitations of disaccharides derived from der-
matan, heparan, and keratan sulfates in urine applied for the diagnosis of mucopolysaccharidosis ·············· 932
Chih-Kuang Chuang（Medical Research Department, MacKay Memorial Hospital, Taiwan）
Mon(2)-P-274 Severe glutathione synthetase deficiency: clinical outcome after a 6-year follow-up ·························· 933
Jirat Chenbhanich（Faculty of Medicine, Chulalongkorn University, Thailand）
Mon(2)-P-275 A newborn patient with carbonic anhydrase VA deficiency presenting with hyperammonemic encephalopathy
······················································································································································ 933
Shoko Komatsuzaki（Department of Neuropediatrics and Inherited Metabolic Disorders, University Children’s
Hospital Heidelberg, Germany）
Mon(2)-P-276 Microbial enzymes contaminate urine in newborn urine and alter the results of metabolic screening
······················································································································································ 934
John A. Duley（School of Pharmacy, University of Queensland, Australia/Mater Research Institute, University
of Queensland）
Mon(2)-P-277 Find-GEMS (Gaucher patients in Epilepsy and MyoclonuS): Screening for Gaucher’s disease with enzyme assay
among patients with early-onset seizures ···························································································· 934
Kimitoshi Nakamura（Pediatrics, Kumamoto University, Japan）
Mon(2)-P-278 Unexpected persistent gastrointestinal mucosal infiltration of Gaucher cells in identical twin patients with
non-neuronopathic Gaucher disease despite long-term enzyme replacement therapy ································· 935
Yoo-Mi Kim（Department of Pediatrics, College of Medicine, Pusan National University Children’s Hospi-
tal,Yangsan, Korea, South）
Mon(2)-P-279 Lysine homocysteinylation inactivates ATR pathway and contributes to colorectal cancer onset ············· 935
Jian-Yuan Zhao（School of Life Sciences, Fudan University, China/State Key Lab of Genetic Engineering, Fudan
University/Collaborative Innovation Center for Genetics and Development, Fudan University）
Mon(2)-P-280 Clinical and laboratory evaluation of patients with mucopolysaccharidosis types I, II and VI receiving Enzyme
Replacement Therapy (ERT) ············································································································ 936
Chong Ae Kim（Pediatrics, Instituto da Criança, Brazil/Pediatrics, Instituto da Crianca）
Mon(2)-P-281 Evaluation of Wilson ｀ s disease in patients with a primary diagnosis other than WD: an inspiration for
reviewing the course of Robert Schumann ´ s illness ··········································································· 936
Teodor Podskarbi（Molecular Genetics and Metabolism Laboratory, Germany）
Mon(2)-P-282 Cytokine profile of patients with Gaucher disease type I and its response to enzyme replacement therapy
······················································································································································ 937
Filippo Vairo（Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Brazil/BRAIN Laboratory, Hospital
de Clínicas de Porto Alegre）
Mon(2)-P-283 Molecular and clinical heterogeneity in pyruvate dehydrogenase complex deficiency: the role of high throughput
sequencing approach ························································································································ 937
Elzbieta Ciara（The Children’s Memorial Health Institute, Poland）
Mon(2)-P-284 Investigation of clinical differences between MODY1 and MODY3 in Japanese ································· 938
Mayumi Enya（Gifu university, Japan）
Mon(2)-P-285 In search for low excretor genotype in Indian patients with Glutaric Acidemia Type I ························· 939
Kruthika-Vinod T.P（Neurochemistry, National Institute of Mental Health and Neuroscience, Bangalore, India）
Mon(2)-P-286 Therapeutic effects of dietary supplementation with glycine, L-carnitine, or both in combination in isovaleric
acidemia ······································································································································· 940
Yasutsugu Chinen（Pediatrics, Faculty of Medicine, University of the Ryukyus, Japan）
ICHG2016 30
Mon(2)-P-287 New indexes of neonatal tandem mass-screening for early detection of citrin deficiency (NICCD)
······················································································································································ 940
Hiroko Shigetomi（Center for Pediatric Genetics & Metabolic disorder, Clinical Research, NHO Hokkaido Medical
Center, Japan）
Mon(2)-P-288 Utility of CCL18/PARC and Heparin Cofactor II - Thrombin for diagnosis and monitoring of Lysosomal Storage
Disorders ········································································································································ 941
Day 2
Sanjeev Kumar Pandey（Biochemical Genetics Division, Sir Ganga Ram Hospital, India）
Mon(2)-P-289 KLF14 involves in controlling inflammation in the white adipose tissue ··········································· 942
Chiharu Tayama（National Research Institute for Child Health and Development, Japan）
Mon(2)-P-290 POLG-related disorders in Polish population - a comprehensive study ·············································· 942
Dorota Piekutowska-Abramczuk（Medical Genetics, The Children’s Memorial Health Institute, Poland）
Mon(2)-P-291 A long term follow-up study of 8 individuals with asymptomatic propionic acidemia ·························· 943
Yoriko Watanabe（Pediatrics and Child Health, Kurume University, Japan/Research Institute of GC/MS, Kurume
University）
Mon(2)-P-292 Mutation Spectrum of Japanese Patients with Fabry Disease- Correlation between genotype and phenotype
······················································································································································ 944
Masahisa Kobayashi（Department of Pediatrics, The Jikei University School of Medicine, Japan）
Mon(2)-P-293 Analysis of ABCG2 allelic variants in primary gout ········································································ 944
Blanka Stiburkova（Molecular Biology and Immunogenetics, Institute of Rheumatology, Czech Republic/Institute
of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Repub-
lic）
Mon(2)-P-294 PNPLA4 is a novel causative gene for mitochondrial respiratory chain disorder presenting with apparent life-
threatening event ···························································································································· 945
Hiromi Nyuzuki（Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine,
Saitama Medical University, Japan/Department of Pediatrics, Niigata University Graduate School of Medical and
Dental Sciences）
Mon(2)-P-295 Spectrum of AGL mutations in Chinese patients with glycogen storage disease type III: identification of 31
novel mutations ······························································································································ 946
Chaoxia Lu（McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences & Peking Union
Mon(2)-P-296 Two Filipino siblings with Glutaric Aciduria Type 1 ······································································· 946
Barbra Charina V. Cavan（Pediatrics, Cebu Doctors’ University Hospital, Philippines）
Mon(2)-P-297 Biochemical and molecular characteristics of Korean children with citrin deficiency ··························· 947
Jae-Min Kim（Medical Genetics Center, Asan Medical Center, Korea, South）
Mon(2)-P-298 Diverse clinical phenotypes of mitochondrial trifunctional proteindeficiencyaccording to mutations in HADHA
and HADHB ·································································································································· 947
Gu-Hwan Kim（Medical Genetics Center, Asan Medical Center, Korea, South）
Mon(2)-P-299 A Nationwide Survey on Fabry disease in Korea ············································································ 948
In Hee Choi（Medical Genetics Center, Asan Medical Center, Korea, South）
Mon(2)-P-300 Combined Effect of Celastrol and Chemical Chaperone on glucocerebrosidase (GBA) activities of skin fibroblasts
from Gaucher patients ····················································································································· 948
Sun Hee Heo（Asan Institute for Life Sciences, Asan Medical Center, Korea, South）
Mon(2)-P-301 Clinical And Molecular Updates Of Infantile Systemic Hyalinosis In Arab Populations ······················· 949
Sahar AF Hammoudah（Department of Clinical and Chemical Pathology, Tanta University）
Mon(2)-P-302 Analysis of inverted chromosome from phosphoglucomutase 1 deficiency patient ······························ 949
Tamae Ohye（Department of Clinical Hematology, Faculty of Medical Technology, Fujita Health University, Japan）
Mon(2)-P-303 Mutational Analysis of Egyptian Morquio Patients ········································································ 950
Ekram M.A. Fateen（Biochemical Genetics, National Research Centre, Egypt）
Mon(2)-P-304 NEWBORN SCREENING FOR MUCOPOLYSACCHARIDOSES: DETERMINATION OF SENSITIVITY,
SPECIFICITY AND CUTOFF VALUES ····························································································· 951
Adriana M Montano（Pediatrics, Saint Louis University, USA/Biochemistry and Molecular Biology, Saint Louis
University）
Mon(2)-P-305 Development of a Less Immunogenic Protein for Enzyme Replacement Therapy of Morquio A Disease
······················································································································································ 951
University）
ICHG2016 31
Mon(2)-P-306 Age-dependent gene expression profile analysis in Morquio cartilage tissue ······································ 952
University）
Mon(2)-P-307 Evaluation of Homocysteine Levels in Cuban Patients with Homocystinuria and Methylmalonic Aciduria by
HPLC ············································································································································ 952
Alina Concepcion（Laboratory of Biochemical Genetics, National Center of Medical Genetics, Cuba）
Day 2
Mon(2)-P-308 Galsulfase hypersensitivity and desensitization of mucopolysaccharidosis VI patients ·························· 953
Ana Maria Martins（Pediatrics, Universidade Federal de Sao Paulo, Brazil）
Mon(2)-P-309 The little things that matter: A qualitative study of the disease management experiences of caregivers of
children with inherited metabolic diseases ··························································································· 953
Mon(2)-P-310 Altered pre-mRNA splicing due to novel intronic mutation c.1443+5G>A in the dihydropyrimidinase (DPYS)
gene ·············································································································································· 954
Yoko Nakajima（Pediatrics, Fujita Health University School of Medicine, Japan）
Mon(2)-P-311 A novel, hybrid method of blue and clear native polyacrylamide gel electrophoresis (BCN-PAGE): a mini-
mally invasive method to detect electron transport chain abnormalities in cultured skin fibroblasts in patients with
mitochondrial disease ······················································································································· 955
Christopher Newell（Department of Medical Science, Cumming School of Medicine, University of Calgary, Calgary,
Canada）
Mon(2)-P-312 Plasma cell-free mitochondrial DNA: A novel and non-invasive method to detect mutations in mitochondrial
DNA ············································································································································· 955
Christopher Newell（Department of Medical Science, Cumming School of Medicine, University of Calgary, Calgary,
Canada）
Mon(2)-P-313 Sulfated disaccharides improve the iduronate-2-sulfatase function in fibroblasts from patient with mucopolysac-
charidosis type II ····························································································································· 956
Hiroo Hoshina（Department of Pediatirics, Jikei Univ Sch of Med, Japan/Div of Gene Thera, Res Cent for Med
Sci, Jikei Univ Sch of Med）
Mon(2)-P-314 Expert recommendations for the laboratory diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease):
diagnostic algorithm and best practice guidelines for a timely diagnosis ·················································· 957
Emanuela Izzo（Scientific Affairs, BioMarin Pharmaceuticals Inc, USA）
ICHG2016 32
Tue.,April 05
Day 3
Annex 1 (1F)

Frontiers of Human Genomics 8:00-10:00
Convener：Shinichi Morishita（Department of Computational Biology and Medical Sciences, Graduate School of Frontier
Sciences, the University of Tokyo, Japan）
Convener ：Jun Wang（iCarbonX, China）
Day 3
Tue(3)-CIS11-1 Million Genomes Ahead ··········································································································· 204
Jun Wang（iCarbonX, China）
Tue(3)-CIS11-2 New human genome reference structures ··················································································· 206
Richard Durbin（Wellcome Trust Sanger Institute, UK）
Tue(3)-CIS11-3 Reading and Writing Genomes in 3D: The CTCF code and how to hack it ····································· 207
Erez Lieberman Aiden（Molecular & Human Genetics, Baylor College of Medicine, USA）
Tue(3)-CIS11-4 An ’omic checkup: Longitudinal multi-omics for personalized medicine ·········································· 208
Brian D. Piening（Genetics, Stanford University, USA）

Variations in Genome Structure 10:20-12:20
Convener：Hiroki Kurahashi（Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health
University, Japan）
Convener ：Wigard P. Kloosterman（Dept. of Medical Genetics, Center for Molecular Medicine, University Medical Center
Utrecht, The Netherlands）
Tue(3)-CIS12-1 Somatic mosaicism - How much of de novo is mitotic? ······························································ 209

Pawel Stankiewicz（Molecular & Human Genetics, Baylor College of Medicine, USA/Institute of Mother and
Child, Warsaw, Poland）
Tue(3)-CIS12-2 Palindrome-mediated recurrent translocations in humans ····························································· 211
Hiroki Kurahashi（Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health
Tue(3)-CIS12-3 Detection and interpretation of complex structural variations in human genomes ···························· 212
Wigard Kloosterman（Dept. of Medical Genetics, Center for Molecular Medicine, University Medical Center
Tue(3)-CIS12-4 Genome-first detection of variation with single-molecule sequencing ·············································· 213
Mark J.P. Chaisson（Genome Sciences, University of Washington, USA）
[YIA1] Young Investigator Awards Session 1 13:50-15:20

Chair：Brunhilde Wirth（Institute of Human Genetics, University of Cologne, Germany）
Chair ：Stephen T.S. Lam（Faculty of Medicine, The Chinese University of Hong Kong, China）
Tue(3)-YIA1-1 Association between the literacy on genomics and health status; encouraging genomics education in personal-
ized preventive medicine era ············································································································ 479
Sho Nakamura（Department of Clinical Oncology, Yamagata University Faculty of Medicine, Japan/Cancer Pre-
vention and Control Division, Kanagawa Cancer Center Research Institute）
Tue(3)-YIA1-2 A molecular study on Stevens-Johnson syndrome patients with ocular manifestations ······················ 480
Sushil Kumari Sangwan（Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India）
Tue(3)-YIA1-3 Investigation of Variants within Antipsychotic Pharmacogenes Associated with Treatment Outcome in a South
African First Episode Schizophrenia Cohort ······················································································· 481
Faatiemah Higgins（Genetics, Stellenbosch University, South Africa）
Tue(3)-YIA1-4 Biallelic truncating mutations in ALPK3 cause severe pediatric cardiomyopathy ······························ 482
Judith M.A. Verhagen（Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the
Netherlands, Netherlands）
ICHG2016 33
Tue(3)-YIA1-5 Genetic association study identifies common variation in PHACTR1 to associate with fibromuscular dysplasia
···················································································································································· 483
Nabila Bouatia-Naji（Paris Cardiovacular Research Center, INSERM, France/INSERM UMR970, Paris,
France/Faculty of medicine, Paris-Descartes University, Sorbonne Paris Cite）
Tue(3)-YIA1-6 Size-based molecular diagnostics using plasma DNA for noninvasive prenatal testing ······················· 484
Stephanie C. Y. Yu（Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales
Hospital, Shatin, NT, Hong Kong SAR, China, Hong Kong/Centre for Research into Circulating Fetal Nucleic
Acids, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong
SAR, China）
[YIA2] Young Investigator Awards Session 2 15:40-17:10
Day 3
Chair：Joris A. Veltman（Human Genetics, Radboud University Medical Centre, The Netherlands）
Chair ：Naomichi Matsumoto（Department of Human Genetics, Yokohama City University Graduate School of Medicine,
Japan）
Tue(3)-YIA2-1 LAT2 transporter is involved in age-related hearing loss ······························································· 485

Meritxell Espino Guarch（Experimental Genetics, Sidra Medical and Research Center, Qatar/Molecular Genet-
ics Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain/Institute of Research in
Biomedicine (IRB), Barcelona, Spain）
Tue(3)-YIA2-2 Whole-genome sequencing of monozygotic twins discordant for schizophrenia ································· 486
Yu Fan（Kunming Institution of Zoology, Chinese Academy of Sciences, China/Kunming College of Life Science,
University of Chinese Academy of Sciences）
Tue(3)-YIA2-3 Towards clinical accreditation of structural variation calling from HiSeq X whole genome sequencing data
······················································································································································ 487
Andre E Minoche（Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Australia）
Tue(3)-YIA2-4 Thousands of novel translated open reading frames in humans inferred by ribosome footprint profiling
······················································································································································ 488
Anil Raj（Department of Genetics, Stanford University, USA）
Tue(3)-YIA2-5 Visualizing structural variation at the single cell level to explore human genome heterogeneity ············· 489
Ashley D Sanders（BC Cancer Agency, University of British Columbia, Canada）
Tue(3)-YIA2-6 Genome-wide multi-phenotype analysis of rare variants boosts power for locus discovery and indicates novel
rare variant effects from a known common variant locus on omega fatty acids ······································· 490
Marika Kaakinen（Genomics of Common Disease, Imperial College London, UK）
Annex 2 (1F)

Complex Trait Diseases 1: Common Disease 8:00-10:00
Convener：Michiaki Kubo（Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Japan）
Convener ：Anne M. Bowcock（National Heart and Lung Institute, Imperial College, London, UK）
Tue(3)-CIS13-1 Statistical Genetics for Autoimmune Diseases and Drug Discovery ················································ 214
Yukinori Okada（Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University;
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Japan/Laboratory for Sta-
tistical Analysis, RIKEN Center for Integrative Medical Sciences）
Tue(3)-CIS13-2 DRIVER GENES OF ORAL CANCER, ITS PROGRESSION AND METASTASIS ··························· 216
Partha P. Majumder（National Institute of Biomedical Genomics, India）
Tue(3)-CIS13-3 Transcriptome landscape of chronic traumatic encephalopathy and Alzheimer disease in human brains
······················································································································································ 217
Jeong-Sun Seo（Genomic Medicine Institute, Seoul National University, Korea）
Tue(3)-CIS13-4 Genetic analysis of psoriasis and psoriatic arthritis ······································································· 218
Anne M. Bowcock（National Heart and Lung Institute, Imperial College, London, UK）
ICHG2016 34

Complex Trait Diseases 2: Autoimmune Diseases 10:20-12:20
Convener：Kazuhiko Yamamoto（Department of Allergy and Rheumatology, Graduate School of Medicine, University of
Tokyo, Japan）
Convener ：Soumya Raychaudhuri（Medicine, Harvard Medical School, Divisions of Genetics and Rheumatology, Brigham
and Women’s Hospital; Medical and Population Genetics, Broad Institute; Institute of Inflammation and Repair, University
of Manchester; Department of Medicine, Karolinska Institutet, USA）
Tue(3)-CIS14-1 Fine-mapping the HLA and other autoimmune loci ····································································· 219
Soumya Raychaudhuri（Medicine, Harvard Medical School, Divisions of Genetics and Rheumatology, Brigham
and Women’s Hospital; Medical and Population Genetics, Broad Institute; Institute of Inflammation and Re-
pair, University of Manchester; Department of Medicine, Karolinska Institutet, USA/Divisions of Genetics and
Rheumatology, Brigham and Women’s Hospital/Medical and Population Genetics, Broad Institute/Institute of
Day 3
Inflammation and Repair, University of Manchester/Department of Medicine, Karolinska Institutet）
Tue(3)-CIS14-2 GWAS and functional genomics of autoimmune diseases ······························································ 221
Yuta Kochi（Laboratory for Autoimmune Diseases, IMS, RIKEN, Japan）
Tue(3)-CIS14-3 Combining population and clinical biobanks to translate genetic variation into immune function
······················································································································································ 222
Cisca Wijmenga（Genetics, University Medical Center Groningen, Netherlands）
Tue(3)-CIS14-4 Transcriptome variation in human immunity ··············································································· 223
Barbara E. Stranger（Section to Genetic Medicine, University of Chicago, USA/Institute for Genomics and Systems
Biology, University of Chicago）

Asian Genome Project 12:40-13:40
Chair：Trystan Whang（Macrogen APAC Manager）
MACROGEN JAPAN
Asian Genome Project ····················································································································· 497

Changhoon Kim（Macrogen, Inc., Korea）
Asian Genome Project ····················································································································· 498
Ryo Yamada（Kyoto University, Japan）

Chair：Stacey Edwards（Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Australia）
Chair ：Hiroyuki Aburatani（Research Center for Advanced Science and Technology, The University of Tokyo, Japan）
Tue(3)-O13-1 Non-random occurrence and early age of onset of diverse lymphoid cancers in families supports the existence
of genetic risk factors for multiple lymphoid cancers ··········································································· 572
Samantha Jones（Medical Genetics, University of British Columbia, Canada/Cancer Genetics, British Columbia
Cancer Agency）
Tue(3)-O13-2 Targeted TET oxidase activity through methyl-CpG binding domain extensively suppresses cancer cell prolifer-
ation ············································································································································ 573
Shinichi Fukushige（Department of Molecular Pathology, Tohoku University School of Medicine, Japan）
Tue(3)-O13-3 Testing of Deletions or Excess Homozygosity for Head and Neck Cancer Association in Whole Genome SNP
Genotyping Studies ························································································································ 573
Chih-Chieh Wu（College of Medicine, Department of Environmental and Occupational Health, National Cheng
Kung University, Taiwan）
Tue(3)-O13-4 Five independent breast cancer risk variants at 6q25 display genotype-phenotype correlations and regulate ESR1
and RMND1 ································································································································· 574
Stacey Edwards（QIMR Berghofer Medical Research Institute, Australia）
Tue(3)-O13-5 Breast cancer pedigree exome sequencing reveals inherited RAD52 truncation mutation implicated in breast
cancer susceptibility ························································································································ 574
Helio A Costa（Genetics, Stanford University, USA/Stanford University School of Medicine, Department of Ge-
netics, Stanford, CA, USA）
Tue(3)-O13-6 High miR-30d expression associates with improved breast cancer survival ········································ 575
Maral Jamshidi（University of Helsinki and Helsinki University Hospital, Finland）
ICHG2016 35

Chair：Denise A.S. Batista（Department of Pathology, Johns Hopkins University, USA）
Chair ：Seigo Nakamura（Division of Breast Surgical Oncology, Showa University, Japan）
Tue(3)-O14-1 Clinical analysis of founder mutations of BRCA1 and BRCA2 in the Japanese population ················· 576
Reiko Yoshida（Breast center, Showa University, Japan）
Tue(3)-O14-2 Exome sequencing reveals new potential markers of therapy efficacy and safe cancellation of targeted therapy
in patients with chronic myeloid leukemia ·························································································· 576
Sergey I Kutsev（Laboratory of Mutagenesis, Research Center for Medical Genetics, Russia/Russian National
Research Medical University）
Tue(3)-O14-3 Next-generation sequencing to analyze ABL1 tyrosine kinase domain mutations in targeted therapeutic chronic
myelogenic leukemia patients ··········································································································· 577
Day 3
Chinh Q Duong（Department of Genetics and Molecular Biology, National Institute of Haematology and Blood
Transfusion, Vietnam）
Tue(3)-O14-4 Increasing diagnostic yield: Addition of next generation sequencing panel to chromosome microarray and kary-
otype in myeloid leukemia ················································································································ 578
Denise A.S. Batista（Pathology, Johns Hopkins University School of Medicine, USA）
Tue(3)-O14-5 The Effects Of JAK2V617F, MPL and CALR Mutations On Diagnosis, Classification, Frequency, Laboratory
Results and Clinical Status In Myeloproliferative Neoplasms ·································································· 578
Hatice Akar（Medical Genetics, Gulhane Military Medical Academy, Turkey）
Tue(3)-O14-6 Germline variants in pediatric leukemia detected by next generation sequence ·································· 579
Akira Shimada（Pediatrics, Okayama University Hospital, Japan）
Room A (2F)

Therapy for Genetic Diseases 8:00-10:00
Convener：Eiji Nanba（Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University,
Japan）
Convener ：Jeffery W. Kelly（Molecular And Experimental Medicine, The Scripps Research Institute; The Skaggs Institute
for Chemical Biology, The Scripps Research Institute, USA）
Tue(3)-CIS15-1 Understanding the Genetics and Biochemistry of the Transthyretin Amyloid Diseases Afforded a Disease-
Modifying Therapy, and Importantly, New Insights about Chaperone Function ········································ 224
Jeffery W. Kelly（Molecular And Experimental Medicine, The Scripps Research Institute; The Skaggs Institute for
Chemical Biology, The Scripps Research Institute, USA/The Skaggs Institute for Chemical Biology, The Scripps
Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037）
Tue(3)-CIS15-2 AUTOPHAGY AND OTHER PATHWAYS THAT PROTECT AGAINST NEURODEGENERATION
······················································································································································ 226
David C. Rubinsztein（Cambridge Institute for Medical Research, University of Cambridge, UK）
Tue(3)-CIS15-3 Treatment of Friedreich’s ataxia and mitochondrial diseases ······················································· 227
Jeanne Amiel（Institute Imagine and University Paris Descartes, Paris, France）
Tue(3)-CIS15-4 Chaperone therapy for lysosomal storage diseases ········································································ 228
Katsumi Higaki（Research Center for Bioscience and Technology, Tottori University, Japan）

Gene Therapy 10:20-12:20
Convener：Keiya Ozawa（Division of Genetic Therapeutics, The Advanced Clinical Research Center, Institute of Medical
Science, The University of Tokyo, Japan）
Convener ：Michel Sadelain（Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, USA）
Tue(3)-CIS16-1 Haematopoietic stem cell- and liver-targeted gene therapy for hereditary disease ····························· 229
Ian E. Alexander（Gene Therapy Research Unit, Sydney Children’s Hospitals Network and Children’s Medical
Research Institute; University of Sydney Medical School, Australia/University of Sydney Medical School）
ICHG2016 36
Tue(3)-CIS16-2 AAV (adeno-associated virus) vector-mediated gene therapy for hereditary and non-hereditory diseases
······················································································································································ 231
Keiya Ozawa（Division of Genetic Therapeutics, The Advanced Clinical Research Center, Institute of Medical
Tue(3)-CIS16-3 Gene editing - From modeling diseases to treating patients ·························································· 232
Toni Cathomen（Institute for Cell and Gene Therapy, Medical Center - University of Freiburg, Germany）
Tue(3)-CIS16-4 CAR Therapy: The CD19 Paradigm ·························································································· 233
Michel Sadelain（Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, USA）

Unzipping the genome: How whole genome and transcriptome sequencing are transforming biology and medicine
Day 3
12:40-13:40
Chair：Hiroya Kumai（Marketing, Illumina K.K.）
Illumina K.K.
Unzipping the genome: How whole genome and transcriptome sequencing are transforming biology and medicine
······················································································································································ 499
Marcel E. Dinger（Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia / St Vincent’s
Clinical School, University of New South Wales, Kensington NSW 2052, Australia）
[WS1] Workshop 1
Global Data Sharing in Human Genetics 13:50-15:20
Moderator：Sharon F. Terry（President and CEO / Genetic Alliance, USA）
Moderator ：Kazuto Kato（Graduate School of Medicine, Osaka University, Japan）
Tue(3)-WS1-1 Global Genomic Data Sharing for Health: A Human Rights Approach ············································· 296
Bartha M. Knoppers（Human Genetics, McGill University, Centre of Genomics and Policy, Canada）
Tue(3)-WS1-2 North-South inequities in global sharing of human genetic data ······················································ 298
Victor B. Penchaszadeh（Latin American Bioethics Network, Argentina）
Tue(3)-WS1-3 How Global is "Global Data sharing" ··························································································· 299
Charles N. Rotimi（Center for Research on Genomics and Global Health, National Human Genome Research
Institute, NIH, USA）
Tue(3)-WS1-4 Sharing Big Data: A Personal Perspective from a Developing Nation ·············································· 300
Partha Majumder（National Institute of Biomedical Genomics, India）

Chair：Marieke Joosten（Clinical Genetics, Erasmus MC, Rotterdam, Netherlands）
Chair ：Takahiro Yamada（Department of Obstetrics, Hokkaido University Graduate School of Medicine, Japan）
Tue(3)-O15-1 A case report of management including perinatal genetic counseling for May Hegglin Anomaly in pregnancy
that low platelets counts made the opportunity to diagnose ·································································· 581
Yuka Yamashita（Department of Obstetrics and Gynecology, Showa University Fujigaoka Hospital, Japan）
Tue(3)-O15-2 Uniparental disomy (UPD) 14 diagnosed by SNP microarray at 16 week amniotic fluid showed distinctive
ultrasonic finding from early 2nd trimester; a case report ······································································ 582
Norio Shinozuka（OBGYN, Seto Hospital, Japan/Clin. Genetics, Seto Hospital）
Tue(3)-O15-3 Prenatal whole genome SNP array diagnosis: relevance of incidental findings in pregnancies with and without
ultrasound anomalies ······················································································································ 582
Marieke Joosten（Clinical Genetics, Erasmus MC, Netherlands）
Tue(3)-O15-4 Postnatal and prenatal diagnosis for neonatal intrahepatic cholestasis caused by citrin deficiency
······················································································································································ 583
Nguyen T.M Huong（Human Genetics Department, National Hospital of Pediatrics, Vietnam）
Tue(3)-O15-5 Prenatal Counseling and Diagnosis of Gaucher Disease In Egypt: 15 Years Experience ······················ 584
Ahmed A.L. Aboulnasr（Obstetrics and Gynecology, Faculty of Medicine, Cairo University, Egypt）
ICHG2016 37
Tue(3)-O15-6 Serious complex-heart disease is hardly predicted by prenatal genetic screening ································ 584
Mika Saito（Pediatric Cardiology, Sakakibara Heart Institute, Japan）
Room E (1F)

ELSI 8:00-10:00
Convener：Masayuki Yoshida（Department of Life Science and Bioethics, Tokyo Medical and Dental University, Japan）
Convener ：Dina N. Paltoo（Genetics, Health and Society Program, Office of Science Policy/National Institute of Health,
USA）
Day 3
Tue(3)-CIS17-1 Patient Preferences for Governance of Use of Genomic Information in Research ······························ 234
Sandra S. Lee（Stanford Center for Biomedical Ethics, Stanford University, USA）
Tue(3)-CIS17-2 Given a Voice: An Update on the Lacks Family-NIH Partnership on Use of HeLa Genome Data
······················································································································································ 235
Dina N. Paltoo（Genetics, Health and Society Program, Office of Science Policy/National Institute of Health,
USA）
Tue(3)-CIS17-3 ELSI practices and regulations for collaboration and public participation in personal genome research
······················································································································································ 236
Kazuto Kato（Biomedical Ethics and Public Policy, Osaka University, Japan）
Tue(3)-CIS17-4 Ethical theory and global challenges in the era of -omics and predictive medicine ···························· 237
Ruth F. Chadwick（Centre for Social Ethics and Policy, University of Manchester, UK）
Tue(3)-CIS17-5 Ethical and Policy Issues in Human Genome Editing and Germline Modifications ···························· 238
Xiaomei Zhai（Peking Union Medical College and Chinese Academy of Medical Sciences, China/Chinese Academy
of Medical Sciences）

Genetic Counseling/Education 10:20-12:20
Convener：Kristine Barlow-Stewart（Sydney Medical School, The University of Sydney; Royal North Shore Hospital, Aus-
tralia）
Convener：Junko Yotsumoto（Natural Science Division, Faculty of Core Research, Ochanomizu University; Showa University,
Japan）
Tue(3)-CIS18-1 Introduction and brief overview of genetic counselling in Japan - Role and training of genetic counselors, and
a topic, “Dealing with BRCA VUS in Japan” ··················································································· 240
Junko Yotsumoto（Natural Science Division, Faculty of Core Research, Ochanomizu University; Showa University,
Japan/Showa University）
Tue(3)-CIS18-2 Genetic Education Strategies to Enhance the Genetic Counselling process in the Genomic Era ············· 242
Kristine K. Barlow-Stewart（Sydney Medical School, The University of Sydney; Royal North Shore Hospital,
Australia）
Tue(3)-CIS18-3 Genetic counselors’ experiences obtaining informed consent for genomic sequencing: Lessons learned
······················································································································································ 243
Barbara A. Bernhardt（Translational Medicine and Human Genetics, University of Pennsylvania, USA）
Tue(3)-CIS18-4 Engaging 7,000 people about the return of results from sequencing research ·································· 244
Anna Middleton（Social Science and Ethics, Wellcome Genome Campus, UK）
Tue(3)-CIS18-5 Genetic Counselling and hereditary testing in low and middle income Asian setting ························· 245
Sook Yee Yoon（Familial Cancer, Cancer Research Malaysia, Malaysia）

Ion PGM™ sequencing system for screening system of genetic skeletal muscle disorders 12:40-13:40
Chair：Hannah Viernes（Global Market Development, Next Generation Sequencing, Life Sciences Solutions）
Thermo Fisher Scientific
ICHG2016 38
Ion PGM™ sequencing system for screening system of genetic skeletal muscle disorders ··························· 500
Satomi Mitsuhashi（Department of Neuromuscular Research, National Institute of Neuroscience, National Center
of Neurology and Psychiatry (NCNP) / Medical Genome Center, National Center of Neurology and Psychiatry
(NCNP)）

Chair：Elizabeth Hauser（Duke Molecular Physiology Institute, Duke University, USA）
Chair ：Tatsuhiko Tsunoda（Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and
Dental University, Japan）
Tue(3)-O16-1 Coding and non-coding transcriptomic landscape of human brain: preliminary analysis of RNA sequencing data
···················································································································································· 586
Day 3
Chao Chen（The State Key Lab of Medical Genetics, Central South University, Changsha, China）
Tue(3)-O16-2 Pleiotropic landscape of anthropometry inferred from 359 novel and 297 established loci discovered in 270,000
individuals ····································································································································· 587
Xia Shen（Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden/University of Edinburgh）
Tue(3)-O16-3 From Paris to Kyoto or from Dermatoglyphics to Exome Sequencing ·············································· 587
Regina M. Zambrano（Department of Pediatrics, Louisiana State University Health Sciences Center and Children’s
Hospital of New Orleans, USA）
Tue(3)-O16-4 QTR1: An Enhanaced, Population-Centric Reference Genome Based on GRCh37 to Facilitate Precision
Medicine in Qatar and the Middle East ····························································································· 588
Khalid Fakhro（Translational Medicine, Sidra Medical Research Center, Qatar/Weill Cornell Medical College in
Qatar）
Tue(3)-O16-5 HOT or not: redefining the origin of high-occupancy target regions ················································ 588
Altuna Akalin（BIMSB, Max Delbrueck Center, Germany）
Tue(3)-O16-6 Short inversion detection by splitting and re-aligning poorly mapped and unmapped next-generation sequencing
reads ············································································································································ 589
Ruoyan Chen（Paediatrics and Adolescent Medicine, The University of Hong Kong, China）

Chair：Davide Cittaro（Center for Translational Genomics and Bioinformatics, San Raffaele Hospital, Italy）
Chair ：Zhaoming Wang（Department of Computational Biology, St. Jude Children’s Research Hospital, USA）
Tue(3)-O17-1 Imputation of KIR types from SNP variation data ········································································· 590
Damjan Vukcevic（Statistical Genetics, Murdoch Childrens Research Institute, Australia/School of Mathematics
and Statistics, University of Melbourne, Australia）
Tue(3)-O17-2 Diagnostic Role of Exome Sequencing in Immune Deficiency Disorders ··········································· 591
Steven E Brenner（University of California, Berkeley, USA）
Tue(3)-O17-3 Using patterns of somatic mutations in cancer to predict disease genes ··········································· 591
Davide Cittaro（Center for Translational Genomics and Bioinformatics, San Raffaele Hospital, Italy）
Tue(3)-O17-4 Telomere Length and Accelerated Aging in Adult Survivors of Childhood Cancer: a report from the St. Jude
Lifetime Cohort ····························································································································· 592
Zhaoming Wang（St. Jude Children’s Research Hospital, USA）
Tue(3)-O17-5 CentoMD  , the largest variant database for rare diseases ······························································ 592
Daniel Trujillano（Centogene AG, Germany）
Tue(3)-O17-6 Patient Archive: An integrated solution for deep phenotyping of clinical cases ································· 593
Tudor Groza（Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Australia/St Vicent’s
Clinical School, Faculty of Medicine, University of New South Wales, Australia）
ICHG2016 39
Room B-1 (2F)

Psychiatric Genetics 8:00-10:00
Convener：Norio Ozaki（Department of Psychiatry, Nagoya University Graduate School of Medicine, Japan）
Convener ：Joseph D. Buxbaum（Icahn School of Medicine at Mount Sinai, USA）
Tue(3)-CIS19-1 Rare and common variation in autism and associated neurodevelopment disorders ··························· 246
Joseph D. Buxbaum（Icahn School of Medicine at Mount Sinai, USA）
Tue(3)-CIS19-2 Genetics of schizophrenia and bipolar disorder ············································································ 247
Michael J. Owen（MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UK）
Day 3
Tue(3)-CIS19-3 Shared Genetic Risk Across Psychiatric Disorders ········································································ 248
Naomi R. Wray（Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia）
Tue(3)-CIS19-4 Pharmacogenomics in Psychiatry ······························································································ 249
Masashi Ikeda（Psychiatry, Fujita Health University School of Medicine, Japan）

Neurogenetics and Neurodegeneration 10:20-12:20
Convener：Tatsushi Toda（Division of Neurology, Kobe University Graduate School of Medicine, Japan）
Convener ：Bryan J. Traynor（Laboratory of Neurogenetics, National Institute on Aging, USA）
Tue(3)-CIS20-1 Molecular genetic basis of multiple system atrophy ······································································ 250

Jun Mitsui（Neurology, The University of Tokyo, Japan）
Tue(3)-CIS20-2 Genetics of Parkinson’s Disease ······························································································ 252
Tatsushi Toda（Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine,
Japan）
Tue(3)-CIS20-3 Genetics of mitochondrial diseases ··························································································· 253
Patrick F. Chinnery（University of Cambridge, UK/MRC Mitochondrial Biology Unit）
Tue(3)-CIS20-4 Genomics of amyotrophic lateral sclerosis and frontotemporal dementia ········································· 254
Bryan J. Traynor（Laboratory of Neurogenetics, National Institute on Aging, USA）

Biobank and Informatics for Cancer Project and Clinical Sequencing 12:40-13:40
Chair：Seigo Nakamura（Director of Breast Center, Showa University Hospital, Japan）
Eisai Co., Ltd.
Biobank and Informatics for Cancer Project and Clinical Sequencing ······················································ 501
Manabu Muto（Department of Clinical oncology, Gradeuate School of Medicine, Kyoto University, Japan）

Chair：Kimihiko Oishi（Genetics and Genomic Sciences, Pediatrics, Icahn School of Medicine at Mount Sinai, USA）
Chair ：Nobuhiko Okamoto（Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal
and Child Health, Izumi, Osaka, Japan）
Tue(3)-O18-1 XRCC4, a novel gene associated with Seckel syndrome and increased genomic instability ·················· 594
Nadine Rosin（Institute of Human Genetics, University of Cologne, Cologne, Germany/Center for Molecular
Medicine Cologne (CMMC), University of Cologne, Cologne, Germany/Cologne Excellence Cluster on Cellular
Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany）
Tue(3)-O18-2 Systematic Cellular Disease Models Reveal Synergistic Interactions of Trisomy 21 and GATA1 Mutations in
Hematopoietic Abnormalities ··········································································································· 594
Kimihiko Banno（Department of Pediatirics, Graduate School of Medicine, Osaka University, Japan）
Tue(3)-O18-3 Novel MCA/ID syndrome with ASH1L mutation ·········································································· 595
Nobuhiko Okamoto（Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal
and Child Health, Japan）
ICHG2016 40
Tue(3)-O18-4 Novel Splicing Mutation in the ASXL3 gene causing Bainbridge-Ropers Syndrome ··························· 596
Ikumi Hori（Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical
Sciences, Nagoya, Japan）
Tue(3)-O18-5 Further characterization of Coffin-Siris syndrome caused by a novel variant in SMARCB1 ················· 596
Kimihiko Oishi（Pediatrics, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, USA）
Tue(3)-O18-6 Broadening the phenotypic spectrum of ANKRD11 -related syndrome [S1] [S1] 62 characters <255 characters
······················································································································································ 597
Satoko Miyatake（Department of Human Genetics, Yokohama City University Graduate School of Medicine,
Japan）
Day 3
Chair：Susan H. Blanton（Dr. John T. Macdonald Department of Human Genetics, University of Miami, USA）
Chair ：Hiroki Kurahashi（Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health
Tue(3)-O19-1 An unique case of a mosaic genome-wide uniparental isodisomy in a newborn with Beckwith-Wiedemann
syndrome ······································································································································ 598
Lars T. van der Veken（Dept of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands, Nether-
lands）
Tue(3)-O19-2 The comprehensive genetic analysis of congenital anomalies of the kidney and urinary tract (CAKUT) in Japan
···················································································································································· 599
Naoya Morisada（Department of Community Medicine and Social Healthcare Science, Kobe University Graduate
School of Medicine, Japan/Department of Pediatrics, Kobe University Graduate School of Medicine）
Tue(3)-O19-3 MOLECULAR DIAGNOSIS OF RWANDAN CHILDREN WITH UNEXPLAINED INTELLECTUAL DISABIL-
ITY/NEURODEVELOPMENTAL DELAY BY a-CGH AND WHOLE EXOME SEQUENCING ·················· 599
Leon Mutesa（Human Genetics, University of Rwanda, Rwanda）
Tue(3)-O19-4 Screening of copy number variants in 450 Japanese subjects presenting with intellectual disability (ID) and
multiple congenital anomalies (MCA) by SNP array unveiling rare small variants and PPFIA2 as a novel candidate
gene for ID ···································································································································· 600
Daniela T. Uehara（Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental
Tue(3)-O19-5 Family-based association analysis of whole exome sequencing data identifies evidence for major role of focal
adhesion pathway ··························································································································· 601
Susan H. Blanton（Department of Human Genetics, University of Miami, USA/John P. Hussman Institute for
Human Genomics, University of Miami）
Tue(3)-O19-6 Clinical utility of next generation sequencing for undiagnosed syndromic disorder in pediatric patients with short
stature or overgrowth ····················································································································· 601
Yoo-Mi Kim（pediatrics, Pusan National University Children’s hospital, Korea, South）
Room B-2 (2F)

Chair：Guillaume Lettre（Department of Medicine, Montreal Heart Institute and Université de Montréal, Canada）
Chair ：Toshihiro Tanaka（Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental
Sciences, Tokyo Medical and Dental University, Japan）
Tue(3)-O20-1 Imputation analysis using reference panel of 1,070 Japanese individuals (1KJPN) and in silico / in vitro func-
tional analyses identified functional variants for primary biliary cirrhosis (PBC) susceptibility ··················· 603
Yuki Hitomi（Department of Human Genetics, Graduate School of Medicine, The University of Tokyo,
Japan/These authors contributed equally to this work）
Tue(3)-O20-2 The Latent Low Rank Model to Colocalize Genetic Risk Variants in Multiple GWAS ························· 604
Jin Liu（Center of Quantitative Medicine, Duke NUS Graduate Medical School, Singapore）
Tue(3)-O20-3 Leveraging Characteristics of Common Genetic Variants to Improve Power of Gene Discovery in Genome-wide
Association Study of Neuroticism ····································································································· 604
Min-Tzu Lo（Department of Radiology, Multimodal Imaging Laboratory, University of California, San Diego,
USA）
ICHG2016 41
Tue(3)-O20-4 Dominant Genetic Variation and Missing Heritability for Human Complex Traits - Insights from Twin versus
Genome-wide Common SNP Models ································································································· 605
Xu Chen（Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden）
Tue(3)-O20-5 Withdrawn ······························································································································· 605
Tue(3)-O20-6 The role of rare and low-frequency coding variants in adult height, a classic polygenic human trait
······················································································································································ 606
Guillaume Lettre（Medicine, Universite de Montreal, Montreal. Canada）
Day 3
Chair：Swapan K. Nath（Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, USA）
Chair ：Katsushi Tokunaga（Department of Human Genetics, University of Tokyo, Graduate School of Medicine, Japan）
Tue(3)-O21-1 Gene-based analysis of regulatory variants identifies P2RY14 as a new asthma risk gene ··················· 607
Manuel AR Ferreira（QIMR Berghofer Medical Research Institute, Australia）
Tue(3)-O21-2 Association analysis of the HLA-DRB1 locus in Immune-mediated necrotizing myopathy ··················· 608
Yuko Ohnuki（Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine,
Tokai University School of Medicine, Japan）
Tue(3)-O21-3 The high comorbidity of inflammatory bowel disease in primary sclerosing cholangitis is only partly explained
by shared genetic risk factors ··········································································································· 608
Sun-Gou Ji（Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK）
Tue(3)-O21-4 Genotyping of relapsing polychondritis for classical HLA genes identified novel susceptibility HLA alleles and
distinct genetic characteristics from other rheumatic diseases ································································ 609
Chikashi Terao（Division of Rheumatology, Immunology, and Allergy and Division of Genetics, Brigham and
Women’s Hospital, USA/Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto,
Japan/Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine,
Kyoto, Japan/Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto,
Japan）
Tue(3)-O21-5 Fine-mapping analysis of TNFSF15 across leprosy, Crohn’s disease and primary biliary cirrhosis
······················································································································································ 609
Astrid Irwanto（Human Genetics, Genome Institute of Singapore, Singapore）
Tue(3)-O21-6 High-density genotyping of immune-related loci and follow-up genetic association study identified ten novel
SLE susceptibility genes in individuals with Asian ancestry ·································································· 610
Swapan K. Nath（Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation,
USA）
Room C-1 (1F)

Chair：Tiong Yang Tan（Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, Australia
/ Department of Paediatrics, University of Melbourne, Melbourne, Australia / Department of Paediatrics and Adolescent
Medicine, University of Hong Kong, Hong Kong）
Chair ：Fuki Marie Hisama（Division of Medical Genetics, Department of Medicine, University of Washington, USA）
Tue(3)-O22-1 Novel mutations in ZNF335 broaden the phenotypic spectrum including less severe microcephaly and surviv-
ability into childhood ······················································································································ 611
Tiong Yang Tan（Victorian Clinical Genetics Services, Australia/Murdoch Childrens Research Institute, Mel-
bourne, Australia/Department of Paediatrics, University of Melbourne, Melbourne, Australia）
Tue(3)-O22-2 ADCY5 -Related Dyskinesia is Likely Under-recognized: Genotype-Phenotype Correlations and Broadening the
Spectrum ······································································································································ 611
Fuki Marie Hisama（Medical Genetics/Medicine, Univ of Washington, USA/Department of Neurology, Univ of
Washington）
Tue(3)-O22-3 Mutations in HACE1 cause an autosomal-recessive neurodevelopmental disorder ······························ 612
Ronja Hollstein（Section for Functional Genetics at the Institute of Human Genetics, Universitaet zu Luebeck,
Germany）
Tue(3)-O22-4 Severe CNS involvement in WWOX mutations: Description of five new cases ·································· 613
ICHG2016 42
Tue(3)-O22-5 Genetic studies on a Portuguese Parkinson disease patient cohort ··················································· 613
Gabriel Miltenberger-Miltenyi（Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa,
Portugal）
Tue(3)-O22-6 Neuron-specific Cul4b knockout mice recapture the cognitive impairment phenotype in human X-linked mental
retardation patients ························································································································ 614
Baichun Jiang（Department of Genetics, School of Medicine, Shandong University, China）

Chair：Claude Ferec（Director of the INSERM UMR1078 “Genetic, Functional Genomic & Biotechnologies”, INSERM,
Brest University, Brest Hospital, France）
Day 3
Chair ：Noriko Miyake（Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan）
Tue(3)-O23-1 The utility of medical exome-based virtual gene panel in the molecular diagnosis of genetically heterogeneous
sensorineural hearing loss ················································································································ 615
Qiaoning Guan（Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, USA）
Tue(3)-O23-2 Targeted screening of 187 genes involved in ocular development increases mutation detection rate by 10 % in
individuals with anophthalmia-microphthalmia spectrum ····································································· 615
Nicolas Chassaing（Medical Genetics, CHU Toulouse, France/Inserm U1056/EA-4555, Universite Toulouse
III/These authors contributed equally to this work）
Tue(3)-O23-3 The p.S178L mutation in TBC1D24 lead to dominant, non-syndromic hearing impairment through a gain-of-
function mechanism ······················································································································· 616
Tao Yang（Xinhua Hospital, Shanghai Jiaotong University School of Medicine, China）
Tue(3)-O23-4 Submicroscopic deletions at 13q32.1 cause congenital microcoria ··················································· 617
Lucas Fares Taie（Imagine - Institute of Genetic Diseases, France）
Tue(3)-O23-5 Biallelic NUP107 mutations cause early childhood-onset steroid resistant Nephrotic syndrome ············· 617
Noriko Miyake（Department of Human Genetics, Yokohama City University, Japan）
Tue(3)-O23-6 Genic and allelic variability in polycystic kidney disease :impact in the erea of precision medicine ············· 618
Claude Ferec（Inserm/university, France）
Room C-2 (1F)

Chair：William K. Scott（Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute
for Human Genomics, University of Miami, USA）
Chair ：Takeshi Ikeuchi（Molecular Genetics, Brain Research Institute, Niigata University, Japan）
Tue(3)-O24-1 Genome-wide interaction study of Parkinson disease and vitamin D deficiency implicates autoimmunity pathways
···················································································································································· 620
William K. Scott（John P. Hussman Institute for Human Genomics, University of Miami, USA/Dr. John T.
Macdonald Foundation Department of Human Genetics, University of Miami）
Tue(3)-O24-2 ABCA7 Frameshift Deletion Associated with Alzheimer’s Disease in African Americans ·················· 621
Holly N Cukier（John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine,
USA/Department of Neurology, University of Miami Miller School of Medicine）
Tue(3)-O24-3 Structural variants and neurodegenerative diseases in aging: regulatory and causality consequences
······················································································································································ 621
Ornit Chiba-Falek（Neurology, Duke University, USA）
Tue(3)-O24-4 Novel candidate genes for early-onset Alzheimer disease identified using whole-exome sequencing
······················································································································································ 622
Gary W Beecham（John P Hussman Institute for Human Genomics, University of Miami Miller School of Medicine,
USA）
Tue(3)-O24-5 Transethnic Genome-Wide Meta-Analysis for Alzheimer Disease identifies Novel Genes ······················ 622
Gyungah R Jun（Medicine, Boston University, USA/Integrated Neurogenetics, Eisai Inc）
ICHG2016 43
Tue(3)-O24-6 CFH variants affect structural and functional brain changes and genetic risk of Alzheimer’s disease
······················································································································································ 623
Deng-Feng Zhang（Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of
Zoology, Chinese Academy of Sciences, China/Kunming College of Life Science, University of Chinese Academy
of Sciences, Kunming, Yunnan, China）

Chair：Dong Hwan Lee（Soon Chun Hyang University Hospital, Korea, South）
Chair ：Naoko Iwasaki（Diabetes Center, Institute of Medical Genetics, Tokyo Women’s Medical University, Japan）
Tue(3)-O25-1 Prevalence of MODY subtype and clinical characteristics in patients with early onset diabetes in Japanese
Day 3
······················································································································································ 624
Naoko Iwasaki（Diabetes Center, Tokyo Women’s Medical University, Japan/Institute of Medical Genetics, Tokyo
Women’s Medical University/Institute of Integrated Medical Science, Tokyo Women’s Medical University）
Tue(3)-O25-2 Relationship between haplotype diversity of the HLA-G gene with type 1 diabetes mellitus and its expression
pattern on dendritic cells DC-10 ········································································································ 624
Rafael de Albuquerque（USP, Brazil）
Tue(3)-O25-3 Protein tyrosine phosphatase 1B (PTP1B) gene polymorphism is associated with obesity and resistance to
weight reduction therapy in the Japanese ··························································································· 625
Noriko Satoh-Asahara（Division of Diabetic Research, Clinical Research Institute, National Hospital Organization
Kyoto Medical Center, Japan）
Tue(3)-O25-4 The Incidence of Congenital Hypothyroidism and Study of Endorine Disruptors in Korea ··················· 626
Dong Hwan Lee（Department of Pediatrics, Soonchunhyang University Hospital, Korea, South）
Tue(3)-O25-5 Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through
puberty ········································································································································· 626
Yoshihiro Maruo（Pediatrics, Shiga University of Medical Sicence, Japan）
Tue(3)-O25-6 Biallelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Rhabdomy-
olysis, Cardiac Arrhythmias, and Progressive Neurodegeneration ·························································· 627
Laura S Kremer（Institute of Human Genetics, Helmholtz Zentrum Muenchen, Neuherberg, Germany）
Room D (1F)

Case Studies in Clinical Genetics: Dysmorphology 8:00-10:00
Moderator：Nobuhiko Okamoto（Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal
and Child Health, Osaka, Japan）
Moderator ：Ritsuko K. Pooh（CRIFM Clinical Research Institute of Fetal Medicine PMC, Osaka, Japan）
Tue(3)-ED3-1 Case Studies in Clinical Genetics: Dysmorphology ········································································· 456

Presenter/Discussant：Nobuhiko Okamoto（Department of Medical Genetics, Osaka Medical Center and Research
Institute for Maternal and Child Health, Osaka, Japan）
Presenter/Discussant：Ritsuko K. Pooh（CRIFM Clinical Research Institute of Fetal Medicine PMC, Osaka,
Japan）
Presenter/Discussant：Louanne Hudgins（Stanford University and Lucile Packard Children’s Hospital, USA）

Case Studies in Clinical Genetics: Lysosomal Storage Disease 10:20-12:20
Moderator/Discussant for 1 and 2：Norio Sakai（Osaka University Graduate School of Medicine, Division of Health Sciences,
Japan）
Moderator/Discussant for 3 and 4 ：Han-Wook Yoo（Medical Genetics Center, Asan Medical Center, University of Ulsan
College of Medicine, Seoul, Korea）
ICHG2016 44
Tue(3)-ED4-1 MPS ······································································································································· 459

Motomichi Kosuga（Department of Clinical Laboratory Medicine, National Center for Child Health and Devel-
opment, Japan）
Tue(3)-ED4-2 Gaucher ··································································································································· 460
Han-Wook Yoo（Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea）
Tue(3)-ED4-3 Luekodystrophy ························································································································ 461
Norio Sakai（Osaka University Graduate School of Medicine, division of Health Sciences, Japan）
Tue(3)-ED4-4 Fabry ······································································································································· 462
Kimitoshi Nakamura（Department of Pediatrics, Kumamoto University, Japan）
Day 3
Newborn Screening for Lysosomal Storage Disease 12:40-13:40
Chair：Fumio Endo（Department of Pediatrics, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University,
Japan）
Genzyme Japan K.K.
Newborn Screening for Lysosomal Storage Disease ·············································································· 502

Kimitoshi Nakamura（Department of Pediatrics, Faculty of Medical and Pharmaceutical Sciences, Kumamoto
Newborn Screening for Lysosomal Storage Disease ·············································································· 503
Joan Keutzer（Vice President and Head, Global Scientific Affairs, Sanofi Genzyme, USA）

Case Studies in Clinical Genetics: Cancer - Part 1: Genomic Medicine of Cancer on the Basis of the Somatic Mutations
/ Part 2: Genetic Counseling of Breast Cancer 13:50-15:20
Moderator：Takashi Kohno（National Cancer Center Research Institute, Japan）
Moderator ：Yoshinori Murakami（Institute of Medical Science, The University of Tokyo, Japan）
Discussant for Part 1 ：Kuniko Sunami（National Cancer Research Center Hospital, Japan）
Discussant for Part 2 ：Seigo Nakamura（Department of Breast Surgical Oncology, Showa University School of Medicine,
Japan）
Discussant for Part 2：Chieko Tamura（Certified Genetic Counselor, Japan / USA; Medical Information & Genetic Counseling
Division, FMC Tokyo Clinic, Japan）
Discussant for Part 2 ：Masami Arai（Cancer Institute Hospital, Division of Clinical Genetic Oncology）
Tue(3)-ED5-1 Part 1: Genomic Medicine of Cancer on the Basis of the Somatic Mutations ···································· 463
Takashi Kohno（National Cancer Center Research Institute, Japan）
Tue(3)-ED5-2 Part 1: Genomic Medicine of Cancer on the Basis of the Somatic Mutations ···································· 464
Sadakatsu Ikeda（Center for Personalized Cancer Therapy, University of California San Diego, Moores Cancer
Center, USA）
Tue(3)-ED5-3 Part 2: Genetic Counseling of Breast Cancer ················································································ 465
Yoshinori Murakami（Institute of Medical Science, The University of Tokyo, Japan）

Case Studies in Clinical Genetics: Neurology 15:40-17:10
Moderator：Thomas Gasser（German Center for Neurodegenerative Diseases (DZNE), Germany）
Moderator ：Hiroyuki Ishiura（The University of Tokyo, Japan）
Discussant ：Bing-wen Soong（Department of Neurology, National Yand-Ming University, Taipei, Taiwan）
Discussant ：Hiroshi Takashima（Neurology and Geriatrics, Kagoshima University, Japan）
Tue(3)-ED6-1 Case Studies in Clinical Genetics: Neurology ················································································· 466

Takashi Matsukawa（Department of Neurology, Graduate School of Medicine, The University of Tokyo, Japan）
Masaki Tanaka（Department of Neurology, The University of Tokyo, Japan）
Yoshio Sakiyama（Department of Neurology, Jichi Medical University, Saitama Medical Center, Japan）
ICHG2016 45
Room I (2F)
[O26] Clinical Genetic Testing 1 13:50-15:20

Chair：Ian G. Campbell（Peter MacCallum Cancer Centre, University of Melbourne, Australia）
Chair ：Shin-ichi Usami（Department of Otorhinolaryngology, Shinshu University School of Medicine, Japan）
Tue(3)-O26-1 Mutation spectrum of Japanese Lynch syndrome patients diagnosed by universal tumor screening for colorectal
cancer ·········································································································································· 628
Kiwamu Akagi（Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Japan）
Tue(3)-O26-2 Breast and Ovarian cancer prevention: Is it time for population screening for BRCA1 and BRCA2 mutations?
······················································································································································ 628
Day 3
Ian G Campbell（Research DIvision, Peter MacCallum Cancer Centre, Australia）
Tue(3)-O26-3 Differences of Clinical Characteristics among Heterozygous Familial Hypercholesterolemia Based on Genetic
Diagnosis ······································································································································ 629
Atsushi Nohara（Department of Advanced Research in Community Medicine, Kanazawa University Graduate
School of Medical Sciences, Japan）
Tue(3)-O26-4 Target resequencing of neuromuscular disease-related genes using next-generation sequencing for patients with
undiagnosed early-onset neuromuscular disorders ················································································· 630
Yuri Kitamura（Institute of Medical Genetics, Tokyo Women’s Medical University, Japan/Affiliated Field of
Medical Genetics, Division of Biomedical Engineering and Science, Graduate School of Tokyo Women’s Medical
University Tokyo）
Tue(3)-O26-5 Deafness gene variations in a 1,120 nonsyndromic hearing loss cohort: Molecular epidemiology and deafness
mutation spectrum of patients in Japan ···························································································· 630
Shin-ya Nishio（Department of Otorhinolaryngology, Shinshu University School of Medicine, Japan）
Tue(3)-O26-6 Improved Performance of Whole Genome Sequencing detects a SYNGAP1 Mutation in siblings with Epilepsy
with Myoclonic-Atonic seizures and photosensitivity ··········································································· 631
Mark J Cowley（Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Australia/St
Vincents Clinical School, University of New South Wales, Darlinghurst, Australia）

Chair：Michael Buckley（Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, Australia）
Chair ：Toshiyuki Yamamoto（lnstitute for lntegrated Medical Sciences, Tokyo Women’s Medical University, Japan）
Tue(3)-O27-1 The use of custom-designed NGS panels and CGH array for population-specific clinical testing ············· 632
Filip Zembol（Laboratory of molecular genetics, Gennet, Czech Republic）
Tue(3)-O27-2 aCGH ANALYSIS AND ITS IMPLICATIONS IN THE CASE OF A r(X) CHROMOSOME; ADVANTAGES IN
AN ERA OF DIAGNOSTIC ODISSEY ······························································································ 632
Ciprian D. Ion（Medical Genetics, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania）
Tue(3)-O27-3 Childhood-onset peripheral neuropathy: gene panel or whole exome? ············································· 633
Maie I Walsh（Clinical Genetics, Murdoch Childrens Research Institute, Melbourne, Australia）
Tue(3)-O27-4 Australian Renal Gene Panels: A National Program of Diagnostic Gene Panels For Multiple Renal Phenotypes
Utilising Massively Parallel Sequencing With Multi-Disciplinary Team Reporting ···································· 634
Hugh J McCarthy（Department of Clinical Genetics, The Children’s Hospital at Westmead, Australia/Department
of Paediatric Nephrology, The Children’s at Westmead, Sydney, Australia/Centre for Kidney Research, University
of Sydney, Sydney, Australia）
Tue(3)-O27-5 Evaluating Whole-Genome Sequencing as a General Purpose Genetic Screen ··································· 635
Mark Pinese（Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Australia）
Tue(3)-O27-6 Clinical Exome in Consanguineous Population Provides Higher Detection Rate ································· 635
Abdul Ali Zada（King Fahad Medical City, Saudi Arabia）
ICHG2016 46
Room J (2F)
[O28] Epigenetics 1 13:50-15:20

Chair：Andrea Riccio（CNR, Institute of Genetics and Biophysics, Italy）
Chair ：Kenichiro Hata（Department of Maternal Fetal Biology, National Research Institute for Child Health and Develop-
ment, Japan）
Tue(3)-O28-1 Identification of genetic determinants of monocyte epigenetic plasticity across differing innate immune stimuli
······················································································································································ 637
Benjamin Fairfax（Wellcome Trust Centre for Human Genetics, University of Oxford, UK）
Tue(3)-O28-2 Novel epigenetic loci associated with Beckwith Wiedemann Syndrome ············································ 637
Day 3
Izabela Krzyzewska（Clinical Genetics, Academic Medical Center, Netherlands）
Tue(3)-O28-3 Genome-Wide DNA Methylation and Gene Expression Analyses in Blood and Dermal Fibroblasts from Twin
Pairs Discordant for Systemic Sclerosis Reveals Distinct Signatures Between Disease Subsets ·················· 638
Paula S Ramos（Medical University of South Carolina, USA）
Tue(3)-O28-4 Deletion of the Williams syndrome region in human and mouse causes systemic, genome-wide changes in DNA
methylation ··································································································································· 639
Emma Strong（Molecular Genetics, University of Toronto, Toronto, Canada）
Tue(3)-O28-5 The zinc-finger protein ZFP57 controls imprinted and non-imprinted genes through different types of cis-acting
regulatory elements ························································································································ 639
Andrea Riccio（CNR, Institute of Genetics and Biophysics, Italy/2nd University of Naples, DiSTABiF, Caserta）
Tue(3)-O28-6 RNF12 is essential for X-inactivation in female mouse embryonic stem cells, is required for female mouse
development, and might be a target for future therapies to treat X-linked disorders in females: evidence from a
mouse knockout model ··················································································································· 640
Stefan Barakat（MRC Centre for Regenerative Medicine, University of Edinburgh, UK/Erasmus MC-University
Medical Center, Rotterdam）
[O29] Epigenetics 2 15:40-17:10

Chair：Hiroyuki Sasaki（Division of Epigenomic and Development, Department of Molecular Genetics, Medical Institute of
Bioregulation, Kyushu University, Japan）
Chair ：Melanie A. Carless（Genetics, Texas Biomedical Research Institute, USA）
Tue(3)-O29-1 Longitudinal changes in DNA methylation influence type 2 diabetes ··············································· 641
Melanie A Carless（Genetics, Texas Biomedical Research Institute, USA）
Tue(3)-O29-2 Genome-wide and targeted analysis of DNA methylation in disease discordant amyotrophic lateral sclerosis
(ALS) cohorts ································································································································ 641
Kelly L Williams（Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia）
Tue(3)-O29-3 Genome-wide analysis of neuron specific DNA methylation in Alzheimer’s disease ···························· 642
Tatsuo Mano（Department of Neurology, Graduate School of Medicine, The University of Tokyo, Japan）
Tue(3)-O29-4 Metabolomic changes fine-map the DNA methylation signature of cigarette smoking ························ 643
Yan V. Sun（Department of Epidemiology, Rollins School of Public Health, Emory University, USA/Department
of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, USA）
Tue(3)-O29-5 Deciphering the role of DNA methylation in SLE pathogenesis through integrative analysis of different types of
genomic data ································································································································· 643
Mengbiao Guo（University of Hong Kong, China）
Tue(3)-O29-6 DNA methylation profiling of Crohn’s disease in peripheral blood and CD14+ cells in women ············· 644
Andrew Y.F. Li Yim（Clinical Genetics, Academic Medical Center, Netherlands/Department of Epigenetics,
GlaxoSmithKline, Stevenage, United Kingdom）
ICHG2016 47
Room K (2F)
[O30] Genome structure, variation and function 1 13:50-15:20

Chair：Andrew H. Sinclair（Deputy Director, Murdoch Children’s Research Institute, Melbourne, Australia）
Chair ：Itsuro Inoue（Division of Human Genetics, National Institute of Genetics, Japan）
Tue(3)-O30-1 Mechanism of transcriptome abnormalies in Cornelia de Lange syndrome: Disturbance of trnascriptional elon-
gation ··········································································································································· 645
Kazuhiro Akiyama（Research Center for Epigenetic Disease, Institute for Molecular and Cellular Biosciences, The
University of Tokyo, Japan/Japan Society for the Promotion of Science）
Tue(3)-O30-2 Comprehensive analyses of the regulatory sequences derived from human endogenous retroviruses
Day 3
······················································································································································ 645
Jumpei Ito（Human Genetics, National Institute of Genetics, Japan）
Tue(3)-O30-3 RNA splicing is a primary link between genetic variation and disease ··············································· 646
Yang I Li（Stanford University, USA）
Tue(3)-O30-4 Global patterns of copy number variation in humans from a population-based analysis ······················ 646
Jean Monlong（Human Genetics, McGill University, Montreal, Canada/McGill University and Genome Quebec
Innovation Center, Montreal, Canada）
Tue(3)-O30-5 Identification and analysis of two novel enhancers of human SOX9: Implications for Disorders of Sex Develop-
ment ············································································································································ 647
Andrew H Sinclair（Molecular Development, Murdoch Children’s Research Institute, Australia）
Tue(3)-O30-6 First genome-wide CNV association meta-analysis on anthropometric traits in 71,288 adults ············· 648
Aurelien Mace（Department of Medical Genetics, University of Lausanne, Switzerland/Swiss Institute of Bioin-
formatics, University of Lausanne, Lausanne, Switzerland）

Chair：Michael A. Hauser（Departments of Medicine and Ophthalmology, Duke Molecular Physiology Institute, Duke Uni-
versity, USA）
Chair ：Shinya Matsuura（Department of Genetics and Cell Biology, Research Institute for Radiation Biology and Medicine,
Hiroshima University, Japan）
Tue(3)-O31-1 Unraveling the role of genomic imprinting at 16q24.1 in pathogenetics of alveolar capillary dysplasia with
misalignment of pulmonary veins and maternal uniparental disomy 16 ···················································· 649
Pawel Stankiewicz（Department of Molecular and Human Genetics, Baylor College of Medicine, USA）
Tue(3)-O31-2 Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a
lncRNA within the LOXL1 locus ······································································································ 649
Michael A Hauser（Medicine, Duke University, USA/Ophthalmology, Duke University/Singapore Eye Research
Institute/Singapore National Eye Center）
Tue(3)-O31-3 Genetic correlations between circulating miRNAs and lipid profiles reveal novel biomarkers of CVD risk
······················································································································································ 650
Joanne E Curran（South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio
Grande Valley, USA）
Tue(3)-O31-4 miRNA expression quantitative trait loci and parent-of-origin effects in human cell lines ···················· 651
Alexander W Drong（Wellcome Trust Centre for Human Genetics, University of Oxford, UK）
Tue(3)-O31-5 Gene co-expression network analysis identifies gene modules associated with clinical phenotype in Williams
syndrome ······································································································································· 652
Ryo Kimura（Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Japan）
Tue(3)-O31-6 Diagnosis of bacterial and viral infection using a minimal host blood RNA expression signature ············· 652
Myrsini Kaforou（Paediatrics, Medicine, Imperial College London, UK/Genomics of Common Disease, School of
Public Health, Imperial College London, UK）
ICHG2016 48
Room H (1F)
[O32] Pharmacogenetics 1 13:50-15:20

Chair：Filippo Martinelli Boneschi（Department of Neuro-rehabilitation & INSPE, Scientific Institute San Raffaele, Italy）
Chair ：Hsin-Chou Yang（Institute of Statistical Science, Academia Sinica, Taiwan）
Tue(3)-O32-1 Regulation of Mucocutaneous Inflammation by Cold Medicine-Related Stevens-Johnson Syndrome susceptibility

gene, IKZF1 ·································································································································· 654
Mayumi Ueta（Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural
University of Medicine, Japan/Department of Human Genetics, Graduate School of Medicine, The University of
Tokyo）
Day 3
Tue(3)-O32-2 Pharmacogenetic and Epigenetic evaluation of CYP19 in PCOS patients underwent ovulation induction cycles
······················································································································································ 655
Parvaneh Afsharian（Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for
Reproductive Biomedicine, ACECR, Tehran, Iran）
Tue(3)-O32-3 Clinical response to Nabiximols (Sativex) on spasticity and pain is paralleled by a down-regulation of immune-
related pathways in Multiple Sclerosis patients ···················································································· 655
Filippo Martinelli Boneschi（Scientific Institute San Raffaele, Italy/Laboratory of Human Genetics of Neurological
Disorders, Scientific Institute San Raffaele）
Tue(3)-O32-4 A comprehensive analysis of genetic diversity in important pharmacogenes in the 1000 Genomes Project Phase
3 populations ································································································································· 656
Galen E.B. Wright（Medical Genetics, University of British Columbia, Canada/Child and Family Research Insti-
tute/Centre for Molecular Medicine and Therapeutics）
Tue(3)-O32-5 Comprehensive exploration of the high-risk rare variants for the cold medicine-related Stevens-Johnson syn-
drome/ toxic epidermal necrolysis (CM-SJS/TEN) with Severe Ocular complications by whole-exome sequencing
······················································································································································ 657
Seik-Soon Khor（Graduate School of Medicine, Department of Human Genetics, The University of Tokyo,
Japan/These author contributed equally to the work）
Tue(3)-O32-6 Ancestry-informative pharmacogenomic loci ················································································· 657
Hsin-Chou Yang（Institute of Statistical Science, Academia Sinica, Taiwan）
[O33] Pharmacogenetics 2 15:40-17:10

Chair：Mia Wadelius（Medical Sciences, Clinical Pharmacology, Uppsala University, Sweden）
Chair ：Pei-Chieng Cha（Division of Molecular Brain Science, Kobe University Graduate School of Medicine, Japan）
Tue(3)-O33-1 The influence of pharmacogenetics on the time to Acute Coronary Syndromes (ACS) recurrence in a UK cohort
study ············································································································································ 659
Peng Yin（Department of Biostatistics, University of Liverpool, UK）
Tue(3)-O33-2 Antithyroid drug-induced agranulocytosis is associated with different human leukocyte antigen alleles in Asia
and Europe ··································································································································· 660
Mia Wadelius（Medical Sciences, Clinical Pharmacology, Uppsala University, Sweden）
Tue(3)-O33-3 Neuronal enrichment analysis of treatment response in obsessive-compulsive disorder ························· 660
Yin Yao（Statistical Genomics, National Institute of Mental Health, USA）
Tue(3)-O33-4 Genome-wide association study (GWAS) identifies genetic determinants of response to Zonisamide treatment
in Parkinson’s disease patients with "wearing-off" ············································································ 661
Pei-Chieng Cha（Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine,
Japan）
Tue(3)-O33-5 Two component mixture modelling approach integrating genetic and clinical variables in analysis of time to
remission in epilepsy. ······················································································································· 662
Ben R Francis（Department of Biostatistics, University of Liverpool, UK）
Tue(3)-O33-6 Genome-wide association study of L-asparaginase-induced pancreatitis in pediatric patients ··············· 662
Britt I Drogemoller（Pediatrics, University of British Columbia, Canada）
ICHG2016 49
Event Hall (1F)
Poster Session
Tue(3)-P-1 Reducing genotoxicity emitted from diesel engines fueled with diesel/biodiesel/butanol blends ··············· 958
Yuan-Chung Lin（Institute of Environmental Engineering, National Sun Yat-Sen University, Kaohsiung, Tai-
wan/Ph.D. Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Taiwan）
Tue(3)-P-2 Ultra-sensitive droplet digital PCR for detecting a low-prevalence somatic GNAQ mutation in Sturge-Weber
syndrome ······································································································································· 958
Day 3
Yuri Uchiyama（Human Genetics, Yokohama City University Graduate School of Medicine, Japan/Medicine and
Clinical Science, Gunma University Graduate School of Medicine）
Tue(3)-P-3 MiR-200a, miR-200b, and miR-429 Are Onco-miRs That Target PTEN Gene in Endometrioid Endometrial Car-
cinomas of The Uterus ····················································································································· 959
Koichi Yoneyama（Obstetrics and Gynecology, Nippon Medical School Musashi Kosugi Hospital, Japan）
Tue(3)-P-4 Furin, a pro-protein convertase, is a novel molecular target for c-Myc driven ovarian cancers ·················· 959
Junko Minato（Tohoku University, Japan）
Tue(3)-P-5 An Incidental Finding of Indolent T-PLL During a Routine Fertility Screen: A Case Study ····················· 960
Charmaine E Pollock（Cytogenetics, Sullivan Nicolaides Pathology, Australia）
Tue(3)-P-6 Comprehensive genetic analysis of a pediatric pleomorphic myxoid liposarcoma reveals near-haploidization and
loss of the RB1 gene ······················································································································· 960
Jakob P Hofvander（Department of Clinical Genetics, Lund University, Sweden）
Tue(3)-P-7 RNA-seq analysis of lung adenocarcinomas reveals different gene expression profiles between smoking and non-
smoking patients ···························································································································· 961
Yafang Li（Dartmouth College, USA）
Tue(3)-P-8 Clinicopathological factors of breast cancer in women under 35 years: A retrospective statistical analysis
······················································································································································ 961
Masahiro Kitada（Department of Breast Disease Center, Asahikawa Medical University, Japan）
Tue(3)-P-9 A competing endogenous RNA (ceRNA) network regulates KRAS gene expression in human colorectal cancer
cells ··············································································································································· 962
Marian Abigaile N Manongdo（National Institute of Molecular Biology and Biotechnology, University of the
Philippines Diliman, Philippines）
Tue(3)-P-10 Enhancing SHP-1 and PRG2 expression by 5-Azacytidine may inhibit STAT3 activation and confer sensitivity in
Lestaurtinib (CEP-701) resistant FLT3 -ITD positive Acute Myeloid Leukemia ········································ 962
Muhammad Farid Johan（Department of Haematology, Universiti Sains Malaysia, Malaysia）
Tue(3)-P-11 Correlation between MGMT promoter methylation and hMSH2 mRNA expression in primary frontal high grade
anaplastic glioma (HGAG) ················································································································ 963
Jeru Manoj Manuel（Human Genetics, National Institute of Mental Health and Neurosciences (NIMHANS), India）
Tue(3)-P-12 Cytotoxic effects of Palladium (II) Complex on Prostate Cancer Cells ················································ 964
Hale Samli（Department of Genetics, Uludag University, Turkey）
Tue(3)-P-13 Detection of p53 gene polymorphisms in patients with Hepatocellular Carcinoma in India ····················· 964
Subramaniam Mohana Devi（Human Molecular Genetics Laboratory, Department of Zoology, Bharathiar Univer-
sity, India）
Tue(3)-P-14 High Mutation Detection Rate and Novel Mutations Identified in Major and Minor- Risk Cancer Genes by
Applying Multigene Panels in Hereditary Cancer Clinic ········································································· 965
Guy Rosner（Gastroenterology, Tel-Aviv Sourasky Medical Center, Israel/Sackler School of Medicine, Tel-Aviv
University, Tel-Aviv, Israel）
Tue(3)-P-15 The importance of multidisciplinary approach to HBOC patients ~ the experience in a general hospital ~
······················································································································································ 966
Daisuke Takabatake（Breast Oncology, Kochi Health Science Center, Japan）
Tue(3)-P-16 Hedgehog signaling and genetic diseases ························································································ 966
Yoshiro Nakano（Genetics, Hyogo College of Medicine, Japan）
ICHG2016 50
Tue(3)-P-17 Genomic copy number changes in CML patients with the Philadelphia chromosome (Ph+): an update
······················································································································································ 967
Yuan Ren（Pediatrics, The university of Oklahoma Health Science Center, China/Hematology, The First Affiliated
Hospital of China Medical University）
Tue(3)-P-18 Exploring clinicians’ attitudes about using aspirin for risk reduction in people with Lynch Syndrome with no
personal diagnosis of colorectal cancer ······························································································· 967
Yanni Chen（School of Medicine, University of Sydney, Singapore/National Cancer Centre Singapore）
Tue(3)-P-19 Genetic and epigenetic alterations of netrin-1 receptors in gastric cancer ············································ 968
Takeshi Nagasaka（Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and
Pharmaceutical Sciences, Japan）
Tue(3)-P-20 Functional characterization of RNAi-mediated regulation of the tumor suppressor gene Neurofibromin 2 (NF2 )
Day 3
······················································································································································ 968
Krizelle Mae M. Alcantara（Disease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular
Biology and Biotechnology, Philippines）
Tue(3)-P-21 CpG island methylator phenotype is associated with the efficacy of chemotherapy for metastatic colorectal cancer
······················································································································································ 969
Hideki Shimodaira（Department of Medical Oncology, Institute of Development, Aging and Cancer, Tohoku
University, Japan/Department of Clinical Oncology, Tohoku University Hospital）
Tue(3)-P-22 BRCA1/2 Mutation Dependent Effect on Survival of Advanced Stage Ovarian Cancer ························· 970
Ramunas Janavicius（Hematology, Oncology and Transfusion Medicine Center, Vilnius University Santariskiu
Hospital Clinics, Lithuania/State Research Innovative Medicine Center）
Tue(3)-P-23 Withdrawn ································································································································· 970
Tue(3)-P-24 A case with pachydermoperiostosis with gastrointestinal malignancy ·················································· 971

Mariko Kakudo（Department of Clinical Genetics, Hyogo College of Medicine, Japan）
Tue(3)-P-25 Integrated analysis of whole-exome and transcriptome sequencing in signet ring cell carcinoma of colorectum
······················································································································································ 971
Jae-Yong Nam（Department of Health Sciences and Technology, SAIHST, Seoul, Korea, South/Samsung Genome
Institute, Seoul, Republic of Korea）
Tue(3)-P-27 Revealing hidden complexity of the cancer genome with the aid of RNA sequencing ···························· 972
Sarah Moore（Genetics and Molecular Pathology, SA Pathology, Australia）
Tue(3)-P-28 Targeted semiconductor sequencing of 409 cancer-related genes for somatic mutations and copy number variations
in multiple myeloma ························································································································ 972
Hisayo Fukushima（Departmant of medical genetics, Sapporo medical University, Japan/Department of Medical
Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University）
Tue(3)-P-29 Variants of uncertain significance in BRCA: Experience from the Japanese HBOC consortium trial survey
······················································································································································ 973
Junko Yotsumoto（Natural Science Division, Faculty of Core Reserch, Ochanomizu University, Japan/Showa
University,Breast Center）
Tue(3)-P-30 Reduction of physiologic endogenous DNA double strand breaks advances genomic instability in chronological
aging yeast ····································································································································· 974
Maturada Patchsung（Biomedical Sciences, Chulalongkorn University, Thailand）
Tue(3)-P-31 ß -catenin controls the expression profiles of KCNQ1OT1/LIT1 long noncoding RNA ·························· 974
Hiroyuki Kugoh（Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Grad-
uate School of Medical Science, Tottori University, Japan/Chromosome Engineering Research Center, Tottori
Tue(3)-P-32 KRAS mutations and intratumoral heterogeneity in rectal adenomas and early carcinomas ···················· 975
Natalia Pospekhova（State Scientific Centre of Coloproctology, Russia）
Tue(3)-P-33 Action of the hereditary breast cancer ovarian cancer syndrome practice cooperation in Kochi ·············· 976
Fuminori Aki（Ito Breast Surgery Clinic, Japan/Hospital Heredity Practice Part Attached to the Kochi University
School of Medicine）
Tue(3)-P-34 Genomic and epigenetic changes underlying retinoblastoma tumors ···················································· 976
Poh-San Lai（Paediatrics, National University of Singapore, Singapore）
Tue(3)-P-35 Identification of driver gene mutations and fusion events in patients with Sezary Syndrome ·················· 977
Aparna Prasad（Centre for Genomic Regulation, Spain/Universitat Pompeu Fabra (UPF), Barcelona,
Spain/CIBER in Epidemiology and Public Health (CIBERESP), Barcelona, Spain）
ICHG2016 51
Tue(3)-P-36 Early development of rare tumors in individuals with congenital malformation syndrome ······················· 977
Mari Minatogawa（Medical Genetics, Kanagawa Children’s Medical Hospital, Japan）
Tue(3)-P-37 The Role of SLURP-1 in melanoma promoting microenvironment ······················································ 978
Pei-Jung Lin（National Taiwan University College of Medicine, Graduate Institute of Clinical Medicine, Tai-
wan/National Taiwan University Hospital, Department of Dermatology）
Tue(3)-P-38 SNPs in MEG3 lncRNA could alter its tumor suppressive capacity ····················································· 978
Martin Daniel C Qui（National Institute of Molecular Biology and Biotechnology, University of the Philippines
Tue(3)-P-39 Withdrawn ································································································································· 979
Tue(3)-P-40 Preliminary Investigations on the Putative PIK3CA-ZNF148 ceRNA Network ······································ 979
Day 3
Alvin B. Bello（National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman,
Philippines）
Tue(3)-P-41 Model comparison of cancer genetics practice in Japan: How to provide genetic counseling, genetic testing,
cancer surveillance, and risk-reducing options for people who may have high cancer risks ························· 980
Chieko Tamura（Medical Information & Genetic Counseling Division, FMC Tokyo Clinic, Japan/Juntendo Uni-
versity Hospital/National Hospital Organization Iwakuni Clinical Center）
Tue(3)-P-42 The new subcellular role of BRCA2 involved in FIP3-dependent endosome function ···························· 980
Miho Takaoka（Molecular genetics of Med. Res., Tokyo Medical & Dental university, Japan）
Tue(3)-P-43 Can surgeon provide early BRCA gene counseling for advanced ovary cancer? ····································· 981
Min Kyu Kim（Obstetrics and Gynecology, Sungkyunkwan University of Medicine,Samsung Changwon Hospital,
Korea, South）
Tue(3)-P-44 Overexpression of miR-127 and miR-375 in Medullary Thyroid Carcinoma Tumors ······························· 982
Marjan Zarif Yeganeh（Cellular and Molecular Research Centre, Research Institute for Endocrine Sciences, Shahid
Beheshti University of Medical Sciences, Tehran, Iran）
Tue(3)-P-45 Germline Mutational Analysis of RET Proto Oncogene in Iranian Medullary Thyroid Carcinoma Patients: a
14-year Study ································································································································· 982
Sara Sheikholeslami（Cellular and Molecular Research Center, Research Institute for Endocrine Sciences, Shahid
Beheshti University of Medical Sciences, Iran）
Tue(3)-P-46 Genome-wide DNA copy number analysis of primary head and neck squamous cell carcinoma (HNSCC) and
second primary esophageal squamous cell carcinoma (ESCC) ································································ 983
Meng-Shin Shiao（Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand）
Tue(3)-P-47 Withdrawn ································································································································· 983
Tue(3)-P-48 Clinical utility of genomic SNP microarrays in hepatosplenic γδ T-cell lymphoma ······························ 984
Reha M Toydemir（Pathology, University of Utah, USA/ARUP Institute for Clinical and Experimental Pathology）
Tue(3)-P-49 Roles of Tyrosine Phosphorylation of histone H4 in Breast Cancer ····················································· 984
Ruey-Hwang Chou（Graduate Institute of Cancer Biology, China Medical University, Taiwan）
Tue(3)-P-50 Targeted Single Cell Sequencing for Accurate Mutation Detection in Heterogeneous Cellular Populations
······················································································································································ 985
Ryoko Shimada（QIAGEN K.K., Japan）
Tue(3)-P-51 Global nuclear radial distribution of chromosome territories in various cancer cell lines ························· 985
Hideyuki Tanabe（Department of Evolutionary Studies of Biosystems, School of Advanced Sciences, SOKENDAI
(The Graduate University for Advanced Studies), Japan）
Tue(3)-P-52 Nonclonal chromosome abnormalities in hematologic malignancies ····················································· 986
Ma. Luisa D. Enriquez（Biology, De La Salle University, Philippines/Research and Biotechnology, St. Lukes
Medical Center）
Poster Session
Complex Traits and Polygenic Disorders 2 17:30-18:30
Tue(3)-P-53 Replication of 49 type 2 diabetes associated risk variants in Punjabi Pakistani population ··················· 987
Asima Zia（Atta ur Rahman School of Applied Biosciences (ASAB), National University of Science and Technology
(NUST), Pakistan）
ICHG2016 52
Tue(3)-P-54 Copy number variations play important roles in heredity of common diseases: a novel method to calculate
heritability of a polymorphism ··········································································································· 987
Yoshiro Nagao（Department of Pediatrics, Takashimadaira Chuo General Hospital, Japan）
Tue(3)-P-55 Determination of IFIT1 Gene Polymorphisms on Human Cerebral Malaria in Thai Population ··············· 988
Pornlada Nuchnoi（Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Thai-
land）
Tue(3)-P-56 Genome-wide association studies (GWAS) for adult height and body mass index in the Japanese population using
the JPDSC database ······················································································································· 988
Daisuke D. Ikeda（Biomedical Technology Research Center, Tokushima Research Institute, Otsuka Pharmaceutical
Co., Ltd., Japan）
Tue(3)-P-57 Mutation identification of ABCA1 gene in subjects with low level of high-density lipoprotein ················ 989
Day 3
Nani Maharani（Center for Biomedical Research, Faculty of Medicine, Diponegoro University, Semarang, Indone-
sia, Japan/Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenera-
tive Therapeutics, Tottori University Graduate School of Medical Science, Yonago, Japan）
Tue(3)-P-58 Leveraging Compartmental Modeling to Assess the Pathophysiologic Effect of Genetic Variation Underlying Risk
for Type 2 Diabetes ························································································································· 989
Richard M Watanabe（Preventive Medicine, Keck School of Medicine of USC, USA/Physiology & Biophysics,
Keck School of Medicine of USC/USC Diabetes and Obesity Research Institute）
Tue(3)-P-59 Location, Loci or Lifestyle? Dissecting Health-Associated Regional Variation in Scotland ····················· 990
Carmen Amador（MRC IGMM, University of Edinburgh, UK）
Tue(3)-P-60 Effects of HLA-DPB1 genotypes on HBV-related diseases in Japanese population ······························· 990
Nao Nishida（The Research Center for Hepatitis & Immunology, National Center for Global Health and Medicine,
Japan/Department of Human Genetics, Graduate School of Medicine, University of Tokyo）
Tue(3)-P-61 Associations between the orexin (hypocretin) receptor 2 gene polymorphism Val308Ile and nicotine dependence
in genome-wide and subsequent association studies ············································································· 991
Daisuke Nishizawa（Addictive Substance Project (Department of Psychiatry and Behavioral Science), Tokyo
Metropolitan Institute of Medical Science, Japan）
Tue(3)-P-62 Meta-analysis of GWAS followed by replication identifies new susceptibility genes on X chromosome for SLE in
cross-ethnic populations ··················································································································· 992
Yan Zhang（The University of Hong Kong, Hong Kong）
Tue(3)-P-63 The power of family: Linkage Analysis vs GWAS in family-based cohorts ············································ 992
Reka Nagy（Institute of Genetics and Molecular Medicine, University of Edinburgh, UK）
Tue(3)-P-64 Decreased Severity of Experimental Autoimmune Arthritis in Peptidylarginine Deiminase Type 4 Knockout Mice
······················································································································································ 993
Akari Suzuki（RIKEN, Japan）
Tue(3)-P-65 A replication study of four candidate loci for sex hormone levels previously identified by genome-wide association
studies ··········································································································································· 994
Youichi Sato（Pharmaceutical Information Science, Biomedical Sciences, Tokushima University Graduate School,
Japan）
Tue(3)-P-66 Genome-wide Association Studies on Immunoglobulin G Glycosylation Patterns ·································· 994
Annika Laser（Institute of Epidemiology 2, Research Unit Molecular Epidemiology, Helmholtz Zentrum
Muenchen - German Research Center for Environmental Health, Neuherberg, Germany/Institute of Epidemiology
2, Helmholtz Zentrum Muenchen - German Research Center for Environmental Health, Neuherberg, Germany）
Tue(3)-P-67 The crispld2 story: From gene function to new NSCLP candidate gene identification ··························· 995
Jacqueline T Hecht（The University of Texas Health Science Center at Houston School of Dentistry, USA/The
University of Texas Health Science Center at Houston Medical School）
Tue(3)-P-68 Combined genome-wide linkage and association analysis of depressive symptomes point to CTNNA3 gene
······················································································································································ 995
Irina V. Zorkoltseva（Institute of Cytology & Genetics, Russia）
Tue(3)-P-69 Shared and unique genetic determinants between pediatric and adult celiac disease ···························· 996
Sabyasachi Senapati（Centre for Human Genetics and Molecular Medicine, Central University of Punjab, In-
dia/Department of Genetics, University of Delhi South Campus, New Delhi）
Tue(3)-P-70 The role of regulatory single-nucleotide genetic polymorphisms of placental tissue in the development of
preeclampsia in different ethnic groups ······························································································· 996
Victoria Serebrova（Research Institute of Medical Genetics SB RAMS, Russia）
Tue(3)-P-71 Genetic Association of HLA-C Region with Kawasaki Disease in the Korean Population ······················· 997
Jae-Jung Kim（Asan Institute for Life Sciences, University of Ulsan College of Medicine, Korea, South）
ICHG2016 53
Tue(3)-P-72 Dissecting the unexpected role of PAG1 in asthma ·········································································· 997

Cristina M.T. Vicente（Genetics & Computational Biology, QIMR Berghofer Medical Research Institute, Aus-
tralia）
Tue(3)-P-73 Gene-gene interaction for markers in 16p13.3 may contribute to the risk of non-syndromic cleft lip with or without
palate in Chinese population ············································································································· 998
Dongjing Liu（School of Public Health, Peking University Health Science Center, Beijing, China）
Tue(3)-P-74 Association of serum biotin and total/specific IgE levels and a common locus for biotin and cedar pollen-specific
IgE levels ······································································································································· 998
Yoichi Suzuki（Education and Training, Division of Genetic Epidemiology Research Support, Tohoku Medical
Megabank Organization, Tohoku University, Japan）
Tue(3)-P-75 Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B
virus-related hepatocellular carcinoma ································································································ 999
Day 3
Hiromi Sawai（Department of Human Genetics, The University of Tokyo, Japan）
Tue(3)-P-76 Metabolomic and transcriptomic fingerprints of menopausal hormone therapy in 3479 Finnish women
······················································································································································ 1000
Anni Joensuu（Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland/Department of Health, Na-
tional Institute for Health and Welfare, Helsinki, Finland）
Tue(3)-P-77 Genome-wide association study on cephalic form in Japanese ···························································· 1001
Kyoko Yamaguchi（School of Natural Sciences and Psychology, Liverpool John Moores University, UK）
Tue(3)-P-78 Identification and Replication of Height Loci in African Ancestry Populations ···································· 1001
Maggie C.Y. Ng（Wake Forest School of Medicine, USA）
Tue(3)-P-79 The h4 curse of genomic prediction ································································································ 1002
Xia Shen（Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden/University of
Edinburgh）
Tue(3)-P-80 Frequent Potential Mutations in 378 Candidate Genes of Glaucoma Identified by Whole Exome Sequencing of
257 Patients with Glaucoma ············································································································· 1002
Xiaobo Huang（State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University,
China）
Tue(3)-P-81 Functional annotation of chronic pancreatitis-associated intronic variants in the SPINK1 gene ·············· 1003
Wen-Bin Zou（U1078, Institut National de la Sante et de la Recherche Medicale (INSERM), France/Department
of Gastroenterology, Changhai Hospital, the Second Military Medical University, Shanghai, China/Etablissement
Francais du Sang (EFS); Bretagne, Brest, France/Shanghai Institute of Pancreatic Diseases, Shanghai, China）
Tue(3)-P-82 Multi-trait GWAS method comparison and application of summary statistic methods to publicly available data
······················································································································································ 1004
Heather F Porter（SGDP Centre, IoPPN, King’s College London, UK）
Tue(3)-P-83 Systems Genetics of Plasma 1 H Nuclear Magnetic Resonance Metabotypes Associated with Cardiometabolic
Diseases in a Lebanese Cohort ·········································································································· 1004
Andrea Rodriguez-Martinez（Surgery and Cancer, Imperial College London, UK）
Tue(3)-P-84 Transcriptomic analysis to identify biological markers for antibody production introduced by seasonal influenza
vaccination ····································································································································· 1005
Maiko Narahara（Medicine, Kyoto University, Canada）
Tue(3)-P-85 Characterizing the genetic architecture of ocular biometrics in an untested south Asian population: the Jirels of
eastern Nepal (Jiri Eye Study) ·········································································································· 1005
Matthew P Johnson（South Texas Diabetes & Obesity Institute, School of Medicine, The University of Texas Rio
Grande Valley, USA）
Tue(3)-P-86 Functional variants in a clinical setting: an example using APOC3 R19X and extreme triglyceride levels extracted
from electronic health records ··········································································································· 1006
Dana C. Crawford（Institute for Computational Biology, Case Western Reserve University, USA/Department of
Epidemiology and Biostatistics, Case Western Reserve University）
Tue(3)-P-87 Genetic variants of FTO, LEPR, MC4R, PON1, SCL6A4, DRD2, MAOA and COMT , associated to the genetic
risk for overweight and obesity in children from Yucatan, Mexico ·························································· 1007
Lizbeth Gonzalez-Herrera（Laboratorio de Genetica. Centro de Investigaciones Regionales, Universidad Autonoma
de Yucatan, Mexico）
Tue(3)-P-88 Improved imputation accuracy using population-specific SNP array and haplotype reference panel
······················································································································································ 1007
Yosuke Kawai（Tohoku Medical Megabank Organization, Tohoku Univeristy, Japan）
ICHG2016 54
Tue(3)-P-89 Allelic imbalance in regulation of ANRIL through chromatin interaction at 9p21 endometriosis risk locus
······················································································································································ 1008
Hirofumi Nakaoka（Division of Human Genetics, National Institute of Genetics, Japan）
Tue(3)-P-90 Stability profiling of HLA class II protein for disease association studies ·············································· 1008
Hiroko Miyadera（Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine,
Japan/Department of Human Genetics, Graduate School of Medicine, The University of Tokyo）
Tue(3)-P-91 SNP-set Kernel Association Tests (SKAT) of the association between interleukin (IL) polymorphisms and risk of
H. pylori infection and related gastric atrophy ····················································································· 1009
Asahi Hishida（Nagoya University Graduate School of Medicine, Japan）
Tue(3)-P-92 Assessment of somatic DNA methylation profiling and copy number variations in atherosclerosis ············· 1009
Maria S. Nazarenko（Research Institute of Medical Genetics, Russia/Tomsk State University）
Day 3
Tue(3)-P-93 Predictive utility of a genetic risk score of common variants associated with type 2 diabetes in a black South
African population ··························································································································· 1010
Tinashe Chikowore（Center of Excellence, North West University, South Africa）
Tue(3)-P-94 Studies of Genetics & Environment interaction and health longevity in Bama population ······················ 1010
Ze Yang（Institute of Geriatrics, Beijing Hospital, Chinese Ministry of Public Health, China）
Tue(3)-P-95 Analysis of the regulatory role of fifty-two genetic loci influencing human electrically active myocardial mass on
epigenetic human heart data ············································································································· 1011
Daiane Hemerich（Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht,
Utrecht, Netherlands/CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil）
Poster Session
Clinical Genetics and Dysmorphology 2 17:30-18:30
Tue(3)-P-96 Waardenburg Syndrome Type IIE in a Japanese Patient Caused by a Novel Missense Mutation in the SOX10
Gene ············································································································································· 1012
Tamio Suzuki（Department of Dermatology, Yamagata University, Japan）
Tue(3)-P-98 A novel HSF4 missense mutation in Iranian siblings causes autosomal recessive congenital cataract
······················································································································································ 1012
Eri Imagawa（Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan）
Tue(3)-P-99 Tatton-Brown-Rahman syndrome due to 2p23 microdeletionTatton-Brown-Rahman syndrome due to 2p23 mi-
crodeletion ····································································································································· 1013
Kimiko Ueda（Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and
Child Health, Japan）
Tue(3)-P-100 Mutational Analysis of TSC1 and TSC2 in Japanese Patients with Tuberous Sclerosis Complex Revealed Higher
Incidence of TSC1 Patients than Previously Reported and unique TSC1 mutational pool ························· 1014
Yo Niida（Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute,
Kanazawa Medical University, Japan）
Tue(3)-P-101 WDR62/MCPH2 mutations identified in patients with primary microcephaly by a combined approach of exome
sequencing and genome editing technology ························································································· 1014
Yoshinori Masatsuna（Department of Genetics and Cell Biology, Research Institute for Radiation Biology and
Medicine, Hiroshima University, Japan）
Tue(3)-P-102 Dyschromatosis symmetrica hereditaria complicated by intracranial hemangiomas and Parry-Romberg syndrome
······················································································································································ 1015
Kazuyoshi Fukai（Dermatology, Osaka City University, Japan）
Tue(3)-P-103 Clinical features and outcomes for infants with an antenatal/ perinatal diagnosis of Tuberous Sclerosis
······················································································································································ 1015
Clara WT Chung（Department of Medical Genetics, Sydney Children’s Hospital, Australia）
Tue(3)-P-104 Clinical and genetic diagnosis of HPT-JT syndrome ······································································· 1016
Yoshiko Matsumoto（Department of Surgery, Noguchi Thyroid Clinic and Hospital Foundation, Japan）
Tue(3)-P-105 De novo DNM1 mutations in two cases of epileptic encephalopathy ················································ 1017
Mitsuko Nakashima（Department of Human Genetics, Yokohama City University Graduate School of Medicine,
Japan）
Tue(3)-P-106 Renal tubular dysgenesis and intellectual disability with uniparental disomy of chromosome 1 ·············· 1017
Hiroshi Yoshihashi（Department of Medical Genetics, Tokyo Metropolitan Children’s Medical Center, Japan）
ICHG2016 55
Tue(3)-P-107 Novel mutation in the COL1A1 gene causes severe scoliosis and valvular heart disease in a Japanese family
with osteogenesis imperfecta ············································································································ 1018
Toshiyuki Seto（Department of Pediatrics, Graduate School of Medicine, Osaka City University, Japan）
Tue(3)-P-108 Clinical utility of medical exome analysis in a tertiary pediatric referral center ··································· 1018
Rika Kosaki（Division of Medical Genetics, National Center for Child Health and Development, Japan）
Tue(3)-P-109 Gross insertion in FBN1 causes Marfan syndrome ·········································································· 1019
Takayuki Yokoi（Division of Medical Genetics, Kanagawa Children’s Medical Center, Japan）
Tue(3)-P-110 Identified novel FBN1 gene mutation in neonatal/infantile Marfan syndrome ··································· 1020
Yoo-MI Kim（Pediatrics, Pusan National University Children’s Hospital, Korea, South）
Tue(3)-P-111 Oro-dental phenotypes associated with rare monogenic disorders ····················································· 1020
Day 3
Emilia Severin（Genetics, Carol Davila University of Medicine and Pharmacy, Romania）
Tue(3)-P-112 Haddad Syndrome due to PHOX2B Gene Mutation in a Filipino Infant ············································ 1021
April Grace D. Berboso（University of the Philippines, Manila, Institute of Human Genetics, National Institutes
of Health, Philippines）
Tue(3)-P-113 The Management of Pregnancy in Two Japanese Sisters who Developed Deep Vein Thrombosis with Congenital
Antithrombin Deficiency ··················································································································· 1021
Yukiko Mikami（Department of Obstetrics and Gynecology, Saitama Medical Center, Saitama Medical University,
Japan）
Tue(3)-P-114 Natural history of motor function changes in childhood-onset spinal muscular atrophy ························ 1022
Kaori Kaneko（Affiliated Field of Genetic Medicine, Division of Biomedical Engineering and Science, Graduate
Course of Medicine, Graduate School of Tokyo Women’s Medical University, Japan/Institute of Medical Genetics,
Tokyo Women’s Medical University）
Tue(3)-P-115 Homozygous 4-bp deletion in the DDHD1 gene, resulting the complete deletion of DDHD domain, as a causative
variant in a SPG28 patient ··············································································································· 1022
Takuya Morikawa（Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Japan）
Tue(3)-P-116 Simultaneous detection of both single nucleotide variations and copy number alterations by next-generation
sequencing in Gorlin syndrome ·········································································································· 1023
Kei-ichi Morita（Oral and Maxillofacial Surgery, Tokyo Medical and Dental University, Japan/Bioresource Re-
search Center, Tokyo Medical and Dental University/Hard Tissue Genome Research Center, Tokyo Medical and
Dental University）
Tue(3)-P-117 Mutation in the genes encoding eukaryotic translation initiation factor 2B in Japanese patients with vanishing
white matter disease ························································································································ 1023
Shino Shimada（Department of Pediatrics, Tokyo Women’s Medical University, Japan）
Tue(3)-P-119 Clinical courses and experiences of seven patients with Ehlers-Danlos syndrome caused by CHST14/D4ST1
deficiency ······································································································································· 1024
Masumi Ishikawa（Division of Clinical and Molecular Genetics, Shinshu University Hospital, Japan）
Tue(3)-P-120 Next-generation sequencing identifies novel ARID1B mutations in patients with Coffin-Siris syndrome
······················································································································································ 1024
Yoshinori Tsurusaki（Clinical Research Institute, Kanagawa Children’s Medical Center, Japan）
Tue(3)-P-121 The comprehensive genetic analysis of Rubinstein-Taybi syndrome (RSTS) ······································· 1025
Yumi Enomoto（Clinical Research Institute, Kanagawa Children’s Medical Center, Japan）
Tue(3)-P-122 A case of mandibulofacial dysostosis with microcephaly presenting with epilepsy ································ 1025
Mari Matsuo（Institute of Medical Genetics, Tokyo Women’s Medical University, Japan）
Tue(3)-P-123 Long-term clinical feature of West syndrome with a de novo mutation in NR2F1 : A case report ············· 1026
Naomi Hino-Fukuyo（Center for Genomic Medicine, Tohoku University Hospital, Japan/Department of Pediatrics,
Tohoku University School of Medicine）
Tue(3)-P-124 Two Japanese patients with two genes mutations, showing congenital sensorineural hearing loss ············· 1027
Kotaro Ishikawa（Hospital, Department of Otolaryngology, National Rehabilitation Center for Persons with Dis-
abilities, Japan）
Tue(3)-P-125 Brain morphology in children with nevoid basal cell carcinoma syndrome ·········································· 1027
Tadashi Shiohama（Department of Pediatrics, Chiba University Graduate School of Medicine, Japan）
Tue(3)-P-126 Genetic evaluation of patients with intellectual disability (ID) using chromosomal microarray and targeted next-
generation sequencing at the "ID clinic" ····························································································· 1028
Kyoko Takano（Department of Medical genetics, Shinshu University School of Medicine, Japan/Division of Clinical
and Molecular Genetics, Shinshu University Hospital）
ICHG2016 56
Tue(3)-P-127 A nationwide survey on genetically confirmed Danon disease in Japan ·············································· 1029
Kazuma Sugie（Department of Neurology, Nara Medical University, Japan）
Tue(3)-P-128 Mental and physical development study of long-term survival patients of thanatophoric dysplasia
······················································································································································ 1030
Hideaki Sawai（Obstetrics and Gynecology, Hyogo College of Medicine, Japan）
Tue(3)-P-129 Microform holoprosencephaly with bilateral congenital elbow dislocation; a further case of Steinfeld syndrome
related to a CDON mutation? ·········································································································· 1030
George A. Tanteles（Department of Clinical Genetics, The Cyprus Institute of Neurology and Genetics, Cyprus）
Tue(3)-P-130 Novel compound heterozygous mutations in ISPD gene from two cases of Japanese Walker-Warburg syndrome
identified by whole-exome sequencing ································································································ 1031
Yonehiro Kanemura（Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital,
Day 3
National Hospital Organization, Japan/Department of Neurosurgery, Osaka National Hospital, National Hospital
Organization, Osaka, Japan）
Tue(3)-P-131 The Myhre syndrome: report of a Japanese Female Case ································································ 1032
Aki Ishikawa（Medical Genetics, Sapporo Medical University, Japan）
Tue(3)-P-132 The minor nasopharyngeal anomaly in a family of Hypoparathyroidism, Deafness, and Renal dysplasia (HDR)
syndrome ······································································································································· 1032
Makoto Kita（Pediatrics, National Hospital Organization Kyoto Medical Center, Japan/Clinical Research Insti-
tute, National Hospital Organization Kyoto Medical Center）
Tue(3)-P-133 SATB2-associated syndrome presenting with Rett like phenotype identified by whole exome sequencing
······················································································································································ 1033
Jin Sook Lee（Pediatrics, Gachon University Gil Hospital, Korea, South）
Tue(3)-P-134 Mismatch repair cancer syndrome caused by homozygous deletion of exons 13-14 of PMS2 gene
······················································································································································ 1033
Fedor A Konovalov（Federal State Budgetary Institution Research Centre for Medical Genetics, Russia）
Tue(3)-P-135 Clinical and genetic characterization of patient with SOX5 haploinsufficiency caused by de novo balanced
chromosomal translocation ··············································································································· 1034
Nobuaki Wakamatsu（Department of Genetics, Institute for Developmental Research, Aichi Human Service Center,
Japan）
Tue(3)-P-136 A Novel Mutation in the Flavin-Containing Monooxygenase 3 Gene (FMO3) of a Korean Family Causes
Trimethylaminuria ··························································································································· 1035
Ji Hyun Kim（Pediatric Endocrinology, Dongguk University Ilsan Hospital, Korea, South）
Tue(3)-P-137 Delineation of the molecular basis of borderline hemoglobin A2 in Chinese individuals ························ 1035
Yanhui Liu（Prenatal Diagnosis Center, Dongguan Maternal and Children Hospital, China）
Tue(3)-P-138 Monochorionic Diamniotic Twins With 45,X/46,XY Mosaic Who Showed Different External Genitals Due To
Different Rates of Mosaicism: A Case Report ····················································································· 1036
Taisuke Sato（Department of Maternal-Fetal Biology, National Research Institute for Child Health and Develop-
ment, Japan/Department of Obstetrics and Gynecology, Jikei University School of Medicine, Tokyo, Japan）
Tue(3)-P-139 Multisystem involvement and progressive course in Woodhouse-Sakati syndrome: from detailed, comprehensive,
and longitudinal observation of the first East Asian patient ·································································· 1037
Motoko Kamiya（Division of Clinical and Molecular Genetics, Shinshu University Hospital, Japan/Department
of Medical Genetics, Shinshu University School of Medicine/Department of Pediatrics, Shinshu University School
of Medicine/Problem-Solving Oriented Training Program for Advanced Medical Personnel: NGSD Project）
Tue(3)-P-140 Caffey disease (CD) or infantile cortical hyperostosis: a novel mutation in COL1A1 detected in a Chilean patient
evidences the locus heterogeneity of the disease ·················································································· 1037
Fanny Cortes（Rare Diseases Center, Clinica Las Condes, Chile/Pediatrics Department, Genetics Unit, Clinica
Las Condes）
Tue(3)-P-141 Withdrawn ································································································································ 1038
Tue(3)-P-142 DLX6 , MSX1, AND EDN1 : DIFFERENTIAL EXPRESSION IN HUMAN MANDIBLES THAT POTENTIALLY
REGULATE MANDIBULAR SIZE ····································································································· 1038
Rachel BV Cooper（Center for Advanced Dental Education, Saint Louis University, USA）
Tue(3)-P-143 Neuroblastoma Amplified Sequence (NBAS) mutation in Recurrent Acute Liver Failure: confirmatory report in
a sibship with very early onset, osteoporosis and developmental delay ···················································· 1039
Jose M Capo-chichi（CHU Sainte-Justine Research Center, Canada）
Tue(3)-P-144 A novel TTN mutation causing Tibial Muscular Dystrophy in a Turkish patient ································ 1039
Evren Gumus（Medical Genetics, Eskisehir Osmangazi University, Turkey）
ICHG2016 57
Tue(3)-P-145 Analysis of mitochondria-related gene from clinically suspected Charcot-Marie-Tooth patients by using whole
exome sequencing ··························································································································· 1040
Yu Hiramatsu（Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences,
Japan）
Tue(3)-P-146 Mulibrey Nanism in an Omani girl with Primary ovarian failure ························································ 1040
Adila M. AlKindy（Department of Genetics, Sultan Qaboos University Hospital, Sultanate of Oman, Oman）
Poster Session
Development 17:30-18:30
Day 3
Tue(3)-P-147 Genetic analysis of 30 families with Joubert syndrome and related disorders ······································ 1042
Toshifumi Suzuki（Human Genetics, Yokohama City University Graduate School of Medicine, Japan/Department
of Obstetrics and Gynecology, Juntendo University Faculty of Medicine）
Tue(3)-P-148 The first Japanese patients with genetically definite Bardet-Biedl syndrome ······································ 1042
Makito Hirano（Department of Neurology, Sakai Hospital Kindai Universtiy, Japan/Department of Neurology,
Kindai University Faculty of Medicine）
Tue(3)-P-149 Placental epigenome vary in relation to inadequate gestational weight gain ······································· 1043
Tomoko Kawai（Department of Maternal-Fetal Biology, National Research Institute for Child Health and Devel-
opment, Japan）
Tue(3)-P-150 Differentiation of iPS cells into cranial neural crest cells to model congenital disorder that arises from defects
in the development of the embryonic cranial neural crest cell lineage ····················································· 1043
Hironobu Okuno（Department of Physiology, Keio University Schoo of Medicine, Japan）
Tue(3)-P-151 Nutrigenomic aspects of adaptive responses to maternal high-sucrose feeding in rat models of metabolic syn-
drome ············································································································································ 1044
Lucie Sedova（Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University in Prague,
Czech Republic）
Tue(3)-P-152 Assessment of EGF gene and EGF-R expression following verification of 2-cell and blastocysts mouse embryos
······················································································································································ 1044
Saima Abbaspour（Cellular and Molecullar Research Center, Faculty of Medicine, Guilan University of Medical
Science, Iran）
Tue(3)-P-153 Lgr4 plays as an anti-testis gene of fetal gonads in mice ································································· 1045
Masae Koizumi（Department of Obstetrics and Gynecology, Ehime University School of Medicine, Japan）
Tue(3)-P-154 VA10, an immortalized broncho-epithelial cell line, as a tool for in vitro lung developmental studies
······················································································································································ 1045
Partha Sen（Pediatrics, Northwestern University, USA）
Tue(3)-P-155 A Boolean network model of normal gonadal sex determination in human and related disorders of sex develop-
ment ············································································································································· 1046
Leda Torres（Human Genetics, Instituto Nacional de Pediatria, Mexico）
Tue(3)-P-156 Identification and characterization of non-coding RNAs associated with chromatin in pluripotency
······················································································································································ 1046
Alessandro Bonetti（RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama,
Kanagawa, Japan）
Poster Session
Evolutionary and Population Genetics 17:30-18:30
Tue(3)-P-157 Fingerprint Pattern and Blood Groups in Twins- A Genetic Perspective ············································ 1048
Fawaz Pullishery（Public Health, Educare Institute of Health Sciences, India）
Tue(3)-P-158 Oral Health Related Habits and Oral Hygiene Practices among Identical and Non-Identical-A Genetic Perspective
······················································································································································ 1048
Fawaz Pullishery（Public Health, Educare Institute of Health Sciences, India）
Tue(3)-P-159 Genetic Analysis Provides Evidence for Increased Disease Prevalence of Systemic Lupus Erythematosus in
Chinese Populations compared to Europeans ······················································································ 1049
Yongfei Wang（Paediatrics & Adolescent Medcine, The University of Hong Kong, Hong Kong）
ICHG2016 58
Tue(3)-P-160 First Report of Hemophilia-A Point Mutation Detection in Egypt: AMean for Providing Proper Genetic and
Prenatal Counseling ························································································································· 1049
Rehab Mostafa Mosaad（Molecular Genetics and Enzymology, National Research Centre, Egypt）
Tue(3)-P-161 Signatures of geographically restricted adaptation in the Sea Island Gullah African Americans ············· 1050
Paula S Ramos（Medical University of South Carolina, USA）
Tue(3)-P-162 Molecular Characterization of G6PD Deficient Variants in Karen and Lao populations in Thailand
······················································································································································ 1051
Chalisa L. Cheepsunthorn（Biochemistry, Faculty of Medicine, Chulalongkorn University, Thailand）
Tue(3)-P-163 Allelic imbalance of mRNA transcription in α 2-HS glycoprotein (fetuin-A) gene ······························· 1051
Motoki Osawa（Department of Forensic Medicine, Tokai University School of Medicine, Japan）
Tue(3)-P-164 Mitochondrial DNA variation at the Sindh population of Pakistan ··················································· 1052
Day 3
Shahzad Bhatti（Human Genetics, University of Health Sciences Lahore, Pakistan）
Tue(3)-P-165 Detection of population specific signals of positive election in Mongolians ········································· 1052
Kazuhiro Nakayama（Jichi Medical University, Japan）
Tue(3)-P-166 Adaptive patterns of genetic diversity in native Siberian populations ················································ 1053
Vadim Stepanov（Institute for Medical Genetics, Russia/Tomsk State University）
Tue(3)-P-167 Analysis of polymorphisms associated with skin pigmentation in Oceanic populations ························· 1053
Izumi Naka（Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Japan）
Tue(3)-P-168 GENETIC TESTING OF HERODOTUS’ THEORY ON THE ORIGIN OF ARMENIANS ···················· 1054
Anahit Hovhannisyan（Institute of Molecular Biology NAS RA, Armenia）
Tue(3)-P-169 Colour-blindness: Impact of Consanguinity and Environment ·························································· 1055
Muhammad Shoaib Akhtar（Human Genetic and Molecular Biology Department, University of Health Sciences
Lahore, Pakistan/Gulab Devi Postgraduate Medical Institute, Lahore/Sundas Foundation Molecular Analysis
Center, Lahore）
Tue(3)-P-170 BCL11A erythroid-specific enhancer and fetal hemoglobin levels among Sickle Cell Disease Patients in
Cameroon: Implications for future therapeutic interventions ································································· 1055
Gift D Pule（Pathology, Division of Human Genetics, University of Cape Town, South Africa）
Tue(3)-P-171 Population genetics analysis of Negrito groups in Southeast Asia ····················································· 1056
Timothy A. Jinam（Division of Population Genetics, National Institute of Genetics, Japan）
Tue(3)-P-172 Geographical and Cultural Influences on Genetic Diversity: Patterns of the Y-Chromosomal Variation in Popu-
lations with Patronymic Tradition ····································································································· 1056
Maxat Zhabagin（Population genetics, Center for life sciences, National Laboratory Astana, Nazarbayev University,
Kazakhstan/Vavilov Institute of General Genetics, Russian Academy of Sciences）
Tue(3)-P-173 Prognostic role of Interleukin-1 α and β gene polymorphisms in preterm birth ································· 1057
Monika Pandey（Department Of Pediatrics, King George ｀ s Medical University, India）
Tue(3)-P-174 An update to the distribution of allele frequencies and forensic parameters for 15 autosomal STRs in the Mestizo
population from Península of Yucatán, Mexico ···················································································· 1057
Javier Sosa-Escalante（DIMYGEN Laboratorio SCP, DIMYGEN Laboratorio SCP, Mexico）
Tue(3)-P-175 Whole genome sequence analysis of fetal hemoglobin in a sickle cell disease cohort ···························· 1058
Evadnie Rampersaud（St Jude Children’s Research Hospital, USA）
Tue(3)-P-176 Molecular-genetic evaluation of G2956A (rs112287730) alteration of FBN1 gene in Russian Marfan patients
······················································································································································ 1059
Aleksandr V. Polyakov（Research Centre of Medical Genetics, Russia）
Tue(3)-P-177 Mutational complexity of a classic founder disease: tyrosinaemia in Quebec ······································ 1059
Francis Rossignol（Ste-Justine University Hospital Centre, University of Montreal, Canada）
Tue(3)-P-178 AIMs and Ascertainment Bias in Genomic Datasets: Considerations for Personalized Medicine ············· 1060
Sara D Niedbalski（Anthropology, University of New Mexico, USA）
Tue(3)-P-179 Where is Brazil located at? A study on 100 Alu insertion polymorphisms ·········································· 1061
Ana C. Arcanjo（Biological Sciences Institute, University of Brasilia, Brazil）
Tue(3)-P-181 A frequent mutation in the DYSF gene in the Avar’s population from northern Caucasus ··················· 1061
Alexander V. Polyakov（Research Centre of Medical Genetics, Russia）
Tue(3)-P-182 Y chromosome haplogrouping using the next generation sequencing system ······································ 1062
Eriko Ochiai（Department of Forensic Medicine, Tokai University School of Medicine, Japan）
ICHG2016 59
Tue(3)-P-183 The genetic landscape of Dagestan from Y-chromosome markers: phylogeny and phylogeography of J1 hap-
logroup and territorial subdivision of native populations ······································································· 1062
Vladimir Kharkov（Institute of Medical Genetics, Russia）
Tue(3)-P-184 Genomic relationships using DNA fractals rather than sequence alignments ······································· 1063
Nike Dattani（Kyoto University, Japan/Oxford University/Cambridge University）
Tue(3)-P-185 Withdrawn ································································································································ 1063
Tue(3)-P-186 Population Structure, Divergence and Admixture of Han Chinese, Japanese and Korean Populations
······················································································································································ 1063
Shuhua Xu（Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for
Computational Biology, China/School of Life Science and Technology, ShanghaiTech University/Collaborative
Day 3
Innovation Center of Genetics and Development）
Tue(3)-P-187 MITOCHONDRIAL GENETIC DIVERSITY OF THE PRE-HISPANIC MEXICAN MAYA POPULATIONS
FROM PALENQUE AND EL REY ···································································································· 1064
Mirna Isabel I.O. Ochoa Lugo（Department of Genetics and Molecular Biology, Center for Research and Advanced
Studies of IPN, Mexico）
Poster Session
Molecular Basis of Mendelian Disorders 1 17:30-18:30
Tue(3)-P-188 Japanese male twins with Leber congenital amaurosis possibly caused by the GUCY2D gene mutation
······················································································································································ 1065
Katsuhiro Hosono（Department of Ophthalmology, Hamamatsu University School of Medicine, Japan）
Tue(3)-P-189 Low-prevalence somatic TSC2 mutations in sporadic lymphangioleiomyomatosis identified by deep-sequencing
······················································································································································ 1065
Atsushi Fujita（Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan）
Tue(3)-P-190 First report of compound heterozygous mutations in the TRAPPC9 gene showing clinical features of autism
and intellectual disability in a Thai family ··························································································· 1066
Pornprot Limprasert（Pathology, Faculty of Medicine, Prince of Songkla University, Thailand）
Tue(3)-P-191 Novel GDAP1 mutations in Japanese patients with Charcot-Marie-Tooth disease ······························ 1067
Akiko Yoshimura（Department of Neurology and Geriatrics, Kagoshima University, Japan）
Tue(3)-P-192 Whole Exome Sequencing revealed a nonsense mutation in STAB2 Gene associated with intellectual disability
and oligodontia ······························································································································· 1067
Huoru Zhang（Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong）
Tue(3)-P-193 Whole Exome Sequencing helps characterize the mysterious skeletal disorder of a village in Jammu and Kashmir,
India ·············································································································································· 1068
Swarkar Sharma（School of Biotechnology, Shri Mata Vaishno Devi University, India）
Tue(3)-P-194 Exome sequencing identifies pathogenic mutations in the patient with severe combined immunodeficiency
······················································································································································ 1068
Hui-Wen Yu（National Cheng Kung University, Institute of Clinical Medicine, College of Medicine, Taiwan）
Tue(3)-P-196 Novel zebrafish models of neuromuscular diseases ·········································································· 1069
Genri Kawahara（Department of Pathophysiology, Tokyo Medical School, Japan）
Tue(3)-P-197 Identification of novel mutations and molecular modelling of novel missense mutations in Pakistani patients of
congenital afibrinogenemia ··············································································································· 1069
Tehmina Nafees Sonia Khan（Coagulation and Hemostasis, National Institute of Blood Diseases and Bone Marrow
Transplantation, Pakistan）
Tue(3)-P-198 Refinement of an Autosomal Dominant Hereditary Gingival Fibromatosis Locus on chromosome 2p23
······················································································································································ 1070
Miao Sun（The First Affiliated Hospital of Soochow University, China）
Tue(3)-P-199 Rare beta-thalassaemia mutation detected in South East Asian population - A dilemma in calling carrier status
······················································································································································ 1071
Hai-Yang Law（Department of Paediatric Medicine, Singapore/National Thalassaemia Registry, KK Women’s
and Children’s Hospital）
ICHG2016 60
Tue(3)-P-200 Novel hearing loss-causative point mutations and copy number variation identified by exon sequencing
······················································································································································ 1071
Aki Sakata（Genome Science Division, Research Center for Advanced Science and Technology, the University of
Tokyo, Japan/Department of Otolaryngology, Faculty of Medicine, the University of Tokyo）
Tue(3)-P-201 Withdrawn ································································································································ 1072
Tue(3)-P-202 Utility of a multigene next-generation sequencing panel for molecular diagnosis of Noonan syndrome and other
RASopathies ··································································································································· 1072
Maggie Brett（KK Research Centre, KK Women’s & Children’s Hospital, Singapore）
Tue(3)-P-203 Whole-exome sequencing identifies a novel mutation in primary ciliary dyskinesia from a Chinese consanguinity
family ············································································································································ 1073
Day 3
Hong Luo（Department of Internal Medicine, the Second Xiang Ya Hospital of Central South University, China）
Tue(3)-P-204 Identification and Functional Analysis for Novel Gene Mutation Responsible for Autosomal Dominant Macular
Dystrophy involved Dysfunction of ON-type Bipolar Cells ····································································· 1073
Yuichi Kawamura（Tokyo Medical Center, National Hospital Organization, National Institute of Sensory Organs,
Japan/Department of Ophthalmology, Juntendo University Graduate School of Medicine）
Tue(3)-P-205 Knockout the ceramide kinase-like gene causes retinal degeneration in zebrafish ································ 1074
Mugen Liu（Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong
University of Science and Technology, China）
Tue(3)-P-206 Molecular genetics analysis of Von Williebrand disease type III: studies in Cohort Pakistani patients
······················································································································································ 1074
Shariq Ahmed（Genomics, National Institute of Blood Diseases & Bone Marrow Transplantation, Pakistan）
Tue(3)-P-207 A loss-of-function mutation in JAK1 is associated with epidermodysplasia verruciformis ····················· 1075
Rongrong Wang（McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences-Peking
Tue(3)-P-208 Molecular genetic study of 12 Pakistani families with autosomal recessive sensorineural hearing loss
······················································································································································ 1075
Rongrong Wang（McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences-Peking
Tue(3)-P-209 Gene-based association analysis of familial pulmonary arterial hypertension ······································· 1076
Koichiro Higasa（Center for Genomic Medicine, Kyoto University, Japan）
Tue(3)-P-210 A de novo mutation of the MYH7 gene in a large Chinese family with autosomal dominant myopathy
······················································································································································ 1076
Kazuhiro Kobayashi（Division of Neurology/Molecular Brain Science, Kobe University Graduate School of
Medicine, Japan）
Tue(3)-P-211 Cystic Fibrosis in Chinese: Frequent and Novel Mutations in CFTR ················································· 1077
Yaping Liu（Department of Medical Genetics, McKusick-Zhang Center for Genetic Medicine, State Key Laboratory
of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking
Tue(3)-P-212 CHCHD2 is novel gene for autosomal dominant Parkinson’s disease ················································· 1078
Manabu Funayama（Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University,
Japan/Department of Neurology, Juntendo University School of Medicine/Center for Genomic and Regenerative
Medicine, Graduate School of Medicine, Juntendo University）
Tue(3)-P-213 Mutations in the patients with Nakajo Nishimura Syndrome - like autoinflammatory diseases ·············· 1078
Akira Kinoshita（Human Genetics, Nagasaki University, Japan/Nagasaki University Research Centre for Genomic
Instability and Carcinogenesis (NRGIC), Nagasaki University）
Tue(3)-P-214 Expanding the clinical phenotype of the novel connective tissue disorder due to variants in the PLOD3 gene
······················································································································································ 1079
Lisa J Ewans（St Vincent’s Clinical School, University of New South Wales, Australia/Kinghorn Centre for Clinical
Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia）
Tue(3)-P-215 Genomics in the genetic clinic: An Australian perspective ······························································· 1079
Lisa J Ewans（St Vincent’s Clinical School, University of New South Wales, Australia/Kinghorn Centre for Clinical
Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia）
Tue(3)-P-216 Clinical application of next generation sequencing in a family with undiagnosed genetic conditions
······················································································································································ 1080
Erina Ozaki（Total Medical Support Center, Ehime University Hospital, Japan/Division of Medical Genetics,
Ehime University Hospital）
ICHG2016 61
Tue(3)-P-217 Mutational analysis of Usher syndrome in Taiwan ·········································································· 1080

Liang-Hsuan Hu Hu（Department of Molecular Biology and Human Genetics, Tzu Chi University, Taiwan）
Tue(3)-P-218 Haplotype analysis combined with whole exome sequencing for the identification of the causative mutation of
a X-linked Retinitis Pigmentosa family ······························································································· 1081
Yung-Hao Ching（Molecular Biology and Human Genetics, Tzu Chi University, Taiwan）
Tue(3)-P-219 Genomics & Social Justice - Diagnosing Cystic Fibrosis in South Africa ············································ 1081
Cheryl S Stewart（Immunology, University of Pretoria, South Africa）
Tue(3)-P-220 Therapeutic research in a mouse model of cardio-facio-cutaneous syndrome ······································ 1082
Daiju Oba（Department of Medical Genetics, Tohoku University School of Medicine, Japan）
Tue(3)-P-221 Expression profile of inflammatory genes in placenta from sickle cell disease patients ·························· 1083
Day 3
Monica B Melo（Center for Molecular Biology and Genetic Engineering, University of Campinas, Brazil）
Tue(3)-P-222 A novel locus for autosomal dominant high hyperopia mapped to chromosomal 11 ···························· 1083
Xueshan Xiao（State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University,
China）
Tue(3)-P-223 Novel gene discovery across a large cohort of patients with syndromic craniofacial anomalies ·············· 1084
Elizabeth J Bhoj（Genetics and Pathology, Children’s Hospital of Philadelphia, USA/Center for Applied Ge-
nomics）
Tue(3)-P-224 Next Generation Sequencing in Spinal muscular atrophy syndromes: involvement beyond the anterior horn cell
······················································································································································ 1084
Tony Roscioli（Kinghorn Centre for Clinical Genomics, Australia/St Vincents Clinical School, University of New
South Wales, Darlinghurst, Australia/Department of Medical Genetics, Sydney Childrens Hospital, NSW, Aus-
tralia）
Tue(3)-P-225 The mechanism study of proximal symphalangism induced by p.Leu373Arg variant in the GDF5 proregion
······················································································································································ 1085
Yang Luo（The Research Center for Medical Genomics, China Medical University, China）
Tue(3)-P-226 Mutations spectrum of COL1A1 /COL1A2 in Chinese with osteogenesis imperfecta ··························· 1085
Xiuli Zhao（McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences - Peking Union
Tue(3)-P-227 Genetic testing of inherited cardiomyopathy by next generation semiconductor sequencing technologies
······················································································································································ 1086
Chaoxia Lu（McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences & Peking Union
Tue(3)-P-228 Withdrawn ································································································································ 1087
Tue(3)-P-229 ISOLATED OPTIC NERVE HYPOPLASIA IN 5 FAMILY TRIOS - A CLINICAL AND EXOME STUDY
······················································································································································ 1087
Pierre Bitoun（Genetique Medicale, France/Embryo-Cyto-Genetique et PMA, CHU Paris-Nord, Hopital Jean
Verdier, Bondy）
Tue(3)-P-230 New mutations in PLOD1 and COL3A1 in two cases with Ehlers-Danlos syndrome ··························· 1088
Hakan Ulucan（Cerrahpasa Medical Faculty, Istanbul University, Turkey）
Tue(3)-P-231 Decreased performance in IDUA knockout mouse mimic limitations of joint function and locomotion in patients
with Hurler syndrome ······················································································································ 1088
Eun Kyung Cho（Department of Pediatrics, Samsung medical Center, Korea, South）
Poster Session
Epigenetics 17:30-18:30
Tue(3)-P-232 Aberrant methylation at imprinted DMRs is associated with placental mesenchymal dysplasia ············· 1090
Saori Aoki（Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of
Medicine, Saga University, Japan/Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto
University）
Tue(3)-P-233 H2A.Z genetically interacts with DRG2 which physically associates with RWDD1 and Nup107 ············· 1091
Masahiko Tanabe（Department of Breast Oncology, Juntendo University, Japan/Kyoundo Hospital）
Tue(3)-P-234 MicroRNA promotes the decidualization of eutopic and ectopic endometrium ···································· 1091
Kentaro Kai（Department of Obstetrics and Gynecology, Oita University Faculty of Medicine, Japan）
ICHG2016 62
Tue(3)-P-235 Epigenetic regulator, Uhrf1, is a positive regulator in chondrocyte differentiation ······························· 1092
Michiko Yamashita（Division of Integrative Pathophysiology, Proteo-Science Center, Ehime university Graduate
School of Medicine, Japan/Department of Hepato Biliary Pancreatic and Breast Surgery）
Tue(3)-P-236 Altered levels of epigenetic marks/factors on regulatory regions of sperm chromatin condensing genes in testic-
ular biopsies infertile men ················································································································ 1093
Maryam Shahhoseini（Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for
Reproductive Biomedicine, ACECR, Tehran, Iran）
Tue(3)-P-237 Is the association between sweet and bitter perception due to genetics? ··········································· 1093
Liang-Dar Hwang（Genetic Epidemiology Lab, QIMR Berghofer Medical Research Institute, Brisbane, Queensland,
Australia/School of Medicine, University of Queensland, Brisbane, Australia）
Tue(3)-P-238 Clinical and molecular findings in a patient with 46,XX/47,XX,+14 mosaicism caused by postzygotic duplication
of a paternally derived chromosome 14 ······························································································ 1094
Day 3
Nobuhiro Suzumori（Department of Obstetrics and Gynecology, Nagoya City University, Graduate School of
Medical Sciences, Japan）
Tue(3)-P-239 Assessment of the oral health status of monozygotic and dizygotic twins - a comparative study ············· 1095
Delfin Lovelina Francis（Public Health Dentistry, Tamil Nadu Dr MGR Medical University, Chennai, India）
Tue(3)-P-240 Association of epigenetic role of BRDT in spermatogenesis and male infertility ································· 1095
Fereshteh Kohandani（Biology Department, Faculty of Sciences, Yazd University, Yazd, Iran/Department of
Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR,
Tehran, Iran）
Tue(3)-P-241 Differential histone modification of marker genes involved in stemness and differentiation in human pluripotent
and differentiated cells ····················································································································· 1096
Raha Favaedi（Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Repro-
ductive Biomedicine, ACECR, Tehran, Iran）
Tue(3)-P-242 Discovering site-specific changes in 5-hydroxymethylcytosine in suicide completers through next-generation
sequencing ····································································································································· 1096
Jeffrey A. Gross（McGill University and the Douglas Hospital Research Centre, Canada）
Tue(3)-P-243 DNA Methylation Reflects Early Life Chronic Stress Environment: A Biomarker for Childhood Cortisol
······················································································································································ 1097
Evan Gatev（Bioinformatics, University of British Columbia, Canada/Centre for Molecular Medicine and Ther-
apeutics）
Tue(3)-P-244 Epigenetic role of the nuclear factor NF-Y on ID family genes in endometrial tissues of women with endometriosis
···················································································································································· 1097
Shirin Amirteimouri（Faculty of Basic Sciences and Technologies, University of Science and Culture, ACECR,
Tehran, Iran/Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Repro-
ductive Biomedicine, ACECR, Tehran, Iran）
Tue(3)-P-245 Monozygotic twins concordant for ICR2 hypomethylation in different tissues but discordant for Beckwith-
Wiedemann syndrome phenotype ······································································································ 1098
Dorota Jurkiewicz（Department of Medical Genetics, Children’s Memorial Health Institute, Warsaw, Poland）
Tue(3)-P-246 Exploration of hydroxymethylation in Kagami-Ogata syndrome caused by hypermethylation of imprinting control
regions ··········································································································································· 1099
Kazuki Yamazawa（Clinical Genetics Center, NHO Tokyo Medical Center, Japan/Department of Molecular En-
docrinology, National Research Institute for Child Health and Development）
Tue(3)-P-247 ANALYSIS OF CHROMOSOMAL ABNORMALITIES AND DNA METHYLATION AT SNRPN GENE IN
PRADER WILLI SYNDROME - COIMBATORE POPULATION ··························································· 1100
Padmavathi Vijaykumar（Department of Human Genetics and Molecular Biology, Bharathiar University, India）
Tue(3)-P-248 Meta-Analysis of Epigenome-wide Association Studies on Serum Urate Levels including 7600 individuals
······················································································································································ 1100
Christian Gieger（Research Unit of Molecular Epidemiology, Helmholtz Center Munich, Germany/Institute of
Epidemiology, Helmholtz Center Munich）
Tue(3)-P-249 Effect of butylated hydroxytoluene (BHT) on BDNF gene methylation, learning and memory in male wistar rats
······················································································································································ 1101
Parvaneh Keshavarz（Cellular and Molecular Research center, Faculty of Medicine, Guilan University of Medical
Science, Iran）
Tue(3)-P-250 Multilocus methylation defects in a patient presenting with both clinical phenotype of pseudohypoparathyroidism
type Ib and Beckwith-Wiedemann syndrome ······················································································· 1101
Shinichiro Sano（Molecular Endocrinology, National Research Institute for Child Health and Development, Japan）
ICHG2016 63
Tue(3)-P-251 The Transcriptome and DNA Methylome Landscapes of Human Primordial Germ Cells ······················ 1102
Fan Guo（Biodynamic Optical Imaging Center and Department of Obstetrics and Gynecology, College of Life
Sciences, Third Hospital, Peking University, China）
Tue(3)-P-252 Investigation of maternal effects, maternal-fetal interactions and parent-of-origin effects (imprinting), using
mothers and their offspring with schizophrenia ···················································································· 1102
Byung Dae Lee（Pusan National University Hospital, Korea, South）
Tue(3)-P-253 Telomere Length and Epigenetics, TERRA Transcript Level and Telomerase Expression as Dynamic Genetic
Parameters in Poly Cystic Ovary Syndrome ························································································ 1103
Narges Ghobadi（Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Re-
productive Biomedicine, ACECR, Tehran, Iran）
Tue(3)-P-254 LRRC37A2 and SNORD42B methylation analysis in gastric cancer tissues using next-generation sequencing
······················································································································································ 1104
Day 3
Fernanda Wisnieski（Morphology and Genetics, UNIFESP, Brazil）
Tue(3)-P-255 A fluorescence polarization-based method with methyl-sensitive one-label extension for quantification of single
CpG dinucleotide methylation ··········································································································· 1104
Cunyou Zhao（Department of Medical Genetics, Southern Medical University, China）
Tue(3)-P-256 Comprehensive methylation microarray analysis for placental genomic DNA in abruption cases ············· 1105
Jun Konno（Obstetrics and Gynecology, Tokyo Women’s Medical University, Japan）
Tue(3)-P-257 Maternal undernutrition alters DNA methylation profiles in rat embryonic kidney ······························· 1105
Mariko Hida（Neonatology, Yokohama Rosai Hospital, Japan）
Tue(3)-P-258 The epigenetic impact of a 6 month lifestyle intervention programme on women aged 18-40 ··············· 1106
Michelle C Thunders（College of Health, Massey University, New Zealand）
Tue(3)-P-259 Skewed pattern of X chromosome inactivation in Brazilian women without familial history of X-linked intellectual
disability ········································································································································ 1106
Silviene F de Oliveira（Genetica e Morfologia, Universidade de Brasilia, Brazil/Programa de Pos-graduacao em
Biologia Animal, Universidade de Brasilia）
Tue(3)-P-260 Functional analysis of Xist long noncoding RNA using mouse artificial chromosome (MAC) ················ 1107
Daigo Inaoka（Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate
School of Medical Science, Tottori University, Japan）
Poster Session
Health Services Research 17:30-18:30
Tue(3)-P-261 Breast cancer, genetics or bad karma: Meanings and experiences of Thai women living with breast cancer in
southern Thailand ··························································································································· 1108
Pranee Liamputtong（Public Health, La Trobe University, Australia）
Tue(3)-P-262 Breast Cancer and Genetical Belief: Barriers to Screening Programmes amongst Thai Migrant Women in
Australia ········································································································································ 1108
Dusanee Suwankhong（Public Health, Thaksin University, Thailand）
Tue(3)-P-263 The relationship between the social competence of children and adults with Down’s syndrome and caregivers’
burden ··········································································································································· 1109
Kanako Morifuji（Department of Nursing, Nagasaki University Graduate School of Biomedical Sciences, Japan）
Tue(3)-P-264 CD44, ALDHI, E-cadherin and Snail gene protein analysis in ameloblastoma ····································· 1110
Chong Huat Siar（Oro-Maxillofacial Surgical and Medical Sciences, University of Malaya, Malaysia）
Tue(3)-P-265 Community Genetics in Cuba ······································································································ 1110
Beatriz Marcheco-Teruel（National Center of Medical Genetics, Cuba）
Tue(3)-P-266 Using Quality Improvement Methods and Time-Driven Activity Based Costing to Improve Value-Based Cancer
Care Delivery at a Cancer Genetics Clinic ··························································································· 1111
Ryan Tan（Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, Singapore）
Tue(3)-P-267 Cost is a barrier to accept germline mutation testing for known cancer syndrome in Japan ················· 1112
Koji Matsumoto（Department of Medical Oncology, Hyogo Cancer Center, Japan）
Tue(3)-P-268 Fulfilling the promise of personalised medicine - prioritising our investment ······································· 1112
Deborah J Schofield（The University of Sydney, Australia/Garvan Institute of Medical Research/Murdoch Chil-
drens Research Institute, Royal Children’s Hospital）
ICHG2016 64
Tue(3)-P-269 The social and economic impacts of childhood syndromes of suspected genetic origin ························ 1113
Deborah J Schofield（The University of Sydney, Australia/Murdoch Children’s Research Institute, Royal Children’s
Hospital/Garvan Institute of Medical Research）
Tue(3)-P-270 Cost effectiveness of whole exome sequencing compared with standard diagnostic care ······················· 1113
Zornitza Stark（Murdoch Childrens Research Institute, Australia）
Tue(3)-P-271 How do people feel on knowing their disease risks by genetic testing? -Attitudinal Study for 4,000 Japanese
Respondents: Behavior Change after knowing their disease Risks and Impact of Communication Ways of Disease
Risk- ············································································································································· 1114
Takashi Kido（Rikengenesis, Japan）
Tue(3)-P-272 A prospective evaluation of whole exome sequencing as a first-tier molecular test in infants with suspected
monogenic disorders ························································································································ 1114
Day 3
Susan M White（Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia/University
of Melbourne, Melbourne, Australia）
Tue(3)-P-273 Resolving barriers to the use of genomic sequencing in clinical practice: evaluation of a whole-of-system approach
······················································································································································ 1115
Tue(3)-P-274 Initiatives on Rare and Undiagnosed Diseases (IRUD) for adults: a national network deciphering rare and
undiagnosed diseases ······················································································································· 1116
Hidehiro Mizusawa（National Center Hospital, National Center of Neurology and Psychiatry, Japan）
Tue(3)-P-275 Family history taking in pediatrics: it’s much more than just a checklist ··········································· 1117
June C Carroll（Family and Community Medicine, Mount Sinai Hospital, University of Toronto, Canada）
Tue(3)-P-276 APPROACH TO PATIENTS WITH GENETIC DISEASES IN EMERGENCY SERVİCE ······················ 1117
Tarik Ocak（Emergency Medicine, Kanuni Sultan Suleyman Research and Training Hospital, Turkey/Abant Izzet
Baysal University Department of Emergency Medicine）
Tue(3)-P-277 INVESTİGATION TO PATIENTS WITH GENETIC DISEASES IN EMERGENCY SERVİCE ··············· 1118
Arif Duran（Emergency Medicine, Abant Izzet Baysal University, Turkey）
Tue(3)-P-278 Patients and their Families and Friends as Developers of Medical Treatments/Devices ······················· 1119
Sofia A Oliveira（Instituto de Medicina Molecular, Portugal）
Tue(3)-P-279 Gender Differences in Genetic Contribution to Longevity ································································· 1119
Min Junxia（Zhejiang University, China）
Tue(3)-P-280 Mainstreaming genomics - A theory-informed systematic review of clinicians’ genetic testing practices
······················································································································································ 1120
Jean L Paul（Molecular Development, Murdoch Childrens Research Institute, Australia）
Tue(3)-P-281 MéXICO ´ S NATIONAL BIOBANKING SERVICE LABORATORY ················································ 1120
Hugo A Barrera-Saldana（Laboratorio Nacional Biobanco, Facultad de Medicina y Hospital Universitario de la
UANL, Mexico）
Poster Session
Genetic Counseling 17:30-18:30
Tue(3)-P-282 The free software "f-tree" for drawing a pedigree in genetic counseling ············································· 1122
Koji Kumagai（Department of Gynecology, Osaka Railway Hospital, Japan）
Tue(3)-P-283 Factors affecting the decision to undertake non-invasive prenatal testing ··········································· 1122
Masahiro Murakami（Clinical Genetics, Shikoku Medical Center for Children and Adults, Japan）
Tue(3)-P-284 The examination about wish of prenatal testing and mental background factorof pregnant women by assited
reproductive technology ··················································································································· 1123
Miwa Sakamoto（Obstetrics and Gynecology, Showa University, Japan）
Tue(3)-P-285 Effect of the mental background factor of after childbirth women who done prenatal testings ·············· 1124
Nahoko Shirato（Obstetrics and Gynecology, SHOWA University, Japan）
Tue(3)-P-286 Genetic counseling in pregnant women whose fetus had Robertson translocation ······························· 1124
Tatsuko Hirose（Obstetrics and Gynecology, Showa University School of Medicine, Japan）
ICHG2016 65
Tue(3)-P-287 Role of Genetic Counseling in Pediatric Transplantation of Genetic Disorders: A Report from Children’s Medical
Center in Japan ······························································································································ 1125
Shiho Ito（Department of Nursing, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan/Department of
Genetic Counseling, Graduate School of Human Genetics and Science, Ochanomizu University, Tokyo, Japan）
Tue(3)-P-288 Uptake of gene test among family members with BRCA 1/2 mutation in Japanese population Uptake of gene
test among family members with BRCA 1/2 mutation in Japanese population ······································ 1125
Megumi Okawa（St Luke’s International Hospital, Japan）
Tue(3)-P-289 Charcot-Marie-Tooth disease (CMT) Patient Registry in Japan ······················································· 1126
Masanori Nakagawa（Neurology, North Medical Center, Kyoto Prefectural University of Medicine, Japan）
Tue(3)-P-290 Current Status of Social Issues for People with Down Syndrome in Japan: From Nationwide Survey
······················································································································································ 1127
Day 3
Hidehiko Miyake（Clinical Genetics Unit, Kyoto University, Japan）
Tue(3)-P-291 Genetic counseling for clinical sequencing using the next-generation sequencincer panel analysis ············· 1127
Tetsuya Okazaki（Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori
University, Japan/Division of Clinical Genetics, Tottori University Hospital,）
Tue(3)-P-292 Characteristics of the Genetic Counseling in Kyoto University Hospital to Figure Out the Genetic Counseling
Needs in Japan ······························································································································· 1128
Manami Matsukawa（Genetic Counselor Course, School of Public Health, Kyoto University, Japan）
Tue(3)-P-293 A case of osteogenesis imperfecta (OI) diagnosed during pregnancy whose mother’s feeling for fetus changed
from denial to acceptance and whose genetic diagnosis was planned after genetic counseling ···················· 1129
Masahiro Shiba（Obstetrics & Gynecology, Teikyo University, Japan）
Tue(3)-P-294 Genetic counsering of 46,XY DSD for eight years -a case report- ····················································· 1129
Nobuko Nishioka（Koshigaya Municipal Hospital, Japan）
Tue(3)-P-295 Mental background of pregnant women in the view point of delivering facilties ·································· 1130
Keiko Miyagami（Showa University School of Medicine, Japan）
Tue(3)-P-296 Genetic diagnosis, counseling and management of androgen insensitivity syndrome : a case report
······················································································································································ 1130
Mizue Teramoto（Department of Obstetrics and Gynecology, Sapporo Medical University, Japan）
Tue(3)-P-297 Genetic Counseling for Patients and Family Members with Endocrine Disease: Experience of Specialized Genetic
Counselor ······································································································································· 1131
Hye In Kang（Department of Surgery, Seoul National University Hospital, Korea, South）
Tue(3)-P-298 Families who were suspected to be HBOC families but didn’t show pathogenic mutations in both BRCA1 and
BRCA2 in genetic testing ················································································································· 1132
Nao Sugimoto（Familial Tumor Counseling Service, NHO Shikoku Cancer Center, Japan）
Tue(3)-P-299 Factors influencing the decision not to choose prenatal aneuploidy screening in pregnant women receiving genetic
counseling for advanced maternal ages ······························································································· 1133
Emiko Kise（Division of Clinical and Molecular Genetics, Shinshu University Hospital, Japan/Department of
Medical Ethics, Kyoto University School of Public Health）
Tue(3)-P-300 Genetic counseling of a woman with malignant pheochromocytoma caused by multiple endocrine neoplasia type
2A ················································································································································ 1133
Misaki Fukue（Clinical&Molecular Genetics Center, Hmamatsu University Hospital, Japan）
Tue(3)-P-301 The positive test result ｀ s effects on condition of health, ability to function and mental health as evaluated
by Finnish male BRCA1/2 mutation carriers ······················································································· 1134
Outi Kajula（Research Unit of Nursing Science and Health Management, University of Oulu, Finland/Medical Re-
search Center, Oulu University Hospital and University of Oulu, Oulu, Finland/Department of Clinical Genetics,
Oulu University Hospital, Oulu, Finland）
Tue(3)-P-302 Genetic counseling to couples having noninvasive prenatal genetic testing ········································ 1134
Mai Sono（Department of Public Health, Graduate School of Medicine, Chiba University, Japan）
Tue(3)-P-303 Genetic Counseling for Hereditary Breast and Ovarian Cancer Syndrome in our hospital ····················· 1135
Hiroyuki Maeda（First Dept.of Surgery, Faculty of Medicine, University of Fukui, Japan）
Tue(3)-P-304 Eleven-year summary of genetic counseling in Kyoto Prefectural University of Medicine ······················ 1136
Tomohiko Taki（Division of Genetic Counseling, Kyoto Prefectural University of Medicine, Japan）
ICHG2016 66
Poster Session
Genetics/Genomics Education 17:30-18:30
Tue(3)-P-305 Genetic Counselling in Practice: an international course for clinical geneticists and genetic counsellors
······················································································································································ 1137
Aad Tibben（Clinical Genetics, Leiden University Medical Centre, Netherlands）
Tue(3)-P-306 Withdrawn ································································································································ 1137
Tue(3)-P-307 Withdrawn ································································································································ 1138
Day 3
Tue(3)-P-308 Exploring education models of genomic medicine for general publics in informal learning settings
······················································································································································ 1138
ShioJean Lin（Genetic Counseling Center, Chi Mei Hospital, Taiwan）
Tue(3)-P-309 Develop multimedia genetic instruction according to the cognitive theory of multimedia learning and cognitive
load theory ····································································································································· 1138
Ting-Kuang Yeh（National Taiwan Normal University, Taiwan）
Tue(3)-P-310 Genetic Counseling Education at Kindai University ········································································· 1139
Junko M Tatsumi（Department of Life Science, Kindai University, Japan/Graduate School of Science and Engi-
neering Research, Kindai University）
Tue(3)-P-311 Knowledge and attitudes of Gastroenterology fellows working in various hospitals of United States of America,
on genetic testing for disease specific biomarkers and knowledge of Precision Medicine ···························· 1139
Shima Ghavimi（Internal Medicine, Howard University Hospital, USA）
Tue(3)-P-312 Analysis of the education guidelines and textbooks to investigate the feasibility of educating human genetic in
primary and secondary education system in Japan ··············································································· 1140
Nana Akiyama（Department of Medical Ethics and Medical Genetics, Kyoto University Graduate School of
Medicine, Japan）
Tue(3)-P-313 The Current Landscape of the After-Sales Services of Direct-To-Consumer (DTC) Genetic Testing in Japan
······················································································································································ 1140
Eriko Takamine（Genetic Counselor Course, Kyoto University, School of Public Health, Japan）
Tue(3)-P-314 Education tools to teach children about genetics, variation, and evolution ········································ 1141
Tomoko Kobayashi（Department of Genomic Medicine Education, Tohoku Medical Megabank Organization
(ToMMo), Tohoku University, Japan/Department of Education and Training, ToMMo, Tohoku University）
Tue(3)-P-315 The survey of recognition of medical students about recent topics related to genetic medicine ············· 1142
Satomi Aihara（Department of Obstetrics and Gynecology, Faculty of Medicine Saga University, Japan）
Tue(3)-P-316 Developing genome science literacy at school: exploring opportunities in the Australian secondary school science
curriculum ······································································································································ 1142
Bronwyn N Terrill（Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Aus-
tralia/Monash University）
Tue(3)-P-317 Genetics Objective Structured Clinical Exam (Genetics OSCE) A tool for assessing and improving medical
genetics communication skills and knowledge ······················································································ 1143
Simon G Kupchik（Pediatrics, Maimonides Infants and Children’s Hospital of Brooklyn at Maimonides Medical
Center, USA）
Tue(3)-P-318 Innovative approaches to workforce transformation: Preparing England’s National Health Service to deliver a
genomic medicine service ················································································································· 1143
Michelle Bishop（Genomics Education Programme, Health Education England, UK）
Tue(3)-P-319 Developing a MANGA cartoon medium that can promote Family Health History and Human Genetics to the
public ············································································································································ 1144
Yumie Hiraoka（Genetic Counselor Course, Kyoto University School of Public Health, Kyoto, Japan）
ICHG2016 67
Wed.,April 06
Day 4
Main Hall (1F)
[PL2] Plenary Lecture 2 8:00-10:00

Chair：Nancy J. Cox（Vanderbilt University Medical Center, USA）
Chair ：Poh-San Lai（National University of Singapore, Singapore）
Wed(4)-PL2-1 Retinal cell therapy using iPS cells ······························································································ 129

Masayo Takahashi（Center for Developmental Biology, Riken, Japan）
Wed(4)-PL2-2 Experience from 10.000 diagnostic exomes ··················································································· 131
Han G. Brunner（Radboud UMC, Department of Human Genetics 855, Nijmegen; Maastricht University Medical
Wed(4)-PL2-3 Genomics View of Neurological Diseases ······················································································ 133
Day 4
Shoji Tsuji（Department of Neurology and Medical Genome Center, The University of Tokyo Hospital; Medical
Annex 1 (1F)

NGS Dissecting Human Genetic Diseases 10:15-12:15
Convener：Naomichi Matsumoto（Department of Human Genetics, Yokohama City University Graduate School of Medicine,
Japan）
Convener ：Xue Zhang（McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences & Peking Union
Wed(4)-CIS21-1 Next Generation Sequencing dissecting human “genetic” diseases ·············································· 255
Naomichi Matsumoto（Department of Human Genetics, Yokohama City University Graduate School of Medicine,
Japan）
Wed(4)-CIS21-2 Exome analysis of autosomal recessive disorders ········································································· 257
Fowzan S. Alkuraya（Genetics, King Faisal Specialist Hospital and Research Center, Saudi Arabia/College of
Medicine, Alfaisal University）
Wed(4)-CIS21-3 PhenoDB and GeneMatcher, solving unsolved whole exome data ················································· 258
Nara Lygia M. Sobreira（McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, USA）
Wed(4)-CIS21-4 Understanding the causes of inherited rare diseases ···································································· 259
William Newman（Manchester Centre for Genomic Medicine, University of Manchester, UK）
[SFS1.1] Special Focus Session 1

GA4GH, IRDiRC, and Matchmaker Exchange "IRDiRC and Matchmaker Exchange" 15:00-16:30
Moderator：Paul Lasko（Former Chair of the IRDiRC Executive Committee; Department of Biology, McGill University,
Canada）
Wed(4)-SFS1.1-1 IRDiRC in its fifth year: A progress report ··············································································· 332

Paul Lasko（Former Chair of the IRDiRC Executive Committee; Department of Biology, McGill University,
Canada）
Wed(4)-SFS1.1-2 The National Institutes of Health Undiagnosed Diseases Program and Undiagnosed Diseases Network
······················································································································································ 334
David R. Adams（Uniagnosed Diseases Program, NIH, USA）
Wed(4)-SFS1.1-3 Japan Agency for Medical Research and Development (AMED), Rare/Intractable Disease Project, and
Initiative on Rare and Undiagnosed Diseases (IRUD) ··········································································· 335
Shigeki Kuzuhara（Suzuka University of Medical Science, Graduate School of Health Science, Japan/Professor
Emeritus, Mie University School of Medicine/Program Director, Practical Research Project for Rare/Intractable
Diseases, Japan Agency for Medical Research and Development (AMED)）
ICHG2016 68
Wed(4)-SFS1.1-4 New Trends and Novel Technologies in Orphan Drug Development ············································ 337
Carlo Incerti（Global Medical Affairs, Sanofi Genzyme, USA）
Wed(4)-SFS1.1-5 If you are not at the table, you are on the menu ······································································ 338
Sharon F. Terry（President and CEO / Genetic Alliance, USA）
Wed(4)-SFS1.1-6 IRDiRC-GA4GH Collaboration: Matchmaker Exchange - Linking International Datasets to １-Enable Rare
Disease Gene Discovery ···················································································································· 339
Han G. Brunner（Radboud University Nijmegen Medical Centre, the Netherlands）
Wed(4)-SFS1.1-7 IRDiRC-GA5GH Collaboration: Matchmaker Exchange -The Challenges and opportunities of connecting
different database ···························································································································· 340
Nara Lygia M. Sobreira（John Hopkins University School of Medicine, USA）

GA9GH, IRDiRC, and Matchmaker Exchange "The Global Alliance for Genomics and Health" 16:45-18:15
Moderator：Peter Goodhand（Global Alliance for Genomics and Health (Executive Director), Canada）
Day 4
Wed(4)-SFS1.2-1 -IRDiRC-GA4GH Collaboration- Automatable Discovery and Access Task Team ··························· 341
Clara Gaff（Melbourne Genomics Health Alliance, Australia）
Wed(4)-SFS1.2-2 -IRDiRC-GA4GH Collaboration- GA4GH Overview ···································································· 342
Tom Hudson（Global Alliance for Genomics and Health (Chair, Steering Committee); Ontario Institute for Cancer
Research, Canada）
Wed(4)-SFS1.2-3 -GA4GH Working Groups: Developing Tools and Solutions for Data Sharing- Clinical Genomic Data Sharing
······················································································································································ 343
Kathryn North（Murdoch Childrens Research Institute, Australia）
Wed(4)-SFS1.2-4 -GA4GH Working Groups: Developing Tools and Solutions for Data Sharing- Family History Collection
······················································································································································ 344
Ingrid M. Winship（Royal Melbourne Hospital; University of Melbourne, Australia）
Wed(4)-SFS1.2-5 -GA4GH Working Groups: Developing Tools and Solutions for Data Sharing- Genomic Data Sharing Enablers
······················································································································································ 345
David Haussler（University of California Santa Cruz, USA）
Wed(4)-SFS1.2-6 -GA4GH Working Groups: Developing Tools and Solutions for Data Sharing- Regulatory and Ethics Working
Group ············································································································································ 346
Kazuto Kato（Osaka University, Japan）
Wed(4)-SFS1.2-7 -GA4GH Demonstration Projects: Data Shared and Lessons Learned- The Beacon Project ············· 347
Marc Fiume（DNAStack, Canada）
Wed(4)-SFS1.2-8 -GA4GH Demonstration Projects: Data Shared and Lessons Learned- Collaborative Ethics and Governance:
From Data Sensitivity to Data Access ································································································ 348
Stephanie Dyke（Centre of Genomics and Policy, McGill University, Canada）
Wed(4)-SFS1.2-9 -GA4GH Demonstration Projects: Data Shared and Lessons Learned- The BRCA Challenge ············· 349
John Burn（Institute of Genetic Medicine Newcastle University Centre for Life, UK）
Wed(4)-SFS1.2-10 -GA4GH Demonstration Projects: Data Shared and Lessons Learned- Public Access Variant Data: Liabil-
ity? ··············································································································································· 350
Adrian Thorogood（Centre of Genomics and Policy, McGill University, Canada）
Annex 2 (1F)

Epigenetic Inheritance and Reprogramming in Biology and Disease 10:15-12:15
Convener：Hiroyuki Sasaki（Medical Institute of Bioregulation, Kyushu University, Japan）
Convener ：Anne Ferguson-Smith（Department of Genetics, University of Cambridge, UK）
Wed(4)-CIS22-1 Epigenetic regulation of gene expression network in human germline cells ····································· 260
Fuchou Tang（BIOPIC, College of Life Sciences, Peking University, China）
ICHG2016 69
Wed(4)-CIS22-2 Incomplete reprogramming of germline DNA methylation in the human placenta ·························· 262
Hiroyuki Sasaki（Medical Institute of Bioregulation, Kyushu University, Japan）
Wed(4)-CIS22-3 Kagami-Ogata syndrome: Clinically recognizable imprinting disorder caused by upd(14)pat and related con-
dition ············································································································································ 263
Masayo Kagami（Department of Molecular Endocrinology, National Research Institute for Child Health and
Development, Japan）
Wed(4)-CIS22-4 Establishment and maintenance of stable and variable epigenetic states in mammals ······················ 265
Anne Ferguson-Smith（Department of Genetics, University of Cambridge, UK）

Insights about Reproductive Genetic Services Today and in The Future 12:30-13:30
Chair：Shoji Okajima（President, LabCorp Japan）
LabCorp Japan
Insights about Reproductive Genetic Services Today and in The Future ·················································· 504
Michael J. Sapeta（Vice President and General Manager, Integrated Genetics and CMBP Labcorp）
Day 4
Insights about Reproductive Genetic Services Today and in The Future ·················································· 505
Akihide Takatani（Genetic Coordinator, LabCorp Japan）
[SFS2] Special Focus Session 2

Genetics and Genomics in Diabetes and Metabolic Diseases 15:00-16:30
Moderator：Mark I. McCarthy（OCDEM, University of Oxford, UK; Wellcome Trust Centre for Human Genetics, University
of Oxford）
Moderator ：Takashi Kadowaki（Department of Diabetes and Metabolic Diseases, The University of Tokyo Hospital, Japan）
Wed(4)-SFS2-1 Genetics in T2D ····················································································································· 351

Torben Hansen（The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen,
Copenhagen, Denmark）
Wed(4)-SFS2-2 Regulatory Variants and Human Diseases ··················································································· 352
Marcelo Nobrega（University of Chicago, USA）
Wed(4)-SFS2-3 From p-values to proteins: understanding the biology of diabetes and diabetic complications using human
genetics and genomics ····················································································································· 353
Mark I. McCarthy（OCDEM, University of Oxford, UK/Wellcome Trust Centre for Human Genetics, University
of Oxford）
Wed(4)-SFS2-4 Type 2 Diabetes: From genes to therapies ················································································· 354
Takashi Kadowaki（Department of Diabetes and Metabolic Diseases, The University of Tokyo Hospital, Japan）

Genetics of Deafness 16:45-18:15
Moderator：Shin-ichi Usami（Department of Otorhinolaryngology, Shinshu University School of Medicine, Japan）
Moderator ：Guy Van Camp（Department of Medical Genetics, University of Antwerp, Belgium）
Wed(4)-SFS3-1 Massively parallel DNA sequencing for deafness applied to social health insurance-based genetic testing
······················································································································································ 356
Shin-ichi Usami（Department of Otorhinolaryngology, Shinshu University School of Medicine, Japan）
Wed(4)-SFS3-2 Diagnostic applications of deafness research in Europe ································································ 358
Guy Van Camp（Department of Medical Genetics, University of Antwerp, Belgium）
Wed(4)-SFS3-3 Genomics of Hereditary Deafness ······························································································ 359
Karen B. Avraham（Tel Aviv University, Israel）
Wed(4)-SFS3-4 Clinical applications of genetic studies for deafness ······································································ 360
Chen-Chi Wu（Department of Otolaryngology, National Taiwan University Hospital; Department of Medical Ge-
netics, National Taiwan University Hospital, Taiwan/Department of Medical Genetics, National Taiwan University
Hospital）
ICHG2016 70
Room A (2F)

Pharmacogenomics 10:15-12:15
Convener：Taisei Mushiroda（Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Japan）
Convener ：Munir Pirmohamed（Department of Molecular and Clinical Pharmacology, University of Liverpool, UK）
Wed(4)-CIS23-1 Prediction of severe adverse drug reactions using pharmacogenomic biomarkers: Current status and future
prospects in Japan ·························································································································· 266
Yoshiro Saito（Medicinal Safety Science, National Institute of Health Sciences, Japan）
Wed(4)-CIS23-2 Genomic Diversity of African populations and pharmacogenomics in the safe and efficacious use of efavirenz
in the treatment of HIV/AIDS ·········································································································· 268
Collen Masimirembwa（African Institute of Biomedical Science and Technology, Zimbabwe）
Wed(4)-CIS23-3 Move Pharmacogenomics Discovery to Medical Practice ····························································· 269
Yuan-Tsong Chen（Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Department of Pediatrics,
Duke University, Durham, NC, USA/Department of Pediatrics, Duke University, Durham, NC USA）
Day 4
Wed(4)-CIS23-4 Pharmacogenomics: The long journey from discovery to implementation ······································ 270
Munir Pirmohamed（Department of Molecular and Clinical Pharmacology, University of Liverpool, UK）

Everything in One Assay: an Inescapable Approach 12:30-13:30
Chair：Heidi Kijenski（Global Marketing Director / Human and Reproductive Genetics / Agilent Technologies, Inc.）
Agilent Technologies Japan，Ltd.
Everything in One Assay: an Inescapable Approach ············································································· 506

Orsetta Zuffardi（Department of Molecular Medicine, University of Pavia and IRCCS Foundation Policlinico San
Matteo, Pavia, Italy）

Integration of Genomic Information and Electric Health Record Systems 15:00-16:30
Moderator：Catherine A. Wicklund（Center for Genetic Medicine, Northwestern University, USA）
Moderator ：Hiroshi Tanaka（Tokyo Medical and Dental University, Japan）
Wed(4)-SFS4-1 Integration of Genomic Information and Electric Health Record Systems ········································ 362
Panelist：Catherine A. Wicklund（Center for Genetic Medicine, Northwestern University, USA）
Panelist：Hiroshi Tanaka（Tokyo Medical and Dental University, Japan）
Panelist：Abel Kho（Northwestern University, USA）

IGEN: Do they know what you think they know? Development and evaluation of health professional education in
genetics and genomics 16:45-18:15
Moderator：Vajira Dissanayake（Human Genetics Unit, Faculty of Medicine, University of Colombo, Sri Lanka）
Moderator ：Akihiro Sakurai（Department of Medical Genetics, Sapporo Medical University, Japan）
Wed(4)-SFS5-1 How program evaluation can be applied to genomics education of health professionals ···················· 365
Sylvia Metcalfe（Genetics Education and Health Research, Genetics Theme; Murdoch Childrens Research Insti-
tute - The Royal Children’s Hospital, Australia）
Wed(4)-SFS5-2 Knowledge translation ············································································································· 366
June C. Carroll（Department of Family & Community Medicine, Mount Sinai Hospital, University of Toronto,
Granovsky Gluskin Family Medicine Centre, Canada）
Wed(4)-SFS5-3 A national coordinated approach to workforce transformation ······················································· 367
Michelle Bishop（Genomics Education Programme, Health Education England, Birmingham, UK）
ICHG2016 71
Wed(4)-SFS5-4 Telemedicine in the education of health professionals: Sickle cell disease as an exemplar ·················· 368
Kunal Sanghavi（McKusick-Nathans Institute of Genetic Medicine - Johns Hopkins University - School of Medicine,
Baltimore, MD, USA; New York Mid-Atlantic Consortium for Genetics and Newborn Screening Services (NY-
MAC), Baltimore, Maryland, USA）
Wed(4)-SFS5-5 Application of evidence-based educational practices ····································································· 369
Michael J. Dougherty（American Society of Human Genetics, USA）
Room E (1F)

The new world of RNA biology: Emerging roles of IncRNAs and RNA modifications 10:15-12:15
Convener：Yukio Kawahara（Department of RNA Biology and Neuroscience, Graduate School of Medicine, Osaka University,
Japan）
Convener ：Marcel Dinger（Kinghorn Centre for Clinical Genomics (KCCG) and St Vincent’s Clinical School, Faculty of
Medicine, UNSW, Australia）
Day 4
Wed(4)-CIS24-1 Journeys through Space and Time: Ultra High-Resolution Expression Profiling of Long Noncoding RNAs
······················································································································································ 271
Marcel Dinger（Kinghorn Centre for Clinical Genomics (KCCG) and St Vincent’s Clinical School, Faculty of
Wed(4)-CIS24-2 Primate-specific A-to-I RNA editing shapes the transcriptome ····················································· 272
Marie Öhman（Dept. of Molecular Biosciences, The WennerGren Institute, Stockholm University, Sweden）
Wed(4)-CIS24-3 The expanding landscape of mRNA methylation ········································································ 273
Gideon Rechavi（Cancer Research Center, Sheba Medical Center Tel Aviv University, Israel）
Wed(4)-CIS24-4 Role of RNA modification in cognition and memory ··································································· 275
Timothy Bredy（University of California Irvine, USA）

Initiative on Rare and Undiagnosed Diseases (IRUD) in Japan 12:30-13:30
Chair：Kenjiro Kosaki（Keio University School of Medicine Center for Medical Genetics, Japan）
SRL,Inc．
Initiative on Rare and Undiagnosed Diseases (IRUD) in Japan ······························································ 507

Yoichi Matsubara（National Center for Child Health and Development, Japan）

Cardiac Genetics 15:00-16:30
Moderator：Julie McGaughran（Genetic Health Queensland, Australia）
Moderator ：Euan Ashley（Medicine/Cardiovascular Medicine and Genetics, Stanford University, USA）
Wed(4)-SFS6-1 Cardiovascular Precision Medicine ····························································································· 370

Euan Ashley（Medicine/Cardiovascular Medicine and Genetics, Stanford University, USA）
Wed(4)-SFS6-2 Successes and Challenges from the Cardiac Genetics Clinic ··························································· 371
Julie McGaughran（Genetic Health Queensland, Australia/University of Queensland School of Medicine）
Wed(4)-SFS6-3 From Mendelian syndromes to blockbuster drugs: The PCSK9 story ············································· 372
Catherine Boileau（Institut National de la Santé et de la Recherche Médicale (INSERM) U698, Hôpital Bichat,
France）
Wed(4)-SFS6-4 Genetics of long QT syndrome ································································································· 373
Wataru Shimizu（Department of Cardiovascular Medicine, Nippon Medical School, Japan）
ICHG2016 72

Genetics of Skin Diseases 16:45-18:15
Moderator：Masashi Akiyama（Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan）
Moderator ：Vinzenz Oji（Department of Dermatology, University Hospital Münster, Münsterr, Germany）
Wed(4)-SFS7-1 Keratinization disorders ··········································································································· 375

Vinzenz Oji（Department of Dermatology, University Hospital Münster, Münster, Germany）
Wed(4)-SFS7-2 Mutational analysis of dystrophic epidermolysis bullosa ································································ 377
Eijiro Akasaka（Dermatology, Hirosaki University Graduate School of Medicine, Japan）
Wed(4)-SFS7-3 Vascular malformations: From diagnosis to therapy ····································································· 379
Miikka Vikkula（Human Molecular Genetics, de Duve Institute, Universite catholique de Louvain; Center for
Vascular Anomalies, Division of Plastic Surgery, Cliniques universitaires Saint Luc, Brussels; Walloon Excel-
lence in Lifesciences and Biotechnology WELBIO, de Duve Institute, Universite catholique de Louvain, Brussels,
Belgium/Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques universitaires Saint Luc, Brussels,
Belgium/Walloon Excellence in Lifesciences and Biotechnology WELBIO, de Duve Institute, Universite catholique
de Louvain, Brussels, Belgium）
Wed(4)-SFS7-4 Genetic background of generalized pustular psoriasis ··································································· 380
Day 4
Kazumitsu Sugiura（Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya,
Japan）
Room B-1 (2F)

Mathematical Analyses on Disease Risk Prediction and Socio-Psychological Insights on Personal Genome Services
12:30-13:30
Chair：Naoyuki Kamatani（StaGen Co., Ltd.）
RIKEN GENESIS CO., LTD.
Mathematical Analyses on Disease Risk Prediction and Socio-Psychological Insights on Personal Genome Services
······················································································································································ 508
Takashi Kido（RIKEN GENESIS CO., LTD.）
[WS2.1] Workshop 2
Human Genetics in the Global Health Service: Genetics and Genomics in Developing Countries-Part 1 15:00-16:30
Moderator：Aida B. Falcón de Vargas（Venezuelan Central University, Venezuela）
Wed(4)-WS2.1-1 TBD ··································································································································· 301

Jorge Sequeiros（Centro de Genética Preditiva e Preventiva - CGPP, Instituto de Biologia Molecular e Celular -
IBMC, Portugal）
Wed(4)-WS2.1-1 Global Genetics Services in a University-affiliated Hospital in Madrid, Spain ································· 302
Pablo Lapunzina（INGEMM-Instituto de Genética Médica y Molecular-, Hospital Universitario La Paz; IdiPAZ-
Instituto de Investigación del Hospital Universitario La Paz; CIBERER-Centro de Investigación Biomédica en Red
de Enfermedades Raras, Spain/IdiPAZ-Instituto de Investigación del Hospital Universitario La Paz/CIBERER-
Centro de Investigación Biomédica en Red de Enfermedades Raras）
Wed(4)-WS2.1-2 Genetic Services and Public Policies in Brazil ··········································································· 303
Ida Vanessa Doederlein Schwartz（Federal University of Rio Grande Do Sul, Brazil/BRAZILIAN MEDICAL
GENETICS SOCIETY）
Wed(4)-WS2.1-3 Genetics and Genomics in Mexico ··························································································· 305
Augusto Rojas-Martinez（Centro De Investigacion Y Desarrollo En Ciencias De La Salud, Universidad Autonoma
De Nuevo Leon, Mexico）
Wed(4)-WS2.1-4 How can genomics contribute to population health in developing countries? A public health perspective
from Latin America ························································································································· 306
Victor B. Penchaszadeh（Latin American Bioethics Network, Argentina）
Wed(4)-WS2.1-5 Human Genetics in the Global Health Service
Genetics and Genomics in Developing Countries
LATIN AMERICAN REGION ············································································································ 307
Aida B. Falcón de Vargas（Clinical Genetics Unit, Hospital Vargas de Caracas, Escuela de Medicina JM Vargas,
Universidad Central de Venezuela. Hospital de Clinicas Caracas, Venezuela）
ICHG2016 73
[WS2.2] Workshop 2
Human Genetics in the Global Health Service: Genetics and Genomics in Developing Countries-Part 2 16:45-18:15
Moderator ：Raj Ramesar（MRC Human Genetics Research Unit, Division of Human Genetics, Institute of Infectious Disease
and Molecular Medicine, University of Cape Town and Affiliated Hospitals, South Africa）
Wed(4)-WS2.2-1 Genetic Services in Mainland China, Taiwan, Hong Kong and Macau ·········································· 309
Stephen T.S. Lam（Faculty of Medicine, The Chinese University of Hong Kong, China）
Wed(4)-WS2.2-2 Evolution of Medical Genetics to Genomic Medicine Services: The Situation in South Africa ············· 311
Raj Ramesar（MRC Human Genetics Research Unit, Division of Human Genetics, Institute of Infectious Disease
and Molecular Medicine, University of Cape Town and Affiliated Hospitals, South Africa）
Wed(4)-WS2.2-3 Genetic Services in the Philippines ·························································································· 313
Carmencita D. Padilla（Department of Pediatrics, College of Medicine, University of the Philippines Manila; Insti-
tute of Human Genetics, National Institutes of Health, University of the Philippines Manila; Philippine Genome
Center, University of the Philippines System, Philippines/Institute of Human Genetics, National Institutes of
Health, University of the Philippines Manila/Philippine Genome Center, University of the Philippines System）
Wed(4)-WS2.2-4 Genetics and Genomics: The Collaboration between Belgium and The Democratic Republic of Congo
······················································································································································ 314
Day 4
Thomy JL de Ravel（Centre for Human Genetics, University Hospitals Leuven, KU Leuven, Belgium）
Wed(4)-WS2.2-5 Genetics and genomic in developing countries: the Malaysian experience ····································· 315
Zilfalil Alwi（Universiti Sains Malaysia, Malaysia）
Wed(4)-WS2.2-6 GENOMIC CHALLENGES AND INITIATIVES IN THE FAST EMERGING ECONOMY OF INDIA- A
PARADIGM FOR THE DEVELOPING COUNTRIES ··········································································· 316
Dhavendra Kumar（Institute of Cancer & Genetics Genetics, University Hospital of Wales, Cardiff, UK; Genomin
Policy Unit, University of South Wales, Pontypridd, UK; The Genome Medicine Foundation, Cardiff, UK/Genomic
Policy Unit, University of South Wales, Pontypridd, UK/The Genomic Medicine Foundation (UK), Cardiff）
Room B-2 (2F)

Genetics of Eye Diseases 15:00-16:30
Moderator：Takeshi Iwata（National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center,
Japan）
Moderator ：Rando Allikmets（Ophthalmology, Columbia University; Pathology & Cell Biology, Columbia University, New
York, USA）
Wed(4)-SFS8-1 Finding new genes for syndromic retinitis pigmentosa by next-generation sequencing ······················· 382
Rando Allikmets（Ophthalmology, Columbia University; Pathology & Cell Biology, Columbia University, New
York, USA/Pathology & Cell Biology. Columbia University, New York, USA）
Wed(4)-SFS8-2 Genetic study on early onset high myopia: A story from whole exome sequencing on 298 probands
······················································································································································ 384
Qingjiong Zhang（Zhongshan Ophthalmic Center, Sun Yat-sen University, China）
Wed(4)-SFS8-3 Investigating gene-gene interactions in AMD to better understand disease ····································· 385
Paul N. Baird（Centre for Eye Research Australia, University of Melbourne, Australia）
Wed(4)-SFS8-4 Genes and molecular mechanisms of hereditary retinal diseases in Japanese population ···················· 386
Takeshi Iwata（National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center,
Japan）

Genetics of Skeletal Diseases 16:45-18:15
Moderator：Shiro Ikegawa（Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Science, Japan）
Wed(4)-SFS9-1 Phenotypic Variations in Congenital Limb Malformations ····························································· 387

Wed(4)-SFS9-2 The Genetic Research on OA: Goals and Challenges of the Translational Research ·························· 388
Qing Jiang（Joint Surgery, Drum Tower Hospital, China）
ICHG2016 74
Wed(4)-SFS9-3 Treatment strategies for short stature in achondroplasia ······························································ 390

Hiroshi Kitoh（Orthopaedic Surgery, Nagoya University, Japan）
Wed(4)-SFS9-4 Use of induced pluripotent stem cell technologies in disease modeling of skeletal dysplasia ··············· 392
Noriyuki Tsumaki（Dept. of Cell Growth and Differentiation, Center for iPS Cell Research and Application,
Kyoto University, Japan）
Room C-1 (1F)

Genetics of Kidney Diseases 15:00-16:30
Moderator：Kazushige Hanaoka（Internal Medicine, Division of Nephrology and Hypertension, The Jikei University, School
of Medicine, Japan）
Wed(4)-SFS10-1 Recent advancement of genetics and therapy in renal genetic diseases ········································· 393
Koichi Nakanishi（Pediatrics, Wakayama Medical University, Japan）
Day 4
Wed(4)-SFS10-2 Genetics and pathophysiology in Fabry nephropathy ·································································· 395
David G. Warnock（University of Alabama at Birmingham, USA）
Wed(4)-SFS10-3 What Makes Tubules Turn Cystic? ·························································································· 396
Gregory Germino（National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National
Institutes of Health, USA; Johns Hopkins School of Medicine, USA/Johns Hopkins School of Medicine, USA）
Wed(4)-SFS10-4 Current strategies for curing autosomal dominant polycystic kidney disease (ADPKD) ··················· 397
Kazushige Hanaoka（Internal Medicine, Division of Nephrology and Hypertension, The Jikei University, School
Room C-2 (1F)
[WS3] Workshop 3
Current Issues of Medical Genetics in Asia 15:00-16:30
Moderator：Poh-San Lai（National University of Singapore, Singapore）
Moderator ：Jin-Sung Lee（Department of Clinical Genetics, Yonsei University College of Medicine, Korea）
Wed(4)-WS3-1 Genomic Medicine and Medical Genetics Service in Vietnam ························································· 317
Vu Chi Dũng（Department of Medical Genetics, Metabolism and Endocrinology, National Hospital of Pediatrics,
Hanoi, Vietnam）
Wed(4)-WS3-2 National genetic screening and molecular testing program in Thailand ··········································· 319
Suthat Fucharoen（Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Salaya
Campus, Nakornpathom, Thailand）
Wed(4)-WS3-3 Medical genetics services in Malaysia: Challenges and the way forward ··········································· 320
Meow-Keong Thong（Genetics and Metabolism Unit, Department of Paediatrics, Faculty of Medicine, University
of Malaya, Kuala Lumpur, Malaysia）
Wed(4)-WS3-4 Genetic Testing in China ·········································································································· 321
Wed(4)-WS3-5 Basic and Expanded Newborn Screening: Setting the Stage for Low Income and Middle Income Countries
······················································································································································ 322
Carmencita D. Padilla（Department of Pediatrics,College of Medicine, University of the Philippines Manila; Insti-
tute of Human Genetics, National Institutes of Health, University of the Philippines Manila; Newborn Screening
Reference Center, National Institutes of Health, University of the Philippines Manila, Philippines/Institute of Hu-
man Genetics, National Institutes of Health, University of the Philippines Manila/Newborn Screening Reference
Center, National Institutes of Health, University of the Philippines Manila）
Wed(4)-WS3-6 Clinical Genetics in Japan ········································································································· 323
Yoshimitsu Fukushima（Ex-President, The Japan Society of Human Genetics; Professor, Department of Medical
ICHG2016 75
[WS4] Workshop 4
HUGO-PAPGI (Pan-Asian Population Genomics Initiative) 16:45-18:15
Moderator：Sumio Sugono（Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University
of Tokyo, Japan）
Moderator ：Poh-San Lai（National University of Singapore, Singapore）
Wed(4)-WS4-1 HUGO-PAPGI (Pan-Asian Population Genomics Initiative) update ················································· 324

Jong Bhak（Biomedical Engineering, UNIST, Korea）
Wed(4)-WS4-2 Spatially explicit models and whole genome analysis for reconstructing the colonisation of Asia
······················································································································································ 326
Anders Eriksson（Integrative Systems Biology Lab, Division of Biological and Environmental Sciences & Engi-
neering, King Abdullah University of Science and Technology, Saudi Arabia/Department of Zoology, University
of Cambridge, UK）
Wed(4)-WS4-3 Population structure and admixture history of East Asian populations ············································ 327
Shuhua Xu（CAS-MPG Partner Institute for Computational Biology (PICB), China）
Wed(4)-WS4-4 Genomic analyses reveal insights into indigenous diversity and divergence in South East Asia ············· 328
Maude Phipps（Jeffrey Cheah School of Medicine & Health Sciences, Monash University Malaysia）
Day 4
Wed(4)-WS4-5 Complete sequencing and characterization of three human genomes from Indian subcontinent ············· 329
Harish Padh（Sardar Patel University, India）
Wed(4)-WS4-6 Search for disease-associated genes by ethnic specific SNP array and genome-wide imputation based on large-
scale whole-genome sequencing: Application to cold medicine related Stevens-Johnson syndrome (CM-SJS) with
severe ocular complications (SOC) ···································································································· 331
Katsushi Tokunaga（Department of Human Genetics, Graduate School of Medicine, The University of Tokyo,
Japan）
Room D (1F)

Autosomal Dominant Polycystic Kidney Disease 12:30-13:30
Chair：Kazushige Hanaoka（Jikei University, Japan）
Otsuka Pharmaceutical Co., Ltd.
Autosomal Dominant Polycystic Kidney Disease ·················································································· 509

Kazushige Hanaoka（Jikei University, Japan）
Autosomal Dominant Polycystic Kidney Disease ·················································································· 510
Gregory G. Germino（National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National
Institutes of Health, USA; Johns Hopkins School of Medicine, USA）

UCSC Genome Browser - A platform for variant analysis 16:45-18:15
Moderator：Robert Kuhn（Center for Biomolecular Science & Engineering, Jack Baskin School of Engineering, University
of California Santa Cruz, USA）
UCSC Genome Browser - A platform for variant analysis ······································································ 398
Sakura (1F)

Genetic Counseling 1 15:00-16:30
Moderator：Anita Y. Kinney（Cancer Population Sciences, University of New Mexico Comprehensive Cancer Center, USA）
Moderator ：Hironao Numabe（Genetic Counselling Course, Ochanomizu University, Japan）
ICHG2016 76
Wed(4)-SFS12-1 Expanding Reach and Access to BRCA1/2 Counseling and Testing: One-year Follow-up Outcomes of a
Randomized Non-Inferiority Trial Comparing Telephone and In-Person Delivery ······································ 399
Anita Y Kinney（Cancer Population Sciences, University of New Mexico Comprehensive Cancer Center, USA）
Wed(4)-SFS12-2 Trend analysis of the cases received genetic counseling for HBOC in the Shinshu University Hospital
······················································································································································ 400
Asumi Iesato（Division of Breast and Endocrine Surgery, Department of Surgery, Shinshu University School of
Medicine, Japan）
Wed(4)-SFS12-3 Genetic counselling for a case with breast cancer who underwent a whole-exome sequencing in a private
company ······································································································································· 401
Yusuke Ebana（Life Science and Bioethics Research Center, Tokyo Medical and Dental University, Japan）
Wed(4)-SFS12-4 Exploring the return of precision oncology results and the implementation of genetic counselling in Singapore
······················································································································································ 402
Yasmin M Bylstra（Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singa-
pore/Inherited Cardiac Clinic, National University Heart Centre, Singapore/Singapore Health Services, Singa-
pore）
Wed(4)-SFS12-5 WISKOTT-ALDRICH SYNDROME: Genetic counseling issues in a large Malaysian family ············· 403
Premala Muthukumarasamy（Genetics and Metabolism Unit, Paediatric Department, University Malaya Medical
Centre, Malaysia）
Day 4
Wed(4)-SFS12-6 A review of reproductive decisions made by patients with vascular Ehlers-Danlos syndrome ············· 404
Jessica M Bowen（Ehlers-Danlos Syndrome National Diagnostic Service, UK）

Genetic Counseling 2 16:45-18:15
Moderator：Rosalind J. Hastings（CEQAS, Oxford University Hospitals NHS Foundation Trust, UK）
Moderator ：Shinji Kosugi（Department of Medical Ethics/Medical Genetics, Kyoto University School of Public Health,
Japan）
Wed(4)-SFS13-1 Genomic genetic counselling: same but different ······································································ 405

Gemma Brett（Victorian Clinical Genetics Services, Australia/Melbourne Genomics Health Alliance）
Wed(4)-SFS13-2 Genetic counseling: when the east meets the west, can it be modeled? ······································ 406
Anne C Tsai（Pediatics/Genetics, University of Colorado School of Medicine, USA）
Wed(4)-SFS13-3 Comparison of two selection strategies based on genetic information when only small sample size is available
···················································································································································· 407
Juan Wang（Statistical Genetics, Center for Genomic Medicine, Graduate School of Medicine Kyoto University,
Japan）
Wed(4)-SFS13-4 External Quality Assessment of Genetic Counselling: experiences with the first pilot assessment
······················································································································································ 408
Rosalind J Hastings（CEQAS, Oxford University Hospitals NHS Foundation Trust, UK）
Wed(4)-SFS13-5 To assess knowledge and attitudes of Indian patients with inherited retinal disease (IRD) towards genetic
testing and counseling ····················································································································· 409
Siddhita S. Nare（Research Department, Aditya Jyot Foundation for Twinkling Little Eyes, India）
Wed(4)-SFS13-6 "Living with Down Syndrome" -Systematic approach of a communication support tool for notification of
Down syndrome ····························································································································· 410
Hiroko Kondo（Yokohama Project, Japan）
Room I (2F)

Moderator：Tomas Kirchhoff（NYU Cancer Institute, New York University School of Medicine, USA）
Moderator ：Mariko Eguchi（Department of Pediatrics, Ehime University Graduate School of Medicine, Japan）
Wed(4)-SFS14-1 Immunomodulatory expression quantitative trait loci (eQTLs) and their role in modulation of cutaneous
melanoma (CM) survival and immunotherapy response ······································································· 411
Tomas Kirchhoff（Perlmutter Cancer Center, New York University School of Medicine, USA/Departments of
Population Health and Environmental Medicine, New York University School of Medicine/The Interdisciplinary
Melanoma Cooperative Group, New York University School of Medicine）
ICHG2016 77
Wed(4)-SFS14-2 Identification of a lung cancer growth factor, LASEP1 as a serological and prognostic biomarker and a
therapeutic target ·························································································································· 412
Atsushi Takano（Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The
University of Tokyo, Japan/Departments of Medical Oncology and Cancer Center, Shiga University of Medical
Science）
Wed(4)-SFS14-3 Germline variant analysis and ancestry inference of 2,153 high-depth whole genomes of patients afflicted
with diverse cancers ······················································································································· 413
Francisco M De La Vega（Genetics, Stanford University, USA/TOMA Biosciences Inc., Foster City, CA USA）
Wed(4)-SFS14-4 Alternative splicing as biomarkers for DNA damage response: A novel mechanism of cancer progression
through a single-nucleotides binding/multi-functional protein, FIR ························································· 414
Kazuyuki Matsushita（Department of Molecular Diagnosis, Chiba University Graduate School of Medicine,
Japan/Chiba University Hospital, Division of Laboratory Medicine/Chiba University Hospital, Division of Clinical
Genetics）
Wed(4)-SFS14-5 Targeted Next-Generation Sequencing Identifies a Recurrent Mutation in MCPH1 Associating with Breast
Cancer Susceptibility ······················································································································ 415
Katri Pylkas（University of Oulu, Finland/Northern Finland Laboratory Centre NordLab Oulu）
Wed(4)-SFS14-6 HMGA2 as a potential molecular target in MLL-AF4 positive infant acute lymphoblastic leukemia
Day 4
······················································································································································ 416
Mariko Eguchi（Department of Pediatrics, Ehime University Graduate School of Medicine, Japan/Division of
Medical Genetics, Ehime University Hospital）

Moderator：Gong-Hong Wei（Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Finland）
Moderator ：Yoshinori Murakami（Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo,
Japan）
Wed(4)-SFS15-1 Towards systems understanding of prostate cancer GWAS discoveries ········································· 417
Gong-Hong Wei（Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Fin-
land）
Wed(4)-SFS15-2 Population-based assessment of HOXB13 gene for prostate cancer risk, progression and survival of Finnish
men ············································································································································· 418
Csilla Sipeky（Medical Biochemistry and Genetics, University of Turku, Finland）
Wed(4)-SFS15-3 Whole exome sequencing identifies genomic drivers of local lymph node metastasis in oral cancer
······················································································································································ 419
Nidhan K Biswas（Cancer Genomics Group, National Institute of Biomedical Genomics, India）
Wed(4)-SFS15-4 Generation of high-quality DNA from formalin-fixed paraffin embedded tissue for clinical grade whole genome
sequencing: a Genomics England Pilot Study ······················································································ 420
Pauline Robbe（Oxford Molecular Diagnostics Centre, University of Oxford, Oxford, UK）
Wed(4)-SFS15-5 Dual roles of a cell adhesion molecule, CADM1, in human oncogenesis and its application to diagnosis and
treatment of cancer ························································································································ 421
Yoshinori Murakami（Division of Molecular Pathology, Institute of Medical Sicence, The University of Tokyo,
Japan）
Wed(4)-SFS15-6 Rare mutations in base excision repair (BER) pathway genes implicated in breast cancer susceptibility
······················································································································································ 422
Ian Campbell（Peter MacCallum Cancer Centre, Australia）
Room J (2F)

Clinical Genetics 1 15:00-16:30
Moderator：Eric Legius（Department of Human Genetics, University of Leuven, Belgium）
Moderator ：Tomoki Kosho（Department of Medical Genetics, Shinshu University School of Medicine, Japan）
Wed(4)-SFS16-1 NF1 mutation analysis in segmental neurofibromatosis. New diagnostic technique and implications for
genetic counseling ··························································································································· 423
Eric Legius（Department of Human Genetics, Catholic University of Leuven, Belgium）
ICHG2016 78
Wed(4)-SFS16-2 Pathophysiological investigation of Ehlers-Danlos syndrome caused by CHST14/D4ST1 deficiency using iPS
cells and knockout mice ·················································································································· 424
Tomoki Kosho（Division of Clinical and Molecular Genetics, Shinshu University Hospital, Japan/Department of
Medical Genetics, Shinshu University School of Medicine）
Wed(4)-SFS16-3 A child presenting distinct phenotype in severe alternating hemiplegia with a novel ATP1A3 mutation
······················································································································································ 425
Naoko Ishihara（Pediatrics, Fujita Health University School of Medicine, Japan）
Wed(4)-SFS16-4 Severe acne scar of the neck in pseudoxanthoma elasticum: Acne as a modifier? ························· 426
Naoki Oiso（Department of Dermatology, Kinki University Faculty of Medicine, Japan）
Wed(4)-SFS16-5 Clinical and demographic evaluation of a holoprosencephaly cohort from the Kyoto Collection of human
embryos ········································································································································ 427
Yu Abe（Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health,
USA）
Wed(4)-SFS16-6 The Clinical Geneticist as an Expert Witness in Court ······························································ 428
Michael A Patton（Medical Genetics, St Georges University of London, UK）
Day 4
Clinical Genetics 2 16:45-18:15
Moderator：Richard H. Finnell（Dell Pediatric Research Institute, The University of Texas at Austin, USA）
Moderator ：Atsushi Watanabe（Division of Clinical Genetics„ Nippon Medical School Hospital, Japan）
Wed(4)-SFS17-1 Hypophosphatasia diagnosed during childhood in Japan ···························································· 429

Atsushi Watanabe（Division of Clinical Genetics, Nippon Medical School Hospital, Japan/Department of Bio-
chemistry and Molecular Biology, Nippon Medical School）
Wed(4)-SFS17-2 Withdrawn ··························································································································· 430
Wed(4)-SFS17-3 A missense mutation of the SLCO2A1 gene underlies a complete type of pachydermoperiostosis in 3 Japanese
families ········································································································································· 431
Hironori Niizeki（Dermatology, National Center for Child Health and Development, Japan）
Wed(4)-SFS17-4 Clinical and experimental evidence for OTX2 dosage sensitivity in individuals with Oculo-Auriculo-Vertebral
Spectrum ······································································································································ 432
Tiong Yang Tan（Victorian Clinical Genetics Services, Australia/Murdoch Childrens Research Institute, Mel-
bourne, Australia/Department of Paediatrics, University of Melbourne, Melbourne, Australia）
Wed(4)-SFS17-5 Mutations in Human Capicua Gene Found in Patients with Cerebral Folate Deficiency Syndrome and in
Patients with Spina Bifida ··············································································································· 433
Richard H Finnell（Nutritional Sciences and Chemistry, The University of Texas at Austin, USA）
Wed(4)-SFS17-6 A New Subtype of Multiple-Synostoses Syndrome is caused by a Gain-of-Function Mutation in GDF6 that
Enhances BMP Signaling during Skeletal Development ······································································· 434
Jian Wang（Department of Medical Genetics, Shanghai Children Medical Center, Shanghai Jiaotong University
School of Medicine, China）
Room K (2F)

Complex Traits Disorders 15:00-16:30
Moderator：Jeffery M. Vance（John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine,
USA）
Moderator ：Tatsushi Toda（Division of Neurology / Molecular Brain Science, Kobe University Graduate School of Medicine,
Japan）
Wed(4)-SFS18-1 Full Mitochondrial Genome Sequencing Reveals that the 12S rRNA Mitochondrial sub-unit is Involved in
Migraine Susceptibility in the Genetically Isolated Norfolk Island Population ·········································· 435
Shani Stuart（Genomics Research Centre, Queensland University of Technology, Australia）
Wed(4)-SFS18-2 Genome-wide association meta-analysis of intracranial aneurysm identifies 8 previously unknown loci and
genes underlying the association ······································································································ 436
Katsuhito Yasuno（Neurosurgery, Yale University School of Medicine, USA）
ICHG2016 79
Wed(4)-SFS18-3 ABC transporters confer risk in Parkinson Disease ···································································· 437

Jeffery M. Vance（John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine,
USA/Dr. John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of
Medicine）
Wed(4)-SFS18-4 Exome Association study and 2nd SNP-GWAS of Parkinson’s disease in Japan ·························· 438
Wataru Satake（Div Neurol/Mol Brain Sci, Kobe Univ, Japan）
Wed(4)-SFS18-5 A multi-step approach identifies regions on chromosomes 3 and 17 as highly associated with Multiple Sclerosis
in Italian population ······················································································································· 439
Melissa Sorosina（Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology,
Division of Neuroscience, San Raffaele Scientific Institute, Italy）
Wed(4)-SFS18-6 Gene Discovery in Autism Using a Quantitative Autism Score ···················································· 440
Michael Cuccaro（Dr. John. T. Macdonald Department of Human Genetics, University of Miami Miller School of
Medicine, USA/John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine,
Miami, FL）

Molecular Basis of Mendelian Disorders 16:45-18:15
Day 4
Moderator：Mark J. Cowley（Kinghorm Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, Aus-
tralia）
Moderator ：Hirotomo Saitsu（Department of Biochemistry, Hamamatsu University School of Medicine, Japan）
Wed(4)-SFS19-1 Developing WGS as a First Line Diagnostic Test for Patients with Mendelian Disorders ················ 441
Mark J Cowley（Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Australia/St
Vincent’s Clinical School, University of New South Wales, Darlinghurst, NSW, Australia）
Wed(4)-SFS19-2 Clinical efficiency of exome sequencing as a service for diagnosing hereditary diseases in Russia
······················································································································································ 442
Fedor A Konovalov（Genomed Ltd., Russia/Research Centre for Medical Genetics, Russia）
Wed(4)-SFS19-3 Gene Mapping in the Finnish National Collection of Balanced Translocations and Inversions ············· 443
Teppo Varilo（Department of Medical Genetics, University of Helsinki, Finland/National Institute for Health and
Welfare, Helsinki, Finland）
Wed(4)-SFS19-4 Defining Genetic Causes of Hereditary Spastic Paraplegia with Whole Genome Sequencing ············· 444
Kishore R Kumar（Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Aus-
tralia/Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Australia）
Wed(4)-SFS19-5 Defective RNA metabolism is involved in Hereditary Spastic Paraplegia ······································ 445
Rebecca Schule（Hertie Institute for Clinical Brain Research, University of Tubingen, Germany/Hussman Institute
for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida）
Wed(4)-SFS19-6 The molecular genetic mechanism of Fahr’s disease and its prevention and treatment ················· 446
Jing Yu Liu（Key Laboratory of Molecular Biophysics of the Ministry of Education, School of Life Science and
Technology, Huazhong University of Science and Technology, China）
Event Hall (1F)
Poster Session
Statistical Genetics and Genetic Epidemiology 13:45-14:45
Wed(4)-P-1 Effect sizes in genetic-epidemiological studies of complex diseases ······················································ 1145

Michael Nothnagel（Cologne Center for Genomics, University of Cologne, Germany）
Wed(4)-P-3 Comparison of methods for meta-analysis of binary traits with linear mixed models ······························ 1145
James P Cook（Department of Biostatistics, University of Liverpool, UK）
Wed(4)-P-4 High-density Association Mapping and Interaction Analysis of PLA2R1 and HLA Regions with Idiopathic Mem-
branous Nephropathy in Japanese ····································································································· 1146
Myo Thiri（Department of Human Genetics, School of International Health, The University of Tokyo, Japan）
Wed(4)-P-5 Familial aggregation of Dupuytren’s disease ···················································································· 1147
Laetitia Michou（CHU de Quebec-Laval University, Canada/Division of Rheumatology, Department of Medicine,
Laval University and CHU de Quebec Research Centre, Quebec, QC, Canada）
ICHG2016 80
Wed(4)-P-6 Autosomal SNPs Genotyping for Identification of Missing Casualties ··················································· 1147
Jung-Hyun Park（Division of DNA Analysis, Scientific Investigation Laboratory, Criminal Investigation Command,
Ministry of National Defense, Korea, South）
Wed(4)-P-7 Understanding gene expression changes in Systemic Lupus Erythematosus through a systems approach
······················································································································································ 1148
Tingyou Wang（The University of Hong Kong, Hong Kong）
Wed(4)-P-8 Identification of predisposing genes in severe neural tube defects by whole exome sequencing in multiplex families
······················································································································································ 1148
Philippe Lemay（Universite de Montreal, Canada）
Wed(4)-P-9 Multivariate binary model for powerfull disease mapping ··································································· 1149
Susana Eyheramendy（Statistics Department, Pontificia Universidad Catolica de Chile, Chile）
Wed(4)-P-10 A novel computational tool for genome-to-phenotype prediction using VaDE, a manually-curated database of
reproducible associations between various traits and genomic polymorphisms ·········································· 1149
Tadashi Imanishi（Department of Molecular Life Science, Tokai University School of Medicine, Japan）
Wed(4)-P-11 Comparison of different approaches to gene-based association analysis of complex traits ····················· 1150
Nadezhda M. Belonogova（Institute of Cytology & Genetics, Russia）
Day 4
Wed(4)-P-12 Smooth-threshold multivariate genetic prediction with unbiased model selection ································· 1150
Masao Ueki（Biostatistics Center, Kurume Unviersity, Japan）
Wed(4)-P-13 Genetic Epidemiology of Breast Cancer in a Less Developed District Bahawalnagar, Pakistan ·············· 1151
Shamsa Kanwal（Human Genetics and Molecular Biology Department, University of Health Sciences, Pakistan）
Wed(4)-P-14 Detecting gene-gene interactions for survival phenotypes using a unified multifactor dimensionality reduction
analysis ·········································································································································· 1152
Taesung Park（Statistics, Seoul National University, Korea, South）
Wed(4)-P-15 Risk factors, Insulin-Like Growth Factor-1 gene polymorphism and Breast Cancer Risk among Omani Women:
A Case-Control Study ······················································································································ 1152
Kawthar Alajmi（Family Medicine and Public Health, Sultan Qaboos University, UK/University of Manchester）
Wed(4)-P-16 Detecting and simulating heritability due to large-scale, cumulative epistatic effects ···························· 1153
Jacob B. Hall（Department of Epidemiology and Biostatistics, Institute for Computational Biology, USA）
Wed(4)-P-17 A comprehensive evaluation of family-based association tests for qualitative traits; usability, type-I error and
power ············································································································································ 1153
Tero S Hiekkalinna（Genomics and Biomarkers Unit, National Institute for Health and Welfare, Finland/Institute
for Molecular Medicine Finland FIMM）
Wed(4)-P-18 Properties of Global and Local Ancestry Adjustments in Genetic Association Tests ····························· 1154
Eden R. Martin（Hussman Institute for Human Genomics, University of Miami, USA）
Wed(4)-P-19 Gene-Environment Interactions using time to event is more effective than using case-control approach: VTE
case study ······································································································································ 1155
Mariza Andrade（Health Sciences Research, Mayo Clinic, USA）
Wed(4)-P-20 Gene-gene interaction among genes on transforming growth factor-β signaling pathway for non-syndromic cleft
lip with or without cleft palate in Chinese populations ········································································· 1155
Zhuqing Wang（Peking University, China）
Wed(4)-P-21 Exploring Disease Co-inheritance Patterns in High Quality Pedigrees from Collection of Family Health History
Obtained in a Primary Care Setting ··································································································· 1156
Lori A Orlando（Medicine, Duke University, USA）
Wed(4)-P-22 Evidence of Gene-Gene Interaction among Cell-Cell Adhesion Genes for Nonsyndromic Cleft Palate in Chinese
······················································································································································ 1157
Yuan Yuan（Department of Epidemiology and Bio-statistics, Peking University Health Science Center, Beijing,
China）
Wed(4)-P-23 A workbench for family-based genetic analysis using next-generation DNA sequencing data ················· 1157
Sungyoung Lee（Interdisciplinary Program in Bioinformatics, Seoul National University, Korea, South）
Wed(4)-P-23A Targeted sequencing of Late-Onset Alzheimer Disease Loci Identifies Genomic Regions with Potential Func-
tional Variants ································································································································ 1158
Margaret Pericak-Vance（John P. Hussman Institute for Human Genomics, University of Miami, USA）
ICHG2016 81
Poster Session
Genome structure, variation and function 13:45-14:45
Wed(4)-P-24 The functional RAI1-interactome analysis: Implications for molecular pathogenesis of Smith-Magenis syndrome
······················································································································································ 1159
Shu-Ting Chen（Molecular and Cellular Biosciences, The University of Tokyo, Japan）
Wed(4)-P-25 Whole-exome sequencing enables copy-number variation analysis in the lower kilobase range ··············· 1159
Maria Schotik（Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany/Cologne Graduate
School of Ageing Research, Cologne, Germany/Center for Molecular Medicine Cologne (CMMC), Cologne, Ger-
many/Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne,
Germany）
Wed(4)-P-26 Gene Expression Profiling of Motor Neuron in Motor Neuron-Specific 26S Proteasome Conditional Knockout
Mice ·············································································································································· 1160
Tomonori Hoshino（Department of Neurology, Graduate School of Medicine, Kyoto University, Japan）
Wed(4)-P-27 Signature microRNA expression patterns identified in Williams syndrome ·········································· 1161
Masatoshi Nakata（Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Japan）
Day 4
Wed(4)-P-28 Sex-specific eQTLs and Their Implications in Gene Expression Regulation and Disease ························ 1161
Jiangshan Shen（HKU, Hong Kong）
Wed(4)-P-29 Effects of topical mupirocin on the composition and abundance of the nasal microbiome in healthy carriers with
Staphylococcus aureus ····················································································································· 1162
Su-Hsun Liu（Chang Gung University, Taiwan/Chang Gung Memorial Hospital）
Wed(4)-P-30 Inherited genes without SNP defects (that could predispose a person to diseases), is the single most key to
longevity among 95+ individuals ······································································································· 1162
Girish J Kotwal（Medicine, UMass Medical School, USA）
Wed(4)-P-31 Identification of OCTN2 variants and their association with phenotypes of Crohn’s disease ················· 1163
Eun Young Kwon（Department of Pharmacology, Tissue Injury Defense Research Center, School of Medicine,
Ewha Womans University, Korea, South）
Wed(4)-P-32 Diagnostic Yield in Autism Spectrum Disorder using Illumina Dense SNP Array and Association of CNVs in
ASD/ID genes and ASD-subphenotyes ······························································································· 1163
Sulman Basit（Taibah University Almadinah, Saudi Arabia/Quaid-i-Azam University Islamabad）
Wed(4)-P-33 The autism-associated long noncoding RNA MSNP1AS regulates a network of genes involved in neuronal process
stability ·········································································································································· 1164
Jessica DeWitt（University of Southern California, USA）
Wed(4)-P-34 Anti-dsDNA IgG antibodies down-regulated mesangial cells miR-10a expression and increased CREB1 gene
expression inducing cell proliferation ·································································································· 1164
Pattarin Tangtanatakul（Chulalongkorn University, Thailand）
Wed(4)-P-35 Plasma miRNA Expression Profiles in Rheumatoid Arthritis Associated Interstitial Lung Disease ············· 1165
Shomi Oka（Faculty of Medicine, University of Tsukuba, Japan/Sagamihara Hospital, National Hospital Organi-
zation）
Wed(4)-P-36 Analysis of copy number alteration andclinicopathological features in breast cancer ···························· 1166
Fumi Taira（Breast Surgery and Oncology, Juntendo University, Japan/Division of Molecular Pathology, The
Institute of Medical Science, The Univ. of Tokyo）
Wed(4)-P-37 Identification of the genes regulated by ZFAT in T cells through ChIP-seq analysis ····························· 1166
Keiko Doi（Department of Cell Biology, Faculty of Medicine, Fukuoka University, Japan/Central Research Institute
for Advanced Molecular Medicine, Fukuoka University）
Wed(4)-P-38 The evaluating of methods for the inference of ecological interactions in bacterial communities using horizontal
gene transfer events ························································································································· 1167
Ben-Yang Liao（Intitute of Population Health Sciences, National Health Research Institutes, Taiwan）
Wed(4)-P-39 One cannot presume siblings with similar clinical findings result from the same underlying genetic cause!-familial
genome instability or leaky proof reading mechanism as a genetic predisposition? ·································· 1167
Anne Chun-hui Tsai（Pediatrics/Genetics and Metabolism, University of Colorado School of Medicine,
USA/Division of Genetics and Metabolism, OHSU）
Wed(4)-P-41 Association analysis between the clinical factors of primary open-angle glaucoma and the risk allele of CDKN2B-
AS1 variant ···································································································································· 1168
Yoko Ikeda（Ophthalmology, Kyoto Prefectural University of Medicine, Japan）
ICHG2016 82
Wed(4)-P-42 The detection of transposon sequences in RNA sequence ································································ 1168

Shiro Yamada（Department of Human Genetics, National Institute of Genetics, Japan/Children Clinic Sone,
Takasaki, Japan）
Wed(4)-P-43 Microelectrode array captures seizure-like activity due to down-regulation of microRNA-128 ················ 1169
K. Melodi McSweeney（Genetics; Institute for Genomic Medicine, Columbia University, USA/University Program
in Genetics and Genomics; Duke University, Durham NC 27708）
Wed(4)-P-44 Persistent and stability of circulating miRNAs in postmortem blood sample ······································· 1169
Kornkiat Vongpaisarnsin（Forensic Medicine, Faculty of Medicine, Chulalongkorn University, Thailand）
Wed(4)-P-45 Functional partitioning of local and distal gene expression regulation in human tissues ························ 1170
Xuanyao Liu（Harvard Chan School of Public Health, USA）
Wed(4)-P-46 Correlation of the expression with FLT3 and RAC1 with the leukaemic fusion gene AML1-MTG8 in AML M2
······················································································································································ 1170
Adam Azlan（Faculty Of Applied Sciences, Universiti Teknologi MARA, Malaysia）
Wed(4)-P-47 Improving smear-negative tuberculosis diagnosis through gene expression signatures ··························· 1171
Nusara Satproedprai（Department of Medical Sciences, Medical Life Science Institute, Thailand）
Wed(4)-P-48 Characterization of HTRA1 regulatory element in Patients with Exudative Age-Related Macular Degeneration.
Day 4
···················································································································································· 1171
Daisuke Iejima（National Institute of Sensory Organs, National Hospital Organizaiton Tokyo Medical Center,
Japan）
Wed(4)-P-49 Genetic alteration in the Exon 3 of SEPTIN12 gene in infertile men referred to Royan Institute ············· 1172
Amir Parhizkar（Department of Biology, Science and Research Branch, Islamic Azad University, Tehran,
Iran/Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive
Biomedicine, ACECR, Tehran, Iran）
Wed(4)-P-50 Global transcriptome profiling during acute anaphylactic reaction reveals involvement of complex networks of
signaling, interactions and recruitment of distinct immune cell types ······················································ 1173
Matija Rijavec（University Clinic of Respiratory and Allergic Diseases Golnik, Slovenia）
Wed(4)-P-51 Expression profiling of long non-coding RNA ecCEBPA in cell lines and gastric cancer tissues ·············· 1173
Mojdeh Nasrollahzadeh Khakiani（genetics and molecular biology, Isfahan university of medical science,
Iran/Applied Physiology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran）
Wed(4)-P-52 Regulation of human natural killer cells by genetically variable and conserved receptor systems - adenoviruses
target a conserved receptor-ligand axis for immune escape ···································································· 1174
Makoto Yawata（Pediatrics, National University of Singapore, Singapore/Singapore Institute for Clinical Sciences）
Wed(4)-P-53 Methyleugenol DNA-Adducts in Human Liver are Associated with SULT1A1 Copy Number Variations
······················································································································································ 1175
Roman Tremmel（Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Ger-
many/University Tuebingen, Tuebingen, Germany）
Wed(4)-P-54 Homozygous deletions of non-coding DNA sequences in Autism spectrum disorder ····························· 1175
Klaus E Schmitz-Abe（Division of Genetics and Genomics, Harvard Medical School and Children Hospital Boston,
USA/Department of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA/Manton Center for
Orphan Disease Research/Broad Institute of Harvard and MIT, Cambridge, MA, USA）
Wed(4)-P-55 Genome-wide landscape of insersions/deletions with a functional impact on transcription factor binding sites
······················································································································································ 1176
Francesco Lescai（Department of Biomedicine, Aarhus University, Denmark/iSEQ - Centre for Integrative Se-
quencing, Aarhus C, Denmark/iPSYCH - Lundbeck Foundation Initiative for Integrative Psychiatric Research,
Denmark）
Wed(4)-P-56 Genetics of gut microbiome composition in healthy individuals ························································· 1176
Alexandra Zhernakova（Department of Genetics, University of Groningen, University Medical Center Groningen,
Netherlands）
Wed(4)-P-57 Genetic control of ADCY3 and IRF4 expression is critical for the Mycobacterium leprae triggered immune
response ········································································································································· 1177
Jeremy Manry（Human Genetics, Program in Infectious Diseases and Immunity in Global Health, The Research
Institute of the McGill University Health Centre, Montreal, Quebec, Canada/McGill International TB Centre
and Departments of Medicine and Human Genetics, McGill University, Montreal, Quebec, Canada）
Wed(4)-P-58 Rare variant discovery by deep whole-genome sequencing of thousands Japanese individuals and bioinformatics
···················································································································································· 1178
Masao Nagasaki（Tohoku Medical Megabank Organization, Tohoku University, Japan/Graduate School of
Medicine, Tohoku University/Graduate School of Information Sciences, Tohoku University）
ICHG2016 83
Wed(4)-P-59 Coordinated Regulation of DNMT3B, PTEN, and TET3 via a Competing Endogenous RNA (ceRNA) Network
······················································································································································ 1178
Kenneth Anthony R Roquid（National Institute of Molecular Biology and Biotechnology, University of the
Philippines-Diliman, Philippines）
Wed(4)-P-60 High-throughput sequencing method of the KIR haplotype for integrated HLA-KIR genotyping approach for
clinical applications ························································································································· 1179
Kazuyoshi Hosomichi（Department of Bioinformatics and Genomics, Graduate School of Medical Sciences,
Kanazawa University, Japan）
Wed(4)-P-61 Preliminary Investigations on the Putative Role of the Antisense Transcripts DYT3 and INGX in X-linked
Dystonia Parkisonism ······················································································································· 1179
Jian Kenzo O. Leal（National Institute of Molecular Biology and Biotechnology, Philippines）
Wed(4)-P-62 The CRNDE lncRNA instigates distinct programs of stemness, chemoresistance, proliferative capacity and in-
vasiveness ······································································································································ 1180
Jose Lorenzo M. Ferrer（Disease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular
Biology and Biotechnology, University of the Philippines Diliman, Philippines）
Wed(4)-P-63 S100PBP, TET3 and their shared microRNA response elements (MREs) suggest existence of a competitive
endogenous RNA (ceRNA) network ··································································································· 1180
Day 4
Lech Havel O. Tizon（National Institute of Molecular Biology and Biotechnology, University of the Philippines -
Wed(4)-P-64 The effect of high copy number of salivary amylase gene on adiposity in Korean ································ 1181
Ho-Young Son（Department of Biochemistry, Seoul National University college of medicine, Korea, South）
Wed(4)-P-65 Ribosomal RNA deplection from Single Cell RNA Sequencing ·························································· 1181
Colin A Baron（Qiagen, Germany）
Wed(4)-P-66 Functional characterization of long non-coding RNAs in FANTOM6 ················································· 1182
Michiel de Hoon（RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama,
Japan）
Poster Session
Molecular Basis of Mendelian Disorders 2 13:45-14:45
Wed(4)-P-67 ROCK inhibition is essential during in vitro neurogenesis and promotes phenotypic rescue of human iPSCs-derived
neurons with Oligophrenin-1 loss of function ······················································································· 1183
Ginevra Zanni（Depatment of Neurosciences, OPBG, Italy）
Wed(4)-P-68 Epidermodysplasia verruciformis lacking TMC6 and TMC8 mutations ·············································· 1183
Tokimasa Hida（Department of Dermatology, Sapporo Medical University School of Medicine, Japan）
Wed(4)-P-69 Clinical and Genetic Characteristics of Thai Patients with 46, XY Disorders of Sex Development ············· 1184
Chupong Ittiwut（Pediatrics, Chulalongkorn University, Thailand）
Wed(4)-P-70 Two cases with miscarriages caused by resistance to thyroid hormone ··············································· 1185
Katsuhiko Tsunekawa（Department of Clinical Laboratory Medicine, Gunma University Graduate School of
Medicine, Japan）
Wed(4)-P-72 Phenotypic and Genetic Spectrum of Hereditary Sensory and Autonomic Neuropathy in Japan ············· 1185
Junhui Yuan（Kagoshima University, Japan）
Wed(4)-P-74 Novel homozygous MAGMAS/PAM16 mutation in a patient with radiological features of odontochondrodys-
plasia: first evidence for phenotypic overlap? ······················································································ 1186
Shahida Moosa（Institute of Human Genetics, University of Cologne, Germany/Institute of Human Genetics,
University Medical Center Goettingen, Goettingen, Germany/Center for Molecular Medicine Cologne (CMMC),
University of Cologne, Cologne, Germany/Cologne Excellence Cluster on Cellular Stress Responses in Aging-
Associated Diseases (CECAD), University of Cologne, Cologne, Germany）
Wed(4)-P-75 De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing ································ 1186
Hirotomo Saitsu（Human Genetics, Yokohama City University, Japan）
Wed(4)-P-76 Advantage of next generation sequencing in molecular diagnosis in DMD -mutation screening with long preserved
dried umbilical cord and detection of mosaicism- ················································································· 1187
Ai Unzaki（Pediatrics, Kobe University Graduate School of Medicine, Japan）
ICHG2016 84
Wed(4)-P-77 Homozygous ADCY5 mutation causes movement disorder with severe intellectual disability ················· 1187
Nobuhiko Okamoto（Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal
and Child Health, Japan）
Wed(4)-P-78 A surgical case of chronic pancreatitis with SPINK1p.N34S mutation ··············································· 1188
Koji Tezuka（First Department of Surgery (Department of Gastroenterological, Breast, Thyroid and General
Surgery), Yamagata University Faculty of Medicine, Japan）
Wed(4)-P-79 Next Generation Sequencing as a Clinical Diagnostic Tool for Hereditary Spinocerebellar Degeneration
······················································································································································ 1189
Katsuya Nakamura（Division of Clinical and Molecular genetics, Shinshu University School of Medecine, Japan）
Wed(4)-P-80 Gender effects on the severity of spinal muscular atrophy (SMA) in 286 Japanese patients diagnosed in 1996-2015
······················································································································································ 1189
Ai Shima（Department of Community Medicine and Social Healthcare Sciecnce, Kobe University Graduate School
Wed(4)-P-81 Association study between CAG repeats of PolyQ-related genes and SCA3/MJD ································ 1190
Hong Jiang（Department of Neurology, Xiangya Hospital, Central South University, China/Key Laboratory of
Hunan Province in Neurodegenerative Disorders, Central South University/State Key Laboratory of Medical
Genetics, Central South University）
Day 4
Wed(4)-P-82 Genetic analysis in West syndrome and Ohtahara syndrome: a single center study ······························ 1190
Jun Tohyama（Department of Child Neurology, Nishi-Niigata Chuo National Hospital, Japan/Niigata University
Medical and Dental Hospital）
Wed(4)-P-83 Genetic analysis of HPRT1 gene in five patients with HPRT deficiency ············································· 1191
Atsuo Taniguchi（Institute of Rheumatology, Tokyo Women’s Medical University, Japan）
Wed(4)-P-84 Whole-exome sequencing combined with homozygosity mapping reveals a novel TCAP gene mutation in a
consanguineous family with LGMD2G initially diagnosed as heredity inclusion body myopathy ·················· 1192
Qiji Liu（Department of Medical Genetics, Shandong University, China）
Wed(4)-P-85 Gender difference in effect of artificial ventilation in patients with myotonic dystrophy ························ 1192
Toshio Saito（Division of Child Neurology, Department of Neurology, National Hospital Organization Toneyama
National Hospital, Japan）
Wed(4)-P-86 Identification of novel mutations in C21ORF2 from Japanese patients with early-onset retinitis pigmentosa
······················································································································································ 1193
Akiko Suga（Division of Molecular and Cellular Biology, National Institute of Sensory Organs, Tokyo Medical
Center, Japan）
Wed(4)-P-87 Parathyroid hyperplasia induced by uniparental disomy in a MEN1 patient with a frame-shift mutation
······················································································································································ 1193
Hidenori Koyama（Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Hyogo
College of Medicine, Japan）
Wed(4)-P-88 Identification of DGUOK and MPV17 Mutations in Patients with Hepatocerebral Mitochondrial DNA Depletion
Syndrome ······································································································································· 1194
Minji Kang（Asan Institute for Life Sciences, Asan medical center, Korea, South）
Wed(4)-P-89 Characterization of Japanese patients with FHL1 myopathy ····························································· 1194
Yukiko K. Hayashi（Pathophysiology, Tokyo Medical University, Japan）
Wed(4)-P-90 Novel SACS gene mutations in Japanese patients lacking spasticity ················································· 1195
Mridulata Bohara（Neurology, Kagoshima University, Japan）
Wed(4)-P-91 A case of osteogenesis imperfecta caused by PPIB mutation (First Japanese case) ····························· 1196
Junko Kanno（Department of Pediatrics, Tohoku University school of Medicine, Japan）
Wed(4)-P-92 Development of SMN protein analysis in human blood cells as a spinal muscular atrophy biomarker
······················································································································································ 1196
Reiko Arakawa（Institute of Medical Genetics, Tokyo Women’s Medical University, Japan）
Wed(4)-P-93 Detecting mutations in PRPH2 in 407 families with non-syndromic high myopia by exome sequencing
······················································································································································ 1197
Bei Gao（Genetics Lab, Zhongshan ophthalmic center of Sun Yat-sen University, China）
Wed(4)-P-94 Clinical and genetic characteristics of the Russian patients with Lynch syndrome ································ 1197
Alexei Tsukanov（State Scientific Centre of Coloproctology, Russia）
Wed(4)-P-95 High prevalence of CDH23 mutations in patients with a common clinical characteristics of early childhood
hearing loss and the genotype-phenotype correlations ··········································································· 1198
Tatsuo Matsunaga（National Institute of Sensory Organs, National Tokyo Medical Center, Japan）
ICHG2016 85
Wed(4)-P-96 Novel missense and nonsense mutations in the LRP5 gene in patients with osteoporosis-pseudoglioma syndrome
······················································································································································ 1199
Minna Pekkinen（Folkhalsan Institute of Genetics, Folkhalsan Research Center, Finland）
Wed(4)-P-97 No parent-of-origin effects detected in a large group of children with Williams syndrome ····················· 1199
Elaine Tam（Medicine, University of Toronto, Canada）
Wed(4)-P-98 Panel-based next generation sequencing identifies novel compound heterozygous variants of BMP1 underlying
osteogenesis imperfecta ···················································································································· 1200
Agnieszka Gach（Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland）
Wed(4)-P-99 SNCA p.Ala53Glu mutation in Parkinson’s disease ·········································································· 1201
Petra Pasanen（Department of Medical Biochemistry and Genetics, University of Turku, Finland）
Wed(4)-P-100 Genetic heterogeneity of muscular dystrophy in Mali ····································································· 1201
Guida Landoure（Service de Neurologie, Centre Hospitalier Universitaire du Point G, Mali/Neurogenetics Branch,
NINDS, NIH, Bethesda, MD）
Wed(4)-P-101 Mutational analysis of TBK1 in Taiwanese patients with amyotrophic lateral sclerosis ······················· 1202
Yi-Chung Lee（Neurology, Taipei Veterans General Hospital, Taiwan/Department of Neurology, National Yang-
Ming University, Taipei, Taiwan）
Day 4
Wed(4)-P-102 Differentiated genetic landscape of familial and sporadic amyotrophic lateral sclerosis ······················· 1202
Qing Liu（Department of Neurology and Laboratory of Clinical Genetics, Peking Union Medical College Hospital,
China/Neuroscience Center, Chinese Academy of Medical Sciences & Peking Union Medical College）
Wed(4)-P-103 Ribosomal Dysfunction Leads to Erythropoiesis Failure in a Zebrafish Model of Diamond-Blackfan Anemia
······················································································································································ 1203
Naoya Kenmochi（Frontier Science Research Center, University of Miyazaki, Japan）
Wed(4)-P-104 Molecular genetic and clinical characterization of male Rett syndrome ············································· 1204
Hyun-Joo Lee（Pediatrics, Yonsei University College of Medicine, Korea, South）
Wed(4)-P-105 Molecular genetic study of 80 patients with ATR-X syndrome in Japan ··········································· 1204
Hiroko Shimbo（Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama, Japan）
Wed(4)-P-106 Clinicogenetic features of PLOSL (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopa-
thy) ··············································································································································· 1205
Takao Kiriyama（Department of Neurology, Nara Medical University）
Wed(4)-P-107 SMN1 , SMN2 and hybrid SMN gene analysis in spinal muscular atrophy using long-range PCR followed by
sequencing ····································································································································· 1205
Yuji Kubo（Institute of Medical Genetics, Tokyo Women’s Medical University, Japan/Toppan Printing Co.,
Ltd./Riken Genesis Co., Ltd.）
Wed(4)-P-108 Spectrum and frequency of STK11 mutations of Russian patients with Peutz-Jeghers syndrome
······················································································································································ 1206
Vitaly Shubin（State Scientific Centre of Coloproctology, Russia）
Poster Session
Therapy for Genetic Disorders 13:45-14:45
Wed(4)-P-109 Dendrosomal Curcumin Nanoformulation is Inducing Apoptosis and Up-Regulates Long Non-Coding RNA
CCAT2 in Human Breast Cancer MCF-7 And T47D Cell Lines ····························································· 1207
Aref Sobhkhizy（Natural Science faculty, University of Tabriz, Iran）
Wed(4)-P-110 CHO-intermediated Chromosome Engineering (CHOiCE) technique using CRIPSR/Cas9 ··················· 1208
Narumi Uno（Chromosome Engineering Research Center, Tottori University, Japan/Department of Biomedical
Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori Uni-
versity）
Wed(4)-P-111 Hematopoietic stem cell transplantation for adolescent and adult onset cerebral X-linked adrenoleukodystrophy
······················································································································································ 1208
Takashi Matsukawa（Department of Neurology, The University of Tokyo, Japan）
Wed(4)-P-112 The analysis of suppressive effects of citrus peel ingredient on the abnormal protein accumulation-related
phenomena induced by mutant proteins of glaucoma and amyotrophic lateral sclerosis causative genes (OPTN and
TARDBP) ······································································································································ 1209
Masafumi Ohtsubo（Department of Photomedical Genomics, Hamamatsu University School of Medicine, Japan）
ICHG2016 86
Wed(4)-P-113 Targeting Heat Shock Protein 90 with Ganetespib for the Treatment of Lymphoma ·························· 1209
Hanqing Liu（School of Pharmacy, Jiangsu University, China）
Wed(4)-P-114 Role of Fmr1 (Fragile X Mental Retardation gene 1) mRNA level during neurodevelopment: implication in the
pathophysiology of FXTAS (Fragile X-Associated Tremor/Ataxia Syndrome) ·········································· 1210
Bardoni Bardoni（CNRS UMR7275, France）
Wed(4)-P-115 Methionyl-tRNA Synthetase Promotes Reactive Oxygen Species Accumulation by Producing Homocysteine
Thiolactone that Induces Lysine Homocysteinylation ············································································ 1211
Wei Xu（Institutes of Biomedical Sciences, Fudan University, China）
Wed(4)-P-116 Generation of a non-cytotoxic herpes simplex based vector for neural transduction ···························· 1211
Yoshitaka Miyagawa（Department of Biochemistry and Molecular Biology, NIPPON MEDICAL SCHOOL,
Japan/Department of Microbiology and Molecular Genetics, University of Pittsburgh, USA）
Wed(4)-P-117 MOLECULAR MEASURING OF BCR-ABL1 TRANSCRIPTS ON INTERNATIONAL REPORTING SCALE IN
CHRONIC MYELOID LEUKEMIA PATIENTS ···················································································· 1212
Shariq Ahmed（Genomics, National Institute of Blood Diseases & Bone Marrow Transplantation, Pakistan）
Wed(4)-P-118 rFSH monotherapy prior to hCG-rFSH combination therapy is an effective new treatment to achieving future
fertility in adolescent patients with congenital male hypogonadotropic hypogonadism ······························ 1213
Day 4
Naoko Sato（Department of Pediatrics, Tokyo University, Japan/Tanaka Growth Clinic）
Wed(4)-P-119 Therapeutic effects of recombinant adeno-associated virus-mediated muscle transduction to express bone-
targeted alkaline phosphatase of lethal hypophosphatasia model mice ···················································· 1213
Aki Nakamura-Takahashi（Department of Biochemistry and Molecular Biology, Nippon Medical School, Japan）
Wed(4)-P-120 Dual-vector suicide gene therapy using retroviral replicating vectors derived from amphotropic murine leukemia
virus and gibbon ape leukemia virus ·································································································· 1214
Shuji Kubo（Genetics, Hyogo College of Medicine, Japan）
Wed(4)-P-121 ER-Golgi transport may serve as a novel drug target for Pelizaeus-Merzbacher disease caused by PLP1 amino
acid substitutions ···························································································································· 1215
Ken Inoue（Dept. of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National
Center of Neurology and Psychiatry, Japan）
Wed(4)-P-122 Improved transduction of canine X-linked muscular dystrophy with rAAV9-microdystrophin by MSCs pre-
treatment ······································································································································· 1215
Hiromi Hayashita-Kinoh（Department of Biochemistry and Molecular Biology, Nippon Medical School,
Japan/Department of Molecular Therapy, National Institute of Neuroscience, NCNP）
Wed(4)-P-123 Development of a safeguard system for an ideal gene- and cell- therapy vector ································· 1216
Shinya Komoto（Molecular and Cellular Biology, Tottori University, Japan）
Wed(4)-P-124 CORRELATION LEVELS OF ACTIVITIES OF DAILY LIVING AND DISACCHARIDE CONCENTRATIONS
IN MUCOPOLYSACCHARIDOSES ··································································································· 1217
University）
Wed(4)-P-125 Exacerbation in the IL-10 deficient dystrophic mice and an anti-inflammatory strategy with mesenchymal
stromal cells ··································································································································· 1217
Yuko N Kasahara（Biochemistry and Molecular Biology, Nippon Medical School, Japan/Molecular Therapy,
National Institute of Neuroscience, NCNP）
Wed(4)-P-126 Lentiviral Vector and Zinc Finger Nucrease System mediated Gene Therapy for Krabbe disease ············· 1218
Hiroshi Kobayashi（Research Center for Medical Sciences, The Jikei University School of Medicine,
Japan/Department of Pediatrics, The Jikei University School of Medicine）
Wed(4)-P-127 J-RARE: patient registry for the better life of rare and intractable diseases’ patients ························· 1219
Soichi Ogishima（Tohoku Medical Megabank Organization, Tohoku University, Japan/ASrid）
Wed(4)-P-128 Androgens & Antioxidants Management Facing Controversy &/or Unavailability of Hematopoietic Stem Cell
Transplantation: Clinical & Hematologic Response in Fanconi Anemia Egyptian Patients ························· 1219
Aya Tarek（Clinical Genetics, National Research Centre, Egypt）
Wed(4)-P-129 AAV8-mediated Expression of N-acetylglucosamine-1-phosphate Transferase Attenuates Bone Loss in a Mouse
Model of Mucolipidosis II ················································································································· 1220
Young Bae Sohn（Medical Genetics, Ajou University Hospital, Korea, South）
Wed(4)-P-130 Clinical features, molecular analysis and outcome of ERT in Korean patients with Mucopolysaccharidosis type
VI ················································································································································· 1220
Eun Kyung Cho（Department of Pediatrics, Samsung Medical Center, Korea, South）
ICHG2016 87
Poster Session
Psychiatric Genetics, Neurogenetics and Neurodegeneration 13:45-14:45
Wed(4)-P-131 Polygenic Risk Score, Parental Socioeconomic Status, Family History of Psychiatric Disorders, and the Risk
for Schizophrenia ···························································································································· 1222
Esben Agerbo（Aarhus University, Centre for Integrated Register-Based Research and National Centre for Register-
Based Research, Denmark/Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Den-
mark/National Centre for Register-Based Research, Aarhus University, Denmark）
Wed(4)-P-132 Clinical phenotype-genotype correlation of Alexander disease with GFAP mutation: Analysis of 34 Japanese
cases ············································································································································· 1223
Tomokatsu Yoshida（Neurology, Kyoto Prefectural University of Medicine, Japan）
Wed(4)-P-133 Detection of CYP2D6 polymorphism using Luminex xTAG technology in Autism spectrum disorder: CYP2D6
activity score and its association with risperidone levels ········································································ 1223
Natchaya Vanwong（Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty
of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, Mahidol University, Thailand）
Wed(4)-P-134 A polymorphism in CRAT is associated with HLA-DQB1*06:02 negative essential hypersomnia
······················································································································································ 1224
Day 4
Taku Miyagawa（Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan
Institute of Medical Science, Japan/Department of Human Genetics, Graduate School of Medicine, The University
of Tokyo）
Wed(4)-P-135 Copy number variations in pediatric obsessive-compulsive disorder: First high-resolution chromosomal microar-
ray analysis ··································································································································· 1224
Beatrice Oneda（Institute of Medical Genetics, University of Zurich, Switzerland）
Wed(4)-P-136 A selective detection of lysophosphatidylcholine in dried blood spot for diagnosis of adrenoleukodystrophy by
LC-MS/MS ···································································································································· 1225
Ryuichi Mashima（Department of Clinical Laboratory Medicine, National Center for Child Health and Develop-
ment, Japan）
Wed(4)-P-137 CHCHD2 is down-regulated in neuronal cells differentiated from iPS cells derived from patients with
lissencephaly ··································································································································· 1225
Keiko Shimojima（Institute for Integrated Medical Sciences, Tokyo Women’s Medical University, Japan/Precursory
Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST),
Kawaguchi, Japan）
Wed(4)-P-139 A Rare Clinical Condition Apert Syndrome Associated with Autistic Spectrum Disorder ····················· 1226
Yeliz Cengiz（Child and Adolescent Psychiatry, Near East University, Medical Faculty Hospital, Cyprus）
Wed(4)-P-140 Genome-wide association study identifies SESTD1 as a novel risk gene for lithium responsive bipolar disorder
······················································································································································ 1227
Jie Song（Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden）
Wed(4)-P-141 Genetic Variants in N-Methyl-D-Aspartate Glutamate Receptor influence Emotion Performance in Adolescents
······················································································································································ 1227
Pei-Jung Lin（National Taiwan University, Taiwan）
Wed(4)-P-142 Frequency and complexity of de novo structural mutation in autism ················································ 1228
William M Brandler（Psychiatry, University of California, San Diego, USA）
Wed(4)-P-143 Aging and Alzheimer’s disease connections derived from dysregulation and comorbidity networks suggest new
counteractions and treatments ·········································································································· 1228
Yi-Shian Peng（Department of Biomedical Sciences and Engineering, National Central University, Taiwan）
Wed(4)-P-144 Aicardi-Goutieres and Singleton-Merten overlapping phenotype due to IFIH1 mutation ······················ 1229
Yuji Sugawara（Pediatrics, Soka Munincipal Hospital, Japan/Pediatrics, Tokyo Medical and Dental University）
Wed(4)-P-145 Milder progressive cerebellar atrophy caused by biallelic SEPSECS mutations ··································· 1229
Kazuhiro Iwama（Human Genetics, Yokohama City University, Japan/Pediatrics, Yokohama City University）
Wed(4)-P-146 Familial aggregation of patients with early-and adult-onset schizophrenia and their nonpsychotic relatives using
neurological soft signs ······················································································································ 1230
I-Ning Tsai（National Cheng Kung University, Taiwan）
Wed(4)-P-147 Nano-interventions for Alzheimer’s disease. Role of Dendrimers ······················································ 1230
Jerzy W. Leszek（Psychiatry, Wroclaw Medical University, Poland）
ICHG2016 88
Wed(4)-P-148 Familial spinocerebellar ataxia with sensory neuropathy associated with compound heterozygous intermediate
CAG expansions in MJD locus ·········································································································· 1231
Masahiro Kanai（Department of Neurology, National Center of Neurology and Psychiatry, Japan）
Wed(4)-P-149 Methadone Use in a Male With the FMRI Premutation and FXTAS ··············································· 1231
Zukhrofi Muzar（Histology, Muhammadiyah University of North Sumatera, Faculty of Medicine, Indone-
sia/University of California Davis MIND Institute, USA）
Wed(4)-P-150 Genome-wide association study in a Japanese sample identified candidate loci for HLA-DRB1*13:02 -negative
panic disorder ································································································································· 1232
Mihoko Shimada（Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo,
Japan）
Wed(4)-P-151 Mutational analysis of causative genes for autosomal recessive spinocerebellar degeneration (SCD) to delineate
molecular epidemiology of early-onset SCD ························································································· 1233
Yuka Hama（Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry,
Japan）
Wed(4)-P-152 Mapping of novel homozygous loci for cognitive dysfunction in consanguineous families ···················· 1234
Muhammad Y Zahoor（Molecular Biology & Forensic Sciences Laboratory, Institute of Biochemistry & Biotechnol-
ogy, Faculty of Biosciences, University of Veterinary & Animal Sciences, Pakistan/National Centre of Excellence
Day 4
in Molecular Biology, University of the Punjab, Lahore Pakistan）
Wed(4)-P-153 Retinitis pigmentosa is a common phenotype in affected females with mutations in PRPS1 ··············· 1234
Prasit Phowthongkum（Medical Genetics, University of Washington, USA）
Wed(4)-P-154 Combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway associated
megalencephaly syndromes ··············································································································· 1235
Yutaka Negishi（Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical
Sciences, Japan）
Wed(4)-P-155 Novel PLA2G6 mutations associated with an exonic deletion due to non-allelic homologous recombination in
a patient with infantile neuroaxonal dystrophy ···················································································· 1236
Toshiyuki Yamamoto（Tokyo Women’s Medical University Institute for Integrated Medical Sciences, Japan）
Wed(4)-P-156 Single nucleotide variations in CLCN6 identified in patients with benign partial epilepsies in infancy and/or
febrile seizures ································································································································ 1236
Toshiyuki Yamamoto（Institute for Integrated Medical Sciences, Tokyo Women’s Medical University, Japan）
Wed(4)-P-157 Withdrawn ······························································································································· 1237
Wed(4)-P-158 The immunogenetic basis of auditory hallucinations in schizophrenia: Role for HLA-G ······················· 1237
Ashwini Rajasekaran（Human Genetics, National Institute of Mental Health and Neurosciences, In-
dia/Translational Psychiatry Lab, Dept. of Psychiatry, National Institute of Mental Health and Neurosciences）
Wed(4)-P-159 Progression and sex difference of multiple sclerosis is associated with chondroitin sulfate β-1,4-N-
acetylgalactosaminyltransferase-1 polymorphism ·················································································· 1238
Kazumasa Saigoh（Department of Life Science, Kinki University Faculty of Science and Engineering,
Japan/Department of Neurology, Kinki University Faculty of Medicine）
Wed(4)-P-160 Regional Heritability Analysis Indicates NETRIN1 Signaling Pathway is Associated with Major Depressive
Disorder ········································································································································· 1238
Yanni Zeng（Division of Psychiatry, University of Edinburgh, UK）
Wed(4)-P-161 Mutational and functional studies on HNRNPA1 mutations in familial amyotrophic lateral sclerosis in the
Japanese population ························································································································ 1239
Hiroya Naruse（Department of Neurology, Graduate School of Medicine, The University of Tokyo, Japan）
Wed(4)-P-162 Transcriptome responses to lithium in microglia and peripheral blood monocyte ······························· 1240
Yuta Takahashi（Department of Disaster Psychiatry, International Research Institute of Disaster Science, Tohoku
University, Japan/Department of Psychiatry, Tohoku University Hospital）
Wed(4)-P-163 Involvement of lncRNAs in CNV deletions in schizophrenia risk ······················································ 1240
Qingtuan Meng（The State Key Lab of Medical Genetics, Central South University, Changsha, China）
Wed(4)-P-164 Variants in the PARL gene confer genetic susceptibility to Alzheimer’s disease in Han Chinese ············· 1241
Rui Bi（Kunming Institute of Zoology, Chinese Academy of Sciences, China）
Wed(4)-P-165 C2822T in ARHGAP4 gene, a candidate disease mutation in a family with mental retardation ············· 1241
Hui Guo（ShenZhen People’s Hospital, China）
Wed(4)-P-166 Mutation analysis of the myocyte enhancer factor 2C gene (MEF2C ) in Japanese patients with febrile seizures
······················································································································································ 1242
Junko Nakayama（Pediatrics, Ibaraki Prefectural University of Health Sciences, Japan）
ICHG2016 89
Wed(4)-P-167 Search for a novel causative gene of hereditary spastic paraplegia ··················································· 1242
Miho Kawabe（Department of Neurology, Graduate School of Medicine, the University of Tokyo, Japan）
Wed(4)-P-168 New results from the largest GWAS of Autism to date ·································································· 1243
Jakob Grove（Biomedicine, Aarhus University, Denmark）
Wed(4)-P-169 Investigating functional deficits of the intellectual disability gene, IQSEC2 on dendritic spine morphogenesis
······················································································································································ 1244
Cheryl Shoubridge（Pediatrics, University of Adelaide, Australia/Robinson Research Institute, University of Ade-
laide, Australia）
Wed(4)-P-170 Rare variants in histone methyl transferase genes involved in H3K9 methylation in Autism Spectrum Disorders
······················································································································································ 1245
Shabeesh Balan（Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Japan）
Wed(4)-P-171 Correlation between brain atrophy and clinical severity in patients with xeroderma pigmentosum group A
harboring the founder mutation in Japan ···························································································· 1245
Takehiro Ueda（Division of Neurology, Kobe University Graduate School of Medicine, Japan）
Wed(4)-P-172 Copy number variation analysis using whole-exome sequencing data for the diagnosis of neurodegenerative
diseases ········································································································································· 1246
Day 4
Masaki Tanaka（Department of Neurology, University of Tokyo, Graduate School of Medicine, Japan）
Wed(4)-P-173 Japan Consortium of Ataxias (J-CAT): a Cloud -based national registry for ataxias integrating genetic diagnosis
networks and prospective natural history researches ············································································· 1247
Yuji Takahashi（Department of Neurology, National Center of Neurology and Psychiatry, Japan）
Wed(4)-P-174 Functional Analysis of COQ2 V393A Variant Associated with Multiple System Atrophy Based on Measurement
of Oxygen Consumption Rate of Transformed Yeasts Carrying human COQ2 cDNAs ······························· 1248
Tsutomu Yasuda（Neurology, The University of Tokyo, Japan）
Wed(4)-P-175 Common inversion polymorphisms under selection are susceptibility factors for autism and schizophrenia
······················································································································································ 1248
Luis A Perez-Jurado（Universitat Pompeu Fabra, Spain/Hospital del Mar Research Institute (IMIM)/Centro de
Investigacion Biomedica en Red de Enfermedades Raras (CIBERER)）
Wed(4)-P-176 Manic State-Related Biomarkers Using Co-Expressed Transcriptome Analyses ·································· 1249
Ya-Chin Lee（College of Public Health, National Taiwan University, Institue of Epidemiology and Preventive
Medicine, Taiwan）
Wed(4)-P-177 Genetic determinants of multiple sclerosis susceptibility in populations with non-European ancestry
······················································································································································ 1249
Jacob L. McCauley（John P. Hussman Institute for Human Genomics, University of Miami, USA/Dr. John T.
Macdonald Department of Human Genetics, Miller School of Medicine, University of Miami, Miami FL, USA）
Wed(4)-P-178 Improving Autism Spectrum Disorder (ASD) specific diagnosis with Copy Number Variant (CNV) profiling:
results in a cohort of children with neurodevelopmental problems under age five ····································· 1250
Astrid M Vicente（Dep Health Promorion and Non Communicable Disease Prevention, Instituto Nacional de Saude
Doutor Ricardo Jorge, Portugal/Biosytems and Integrative Sciences Institute/Instituto Gulbenkian de Ciencia）
Wed(4)-P-179 Expression profile of candidate genes in children and adolescents with major depressive disorder ············· 1251
Vanessa K Ota（Psychiatry, Universidade Federal de Sao Paulo, Brazil/Genetics Division, Universidade Federal
de Sao Paulo/Interdisciplinary Laboratory of Clinical Neurosciences, Universidade Federal de Sao Paulo/National
Institute of Developmental Psychiatry for Children and Adolescents (INPD)）
Wed(4)-P-181 Oligogenic model in Amyotrophic Lateral Sclerosis? ······································································ 1251
Claire S Leblond（Human Genetics Department, McGill University, Canada/Montreal Neurological Institute and
Hospital, Mc Gill University, Montreal Qc Canada）
Wed(4)-P-182 Novel compound heterozygous mutations of SPG11 gene in sporadic spastic paraplegia with thin corpus
callosum ········································································································································ 1252
Haruo Shimazaki（Neurology, Jichi Medical University, Japan）
Wed(4)-P-183 The association between GWAS peak on 6p21.3-22.1 and cognitive impairment in trio-families with schizophre-
nia ················································································································································ 1253
Wan-Jung Lui（Epidemiology, Institute of Epidemiology and Preventive Medicine, College of Public Health,
National Taiwan University, Taiwan）
Wed(4)-P-184 Clinical Utility of Next Generation Sequencing for Undiagnosed Genetic Disorders ····························· 1253
Younhee Ko（Department of Clinical Genetics, Department of Pediatrics, Yonsei University, College of Medicine,
Korea, South）
ICHG2016 90
Wed(4)-P-185 Novel rare variations of oxytocin receptor (OXTR) gene in autism spectrum disorder individuals Novel rare
variations of oxytocin receptor (OXTR) gene in autism spectrum disorder individuals ······························ 1254
Xiaoxi Liu（Department of Human Genetics, University of Tokyo, Japan）
Wed(4)-P-186 The effects of tooth loss and APOE ε 4 allele on mild memory impairment in the Fujiwara-kyo study of Japan
······················································································································································ 1254
Nozomi Okamoto（Community Health and Epidemiology, Nara Medical University, Japan）
Wed(4)-P-187 Polygenic risk for schizophrenia and neurocognitive performance in patients with schizophrenia ············· 1255
Shi-Heng Wang（Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan
University, Taiwan）
Wed(4)-P-188 Effect of CX3CR1 polymorphisms on the structure and function in the human brain ························· 1256
Mai Sakai（Disaster Psychiatry, Graduate School of Medicine, Tohoku University, Japan）
Wed(4)-P-189 Withdrawn ······························································································································· 1256
Wed(4)-P-190 Identification of SPG11/KIAA1840 mutations in patients with an autosomal recessive form of Charcot-Marie-
Tooth disease type 2 ······················································································································· 1256
Celeste Montecchiani（Laboratorio di Neurogenetica, IRCCS Santa Lucia, Rome, Italy）
Day 4
Wed(4)-P-191 A clinico-genetic study in a large cohort of patients with herediatry spastic paraplegia type 4 (SPG4)
······················································································································································ 1257
Lucia Pedace（Laboratorio di Neurogenetica, IRCCS Santa Lucia, Rome, Italy）
Wed(4)-P-192 Analysis of retrotranposition in neurodegenerative disorders ··························································· 1258
Giovanni Pascarella（RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Life Science
Accelerator Technology Group, Transcriptome Technology Team, Yokohama, Japan）
Poster Session
Pharmacogenetics 13:45-14:45
Wed(4)-P-193 A TALE OF GENETIC VARIATION IN THE HUMAN SLC22A1 GENE ENCODING OCT1 AMONG TYPE 2
DIABETES MELLITUS POPULATION GROUPS OF WEST BENGAL, INDIA ······································· 1259
Dipanshu Sur（Dept. of Zoology, University of Calcutta, India）
Wed(4)-P-194 Correlation of UGT1A1*28 and *6 polymorphisms with irinotecan-induced neutropenia in Thai colorectal
cancer patients ······························································································································· 1259
Chalirmporn Atasilp（Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Fac-
ulty of Medicine Ramathibodi Hospital, Mahidol University, Thailand/Laboratory for Pharmacogenomics, Clinical
Pathology, Somdetch Phra Debharatana Medical Centre, Ramathibodi Hospital）
Wed(4)-P-195 Impact of serotonin receptor 1A haplotypes on risperidone-induced weight gain in schizophrenia patients
······················································································································································ 1260
Ying-Tzu Chang（Department of Pharmacy, College of Pharmacy, China Medical University, Taiwan）
Wed(4)-P-196 Effects of Hyptis suaveolens and Boerhavia diffusa herbal extracts on recombinant human CYP enzyme activity
and cell cycle regulation ·················································································································· 1261
Nicholas E Thomford（Pathology, Division of Human Genetics, University of Cape Town, Ghana）
Wed(4)-P-197 The associations between DRD2 and ANKK1 genetic polymorphisms and response to risperidone in patients
with schizophrenia ··························································································································· 1261
Ying-Chieh Chen（Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan）
Wed(4)-P-198 Impact of HTR2A genetic polymorphisms on treatment outcomes of risperidone in patients with schizophrenia
······················································································································································ 1262
Jia Lian Yang（Department of Pharmacy, College of Pharmacy, China Medical University, Taiwan）
Wed(4)-P-199 Frequency of CYP2D6 poor metabolizers in a sample of Cuban patients with schizophrenia ··············· 1263
Hilda Roblejo-Balbuena（National Center of Medical Genetics, Medical University of Havana, Cuba）
Wed(4)-P-200 Trans-ethnic Study of N-acetyltransferase 2 diplotypes in anti-tuberculosis drug-induced liver injury across
Thai, Japanese, and Indonesian patients ····························································································· 1263
Supharat Suvichapanich（Department of Human Genetics, Graduate School of Medicine, University of Tokyo,
Bunkyo-ku, Tokyo, Japan）
Wed(4)-P-201 Methadone Maintenance Treatment Combine use of Amphetamine is Associated with APBB2 Genetic Variants
······················································································································································ 1264
Chia-Chen Liu（Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan）
ICHG2016 91
Wed(4)-P-202 Systemic analyses of a methadone maintenance population reveal plasma N-cadherin network to treatment
outcome ········································································································································· 1265
Yu-Li Liu（Center for Neuropsychiatric Research, National Health Research Institutes, Taiwan/Graduate Institute
of Clinical Medical Science, China Medical University）
Wed(4)-P-203 The frequencies of pharmacogenomically relevant rare variants in the Lithuanian population ·············· 1265
Vaidutis Kucinskas（Department of Human and Medical Genetics, Vilnius University, Lithuania）
Wed(4)-P-204 Genetic risk factors for phenobarbital and phenytoin-induced cutaneous adverse drug reactions in Japanese
population ······································································································································ 1266
Takeshi Ozeki（Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Japan）
Wed(4)-P-205 Opportunities and Obstacles to International Implementation of Genetic Screening for Stevens Johnson Syn-
drome/Toxic Epidermal Necrolysis: The Global Genomic Medicine Collaborative (G2MC) ························ 1267
Teri A. Manolio（Division of Genomic Medicine, National Human Genome Research Institute, National Institutes
of Health, Bethesda MD, USA）
Wed(4)-P-206 NUCLEOTIDE VARIANTS IN THE PROMOTER REGION OF THE THYMYDILATE SYNTHASE GENE
PREDICT FOR TOXICITY TO FLUOROPYRIMIDINES IN COLORECTAL CANCER PATIENTS ············· 1267
Augusto Rojas-Martinez（Centro de Investigacion y Desarrollo en Ciencias de la Salud, Universidad Autonoma
de Nuevo Leon, Mexico/School of Medicine, Universidad Autonoma de Nuevo Leon (Monterrey, Mexico)）
Day 4
Wed(4)-P-207 Performance of Novel Direct NAT2 haplotyping in Thai populations ··············································· 1268
Nuanjun Wichukchinda（Department of Medical Sciences, Medical Life Sciences Institute, Thailand）
Wed(4)-P-208 The Evaluation of AmpliChip ™ CYP450 Test and Luminex xTAG  platforms for detection of polymorphisms
in genes encoding CYP2D6 drug metabolizing enzyme in Thai subjects ················································· 1269
Monpat Chamnanphon（Pathology, Division of Pharmacogenomics and Personalized Medicine, Faculty of
Medicine, Mahidol University, Thailand）
Wed(4)-P-209 Development of a method for targeted resequencing of 100 pharmacogenes ····································· 1269
Koya Fukunaga（Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Japan）
Wed(4)-P-210 Risking Cardiac Failure to Cure Cancer: Identifying the Risk Factors for Adverse Drug Events ············· 1270
Horacia Naidoo（Pathology - Human Genetics, University of Cape Town, South Africa）
Wed(4)-P-211 Determinants of plasma concentrations of rosuvastatin and its metabolite in Chinese patients with hyperc-
holesterolaemia by genome-wide analysis ···························································································· 1271
Miao Hu（Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong）
Wed(4)-P-212 Genome-wide analysis for determinants of plasma concentrations of simvastatin and simvastatin acid in Chinese
patients with hypercholesterolaemia ··································································································· 1271
Tomlinson Brian（Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong）
Wed(4)-P-213 Targeted resequencing of 340 ADME genes in human liver ···························································· 1272
Kathrin Klein（Pharmacogenetics, Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Ger-
many/University Tuebingen）
Poster Session
Cytogenetics 13:45-14:45
Wed(4)-P-214 Two novel constitutional incidental findings discovered during cancer workout may explain patient excessive
clinical feature ································································································································ 1273
Jacqueline R Batanian（Pediatrics, Saint Louis University, USA/Cardinal Glennon Children’s SSM Medical Cen-
ter）
Wed(4)-P-215 Interstitial Structural Variations associated with Congenital Anomalies ············································ 1273
Mariluce Riegel（Service of Medical Genetics,Hospital de Clinicas de Porto Alegre, Porto Alegre, RS,
Brazil/Postgraduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Porto
Alegre, RS, Brazil）
Wed(4)-P-216 Genomic imbalances associated with conotruncal heart defects ······················································· 1274
Mariluce Riegel（Service of Medical Genetics, Hospital de Clinicas de Porto Alegre, RS, Brazil）
Wed(4)-P-217 Consanguinity and its genetic consequences: a detailed analysis of a cohort with multiple disabilities using SNP
array ·············································································································································· 1274
Frenny J Sheth（Cytogenetics and Molecular Cytogenetics, FRIGE’s Institute of Human Genetics, India）
ICHG2016 92
Wed(4)-P-218 Molecular cytogenetic characterization of an analphoid marker chromosome derived from 12 pter in Pallister
Killian diagnosis: First case report in Canada and review of the reported cases ······································· 1275
Faezeh Vasheghani Farahani（Human Genetics, McGill university, Canada）
Wed(4)-P-219 Visualization of Cytogenetic Testing in Clinical Genetics ································································ 1275
Mamoru Ozaki（Medical Research Institute, Kanazawa Medical University, Japan）
Wed(4)-P-220 The importance of root cause analysis following an external quality assessment (EQA) to improve the quality
of a diagnostic service ······················································································································ 1276
Rosalind J Hastings（CEQAS, Oxford University Hospitals NHS Foundation Trust, UK）
Wed(4)-P-221 MODIFYING INFLUENCE OF OCCUPATIONAL INFLAMMATORY DISEASES ON THE LEVEL OF CHRO-
MOSOME ABERRATIONS IN COAL MINERS ··················································································· 1277
Maxim Yu. Sinitsky（Biology Faculty, Department of Genetics, Kemerovo State University, Russia/Laboratory
of Cytogenetics, Institute of Human Ecology of SB RAS）
Wed(4)-P-223 Paternal Uniparental Disomy (UPD) Chromosome 14-like syndrome due to a rare case of partial deletion of
the imprinting region at 14q32.1-32.2. ······························································································· 1278
Susan G. Brown（Genetics and Molecular Pathology, SA Pathology, Australia）
Wed(4)-P-224 Duplication/Deletion in chromosome 13 arising from a maternal paracentric inversion: A U-Type Recombina-
Day 4
tion Event ······································································································································ 1278
Ben A Lundie（Sullivan Nicolaides Pathology, Australia）
Wed(4)-P-225 Chromosomal aberrations detected in Idiopathic mental retardation and multiple congenital abnormalities
(MCA): Validation of molecular cytogenetic techniques High resolution banding (HRB) and Fluorescent in Situ
Hybridization (FISH) ······················································································································· 1279
Venkatesh Huskur Narayana Rao（Human Genetics, NIMHANS, India）
Wed(4)-P-226 Clinical and Molecular Delineation of Duplication 19p13.2 encompassing NFIX ······························· 1280
Carlos Venegas（Servicio de Genetica, Hospital General de Mexico, Mexico/Facultad de Medicina UNAM）
Wed(4)-P-227 SCREENING OF MARKER CHROMOSOMES AND METHYL CpG BINDING PROTEIN-2 (MeCP2) POLY-
MORPHISM IN SCHIZOPHRENIA PATIENTS IN COIMBATORE - A PILOT STUDY ··························· 1280
Gomathi Mohan（Department of Human Genetics and Molecular Biology, Bharathiar University, India）
Wed(4)-P-228 Turner Syndrome Caused by Rare Complicated X Chromosomal Structural Abnormalities ·················· 1281
Niu Li（Institute of Pediatric Translational Medicine, Shanghai Children Medical Center, Shanghai Jiaotong Uni-
versity School of Medicine, China/Department of Medical Genetics, Shanghai Children Medical Center, Shanghai
Jiaotong University School of Medicine）
Wed(4)-P-229 array CGH analysis of first and second trimester euploid miscarriages ·············································· 1281
Alihossein Saberi（Medical Genetics, Ahvaz Jundishapour University of Medical Sciences, Iran）
Wed(4)-P-230 VRK2 : A Novel Gene Causing Isolated Autosomal Dominant Bilateral Congenital Optic Nerve Hypoplasia
······················································································································································ 1282
Eva Pipiras（Service d’histologie embryologie et cytogenetique, Hopital Jean Verdier, France）
Wed(4)-P-231 FREQUENCY OF CHROMOSOMAL BREAKS IN SUSPECTED CASES OF FANCONI’S ANAEMIA- A SIN-
GLE CENTER EXPERIENCE ··········································································································· 1283
Saira Shan（Clinical & Molecular Cytogenetics, National Institute of Blood Disease & Bone Marrow Transplan-
tation Karachi, Pakistan）
Wed(4)-P-232 Computer simulation analysis of the three-dimensional relative positioning of chromosome 21 territories in the
human 21 trisomy cell nuclei ············································································································ 1283
Koichi Sekizawa（Faculty of Health Sciences, Kyorin University, Japan）
Wed(4)-P-233 Prenatal diagnosis of the unbalanced translocation between chromosome 15 and Y-chromosome in a female
fetus ·············································································································································· 1284
HeeJu Park（Hamchoon Women’s Clinic, Korea, South）
Wed(4)-P-234 A novel Four-way Philadelphia translocation t(9;22;3;1)(q34;q11.2;q26;q32) along with unusual t(8;17) in a
chronic myeloid leukemia patient in chronic phase ··············································································· 1285
Sonika Sharma（Cytogenetics, Dr Lal Path Labs, New Delhi, India）
Wed(4)-P-235 The role of ROS in the context of the arecoline-induced mitotic chromosome fragmentation and nonapoptotic
cell death ······································································································································· 1285
Yueh-Chun Li（Biomedical Sciences, Chung-Shan Medical University, Taiwan）
Wed(4)-P-236 Mechanisms of Interchromosomal Insertional Translocation ···························································· 1286
Takema Kato（Division of Molecular Genetics, Fujita Health University, Japan）
ICHG2016 93
Wed(4)-P-237 Chromosomal instability and genomic diversity of neurons in aging brain and in neurodegeneration
······················································································································································ 1286
Kazimierz Gasiorowski（Department of Basic Medical Sciences, Wroclaw Medical University, Poland）
Wed(4)-P-238 Xq DISOMY IN A MALE PATIENT WITH AN UNBALANCED t (X;15)(p11.1;p13) TRANSLOCATION AND
A RARE X-INACTIVATION PATTERN ····························································································· 1287
Gianna Carvalheira（Morphology and Genetics, UNIFESP, Brazil）
Wed(4)-P-239 A 3-way balanced interstitial translocation between chromosome 3, 4, 1 leads to male infertility
······················································································································································ 1288
Arda Cetinkaya（Medical Genetics, Zeynep Kamil Women and Children’s Hospital, Turkey）
Wed(4)-P-240 Genetic analyses of Korean patients with unexplained mental retardation and developmental delay using the
multiple ligation-dependent probe amplification (MLPA) and array-based comparative genomic hybridization (array
CGH) ············································································································································ 1288
Se Ra Sung（Genetics Laboratory of Fertility Center, CHA University School of Medicine, Korea, South）
Wed(4)-P-241 Postnatal diagnosis for DiGeorge syndrome in National Hospital of Pediatrics, Viet Nam by using FISH tech-
nique ············································································································································· 1289
Le T. Lieu（Human Genetic Department, National Hospital of Pediatrics, Vietnam）
Day 4
Wed(4)-P-242 Cytogenetic characterization of Sri Lankan patients with de novo Myelodysplastic Syndromes ············· 1289
W. M. Manoj S Bandara（Hunam Genetics Unit, Faculty of Medicine, University of Colombo, Sri
Lanka/Department of Pre-Clinical Sciences Faculty of Medicine, General Sir John Kotelawala Defence University）
Wed(4)-P-243 A case of Langer-Giedion syndrome with a deletion on chromosome 8q and a balanced reciprocal translocation
between chromosomes 2 and 4 ·········································································································· 1290
Emre Kirat（Cerrahpasa Medical School of Istanbul University, Turkey）
Wed(4)-P-244 A rare case of long term survival in a girl with Patau syndrome ······················································ 1290
Mehmet B Duz（Medical Genetics, Istanbul University, Cerrahpasa Medical School, Turkey）
Poster Session
Prenatal, Perinatal and Reproductive Genetics 13:45-14:45
Wed(4)-P-245 The regulatory micro-RNAs of EG-VEGF and their effects on trophoblastic cell function ··················· 1291
Meitsz Su（National Cheng Kung University, Taiwan）
Wed(4)-P-246 False positive cases from non-invasive prenatal testing at a single tertiary hospital ···························· 1291
Takol Chareonsirisuthigul（Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol Uni-
versity, Thailand）
Wed(4)-P-247 Maternal mental stress and background of pregnant women who underwent NIPT at Nagoya City University
Hospital ········································································································································· 1292
Kyoko Kumagai（Obstetrics and Gynecology, Clinical Genetics, Nagoya City University, Japan）
Wed(4)-P-248 Clinical study of pregnant women with myotonic dystrophy and their new born babies ······················ 1292
Yoshika Akizawa（Obstetrics and Gynecology, Tokyo Women’s Medical University, Japan/Institute of Medical
Genetics, Tokyo Women’s Medical University）
Wed(4)-P-249 Survey of University Student Attitude Toward Pre-conception Carrier Screening in Japan ·················· 1293
Akane Kondo（Clinical Genetics, OBGYN, Shikoku Medical Center for Children and Adults, Japan/Clinical
Genetics, Toaki University School of Medicine）
Wed(4)-P-250 Evaluation of non-invasive prenatal testing of aneuploidy from maternal plasma in our hospital ············· 1293
Yuko Matsubara（Obstet and Gynecology, Ehime University Graduate School of Medicine, Japan）
Wed(4)-P-251 Prenatal diagnosis of the Premature chromosome separation/ mosaic variegated aneuploidy (PCS/MVA) syn-
drome in fetus with microcephalus ···································································································· 1294
Masanao Ohashi（Obstetrics and Gynecology, University of Miyazaki, Japan）
Wed(4)-P-252 The importance of pre-screening counseling - parents need more and precise information about fetal anomaly
and aneuploidy screening scan ·········································································································· 1294
Masahito Mizuuchi（Dept. of Obstetrics, Sapporo Medical University, Japan）
Wed(4)-P-253 Can we construct a genetic prediction model for gestational diabetes mellitus in a Japanese population?
······················································································································································ 1295
Yoshifumi Kasuga（Department of Obstetrics and Gynecology, Keio University, School of Medicine,
Japan/Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development）
ICHG2016 94
Wed(4)-P-254 Background of couples undergoing non-invasive prenatal testing (NIPT) in Japan ····························· 1296
Eri Takeda（Nagoya City University Hospital, Japan/Ochanomizu University）
Wed(4)-P-255 Abnormally high levels of serum α-klotho result in a poor outcome for clinical pregnancy-A prospective cohort
study ············································································································································· 1296
Miyako Funabiki（Oak Clinic, Japan）
Wed(4)-P-256 Fetal Pallister-Killian syndrome with congenital diaphragmatic hernia, umbilical hernia and hydrops: a case
report of prenatal genetic counseling and grief care ············································································· 1297
Susumu Miyashita（Perinatal Medical Center, Dokkyo Medical University, Japan）
Wed(4)-P-257 Variants in maternal effect genes NLRP7 and C6orf221 are not a common risk factor for molar pregnancy
manifesting as sporadic or familiar cases ···························································································· 1297
Iwona Pinkier（Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland）
Wed(4)-P-258 Superimposed preeclampsia complicated with multiple endocrine neoplasia type 1 ···························· 1298
Yoshinori Moriyama（Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine,
Japan）
Wed(4)-P-259 The Usefulness of Interphase Fluorescence In Situ Hybridization (iFISH) for Prenatal Diagnosis ············· 1299
Hiroaki Nakamura（Genetic Medicine, Osaka City General Hospital, Japan/Obstetrics, Osaka City General Hos-
Day 4
pital）
Wed(4)-P-260 Prenatal diagnosis of microdeletion/microduplication syndrome using MLPA (Multiple Ligation -dependent
Probe Amplification) in Korean ········································································································· 1299
Sohyun Na（Hamchoon Institute of Fertility & Genetics, Korea, South）
Wed(4)-P-261 Current condition and issues of prenatal testing at a tertiary center for maternal-fetal and neonatal medicine
······················································································································································ 1300
Hironobu Hyodo（Department of Obstetrics and Gynecology, Tokyo Metropolitan Bokutoh Hospital, Japan）
Wed(4)-P-262 Outcomes of 31 cases of trisomy 13 diagnosed in utero: A single center experience ·························· 1301
Ken Takahashi（Division of Obstetrics, Center for Maternal-Fetal, Neonatal and Reproductive Medicine National
Center for Child Health and Development, Japan）
Wed(4)-P-263 Clinical Significance of Introduction of Y Chromosome Microdeletion Screening in Assisted Reproductive Tech-
nology Clinics ································································································································· 1301
Sumihide Okamoto（ART Okamoto Women’s Clinic, Japan）
Wed(4)-P-264 Genetic counseling for recurrent miscarriage patients with abnormalities of chromosome structure who have
already had live children with duplication or deletion of the involved chromosomal region ························· 1302
Toshiaki Endo（Obstetrics and Gynecology, Sapporo Medical University, Japan/Ena Ladies’ Clinic）
Wed(4)-P-265 A pilot study: function-based analysis of cell free RNA using amniotic fluid supernatant in small-for-gestational-
age group ······································································································································· 1303
Dong Hyun Cha（Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University,
Seoul, Korea, South/Genetics Laboratory, CHA Gangnam Medical Center, CHA University, Seoul, Korea）
Wed(4)-P-266 Provided information and psychosocial support for decision-making process of pregnant women with incidental
diagnosis of fetal abnormalities in Japan - Online based survey ····························································· 1303
Sayaka Honda（Genetic Counselor Course, Kyoto University School of Public Health, Kyoto, Japan）
Wed(4)-P-267 Investigation of False Positive Rates Newborn Screening Using Tandem Mass Spectrometry Technology in
Korea, Single Center Study ··············································································································· 1304
Sung Won Park（Pediatrics, Cheil General Hospital & Wonmen’s Health Care Center, Korea, South）
Wed(4)-P-268 Association analyses between copy numbers of genes in the azoospermia factor c (AZFc) region on the Y
chromosome and male infertility ········································································································ 1305
Soushi Imani（Pharmaceutical information Science, Biochemical Science, Tokushima University Graduate School,
Japan）
Wed(4)-P-269 A short-term non-verbal psychotherapeutic intervention on patients in perinatal period with high anxiety
······················································································································································ 1305
Kaori T Mori（Clinical Research Department, NHO: Shikoku Medical Center for Children and Adults,
Japan/Clinical Genetics Center, NHO: Shikoku Medical Center for Children and Adults）
Wed(4)-P-270 The effect that chromosome aneuploidy screening using the ultrasound testing gives for the decision making
of the pregnant woman ···················································································································· 1306
Ryuhei Nagai（Obstetrics, Kochi Health Sciences Center, Japan）
Wed(4)-P-271 A present situation of prenatal diagnosis in our hospital after non invasive prenatal genetic testing has started
······················································································································································ 1307
Takayo Shoji（Obstetrics and Gynecology, Chuden Hospital, Japan）
ICHG2016 95
Wed(4)-P-272 Prenatal testing for genetic disease at NCCHD in Japan ································································ 1307
Aiko Sasaki（National Center for Child Health and Development (NCCHD), Japan）
Wed(4)-P-273 Prediction of pregnancy with hypertensive disorders using epigenetic and biochemical markers ············· 1308
JinWoo Kim（Laboratory of Medical Genetics, Cheil General Hospital and Women’s Healthcare Center, Korea,
South）
Wed(4)-P-274 Integrative analysis of DNA methylation and gene expression in trisomy 21 placenta ························· 1309
Hyun Mee Ryu（Laboratoy of Medical Genetics, Cheil General Hospital and Women’s Healthcare Center, Korea,
South/Department of Obstetrics and Gynecology, Cheil General Hospital and Women’s Healthcare Center）
Wed(4)-P-275 Nuchal Translucency (NT) doubled the detection rate of Down syndrome and other chromosome abnormalities
in our experience of 1441 case of amniocenthesis ················································································ 1309
Kenji Ida（IDA clinic, Japan）
Wed(4)-P-276 Spermatogenic failure by impaired meiotic sex chromosome inactivation in a mouse with reciprocal translocation
······················································································································································ 1310
Makiko Tsutsumi（ICMS, Fujita Health Univ., Japan）
Wed(4)-P-277 A case of Antley-Bixler syndrome with hypospadias: prenatal course and key images for prenatal diagnosis
······················································································································································ 1310
Day 4
Aya Harada（Department of Maternal and Fetal Medicine, Miyagi Children’s Hospital, Japan）
Wed(4)-P-278 Comparison of FISH and array CGH in the practice of PGD ··························································· 1311
Risa Mori（IVF OSAKA Clinic, Japan）
Wed(4)-P-279 Cytogenetic analysis of products of conception during 10 years ······················································· 1312
Nobuaki Ozawa（Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health
and Development, Japan）
Wed(4)-P-280 Factors influencing the uptake of noninvasive prenatal testing among women of advanced maternal age
······················································································································································ 1312
Shusaku Hayashi（Maternal-Fetal Medicine, Osaka Medical Center and Research Institute for Maternal and Child
Health, Japan）
Wed(4)-P-281 Decision-making after prenatal genetic screening testing for fetal trisomies ······································ 1313
Rina Akaishi（Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health
Wed(4)-P-282 Increased levels of soluble corin in patients with pre-eclampsia and fetal growth restriction ················ 1314
Jun Miyazaki（Obstetrics and Gynecology, Fujita Health University, Japan/Division of Molecular Genetics, In-
stitute for Comprehensive Medical Science, Fujita Health University）
Wed(4)-P-283 Three cases of fetal cerebral ventriculomegaries suggesting inherited hydrocephalus ·························· 1315
Satoko Osuka（Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine,
Nagoya, Japan）
Wed(4)-P-284 Fetal trisomy 3 and trisomy 18 mosaicism case detected by non-invasive prenatal screening (NIPS)
······················································································································································ 1315
Chia-Cheng Hung（Sofiva Genomics Co., Ltd., Taiwan）
Wed(4)-P-285 Withdrawn ······························································································································· 1316
Wed(4)-P-287 Cytogenetic confirmation of a positive NIPT result: chorionic villus sampling or amniocentesis?
······················································································································································ 1316
Diane Van Opstal（Clinical Genetics, Erasmus MC, Netherlands）
Wed(4)-P-288 AZF/Y chromosome microdeletions - when a deletion isn’t there ···················································· 1317
Peter D Field（Molecular Genetics, Virtus Health Specialist Diagnostics, Australia）
Wed(4)-P-289 A rare case report: monozygotic quadruplets following intracytoplasmic sperm injection (ICSI) and single
blastocyst transfer (SBT) ················································································································· 1317
Maki Kusumi（Sanno Hospital, Japan/National Center for Child Health and Development）
Wed(4)-P-290 Where our clients actually come from for genetic counseling/prenatal testing: The Hokkaido survey
······················································································································································ 1318
Yuka Shibata（Hokkaido University Hospital, Japan）
Wed(4)-P-291 Circulating levels of C19MC-cluster microRNAs in pregnant women with abruptio placentaCirculating levels of
C19MC-cluster microRNAs in pregnant women with abruptio placenta ··················································· 1318
Yuri Hasegawa（Obstetrics and Gynecology, Nagasaki University, Japan）
Wed(4)-P-292 Pre-implantation genetic diagnosis for 2 spinal muscular atrophy pedigrees in Japan ························· 1319
Hiroshi Senba（Department of Obstetrics and Gynecology, Keio University School of Medicine, Japan）
ICHG2016 96
Wed(4)-P-293 Normal ranges of plasma concentrations of pregnancy-associated microRNAs during pregnancy

······················································································································································ 1319
Yuko Murakami（Departments of Obstetrics and Gynecology, Nagasaki University Graduate School of Biomedical
Sciences, Japan）
Wed(4)-P-294 Single cell analysis for adrenoleukodystrophy by long range PCR: approach for ABCD1 gene having homologous
pseudogenes ··································································································································· 1320
Akira Nakabayashi（Department of Obstetrics and Gynecology, Keio University School of Medicin, Japan）
Wed(4)-P-295 Zygosity and pregnancy complications according to mode of conception in triplet pregnancy ·············· 1321
Seung Mi Lee（Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Korea,
South）
Wed(4)-P-296 Two-year experience of a prenatal genetics clinic in Japan: what are the problems that we need to consider?
······················································································································································ 1321
Yasushi Nakamura（FMC Tokyo Clinic, Japan）
Wed(4)-P-297 Sex determination of the fetus by noninvasive prenatal testing (NIPT) with maternal blood. ·············· 1322
Yoshiteru Noda（Department of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Fujita
Health University School of Medicine, Toyoake, Japan/Division of Molecular Genetics, Institute for Comprehensive
Medical Science, Fujita Health University, Toyoake, Japan）
Day 4
Wed(4)-P-298 Combination of gene mutation analysis and tandem mass using amniotic fluid enhances the accuracy of prenatal
diagnosis of congenital metabolic disorders ························································································· 1322
Hiroko Nakagami（Saitama Medical University Hospital, Obstrics and Gynecology, Japan）
Wed(4)-P-299 Confined Placental Mosaicism among 1,326 CVSs, including Cases with Non-Mosaic Aneuploidy with Euploidy
Fetus ············································································································································· 1323
kayo Inoue（CRIFM Clinical Research Institute of Fetal Medicine PMC, Japan/Ochanomizu University）
Wed(4)-P-300 Spinal Muscular Atrophy carrier analysis in Thailand ····································································· 1324
Donniphat Dejsuphong（Translational Medicine, Ramathibodi Hospital, Mahidol University, Thailand）
Wed(4)-P-301 Accuracy of Prenatal Fast QF-PCR for Aneuploidy Detection ························································ 1324
Hiroyasu Ohashi（Clinical Laboratory, Ritz Medical Co., Ltd., Japan）
Wed(4)-P-302 Association of VEGF polymorphisms (-460T>C, -7C>T, -583C>T) and haplotypes with the idiopathic recur-
rent pregnancy loss in the Korean population ······················································································ 1325
Yong Wook Jung（Obstetrics and Gynecology, CHA University, Korea, South）
Wed(4)-P-303 Evaluation of Group Genetic Counselling for preimplantation genetic screening ································· 1325
Amanda Springer（Genetics Department, Monash Health, Australia/Genetics Department, Monash IVF）
Poster Session
Ethical, Legal, Social and Policy Issues in Genetics 13:45-14:45
Wed(4)-P-304 100 RECORDED INTERVIEWS WITH HUMAN AND MEDICAL GENETICISTS ···························· 1327
Peter S Harper（University Research Professor (Emeritus) in Human Genetics, Institute of Medical Genetics,
Cardiff University, School of Medicine, UK）
Wed(4)-P-305 Stakeholder views on secondary findings in whole-genome and whole-exome sequencing: a systematic review
······················································································································································ 1327
Michael P Mackley（Radcliffe Department of Medicine, University of Oxford, UK）
Wed(4)-P-306 A genome cohort participants’ genetic knowledge and their needs to obtain their genetic test results
······················································································································································ 1328
Kayono Yamamoto（Department of Clinical Genetics, School of Medicine, Iwate Medical University,
Japan/Department of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization）
Wed(4)-P-307 Study of newspaper reports regarding Artificial Intelligence and Genomics in Japan ··························· 1329
Koichiro Yuji（Project Division of International Advanced Medical Research, the Institute of Medical Science, the
University of Tokyo, Japan）
Wed(4)-P-308 Incidentalome from Genomic Sequencing: A Barrier to Personalised Medicine? ································ 1329
Saumya Jamuar（KK Women’s and Children’s Hospital, Singapore）
Wed(4)-P-309 Tiered Protection to Share Health-Related Data? ········································································· 1330
Stephanie OM Dyke（Human Genetics, McGill University, Canada）
ICHG2016 97
Wed(4)-P-310 Views of Patients and Their Parents Regarding the Incidental or Secondary Findings Obtained from Whole
Exome and Genome Sequencing: a Literature Review ·········································································· 1330
Akira Inaba（Genetic Counselor Course, Kyoto University, School of Public Health, Japan）
Wed(4)-P-311 The current regulatory landscape of genetic tests for health-related purposes ··································· 1331
Rei Fukuda（Department of Medical Genetics and Genomics, Kitasato University Graduate School of Medical
Sciences, Japan）
Wed(4)-P-312 Evaluation of the management of incidental findings in next-generation sequencing: A questionnaire survey
involving genetics professionals ········································································································· 1332
Mio Tsuchiya（Department of Medical Ethics and Genetics, School of Public Health, Graduate School of Medicine,
Kyoto University, Japan）
Wed(4)-P-313 Informed Consent Issue in Genome Diversity Research and Establishment of Genome Bank of Different Ethnic
Groups in China ······························································································································ 1332
Jiayou Chu（Institute of Medical Biology, Chinese Academy of Medical Sciences, China）
Wed(4)-P-314 Points to consider in family health histories and electronic health records ········································ 1333
Howard P Levy（Medicine, Johns Hopkins University, USA）
Wed(4)-P-315 Research findings from the bioethics survey on genetic tests among Mongolian university students
······················································································································································ 1333
Day 4
Hironao Numabe（Department of Genetic Counselling, Ochanomizu University, Japan）
Wed(4)-P-316 Analysis of a new national policy for the implementation of genome medicine in Japan ····················· 1334
Jusaku Minari（Osaka University, Japan）
Wed(4)-P-317 How to share the genetic information in the electronic medical chart system protecting privacy ············· 1334
Takeki Sugimoto（Clinical Genetics Department, Kochi Medical School Hospital, Japan/Breast Center, Kochi
Medical School Hospital）
Wed(4)-P-318 Revisions of Japanese Personal Data Protection Laws and Challenges in Promoting Biomedical Research Using
Human Genetic/Genomic Data ········································································································· 1335
Natsuko Yamamoto（Osaka University, Japan）
Wed(4)-P-319 First year report of Kohnodai Hospital Biobank: Construction of Biobank-coordinator workflow ············· 1336
Kumiko Suekuni（Kohnodai Hospital, National Center for Global Health and Medicine, Japan）
Prince Hall at Kyoto Grand Prince Hotel
Gala Dinner 19:00-21:00
···················································································································································· 517
ICHG2016 98
Thu.,April 07
Day 5
Main Hall (1F)
[PCS] Plenary Closing Symposium

New Technology of Single Molecule Genome Sequencing 15:00-16:30
Chair：Shinichi Morishita（Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences,
The University of Tokyo, Japan）
Chair ：Yutaka Suzuki（Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of
Tokyo, Japan）
Thu(5)-PCS-1 What do you call a complete, contiguous and accurate sequence? A SMRT Sequence! ····················· 134
Stephen Turner（Founder and CTO, Pacific Biosciences, Menlo Park, CA, USA）
Thu(5)-PCS-2 Real time, portable DNA sequencing using nanopore sensing ·························································· 135
Clive G. Brown（Chief Technology Officer at Oxford Nanopore Technologies Ltd., UK）
Thu(5)-PCS-3 Single-molecule Electrical Sequencing of DNA, RNA, and Peptide ·················································· 136
Tomoji Kawai（The Institute of Scientific and Industrial Research, Osaka University, Japan）
Closing Ceremony 16:30-17:00
Day 5
···················································································································································· 516
Annex 1 (1F)

Chair：Anne Goverde（Department of Clinical Genetics / Department of Gastroenterology & Hepatology, Erasmus MC,
University Medical Center Rotterdam, Netherlands）
Chair ：Hideki Makishima（Department of Pathology and Tumor Biology, Kyoto University）
Thu(5)-O34-1 Germline mutations in familial prostate cancer ············································································· 664

Takahide Hayano（Division of Human Genetics, National Institute of Genetics, Japan）
Thu(5)-O34-2 Imbalance of miR-194 -CUL4B negative feedback loop favoring CUL4B upregulation enhances the malignancy
of non-small-cell lung carcinoma ······································································································ 665
Yongxin Zou（Institute of Medical Genetics, School of Medicine, Shandong University, China）
Thu(5)-O34-3 Withdrawn ······························································································································· 665
Thu(5)-O34-4 Cost-effectiveness of routine screening for Lynch syndrome in endometrial cancer patients up to 70 years of
age ··············································································································································· 665
Anne Goverde（Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Nether-
lands/Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the
Netherlands）
Thu(5)-O34-5 Universal testing of mismatch repair protein deficiency in colorectal cancer and its usefulness for identification
of Lynch syndrome patient ·············································································································· 666
Takeshi Nakajima（Endoscopy Division, National Cancer Center Hospital, Japan/Department of Genetic Coun-
seling, National Cancer Center Hospital）
Thu(5)-O34-6 Comprehensive methylation analysis of imprinting-associated differentially methylated regions in colorectal
cancer ·········································································································································· 667
Hidenori Hidaka（Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty
of Medicine, Saga University, Saga, Japan/Department of Internal Medicine and Gastrointestinal Endoscopy, Saga
Medical School, Saga, Japan）
ICHG2016 99

Chair：Stuart MacGregor（Statistical Genetics Laboratory, QIMR Berghofer Medical Research Institute, Australia）
Chair ：Mitsuru Emi（Thoracic Oncology, University of Hawaii Cancer Center, USA）
Thu(5)-O35-1 Whole-exome Analysis of Hereditary Microsatellite-stable Colorectal cancer in Israel ························· 668
Revital Kariv（Tel aviv sourasky Medical center, Israel）
Thu(5)-O35-2 Hepatitis B Virus HBx Activates Notch Signaling via Delta-like 4/Notch1 in Hepatocellular Carcinoma
······················································································································································ 668
Pornrat Kongkavitoon（Chulalongkorn university, Thailand）
Thu(5)-O35-3 miR-19b up-regulates hTERT expression by inhibition of PITX1 in melanoma cells ························· 669
Takahio Ohira（Division of Molecular Genetics and Biofunction, Tottori University Graduate School of Medical
Science, Japan）
Thu(5)-O35-4 The role of germline genetic variation in Breslow’s depth, a predictor of survival after melanoma
······················································································································································ 669
Matthew H Law（Statistical Genetics, QIMR Berghofer Medical Institute, Australia）
Thu(5)-O35-5 Founder BAP1 Mutation in Four American Families Predisposes to Malignant Peritoneal Mesothelioma, Uveal
Melanoma, and other cancers ·········································································································· 670
Mitsuru Emi（Thoracic Oncology, University of Hawaii Cancer Center, USA）
Thu(5)-O35-6 Large scale meta-analysis identifies several new risk loci for development of esophageal adenocarcinoma and
Barrett’s esophagus ······················································································································ 671
Stuart MacGregor（Statistical Genetics, QIMR Berghofer Medical Research Institute, Australia）
Day 5
Recent progress in the treatment of hereditary ATTR amyloidosis
-beginning of a new era of hereditary neurodegenerative disease therapy and genetic counseling- 11:30-12:30
Chair：Tatsushi Toda（Division of Molecular Brain Science, Kobe University Graduate School of Medicine）
Pfizer Japan Inc.

-beginning of a new era of hereditary neurodegenerative disease therapy and genetic counseling- ··············· 511
Yoshiki Sekijima（Department of Medicine (Neurology and Rheumatology), Shinshu University School of
Medicine）

Databases and Data Sharing for Cross-border Genomics 12:45-14:45
Convener：Yasukazu Nakamura（Genome Informatics Laboratory, National Institute of Genetics, Japan）
Convener ：Guy Cochrane（European Nucleotide Archive/European Bioinformatics Institute (EMBL-EBI), UK）
Thu(5)-CIS25-1 Data coordination in cross-border genomics: A very human challenges ·········································· 276
Guy Cochrane（European Nucleotide Archive/European Bioinformatics institute (EMBL-EBI), UK）
Thu(5)-CIS25-2 Genome graphs: A new kind of reference from human genetic variation ········································ 277
David Haussler（UC Santa Cruz Genomics Institute, University of California, Santa Cruz/Howard Hughes Medical
Institute）
Thu(5)-CIS25-3 The 100,000 Genome Project, UK ···························································································· 278
Mark Caulfield（William Harvey Research Institute, Barts and The London School of Medicine and Dentistry,
Queen Mary, UK）
Thu(5)-CIS25-4 The Human Phenotype Ontology: A Resource for Clinical Data Sharing and Phenotype-Driven Genomic
Diagnostics ···································································································································· 279
Peter N. Robinson（Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin;
Free University Berlin; Berlin-Brandenburg Center for Regenerative Therapy; Max Planck Institute for Molecular
Genetics, Germany/Free University Berlin/Berlin-Brandenburg Center for Regenerative Therapy/Max Planck
Institute for Molecular Genetics）
ICHG2016 100
Annex 2 (1F)
[O36] Ethical, Legal, Social and Policy Issues in Genetics 8:00-9:30

Chair：Adrian Thorogood（Centre of Genomics and Policy, McGill University, Canada）
Chair ：Kaori Muto（Department of Public Policy, The Institute of Medical Sciences, The University of Tokyo, Japan）
Thu(5)-O36-1 Care to share? An international comparison of research directives to promote data sharing among decisionally-
incompetent adults living with dementia ··························································································· 672
Thu(5)-O36-2 Holding Researchers to Account for Responsible Genomic Data Sharing ·········································· 672
Thu(5)-O36-3 European Legal Perspectives on Cloud Computing in Cross-Border Translational Genome Research
······················································································································································ 673
Fruzsina Molnar Gabor（Heidelberg Academy of Sciences and Humanities, Germany）
Thu(5)-O36-4 Return of individual genomic research results in patient biobanks: Ethical challenges for Biobank Japan
······················································································································································ 673
Kaori Muto（The Institute of Medical Science, The University of Tokyo, Japan）
Thu(5)-O36-5 Ethical premises in the prenatal diagnosis of birth defects in Cuba ·················································· 674
Thu(5)-O36-6 Socialising the Genome ············································································································· 674
Anna Middleton（Wellcome Genome Campus, UK）
Day 5
[O37] Therapy for Genetic Disorders 9:45-11:15
Chair：Jan P. Kraus（Dept. of Pediatrics, University of Colorado School of Medicine, USA）
Chair ：Yu-ichi Goto（Medical Genome Center, National Center of Neurology and Psychiatry, Japan）
Thu(5)-O37-1 Disruption of Microtubule Dynamics in Rett Syndrome (RTT): a Possible New Therapeutic Target
······················································································································································ 676
John Christodoulou（Western Sydney Genetics Program, Children’s Hospital at Westmead, Australia/Discipline
of Paediatrics and Child Health, Sydney Medical School, University of Sydney/Discipline of Genetic Medicine,
Sydney Medical School, University of Sydney）
Thu(5)-O37-2 Vosoritide (BMN 111) in Children with Achondroplasia: Initial results from a Phase 2, open-label, sequential
cohort, dose-escalation study ··········································································································· 677
Sagar A. Vaidya（BioMarin Pharmaceutical Inc., USA）
Thu(5)-O37-3 Salbutamol inhibits ubiquitin-mediated survival motor neuron protein degradation in spinal muscular atrophy
cells ············································································································································· 677
Nur Imma Fatimah Harahap（Community Medicine and Social Healthcare Science, Kobe University, Graduate
School of Medicine, Japan）
Thu(5)-O37-4 Enzyme replacement therapy for homocystinuria ·········································································· 678
Jan P. Kraus（Pediatrics, University of Colorado School of Medicine, USA）
Thu(5)-O37-5 Development of a novel pig model of Duchenne muscular dystrophy and evaluation of antisense-mediated exon
skipping ········································································································································ 678
Kana Hosoki（Department of Medical Genetics, University of Alberta Faculty of Medicine and Dentistry, Canada）
Thu(5)-O37-6 RNA/ENA chimera antisense oligonucleotide (AO85) was safely administered and shown to induce dystrophin
exon 45 skipping in Duchenne muscular dystrophy patient: the first clinical study ·································· 679
Yasuhiro Takeshima（Department of Pediatrics, Hyogo College of Medicine, Japan）

Six-layer Structure for Genomics: A Powerful Conceptual Framework Useful for a Comprehensive Understanding of
Studies, Tests and Treatments in This Field... 11:30-12:30
Chair：Matthew Levy（Affymetrix Inc.）
Affymetrix Japan K.K.
ICHG2016 101
Six-layer Structure for Genomics: A Powerful Conceptual Framework Useful for a Comprehensive Understanding of
Studies, Tests and Treatments in This Field, and for A Translation of The Results of Genomic Studies to Medicine
and Healthcare ······························································································································· 512
Naoyuki Kamatani（Institute of Rheumatology, Tokyo Women’s Medical University, Japan）

Clinical Sequencing 12:45-14:45
Convener：Kenjiro Kosaki（Center for Medical Genetics, Keio University School of Medicine, Japan）
Convener ：Leslie G. Biesecker（National Human Genome Research Institute, National Institute of Health, USA）
Thu(5)-CIS26-1 A technology driven approach toward deriving high resolution human genome reference materials and the
future of niche NGS diagnostic assays ································································································ 280
Robert Sebra（Department of Genetics, and Genomic Science,Icahn School of Medicine at Mount Sinai, New York,
NY, USA）
Thu(5)-CIS26-2 Towards single-test genomics ··································································································· 282
Joris A. Veltman（Department of Human Genetics, Radboud University Medical Center; Department of Clinical
Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands/Department of Clinical Genetics,
Maastricht University Medical Centre, Maastricht, The Netherlands）
Thu(5)-CIS26-3 Hypothesis-generating research and predictive genomics ······························································ 283
Leslie G. Biesecker（National Human Genome Research Institute, National Institute of Health, USA）
Thu(5)-CIS26-4 Genome-scale sequencing in clinical settings ·············································································· 284
Kenjiro Kosaki（Center for Medical Genetics, Keio University School of Medicine, Japan）
Day 5
Room A (2F)

Chair：Desheng Liang（State Key Laboratory of Medical Genetics, Central South University, China）
Chair ：Mayumi Sugiura-Ogasawara（Obstetrics and Gynecology, Research Center for Recurrent Pregnancy Loss, Nagoya
City University, Graduate School of Medical Sciences, Japan）
Thu(5)-O38-1 Risk assessment of medically assisted reproduction and advanced maternal ages in the development of Prader-
Willi syndrome due to UPD(15)mat ································································································· 680
Keiko Matsubara（Department of Molecular Endocrinology, National Research Institute for Child Health and
Development, Japan/Department of Pediatrics, Dokkyo Medical University Koshigaya Hospital）
Thu(5)-O38-2 SNP Testing before IVF: searching for optimal number and contain ················································ 680
Andrei V Ivanov（Human Genetics, University Hospital of Saint-Petersburg State University, Russia）
Thu(5)-O38-3 The examination of chromosome abnormality in couples with recurrent pregnancy loss ····················· 681
Hiroaki Aoki（Obstetrics and Gynecology, The Jikei University School of Medicine, Japan）
Thu(5)-O38-4 Day 5 embryos show reduced aneuploidy rate compared to day 3 embryos in preimplantation genetic diagnosis
for reciprocal translocation carriers ··································································································· 682
Yoshiharu Nakaoka（IVF Namba Clinic, Japan）
Thu(5)-O38-5 Preimplantation genetic diagnosis and natural conception: a comparison of live birth rates in patients with
recurrent pregnancy loss associated with translocation ········································································ 683
Shinichiro Ikuma（Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine,
Japan/Saint Mother Obstetrics and Gynecology Hospital）
Thu(5)-O38-6 Genetic Counsellor’s Preferences for Public Coverage of Preimplantation Genetic Diagnosis: A Discrete Choice
Experiment ····································································································································· 683
Elaine S Goh（Institute of Health Policy, Management and Evaluation, University of Toronto, Canada/Child
Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, Canada）

Chair：Do Yeong Hwang（Department of OB & Gyn, Hamchoon Women’s Clinic, Korea, South）
Chair ：Haruhiko Sago（Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health
ICHG2016 102
Thu(5)-O39-1 Risk level of intracytoplasmic sperm/spermatid injection for 116 non-mosaic Klinefelter syndrome (KS) patients
···················································································································································· 685
Atsushi Tanaka（Saint Mother Hospital, Japan）
Thu(5)-O39-2 New candidate genes for NTD and CHD screened from a PiggyBac transgenic mice library have higher mutation
rates in human NTD ······················································································································ 686
Yufang Zheng（State Key Laboratory of Genetic Engineering and Ministry of Education (MOE) Key Laboratory
of Contemporary Anthropology, School of Life Science, Fudan University, China/The Institute of Developmental
Biology and Molecular Medicine, Fudan University/8. Obstetrics and Gynecology Hospital, Fudan University）
Thu(5)-O39-3 Mutations in CYP11B1 Gene of Vietnamese Patients with 11ß -hydroxylase Deficiency ···················· 686
Mai T.P. Nguyen（Human genetics, National Hospital of Pediatrics, Vietnam/Institute of Genome Research）
Thu(5)-O39-4 Withdrawn ······························································································································· 687
Thu(5)-O39-5 Parental decisions on prenatally diagnosed chromosome abnormalities before 22 weeks of gestation: A Japanese
multicenter retrospective study ········································································································ 687
Miyuki Nishiyama（Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child
Health and Development, Japan）
Thu(5)-O39-6 Isolation of mesenchymal stem cells derived from human placental tissue and their expression of C19MC
microRNAs ····································································································································· 688
Naoki Fuchi（Department of Obstetrics and Gynecology, Nagasaki University Graduate School of Medicine, Japan）

Transforming the State of Genomic Biomarker Discovery and Diagnostic Testing with High-throughput Long-read
Day 5
DNA Sequencing Technologies 11:30-12:30
Chair：William LaRochelle（Roche Sequencing Solutions）
Roche Diagnostics K.K.
Transforming the State of Genomic Biomarker Discovery and Diagnostic Testing with High-throughput Long-read
DNA Sequencing Technologies ·········································································································· 513
Robert Sebra（Assistant Professor, Department of Genetics and Genomic Science, Icahn School of Medicine at
Mount Sinai, New York, NY）

Effects of Genetic and Epigenetics, Geno-environmental Interactions on Healthy Aging and Longevity 12:45-14:45
Convener：Yi Zeng（Center for the Study of Aging and Human Development, Medical School of Duke University, Durham,
NC, USA; Center for Healthy Aging and Development Studies, National School of Development, Peking University, Beijing,
China, China/USA）
Convener ：Makoto Suzuki（Okinawa Research Center for Longevity Science, Japan）
Thu(5)-CIS27-1 Genetic studies of the oldest old: Somatic and germline variation ················································· 285
Eline Slagboom（Molecular Epidemiology Section, Department of Medical Statistics and Bioinfomatics, Leiden
University Medical Centre, The Netherlands）
Thu(5)-CIS27-2 Energy Sensing Genes and Longevity: Novel Findings from Multi-Ethic Populations ························ 287
Bradley J. Willcox（Department of Geriatric Medicine / Department of Research, University of Hawaii / Kuakini
Medical Center, USA）
Thu(5)-CIS27-3 Meta-analysis of 4 genome-wide association studies identify new longevity genes ···························· 288
Paola Sebastiani（Department of Biostatistics, Boston University, USA）
Thu(5)-CIS27-4 Associations of novel loci, pathway-specific polygenic scores and GxE interactions with longevity and cognition
in Han Chinese ······························································································································· 289
Yi Zeng（Center for the Study of Aging and Human Development, Medical School of Duke University USA;
Center for Healthy Aging and Development Studies, National School of Development, Peking University, Beijing,
China/Center for Healthy Aging and Development Studies, National School of Development, Peking University,
Beijing, China）
ICHG2016 103
Room E (1F)

Chair：Jozef Gecz（Paediatrics, The University of Adelaide, Australia）
Chair ：Ryota Hashimoto（Molecular Research Center for Children’s Mental Development, United Graduate School of Chid
Development, Osaka University, Japan）
Thu(5)-O40-1 Exome Sequencing of Pakistani Consanguineous Families Identifies 31 Novel Candidate Genes for Recessive
Intellectual Disability ······················································································································ 689
Hans van Bokhoven（Human Genetics 855, Radboud University Medical Center, Netherlands）
Thu(5)-O40-2 Protocadherin 19 (PCDH19) epilepsy, intellectual disability and autism limited to females ················· 689
Jozef Gecz（Paediatrics, The University of Adelaide, Australia）
Thu(5)-O40-3 Maternal Copy Number Variants (CNV) transmission to their Autism Spectrum Disorder (ASD) sons correlates
with phenotypic traits ····················································································································· 690
Astrid Moura Vicente（Faculdade de Ciencias da Universidade de Lisboa, Pakistan/Instituto Nacional de Saude
Doutor Ricardo Jorge, Lisboa, Portugal/Biosytems and Integrative Sciences Institute, Lisboa, Portugal/Instituto
Gulbenkian de Ciencia, Oeiras, Portugal）
Thu(5)-O40-4 Massively parallel sequencing in a case control cohort and extended families identifies noncoding risk variants
for autism spectrum disorder ··········································································································· 691
Anthony J Griswold（John P. Hussman Insitute for Human Genomics, University of Miami, USA）
Thu(5)-O40-5 Identification of rare risk variants in voltage-gated channel genes (CACNA1C, CACNA1D, CACNA1S,
CACNA1I) in Japanese population of schizophrenia and autism spectrum disorder using Ion PGM platform
Day 5
······················································································································································ 691
Chenyao Wang（Nagoya University, Japan）
Thu(5)-O40-6 Systematic integration of brain eQTL and GWAS identifies ZNF323 as a novel schizophrenia risk gene and
suggests recent positive selection based on compensatory advantage on pulmonary function ···················· 692
Xiong-jian Luo（Genetic and Psychiatry, Kunming Institute of Zoology, Chinese Academy of Sciences, China）

Chair：Murim Choi（Department of Biomedical Sciences, Seoul National University College of Medicine, Korea, South）
Chair ：Kazuya Iwamoto（Department of Molecular Brain Science, Faculty of Life Sciences, Kumamoto University, Japan）
Thu(5)-O41-1 Investigating the transcriptome wide impact of expanded polyalanine tract mutations in ARX contributing to
intellectual disability and seizures ······································································································ 693
Tessa R Mattiske（School of Medicine, The University of Adelaide, Australia）
Thu(5)-O41-2 Maternal Effects and Maternal Factors in OCD and Tourette Disorder ··········································· 693
Dorothy E Grice（Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA）
Thu(5)-O41-3 Genome-Wide Analysis of Attention-Deficit/Hyperactivity Disorder in Korean Children ····················· 694
Hyo-Won Kim（Department of Psychiatry, University of Ulsan College of Medicine, Asan Medical Center, Korea,
South）
Thu(5)-O41-4 An Ultraconserved Brain-specific Transcriptional Enhancer within the ADGRL3 (LPHN3) Gene Underpins
ADHD Susceptibility ······················································································································ 695
Ariel F Martinez（Medical Genetics Branch, National Institutes of Health, USA）
Thu(5)-O41-5 Autistic MeCP2 mutations lost regulation on miR197/ADAM10/NOTCH and affected neural progenitor cells
differentiation ································································································································ 695
Hongyan Wang（State Key Laboratory of Genetic Engineering and Ministry of Education (MOE) Key Laboratory
of Contemporary Anthropology, School of Life Science, Fudan University, China/The Obstetrics & Gynecology
Hospital of Fudan University）
Thu(5)-O41-6 A recurrent mutation in γ-aminobutyric acid type B (GABAB) receptor R2 causes a Rett-like phenotype
······················································································································································ 696
Murim Choi（Department of Biomedical Sciences, Seoul National University, Korea, South）
ICHG2016 104

Current Aspects of Inborn Error of Metabolism 12:45-14:45
Convener：Shigeo Kure（Department of Pediatrics, Tohoku University School of Medicine, Japan）
Convener ：Wuh-Liang Hwu（Department of Pediatrics and Medical Genetics, National Taiwan University Hospital, Taiwan）
Thu(5)-CIS28-1 Novel mitochondrial diseases identified by NGS ·········································································· 291

David R. Thorburn（Genetics, Murdoch Childrens Research Institute; University of Melbourne, Dept of Pae-
diatrics; Victorian Clinical Genetics Services, Australia/University of Melbourne, Dept of Paediatrics/Victorian
Clinical Genetics Services）
Thu(5)-CIS28-2 Current topics in inborn errors of amino acid metabolism ···························································· 293
Henk Blom（Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent
Medicine and Neonatology, University Medical Centre Freiburg, Netherlands）
Thu(5)-CIS28-3 Clinical and molecular spectrum of Wilson disease (WD) patients with understanding of molecular patho-
physiology of WD in animal model, Long-Evans Cinnamon rats ···························································· 294
Han-Wook Yoo（Pediatrics & Medical Genetics, Asan Medical Center Childrens Hospital, University of Ulsan
College of Medicine, Korea）
Thu(5)-CIS28-4 Gene therapy for aromatic L-amino acid decarboxylase (AADC) deficiency ····································· 295
Wuh-Liang Hwu（Department of Pediatrics and Medical Genetics, National Taiwan University Hospital, Taiwan）
Room B-1 (2F)
Day 5
Chair：Reha M. Toydemir（Pathology, University of Utah, USA）
Chair ：Hiroshi Kawame（Division of Genomic Medicine Support and Genetic Counseling, Tohoku University, Japan）
Thu(5)-O42-1 MICRODELETION OF 12q14.2q14.3 IN THREE MEMBERS OF A FAMILY DETECTED BY SNP-ARRAY

ANALYSIS ····································································································································· 697
Rita Fischetto（U.O.C. Malattie Metaboliche-Genetica-Medica, A.O.U. Policlinico Consorziale Bari, Italy/Istituto
Biologia e Genetica; Medicina e Chirugia; Università degli Studi di Bari）
Thu(5)-O42-2 Expressive Language Delay and Characteristic Facial Features - A Novel 7p22.3p22.2 Microdeletion Syndrome?
···················································································································································· 697
Andrea C Yu（Department of Genetics, Children’s Hospital of Eastern Ontario, Canada）
Thu(5)-O42-3 Delineation of the 9q31 microdeletion syndrome ·········································································· 698
Reha M Toydemir（Pathology, University of Utah, USA/Pediatrics, University of Utah）
Thu(5)-O42-4 Noonan syndrome and related disorders associated with coloboma: five case reports and review of literature
······················································································································································ 699
Yline Capri（Clinical Genetics, CHU Robert Debre, France）
Thu(5)-O42-5 Sex chromosomal Abnormalities in Egyptian DSD patients ···························································· 699
Inas M Mazen（Clinical Genetics and Endocrinology, National Research Centre, Egypt）
Thu(5)-O42-6 Male-to-female (XY) sex reversal and systemic lupus erythematosis: Association of functional Xp disomy
including DAX-1 and TLR7 ············································································································ 700
Rie Kawakita（Department of Pediatric Endocrinology and Metabolism, Osaka City General Hospital,
Japan/Department of Genetic Medicine, Osaka City General Hospital）

Chair：Hsiang-Yu Lin（Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan）
Chair ：Tomoki Kosho（Department of Medical Genetics, Shinshu University School of Medicine, Japan）
Thu(5)-O43-1 Clinical and Molecular Characterisation of Frontonasal Dysplasia ··················································· 701

Patrick JJ Yap（Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Australia）
Thu(5)-O43-2 Co-occurrence of Sturge-Weber syndrome phenotype and Klippel-Trenaunay-Weber syndrome phenotype in a
patient: Molecular evidence of the shared pathological basis of the two conditions ································· 701
Yuri Sakaguchi（Department of Pediatrics, Keio University School of Medicine, Japan）
Thu(5)-O43-3 CDC42 as a new human disease causative gene ············································································ 702
Tomoko Uehara（Center for Medical Genetics, Keio University School of Medicine, Japan）
ICHG2016 105
Thu(5)-O43-4 Two novel mutations in the FUCA1 gene causing fucosidosis ························································ 703
Wipa Panmontha（Chulalongkorn University, Thailand）
Thu(5)-O43-5 Ocular Features in Patients with Mucopolysaccharidosis ······························································· 703
Hsiang-Yu Lin（Department of Pediatrics, Mackay Memorial Hospital, Taiwan/Department of Medical Research,
Mackay Memorial Hospital, Taipei, Taiwan/Department of Medicine, Mackay Medical College, New Taipei City,
Taiwan/Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan）
Thu(5)-O43-6 Two-dimensional Speckle Tracking Echocardiography in 53 Patients with Mucopolysaccharidosis
······················································································································································ 704
Hsiang-Yu Lin（Department of Pediatrics, Mackay Memorial Hospital, Taiwan/Department of Medical Research,
Mackay Memorial Hospital, Taipei, Taiwan/Department of Medicine, Mackay Medical College, New Taipei City,
Taiwan/Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan/Institute of Clinical
Medicine, National Yang-Ming University, Taipei, Taiwan）

HVP (Sharing Human Variant Data Globally - Challenges and Opportunities for 2020) 12:45-14:45
Moderator：Helen Robinson（Liason-World Health Organization / The Human Variome Project International Coordinating
Office / University of Melbourne, Australia）
Thu(5)-SFS20-1 TBD ···································································································································· 447

Finlay Macrae（Department of Medicine, University of Melbourne, Australia）
Thu(5)-SFS20-1 What can be achieved on the African Continent by 2020? ·························································· 448
Raj Ramesar（Division of Human Genetics, University of Cape Town, South Africa）
Day 5
Thu(5)-SFS20-2 Human Variome Project and the Latin American region ······························································ 449
Aida B. Falcón de Vargas（Clinical Genetics Unit, Hospital Vargas de Caracas, Escuela de Medicina JM Vargas,
Universidad Central de Venezuela. Hospital de Clinicas Caracas, Venezuela）
Thu(5)-SFS20-3 Human Variome Project: The Global Globin 2020 Challenge (Southeast Asia) ······························· 450
Zilfalil Alwi（Universiti Sains Malaysia, Malaysia）
Thu(5)-SFS20-4 The value of accurate assignment of pathogenicity of variants in clinical genetic practice ················ 451
Ingrid M. Winship（University of Melbourne, Australia/Melbourne Health）
Room B-2 (2F)

Chair：Andrew P. Morris（Department of Bioinfomatics, University of Liverpool, UK）
Chair ：Akira Hata（Department of Public Health, Chiba University Graduate School of Medicine, Japan）
Thu(5)-O44-1 Trans-ethnic meta-analysis and genomic annotation reveals novel loci and effector genes for kidney function in
diverse populations ························································································································· 705
Andrew P Morris（Department of Biostatistics, University of Liverpool, UK/Wellcome Trust Centre for Human
Genetics, University of Oxford）
Thu(5)-O44-2 MicroRNA Transcriptome Changes in Multiple Brain Regions of Subjects with Alcohol Use Disorders
······················································································································································ 706
Huiping Zhang（Psychiatry, Yale University School of Medicine, USA）
Thu(5)-O44-3 Targeted-bisulfite sequence analysis of the methylation of CpG islands in the PNPLA3 , SAMM50 , and PARVB
of patients with nonalcoholic fatty liver disease: relationship to their mRNA expression and rs738409 genotype
······················································································································································ 706
Kikuko Hotta（Department of Medical Innovation, Osaka University Hospital, Japan）
Thu(5)-O44-4 Genome-wide multi-phenotype and eQTL analyses detect novel signals for omega fatty acids and provide
insights into their biology ················································································································ 707
Annique J. Claringbould（Department of Genetics, University Medical Centre Groningen, Nether-
lands/Department of Genomics of Common Disease, Imperial College London, United Kingdom）
Thu(5)-O44-5 Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects for LPA
······················································································································································ 707
Johannes Kettunen（Computational medicine, University of Oulu, Finland/National Institute for Health and
Welfare, Helsinki, Finland/NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland,
Kuopio, Finland）
ICHG2016 106
Thu(5)-O44-6 Exome chip meta-analysis identifies novel low-frequency variants contributing to central body fat distribution
······················································································································································ 708
Tugce Karaderi（Wellcome Trust Centre for Human Genetics, University of Oxford, UK）

Chair：Derek M. Dykxhoorn（John P. Hussman Institute for Human Genomics, Universty of Miami Miller School of Medicine,
USA）
Chair ：Michiaki Kubo（Center for Integrative Medical Sciences, RIKEN, Japan）
Thu(5)-O45-1 Pathogen lineage based analysis of host genetic risk factor in young onset tuberculosis ····················· 709
Yosuke Omae（Faculty of Medicine, The University of Tokyo, Japan）
Thu(5)-O45-2 Transcriptome analysis reveals autism-specific convergent molecular pathways during neurogenesis
······················································································································································ 709
Derek M. Dykxhoorn（John P. Hussman Institute for Human Genomics, Universty of Miami Miller School of
Medicine, USA/Dr. John T. Macdonald Foundation Department of Human Geneics, University of Miami Miller
Thu(5)-O45-3 Analysis of the planar cell polarity regulator gene PTK7 in neural tube defects ································ 710
Richard H Finnell（Nutritional Sciences and Chemistry, The University of Texas at Austin, USA/Fudan Univer-
sity）
Thu(5)-O45-4 Rare variants in the COL5A1 gene are associated with risk for keratoconus, a blinding eye disease
······················································································································································ 711
Kathryn P Burdon（Menzies Institute for Medical Research, University of Tasmania, Australia）
Day 5
Thu(5)-O45-5 Examining the Genetic Architecture of Age-related Macular Degeneration (AMD) in the Amish
······················································································································································ 711
Jonathan L Haines（Epidemiology & Biostatistics, Case Western Reserve University, USA）
Thu(5)-O45-6 Familial insight: Identifying glaucoma susceptibility variants by exome sequencing in extended pedigrees
······················································································································································ 712
Jac Charlesworth（University of Tasmania, Menzies Institute for Medical Research, Australia）
Room C-1 (1F)

Chair：Christian T. Thiel（Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nuremberg, Germany）
Chair ：Tadashi Kaname（Genome Medicine, National Center for Child Health and Development, Japan）
Thu(5)-O46-1 Identifying a splice site mutation in RAB3GAP1 in Martsolf Syndrome by whole exom sequencing and revealing
the function of the novel mutation ··································································································· 713
Mustafa Ozen（Department of Medical Genetics, Biruni University, Istanbul, Turkey/Department of Medical
Genetics, Istanbul University Cerrahpasa Medical School, Istanbul, Turkey/Department of Pathology and Im-
munology, Baylor College of Medicine, Houston, TX, USA）
Thu(5)-O46-2 Adult mice expressing a Braf Q241R mutation on an ICR/CD-1 background exhibit a cardio-facio-cutaneous
syndrome phenotype ······················································································································· 713
Shin-ichi Inoue（Department of Medical Genetics, Tohoku University School of Medcine, Japan）
Thu(5)-O46-3 Massively parallel sequencing of a targeted panel for the diagnosis of Disorders of Sex Development
······················································································································································ 714
Andrew H Sinclair（Molecular Development, Murdoch Children’s Research Institute, Australia）
Thu(5)-O46-4 Systematic evaluation of patients with idiopathic short stature using whole exome sequencing ············· 715
Christian T Thiel（Institute of Human Genetics, Friedrich-Alexander-University of Erlangen-Nuremberg, Ger-
many）
Thu(5)-O46-5 Novel candidate gene for congenital alveolar proteinosis with hypogammaglobulinemia identified by whole
exome sequencing analysis ··············································································································· 715
Kazutoshi Cho（Maternity and Perinatal Care Center, Hokkaido University Hospital, Japan）
Thu(5)-O46-6 Whole exome sequencing identifies homozygous mutation in ERCC1 in three sibling with a complex phenotypic
disorder ········································································································································ 716
Zeynep Ocak（Medical Genetics, Kanuni Sultan Suleyman Research and Training, Turkey）
ICHG2016 107

Chair：Vanessa Sancho-Shimizu（Department of Virology and Paediatrics, Imperial College London, UK）
Chair ：Yoko Aoki（Department of Medical Genetics, Tohoku University School of Medicine, Japan）
Thu(5)-O47-1 Study on molecular mechanism of episodic pain with Nav 1.9 channel mutations ······························ 717
Jing Yu Liu（Key Laboratory of Molecular Biophysics of the Ministry of Education, School of Life Science and
Technology, Huazhong University of Science and Technology, China）
Thu(5)-O47-2 Assembling the complex immune region haplotypes using Long Read Single Molecule Real-Time Sequencing
······················································································································································ 717
Swati S Ranade（Pacific Biosciences, USA）
Thu(5)-O47-3 Mutations in MECOM, encoding oncoprotein EVI1, cause radioulnar synostosis with amegakaryocytic throm-
bocytopenia ···································································································································· 718
Tetsuya Niihori（Department of Medical Genetics, Tohoku University School of Medicine, Japan）
Thu(5)-O47-4 Beta-globin haplotypes in Hemoglobin E and normal individuals from seven minority groups of Yunnan province,
China ··········································································································································· 719
Zhaoqing Yang（Institute of Medical Biology, Chinese Academy of Medical Sciences, China）
Thu(5)-O47-5 Heterozygous mutations in NFKB1 cause immunodeficiency and autoinflammatory episodes ············· 719
Meri Kaustio（Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland）
Thu(5)-O47-6 Whole exome sequencing of an extended family with invasive meningococcal disease ························ 720
Vanessa Sancho Shimizu（Dept of Paediatrics and Virology, Imperial College London, UK）
Day 5
Room C-2 (1F)

Chair：Roberto Giugliani（Department of Genetics, Federal University of Rio Grande Do Sul, Brazil）
Chair ：Yoshikatsu Eto（Advanced Clinical Research Center & Institute of the Treatment of Genetic Disorders, Southern
Tohoku Brain Research Institute, Japan）
Thu(5)-O48-1 Phenotypic variability in the form of pulmonary manifestations and molecular analysis in two patients with
Niemann Pick-disease type C from India ··························································································· 721
Krati R Shah（Institute of Human Genetics, India）
Thu(5)-O48-2 The Canadian Inherited Metabolic Diseases Research Network: Initial findings from a pan-Canadian longitudinal
study of affected children ················································································································ 721
Thu(5)-O48-3 Relative Frequency of Lysosomal Storage Diseases in Brazil: 1982-2015 Report from a Reference Center
······················································································································································ 722
Roberto Giugliani（Department of Genetics, UFRGS - Federal University of Rio Grande do Sul, Brazil/Medical
Genetics Service, Hospital de Clinicas de Porto Alegre, Brazil/INAGEMP, National Institute of Population Med-
ical Genetics, Brazil）
Thu(5)-O48-4 Plasma Oxysterol and Lysosphingomyelin-509 as Potential Biomarkers for Japanese Patients with Niemann-Pick
C disease measured by Tandem MS and their Changes with Miglustat Treatment ·································· 723
Yoshikatsu Eto（Advanced Clinical Research Center, Institute of Neurological Diseases, Japan）
Thu(5)-O48-5 Pharmacological chaperones for the cure of metabolic diseasesPharmacological chaperones for the cure of
metabolic diseases ·························································································································· 723
Maria Vittoria Cubellis（Biology, University Federico II, Italy）
Thu(5)-O48-6 Transthyretin-type Cerebral Amyloid Angiopathy in Post-transplant Patients with Hereditary ATTR Amyloido-
sis: Correlates between Clinical Findings and Amyloid-PET Imaging ····················································· 724
Yoshiki Sekijima（Department of Medicine (Neurology & Rheumatology), Shinshu University, Japan/Institute for
Biomedical Sciences, Shinshu University/Jisenkai Brain Imaging Research Center）

Chair：Amal M. Alhashem（Pediatrics- Division of Medical Genetics, Prince Sultan Military Medical City, Saudi Arabia）
Chair ：Seiji Yamaguchi（Pediatrics, Shimane University School of Medicine, Japan）
ICHG2016 108
Thu(5)-O49-1 Molecular genetic study of PKU patients from Russia with a view to their subsequent treatment with BH4
······················································································································································ 725
Polina Gundorova（Federal State Budgetary Institution Research Centre for Medical Genetics, Russia）
Thu(5)-O49-2 Molecular Characterisation of Hyperphenylalaninemia in Korea ······················································ 726
Yong Hee Hong（Department of Pediatrics, Soonchunhyang University Bucheon Hospital, Korea, South）
Thu(5)-O49-3 Treatment of biotin-responsive basal ganglia disease: Open comparative study between the combination of
biotin plus thiamine versus thiamine alone ························································································· 726
Thu(5)-O49-4 Diversity of disease distribution and genetic background of inherited metabolic diuseases of organic and fatty
acids in Asian countries ·················································································································· 727
Seiji Yamaguchi（Pediatrics, Shimane University School of Medicine, Japan）
Thu(5)-O49-5 Molecular characterization of beta-ketothiolase deficiency in 9 Indians: Discovery of 3 novel mutations in
ACAT1 gene ································································································································· 728
Elsayed Abdelkreem（Department of Pediatrics, Gifu University, Japan/Department of Pediatrics, Sohag Univer-
sity, Egypt）
Thu(5)-O49-6 Human thioredoxin-2 deficiency impairs mitochondrial redox homeostasis and causes early-onset neurodegen-
eration ·········································································································································· 728
Eliska Holzerova（Institute of Human Genetics, Technische Universitaet Muenchen, Germany/Institute of Human
Genetics, Helmholtz Zentrum Muenchen, Germany）
Room D (1F)
Day 5
Education of Genetics: Genetics Education for Undergraduate Medical Students in Asia 8:00-9:30
Moderator：Akihiro Sakurai（Sapporo Medical University, Japan）
Moderator ：Meow-Keong Thong（Genetics and Metabolism Unit, Department of Paediatrics, Faculty of Medicine, University
Thu(5)-ED7-1 Problem-based learning in genetics education in a developing country ············································· 469

Meow-Keong Thong（Genetics and Metabolism Unit, Department of Paediatrics, Faculty of Medicine, University
Thu(5)-ED7-2 Genetics education in Philippine medical schools ·········································································· 471
Maria Melanie Liberty B. Alcausin（Newborn Screening Reference Center, National Institutes of Health-University
of the Philippines, Manila, Philippines）
Thu(5)-ED7-3 Integrating genetics in undergraduate curriculum - Indian perspective ·············································· 472
Seema Kapoor（Department of Pediatrics, Maulana Azad Medical College, New Delhi, India）
Thu(5)-ED7-4 Genetic Education for Undergraduate Medical Students in Japan ···················································· 473
Atsushi Watanabe（Division of Clinical Genetics, Nippon Medical School, Japan）

Education of Genetics: Genetics Education for Public 9:45-11:15
Convener：Takahito Wada（Kyoto University, Japan）
Moderator ：Michael J. Dougherty（American Society of Human Genetics, USA）
Thu(5)-ED8-1 Educating the Public about Genetics: A Perspective from the U.S. ················································· 474
Michael J. Dougherty（American Society of Human Genetics, USA）
Thu(5)-ED8-2 The Australian experience with genetics education for primary and high school students and current challenges
······················································································································································ 476
Kristine Barlow-Stewart（Sydney Medical School Northern, University of Sydney, Australia）
Thu(5)-ED8-3 The changing face of genomics learning and its drivers in the UK ··················································· 477
Mat Hickman（Wellcome Trust, UK）
Thu(5)-ED8-4 Genetic Education for Children: A Nagasaki University Initiative ····················································· 478
Kanako Morifuji（Department of Nursing, Health Sciences, Nagasaki University Graduate School of Biomedical
Sciences, Japan）
ICHG2016 109

Update on the molecular genetics and pathogenesis of RASopathies 11:30-12:30
Chair：Yoichi Matsubara（Director of the Research Institute National Center for Child Health and Development）
Novo Nordisk Pharma Ltd.
Update on the molecular genetics and pathogenesis of RASopathies ······················································ 514

Yoko Aoki（Professor of Department of Medical Genetics, Tohoku University School of Medicine）
Sakura (1F)

Chair：Noah Zaitlen（Medicine, University of California San Francisco, USA）
Chair ：Qihua Tan（Department of Public Health and Department of Clinical Research, University of Southern Denmark,
Denmark）
Thu(5)-O50-1 Gene Network: Accurate prediction of gene functions and prioritization of disease variants ················ 730
Juha Karjalainen（Genetics, University Medical Center Groningen, Netherlands）
Thu(5)-O50-2 Joint whole-genome analysis of associations between host and hepatitis C virus diversity in a patient cohort
······················································································································································ 731
Vincent Pedergnana（Wellcome Trust Center for Human Genetics, UK）
Thu(5)-O50-3 Powerful and efficient association testing in cohorts with large phenotypic collections ························ 731
Noah Zaitlen（Medicine, UCSF, USA）
Day 5
Thu(5)-O50-4 Metabolic and transciptomic associations of change in body fat percentage.Metabolic and transciptomic asso-
ciations of change in body fat percentage ··························································································· 732
Annika Wennerstrom（THL, Finland/University of Helsinki, The Institute for Molecular Medicine Finland
(FIMM), Biomedicum Helsinki, Finland, Nordic EMBL Partnership for Molecular Medicine）
Thu(5)-O50-5 Gene by environment interaction in human longevity as observed in Danish birth cohorts from 1895 to 1915
······················································································································································ 733
Qihua Tan（EBB, Dept of Public Health, University of Southern Denmark, Denmark）
Thu(5)-O50-6 A linear algebraic method for evaluating the relation between power and the pattern of linkage disequilibrium
in multiple testing ·························································································································· 733
Tapati Basak（Statistical Genetics, Unit of Statistical Genetics, Graduate School of Medicine, Kyoto University,
Kyoto, Japan）

Chair：Jonathan Marchini（Department of Statistics, University of Oxford, UK）
Chair ：Atsuko Imai（Department of Cardiovascular Medicine / Genome Informatics, Osaka University Graduate School of
Medicine, Japan）
Thu(5)-O51-1 A genome wide association study of pathological inflammatory responses in leprosy ························· 734
Vinicius M Fava（Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill
University Health Centre, Canada/The McGill International TB Centre, Departments of Human Genetics and
Medicine, McGill University）
Thu(5)-O51-2 Empirical estimation of genome-wide significance thresholds based on the 1000 Genomes Project dataset
······················································································································································ 735
Masahiro Kanai（Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental
Thu(5)-O51-3 Family-Control analysis based on Hamming distance for prioritizing candidate pathogenic variants
······················································································································································ 735
Atsuko Imai（Department of Genome Informatics, Osaka University Graduate School of Medicine,
Japan/Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine）
Thu(5)-O51-4 Significant impact of miRNA-target gene networks on genetics of human complex traits ··················· 736
Masahiro Kanai（Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University,
Japan）
Thu(5)-O51-5 Tensor decomposition uncovers trans eQTL networks in the multi-tissue EuroBATS study ················ 736
Jonathan Marchini（Department of Statistics, University of Oxford, UK）
ICHG2016 110
Thu(5)-O51-6 Estimating the shared genetic basis of complex phenotypes between populations from summary statistics gives
evidence for widespread non-additive and rare variant effects ······························································· 737
Brielin C Brown（Department of Computer Science, University of California Berkeley, USA）
Room I (2F)
[O52] Evolutionary and Population Genetics 1 8:00-9:30

Chair：Arbel Harpak（Department of Biology, Stanford University, USA）
Chair ：Yoko Satta（Department of Evolutionary Studies of Biosystems, SOKENDAI (The Graduate University for Advanced
Studies), Japan）
Thu(5)-O52-1 Large effects of mutation rate variation and epistasis on the distribution of allele frequencies in humans
······················································································································································ 738
Arbel Harpak（Biology, Stanford University, USA）
Thu(5)-O52-2 Whole-genome reference panel of Tohoku Medical Megabank Organization (ToMMo) and allele frequency of
pathological variants ······················································································································· 738
Yumi Yamaguchi-Kabata（Tohoku University, Japan）
Thu(5)-O52-3 Touching the limits of being alive: the distribution of genome-wide CNV loads in healthy human cohort is right
truncated due to ongoing purifying selection ······················································································· 739
Konstantin Popadin（Center for Integrative Genomics, University of Lausanne, Switzerland）
Thu(5)-O52-4 Health and population effects of rare gene knockouts in adult humans with related parents ··············· 739
Day 5
Vagheesh M Narasimhan（Wellcome Trust Sanger Institute, UK）
Thu(5)-O52-5 Spread of reduced activity of STX promoter in modern humans ····················································· 740
Naoko T. Fujito（School of Advanced Sciences, SOKENDAI (The Graduate University for Advanced Studies),
Japan）
Thu(5)-O52-6 Evolution of the ‘fused’ gene family across primates ·································································· 740
Hirofumi Nakaoka（National Institute of Genetics - Japan, Ecuador）
[O53] Evolutionary and Population Genetics 2 9:45-11:15

Chair：Anders Eriksson（Biological and Environmental Sciences & Engineering Division, King Abdullah University of Science
and Technology, Saudi Arabia）
Chair ：Jong Bhak（Biomedical Engineering, UNIST (Ulsan National Institute of Science and Technology), Korea, South）
Thu(5)-O53-1 HUGO-Pan Asian Population Genomics Initiative (PAPGI) project for mapping genomic diversity of Asia
······················································································································································ 742
Jong Bhak（The Genomics Institute, Ulsan National Institute of Science and Technology (UNIST), Korea, South）
Thu(5)-O53-2 Spatially explicit models and whole genome analysis for reconstructing the colonisation of Asia ············· 742
Anders Eriksson（Integrative Systems Biology Laboratory, King Abdullah University of Science and Technology,
Saudi Arabia/Department of Zoology, University of Cambridge）
Thu(5)-O53-3 Large-scale whole genome sequencing of the Estonian population reveals novel loss-of-function variants and
new insights into the population history ···························································································· 743
Reedik Magi（Estonian Genome Center, University of Tartu, Estonia）
Thu(5)-O53-4 Fine-Scale Population Structure in Europe ·················································································· 743
Stephen Leslie（Statistical Genetics, Murdoch Childrens Research Institute, Australia/School of Mathematics and
Statistics, University of Melbourne）
Thu(5)-O53-5 SNPs associated for height explain about half of the height difference between two historical subpopulations
in Finland ····································································································································· 744
Markus Perola（Health, National Institute for Health and Welfare, Finland/University of Helsinki, Institute for
Molecular Medicine, Finland (FIMM) and Diabetes and Obesity Research Program/University of Tartu, Estonian
Genome Center, Tartu, Estonia）
Thu(5)-O53-6 Characterization of 20,000 Clinically Relevant Variants in 50,000 Non-European Individuals ·············· 744
Eimear E Kenny（Icahn School of Medicine at Mo, USA）
ICHG2016 111
Room J (2F)

Chair：Roberto Mendoza-Londono（Medical Genetics, The Hospital for Sick Children and University of Toronto, Canada）
Chair：Tomohiro Nakayama（Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University
Thu(5)-O54-1 Genetic causes of Intellectual disability ······················································································· 746

Amal M Mohamed（Human Cytogenetics, National Research Center, Egypt）
Thu(5)-O54-2 Triaging of epileptic encephalopathy patients for massive parallel sequencing testing ························ 746
Bruce H. Bennetts（Sydney Genome Diagnostics, The Children’s Hospital at Westmead, Australia/Discipline of
Paediatric and Child Health, The University of Sydney/Discipline of Genetic Medicine, The University of Sydney）
Thu(5)-O54-3 Diagnostic whole exome sequencing of danish families with rare genetic diseases ····························· 747
Lotte Risom（Dept. of Clinical Genetic, Copenhagen University Hospital, Rigshospitalet, Denmark）
Thu(5)-O54-4 Diagnosis of Skeletal Dysplasias by Exome Sequencing: The Canadian Experience ··························· 748
Roberto Mendoza-Londono（Medical Genetics, The Hospital for Sick Children and University of Toronto, Canada）
Thu(5)-O54-5 Clinical validation of a Targeted Massively Parallel Sequencing Panel for Craniosynostosis ················· 748
Tony Roscioli（Kinghorn Centre for Clinical Genomics, Kinghorn Centre for Clinical Genomics, Australia/St Vin-
cents Clinical School, University of New South Wales, Darlinghurst, Australia/Department of Medical Genetics,
Sydney Childrens Hospital, Randwick, NSW, Australia）
Thu(5)-O54-6 NGS-based diagnostic DNA analysis in syndromal and nonsyndromal obesity.NGS-based diagnostic DNA anal-
ysis in syndromal and nonsyndromal obesity ······················································································· 749
Day 5
Bert van der Zwaag（Department of Genetics, UMC Utrecht, Utrecht, The Netherlands）

Chair：Paul F. Lasko（McGill University, Canada）
Chair ：Jun Mitsui（Department of Neurology, The University of Tokyo, Japan）
Thu(5)-O55-1 Beyond the ACMG 56: Parental choices and initial results from a comprehensive whole genome sequencing-
based search for predictive genomic variants in children ······································································ 750
M Stephen Meyn（Program in Genetics and Genome Biology, The Hospital for Sick Children, Canada/Division of
Clinical and Metabolic Genetics, The Hospital for Sick Children/Department of Molecular Genetics, University
of Toronto/Department of Paediatrics, University of Toronto/Centre for Genetic Medicine, The Hospital for Sick
Children）
Thu(5)-O55-2 EuroGentest Guidelines for Diagnostic Next Generation Sequencing ··············································· 751
Gert Matthijs（Center for Human Genetics, University of Leuven, Belgium）
Thu(5)-O55-3 Data sharing improves the diagnostic yield of clinical exome sequencing and identifies new disease genes
······················································································································································ 751
Koen L.I. van Gassen（Department Genetics, University Medical Center Utrecht, Netherlands）
Thu(5)-O55-4 The Undiagnosed Diseases Network International (UDNI): Clinical and Laboratory Research to Meet Patient
Needs ··········································································································································· 752
Paul F. Lasko（McGill University）
Thu(5)-O55-5 Need to concern about contamination by circulating fetal DNA ····················································· 752
Jianli Dong（Pathology, University of Texas Medical Branch, USA）
Thu(5)-O55-6 Preconception screening results for Mendelian diseases in East Asian populations ···························· 753
Michal Golan-Mashiach（Dr Gene Honk Kong limited, Hong Kong）
Room K (2F)
[O56] Cardiovascular Genetics 1 8:00-9:30

Chair：Elena V. Zaklyazminskaya（Medical Genetics Laboratory, Petrovsky Russian Research Centre of Surgery, Russia）
Chair ：Hiroko Morisaki（Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research
Institute, Japan）
ICHG2016 112
Thu(5)-O56-1 TTN truncating mutations double the diagnostic yield for DCM and NCCM patients; three years of experience
with a targeted panel for cardiomyopathies ························································································ 754
Marjon A van Slegtenhorst（Department of Clinical Genetics, Ee2475, Erasmus Medical Center, Netherlands）
Thu(5)-O56-2 Characterizing functional regulatory variants in iPSC-derived human cardiomyocytes ························ 754
Paola Benaglio（Pediatrics, UC San Diego, USA）
Thu(5)-O56-3 Genomic prediction of coronary heart disease ················································································ 755
Michael Inouye（Centre for Systems Genomics, University of Melbourne, Australia）
Thu(5)-O56-4 Fatty Acid Oxidation Genes in Childhood Arrhythmia: A Pathway Forgotten ··································· 756
Zahurul A Bhuiyan（Laboratoire de diagnostic moleculaire, University Hospital Lausanne (CHUV), Switzerland）
Thu(5)-O56-5 High prevalence of psycho-neurological complications are associated with mutation in SCN5A gene
······················································································································································ 756
Elena V. Zaklyazminskaya（Medical Genetics Laboratory, Petrovsky Russian Research Centre of Surgery, Rus-
sia/Pirogov Russian National Research Medical University）
Thu(5)-O56-6 Up-regulation of FLT1 by a novel functional SNP increases risk of coronary artery disease through an inflam-
matory activation ··························································································································· 757
Kouichi Ozaki（Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Japan）
[O57] Cardiovascular Genetics 2 9:45-11:15

Chair：Geneviève Galarneau（The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount
Sinai, USA）
Chair ：Takayuki Morisaki（Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Japan）
Day 5
Thu(5)-O57-1 Two common single nucleotide polymorphisms in the Renalase gene increase the susceptibility to essential
hypertension ·································································································································· 758
Amrita Anand Iyer（Department of Biotechnology, Indian Institute of Technology, Madras, India）
Thu(5)-O57-2 APOL1 risk allele is associated with early diagnosis of hypertension and a 2-3 mmHg increase in systolic blood
pressure in young African American adults ························································································ 758
Genevieve Galarneau（Icahn School of Medicine at Mount Sinai, USA）
Thu(5)-O57-3 DNA methylation in arteries and peripheral blood of patients with atherosclerosis ···························· 759
Anton V. Markov（Laboratory of Population Genetics, Research Institute of Medical Genetics, Russia/Tomsk
State University）
Thu(5)-O57-4 A locus near GRAMD1B is associated with serum level of atheroprotective anti-phosphorylcholine: genetic
effects shared with chronic lymphocytic leukemia ··············································································· 760
Xu Chen（Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden）
Thu(5)-O57-5 Familial Thoracic Aortic Aneurysms and Dissections (FTAAD) with ACTA2 Mutation in Japanese
······················································································································································ 760
Takayuki Morisaki（Bioscience and Genetics, and Medical Genetics, National Cerebral and Cardiovascular Center,
Japan）
Thu(5)-O57-6 Context-specific eQTLs implicate potential obesity-related transcriptional control by diet in men
······················································································································································ 761
Arthur Ko（Department of Human Genetics, University of California, Los Angeles, USA/Molecular Biology In-
stitute at UCLA）
Room H (1F)

Chair：Jian-Min Chen（INSERM U1078 and EFS-Bretagne, Brest, France）
Chair ：Issei Imoto（Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate
School, Japan）
Thu(5)-O58-1 Alternative Splicing in Response to Ionizing Radiation ·································································· 762

Niema Razavian（University of Michigan, Department of Pediatrics, Howard Hughes Medical Institute, USA）
Thu(5)-O58-2 RNA sequencing reveals stress responses of iPSC-derived endothelial cells isolated from peripheral blood
mononuclear cells of supercentenarians ····························································································· 762
Cristine R. Casingal（Division of Human Genetics, National Institute of Genetics, Japan/Department of Genetics,
The Graduate School for Advanced Studies, Kanagawa, Japan）
ICHG2016 113
Thu(5)-O58-3 Differential extracellular abundance of COG5 in synovial fluid following meniscal injury supports its role as a
major susceptibility gene for knee osteoarthritis ·················································································· 763
Liyong Wang（John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine,
USA/Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of
Medicine）
Thu(5)-O58-4 Heterogeneity in the individual transcriptomic response to severe sepsis ·········································· 764
Katie L Burnham（Wellcome Trust Centre for Human Genetics, UK）
Thu(5)-O58-5 Inter-individual Variations in Nature and Diversity of Human Facial Skin Microbiome are Significantly Predicted
by Sebum and Hydration Levels in Specific Facial Regions ··································································· 764
Souvik Mukherjee（BioMedical Genomics Centre, National Institute of Biomedical Genomics, India）
Thu(5)-O58-6 Meta-analysis of 1343 small complex mutations causing human inherited disease reveals a new mutational
signature characteristic of the action of translesion synthesis DNA polymerases in the human genome
······················································································································································ 765
Jian-Min Chen（Institut National de la Sante et de la Recherche Medicale (INSERM), U1078, Brest,
France/Etablissement Francais du Sang (EFS) Bretagne, Brest, France/Faculte de Medecine et des Sciences
de la Sante, Universite de Bretagne Occidentale (UBO), Brest, France）
[O59] Health Services Research 9:45-11:15

Chair：Beatriz Marcheco-Teruel（National Center of Medical Genetics, Havana, Cuba）
Chair ：Hiroshi Tanaka（Tohoku Medical Megabank Organization, Tohoku University, Japan）
Thu(5)-O59-1 Impact of Genome Sequencing on the Medical Care of Healthy Adults: A Randomized Controlled Trial
Day 5
······················································································································································ 766
Jason L. Vassy（VA Boston Healthcare System, Harvard Medical School, USA/Brigham and Womens Hospital,
Harvard Medical School）
Thu(5)-O59-2 Assessing the Clinical Utility of Family Health History for Guiding Preventive Care in the General Population
······················································································································································ 766
Lori A Orlando（Medicine, Duke University, USA）
Thu(5)-O59-3 A national program for preventing sickle cell anemia: the 30 years Cuban experience ························· 767
Thu(5)-O59-4 Epidemiology and health system impact of true-positive and false-positive newborn screening results for
phenylketonuria in Ontario, 2006-2012 ······························································································ 768
Thu(5)-O59-5 Three Dimentional Motion Capture System for Quantitative Evaluation of Motor Functions applied to Healthy
Adult and Spinal Muscular Atrophy Patient with Thyrotropine Releasing Hormone Therapy ···················· 768
Naoki Matsumaru（Global Regulatory Science, Gifu Pharmaceutical University, Japan/Division of Structural
Medicine, The United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University）
Thu(5)-O59-6 Informing policy and practice: a 360 degree evaluation of the impact of prospective WES in comparison to
standard care ································································································································· 769
Program
The 40th Annual Meeting of the Japanese Society for Genetic
Counseling
ICHG2016 115
Sun.,April 03
Day 1
Day 1
Sakura (1F)
[40th JSGC] Opening Remarks 13:10-13:15
···················································································································································· 1354
[40th JSGC] [SY1] Symposium 1

Lessons that Jaoan Can Learn from Other Genetic Counseling Systems 13:15-15:30
Chair：Akihiro Sakura（Department of Medical Genetics, Sapporo Medical University School of Medicine）
Chair：Rei Fukuda（Department of Medical Genetics and Genomics, Kitasato University Graduate School of Medical Sciences）
SY1-1 The Current Status of Genetic Counselors in Japan ············································································· 1343

Yasuko Yamanouchi（Genetic Counceling Program, Department of Social Work, Faculty of Health and Welfare,
Graduate School of Health and Welfare, Kawasaki University of Medical Welfare）
SY1-2 The Current Status of Genetic Counselors in the US ············································································ 1344
Anne Greb（Joan H. Marks Graduate Program in Human Genetics, Sarah Lawrence College）
SY1-3 The Current Status of Genetic Counselors in the UK and Australia ························································ 1345
Clara Gaff（Melbourne Genomics Health Alliance, University of Melbourne）
SY1-Closing Remarks ···································································································································· 1346
ICHG2016 116
Mon.,April 04
Day 2
Sakura (1F)
Day 2
[40th JSGC] [O1] Genetic counseling 1 8:10-9:00
Chair：Hiroki Kurahashi（Division of Molecular Genetics, ICMS, Fujita Health University）
Chair ：Mari Urano（Institute of Medical Genetics, Tokyo Women’s Medical University）
O-01 A case study of a baby with CHARGE syndrome and the family -involvement from hospitalization in the NICU,
transfer to pediatrics pregnancy and giving a second baby birth- ··························································· 1357
Mikiko Kaneko（Institute of Medical Genetics, Tokyo Women’s Medical University）
O-02 A case with de novo 4q deletion ········································································································ 1357
Akio Shibata（Department of Pediatrics, Hyogo College of Medicine, Nishinomiya, Japan）
O-03 Treatment and Education for autism spectrum disorder in Down syndrome children. ······························· 1358
Junko Kato（Genetic Counseling Department of Clinical Laboratory Medicine, Graduate School of Health Sciences,
Fujita Health University, Aichi, Japan）
O-04 A patient diagnosed as Noonan syndrome by pediatric cardiologist, whose guardian is able to accept the diagnosis
at outpatient under diagnosed congenital chylothorax and Mental retardation. ········································ 1358
Kenta Tominaga（Department of Cardiology, Hyogo Prefectural Kobe Children’s Hospital）
O-05 4 cases of 13trisomy under cardiac surgery at pediatric heart Center in Kobe Children’s Hospital ·············· 1359
Kenta Tominaga（Department of Cardiology, Hyogo Prefectural Kobe Children’s Hospital）

Chair：Osamu Samura（Department of Obstetrics and Gynecology, The Jikei University School of Medicine）
Chair ：Kayono Yamamoto（Department of Clinical Genetics, Iwate Medical University）
O-06 Learning from 3 adult cases of genetic counseling provided to inherited carriers diagnosed in the neonatal period
······················································································································································ 1361
Toshiya Nishikubo（Division of Neonatal Intensive Care, Center for Perinatal Medicine, Nara Medical University
Hospital）
O-07 Genetic counseling for couples with balanced structural chromosomal aberrations (couples) ······················ 1361
Michiko Ammae（IVF Namba Clinic）
O-08 Genetic counseling for chromosome abnormality found in the examine of infertility or miscarriage - the role of clinical
genetics division ······························································································································ 1362
Motoko Sasaki（Devision of Clinical Genetics, Nippon Medical School Hospital）
O-09 The current state of our genetic counseling and chromosome analysis ···················································· 1363
Mayuko Machida（Kyono ART Clinic Takanawa）
O-10 A genetic counseling case in which the confirmation of the intention of the couple became difficult because of the
presence of their mother ·················································································································· 1363
Saeko Katsumoto（Adachi Hospital）
[40th JSGC] [SL] Special Lecture

Psychosocial Genetic Counseling 13:30-14:30
Chair：Shinji Kosugi（Department of Medical Ethics/Medical Genetics / School of Public Health,Kyoto University / Clinical
Genetics Unit,Kyoto University Hospital）
SL Psychosocial Genetic Counseling ······································································································· 1342

Anne Greb（Joan H. Marks Graduate Program in Human Genetics, Sarah Lawrence College）
[40th JSGC] [EL1] Educational Lecture 1

TEACCH Autism Program 14:40-15:30
Chair：Tomoko Hashimoto-Tamaoki（Department of Genetics, Hyogo College of Medicine）
ICHG2016 117
EL1 TEACCH Autism Program ··············································································································· 1338

Toshiaki Suwa（Department of Social Work, Faculty of Health and Welfare, Graduate School of Health and
Welfare, Kawasaki University of Medical Welfare）
Day 2
Chair：Fumio Nomura（Divisionsof Clinical Mass Spectrometry and Clinical Genetics, Chiba University Hospital）
Chair ：Naomi Araki（Department of Genetics and Genomics, Kitasato University Hospital）
O-11 The role of certified genetic counselor in autosomal dominant polycystic kidney disease (ADPKD) medical team
······················································································································································ 1365
Yuri Yasuda（Japanese Red Cross Ishinomaki Hospital, Genetic Counseling and Clinical Study Support Section）
O-12 Factors that affect decision in pregnancy and delivery in Marfan syndrome ············································· 1365
Ikumi Moriyama（Division of Genetic Counseling, Department of Clinical Laboratory Medicine, Graduate School
of Health Science, Fujita Health University, Aichi, Japan）
O-13 Looking for an ideal genetic team?–Review of three genetic centres in Japan and UK- ····························· 1366
Akane Kondo（Clinical Genetics Center, Shikoku Medical Centre for Children and Adults/Clinical Genetics, Tokai
University School of Medicine）

Chair：Mitsuo Masuno（Department of Social Work, Faculty of Health and Welfare, Graduate School of Health and Welfare,
Kawasaki University of Medical Welfare）
Chair ：Junko Yotsumoto（Genetic Counseling Program, Natural Sciences Division, Faculty of Core Research, Ochanomizu
University）
O-14 Effects of genetic counselor self-disclosure on clients ············································································ 1367

Yosuke Konishi（Genetic Counseling Program, Master’s Program in Social Work, Graduate School of Health and
Welfare, Kawasaki University of Medical Welfare, Kurashiki, Japan）
O-15 Developing a tool for genetic counseling generating a log file to assess charactristics of genetic counseling contents
······················································································································································ 1368
Kyoko Takai（Cancer Prevention & Cancer Gene Laboratory, Tochigi Cancer Center/Cancer Prevention & Genetic
Counseling Clinic, Tochigi Cancer Center）
O-16 GenieDraw; Genetic trace, Interactive and Easy Draw tool in genetic counseling ······································ 1368
Junko Tatsumi-Miyajima（Deparatment of Life Science, Faculty of Science and Engineering, Kinki Univer-
sity/Genetic Counselor Training Course, Graduate School of Science and Engineering, Kinki University）

Chair：Tomoki Kosho（Department of Medical Genetics, Shinshu University School of Medicine）
Chair ：Hiromi Murakami（Clinical Genetic Unit, Kyoto University Hospital）
O-17 Problems of genetic counseling for children that diagnosed definitively NF1 or suspected of NF1 ··············· 1370
Noriyasu Sakai（Department of Dermatology, Tokyo Medical University）
O-18 Genetic counseling on preimplantation/prenatal genetic diagnosis for incontinentia pigmenti ····················· 1370
Miki Kawai（Division of Genetic Counceling, Department of Clinical Laboratory Medicine, Graduate School of
Health Sciences, Fujita Health University）
O-19 Prenatal genetic test for rare diseases ······························································································· 1371
Mariko Taniguchi-Ikeda（Kobe University, Department of Pediatrics/Kobe University Hospital, Division of Genetic
Counseling）
O-20 The Client’s Attitude Surrvey after Invasive or Non-Invasive prenatal testing ·········································· 1371
Midori Fujita（Departmernt of Genetic Medicine, Osaka City General Hospital/Nursing Section, Osaka City
General Hospital）
O-21 Gender differences in thinking affect the choice to pursue pregnancy by gamete donation and/or adoption
······················································································································································ 1372
Maki Kato（Division of Genetic Counseling, Department of Clinical Laboratory Medicine, Graduate School of
Health Sciences, Fujita Health University, Aichi, Japan）
ICHG2016 118
O-22 Exploration of pregnancy conflict counseling in Germany - construction of a support system for couples after prenatal
testing in Japan - ···························································································································· 1372
Motoko Watanabe（Graduate School of Humanities and Sciences, Ochanomizu University/Institute of Medical
Genetics, Tokyo Women’s Medical University）
Day 2
[40th JSGC] [O6] Hereditary tumor 18:05-18:45
Chair：Kazuo Tamura（Department of Life Science, Faculty of Science and Engineeering, Kindai University）
Chair ：Emi Utsuno（Clinical Genetics, Chiba University Hospital）
O-23 A retrospective cohort of Asian patients with Birt-Hogg-Dube syndrome ················································ 1374
Mitsuko Furuya（Dept. Mol. Pathol., Yokohama City Univ. Grad. Sch. Med.）
O-24 Clinical features of colorectal cancer in proven mutation carriers of Lynch syndrome in a Japanese population
······················································································································································ 1374
Kohji Tanakaya（Department of Surgery, Iwakuni Clinical Center）
O-25 Genetic counseling for familiar or hereditary breast and ovary cancer syndrome in Chiba University Hospital -From
a standpoint of a genetic counselor ···································································································· 1375
Emi Utsuno（Clinical Genetics Chiba University Hospital）
O-26 Communication with children and siblings before and after BRCA1/2 testing among Japanese breast cancer patients
······················································································································································ 1375
Mayuko Inuzuka（Showa University, Breast Center）
[40th JSGC] [O7] Genetics education 18:45-19:35

Chair：Akihiro Sakurai（Departmeint of Medical Genetics, Sapporo Medical University School of Medicine）
Chair ：Noriko Sasaki（Unit of Nursing, Health Science, Nagasaki University Graduate School of Biomedical Sciences）
O-27 Local residents’ attitude about cancer family and the future task found out by conducting trial genetic counseling
······················································································································································ 1377
Hitomi Yoshida（Daiyukai Health System, Genetic Counseling Room）
O-28 The CiTi Japan Program introduced into undergraduate medical education ············································ 1377
Tomoko Hashimoto-Tamaoki（Department of Genetics, Hyogo College of Medicine/Department of Clinical Ge-
netics, Hyogo College of Medicine）
O-29 Genetics study seminar for all medical staffs arranged by cytogenetics laboratory -Improvement of genetics literacy
in a medical center in Japan- ············································································································ 1378
Michiko Sone（Laboratory of Cytogenetics of Shikoku Medical Center for Children and Adults/Clinical Genetics
of Shikoku Medical Center for Children and Adults）
O-30 Intention Changes in the Participants of JSND Annual Meeting after the Symposium on Genetics ············· 1379
Ruriko Horio（Center for Advanced Medical Science and Technology, Midtown Clinic Medical Corporation）
O-31 Tasks of Department of Clinical Genetics and a genetic counselor for the institutional Ethical Committee
······················································································································································ 1379
Chika Sato（Department of Clinical Genetics, Hyogo College of Medicine）
ICHG2016 119
Tue.,April 05
Day 3
Sakura (1F)
[40th JSGC] [O8] Perinatal period 8:10-9:00

Chair：Akimune Fukushima（Department of Clinical Genetics, School of Medicine, Iwate Medical University）
Chair ：Yuki Sato（Department of Genetic Counseling, Osaka University Hospital）
O-32 Decision making for maternal serum screening (MSS) users ·································································· 1380
Day 3
Akiko Toko（Yamaguchi Women’s Hospital）
O-33 Features of genetic counseling in noninvasive prenatal genetic testing in our hospital: Study of factors that inhibit
the autonomous decision-making of the couple ··················································································· 1380
Kosuke Kawakami（National Hospital Organization Kokura Medical Center）
O-34 Collaboration of Multiple Specialties for Education of Infertile Patients about Pregnancy at Advanced Women’s
Age ··············································································································································· 1381
Ayumi Yamamoto（Sunkaky Medical Corporation IVF Osaka Clinic）
O-35 A Case in Which Trisomy 18 Positive Was Detected At a Re-examination Following Indeterminant NIPT with Normal
Fetal Karyotype by Amniotic Fluid Chromosomal Test and The Confined Placental Mosaicism by a Microarray
Analysis ········································································································································· 1382
Kei Hayata（Departments of Obstetrics and Gynecology, Okayama University Graduate School of Medicine,
Dentistry and Pharmaceutical Science）
O-36 Successful management of pregnant patient with ornithine transcarbamylase deficiency (OTCD): a case report
······················································································································································ 1382
Tomo Suzuki（Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health
and Development）

Social support to the Genetic Diseasepatients and their families 9:10-10:00
Chair：Junko Tatsumi-Miyajima（Department of Life Science, Faculty of Science and Engineering, Kindai University）
EL2 Social support to the Genetic Diseasepatients and their families ···························································· 1339
Kenichi Ono（Department of Psychiatry, Tokyo Women’s Medical University Hospital / Department of Studies
on Contemporary Society, Keisen University）
[40th JSGC] General Meeting 13:45-14:45
···················································································································································· 1353
[40th JSGC] [PL] Presidential Lecture

The Future of Genetic Counseling - The Certified Genetic Counselor 14:50-15:20
Chair：Hiroshi Kawame（Department of Education and Training, Tohoku University）
PL The Future of Genetic Counseling - The Certified Genetic Counselor ······················································ 1341
Yasuko Yamanouchi（Genetic Counceling Program, Department of Social Work, Faculty of Health and Welfare,
Graduate School of Health and Welfare, Kawasaki University of Medical Welfare）
[40th JSGC] [SY2] Symposium 2

What’s the future of genetic counseling for prenatal diagnosis? 15:40-17:30
Chair：Hiroshi Kawame（Department of Education and Training, Tohoku University）
Chair ：Hidehiko Miyake（Clinical Genetic Unit, Kyoto University Hospital）
ICHG2016 120
SY2-1 Clinical utility of prenatal imaging in detection of fetal anomaly. ··························································· 1347
Kiyonori Miura（Department of Obstetrics and Gynecology, Nagasaki University Graduate School of Biomedical
Sciences）
SY2-2 The merits and demerits of obtaining genomewide information of the fetus. ··········································· 1348
Tamae Ohye（Faculty of Medical Technology, School of Health Sciences, Fujita Health University）
SY2-3 Advances in Fetal Therapy ··············································································································· 1349
Seiji Wada（Devision of Fetal Medicine, National Center for Child Health and Development）
SY2-4 Changing Points and Unchanging Ones of Ethical issues on Prenatal Diagnosis in the near future ············· 1350
Naoto Kawahara（Department of Clinical Research Promotion, Kyushu University Hospital）
SY2-5 How to manage large quantities of information regarding fetuses in prenatal genetic counseling: a clinical report.
······················································································································································ 1351
Kayono Yamamoto（Iwate Medical University, Department of Clinical Genetics）
Day 3
Closing Remarks What’s the future of genetic counseling for prenatal diagnosis? ··················································· 1352
[40th JSGC] Poster Discussion (odd number) 17:30-18:30
P-01 A case of ring Y chromosome in male infertility ·················································································· 1391

Sachi Morimoto（Department of Gynecology, Chiba University Graduate School of Medicine）
P-03 Wolf-Hirschhorn syndrome and 22q11.2 deletion syndrome in a patient ·················································· 1391
Yuko Mishima（Osaka Medical Center and Research Institute for Maternal and Child Health Department of
Medical genetics）
P-05 An atypical case of Sotos syndrome with diaphragmatic hernia ····························································· 1392
Naomi Araki（Department of Genetics and Genomics, Kitasato University Hospital/Department of Medical Ge-
netics and Genomics, Kitasato University Graduate School of Medical Sciences）
P-07 The genetic counceling of two cases which were suspected of lethal body stalk anomaly ·························· 1393
Mariko Matsumoto（Japanese Red Cross Kyoto Daiichi Hospital）
P-09 Current status and issues of genetic counseling for the HBOC in Hiroshima University Hospital ················ 1393
Yasuko Yamamoto（Department of Obstetrics and Gynecology, Graduate School of Biomedical and Health Sci-
ences, Hiroshima University）
P-11 Feasible surveillance program in genetic counseling for Li-Fraumeni syndrome ········································· 1394
Shigeko Kido（Genetic Counselor Training Program, Division of Biological and Environmental Chemistry, Master
of Science, Graduate School of Science and Engineering Reserach, Kinki University）
P-13 Survey regarding genetic counseling, health management, and registration of female dystrophinopathy patients
······················································································································································ 1394
Michio Kobayashi（Department of Neurology, National Hospital Organization Akita National Hospital）
P-15 Dilemma in data provision related to the variants of unknown significance on X-chromosome identified in male
propositus ····································································································································· 1395
Toshiyuki Yamamoto（Tokyo Women’s Medical University Institute for Integrated Medical Sciences）
P-17 A simple preprocessing method for whole sequencing of human mitochondrial genome ····························· 1396
Motoi Nishimura（Division of Clinical Genetics, Chiba University Hospital/Department of Molecular Diagno-
sis,Graduate School of Medicine, Chiba University/Division of Laboratory Medicine Chiba University Hospital）
P-19 Two cases of trisomy 18, with different responses by the parents upon prenatal diagnosis ························· 1396
Kimi Nakashima（University of Occupational and Environmental Health, Japan Perinatal Medicine Center）
P-21 The management of the cases suspected trisomy 18 in fetal ultrasonography ·········································· 1397
Emi Kondo（Department of Obstetrics and Gynecology, National Hospital Organization Kokura Medical Center）
P-23 A case of Kagami-Ogata syndrome due to low methylation in the region 14q32 ······································ 1397
Yoko Onishi（Center for Perinatal Care, Child Health and Development, Kitasato University Hospital）
P-25 Counseling experience following recurrent prenatal diagnosis of autosomal recessive polycystic kidney disease
(ARPKD) in consecutive pregnancy case ···························································································· 1398
Mayumi Okada（Toyohashi Municipal Hospital, Department of Obstetrics and Gynecolocy）
P-27 Study of noninvasive prenatal genetic testing cases in our center ··························································· 1399
Yuko Tamaki（Toho University Omori Medical Center, Department of Obstetrics and Gynecology/Toho University
Omori Medical Center, Department of Medical Genetics）
ICHG2016 121
P-29 Villous chromosomal analysis of the spontaneous abortion of patients with infertility or habitual abortion and the
significance of genetic counseling ······································································································ 1399
Tetsuaki Hara（Division of Reproductive Medicine, Hiroshima Prefectural Hospital, Hiroshima, Japan）
P-31 Various backgrounds of amniocentesis examinees under 35 years of age at our hospital ···························· 1400
Maya Takamoto（Department of Obstetrics and Gynecology, National Center for Global Health and Medicine）
P-33 The Complications of Amniocentesis in St. Luke’s International Hospital ··············································· 1400
Fumi Akitani（Department of Clinical Genetics, St.Luke’s International Hospital）
P-35 Does the prenatal counseling not specialized in NIPT affect the client’s decision of prenatal diagnosis?
······················································································································································ 1401
Yoko Okamoto（Osaka Medical Center and Research Institute for Maternal and Child Health, Department of
Obstetrics）
Day 3
P-37 Role of the area core hospital in heredity practice considered from the viewpoint of genetic amniocentesis
······················································································································································ 1402
Chikako Ogawa（Fukuyama Medical Center）
P-39 The psychological effect of a new experiment of feeling a new life "on prenatal diagnosis" ························ 1402
Yutaka Kyukawa（Yutaka Maternity Ultrasound Clinic）
P-41 Genetic counseling for non-invasive prenatal testing ············································································· 1403
Mina Nakama（Department of Clinical and Molecular Genetics, Gifu University Hospital）
P-43 An approach of genetic counseling for infertility women of advanced maternal age ·································· 1403
Fumiko Tawara（Tawara IVF Clinic）
P-45 A descriptive study on fulfilling fundamental human needs of adults with Prader-Willi Syndrome ·············· 1404
Satoko Nakagomi（University of Yamanashi）
P-47 Changes in awareness regarding genetic examination and genetic counseling among patients with breast cancer who
experienced the Great East Japan Earthquake ····················································································· 1405
Kenji Gonda（International Medical Center Saitama Medical University）
P-49 The Current Situation of a Care System Intended for Certified Genetic Counselors(CGCs): A Literature Review
······················································································································································ 1405
Ayumi Yonei（Genetic Counselor Course, Kyoto University School of Public Health, Kyoto, Japan）
P-51 Genetic counseling for a family with Charcot-Marie-Tooth disease ························································· 1406
Yoko Kanbara（Tokyo Metropolitan Kita Medical and Rehabilitation Center for the Disabled, Nursing Depart-
ment/Department of Genetic Counseling, Graduate School of Humanities and Sciences, Ochanomizu University,
Tokyo, Japan）
P-53 Genetic counseling for the result of a company’s personal exome sequencing: a case report ······················ 1407
Hiroko Terui-Kohbata（Bioethics Research Center, Tokyo Medical and Dental University/Department of Medical
Genetics, Medical Hospital of Tokyo Medical and Dental University）
P-55 Trial of Genetic Education for Elementary School Students ··································································· 1407
Kaoru Masui（Kinki University, Graduate School of Science and Engineering, Genetic Counselor Training Course）
P-57 Genetic Education in Department of Clinical Genetics in Tokai University Hospital ·································· 1408
Yuko Ohnuki（Department of Clinical Genetics Tokai University Hospital/Department of Molecular Life Science,
Basic Medical Science and Molecular Medicine, Tokai University School of Medicine）
P-59 The survey on psychological situation of pregnant women and their partners interested in prenatal testing: a
single-site study ······························································································································ 1408
Mikiko Izumi（Center for Clinical Genetics, Showa University Hospital/Department of Obstetrics and Gynecology,
Showa University School of Medicine）
P-61 Public attitude and opinions toward genetic technology: A cross-sectional survey in Japan ······················· 1409
Tomoko Watanabe（Center for Medical Genetics, Keio University School of Medicine）
P-63 Evaluating the online utilization of educational materials about genetics for client ··································· 1409
Daiki Ae（Kinki University, Graduate School of Science and Engineering, Genetic Counselor Training Course）
ICHG2016 122
Wed.,April 06
Day 4
Sakura (1F)

A comprehensive team approach for a patient with a cleft lip and cleft palate 10:05-10:55
Chair：Norio Sakai（Division of Health Sciences, Child Healthcare and Genetic Science Laboratory, Osaka University Graduate
EL3 A comprehensive team approach for a patient with a cleft lip and cleft palate ········································· 1340
Hiroshi Kamioka（Department of Orthodontics, Okayama University Graduate School of Medicine, Dentistry, and
Pharmaceutical Sciences）
[40th JSGC] [O9] Neuromuscular disease 11:00-11:50
Day 4
Chair：Kayoko Saito（Institute of Medical Genetics, Tokyo Women’s Medical University）
Chair ：Chika Sato（Department of Clinical Genetics, Hyogo College of Medicine）
O-37 Longitudinal research on psychological changes in a subject clinically diagnosed as spinocerebellar degeneration
(SCD) and his spouse following genetic counseling ·············································································· 1384
Ikuyo Mochiki（Center for Medical and Nursing Education, Mie University Faculty of Medicine/Division of Per-
sonalized Medicine, Mie University Hospital）
O-38 Genetic counseling for Spinal and Bulbar Muscular Atrophy ·································································· 1384
Miki Hida（Department of Clinical Genetics, National Hospital Organization Kyoto Medical Center/Department
of Clinical Laboratory, National Hospital Organization Kyoto Medical Center）
O-39 Intelligent quotient profile in spinal muscular atrophy ··········································································· 1385
Mari Urano（Tokyo Women’s Medical University, Institute of Medical Genetics）
O-40 Toward construction of support systems for female dystrophinopathies ··················································· 1386
Tsuyoshi Matsumura（Department of Neurology, National Hospital Organization Toneyama National Hospital）
O-41 Questionnaire survey of mothers of Duchenne muscular dystrophy patients on received treatment, genetic testing,
and genetic counseling ····················································································································· 1386
Masatoshi Ishizaki（Department of Neurology, National Hospital Organization Kumamoto Saishunso National
Hospital）
[40th JSGC] [O10] Genetic testing 11:50-12:10

Chair：Kenji Kurosawa（Division of Medical Genetics, Kanagawa Children’s Medical Center）
Chair ：Tamae Ohye（Faculty of Medical Technology, School of Health Sciences, Fujita Health University）
O-42 Public attitude survey for the reporting incidental findings of clinical genome sequence ···························· 1388
Kazuo Kanyama（Division of Genetic Counseling, Department of Clinical Laboratory Medicine, Graduate School
of Health Sciences, Fujita Health University, Aichi, Japan）
O-43 The management of secondary findings with genetic counseling in human genome sequencing. ················· 1389
Kazuyuki Matsushita（Graduate School of Medicine, Chiba University, Department of Molecular Diagnosis/Chiba
University Hospital, Division of Clinical Laboratory/Chiba University Hospital, Division of Clinical Genetics）
[40th JSGC] Poster Discussion (even number) 13:45-14:45
P-02 Genetic counseling for parents of an Emanuel syndrome patient five years after diagnosis ························· 1411
Mari Tsubata（Center for Genomic Medicine, Tohoku University Hospital, Sendai, Japan）
P-04 Two cases with MECP2 duplication syndrome ····················································································· 1411
Hideki Shimomura（Department of Pediatrics, Hyogo College of Medicine, Nishinomiya, Japan）
P-06 Genetic counseling and comprehensive care of Pitt-Hopkins syndrome ···················································· 1412
Keiko Matsuda（Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and
Child Health）
ICHG2016 123
P-08 The onset frequency of various symptoms in Fabry females : meta-analysis ············································· 1413
Satomi Higashigawa（Department of Genetic Counseling, Graduated School of Humanities and Sciences, Ochan-
omizu University）
P-10 Two cases of women with suspected hereditary breast and ovarian cancer and teenage relatives ················ 1413
Koji Kumagai（Department of Gynecology, Osaka Railway Hospital）
P-12 Genetic counseling for cases of spinocerebellar ataxia with combined deleterious mutations of two different genes
······················································································································································ 1414
Minako Beppu（Chiba University Hospital, Division of Clinical Genetics）
P-14 Genetic counseling for sensorineural hearing loss with dominant inheritance of the R143Q mutation in GJB2 in a
Japanese family ······························································································································ 1414
Hirokazu Sakamoto（Hyogo Prefectural Kobe Children’s Hospital）
P-16 Clinical next generation sequencing for genetic counseling of genetic syndromes ······································ 1415
Yuto Yamamoto（Osaka Medical Center and Research Institute for Maternal and Child Health）
P-18 Genetic Counseling for Down syndrome with Dementia ········································································ 1416
Chisen Takeuchi（Tokyo Metropolitan Kita Medical and Rehabilitation Center for the Disabled, Department of
Neurology/Tokyo Women’s Medical University, Department of Neurology）
Perinatal management of 18 trisomy cases in our intitute ····································································· 1416
Day 4
P-20
Takako Suzuki（Amagasaki General Medical Center）
P-22 Three Repeated Cases of Fetal Cystic Hygroma in the First Trimester ·················································· 1417
Yukiko Chinen（The University of the Ryukyus Hospital, Obstetrics Department）
P-24 An experience of preclinical diagnosis of ADPKD that following neonatal death through potter sequence
······················································································································································ 1417
Haruka Muto（Osaka Medical Center and Research Institute for Maternal and Child Health）
P-26 Considering of the effect and issue of NIPT from the change in the system of the Prenatal Test ··············· 1418
Maki Hyodo（Hiroshima University Hospital Obstetrics and Gynecology / Clinical and Molecular Genetics）
P-28 The background of the couples who received the non-invasive prenatal testing in Japan, a single center analysis
······················································································································································ 1418
Yuki Fujiwara（Genetic Counseling Center, Dokkyo Medical University Koshigaya Hospital）
P-30 Relation between maternal age and decision to choose prenatal tests ····················································· 1419
Kaori Arima（Department of Obstetrics and Gynecology, Japanese Red Cross Medical Center, Tokyo, Japan）
P-32 The examination of amniocentesis cases in first trimester prenatal screening unit ···································· 1420
Takumi Sano（Department of Obstetrics and Gynecology Osaka Medical College）
P-34 Current Practice of Perinatal Genetic Counseling at St. Luke’s International Hospital ······························ 1420
Yoshiaki Mizuno（Department of Clinical Genetics, St. Luke’s International Hospital）
P-36 Prenatal genetic counseling for women of advanced maternal age at Adachi hospital: a comparison of attitude by
parity ············································································································································· 1421
Ichiro Yamade（Adachi Hospital）
P-38 Examination of the sex chromosomes constitution disclosure of amniotic diagnosis ·································· 1421
Rina Takahashi（Department of Genetic Counseling, Graduate School of Humanities and Sciences, Ochanomizu
University）
P-40 NIPT carried out in our hospital ······································································································· 1422
Hiromi Sanai（Yamaguchi Grand Medical Center）
P-42 Our new approach about prenatal genetic consultations ~ with the aim of cooperation between ambulatory and
delivery ward ~ ······························································································································ 1423
Mari Shinoda（Department of Obstetrics and Gynecology, Tokai University School of Medicine/Department of
Clinical Genetics, Tokai University Hospital）
P-44 Timing of Gonadectomy in Patients with Complete Androgen Insensitivity Syndrome ······························· 1423
Ayaka Sakakibara（Department of Medical Genetics and Genomics, Kitasato University Graduate School of
Medical Sciences, Genetic Counseling Training Program in Master’s Course）
P-46 Genetic counseling of Noonan syndrome ··························································································· 1424
Kazumi Kawato（Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal
and Child Health, Osaka, Japan）
P-48 A client’s companion shows the client’s social and psychological situation ·············································· 1424
Manami Matsukawa（Genetic Counselor Course, Kyoto University School of Public Health, Kyoto, Japan）
P-50 Who could have imagined? She is alive at home happily. A Case of Hypophosphatasia ···························· 1425
Kiyoko Sameshima（Division of Medical Genetics, Gunma Children’s Medical Center）
ICHG2016 124
P-52 Support for the mother having the children who had a diagnosis of trisomy 21 after birth ························ 1425
Yuko Sato（Tokyo Women’s Medical University Hospital）
P-54 Discussion of the relationship how to the client after delivery and treatment of genetic counselors in our hospital
······················································································································································ 1426
Yuki Kuwahara（Ladies & Maternity Clinic SANTA CRUZ）
P-56 Improving Genetic Literacy Using Family Trees and Good Health for Local Residents ······························· 1427
Naoko Nakagawa（Center for Promoting Next-Generation Highly Advanced Medicine, Tottori University Hospi-
tal/Department of Clinical Genetics, Tottori University Hospital）
P-58 Concern of pregnant women in the first trimester with regard to diagnostic methods, therapy, and heredity of
diabetes mellitus ····························································································································· 1427
Hisaaki Kobayashi（Dept. of Obstetrics & Gynecology, Nishisaitama Chuo National Hospital）
P-60 Self-Perception of People with Down Syndrome in Japan ····································································· 1428
Mio Wakai（Department of Genetic Counseling, Graduate School of Humanities and Sciences, Ochanomizu Uni-
versity）
P-62 The concern about the medical ethics in a district children hospital and current approach to the ethical problems
······················································································································································ 1428
Yuri Dowa（Department of Neurology, Gunma Children’s Medical Center）
Day 4
P-64 Development of Family medical tree drawing software for genetic counseling ·········································· 1429
Shuhei So（Tawara IVF Clinic）
[40th JSGC] Greeting from President-elect / Closing Remarks 18:20-18:30
···················································································································································· 1355
Abstracts
Plenary Lecture
Plenary Closing Symposium
Pre-Congress Symposium
Concurrent Invited Session
Workshop
Special Focus Session
Educational Program
Young Investigator Awards Session
Luncheon Seminar
Opening/Closing Ceremony
Gala Dinner
Get-together
ICHG2016 126
[PL1] Plenary Lecture 1
Plenary Lecture
Mon., April 04, 2016 10:30-12:00 Main Hall (1F)
Chair：Helena Kääriäinen（Research Professor at National Institute for Health and Welfare, Helsinki; Clinical Geneticist,
Finland）
Chair ：Shoji Tsuji（Department of Neurology and Medical Genome Center, The University of Tokyo Hospital; Medical
Mon(2)-PL1-1
Recent Progress in iPS Cell Research and Application
1
Shinya Yamanaka
1:Center for iPS Cell Research and Application (CiRA), Kyoto University, Japan
The appeal of induced pluripotent stem cells (iPSCs) is that they can proliferate almost indefinitely and differentiate into
multiple lineages. As a result, cell-based therapies, disease mechanisms and new drug development are being studied world-
wide using iPSC technology.We are currently establishing technologies for the efficient generation of safe iPSCs. The original
iPSCs were made from retroviral transduction, which risks chromosomal damage. We have since reported an integration-free
method using episomal vectors. Further, we have proposed the use of L-Myc to reduce the risk of tumorigenicity while main-
taining iPSC induction at high efficiency. We have also removed the need for conventional feeder cells or culture materials
from different species but consistent with regulatory requirements for medical practice by having developed a recombinant
laminin-based matrix and a culture medium free of animal-derived constituents (xeno-free). Regarding quality control, some
marker genes for neural differentiation-defective clones were identified, indicating the possibility of screening out low-quality
iPSCs before use.In 2014, the world’s first clinical study using iPSCs was initiated. iPSC-based therapies for other disorders
are also nearing clinical study, suggesting applicability to many diseases. To push these efforts, we are proceeding with an
iPSC stock project in which iPSC clones are established from donors with a homologous HLA haplotype, which lessens the
risk of transplant rejection, with the aim of quality-assured iPSCs for future cell therapies.Another application of iPSCs is
drug screening, toxicity studies and the elucidation of disease mechanisms. In addition, iPSCs may be resourceful for preven-
tative measures, as they make it possible to predict the patient condition and provide a preemptive therapeutic approach to
protect against the onset of the disease. Additionally, accumulating evidence is demonstrating the benefits of iPSCs in drug
repositioning.
[Introduction]
Professor Shinya Yamanaka is most recognized for his discovery of induced pluripotent stem cells (iPSC), which are differen-
tiated cells that have been reprogrammed to the pluripotent state. He is Director of the Center for iPS Cell Research and
Application (CiRA), which was founded in 2008 at Kyoto University in response to his discovery, and Senior Investigator
at the Gladstone Institutes in San Francisco. He has received many prestigious awards, and the significance of iPSC was
culminated with Dr. Yamanaka being awarded the Nobel Prize in 2012. To bring iPSC technology to human health care,
at CiRA, he has recruited a mixture of scientists conducting basic research and clinicians applying this research to disparate
diseases.
[Biography]
Shinya Yamanaka received a M.D. from Kobe University in 1987 and a Ph.D. from Osaka City University in 1993. He was
a postdoctral fellow at the the Gladstone Institutes between 1993 and 1996, Assistant Professor at Osaka City University
between 1996 and 1999, and finally Associate Professor and then Professor at Nara Institute of Science and Technology
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ICHG2016 127
between 1999 and 2004. Thereafter he joined Kyoto University, where he is currently Director and Professor of the Center
Plenary Lecture
for iPS Cell Research and Application and is also now Senior Investigator at Gladstone. Dr. Yamanaka received the Nobel
Prize in 2012 for the discovery of induced pluripotent stem cells (iPSCs). His vision is to bring iPSC-based therapeutices to
the clinic.
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ICHG2016 128
Mon(2)-PL1-2
Plenary Lecture
Secrets of the Human Genome: The 35-year journey of genomic medicine
1
Eric S. Lander
1:The Eli and Edythe L. Broad Institute; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
The talk will discuss the foundations for discovering the genetic basis of common human diseases―including the early de-
velopment of theoretical methods for mapping the genes underlying polygenic traits; sequencing of the human genome com-
prehensive discovery of the genetic variation in the human population; systematic characterization of genomic features; and
empirical insights into the genetic architecture of common human disease. It will then describe recent progress in genetic
analysis of important diseases―such as schizophrenia, heart disease, inflammatory bowel disease and obesity―and close by
looking forward to the years ahead.
[Introduction]
ERIC LANDER is the President and Founding Director of the Broad Institute of Harvard and MIT. Dr. Lander was one of
the principal leaders of the Human Genome Project, directing the largest center in the international project. He has developed
many of the key concepts, tools and information resources in modern genomics, propelling a revolution in our understanding
of inherited disease and cancer, genetic regulation and evolution. The recipient of numerous awards, he was elected a member
of the US National Academy of Sciences and Institute of Medicine.
Dr. Lander was appointed by President Obama to co-chair the President’s Council of Advisors on Science and Technology,
which advises the White House on matters including health, advanced manufacturing, energy policy, information technology,
nanotechnology and national security.
[Biography]
Dr. Lander earned his B.A. from Princeton (1978) and his Ph.D. from Oxford (1981) as a Rhodes Scholar. He teaches on
the faculty of MIT and the Harvard Medical School. From 1981-1989, he taught managerial economics on the faculty of the
Harvard Business School. He has been a co-founder of several successful biotechnology firms.

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[PL2] Plenary Lecture 2
Plenary Lecture
Wed., April 06, 2016 8:00-10:00 Main Hall (1F)
Chair：Nancy J. Cox（Vanderbilt University Medical Center, USA）

Chair ：Poh-San Lai（National University of Singapore, Singapore）
Wed(4)-PL2-1
Retinal cell therapy using iPS cells
1
Masayo Takahashi
1:Center for Developmental Biology, Riken, Japan
The first in man application of iPS-derived cells started in September 2014 targeted age-related macular degeneration (AMD).
AMD is caused by the senescence of retinal pigment epithelium (RPE), so that we aim to develop a treatment that replace
damaged RPE with normal, young RPE made from iPS cells.
In the first clinical study, we generated iPS cells from patient’s skin fibroblast using the episomal plasmid vector. RPE cells
were differentiated from iPS cells using SFEBq. Picking up the brown cluster of cells, hiPS-RPE cells were purified. Cells
were evaluated their purity, function, and various genetic examination. Grafted cell sheet went through various tests and
tumorigenicity test using immunodeficient mice to check the safety. We judge the outcome 1 year after the surgery. Primary
endpoint is the safety and mainly the tumor formation and immune rejection will be checked.
We evaluated plasmid remnant & gene alteration using WGS, epigenetic characteristics and purity using single cell RT-PCR
other than our original quality control (QC). From these experiences, we think we should distinguish between basic research
and regulatory science in order to promote regenerative medicine promptly.
Since autologous transplantation is time consuming and the cost is high, it is necessary to prepare allogeneic transplantation
to establish a standard treatment. RPE cells are suitable for allogeneic transplantation because they suppress the activation
of the T-cell and it is possible that the rejection is considerably suppressed by using the iPS cell with matched three loci of
HLA.
In Japan pharmaceutical law has been changed and a new chapter for regenerative medicine was generated. This is the first
law specific for regenerative medicine in the world. It was determined in the co-operation with ministry & academia and its
success will depend on the co-operation of them. I will discuss about the future of retinal regenerative medicine.
[Introduction]
The retina has been called the“approachable part of the brain,” owing to its relatively simple structure and its location
near the body surface, and for these reasons it serves as a useful and experimentally amenable model of the central nervous
system. Recently, it has been shown that new retinal neurons can be generated after being damaged. This has opened up
new hope that the ability to regenerate neurons and even to reconstitute the neural network may be retained in the adult
retina. We are now exploring the exciting prospect that, by transplanting cells from outside of the retina or by regeneration
from intrinsic progenitor cells, it may one day be possible to restore lost function to damaged retinas. Our goal is to study
retinal regeneration based on both a strong foundation in basic research and solid clinical evidence.
[Biography]
"Project leader, Laboratory for Retinal Regeneration Research at RIKEN.
Masayo Takahashi received her M.D. in 1986, and her Ph.D. in 1992 from Kyoto University. After an assistant professorship in
the Department of Ophthalmology, Kyoto University Hospital, she moved to the Salk Institute in 1995, where she discovered
the potential of stem cells as a tool for retinal therapy. She returned to Kyoto University Hospital in 1997, and was appointed
associate professor at the Translational Research Center in the same hospital in 2001. She joined the CDB as a team leader
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of the Lab for Retinal Regeneration in 2006. In 2013, her team launched a pilot clinical study of autologous iPS cell-
Plenary Lecture
derived RPE cell sheets for exudative aged-related macular degeneration (AMD), and performed the first RPE cell sheet graft
transplantation in Sept. 2014. Her clinical specialty is retinal disease-specifically, macular diseases and retinal hereditary
diseases. Her aim is to understand these diseases at a fundamental level and develop retinal regeneration therapies."
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Wed(4)-PL2-2
Plenary Lecture
Experience from 10.000 diagnostic exomes
1
Han G. Brunner
1:Radboud UMC, Department of Human Genetics 855, Nijmegen; Maastricht University Medical Center, Department
of Clinical Genetics, Maastricht, The Netherlands
We are using exome sequencing in clinical diagnosis for a broad range of diseases. For the year 2016, we expect to run 8000
diagnostic exome tests. We have reviewed our experience of the first 10.000 exome tests, and find that this has now become
an integrated part of modern medical care for patients with rare diseases.
After 5 years of experience with exomes in a clinical setting, the following conclusions are drawn:
· Exomes do better than doctors most of the time
· Exomes do not generate large numbers of incidental findings
· Incidental findings can be managed by a combination of careful informed consent, targeted analysis where possible, and
informed genetic counseling
· Genomes do better than exomes, but not much at this point
· We do not understand enough of non-coding DNA to allow easy detection of variants that impact disease
· We find similar mutations for seemingly disctinct neurodevelopmental disorders suggesting broad clinical heterogeneity,
and fueling nosological debate
· De novo mutations are an important cause of severe genetic disease in non-consaguineous populations
"We are using exome sequencing in clinical diagnosis for a broad range of diseases. For the year 2016, we expect to run 8000
diagnostic exome tests. We have reviewed our experience of the first 10.000 exome tests, and find that this has now become
an integrated part of modern medical care for patients with rare diseases.
After 5 years of experience with exomes in a clinical setting, the following conclusions are drawn:
· Exomes do better than doctors most of the time
· Exomes do not generate large numbers of incidental findings
· Incidental findings can be managed by a combination of careful informed consent, targeted analysis where possible, and
informed genetic counseling
· Genomes do better than exomes, but not much at this point
· We do not understand enough of non-coding DNA to allow easy detection of variants that impact disease
· We find similar mutations for seemingly disctinct neurodevelopmental disorders suggesting broad clinical heterogeneity,
and fueling nosological debate
· De novo mutations are an important cause of severe genetic disease in non-consaguineous populations
[Introduction]
Han Brunner pursues the scientific understanding of the connections between clinical and molecular features of rare diseases,
including applications to patient care. He has pioneered the discovery of a large number of disease genes, and the application
of cutting-edge genomic technologies (genomic microarrays, exome sequencing, and whole genome sequencing) to discover
the causes of genetic diseases. Much of this work focuses on neurodevelopmental conditions such as intellectual disability
and abnormal behavior. A pertinent finding is that in non-consaguineous populations, the major cause for severe intellectual
disability lies in spontaneous mutations.
[Biography]
Han Brunner trained as a clinical geneticist at Nijmegen University. In 1998 he was appointed full professor and head of the
department of Human Genetics at Nijmegen University Hospital. In 2014 he was also appointed chairman of the Department
of Clinical Genetics at Maastricht University Medical Center in the Netherlands. He was elected member of the board of
directors of the Dutch, European (president in 2014-2015) and of the American Societies of Human Genetics. Han Brunner
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was elected member of the Royal Netherlands Academy of Arts and Sciences in 2013, and of the Academia Europea in 2012.
Plenary Lecture
He is a Knight in the Order of the Dutch Lion since 2013. He is a co-winner of the King Faisal International Prize in Medicine
2016, with Joris Veltman.
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Wed(4)-PL2-3
Plenary Lecture
Genomics View of Neurological Diseases
1
Shoji Tsuji
1:Department of Neurology and Medical Genome Center, The University of Tokyo Hospital; Medical Genomics Re-
search Initiative, The University of Tokyo, Japan
The availability of massively parallel genome sequencing technologies has been revolutionizing our understanding of neurolog-
ical diseases. These technologies have dramatically accelerated discovery of new genes for a number of hereditary neurological
diseases, and, furthermore, opening a new avenue to better understand molecular bases of sporadic neurological disease. In
general, hereditary neurological diseases comprise only 5-10%. It is of note that the majority of patients with neurological
diseases has sporadic neurological diseases, despite that both forms share quite similar clinical and pathological presenta-
tions. Previous studies have shown involvement of genetic factors with large effect sizes in sporadic neurological diseases.
Genome-wide association studies based on the common disease-common variants hypothesis, however, revealed only genes
with small effect sizes. Given these experiences, a new research paradigm of common disease-multiple rare variants hypothesis,
is emerging, which requires a large-scale comprehensive genome sequencing to identify disease-relevant rare variants. Based
on this research paradigm, we have identified GBA and COQ2 as strong genetic risk factors for Parkinson disease (PD) and
multiple system atrophy (MSA), respectively. Association of the GBA variants with PD has been observed irrespective of
ethnic backgrounds, while association of COQ2 variants has been demonstrated mainly in MSA patients in East Asia including
Japanese and Chinese populations. COQ2 codes for an enzyme essential for coenzyme Q10 (CoQ10) biosynthesis, raising
a possibility that supplementation of CoQ10 may be efficacious for treatment of MSA. Currently a phase I clinical trial of
CoQ10 is being conducted. Thus, high-throughput genome sequencing technologies will enable us to explore molecular bases
of neurological diseases with an unprecedentedly robust power and we expect a new era of data-centric clinical practice.
[Introduction]
Dr. Tsuji is Professor of Neurology and Director of Medical Genome Center at the University of Tokyo Hospital. He has
worked on the molecular analysis and development of treatment for neurological diseases. He has identified causative genes
for neurological diseases including dentatorubral-pallidoluysian atrophy (DRPLA). The University of Tokyo Hospital recently
established Medical Genome Center with installation of next generation sequencers. He is applying these new technologies to
elucidate molecular bases of hereditary and sporadic neurological diseases. His team has recently discovered that COQ2 gene
is associated with familial as well as sporadic multiple system atrophy (MSA).
[Biography]
1984 Visiting Fellow, National Institutes of Health, USA
1991 Professor and Chair, Department of Neurology, Niigata University
2001 Director, Brain Research Institute, Niigata University
2002 Professor and Chair, Department of Neurology, The University of Tokyo
2011 Director, Medical Genome Center, The University of Tokyo Hospital
2015 Director, Medical Genomics Research Initiative, The University of Tokyo
Honors and Awards:
2011 Medal of Honor with Purple Ribbon (the Government of Japan)
2015 Medal for Scientific Achievement of Neurology (World Federation of Neurology)
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[PCS] Plenary Closing Symposium

New Technology of Single Molecule Genome Sequencing
Thu., April 07, 2016 15:00-16:30 Main Hall (1F)

Chair：Shinichi Morishita（Department of Computational Biology and Medical Sciences, Graduate School of Frontier
Sciences, The University of Tokyo, Japan）
Chair ：Yutaka Suzuki（Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University
of Tokyo, Japan）
Thu(5)-PCS-1
What do you call a complete, contiguous and accurate sequence? A SMRT Sequence!
1
Stephen Turner
1:Founder and CTO, Pacific Biosciences, Menlo Park, CA, USA
Within the field of human genomics, awareness is emerging of the scope of what is missing from second-generation assemblies.
Sensitivity to sequence context rendered short-read unable to access both high and low G+C content regions as well as
palindromic regions than resist amplification. Systematic errors intrinsic to the short-read sequencing methods were causing a
level of false-positive variant calls that interferes with both research and clinical applications. The short reads made assembly
and structural variant discovery close to impossible. Advances in Single Molecule Real-Time (SMRTtm ) sequencing have
allowed recent whole-genome human studies that are triggering a re-evaluation of the standards for human genome studies.
Average read lengths over 10,000 bases are leading to de novo assemblies with contig N50 values over 30 million bases―rivaling
the quality of the human reference genome. These studies have revealed that perhaps less than 15% of the common structural
variants present in the population have been documented. The absence of sequence context bias in SMRT sequencing has
provided access to the 10-15% of the genome that was inaccessible to short-read sequencing systems. Long reads and freedom
from systematic error has allowed a de novo approach to sequence analysis in areas where reference-guided assemblies were
plagued with false positives, now providing accurate sequence and even haplotype phase over long genomic distances. The
long readlength has enabled Iso-Seq, a system in which entire gene transcripts are sequenced in single reads, permitting
unambiguous identification of splice isoforms for the first time. Today, using target pull-down and amplicon sequencing we
already have affordable access to all these benefits in targeted panels. However with the release of Sequel System, which has
increased throughput by 7-fold at the same time as decreasing instrument cost within a scalable architecture, we can envision
a time in the not-too-distant future where Platinum-grade human genomes can be produced at an affordable cost.
[Biography]
Dr. Turner founded Pacific Biosciences and served as CEO until its series A funding in 2004. He served on the Board of
Directors from inception until 2010. He was awarded a Ph.D. in Physics by Cornell University in 2000, where he worked with
Prof. Harold Craighead to study the behavior of biomolecules in nano-fabricated structures. He was a member of the project
team at Cornell which developed the technology now employed by Pacific Biosciences and was co-author of the cover story in
Science magazine (January 31, 2003) that introduced the technology to the scientific community. Dr. Turner’s undergraduate
work was at the University of Wisconsin, Madison, where he received a Bachelor of Science in Applied Mathematics, Electrical
Engineering and Physics. He is the author of over 50 scientific papers in fields ranging from DNA sequencing technology
and biophysics to genomics and epigenomics. He is listed as the inventor on over 50 U.S. patents and numerous published
patent applications. Dr. Turner was recipient of the MIT Technology Review "TR100" Award in 2003 and the University of
Wisconsin Madison Distinguished Young Alumnus Award in 2008.
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Thu(5)-PCS-2
Real time, portable DNA sequencing using nanopore sensing

1
Clive G. Brown
1:Chief Technology Officer at Oxford Nanopore Technologies Ltd., UK
Nanopore sensing technology can perform direct, electronic DNA sequencing in real time. The USB-powered MinION device
is currently being used in 34 countries for a wide variety of applications, including pathogen analysis and surveillance, rapid
species identification, the identification of structural variants in cancer, and aneuploidy detection. Entire strands of DNA are
sequenced as they pass intact through a protein nanopore. As a consequence, real-time analysis workflows are possible, such
as ‘What’s in my Pot?’ for the rapid identification of species in a complex sample. The MinION user community is also
driving the development of novel features, such as real-time selective sequencing, where the device can select specific DNA
molecules to sequence, while rejecting those that are not of scientific interest to the user. The sequencing technology can be
scaled to higher-throughput devices such as the PromethION.
[Biography]
Clive is Chief Technology Officer at Oxford Nanopore. On the Executive team, he is responsible for all of the Company’s
product-development activities. Clive leads the specification and design of the Company’s nanopore-based sensing platform,
including strand DNA/RNA sequencing and protein-sensing applications with a strong focus on scientific excellence and
successful adoption by the scientific community.
Clive joined Oxford Nanopore from the Wellcome Trust Sanger Institute (Cambridge, UK) where he played a key role in the
adoption and exploitation of ’next generation’ DNA sequencing platforms. This involved helping to set up the world’s largest
single installation of Illumina (formerly Solexa) Genome Analyzers in a production sequencing environment, initially used to
pioneer the 1000 genomes project.
From early 2003 he was Director of Computational Biology and IT at Solexa Ltd, where he was central to the development and
commercialisation of the Genome Analyzer (GA). Solexa was sold to Illumina for ＄ 650m in early 2007 after the successful
placement and adoption of 12 instruments. The Solexa technology, now commercialised by Illumina, is the market-leading
DNA sequencing technology driving the renaissance in DNA-based discovery.
He has a strong background in computer science and genetics/molecular biology and manages interdisciplinary teams including
mechanical engineering, electronics, physics, surface chemistry, electrophysiology, software engineering and applications (of
the technology). Clive applies modern agile management techniques to the entire product-development lifecycle.
Clive has also held various management and consulting positions at GlaxoWellcome, Oxford Glycosciences and other EU- and
US-based organisations. He has worked at the interface between computing and science, ranging from genetics to proteomics.
He holds degrees in Genetics and Computational Biology from the University of York.
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Thu(5)-PCS-3
Single-molecule Electrical Sequencing of DNA, RNA, and Peptide

1
Tomoji Kawai
1:The Institute of Scientific and Industrial Research, Osaka University, Japan
The NIH has launched a ＄ 1000 genome project aimed at the practical realization of label-free, low-cost, and high-throughput
DNA sequencers for use in personalized medicine and therapeutics based on genomic information. The targeted technologies
include nanogap electrodes within nanopores and nanofluids, which can identify single-base molecules passing through a
nanogap electrode due to changes in electric current. The electric currents come from tunneling currents that are conducted
via single-base molecules. Although the fabrication of nanogap electrodes with dimensions on the order of 1 nm (equal
to the diameter of single-stranded DNA) has proven challenging, we have successfully fabricated nanogap electrodes using
mechanically controllable break junctions and demonstrated the proof of concept of the sequencing technology. We have
also identified sequences of base molecules in DNA and miRNA and sequences of amino acids in peptides using tunneling
currents. Currently, we are developing ways to control the translocation speeds of single biopolymer molecules to determine
sequences of base molecules and amino acids with high accuracy. Our technique can also identify chemically modified base
molecules and amino acids, which are important biomarkers. Recent studies demonstrated that our technique can sequence
the let7-miRNA family, whose members are well-known cancer markers, and identify sequences formed by base molecules and
methylated cytosine. Furthermore, our method has the potential to quantitatively evaluate the mixture ratio of two different
peptides and identify the peptide sequences.
[Biography]
Education:
1965-1969: B.Science, Chemistry, University of Tokyo

1969-1971: M.Science, Chemistry, University of Tokyo
1971-1974: Ph.D., Physical Chemistry, University of Tokyo, Doctor of Science
Professional Experience:
1975-1976: Research Associate, School of Engineering, Tokyo Institute of Technology

1976-1983: Research Associate, Institute for Molecular Science
1983-1992: Associate Professor, The Institute of Scientific and Industrial Research, Osaka University
1992- 2010: Professor, The Institute of Scientific and Industrial Research, Osaka University
2001-2002: Director, Intermaterial Research Center, The Institute of Scientific and Industrial Research, Osaka University
2002-2004: Director, Nanoscience and Nanotechnology Center, The Institute of Scientific and Industrial Research, Osaka
University
2004-2008: Director, The Institute of Scientific and Industrial Research, Osaka University
2007- 2008: Presidential Aide, Osaka University
2006- Present: The member of Science Council of Japan
2009- 2013: WCU Professor, Konkuk University, Korea
2010- Present: Specially Appointed Professor, ISIR, Osaka University
2014-Present: Executive Director, Technology Strategy Center, NEDO
2014-Present: Distinguished professor, Tokyo City University
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[PrCS] Pre-Congress Symposium

Human Genetics on the Globe
Sun., April 03, 2016 16:00-18:30 Main Hall (1F)
Chair (Keynote)：Shoji Tsuji（Department of Neurology and Medical Genome Center, The University of Tokyo Hospital;
Medical Genomics Research Initiative, The University of Tokyo, Japan）
Chair ：Yoshimitsu Fukushima（Ex-President, The Japan Society of Human Genetics; Professor, Department of Medical
Chair：Han G. Brunner（Radboud UMC, Department of Human Genetics 855, Nijmegen; Maastricht University Medical
Sun(1)-PrCS-1 (Keynote)
DOCUMENTING AND PRESERVING THE HISTORY OF HUMAN GENETICS -
WHAT HAVE WE ACHIEVED?
1
Peter S. Harper
1:Institute of Medical Genetics, Cardiff University, UK
Human Genetics, both in its medical applications and as a scientific discipline, has developed so rapidly over the past 60
years that its origins and key landmarks are in danger of being forgotten. With this in mind, in 2002 a small group of
concerned workers in the field founded the Genetics and Medicine Historical Network and its website (www.genmedhist.org),
with the principal aim of bringing together geneticists and historians to preserve and document the key aspects of our history
world-wide.
Among the main targets have been a series of recorded interviews with early workers in the field (now over 100); the
identification and preservation of major record sets of important workers; the creation of the Human Genetics Historical
Library as a physical collection of books relating to human genetics since its beginnings; and alternate yearly workshops
focusing on particular topics in the history of the area. Thanks to the enthusiasm of the human genetics community and the
help of interested historians and archivists, a considerable amount has been achieved.
Now, almost 15 years later, it is time to review the progress that has been made so far, what still needs to be done around
the world, and how this work can best be further developed into the future, to ensure that more recent achievements are
remembered as fully as those of the founding generation.
[Biography]
Peter Harper trained in medicine at Oxford and London universities, and in medical genetics with Professors Cyril Clarke and
Victor McKusick at Liverpool and Johns Hopkins Universities. On his return to UK in 1971 he established a department of
medical genetics at Cardiff University, focusing his research on inherited neurological disorders, notably Huntington’s disease
and myotonic dystrophy, his group playing a major role in the mapping and isolation of the genes for both these conditions.
His book ‘Practical Genetic Counselling’ has had a major influence on the development of this internationally, while he has
also been involved in ethical and social aspects of medical genetics, and on policy development relating to genetic services.
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Since 2002 he has concentrated on ensuring that the key aspects of the history of human and medical genetics are as fully
documented and preserved as possible, through his founding of the Genetics and Medicine Historical Network, its different
activities, and his books on this theme, including ‘A Short History of Medical Genetics’ (2008).
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Sun(1)-PrCS-2
The mission of International Federation of Human Genetic Societies
1
Helena Kääriäinen
1:Research Professor at National Institute for Health and Welfare, Helsinki; Clinical Geneticist, Finland
International Federation of Human Genetic Societies (IFHGS) was founded in 1996 to provide a transparent structure to
facilitate communication throughout the international community of human geneticists. The Federation presently has two
levels of membership. The multinational societies are Full Members. They are
The American Society of Human Genetics (ASHG), Asia-Pacific Society of Human Genetics (APSHG), East Asian Union of
Human Genetics Societies (EAUHGS), The European Society of Human Genetics (ESHG), The Human Genetics Society of
Australasia (HGSA), Latin American Network of Human Genetics Societies and African Society of Human Genetics (AfSHG).
Representatives of the Full Members form the Executive Board. National Human Genetics Societies (which are numerous) can
be Corresponding Members. The aim of IFHGS is to widely promote genetics via global collaboration. In practice, however,
the main achievement has been to support choosing the sites for ICHG-conferences and helping, when needed, in the planning
and organizing of these conferences. The ICHG-conferences have a longer tradition, the first one was held already in 1956
According to the Bylaws of IFHGS, the main purpose is to enable communication among its member groups and encourage
interaction. The ways to achieve this are 1. facilitating communication among the member societies, 2. developing a consensus
of these organizations on policy matters of international concern and
3. transmitting policy statements and opinions to appropriate parties and organizations. So far, the main action has been
supporting the ICHG Conferences. The Executive Committee of IFHGS is open to suggestions for reacting to important
issues in genetics at the global level.
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Sun(1)-PrCS-3
The American Society of Human Genetics and International Human Genetics
1
Nancy Cox
1:Vanderbilt University Medical Center, USA
The American Society of Human Genetics is an international society with a variety of activities and programs of interest to
the international community of human genetics scientists. I will highlight activities and interests of the society that may be
of interest to the ICHG audience and will also discuss current activities in our society that may be of interest within the
international community.
[Biography]
Nancy J. Cox is President-elect of the American Society of Human Genetics and is the Mary Phillips Edmonds Gray Professor
of Genetics, and Director of the Vanderbilt Genetics Institute and the Division of the Genetic Medicine at Vanderbilt University
Medical Center. Dr. Cox is a quantitative human geneticist with a long-standing research intererest in identifying and
characterizing the genetic component to common human diseases.
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Sun(1)-PrCS-4
Human Genetics in Europe: Exciting history, present fact and future1challenges
1
Feliciano J. Ramos
1:President of European Society of Human Genetics (ESHG), Spain
Europe is a continent composed of nations of different origins that form a multicultural society with very different character-
istics and needs. Over the last 50 years ESHG has been the main driving force that brought the advances of Human Genetics
to improve the health the european citizens based on the efforts, in research and in the clinic, of all professionals working in
the field. Currently, Europe is involved in the so called “cross-border healthcare”, a directive in which genetic testing will be
an important issue since in some EU countries genetic testing is not part of the public health care. Here, ESHG is playing
a leading role, together with other partners as Eurogentest (EuGT) and Orphanet. Rare diseases (RD) has been another
priority for Europe for more than a decade. This year efforts have started to establish the “European Reference Networks”
with the goal of connecting groups working in the same disease field optimizing the use of available resources. In march 2011,
the EU Comission adopted a regulation in which the clinical/medical genetics specialty was officially recognised as an EU-wide
specialty. The following year the European Board of Medical Genetics (EBMG) was created to lead the efforts regarding
the professional training, best practices and ethical issues of clinical and laboratory geneticists and genetic counsellors in
Europe. ESHG organizes the annual ESHG Conferences, where human geneticists from all over the world have shared their
research advances and knowledge with colleagues. The Conference is, every year, the place where young geneticists interact
with senior geneticists of all the fields, and where world-class geneticists have participated in the Mendel Lecture or received
the prestigiuos ESHG Award. Next year, the European Society of Human Genetics will celebrate its 50th Anniversary, fifty
years of exciting discoveries that were successfully used to improve the welfare of our citizens.
[Biography]
Obtained his M.D. Degree at the University of Extremadura Medical School in 1983 and his Ph.D. in Genetics at the Uni-
versity of Zaragoza Medical School, Spain in 1988. He finished the specialty of Pediatrics at the University Hospital “Lozano
Blesa” in 1988. He had Fulbright Scholarship at The Children´s Hospital of Philadelphia, USA, where he did his Postdoctoral
Fellowship at the Division of Human Genetics from 1990-92. He is Board-Certified in Clinical Genetics by the ABMG, USA.
He was Assistant Professor of Pediatrics at University of Zaragoza Medical School from 1993-1996, Full Professor from 1996-
2006 and Chair Professor from 2006. He was President of the Spanish Society of Human Genetics (AEGH) from 2005-2013
and he is the current President of the European Society of Human Genetics (ESHG). He is member of the Royal Medical
Academy of Zaragoza since 2011 and correspondent member of the Spain´s Royal National Academy of Medicine. Last year
he was elected President of the National Commission of Clinical Genetics of the Spain´s Ministry of Health. He is member of
the Experts Committee of the Spain´s National Strategy for Rare Diseases and Coordinator of the National Reference Center
of Cornelia de Lange and Cohesinopathies.
He is author of more than 100 scientific papers, 48 book chapters, and principal investigator of more than 20 research projects.
He is member of the Spanish Pediatric Society (AEP), Spanish Society of Human Genetics (AEGH), ASHG and ESHG.
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Sun(1)-PrCS-5
The Human Genetics Society of Australasia (HGSA) - Current challenges
1
Eric Haan
1:SA Pathology, Adelaide, Australia
Incorporated in 1977, the HGSA is a vibrant professional society, with over 1000 members, which promotes clinical and
laboratory genetics practice in Australia (pop. 24m) and New Zealand (pop. 4.5m). It trains and accredits genetic health
professionals, has an advocacy and advisory role with government, participates in setting standards for clinical and laboratory
genetics practice, fosters research and promotes ‘genetic literacy’through the education of health professionals and the public.
The Society faces a number of challenges:
- How best to mainstream diagnostic genetic testing, which will involve changing how specialist genetic services relate to other
health professionals
- Meeting the educational needs of health professionals, who lack the training needed to use the new genetic technologies
appropriately
- Reducing unequal access to genetic services resulting from populations concentrated in large coastal cities, with the remain-
der spread over a large area, and under-servicing of lower socio-economic groups
- Responding to the consequences of immigration
- As the result of a federal health system, Australia, in contrast to New Zealand, lacks a coordinated national approach to
genetic services, and the structural complexity works against effective advocacy with government and the health systems
- Increased health professional and community expectations of genetic services at a time when constraints in health funding
limit expansion of the genetics workforce.
- Ensuring high quality training, maintenance of professional standards and registration for health professionals working in
human genetics
- Providing adults with genetic disorders with services that are comparable to those provided to children and pregnant women
- Encouraging medical schools to place greater emphasis on genetics and genomic medicine.
- Promoting the continuation of strong links between clinical services and research.
[Biography]
Eric Haan is a clinical geneticist in the South Australian Clinical Genetics Service and Clinical Affiliate Professor in the
School of Medicine, University of Adelaide. Following graduation from Monash University in 1972, he trained in paediatrics
and clinical genetics at the Royal Children’s Hospital in Melbourne and gained research experience at the Institute of Neu-
rochemistry, London and Salk Institute, San Diego. After a further period in Melbourne, he moved to Adelaide in 1985.
He has contributed to research in a number of areas: inborn errors of metabolism; phenotypic description, mapping and
gene identification of genetic disorders; familial breast cancer; epidemiology of birth defects; the impact of prenatal screening
for birth defects; and the association between assisted reproductive technology and birth defects. He has played a role in
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public health campaigns promoting periconceptional folic acid supplementation and avoidance of alcohol in pregnancy. As a
member of the Australian Health Ethics Committee he participated in development of ethical guidelines for genetic research
in Australia. He is a former President of the Human Genetics Society of Australasia and of the International Federation of
Human Genetics Societies. He currently spends most of his professional time providing individuals and families with genetic
diagnosis, counselling and testing, and in collaborative research.
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Asia Pacific Society of Human Genetics
1,2,3
Carmencita D. Padilla
1:Department of Pediatrics, College of Medicine, University of the Philippines Manila; Institute of Human Genet-
ics, National Institutes of Health, University of the Philippines Manila; Philippine Genome Center, University of
the Philippines System, Philippines、2:Institute of Human Genetics, National Institutes of Health, University of the
Philippines Manila、3:Philippine Genome Center, University of the Philippines System
A group of medical and human geneticists together with physicians and scientists interested in genetics started an informal
fraternity in the Asia Pacific Region by hosting conferences to discuss topics relevant to the region. The First Asia Pacific
Conference on Human Genetics (APCHG) was held in July 1994 in Bangkok, Thailand. Subsequently, APCHG was held in
Jakarta, Indonesia and Kuala Lumpur, Malaysia. The next 3 conferences were held in conjunction with the HUGO Pacific in
Shanghai China, Bangkok, Thailand and Singapore.
In 2005, the group decided to formalize its informal organization with the establishment of the Asia Pacific Society of Hu-
man Genetics (APSHG). The inaugural meeting of the APSHG was held on November 12, 2005 in Bangkok, Thailand and
registered in Singapore on February 17, 2006. It is a non-profit organization, comprising persons involved or interested in the
study of human genetics. The principal objectives are: to promote research in basic and applied human and medical genetics;
to integrate professional and public education in all areas of human genetics; and to provide a forum where scientists can share
their research findings as well as increase knowledge and understanding of human genetics among the various professionals
including health policy makers, legislators and the general public. The membership includes scientists, clinical geneticists, ge-
netic counselors and students. The APSHG was accepted as Full Member of the International Federation of Human Genetics
Societies (IFHGS) on August 6, 2006 in Brisbane, Australia during the 11th International Congress of Human Genetics.
As APSHG, it continued to host conferences - Taipei, Taiwan and Cebu, Philippines jointly with HUGO-Pacific. By 2010,
the APSHG held APCHG by itself in Hong Kong, Kuala Lumpur, Malaysia and 11th APCHG in Hanoi, Vietnam in 2015.
The APSHG hosts workshops on birth defects surveillance, dysmorphology, newborn screening, genetics/genomics and bioin-
formatics.
[Biography]
Dr. Padilla is Professor of Pediatrics and currently Chancellor of University of the Philippines Manila. She was conferred
Academician of the National Academy of Science and Technology in 2008. Dr. Padilla is a pioneer in genetics in the Philip-
pines and the Asia Pacific region. In the Philippines, she is responsible for setting up the clinical genetic services and the
various genetic laboratories now housed at the Institute of Human Genetics - National Institutes of Health Philippines. She is
also responsible for setting up of national newborn screening services in the Philippines, currently available in 6000+ health
facilities in the country. In the Asia Pacific region, she is part of the pioneering group that established the Asia Pacific Society
for Human Genetics and served as president in 2008-2010. Dr. Padilla is Council member of the Human Genome Organiza-
tion, an international organization of scientists from 69 countries. She is Vice President and Treasurer of the International
Society for Neonatal Screening. In 2010, she was appointed country representative to the InterAcademy Medical Panel, a
global network of more than 60 academies in the world. Dr Padilla has more than 100 publications. In the area of policy
making, she is responsible for the Newborn Screening Act of 2004 and the Rare Disease Act that was recently passed into
law.
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Human Genetics in Latin America
1,2,3
Roberto Giugliani
1:Department of Genetics, Federal University of Rio Grande do Sul (UFRGS)l; Medical Genetics Service, Hospital de
Clinicas de Porto Alegre (HCPA); National Institute of Population Medical Genetics (INAGEMP), Brazil、2:Medical
Genetics Service, Hospital de Clinicas de Porto Alegre (HCPA), Brazil、3:National Institute of Population Medical
Genetics (INAGEMP), Brazil
Latin America is an emerging region with 620 million inhabitants, which genetic heritage represent the 3 major population
groups: Europeans (who initially came to colonize the continent), African (who initially came as slaves), and natives (first
settlers, who came from Asia). This makes the region a very interesting place for population genetics studies. One third
of this population is in Brazil, one third in the rest of South America and one third on Central America, Caribbean and
Mexico. The main languages are Portuguese (in Brazil) and Spanish (in most other countries), facilitating communication
across the continent. Human genetics is a well established discipline in Brazil, Mexico, Colombia, Argentina, Venezuela,
Chile, Uruguay and some other countries, with several active human genetics societies or human genetic branches as part
of more general genetic societies. The Latin American Association of Genetics (ALAG) was the first attempt to set up a
regional organization, and a dedicated human genetics web was founded in 2001, the Latin American Network of Human
Genetics (RELAGH). Among other initiatives, RELAGH hosts the Latin American School of Human Genetics (ELAG),
which organizes an intensive course on human and medical genetics held every year (now on the XII edition). RELAGH will
organize a congress in Belem (Brazil) in June 2016 to celebrate the 15th anniversary of this tool created to bring together the
people who work with human genetics in the Latin American region.
[Biography]
Dr. Roberto Giugliani is Professor at the Department of Genetics of the Federal University of Rio Grande do Sul (UFRGS),
Founder and Chief of the Medical Genetics Service of Hospital de Clinicas de Porto Alegre (HCPA) and Director of the WHO
Collaborating Centre for the Development of Medical Genetics Services in Latin America, in Porto Alegre, Brazil. He is also
Coordinator of the Brazilian Institute of Population Medical Genetics (INAGEMP) and Chairman of the Latin American
School of Human and Medical Genetics. His main research interests are the inborn errors of metabolism, particularly the
lysosomal storage disorders. He is a medical doctor specialized in clinical genetics, with post-doctoral trainings in London,
Genoa, Paris, Zurich, Oakland and Sydney. Prof. Giugliani is member of 13 scientific societies, and chairs the International
Committee of Inborn Errors of Metabolism. He participates in the Editorial Board of several international scientific journals,
and is the Editor-in-Chief of Journal of Inborn Errors of Metabolism and Screening. He has been President of medical and
scientific societies, including the Brazilian Society of Clinical Genetics and the Latin American Network of Human Genetics,
and is presently President of the Latin American Society of Inborn Errors of Metabolism and Screening. He has supervised the
post-graduate studies of more than 100 MScs/PhDs, and is author of over 450 papers, most of them published in peer-reviewed
international journals.
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The African Society of Human Genetics
1
Charles N. Rotimi
1:Center for Research on Genomics and Global Health, National Human Genome Research Institute, NIH, USA
TBA
[Biography]
Dr. Charles Rotimi, a genetic epidemiologist, is the Director of the Center for Research on Genomics and Global Health at
NIH. His lab conducts genomic and epidemiologic studies that explore the patterns and determinants of metabolic disorders
including diabetes, hypertension and obesity with particular emphasis on health disparities in African ancestry populations.
His lab gives particular attention to ways in which scientists document and describe the non-random pattern of human
genetic variation with respect to human history, notions of identity and disease risks in different populations. He is a
member of board of the American Society of Human Genetics, a member of the Executive and Scientific Committee for the
International Federation of Human Genetics Societies, member of Human Genome Organization (HUGO) council and the
founding president of the African Society of Human Genetics. Recently, he successfully led the establishment of the Human
Heredity and Health in Africa (H3Africa) initiative with over ＄ 76 million commitment from the NIH and Wellcome Trust.
H3Africa is revolutionizing genomic research across the African continent.
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Medical Genetics Services in China
1
Xue Zhang
1:McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, China
TBA

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Human Genetics in Korea as a member of the EAUHGS
1
Jin-Sung Lee
1:Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
The Korean Society of Medical Genetics (KSMG) is an academic society representing the professionals of human genetics in
Korea. The KSMG was established in 1981 and currently the association is composed of approximately 350 members. Many
of the members are clinicians specializing in pediatrics, obstetrics and neurology, etc. The rest are researchers, technologists,
and genetic counselors. The KSMG was a founding member of the EAUHGS, organizes domestic scientific meetings twice a
year and hosts the EAUHGS meeting once in every three years. During the meetings, education programs are provided to the
laboratory technologists. Since 2014, there is another educational program for the genetic counselors in an aim to set genetic
counseling as a method for certified medical care.
The KSMG also runs certification program for clinical geneticists, genetic laboratories, laboratory technologists, and genetic
counselors. The society publishes the Journal of Genetic Medicine, an online-based peer-reviewed academic journal, four
times a year.
From the clinical point of view, there are three medical centers officially running genetics clinic. Other major medical centers
deal with genetics patients at different clinics even if they do not have separate genetics clinic. Cytogenetic and molecular
analyses are popular techniques nationwide. Around 170 kinds of rare diseases are categorized as a group with easier access to
financial support from national medical insurance. And the number of these diseases are increasing every year after reviewing
process conducted by the specialized committee.
In Korea, clinical services on medical genetics are almost the same as those of other developed countries. Researches on
human genetics or genetic diseases are common and the Korean government has been encouraging translational research
on biotechnology. At present, the NIPS (non-invasive prenatal screening) and clinical application of the next generation
sequencing are issues at both of the clinical and research side.
[Biography]
1974-1980 Graduate Yonsei university College of Medicine
1982-1985 Korean Board of Pediatrics
1986-1991 Department of Clinical Genetics, Karolinska Institute, Stockholm, SWEDEN
1992-Present Assistant, Associate, Professor, Department of Pediatrics, Yonsei University College of Medicine
1997-2001 Division Chief, Department of Genetic diseases, Korean NIH
2006-2010 President, The Korean Society of Inherited Metabolic Diseases
2008-2011 President, EAUHGS
2013-2015 President, The Koran Society of Medical Genetics
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Human Genetics in Japan
1
Yoichi Matsubara
1:National Center for Child Health and Development, Japan
TBA

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Functional and Computational Genomics
Mon., April 04, 2016 13:30-15:30 Annex 1 (1F)
Convener：Hiroyuki Aburatani（Research Center for Advanced Science and Technology, The University of Tokyo, Japan）
Convener ：Manolis Kellis（MIT Computational Biology, USA）

Recent progress in next generation sequencing technologies generated unprecedented amount of genomic data, from
genome to epigenome. Integration of individual omics data, particularly in relation to phenotype information, will be
crucial in annotating human genome and elucidating disease mechanisms. This session will assemble leaders who studies
computational/functional genomics.
Mon(2)-CIS1-1
Dissecting the circuitry of FTO and adipocyte browning in human obesity
1
Melina Claussnitzer
1:BIDMC, Harvard Medical School, USA
TBA
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Mon(2)-CIS1-2
Histone Acetylome-wide Association Studies
1
Shyam Prabhakar
1:Computational and Systems Biology, Genome Institute of Singapore, Singapore

Epigenome-wide association studies (EWAS) use epigenetic profiling of case-control cohorts to uncover disease mechanisms,
biomarkers and potentially drug targets. However, such studies have almost exclusively focused on DNA methylation. We
recently showed that histone acetylation profiling in a normal cohort could detect disease-causing polymorphisms with un-
precedented sensitivity. We have now extended this paradigm to case-control cohorts for autism and tuberculosis. Such
histone acetylome-wide association studies (haWAS) serve a dual function: they reveal shared disease mechanisms and also
simultaneously uncover genetic variants that drive population variation in gene regulation. Our results indicate that haWAS
can robustly detect disease signatures and dysregulated pathways in primary samples.
[Biography]
Shyam Prabhakar obtained a B.Tech in Electronics and Communications Engineering from the Indian Institute of Technology,
Madras and a PhD in Applied Physics from Stanford University. He was the sole recipient of the American Physical Society
Award for Outstanding Doctoral Thesis Research in Beam Physics in 2001. As a postdoctoral fellow under Eddy Rubin at the
Lawrence Berkeley National Laboratory, he developed and validated algorithms for detecting transcriptional enhancers active
during mammalian development, and discovered the first known human-specific developmental enhancer. His research group
at the Genome Institute of Singapore uses single-cell RNA-seq, cohort-scale ChIP-seq and other high-throughput assays to
uncover molecular mechanisms of autism, psychiatric drug response, lung and colon cancer, autoimmune disorders and human
development. In parallel, the group develops algorithms for deriving biological insights from omics data. Major achievements
include the first large-scale study of disease-causing genetic variants that affect histone acetylation, the first genome-wide
analysis of anthropoid primate-specific functional elements and the first unified signal-processing method for peak detection
in whole-genome functional profiling data.
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Mon(2)-CIS1-3
A human variation panel of genetic influences on epigenomes and transcriptomes in three immune cells
1,2
Nicole Soranzo ，BLUEPRINT Consortium
1:Human Genetics, Wellcome Trust Sanger Institute, UK、2:Department of Hematology, University of Cambridge

Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge
in human genetics and medicine. As part of the BLUEPRINT Epigenome Project, we carried out high-resolution genetic,
epigenetic and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils and
naive CD4+ T cells) from up to 197 individuals. Here I will describe analyses to (i) assess quantitatively the contribution of
cis-genetic effects to transcriptional variance compared to epigenetic effects; (ii) characterise highly coordinated genetic effects
on gene expression, methylation and histone variation through quantitative trait locus (QTL) mapping and allele specific (AS)
analysis; (iii) describe genetic and epigenetic influences at human disease loci and key immune pathways. Our results provide
an expansive, high-resolution atlas of multi-omics changes in three major human immune cell types.
[Biography]
Professor Nicole Soranzo
Group leader in Human Genetics, Wellcome Trust Sanger Institute (WTSI),
Professor of Human Genetics, University of Cambridge
Prof. Soranzo graduated in biological sciences at the University of Milano, Italy, with a dissertation on population and
evolutionary genetics. She later obtained a PhD in genetics from the University of Dundee, and undertook post-doctoral
training in human population and statistical genetics at University College London, conducting applied and methodological
work in evolutionary genetics and association studies. In 2005 Prof. Soranzo joined the Pharmacogenomics Department
at Johnson & Johnson Pharmaceutical Research and Development (Raritan, USA). In 2007 she joined the Wellcome Trust
Sanger Institute, and since 2009 she has led her own team. In 2015 she was additionally appointed as Professor of Human
Genetics at the School of Clinical Medicine of the University of Cambridge. Furthermore, Prof. Soranzo is a member of
the Cambridge University Platelet Biology and Cardiovascular groups, the NIHR Blood and Transplant Research Unit in
Donor Health and Genomics and the EU BLUEPRINT and EpiGeneSys projects. She serves in several steering committees
and scientific advisory boards, and is on the editorial board of several journals including the European Journal of Human
Genetics, Genome Medicine, Trends in Genetics, and Molecular Biology and Evolution.
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Mon(2)-CIS1-4
Integrated genomic analysis of liver cancer progression
1
Hiroyuki Aburatani
1:Research Center for Advanced Science and Technology, The University of Tokyo, Japan

Hepatocellular carcinoma (HCC) often arises in chronic liver disease cases as a small nodule and develops into overt HCC. Such
a small precursor lesion is a highly differentiated cancer and is macroscopically characterized by indistinct margins. To identify
molecular alterations in early lesions and additional molecular events that occur during stepwise hepatocarcinogenesis, we
comprehensively analyzed genetic/epigenetic alterations in early HCCs and overt HCCs by exome sequencing, RNA sequencing
and DNA methylome analysis. Among all, TERT was the most frequently mutated gene in early HCC, presumably leading to
immortalization. Somatic mutations in WNT pathways are present in early HCC, as well as in advanced HCCs. Despite the
presence of activating mutation of CTNNB1 , conventional WNT-target genes were not up regulated in early HCC, but highly
up-regulated in advanced HCCs, which was accompanied by demethylation of CpG islands in their promoter. While gene
expression profiles are not very heterogeneous among early HCCs, two distinct groups were observed by DNA methylation
patterns. In summary, there are several oncogenic molecular alterations, such as TERT, CTNNB1 and TP53 , in early
HCC, while additional molecular events, other than oncogenic driver mutations, cooperatively contribute to transcriptional
activation of their downstream targets in progression to advanced HCC.
[Biography]
Hiroyuki Aburatani is a Professor of Genome Science at Research Center for Advanced Science and Technology, The University
of Tokyo, since 2001. In 2008 his group participated in the International Cancer Genome Consortium, where they studied
the genomic alterations in liver and gastric cancers. He also contributed to P-DIRECT project in Japan (2011 ~ 2015),
providing their expertise in genomic analysis to analyze various cancers, e.g. clonal evolution of brain tumors after alkylating
agent treatment. He also applied genomic technology to reveal epigenetic landscape, serving as a NEDO project leader of
‘Technology Development for Drug Discovery Platform Based on the Mechanism of Epigenetic Modification’ (2010 ~ 2014).
His group has participated in International Human Epigenome Consortium (2011 ~ ). He has co-authored more than 420
peer-reviewed scientific publications.He obtained his M.D.(1980) and Ph.D.(1988) from The University of Tokyo and worked
as a postdoctoral scientist at Center for Cancer Research, MIT (1988 ~ 1994).
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New Technology: Single Cell Sequencing
Mon., April 04, 2016 15:50-17:50 Annex 1 (1F)
Convener：Sumio Sugano（Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University
of Tokyo, Japan）
Convener：Stephen Quake（Departments of Applied Physics and Bioengineering, Stanford University and Howard Hughes

Because cell is the ultimate functional unit that composes the living organism, the quantitative and comprehensive
analysis of biomolecules in a single cell is required for understanding the real picture of the life at the molecular level.
Such an analysis have been a “dream” for the long period of time. The recent advancement in the sequence technology
and in the fluid handling technology at the nano-liter level scale is now allowing us to achieve such a “dream” at least
for RNA and DNA. In this "New Technology: Single Cell Sequencing" session, we tried to invite scientists at the forefront
of this area not only for the technology but also for the real analysis. Thus, you will hear not only the cutting edge
microfluidics and massive single cell sequencing but also the comprehensive picture of gene expression diversities among
a cell population and the heterogeneity of cell seen from the single cell RNA and DNA sequences. We wish this session
will help you to envisage future of biology as well as to understand the current status of the single cell sequence.
Mon(2)-CIS2-1
Highly accurate and precise single-cell sequencing facilitated by microfluidics
1
Yanyi Huang
1:Biodynamic Optical Imaging Center, Peking University, China
Phenotype classification of single cells reveals biological variation that is masked in ensemble measurement. This hetero-
geneity is found in genomic variation and gene expression as well as in cell morphology. Many techniques are available to
probe phenotypic heterogeneity at the single cell level, for example single-cell genomic sequencing, RNA sequencing, and
quantitative imaging, but it is difficult to perform multiple assays on the same single cell.
On one hand, to better assessing the genomic variations between single cells, we developed a microfluidic-based emulsion
whole genome amplification (eWGA) method to overcome the technical limitations existing in prevailing single-cell WGA
approaches. We divide single-cell genomic DNA into a large number of picoliter aqueous droplets in oil. This easy-to-operate
approach enables simultaneous detection of CNVs and SNVs in an individual human cell, exhibiting significantly improved
amplification evenness and accuracy.
On the other hand, in order to directly track correlation between gene expression and morphology of each single cell, we de-
veloped a microfluidic platform for quantitative label-free imaging and immediate RNA sequencing (RNA-Seq) of single cells.
With this device we actively screen and trap cells for analysis with coherent Raman microscopic imaging. The cells are then
processed in parallel pipelines for lysis, and preparation of cDNA for high-throughput transcriptome sequencing. Coherent
Raman microscopy offers three-dimensional imaging with chemical specificity for quantitative analysis of protein and lipid
distribution in single cells. Meanwhile, the microfluidic platform facilitates single-cell manipulation, minimizes contamina-
tion, and furthermore, provides improved RNA-Seq detection sensitivity and measurement precision, which is necessary for
differentiating biological variability from technical noise.
[Biography]
Yanyi Huang received his Bs (Chemistry) and ScD (Inorganic Chemistry) from Peking University in 1997 and 2002, respec-
tively. He did his postdoc works with Amnon Yariv at Caltech (Applied Physics, 2002-2005) and with Stephen Quake at
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Stanford (Bioengineering, 2005-2006). He joined Peking University faculty in 2006. He is Professor of Materials Science and
Engineering, Principal Investigator of Biodynamic Optical Imaging Center, Principal Investigator of Peking-Tsinghua Center
for Life Sciences.
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Mon(2)-CIS2-2
Molecular Anatomy of the Brain by Large-Scale Single-Cell RNA-Seq
1
Sten Linnarsson
1:Medical Biochemistry and Biophysics, Karolinska Institutet, Sweden

The brain is arguably the most complex organ in all biology. To understand how it works, at a minimum, we need to learn
how it’s built: what are the components, how are they connected, and how do they talk to each other? With the recent
development of single-cell RNA-seq, it has become increasingly feasible to map the cell types of the brain without the use of
predefined markers.
With the aim of ultimately revealing the molecular anatomy of the whole mouse brain, we have performed pilot experiments
on ten selected regions. A total of 26,485 cells were sequenced and passed QC. We found hundreds of molecularly distinct
cell types, including neurons, glia and vascular cells. Neuronal diversity greatly exceeds that of glia and other cell types,
and particular regions are especially diverse (e.g. hypothalamus). Interestingly, molecular similarity largely conforms to
developmental lineage ancestry. We discuss the implications of these findings, as well as the prospects of generating a
complete molecular atlas of the brain.
[Biography]
Sten Linnarsson took his PhD at Karolinska Institute in 2001, studying neurotrophic factors regulating neuronal survival,
growth and plasticity. He then founded Global Genomics, a company focused on genome-wide expression analysis and
next-generation DNA sequencing. In 2007, he was appointed as assistant professor at the Karolinska Institute, Department
of Medical Biochemistry and Biophysics, and in 2015, was appointed Professor of Molecular Systems Biology at the same
department. Also in 2015, he was awarded the Erik K. Fernström Prize for his work in single-cell biology.
Linnarsson’s research focuses on single-cell biology, in particular applying single-cell gene expression analysis to characterize
the cell types and lineages of the mouse nervous system. The long-term goal of his research is to map the stable cellular states
(‘cell types’) that human organs are made of, and to understand the regulatory networks that induce and maintain them;
both in normal tissues and in cancer.
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Mon(2)-CIS2-3
Immunology from the “Bottom-Up” with Single-Cell Genomics
1
Alex K. Shalek
1:IMES & Chemistry, MIT, Ragon Institute & Broad Institute, USA

Diversity in the mammalian immune system is essential for protecting the host against a broad range of threats, and is
most clearly evident during dynamic processes such as differentiation and antigenic response. Recent years have witnessed
transformative and intersecting advances in nanofabrication and molecular biology that enable deep profiling of low-input
samples. These afford new and exciting opportunities to study heterogeneity in the immune response, starting from the
level of a single cell, with the potential to fundamentally advance our understanding of immune regulation in health and
disease. Illustratively, I will discuss how we can leverage single cell genomic approaches - and, in particular, single-cell RNA-
Seq - to explore the extensive functional diversity between immune cells and uncover, from the “bottom-up”, distinct cell
states and their molecular drivers. Finally, I will discuss emerging high-throughput experimental strategies for achieving the
statistical power necessary to reconstruct intracellular circuits, enumerate and redefine cell states and types, and transform
our understanding of cellular decision-making on a genomic scale.
[Biography]
Alex K. Shalek is currently the HLF von Helmholtz Career Development Assistant Professor of Health Sciences and Technology
at MIT, as well as a Core Member of the Institute for Medical Engineering and Science (IMES) and an Assistant Professor
of Chemistry. He is also an Associate Member of the Ragon and Broad Institutes, and an Assistant in Immunology at MGH.
His research is directed towards the development and application of new technologies that facilitate understanding of how
cells collectively perform systems-level functions in healthy and diseased states. Dr. Shalek received his bachelor's degree
summa cum laude from Columbia University and his Ph.D. from Harvard University in chemical physics under the guidance
of Hongkun Park, and performed postdoctoral training under Hongkun Park and Aviv Regev (Broad/MIT). To date, his
interdisciplinary research has focused on realizing and utilizing nanoscale manipulation and measurement technologies to
examine how small components (molecules, cells) drive systems of vast complexity (cellular responses, population behaviors).
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Mon(2)-CIS2-4
Single Cell Genomics
1
Stephen Quake
1:Departments of Applied Physics and Bioengineering, Stanford University and Howard Hughes Medical Institute, USA

An exciting emerging area revolves around the use of microfluidic tools for single-cell genomic analysis. We have been using
microfluidic devices for both gene expression analysis and for genome sequencing from single cells. In the case of gene
expression analysis, it has become routine to analyze hundreds of genes per cell on hundreds to thousands of single cells per
experiment. This has led to many new insights into the heterogeneity of cell populations in human tissues, especially in the
areas of cancer and stem cell biology. These devices make it possible to perform “reverse tissue engineering” by dissecting
complex tissues into their component cell populations, and they are also used to analyze rare cells such as circulating tumor
cells or minor populations within a tissue.
We have also used single-cell genome sequencing to analyze the genetic properties of microbes that cannot be grown in culture
―the largest component of biological diversity on the planet―as well as to study the recombination potential of humans
by characterizing the diversity of novel genomes found in the sperm of an individual. We expect that single cell genome
sequencing will become a valuable tool in understanding genetic diversity in many different contexts.
[Biography]
Stephen Quake studied physics (BS 1991) and mathematics (MS 1991) at Stanford University, after which he earned a
doctorate in theoretical physics from Oxford University (1994) as a Marshall Scholar. He then returned to Stanford University,
where he spent two years as a postdoc in Steven Chu’s group.
Quake joined the faculty of the California Institute of Technology in 1996, where he rose through the ranks and was ultimately
appointed the Thomas and Doris Everhart Professor of
Applied Physics and Physics. At Caltech, Quake received“Career”and“First”awards from the National Science Foundation
and National Institutes of Health and was named a Packard Fellow. These awards supported a research program that began
with single molecule biophysics and soon expanded to include the inventions of single molecule sequencing and microfluidic
large scale integration, and their applications to biology and human health. He moved back to Stanford
University in 2005 to help launch a new department in Bioengineering, where he is now the Lee Otterson Professor and an
investigator of the Howard Hughes Medical Institute.
Quake’s contributions to the development of new biotechnology at the interface between physics and biology have been
widely recognized. Honors include the Human Frontiers of Science Nakasone Prize, the MIT-Lemelson Prize, the Raymond
and Beverly Sackler International Prize in Biophysics, the American Society for Microbiology Promega Biotechnology Research
Award, the Royal Society of Chemistry Publishing Pioneer of Miniaturization Award, and the NIH Director’s Pioneer Award.
He is an elected fellow of the American Academy of Arts and Sciences, the National Academy of Inventors, the National
Academy of Sciences, the National
Academy of Engineering, the Institute of Medicine, the American Institute for Medical and Biological Engineering and of the
American Physical Society.
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Implementation of Genome Information for Health Care and Drug Discovery
Mon., April 04, 2016 13:30-15:30 Annex 2 (1F)
Convener：Robyn Ward（The University of Queensland, Australia）

Convener ：Geoffrey Ginsburg（Duke University, School of Medicine; Pratt School of Engineering, USA）

This year marks the 25th anniversary of the initiation of the human genome project (HGP). At the same time many
nations are grappling with health care reform aiming to reduce costs, increase access and improve outcomes and quality.
What is the potential for genome information to contribute to advances in health care? Despite the fact that the HGP
was not conceived with these goals in many life science organizations are harnessing this knowledge to achieve those
lofty goals. This session will highlight the global landscape for implementation of genomic medicine. An international
community focused on common challenges might have an opportunity to accelerate achieving fundamental changes in
health care (Ginsburg). A key success factor is the ability to demonstrate the value proposition for genomic medicine to a
broad stakeholder group of policy makers, payers, providers, and to patients (Ward). The pharmaceutical industry is re-
investing in genome based drug discovery and precision medicine driven clinical trials to improve its success/failure rate
and to deliver safer and more effective genome-based medicines (Plump). Now more than ever in the history of medicine,
the patients and the public are looking for access to their data as part of the health care experience. Consumer driven
genomics has emerged as a powerful platform to aggregate this data along with phenotypes that in turn are poised to
have significant impact on health and disease management (Wojcicki).
Mon(2)-CIS3-1
Assessing the value of genomics
1
Robyn Ward
1:The University of Queensland, Australia
In an effort to accelerate the translation of genomics research into health practice, a number large scale genomic initiatives have
been established throughout the world. In Australia these initiatives have taken the form of alliances to drive collaboration
between health systems, research and academic communities. The goal of these type of alliances is to generate the evidence
base and economic arguments which will justify public or personal expenditure on genomics. Cognisant of the increasing
pressure to fund new technologies, some government payers have restated their commitment to only funding genomic tests
which deliver cost effective improvements in health outcomes. This traditional framework for assessing “value” has however
been challenged by claims that this approach underestimates the health and societal benefits of genomics. In part this relates
to fact that genomics has value to biological relatives of disease affected individuals and can be used for family planning. On
the hand uninformative genomic tests or tests used inappropriately will reduce the value of genomics to society. Strategies to
balance these competing priorities will be considered in this session.
[Biography]
Prof Robyn Ward is Deputy Vice-Chancellor (Research) at the University of Queensland, and Director of the Cancer Centre
at Prince of Wales Hospital, Sydney. She is an academic leader, cancer researcher and clinician. Her significant record of
achievement in translational and clinical cancer research includes over 220 peer-reviewed publications, and has been recognised
by a Commonwealth and State awards. She has over 20 years experience as a specialist in medical oncology, with particular
interests in the bowel and hereditary cancer, and the rational use of cancer therapeutics. She invented and remains Director
of eviQ, a nationally-endorsed web-based system for the display of cancer treatment protocols. She is passionate about
the central role of the medical practitioner in the enterprise of health and medical research. Prof Ward is a member of
the Pharmaceutical Benefits Advisory Committee (PBAC), chairs the Commonwealth Medical Services Advisory Committee
(MSAC), and serves on the Council and Executive of the Australian Academy of Health and Medical Sciences. In 2013 she
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was made Member of the Order of Australia (AM) for significant service to medical research and patient care in the field of
oncology.
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Mon(2)-CIS3-2
Implementation of Genome Information for Health Care and Drug Discovery
1
Geoffrey Ginsburg
1:Duke University, School of Medicine; Pratt School of Engineering, USA

TBA

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Mon(2)-CIS3-3
The New Era of Drug Discovery: Human Genetics, Data Science & New Modalities
1
Andrew S. Plump
1:Chief Medical & Scientific Officer, Takeda Pharmaceutical Co., Ltd., USA

The discovery, successful development and introduction of a truly novel therapy for patients represents one of the greatest
challenges in biomedical research. The cost of developing a single new medicine, when factoring the cost of failure, approaches
＄ 5 billion. Attrition for truly novel mechanisms is driven primarily by lack of sufficient efficacy and secondarily lack of safety.
Finding mechanisms to enhance success and reduce attrition in drug discovery is paramount. Through a growing understanding
of human disease, predominantly from an exploding base of data, knowledge in human genetics and an emerging array of new
therapeutic modalities, we are making strides in our ability to make rapid, informed decisions, reduce costs and focus our
efforts on those therapies with greatest impact.
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Mon(2)-CIS3-4
Making Discoveries on the 23andMe Platform
1
Anne Wojcicki
1:23andMe., USA

The mission of 23andMe is to help people access, understand and benefit from the human genome. A key component of how
we execute this mission is our innovative research platform. 23andMe has the largest consented, re-contactable database for
genetic research in the world. By combining phenotypic data collected through online surveys with our customers’ genotype
data we are able to conduct a variety of types of studies to elucidate the effects of genetic variants on health. We have also
recently established a therapeutics unit that will leverage our unique research capabilities to accelerate the discovery of novel
treatments. At the heart of everything we do is our dedication to treating our customers not as research subjects, but true
partners.
[Biography]
Anne co-founded 23andMe in 2006 after a decade spent in healthcare investing, focused primarily on biotechnology companies.
Her hope was to empower consumers with access to their own genetic information and to create a way to generate more
personalized information so that commercial and academic researchers could better understand and develop new drugs and
diagnostics. Presently, 23andMe has built one of the world’s largest databases of individual genetic information. Its novel,
web-based research approach allows for the rapid recruitment of participants to many genome-wide association studies at
once, reducing the time and money needed to make new discoveries, and the company has created a proven and standardized
resource for finding new genetic association and confirming genetic loci discovered by others. Under Anne’s leadership
23andMe has made significant advances in bringing personalized medicine directly to the public. Anne graduated from Yale
University with a BS in Biology.
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Regenerative Medicine
Mon., April 04, 2016 15:50-17:50 Annex 2 (1F)
Convener：Haruhisa Inoue（Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application
(CiRA), Kyoto University, Japan）
Convener ：John D. Sinden（ReNeuron Limited, UK）

In Japan, after the recent implementation of the new law for regulating regenerative medicine, the landscape of stem
cell-based medicine has been changing very rapidly. In addition, the world’s first clinical trial using patient iPSCs was
started last September. Now an opportunity to lead the world has presented itself to Japan.
Speaking attending this symposium, we have 4 leading researchers in the translation of stem cell science into regenerative
medicine and towards clinical trials. We look forward to vibrant and rewarding discussions.
Mon(2)-CIS4-1
Stem cell therapies in Europe: Taking the CTX human neural stem cell product to
clinical trials in disabled stroke patients
1
John D. Sinden
1:ReNeuron Limited, UK
CTX0E03 is a conditionally immortalised clonal human neural stem (hNSC) line currently being developed for the treatment
of chronic neurological and vascular diseases. From large scale GMP manufacturing, the resulting clinical product is a frozen
allogeneic cell therapy with a long shelf life (currently 6 months - CTX-DP). Several published studies have shown that
intracerebral implantation of CTX-DP four weeks after middle cerebral artery occlusion in rats was associated dose-related
improvements in sensorimotor function, with increased stroke host striatal angiogenesis and neurogenesis. In this talk I will
outline the particular characteristics of CTX-DP as a clinical resource for regenerative medicine, including preclinical studies
and a recently completed Phase I study in Scotland and an ongoing UK multicentre phase II trial focusing in on upperlimib
disability in the early months of stable stroke disability. In addition I will explore the clinical potential of using the exosomes
produced by these cells in other neurological indications.
[Biography]
John Sinden is Chief Scientific Officer of ReNeuron. From 1998 to 2015 he was a director of the ReNeuron companies. Prior
to founding ReNeuron and becoming its first employee, he was Reader in Neurobiology of Behaviour at the Institute of
Psychiatry at Kings College London. He graduated in Psychology from the University of Sydney and completed a Ph.D.
in Neuroscience from the University of Paris at the College de France. He subsequently held post-doctoral appointments at
Oxford University and the Institute of Psychiatry prior to joining the tenured staff of the Institute in 1987. Dr. Sinden is an
Honorary Professor in the Faculty of Medical Sciences at University College London and has over 140 scientific publications
and book chapters. He holds Fellowships of the Royal Society of Medicine and the Royal Society of Biology and is a member
of the International Society for Stem Cell Research and the Expert Working Group on Cell and Gene Therapies for the
Bioindustry Organization BioSafe Committee.
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Mon(2)-CIS4-2
Engineering the Morphogenesis of Pluripotent Stem Cells
1
Todd C. McDevitt
1:Gladstone Institutes of Cardiovascular Diseases; Bioengineering and Therapeutics at the University of California, San Francisco, USA

Pluripotent stem cells (PSCs) exhibit a unique ability to recapitulate dynamic morphogenic processes that parallel analogous
developmental biology events, ultimately yielding complex tissue structure and function that results from coordinated
multicellular interactions. The recent successes in generating a diverse set of “organoids” from PSCs demonstrates their
tremendous inherent potential for complex tissue formation. However, the inability to robustly and predictably generate
organoids currently limits their use for drug discovery and development, modeling of human development and disease, and
regenerative medicine therapies. Thus, we have sought to develop methods to reproducibly and robustly direct the morpho-
genesis of pluripotent stem cell aggregates by controlling physical and biochemical elements of the 3D microenvironment. We
have systematically examined the effects of numerous factors, such as aggregate formation methods, hydrodynamic forces
and presence of various types of biomaterials, on the differentiation and morphogenesis of PSCs. In addition, we are now
combining these approaches with novel cell engineering methods in PSCs to spatially and temporally control the initiation of
morphogenic processes. We anticipate that these studies will lead to a greater mechanistic understanding of stem cell biology
as well as scalable and translatable technologies for manufacturing of PSC-derived products for regenerative medicine.
[Biography]
Dr. McDevitt is a Senior Investigator at the Gladstone Institute of Cardiovascular Disease and a Professor of Bioengineering
and Therapeutics at the University of California, San Francisco. He was previously the founding Director of the Stem
Cell Engineering Center at Georgia Tech, the Carol Ann and David D. Flanagan Professor in the Wallace H. Coulter
Department of Biomedical Engineering, and a Petit Faculty Fellow in the Parker H. Petit Institute for Bioengineering and
Bioscience. Dr. McDevitt has 18 years of experience in biomaterials and tissue engineering research and for the past 14
years has focused primarily on stem cell biology and engineering. The objective of Dr. McDevitt’s research is to develop
enabling technologies for the directed differentiation and morphogenesis of stem cells for regenerative medicine and in vitro
diagnostic applications. Much of the research in the McDevitt laboratory focuses on the application of microtechnologies to
engineer stem cell 3D environments in order to more efficiently and effectively direct differentiation and study mechanisms
of morphogenesis, as well as provide scalable and robust approaches for stem cell biomanufacturing. In addition to stem
cell tissue engineering efforts, the McDevitt laboratory is also engineering approaches to develop stem cell-derived molecular
therapies for immunomodulation, tissue repair and regeneration, and anti-aging applications.
1. Bratt-Leal AM, Carpenedo RL, McDevitt TC. Engineering the embryoid body microenvironment to direct embryonic
stem cell differentiation. Biotechnol Prog, 25(1): 43-51 (2009). PMCID: PMC2693014
2. Baraniak PR, McDevitt TC. Stem cell paracrine actions in tissue regeneration. Regen Med, 5(1): 121-143 (2010). PMCID:
PMC2833273
3. Kinney MA, McDevitt TC. Novel emerging strategies to direct stem cell differentiation. Trends Biotechnol, 31(2): 78-84
(2013). PMCID: PMC3557560
4. Murphy WL, McDevitt TC, Engler AJ. Materials as inherent stem cell regulators. Nature Materials, 13(6): 547-57 (2014).
PMCID: PMC4163547
B. Positions and Honors

Positions and Employment
2004 - 2010 Assistant Professor, The Wallace H. Coulter Department of Biomedical Engineering at
Georgia Institute of Technology and Emory University
2004 - 2014 Faculty Member, The Parker H. Petit Institute for Bioengineering and Bioscience,
Georgia Institute of Technology
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2009 - 2014 Director, Stem Cell Engineering Center at Georgia Tech

2010 - 2014 Associate Professor, The Wallace H. Coulter Department of Biomedical Engineering at
2014 Professor, The Wallace H. Coulter Department of Biomedical Engineering at
2014 - Sr. Investigator, Gladstone Institute of Cardiovascular Disease

2014 - Investigator, Roddenberry Center for Stem Cell Biology & Medicine at Gladstone
2014 - Professor, Department of Bioengineering & Therapeutic Sciences, UCSF
Other Experience and Professional Memberships
2007 - American Heart Association, peer reviewer
2007 - National Science Foundation, ad hoc peer reviewer
2007 - Maryland Stem Cell Research Fund, peer reviewer
2007-09 Membership Committee, Society for Biomaterials
2008 New York Stem Cell Foundation, peer reviewer
2008 - 2014 California Institute for Regenerative Medicine (CIRM), Grants Review Working Group
2008 - Editorial Board member, Journal of Biomedical Materials Research A
2009-11 Chair, Cell/Organ Therapy Special Interest Group, Society for Biomaterials
2010 Awards Committee, Society for Biomaterials
2010 - National Institutes of Health, ad hoc peer reviewer
2011-14 TERMIS-NA, Continental Council Member
Honors
1997 Howard Clark Award, Duke University (top undergrad BME independent research)
2000 1st Place Rushmer Lecture Poster Competition, University of Washington
2002-04 NIH Cardiovascular Bioengineering Training Grant Fellow
2004 New Investigator Award, American Heart Association, Basic Cardiovascular Sciences
2008 Merck Best Poster Award, Society for Biological Engineering,
First International Conference on Stem Cell Engineering
2008 UK-US Stem Cell Collaboration Development Award
2009-14 Petit Faculty Fellow, Institute for Bioengineering and Bioscience
2009 Interdisciplinary Research & Education Award, Institute for Bioengineering & Bioscience
2010 Junior Faculty Outstanding Undergraduate Research Mentor Award, Georgia Tech
2010 Young Investigator Award, Society for Biomaterials
2011 UK-US Collaboration Development Award
2011 National Academy of Engineering, China-America Frontiers of Engineering attendee
2011“Above and Beyond” (Eagle) Award, Georgia Tech Biomedical Engineering Society
2013 Best Advisor, Georgia Tech Bioengineering Graduate Program
2013“Best of BIOT” (invited webinar), American Chemical Society
2013“40 Under 40”, Georgia Trend magazine
2013 Carol Ann and David D. Flanagan Professorship
2014 College of Fellows, American Institute for Medical and Biological Engineering
2014 Top Medical Researcher (Georgia), Atlanta Business Chronicle
2014 CIRM Research Leadership Award
C. Contributions to Science
1. Hydrodynamic regulation of stem cell differentiation. Pluripotent stem cells are commonly differentiated as 3D
multicellular aggregates in order to induce morphogenesis to various lineages. Traditional methods for aggregate formation,
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such as hanging drop and static suspension culture, are inherently low throughput, non-scalable and result in heterogeneity
and limited yield of differentiated cells. Our laboratory has developed and characterized the use of controlled hydrodynamic
environments created by“rotary orbital suspension culture” as a means of reproducibly controlling multicellular aggregation
and yielding homogeneous populations of stem cell aggregates. Through a series of systematic studies, we found that
hydrodynamic forces impacted the relative differentiation to different cell lineages and could enhance differentiation to
specific phenotypes, such as cardiomyocytes, due at least in part to temporal differences in endogenous β-catenin signaling

resulting from differences in multicellular aggregation kinetics. Altogether these results demonstrate that hydrodynamic
forces are an important and previously unrecognized parameter capable of modulating the differentiation of stem cells in
suspension culture.
a. Carpenedo RL, Sargent CY, McDevitt TC. Rotary suspension culture enhances the efficiency, yield and homogeneity of
embryoid body differentiation. Stem Cells, 25(9): 2224-2234 (2007).
b. Sargent CY, Berguig GY, McDevitt TC. Cardiomyogenic differentiation of embryoid bodies is promoted by rotary orbital
suspension culture. Tissue Eng Part A, 15(2): 331-342 (2009).
c. Sargent CY, Berguig GY, Kinney MA, Hiatt LA, Carpenedo RL, Berson RE, McDevitt TC. Hydrodynamic modulation
of embryonic stem cell differentiation by rotary orbital suspension culture. Biotechnol Bioeng, 105(3): 611-626 (2010).
d. Kinney MA, Sargent CY, McDevitt TC. Temporal modulation of β-catenin signaling by multicellular aggregation kinetics
impacts embryonic stem cell cardiomyogenesis. Stem Cells Dev, 22(19): 2665-77 (2013). PMCID: PMC3780328
2. Microparticle-mediated stem cell differentiation. Differentiation of stem cells is controlled primarily by addition of soluble
factors to the culture media in order to direct cell fate decisions. In adherent monolayer culture, cells are uniformly exposed
to soluble factors, but when cultured as multicellular aggregates, the inherent 3D geometry of cell organization challenges
molecular presentation due to transport limitations. In order to direct more homogeneous differentiation of stem cells and
tissue morphogenesis, my laboratory has pioneered the incorporation of microparticle biomaterials within 3D stem cell
microenvironments for controlled presentation of differentiation factors locally. Degradable polymeric microspheres and
microgel materials loaded with small molecules and/or growth factors can be incorporated within ESC aggregates during
initial stages of formation and effectively direct differentiation. Dose-dependent control of microsphere incorporation can be
achieved as a function of the ratio of particles-to-cells, particle size, and surface adhesivity. Microsphere-mediated delivery
of signaling factors enables spatiotemporal control and more efficient differentiation of stem cell aggregates than soluble
treatment methods.
a. Carpenedo RL, Bratt-Leal AM, Marklein RA, Seaman SA, Bowen NJ, McDonald JF, McDevitt TC. Homogeneous and
organized differentiation within embryoid bodies induced by microsphere-mediated delivery of small molecules. Biomaterials,
30(13): 2507-2515 (2009). PMCID: PMC2921510.
b. Bratt-Leal AM, Carpenedo RL, Ungrin MD, Zandstra PW, McDevitt TC. Incorporation of biomaterials in multicellular
aggregates modulates pluripotent stem cell differentiation. Biomaterials, 32(1): 48-56 (2011). PMCID: PMC2987521.
c. Bratt-Leal AM, Nguyen A, Hammersmith KA, Singh A, McDevitt TC. A microparticle approach to morphogen delivery
within pluripotent stem cell aggregates. Biomaterials, 34(30): 7227-7235 (2013). PMCID: PMC3800695
d. Wang Y, Yu X, Baker C, Murphy WL, McDevitt TC. Mineral particles modulate the osteo-chondrogenic differentiation
of embryonic stem cell aggregates. Acta Biomater, 29: 42-51 (2016).
3. Stem cell-derived morphogens. My laboratory was the first to decellularize aggregates of ES cells undergoing in vitro
differentiation in order to obtain an acellular matrix containing morphogenic factors capable of directing tissue growth and
differentiation. The spatiotemporal profiles of ECM and morphogenic factors expressed by ESCs throughout differentiation
as“embryoid bodies” (EBs) were characterized using gene, protein and glycosaminoglycan (GAG) analyses. In contrast
to most decellularized tissues from fully mature organs, EB-derived matrices are rich in GAGs and potent morphogens
(i.e. BMPs, Wnts, IGFs), but lack significant amounts of fibrillar collagens. Both solvent-based and physical methods were
developed to effectively decellularize EBs at different stages of differentiation. The resulting matrices retain ECM molecules
present within EBs prior to decellularization and are capable of being repopulated by exogenous cell populations. In vivo
studies in small animals have demonstrated that devitalized EB matrices can promote enhanced healing of dermal excisional
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wounds and induce de novo bone formation at an ectopic tissue site.

a. Nair R, Ngangan AV, McDevitt TC. Efficacy of solvent extraction methods for acellularization of embryoid bodies. J
Biomat Sci Polym Ed, 19(6): 801-819 (2008).
b. Nair R, Shukla S, McDevitt TC. Acellular matrices derived from differentiating embryonic stem cells. J Biomed Mater
Res A, 87A(4): 1075-1085 (2008).
c. Ngangan AV, McDevitt TC. Acellularization of embryoid bodies via physical disruption methods. Biomaterials, 30(6):

1143-1149 (2009). PMCID: PMC2655350.
d. Sutha K, Schwartz Z, Wang Y, Hyzy S, Boyan BD, McDevitt TC. Osteogenic embryoid body-derived material induces
bone formation in vivo. Sci Rep, 5: 9960 (2015). PMCID: PMC4426716
4. Quantitative analysis of pluripotent morphogenesis. Morphogenic differentiation of pluripotent stem cells (PSCs) in 3D
can be challenging to assess and most phenotypic characterization methods rely primarily on destructive forms of analysis
of cell autonomous properties. We have developed novel multivariate analysis methods to quantitatively describe the 3D
morphogenic changes that accompany differentiation of PSC multicellular aggregates, such as gene expression signatures
of secreted molecules and mechanical properties of microscale 3D constructs. In addition, we have complemented our
experimental studies with the development of a rules-based, computational model of 3D stem cell aggregates that can
accurately recapitulate the spatial morphogenic patterns and temporal kinetics of PSC differentiation. The application
of these novel analytical techniques have allowed us to interrogate the complex interactions between cells comprising
multicellular aggregates and the local 3D microenvironment that result in phenotypic patterns of differentiation observed
experimentally.
a. White DE, Kinney MA, McDevitt TC, Kemp ML. Spatial pattern dynamics of 3D stem cell loss of pluripotency via
rules-based computational modeling. PLoS Comp Biol, 9(3): e1002952 (2013). PMCID: PMC3597536
b. Kinney MA, Hookway TA, Wang Y, McDevitt TC. Engineering three-dimensional stem cell morphogenesis for the
development of tissue models and scalable regenerative therapeutics. Ann Biomed Eng, 42(2): 352-67 (2014). PMCID:
PMC3939035
c. Kinney MA, Saeed R, McDevitt TC. Mesenchymal morphogenesis of embryonic stem cells dynamically modulates the
biophysical microtissue niche. Sci Rep, 4: 4290 (2014). PMCID: PMC3944369
d. White DE, Sylvester JB, Levario TJ, Lu H, Streelman JT, McDevitt TC, Kemp ML. Quantitative multivariate analysis
of multicellular morphogenic trajectories. Integr Biol, 7(7): 825-33 (2015) PMCID: PMC4712928
5. Microtechnologies for stem cell culture & analysis. In collaboration with several laboratories, but particularly Dr.
Hang Lu (Georgia Tech), we have applied an array of different microfluidic technologies to manipulate individual stem
cells, colonies and 3D aggregates. Through these studies, we have successfully been able to separate human PSCs and
differentiated derivatives with high efficiency in a label-free manner simply by exploiting relative differences in adhesive
strength to detach cells with well-defined microfluidic forces. We were also able to control the merger of different stem cell
aggregates within actuation of microfluidic traps to form spatially controlled, complex multicellular patterned structures.
Similarly, we could also array all of the single cells dissociated from individual multicellular stem cell aggregates to perform
phenotypic analyses. The combinations of these microfluidic techniques allow for unprecedented experimental abilities to
manipulate and characterize the morphogenic differentiation of PSCs“on-chip” with precise spatial and temporal control of
3D microenvironments.
a. Singh A, Suri S, Lee T, Chilton JM, Cooke MT, Chen W, Fu J, Stice SL, Lu H, McDevitt TC, García AJ. Adhesion-based,
label-free isolation of human pluripotent stem cells. Nature Methods, 10(5): 438-444 (2013). PMCID: PMC3641175
b. Suri S, Singh A, Nguyen AH, Bratt-Leal AM, McDevitt TC, Lu H. Microfluidic patterning of embryonic multicellular
aggregates for in vitro development studies. Lab on a Chip, 13(23): 4617-4624 (2013). PMCID: PMC3844158
c. Wilson JL, Suri S, Singh A, Rivet CA, Lu H, McDevitt TC. Single cell analysis of embryoid body heterogeneity using
microfluidic trap array. Biomed Microdevices, 16(1): 79-90 (2014). PMCID: PMC3945678
d. Hookway TA, Butts JC, Lee E, Tang H, McDevitt TC. Aggregate formation and suspension culture of human pluripotent
stem cells and differentiated progeny. Methods, in press.
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Complete List of Published Work in MyBibliography:

http://www.ncbi.nlm.nih.gov/sites/myncbi/todd.mcdevitt.1/bibliography/40966343/public/?sort=date&direction=ascending.
âĂČ
D. Research support
Ongoing Research Support

NIH Transformative R01 AR062006 McDevitt (PI) 9/15/2011 - 8/31/2016
Stem cell morphogen delivery via engineered biomaterials
The objective of this project is to develop a novel class of materials capable of capturing and releasing morphogenic factors
secreted by stem cells to serve as vehicles for acellular regenerative therapies.
NIH R21 AI109499 McDevitt (PI) 8/1/2014 - 7/31/2016

Engineering mesenchymal stem cell microenvironments to promote immunomodulation
The objective of this proposal is to regulate the immunomodulation and paracrine secretion of human mesenchymal stem
cells through engineering of transplantable 3D stem cell constructions to enhance the efficacy of hMSC-based therapies for
the treatment of inflammatory diseases.
CIRM LA1_C14-08015 McDevitt (PI) 12/1/2014 - 11/30/2019

Engineering microscale tissue constructs from human pluripotent stem cells
The objective of this proposal is to engineer 3D cardiac and neural multicellular constructs from pluripotent stem cell sources
to model human tissue development.
NSF CBET 0939511 Kamm (PI) 9/15/2010 - 8/31/2015

STC: Emergent behaviors of integrated cellular systems
The objective of this multi-investigator, multi-institutional research consortium is to engineer biological machines from
integrated cellular systems.
Role: Project leader
NIH P2C HD086843 Boninger (PI) 9/17/2015 - 6/30/2017

Alliance for regenerative rehabilitation research & training (AR3T)
The objective of this technology development project is to develop and test an ex vivo system for the mechanical conditioning
of stem cell microtissue constructs.
Role: Co-investigator
Completed Research Support

NSF DMR 1207045 Temenoff & McDevitt (co-PIs) 7/1/2012 - 6/30/2015
Tailorable glycosaminoglycans for enhanced stem cell chondrogenesis
The objective of this project was to synthesize and characterize a variety of modified GAG materials for growth factor
retention and release in order to enhance MSC chondrogenesis.
Role: Co-PI
DOD W81XWH-08-1-0704 Boyan (PI) 7/1/2011 - 8/31/2014

Center for Advanced Engineering for Soldier Survivability
The objective of this center was to use advanced bioengineering to develop technologies that will facility the transfer of
research in musculoskeletal biology and regenerative medicine to patient care.
Role: Co-Investigator
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NIH R01 GM088291 McDevitt (PI) 8/1/2009 - 7/31/2014

Microsphere-mediated differentiation of embryonic stem cells
The objective of this project was to control the spatiotemporal delivery of morphogenic factors via biomaterials incorporated
within 3D aggregates of stem cells to more efficiently direct differentiation.

NIH R01 EB010061 McDevitt (PI) 3/1/2010 - 2/28/2014
Microfluidic perfusion control of embryonic stem cell differentiation
The objective of this project was to develop microfluidic perfusion culture systems capable of precise spatiotemporal control
of molecular delivery to stem cells in order to screen morphogen effects on differentiation in a high-throughput manner
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Mon(2)-CIS4-3
Retinal stem cells from bench to clinic
1
Petr Baranov
1:Schepens Eye Research Institute, Mssachusetts Eye & Ear; Department of Ophthalmology, Harvard Medical School, Boston MA, USA

Loss of photoreceptors due to retinitis pigmentosa, age-related macular degeneration and other age, trauma and genetic-
related retinal degenerative disorders currently leads to incurable blindness and a significant decrease in quality of life for
millions worldwide. Since the regenerative capacity of the human neural retina is highly limited, one viable treatment option
is cellular replacement. Human retinal progenitor cell is a candidate cell type for such a therapy. I will describe the methods
for cell isolation and expansion and other aspects of the therapy translation into clinical practice.
[Biography]
Petr Baranov, MD, PhD is an Investigator at the Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard
Medical School. He graduated from Russian State Medical University in 2007 and obtained his PhD in Cell Biology in
2011. Then he trained with Dr. Michael Young in photoreceptor replacement. During his postdoc he studied various
aspects of retinal progenitor cell transplantation, including immunological issues of allotransplantation. He participated in
the development of cell therapy for retinitis pigmentosa, which is now in a Phase I clinical trial.
He started as an Instructor at HMS in 2015 and now his research is focused on different translational approaches for retinal
regeneration: neuroprotection and cell replacement/tissue engineering.
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Mon(2)-CIS4-4
Possible future of regenerative medicine using cell sheet engineering and iPS cell tech-
nology
1
Katsuhisa Matsuura
1:Tokyo Women’s Medical University, Japan

After the biotech medicine era, regenerative medicine is expected to be an advanced medicine that is capable of curing patients
with difficult-to-treat diseases and physically impaired function. Our original scaffold-free cell sheet-based tissue engineering
technology enables to be engrafted for a long time and has already been applied as regenerative medicine in various types of
tissues and organs including cornea, esophagus and heart. On the other hand, because loss of cardiomyocytes is the principal
reason for heart failure, replacement of lost myocardium with regenerated cardiac tissue is thought to be the most promising
strategy as cardiac regenerative medicine for heart failure. Recent advancement of our technologies on tissue vascularization
and scalable suspension culture of human iPS cells enable us to fabricate three-dimensional cardiac tissues. However there
are still some issues to apply the cardiac tissues for transplant and tissue models including cardiomyocyte maturation, the
interaction between cardiomyocytes and interstitial cells in tissues, tumorigenicity and function. In this symposium, I will
present our recent progress of our technologies and perspectives of human bioengineered cardiac tissue for transplantation
and tissue models.
[Biography]
Katsuhisa Matsuura
Associate Professor
Institute of Advanced Biomedical Engineering and Science / Department of Cardiology, Tokyo Women’s Medical University
Personal history
1999 M.D. National Defense Medical College, Japan
1999-2001 Resident, Tokyo Women’s Medical University Hospital
2001-2006 PhD student, Department of Cardiology, Tokyo Women’s Medical University
2006-2009 Assistant Professor, Department of Cardiology, Tokyo Women’s Medical University
2009-2014 Lecturer, Institute of Advanced Biomedical Engineering
and Science / Department of Cardiology, Tokyo Women’s
Medical University
2014- Associate Professor, Institute of Advanced Biomedical Engineering
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and Science / Department of Cardiology, Tokyo Women’s
Medical University

Awards
2005 Young Investigator’s Award 1st prize, The Japanese Circulation Society
2007 Inoue Memorial Foundation Research Award
2008 Yamakawa Hisako Research Award, Tokyo Women’s Medical University
Professional Societies
The Japanese society of Internal Medicine, The Japanese Circulation Society, Japanese College of Cardiology, The Japanese
Heart Failure Society (Councilor), The Japanese Society of Regenerative Medicine (Councilor), American Heart Association,
International Society for Heart Research
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Advances in Cancer Genomics
Mon., April 04, 2016 13:30-15:30 Room A (2F)
Convener：Tatsuhiro Shibata（Laboratory of Molecular Medicine & Laboratory of Genome Technology of Human Genome
Center, Institute of Medical Science, The University of Tokyo, Japan）
Convener ：David A. Wheeler（Human Genome Sequencing Center/ Baylor College of Medicine, USA）

Intensive application world-wide of next generation sequencing technologies has enabled us to define the global genetic
alterations, including driver genes, in a wide range of cancers. Organization of large arrays of driver genes into a small
number of signaling pathways and cellular processes has revealed the inner workings of the cancer cell and led to the
notion of molecular classification of tumors. Limited successes of molecular targeted therapies support the validity of
such molecular classification but demonstrate that there is much still to learn. In this session we will delve into novel
applications of next generation sequencing that are expanding the frontier of tumor biology. Research efforts in rare
cancers identify still missing driver genes, and multi-layered omics approaches improve the functional annotation of
infrequent driver genes. Emerging clinical interests in the development of immunotherapies suggest that a complete
molecular classification of tumors must include immune constituents and the details of the mutational burden. Finally,
intra-tumoral genetic heterogeneity has revealed dynamic changes in clonal constitution of a tumor as it metastasizes and
evolves. The properties of this evolution carry implications for acquired drug resistance. We will present these recent
advances and discuss future directions in the cancer genomics field.
Mon(2)-CIS5-1
Genomic Profiling of a T-cell Leukemia
1
David A. Wheeler
1:Human Genome Sequencing Center/ Baylor College of Medicine, USA
Sézary Syndrome is a rare but aggressive form of cutaneous T-cell lymphoma of unknown etiology characterized by generalized
redness, scaling, itching and increased numbers of circulating atypical lymphocytes. It is rarely curable and has a poor
prognosis. We performed whole exome and RNA Seq on CD4+ T-cells from 37 SS patients using skin fibroblasts as normal
control tissue. These data implicate dysregulation of the cell cycle checkpoint and T-cell signaling as key drivers of the
disease. Recurrent somatic alterations were identified in CARD11, CCR4, PLCG1, RPS6KA1, and ZEB1. Activating CCR4
and CARD11 mutations were detected in nearly a third of patients. ZEB1, a transcription repressor essential for T-cell
differentiation, was deleted in over half of patients. The overall mutation signatures in these patients indicates prolonged
exposure of the malignant cells to UVB radiation, suggesting the cell of origin might be resident memory T cells found
in superficial layers of the skin rather than central memory T-cells found in the circulation. IL32 and IL2RG were over-
expressed in nearly all cases. Analysis of T-cell receptor Vβ and Vα expression revealed bi- and tri-clonal populations of
malignant cells in one third of subjects. Our results demonstrate profound disruption of key signaling pathways in Sézary
Syndrome. Interestingly some of these pathways are common to B-cell malignancies for which novel therapeutic strategies
are in development. These results will be discussed in the context of personalized medicine approaches.
[Biography]
David Wheeler received Bachelor of Science degrees in biochemistry and zoology from the University of Maryland and a
Ph.D in Molecular Genetics from The George Washington University in Washington D.C. His dissertation, under Dr. Gordon
Hager, investigated the regulation of the mouse mammary tumor virus in normal and malignant breast tissue. His Postdoctoral
research was in behavioral genetics at Brandeis University in the field of behavorial genetics in fruitflies. Dr. Wheeler joined
the faculty at Baylor College of Medicine in 1991 to develop computational tools for moloecular biology. He was Director the
Molecular Biology Computation Resource at Baylor College of Medicine for 10 years. In 2001 he joined the Human Genome
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Sequencing Center at BCM where he developed computational methods to guide the finishing of the genome sequences of D.
melanogaster and Homo sapiens. He has been the Director of Cancer Genomics in the Human Genome Sequencing Center,
where he develops methods for discovery and analysis of genetic variation in cancer using DNA sequencing technologies.
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Mon(2)-CIS5-2
Genetic and transcriptomic landscape of biliary tract cancer
1,2
Tatsuhiro Shibata
1:Laboratory of Molecular Medicine, The Institute of Medical Science, The University of Tokyo; Division of Cancer
Genomics, National Cancer Center, Japan、2:Division of Cancer Genomics, National Cancer Center

Biliary tract cancer (BTC) arises from epithelial cells lining the bile duct distributing distinctive anatomical locations (intra-
hepatic, extra-hepatic and gall bladder). The incidence of this tumor is high in East and South Asia and part of South-America;
however, the disease incident has rapidly increased globally. Although clinical prognosis is severely worse than other tumor
types including hepatocellular carcinoma (HCC) (five year survival is about 25%), the genetic and transcriptomic landscape
of this tumor category remains to be poorly uncovered. To elucidate a comprehensive repertoire of molecular alterations
including therapeutic targets, we performed whole exome (200 cases) and transcriptome (125 cases) sequencing of the largest
BTC (including both intra-hepatic and extra-hepatic cases) cohort ever reported, and uncovered somatic coding mutations
as well as novel fusion genes including potential therapeutic targets.
Based on the mutational signature analysis, intra-hepatic cholangiocarcinoma (ICC) showed quite distinctive features com-
pared to HCC although both arise from the liver, suggesting that different carcinogenic factors are responsible for the genetics
of ICC genome. Unique actionable drive genes including FGFR2 and other kinase/kinase-related fusion genes, IDH1/2 and
other epigenetic modulators were identified. Using cell line models, we further evaluated the oncogenic activity and depen-
dency of these target genes. Furthermore integrated analysis of genetic and transcriptomic alterations elucidated molecular
subtypes in BTC, which was associated with patients’ prognosis.
[Biography]
Professor, Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of
Tokyo
Chief, Division of Cancer Genomics, National Cancer Center
1990 M.D., School of Medicine, Faculty of Medicine, The University of Tokyo

1990 University of Tokyo, School of Medicine, Graduating School (Pathology)
1992 Research Fellow, Pathology Division, National Cancer Center
1995 Postdoctoral researcher, Developmental Biology Center, University of California, Irvine, CA, USA
2005 Project Leader, Cancer Genomics Project, National Cancer Center
2010 ~ Chief, Division of Cancer Genomics, National Cancer Center
2014 ~ Professor, Laboratory of Molecular Medicine, The Institute of Medical Science, Human Genome Center, The Univer-
sity of Tokyo
Honors and Academic Activities

Uehara Memorial Research Fellowship (1996)
Incitement Award of the Japanese Cancer Association (2005, Japan Cancer Association)
Tamiya Award (2008, National Cancer Center),
Research Award (2011, The Japanese Society of Pathology)
JCA-Mauvernay Award (2014, Japan Cancer Association)
Tahara Award (2015, Japanese Society for Gastroenterological Carcinogenesis)
Specialty and Research Field of Interest

Cancer Genomics, Tumor Pathology, Bioinformatics
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Mon(2)-CIS5-3
ASIAN CANCER GENOMICS AND ITS CLINICAL IMPLICATIONS
1
Bin Tean Teh
1:National Cancer Centre Singapore, Singapore

Our works focus on the genomic profiling of Asian-centric cancers using high-throughput technologies and the data is correlated
with clinicopathological information. The goals are to 1) understand the molecular mechanism underlying these cancers; and
2) to identify potential therapeutic targets and novel biomarkers related to the behavior of the disease. In this talk, I will first
present our recent genomic studies of the fibroepithelial tumors of the breast, from the very common benign fibroadenoma to
the rare but malignant Phyllodes tumors. Several frequently mutated genes such as MED12 and RARA will be highlighted
and discussed. Second, I will describe our works on cholangiocarcinoma (biliary tract cancer) including cases related to liver
fluke infection. There is significant difference in the spectrum and frequency of the alterations between fluke-related and
non-fluke related cases, explaining the difference in their underlying pathogenesis. Third, I will describe our recent discovery
of the molecular fingerprint of a herbal carcinogen called Aristolochic Acid, which is associated with upper urinary tract
urothelial cancer. This discovery not only enhances our understanding of the molecular mechanism of this carcinogen, but
allows screening for the involvement of this carcinogen in other cancer types such as liver cancer. Finally, I will update on
Singapore efforts on precision medicine which was established about a year ago.
[Biography]
Dr Teh obtained his MD (1992) from the University of Queensland, Australia and his PhD (1997) from the Karolinska
Institute, Sweden. Following postdoctoral works at Karolinska Institute, he joined the Van Andel Research Institute (VARI),
USA in 2000 as a Senior Scientific Investigator heading the Laboratory of Cancer Genetics. From 2003, he served as the Deputy
Director (Research Operations) of VARI and from 2008, Director of VARI International. He established the National Cancer
Centre Singapore (NCCS)-VARI laboratory, which serves as a bridge between translational research and clinical medicine.
In 2010 he received the Singapore Translational Research Investigator Award and relocated to Singapore. He served as the
SingHealth Group Director for Translational Research from 2010-2012. His laboratory focuses on Asian Cancer Genomics
and in the last 5 years have made seminal discoveries in the field including biliary tract cancer, urological cancer and breast
tumors. He holds Adjunct Professorships at several universities worldwide including Baylor College of Medicine, USA, Nanjing
University and Sun Yat-Sen University, China and the Karolinska Institute, Sweden. Dr. Teh has published extensively, with
over 350 publications in high impact scientific journals. He is a past and present member of numerous editorial boards for
journals including Lancet Oncology, Cancer Research, Molecular Cancer Therapeutics. Dr Teh is a recipient of the 2015
Singhealth Distinguished Researcher Award and co-recipient of the 2015 Singapore President Science Award.
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Mon(2)-CIS5-4
The evolutionary history of prostate cancer from pre-malignant lesion to lethal metas-
tasis
1
David Wedge
1:Cancer Genome Project, Wellcome Trust Sanger Institute, UK

Cancers evolve within a complex, changing environment and their evolutionary trajectories are affected by a variety of factors
including: normal cells that make up the microenvironment; germline genetic predisposition; therapeutic interventions. Fur-
ther, the environment in which tumour cells survive and grow changes over time as tumours progress and metastasise. We
whole-genome sequenced 330 tumour and normal samples from 130 men with prostate cancer at various stages of progression,
ranging from benign hyperplasias to metastatic deposits obtained at autopsy. Bioinformatic algorithms were developed to
reconstruct phylogenetic trees for each cancer, representing their subclonal architecture, history and pattern of spread. This
allowed us to answer many questions concerning the evolutionary response of prostate cancers to this changing environment:
• Morphologically normal ageing prostate contains clusters of mutations caused by clonal expansions.
• Multifocal prostate tumours contain multiple tumours that are unrelated genetically, but tumour cells may transit across
regions of morphologically normal tissue.
• Normal and cancerous prostate cells are subject to the same mutagenic processes
• Mutational signatures of prostate cancers change over time.
• Several genetic drivers of prostate cancer are specifically associated with ETS status, progression to metastasis, the acqui-
sition of treatment resistance or outcome.
• Differences in the acquisition of genetic aberrations in ETS-positive and ETS-negative tumours indicate differing routes to
progression.
• Convergent evolution occurs in both early and late-stage tumours.
• Polyclonal seeding of metastases and metastasis-to-metastasis transmission are common.
Together these observations yield remarkable insights into the evolution of prostate cancer, revealing unprecedented tumori-
genic and metastatic complexity and uncovering potential for molecular tracking of disease progression.
[Biography]
David studied Chemistry at the University of Oxford, before obtaining an MSc in Software Development from the Univer-
sity of Huddersfield and a PhD in Computer Science from Manchester Metropolitan University. During three postdoctoral
positions at the University of Manchester he worked in a number of different areas, including metabolomics, proteomics and
vapour sensing.
Since 2011, David has been the senior statistician in the Cancer Genome Project at the Wellcome Trust Sanger Institute.
He works across the field of Cancer Genomics, but has a particular interest in Evolution and Heterogeneity in Cancer and is
currently leading the ICGC pan-cancer working group on Evolution and Heterogeneity and is an organiser of the DREAM
challenge on Tumour Heterogeneity and Evolution.
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David’s publications encompass the development of novel concepts and strategies for the analysis of tumour heterogeneity
(Nik-Zainal, Cell, 149: 994-1007, 2012), the discovery of evolutionary trajectories in haematological cancers (Ortmann, NEJM,
372: 601-12, 2015) and the deconvolution of temporal changes in mutational signatures (de Bruin, Science, 346: 251-6, 2014).
He has a particular interest in the evolution of prostate cancer (Gundem, Nature, 520: 353-357, 2015; Cooper et al, Nature
Genetics, 47, 367-372, 2015; Hong, Nat. Comms., 6: 6605, 2015).

In April 2016, David will take up a position as Group Leader in Cancer Genomics at the Oxford Biomedical Big Data Institute.
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Cancer Genomics: HBOC
Mon., April 04, 2016 15:50-17:50 Room A (2F)
Convener：Seigo Nakamura（Department of Breast Surgical Oncology, Showa University School of Medicine, Japan）
Convener ：Sung-Won Kim（Daerim St. Mary’s Hospital, Korea）

The Current Approach for Hereditary Breast and Ovarian Cancer from the Aspect of Precision Medicine
In the U.S. or in Europe, about 5% to 10% of breast cancers are thought to be hereditary. Most inherited cases
of breast cancer are associated with two abnormal genes: BRCA1 and BRCA2. Germline mutations of BRCA1and
BRCA2 genes can cause very high rates of breast and ovarian cancer, so called Hereditary Breast and Ovarian Cancer
(HBOC) . And the prevalence is almost the same in Asian countries. Management of HBOC family members are,
(1) Intensive screening including Breast MRI (2) Risk reducing mastectomy or Risk reducing salpingo-oophrectomy (3)
Chemoprevention (Tamoxifen for prevention of breast cancer) Proper option for each subject should be selected according
to each view of life or values. Therefore skillful genetic counsellors or geneticists are necessary for breast oncology team,.
The strategies to conquer HBOC are still far behind in Asian countries at present. In this symposium, we will review the
current status of HBOC management and discuss about key issues to improve the management of HBOC in Asia.
In the era of next generation sequencing, we may encounter unexpected rare hereditary disease such as Li-Fraumeni
syndrome or Cowden disease and we shouldn’t miss them and send them to the specialist of each rare disease. In this
symposium, we also focus on how to manage incidental findings among leading hospitals in this field.
Finally, the future vision of precision medicine or preemptive medicine in the management for HBOC will be discussed.
Mon(2)-CIS6-1
The current approach for hereditary breast cancer from the aspect of precision medicine in the U.S.
1
Banu Arun
1:University of Texas MD Anderson Cancer Center, USA
TBA
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Mon(2)-CIS6-2
Current Status and Future of Hereditary Breast Cancer in Asia
1,2,3,4
Ava Kwong
1:Division of Breast Surgery, Department of Surgery, The University of Hong Kong, Hong Kong, China、2:The University of Hong Kong
Shen Zhen Hospital, China、3:The Hong Kong Hereditary Breast Cancer Family Registry、4:Hong Kong Sanatorium and Hospital, Hong
Kong

BRCA1/BRCA2 mutations are the most common high penetrant genes associated with an increased lifetime risk for hereditary
breast and ovarian cancer (HBOC). Although genetic testing is standard of care in Western developed countries, there are
still variations in availability of genetic testing and risk assessment for HBOC in Asia. Depending on the countries, there are
variations in the clinical strategies and cancer management. The Asian BRCA Consortium has grouped together 14 Asian
countries and reviewed genetic counselling/testing uptake rates and clinical management options in these countries. Moreover
economic factors, healthcare and legal frameworks, and cultural issues affecting the genetic service availability in Asia were
discussed. Mutation spectrum, and VUS rates and the increase use of NGS gene panel testing poses more decisional issues in
the clinical management of Hereditary Breast cancer in Asia. These will be discussed.
[Biography]
Dr. Ava Kwong is the Chief of Breast Surgery Division, Clinical Associate Professor and Assistant Dean at the University of
Hong Kong, and University of Hong Kong - Shenzhen Hospital. She had also held the position of Visiting Associate Professor,
Division of Oncology, at the Stanford University, USA.. In 2007, she founded and is Chairman of Hong Kong Hereditary
Breast Cancer Family Registry. In 2012 she is appointed to be the co-leader of Cancer Work Group in the development
of Cancer Services planning of Hong Kong West Cluster, Hong Kong and in 2013 she was elected to be the Deputy Chief
and Committee Member of the Shenzhen Breast and Endocrine Cancer Society, China. She has also been appointed to
be a member of the Cancer Coordinating Committee of the Food and Health Bureau, Government of the Hong Kong in
2014. During her surgical career, she has gained multiple awards and her studies on different aspects of Breast cancer in
Chinese women have gained over 100 publications in reputable international journals . She authored chapters in "ABC of
Breast Disease” published by British Medical Journal, Companion to Specialist Surgical Practice: Breast Surgery Volume:
5th Edition, “Up to Date” on-line medical website based in United States.She is the first women elected on the the council
of College of Surgeons in Hong Kong. She has received various grants including Hong Kong RGC, ITF grants and NIH grant
in USA.
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Mon(2)-CIS6-3
The current approach for hereditary breast cancer from the aspect of basic science
1,2
Soo H. Teo
1:Cancer Research Malaysia; University Malaya Medical Center, Malaysia、2:University Malaya Medical Centre

Breast cancer is rising rapidly in Asia and is the most common cause of cancer related deaths in many Asian countries.
Notably, whereas the majority of breast cancer in Caucasian populations occurs in post-menopausal women, only 40-50%
occurs in post-menopausal women in Asia, suggesting that the proportion of risk attributable to genetic factors is likely to
be correspondingly higher. Unfortunately, there remains a significant gap in knowledge and access to counseling and testing
of BRCA1 , BRCA2 and other cancer predisposition genes in most of Asia. In my talk, I will describe recent efforts to
characterize the prevalence of genetic susceptibility to breast cancer using cancer gene panels and provide an update on the
identification of new genetic loci associated with increased risk to breast cancer using genome wide association studies.
[Biography]
Professor Teo is the Principal Investigator of the Malaysian Breast Cancer Study [MyBrCa] and the Malaysian Mammographic
density study. MyBrCa has been a collaborative partner in the Consortium of Investigators of BRCA1 and BRCA2 (CIMBA),
the Breast Cancer Association Consortium (BCAC) and the Asian Breast Cancer Consortium, and together, these studies have
led to the identification of more than 50 novel genetic loci associated with increased risk to breast cancer. The success of these
studies has only been possible because of the very large sample sizes and the MyBrCa makes a very important contribution
to this work as it is one of only a handful of BCAC studies that have been carried out in Asia (most are European or North
America) enabling the study of common risk alleles in this population.
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Mon(2)-CIS6-4
Updates of the Korean Hereditary Breast Cancer (KOHBRA) Study
1
Sung-Won Kim
1:Surgery, Daerim St. Mary’s Hospital, Korea

The Korean Hereditary Breast Cancer (KOHBRA) study is a prospective multicenter cohort study from 38 major centers
identifying cases and their families. Between May 2007 and July 2011, the KOHBRA study enrolled up to 2530 subjects and
identified 501 mutation carriers. All participants received genetic counseling and BRCA genetic testing; clinical information
and blood samples for blood banking were collected. The primary aim of the KOHBRA study I is to estimate the prevalence
of BRCA1/2 mutations and OC among a high-risk group of patients with hereditary BC and their families. And the purpose
of KOHBRA study II is as follows; first, to develop Korean BRCA mutation prediction model; second, to characterize clinical
phenotype and discover novel prognostic factors for BRCA associated BC; third, to identify environmental and genetic
modifiers of BRCA1/2 mutation; fourth, to develop nationwide network of genetic counseling. We conclude that Korean
familial BC patients are good candidate for BRCA testing even with single- or 3rd degree relative-BC family history and we
conclude that BRCA mutation for non-familial Korean BC patients was detected at a high rate, particularly, in patients with
an earlier onset (age <35 without other risk or age≤40 with other risk), bilateral BC, BC and OC, and two or more high risk
factors.
Our previous study showed that the widely used BRCA risk prediction models BRCAPRO and Myriad II underestimate
the number of mutation carriers in Korean breast cancer patients because these models were developed for Caucasian breast
cancer populations. Therefore, we developed the Korean BRCA risk calculator (KOHCal). Our model is based on personal
and family history of breast and ovarian cancer and the pathologic characteristics; it will be a useful tool for providing genetic
risk assessments in Korean populations.
[Biography]
Position: President & CEO, Daerim St. Mary’s Hospital, 2015.3-Present
Education:
Seoul National University College of Medicine, Seoul, Korea. M.D. 1995
Seoul National University College of Medicine, Seoul, Korea. Ph.D. 2004
Professional positions held:
Academic:
Assistant Prof of Surgery, Seoul National University College of Medicine, 2003.4-2010.3
Associate Prof of Surgery, Seoul National University College of Medicine, 2010.4-2015.2
Hospital:
Associate Attending Surgeon, Seoul National University Bundang Hospital, 2003.4-2015.2.28
Director, The Breast Care Center, Daerim St. Mary's Hospital, 2015.3.1-Present
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Human Evolution: Archaic and Modern Humans
Mon., April 04, 2016 13:30-15:30 Room E (1F)
Convener：Naruya Saitou（Division of Population Genetics, National Institute of Genetics, Japan）

Convener ：Mark Stoneking（Max Planck Institute for Evolutionary Anthropology, Germany）

Analyses of DNA obtained from human fossils (including those of archaic humans such as Neandertals and Denisovans),
combined with the increasing amount of genome-wide data available from various populations of modern humans, are
providing important new insights into human evolutionary history. In particular, the ancestry that archaic humans
provided to modern humans has proven valuable in reconstructing the migration history of human populations and in
identifying genetic changes that differentiate modern from archaic humans. In addition, some studies have found evidence
for positive selection on specific archaic genes in modern humans, indicating that some archaic genes provided an adaptive
advantage to modern humans. Moreover, ancient DNA from modern human skeletons is proving to be a rich source of
new insights into more recent human evolution. This session will provide an overview of some of the latest developments
to arise from genomic studies of archaic and modern humans, including insights into the history of human populations in
Asia and in the Pacific, the distribution of archaic ancestry in modern human genomes, and the overall similarities and
differences between archaic and modern humans.
Mon(2)-CIS7-1
Population genetic analysis of Negrito populations in Southeast Asia
1
Timothy A. Jinam
1:Division of Population Genetics, National Institute of Genetics, Japan
TBA
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Mon(2)-CIS7-2
Ancient DNA of early modern humans
1
Qiaomei Fu
1:Institute of Vertebrate Paleontology and Paleoanthropology, Chinese Academy of Sciences, China

The relationship between early modern humans (EMH) and present-day populations and the interactions between EMH and
archaic populations are particular interest. Here, we present several projects having helped to resolve several questions re-
garding EMH history. 1) Using a capture approach, we sequenced the first whole chromosome of an EMH. Analyses show
that EMH present in the Beijing area 40,000 years ago are related to the ancestors of present-day Asians as well as Native
Americans. Furthermore, this EMH shares an admixture signal with Neandertals common to all non-African populations.
2) A high coverage genome was sequenced from a femur of an EMH individual discovered near Ust-Ishim, Siberia. Analyses
show that he is closely related to the ancestral population shared between present-day Europeans and Asians. The amount of
genomic admixture from Neandertals is similar to that found in present-day non-Africans. However, the size of the genomic
segments of Neandertal ancestry in the this individual is substantially larger than those found in present-day individuals. 3)
We have also captured ancient DNA from a mandible in Oase, Romania. This Oase 1 has a plausible range of ~ 37,000-42,000
14
years based on direct C dates. Analyses of the relationship of this individual to present-day humans show that he is closely
related to the ancestral population shared between present-day Europeans and Asians. The over-all amount of genomic ad-
mixture from Neandertals is higher than that in present-day non-Africans. Importantly, we observe three segments that are
over 50 Mb in size and several that are over 5 Mb, suggesting that the Neanderthal contribution to this individual occurred
so recently in his family tree that the segments of Neandertal have had little time to break up. These projects illustrate how
studying ancient genomes can increase our understanding of the interactions between modern and archaic humans.
[Biography]
Qiaomei Fu finished her PhD under the supervision of Svante Pääbo at the Max Planck Institute for Evolutionary Anthropol-
ogy (MPI-EVA) Leipzig in 2013. Then, she worked as a postdoctoral research fellow in the population genetics group headed
by Professor David Reich of the Genetics Department at Harvard Medical School. From August 2015, she is a research scien-
tist at MPI-EVA. In January 2016, she began a position as the head of the Ancient DNA Lab at the Institute of Vertebrate
Paleontology and Paleoanthropology (IVPP), Chinese Academy of Sciences. Her present research focuses on using ancient
DNA to study gene flow between modern and archaic humans, to determine early modern human migration routes and to
explore how agriculture influences the population structure of the Neolithic expansion in Europe and Asia. Her research
projects have been published in Nature, Science, PNAS, Current Biology and other international high profile journals. One
of these research projects was awarded "one of the top 2014 annual ten scientific events” in Nature.
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Mon(2)-CIS7-3
A Genomic Perspective on the Colonization of the Pacific
1
Mark Stoneking
1:Max Planck Institute for Evolutionary Anthropology, Germany

The colonization of the remote islands of the Pacific represents one of the last major dispersals of modern humans, and
determining when and how humans settled both Near Oceania (Australia, New Guinea, and nearby islands, all reachable
by intervisible voyages) and Remote Oceania (islands to the east of the main chain of the Solomon Islands, which required
travelling across considerable distances) continues to be of great interest. Archaeological, linguistic, and genetic evidence all
point to two major migrations to the Pacific: an early occupation of Near Oceania at least 40,000 years ago, followed by
more recent colonization of Remote Oceania beginning about 3,500 years ago and associated with the spread of Austronesian
languages. Questions that are still being debated include the extent to which additional migrations contributed to the genetic
ancestry of Oceanian populations, as well as to what extent humans traveled by a simple, west-to-east stepping stone model
across the Pacific. I shall present the latest results from investigations of genome-wide data from Oceanian populations, which
are suggesting a more complicated scenario of isolation and migration than previously suspected.
[Biography]
Mark Stoneking received his PhD in genetics from the University of California, Berkeley in 1986. After postdoctoral work
at Berkeley he held research scientist positions at the Human Genome Center at Lawrence Berkeley Laboratory and at
the Cetus Corporation. He joined the faculty of the anthropology department at The Pennsylvania State University as an
assistant professor in 1990, rising to associate professor in 1994 and full professor in 1998. In 1999 he left Penn State for
the newly-established Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, where he supervises the
Human Population History Group and is Honorary Professor of Biological Anthropology at the University of Leipzig. His
research interests involve using molecular genetic methods to address questions of anthropological interest concerning the
origins, migrations, and relationships of human populations, and the influence of selection during human evolution.
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Mon(2)-CIS7-4
Formation of Japonesian from viewpoint of modern human dispersal in East Eurasia
Naruya Saitou 1,2,3 ，Timothy A. Jinam 1,2 ，Hideaki Kanzawa-Kiriyama 4 ，Ituro Inoue 2,5
，
Katsushi Tokunaga 6 ，Keiichi Omoto 7 ，Asian DNA Repository Consortium
1:Division of Population Genetics, National Institute of Genetics; Department of Genetics, SOKENDAI; Depart-
ment of Biological Sciences, Graduate School of Science, University of Tokyo, Japan、2:Department of Genetics,

SOKENDAI、3:Department of Biological Sciences, Graduate School of Science, University of Tokyo、4:Department
of Anthropology, National Museum of Nature and Science、5:Division of Human Genetics, National Institute of
Genetics、6:Department of Human Genetics, Graduate School of Medicine, University of Tokyo、7:Department of
Anthropology, Faculty of Science, University of Tokyo
Japanese Archipelago stretches from Hokkaido to Ryukyu Islands, and modern humans started to live there ~ 40,000 years
ago. The Jomon period, 16,000 to 3,000 years ago, is associated with cord-marked pottery and Jomon people were hunter-
gatherers. Dual-structure model proposes that different proportions of admixture between Jomon descendants and later
migrants resulted in three current-day Japanese; Ainu, Yamato (mainland), and Okinawan. Our genome-wide SNP data for
these three modern populations and genome sequence data of Jomon people confirmed this model. However, detailed analysis
of Yamato people in various areas suggested another wave of migration, possibly at late Jomon period. These three waves of
migrations to Japanese Archipelago are closely related to complex history of human movements in East Eurasia.
We also analyze genome-wide SNP data of Negritos in Philippine Islands (Aeta, Agta, Mamanwa, and Batak), Malay Peninsula
(Jehai, Kintaq, and Batek), and Andaman Islands. After eliminating genetic components derived from recent admixture with
surrounding agriculturists, we found that their divergence was as deep as that of Melanesians. We also found that signature
of gene flow from Denisovan to Aeta, Negritos in Northern Luzon Island, was as high as that to Papuans. This finding shows
unique phylogenetic status of Negrito populations within genomic history of East Eurasians after“out of Africa”.
[Biography]
Naruya Saitou graduated Department of Biology at Faculty of Science, University of Tokyo, in 1979. He received M.S. from
Department of Anthropology, Graduate School of Science, University of Tokyo in 1981 and Ph.D. from Graduate School of
Biomedical Sciences, University of Texas Health Science Center at Houston in 1986. One of his Ph.D. thesis chapters was
proposal of the neighbor-joining method, which is still frequently used for constructing phylogenetic trees. After serving
assistant professor at Department of Anthropology, Faculty of Science, University of Tokyo for two years, he moved to
National Institute of Genetics at Mishima, Japan as associate professor in 1991, and became professor in 2002. He has
joint appointments at Department of Genetics, SOKENDAI (Graduate University for Advanced Studies) and Department of
Biological Sciences, Graduate School of Science, University of Tokyo. His group studies human and non-human evolution using
genomic DNA sequence data. He published ten single-authored books including “Introduction to Evolutionary Genomics” in
2014 from Springer.
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Genetics of Recurrent Pregnancy Loss
Mon., April 04, 2016 15:50-17:50 Room E (1F)
Convener：Mayumi Sugiura-Ogasawara（Obstetrics and Gynecology, Nagoya City University, Graduate School of Medical
Sciences; Center for Recurrent Pregnancy Loss, Japan）
Convener ：Mary D. Stephenson（Department of Obstetrics and Gynecology, University of Illinois at Chicago, USA）

Recurrent miscarriage (RM) is classically defined as three or more consecutive pregnancy losses occurring before 20 weeks
postmenstruation. However, many researchers have now revised the definition to two or more pregnancy losses, because
of the recent increase in the prevalence of childless couples. Thus, recurrent pregnancy loss (RPL) which is defined as
two or more pregnancy losses at any gestational age is used recently. The estimated frequencies of three or more and two
or more consecutive pregnancy losses are 0.9% and 4.2% in the Japanese general population.
Antiphospholipid syndrome (APS), uterine anomalies and abnormal chromosomes in either partner are established causes
of RPL. Only about 30% of cases have an identifiable cause and it is well-known that the cause remains unexplained in
over a half of the cases. The abnormal embryonic karyotype was found in 41.1% of patients in whom both conventional
causes and karyotype of aborted conceptus could be examined in our previous study. Therefore, the prevalence of truly
unexplained, of cases with normal embryonic karyotype, was only 24.5%. An abnormal embryonic karyotype is usually
included in unexplained because the embryonic karyotype is seldom analyzed clinically.
Recently, an association between about 120 kinds of polymorphisms and RPL has been reported. Factor V Leiden
mutation is well-known to be associated with RPL. An association between parental and embryonic chromosome and
candidate genes and RPL are presented in the session.
Mon(2)-CIS8-1
Miscarriage chromosome testing: Conventional cytogenetic analysis vs. molecular
1
Evica Rajcan-Separovic
1:Department of Pathology, University of British Columbia, Canada
Numeric chromosome errors in the conceptus are a common cause of miscarriage, however, for the vast majority of the 40
~ 50% of miscarriages with a normal karyotype (euploid miscarriage), the genetic etiology remains uncertain. The recent
advent of genome-wide high resolution technologies, including chromosome microarray analysis (CMA) and next generation
sequencing (NGS), have opened new possibilities for discovery of genetic changes that are too small to be detected by
traditional miscarriage chromosome analysis. To date, CMA of over 3000 miscarriages has been reported. Clinically relevant
CNVs were identified in ~ 2-7% of cases. Although the impact of CNVs on the function of affected genes in miscarriage was
demonstrated for isolated CNVs, and CNVs as a group, the majority of euploid miscarriages still remain without a diagnosis.
More recently, the development and application of next generation sequencing (NGS), including whole-genome (WGS) or
exome sequencing (WES), allowed screening the whole genome for new genetic causes of human disease at the nucleotide
level. Thus far, over one hundred candidate disease genes have been identified by WES in a variety of developmental disorders.
However, the application of NGS for finding the cause of prenatal lethal or abnormal development, including miscarriages,
has been reported in a very limited number of studies. A review of the genetic findings in miscarriage using cytogenetic and
molecular analysis, as well as pros and cons of different approaches will be provided.
[Biography]
Dr Evica Rajcan-Separovic is Associate Professor at the University of British Columbia in Vancouver, Canada. She is also a
Scientist at the Child and Family Research Institute and works as a Canadian College of Medical Genetics certified clinical
cytogeneticist at BC Children’s Hospital. Her main interest is in finding genomic causes of development disorders that lead
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to miscarriage or abnormal early childhood development. She was a recipient of the Canadian Institutes of Health Research
Clinical Investigatorship Award and a Michael Smith Foundation for Health Research Career Scholar Award.
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Mon(2)-CIS8-2
Recurrent Pregnancy Loss: Miscarriage and Parental Chromosome Testing
1
Mary D. Stephenson
1:Department of Obstetrics and Gynecology, University of Illinois at Chicago, USA

Recurrent pregnancy loss (RPL) is a heterogeneous reproductive problem with multiple etiologies and contributing factors.
As such, evaluation and management of RPL is a complex task, and research is no less daunting.
In the general reproductive population, numeric chromosome errors, including trisomy, monosomy and polyploidy, account
for 50-70% of miscarriages of less than 10 weeks’ size; which is similar to the frequency seen in recurrent pregnancy loss, when
stratified for maternal age. Therefore, accurate miscarriage chromosome testing is essential to differentiate couples who are
having miscarriages due to random chromosome errors versus euploid miscarriages. Routine miscarriage testing would im-
prove our ability to identify causative factors associated with recurrent euploid pregnancy loss, and therapeuitc interventions
that could be of benefit.
Carriers of a a structural chromosome rearrangement, most commonly a translocation, are found in 2.5-7.8% of couples with a
history of recurrent pregnancy loss, compared to 0.2% in the general reproductive population. Although in vitro fertilization
with pre-implantation genetic diagnosis (IVF/PGD) is offered to such carriers, mounting evidence suggests that evaluation
and treatment of concomitant RPL factors, and close monitoring in the first trimester, results in a high likelihood of a
successful pregnancy outcome, in carriers of a structural chromosome rearrangement ascertained on the basis of recurrent
pregnanancy loss.
[Biography]
Dr. Mary D. Stephenson is the Theresa S. Falcon-Cullinan Professor and Head of the Department of Obstetrics and Gynecol-
ogy at the University of Illinois at Chicago. She is the Director of the University of Illinois Recurrent Pregnancy Loss Program.
Dr. Stephenson is recognized internationally for her clinical expertise and translational research in recurrent pregnancy loss.
She has longstanding collaborations studying the genetic basis for miscarriage and candidate genes leading to embryonic
developmental defects. As a clinician-scientist, Dr. Stephenson has led several randomized trials to assess therapeutic in-
terventions to overcome recurrent pregnancy loss. Through the ESHRE Special Interest Group Early Pregnancy, she enjoys
collaborating with other RPL clinician-scientists from the UK, Netherlands and Denmark. Dr. Stephenson is Co-Editor of
the textbook, "Early Pregnancy" with the 2nd Edition in press. She is an Associate Editor of Human Reproduction Update
and is on the Editorial Board for Fertility & Sterility.
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Mon(2)-CIS8-3
Can PGS/PGD improve live birth rate in RPL?
1
Ruth B. Lathi
1:Department of Reproductive Rndocrinology and Infertility, Stanford University, USA

Recurrent pregnancy loss (RPL) is a multifactorial disorder which is often challenging for both patients and providers.
Guidelines for the evaluation and treatment of patients with RPL include screening for uterine abnormalities, parental
chromosomes, and antiphospholipid antibodies, but approximately half of RPL patients remain unexplained. The current
recommendation for patients with unexplained RPL is expectant management which offers most patients a 60 to 80% success
rate over time. Genetic imbalances in the embryo, including inherited unbalanced translocations and de novo aneuploidy,
are frequent causes of miscarriage. Preimplantation genetic screening (PGS) has been proposed as an effective method for
selecting viable embryos for transfer that may result lower risk of miscarriage for patients with unexplained RPL and carriers
of balanced translocations. The current evidence examining the use of in vitro fertilization with PGS in patients with RPL
reveals variable results, due to differences in technologies used and variable patient populations. Newer approaches, which
include blastocyst biopsy and the ability to screen for all 24 chromosomes, show the most promise in reducing miscarriage
rates. Studies that identify which patients are most likely to benefit from PGS and include live birth rates per initiated cycles
are needed before universally recommending this treatment to couples with RPL.
[Biography]
Dr. Ruth Lathi graduated from the Massachusetts Institute of Technology with a Bachelor of Science in Molecular Biology
and received her Doctorate in Medicine from the University of California in San Francisco. She then went on to complete her
Residency at Baylor College and her Fellowship in Reproductive Endocrinology and Infertility at Stanford University School
of Medicine. Dr. Lathi then joined the Stanford faculty in the Department of Obstetrics and Gynecology and is now an
Associate Professor. She is the Founder and Director of the Multispecialty Recurrent Pregnancy Loss Program at Stanford
University and she is also the Director of Clinical Operations for the Stanford Fertility and Reproductive Health Center. Dr.
Ruth Lathi has been nationally recognized for her research in the field of infertility and recurrent pregnancy loss and has an
interest in preimplantation genetic diagnosis in the treatment of reproductive disorders.
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Mon(2)-CIS8-4
Candidate genes associated with recurrent pregnancy loss
1,2 1,2 1,2 1,2
Mayumi Sugiura-Ogasawara ，Tamao Kitaori ，Kinue Katano ，Nobuhiro Suzumori ，
Yasuhiko Ozaki 1,2
1:Obstetrics and Gynecology, Nagoya City University, Graduate School of Medical Sciences; Center for Recurrent
Pregnancy Loss, Japan、2:Center for Recurrent Pregnancy Loss

Established causes of RPL include antiphospholipid syndrome, uterine anomalies, and chromosomal abnormalities, particularly
translocations, in either partner. We found that an abnormal embryonic karyotype was the most frequent cause of RPL,
accounting for as high as 41% of all the cases. Heritable thrombophilia has been reported to be associated with RPL. FV
Leiden mutation and prothrombin mutation are most common candidate genes associated with RPL. Polymorphisms of about
100 genes have been reported to be candidate genes associated with RPL. However, the clinical significance of risk alleles is
not unclear.
We examined the frequency of six SNPs of the ANXA5 and the 46 C/T SNP of FXII or low activity of FXII in RPL patients
versus fertile control women, subsequent live birth rate between with and without risk alleles in RPL patients.
The SNP5 of ANXA5 and the CT, but not the TT, genotype was confirmed to be risk factors for RPL in the cross-sectional
study using multivariate logistic regression analysis (OR, 1.47; 95% CI, 1.00-2.17 and OR, 2.8; 95% CI, 1.37-5.85). From our
cohort study, live birth rate of patients with and without risk alleles of SNP5 were 84.0 % and 84.3 %, respectively after
excluding cases with abnormal embryonic karyotype, with no significant difference. Neither low FXII activity nor the CT
genotype predicted the subsequent pregnancy outcome.
The ANXA5 and FXII gene were found to be the significant susceptibility genes for RPL, similar to the FV Leiden mutation.
However, the clinical influence might be relatively small, because the presence/absence of risk alleles did not have any
predictive value for the subsequent pregnancy outcome.
[Biography]
Professor of Obstetrics and Gynecology and Head of Center for Recurrent Pregnancy Loss. Nagoya City University, Graduate
School of Medical Sciences
Sugiura-Ogasawara M graduated from Nagoya City University in March 1985
Resident, Department of Obstetrics and Gynecology, Nagoya City University since April 1985
MD, National Hamamatsu Hospital since August 1986
MD, Nagoya City Midori Hospital since October 1987
Researcher, MD, Nagoya City University since July 1993
Professor, Nagoya City University, Graduate School of Medical Sciences since January 2006
Head of center for recurrent Pregnancy Loss since April 2015
Articles
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Sugiura-Ogasawara M, Ozaki Y, Katano K, Suzumori N, Kitaori T, Mizutani E. Abnormal embryonic karyotype is the most
frequent cause of recurrent miscarriage. Hum Reprod 2012; 27: 2297-2303.
Sugiura-Ogasawara M, Ozaki Y, Kitaori T, Kumagai K, Suzuki S. Midline uterine defect size correlated with miscarriage of
euploid embryos in recurrent cases. Fertil Steril 2010; 93: 1983-1988.

Sugiura-Ogasawara M, Ozaki Y, Sato T, Suzumori N, Suzumori K. Poor prognosis of recurrent aborters with either maternal
or paternal reciprocal translocations. Fertil Steril 2004; 81: 367-373.
Ogasawara M, Aoki K, Okada S, Suzumori K. Embryonic karyotype of abortuses in relation to the number of previous
miscarriages. Fertil Steril 2000; 73: 300-304.
Ogasawara M, Aoki K, Kajiura S, Yagami Y. Are antinuclear antibodies predictive of recurrent miscarriages? Lancet 1996;
347:1183-1184.
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Clinical Genetics and Dysmorphology
Mon., April 04, 2016 13:30-15:30 Room B-1 (2F)
Convener：Hiroshi Kawame（Department of Education and Training, Tohoku University, Japan）

Convener ：Louanne Hudgins（Pediatrics/Medical Genetics, Stanford University School of Medicine, USA）

This session will illustrate how important dysmorphology is in determining the underlying genetic diagnosis in individuals
from the prenatal period to adulthood.
Dr. Louanne Hudgins will review how important prenatal imaging via ultrasound and magnetic resonance imaging is in
the noninvasive diagnosis of a number of disorders including the RASopathies and skeletal dysplasias.
The importance of ongoing and detailed phenotyping in the interpretation of results from clinical and research-based next
generation sequencing will be discussed by Dr. Raoul Hennekam.
Dr. Alain Verloes will provide a construct for the evaluation of individuals with primary microcephaly including those
associated with dwarfism.
Dr. Tomaki Kosho will describe a unique form of Ehlers-Danlos syndrome which is associated with distinctive dysmorphic
features.
Mon(2)-CIS9-1
Prenatal Presentation of Genetic Disorders
1
Louanne Hudgins
1:Pediatrics/Medical Genetics, Stanford University School of Medicine, USA
With the marked improvement of prenatal imaging including ultrasound and MRI, the ability to detect fetal anomalies has
increased dramatically. The detection of these abnormalities and the recognition of patterns in these anomalies allow clinicians
to make genetic diagnoses prenatally in a noninvasive way. This is helpful in managing pregnancies as well as determining
the most appropriate logistics for delivery and neonatal care. The following are examples of how accurate prenatal diagnosis
via imaging alone allowed for the best possible management during pregnancy and the perinatal period.
The RASopathies are a family of developmental disorders caused by heritable defects of the RAS/MAPK signaling pathway.
As a group, the prevalence approaches 1/700 to 1/1250. As we published in 2014 (Myers et al., Am J Med Genet Part
A 164A:2814-2821), Noonan syndrome, cardiofaciocutaneous syndrome, and Costello syndrome share the following prenatal
findings: polyhydramnios; evidence of lymphatic dysplasia including increased nuchal translucency, increased nuchal fold,
cystic hygroma, pleural/pericardial effusions, skin edema and hydrops; macrosomia; relative macrocephaly; cardiac anomalies
including structural heart defects, valvular dysplasia and hypertrophic cardiomyopathy; and renal anomalies including pelviec-
tasis, hydronephrosis and increased kidney size. In contrast, fetal arrhythmias are relatively specific for Costello syndrome.
Because this group of disorders can be associated with several neonatal issues including respiratory distress, hypotonia and
hypoglycemia, suspicion for the presence of a RASopathy based on the prenatal imaging findings should prompt delivery at
a tertiary care center.
Other illustrative examples that will be discussed include using distinctive ultrasound findings such as the so-called hitchhiker
thumb and single cardiac ventricle in the presence of short limbs to diagnose diastrophic dysplasia and Ellis-van Crevald
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syndrome, respectively.
[Biography]
Louanne Hudgins, MD, FAAP, FACMG, is Professor and Chief of the Division of Medical Genetics in the Department of
Pediatrics at the Stanford University School of Medicine. She also serves as Director of Perinatal Genetics and as Medical
Director for the MS program in Human Genetics and Genetic Counseling at Stanford University. Her editorial contributions

include serving as Clinical Genetics Editor for Genetics in Medicine. She has been very involved in the American College of
Medical Genetics, previously serving on the Board of Directors, as Vice President for Clinical Genetics, and as co-chair for
the ACMG Professional Practice and Guidelines Committee. She is currently President-Elect. In addition, Dr. Hudgins has
volunteered with the March of Dimes, and is a member of the Kabuki Syndrome Network Professional Advisory Group.
Dr. Hudgins has been elected to the Western Society for Pediatric Research and the American Pediatric Society. Her current
areas of clinical investigation include prenatal genetic screening and diagnosis and the use of new technologies in genetic
diagnosis.
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Mon(2)-CIS9-2
Next Generation Sequencing demands Next Generation Phenotyping
1
Raoul C. Hennekam
1:Department of Paediatrics, Academic Medical Center, University of Amsterdam, The Netherlands

Next-generation sequencing (NGS) is the most powerful diagnostic tool since the roentgenogram. NGS facilitates diagnostic
processes on a massive scale, allowing interrogation of all genes in a single assay. It has been suggested that NGS will decrease
the need for phenotyping in general and by medical geneticists in particular. A shift in focus and approach of phenotyping is
more likely however.
In diagnostic care NGS will yield variants in several genes, and consequences of these variants will need to be analysed and
integrated with clinical findings to make a diagnosis. Diagnostic skills of medical specialists will shift from a pre-NGS-test
differential diagnostic mode to a post-NGS-test diagnostic assessment mode. Increasingly variants are found in patients of
which the phenotype does not resemble at all the typical phenotype found in patients with variants in this gene, which causes
significant problems in counselling.
In research phenotyping and medical genetic assessments will remain essential as well. NGS can identify primary causative
variants in phenotypes inherited in a Mendelian pattern, but biology is much more complex. Phenotypes are caused by
the actions of several genes and by epigenetic and environmental influences. Indeed truly monogenic disorders do not exist.
Mosaicism may be much more common than anticipated.
Dissecting all influences necessitates ongoing and detailed phenotyping, refinement of clinical diagnostic assignments, and
iterative analyses of NGS data. A major problem will remain to proof that a finding in NGS is causative for the phenotype.
There has always been a critical need for phenotyping and clinical analysis in medicine, and in the era of NGS this need will
be even more important than ever.
[Biography]
Raoul Hennekam received his specialty trainings in Paediatrics and in Clinical Genetics at Utrecht University. He was
appointed as professor of Paediatrics and Clinical Genetics in 2002 at the AMC of University of Amsterdam. During 2005-
2010 he worked in London at Institute of Child Health and Great Ormond Street Hospital as professor of Clinical Genetics
and Dysmorphology. He is presently working as professor of Paediatrics and Translational Genetics in Amsterdam.
Main scientific interests include intellectual disabilities, autism, connective tissue disorders, and (molecular) dysmorphology.
He is member of the Dutch Health Council, EUCERD, European Research Council, Editor of American Journal of Medical
Genetics and of the European Journal of Medical Genetics, author of 500 papers in peer-reviewed journals (H-index 66) and
24 chapters in international texts, co-chair of the international Morphology Nomenclature Committee, and senior editor of
‘Gorlin’s Syndromes of the Head and Neck’.
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Mon(2)-CIS9-3
Primary microcephalies and primordial microcephalic dwarfisms
1
Alain Verloes
1:Dept of Genetics, Robert DEBRE Univerity Hospital, Sorbonne Paris-Cité University Denis Diderot Medical School
and INSERM UM1141, Paris, France

Primary genetic microcephalies (PGM) are a model disease for studying brain growth and organization. PGM are rare
(usually) autosomal recessive disorders with a cumulate incidence from 1/10.000 to 1/100.000 births, depending on geographic
origin. Six groups of PGM can be distinguished: MicroCephaly, Primitive Hereditary (MCPH), primary microcephaly
with chorioretinopathy (MCCRP), cortical dysplasia, complex, with other brain malformations (CDCBM) and 3 primary
microcephalic dwarfisms (PMDW): Seckel syndrome (SCKS), microcephalic osteodysplastic dwarfism type 2 (MOPD2), and
Meier-Gorlin syndrome (MGS). PGM are defined by an occipito-frontal head circumference (OFC) more than 2 SD below
the mean for sex, age, and ethnicity at birth, and at least below - 3 SD after age six months. Typical patients exhibit
usually no neurologic anomalies except seizures, mild pyramidal syndrome and behavioral disturbances, but expansion of
the phenotype to patients with brain dysgenesis/malfortmations has blurred the phenotype. Ophthalmological anomalies are
associated with some of genetic forms, but are inconstant. Cognitive impairment is described as borderline to severe. No
systematic neuropsychological study has been conducted on PM patients. Reduced brain volume of these patients is usually
associated with a simplified gyral pattern, migration defect or cortical dysgenesis, abnormal basal nuclei, holoprosencephaly
or infratentorial abnormalities are inconstantly observed with mutations of some genes, without clear genotype/phenotype
correlation. Two third to one half of PGM patients have no identified gene mutation. Digenic inheritance has not been
reported.
The cellular defect of most PGM alter fundamental cellular processes linked to the mitotic cell cycle, such as general control
of licensing of DNA replication (in MGS), control of the G1/S, S/M and metaphase/anaphase checkpoints, centrosome
biogenesis and cycle, aster and spindle pole during mitosis, kinetochore function and nuclear membrane reconstruction. Those
mechanisms are tighly intricated and many proteins play a role in more than one process. The common physiopathologic
endpoint of these processes is an alteration in cell cycle timing mitotic disfunction, and/or fate determination of neuronal
progenitors. This may result in a premature neuronal differentiation and a reduced number of neurons, or in premature
loss of progenitors (although the exact mechanisms remain unclear for most MP genes so far) whereas more severe mitotic
dysfunction may explain reduced body size. Besides their canonic role in cell cycle, some genes further have alternative roles
explaining more complex brain malformations (such as holoprosencephaly or schizencephaly), involvement of retina, brain
vessels, bone or skeletal development that characterize the phenotype of some of these them. Unravelling genetic bases of
congenital microcephalies has changed their nosology and expanded their pathogenic heterogeneity. We suggest to define
PGM on a pathophysiological basis: PGM refers collectively to patients with congenital microcephalies due to a genetic
anomaly directly affecting neuronal production by alrring mitotic cycle and its control. We thus disagree with the current
phenotypic series proposed my OMIM to catalog the new genes, based on raw phenotypic grouping, as they mix disorders
with non-related pathophysiologic mechanisms, and create artificial clinical subgroups.
[Biography]
Will be submitted in Word
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Mon(2)-CIS9-4
From dysmorphology to human biology: A lesson from the discovery of Ehlers-Danlos
syndrome caused by CHST14/D4ST1 deficiency
1
Tomoki Kosho
1:Medical Genetics, Shinshu University School of Medicine, Japan

Dysmorphology could be a critical clue to understand human biology. We have learned that through discovery of a recently
delineated disorder, Ehlers-Danlos syndrome (EDS) caused by CHST14/ D4ST1 deficiency. In 2000-2003, we encountered
two unrelated patients with strikingly similar craniofacial features (large fontanelle, hypertelorism, short and downslanting
palpebral fissures, blue sclerae, short nose with hypoplastic columella, low-set and rotated ears, high palate, long philtrum,
thin upper lip vermilion, small mouth, and micro-retrognathia) and other malformations (multiple congenital contractures)
as well as progressive multisystem connective tissue fragility-related complications (skin hyperextensibility and fragility, joint
hypermobility and deformity, massive subcutaneous hematomas), compatible with the diagnosis as EDS [Kosho et al., 2005].
Genetic analysis on these patients and additional four patients with similar symptoms uncovered CHST14 to be causal for
this condition [Kosho et al., 2010; Miyake et al., 2010]. Interestingly, CHST14 was identified almost at the same period as
causal for a rare type of arthrogryposis syndrome“adducted thumb-clubfoot syndrome”[Dündar et al., 2009] and for a subset
of kyphoscoliosis type EDS without lysyl hydroxylase deficiency [Malfait et al., 2010], and all these conditions were concluded
to represent a single clinical entity [Kosho et al., 2011]. Glycobiological and pathological study suggested that multisystem
fragility would be caused by impaired assembly of collagen fibrils resulting from loss of dermatan sulfate (DS), replaced by
chondroitin sulfate, in the decorin glycosaminoglycan side chain that promotes electrostatic binding between collagen fibrils.
This is the first reported human disorder that specifically affects biosynthesis of DS. Its clinical characteristics implicate that
DS play a critical role in the development and the maintenance of connective tissues in multiple organs.
[Biography]
After graduating Keio University, School of Medicine in 1993, clinical training as a pediatrician was started. A PhD degree was
given in 2001 for research on SHOX abnormalities. The career as a pediatric clinical geneticist started at Saitama Children’s
Medical Center, where a girl with an unclassified type of Ehlers-Danlos syndrome (EDS) was encountered, who showed
characteristic craniofacial features, congenital contractures, skin laxity and fragility, joint laxity, and massive subcutaneous
hematomas and was later found to have EDS caused by CHST14/D4ST1 deficiency. After moving to Department of Medical
Genetics, Shinshu University, School of Medicine in 2003, the career as a general clinical geneticist started and the second
patient was encountered, later found to have the same disorder. Collaborative genetic, glycobilogical, and pathological study
uncovered the causative gene and a part of the pathophysiology, and comprehensive clinical observation accomplished the
delineation of the disorder. For this series of achievements, awards by Japan Medical Association, the Japan Society of Human
Genetics, and Japan Pediatric Society were given. Currently, as a principal investigator of a grant from Japan Agency for
Medical Research and Development and as a member of the Rare types committee in the International Consortium for EDS,
international clinical, molecular, glycobiological, pathological, and therapeutic research on the disorder is orchestrated.
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Human Genomics in Infectious Diseases
Mon., April 04, 2016 15:50-17:50 Room B-1 (2F)
Convener：Katsushi Tokunaga（Department of Human Genetics, The University of Tokyo Graduate School of Medicine,
Japan）
Convener ：Adrian V.S. Hill（Director of Jenner Institute & Wellcome Trust Centre for Human Genetics, University of

Oxford, UK）
In this age of rapid globalization, infectious diseases represent a major threat to human health worldwide. In addition
to new outbreaks established endemic diseases cause millions of deaths each year. Combinations of pathogen and host
genetic factors play a major role in both susceptibility to particular organisms and the course of infection and disease. A
variety of approaches including candidate gene, exome-wide and genome-wide studies have identified a number of associ-
ations between human genetic variants and susceptibility to major infectious diseases, some with very large effect sizes.
These contribute to our understanding of both the genetic architecture of infectious disease susceptibility and molec-
ular pathogenic mechanisms, and provide fascinating insights into the impact that evolutionary selection by infectious
pathogens has had on our genome. In addition, some associations point to exciting new possibilities for intervention and
control. In this session, recent progress for major infectious diseases including HIV/AIDS, tuberculosis, leprosy, sepsis
and hepatitis B is reviewed and discussed.
Mon(2)-CIS10-1
Genetic Susceptibility to some Common Bacterial Diseases of Humans
Adrian V.S. Hill 1 ，Kathryn Auckland 1 ，Stephen Chapman 1 ，Kate Elliott 1 ，James Gilchrist 1 ，
Alex Mentzer 1 ，Tara Mills 1 ，Vivek Naranbhai 1 ，Anne Ndungu 1 ，Tom Parks 1 ，Anna Rautanen 1
1:Wellcome Trust Centre for Human Genetics, Oxford University, UK
Bacterial diseases are the biggest infectious killers of humans and, yet, have been less studied by human geneticists than
malaria and many viral diseases. We report on ongoing efforts to identify genetic factors influencing genetic susceptibility to
a range of high impact bacterial diseases using both genome-wide association analyses and, more recently, exomics. These
diseases include sepsis in a range of European countries, bacteraemia in Kenyan children, tuberculosis in a range of populations,
non-typhoidal Salmonella in Africa and rheumatic heart disease secondary to group A streptococci in Melanesia. Significant
associations have also identified been identified for response to vaccines against particular bacteria in African infants. The
data identify associations of interest in the evolution of resistance on bacterial disease and some findings may also provide
new approaches to intervention.
[Biography]
Adrian Hill is Professor of Human Genetics and Director of the Jenner Institute at Oxford University. He leads research
programmes in both the genetics of susceptibility to tropical infectious diseases and in vaccine development.
He trained in medicine at Trinity College Dublin and Oxford before joining the newly opened Institute of Molecular Medicine
in 1988. He studied HLA and other genetic factors in malaria susceptibility and identified protective associations with HLA
types while working at the MRC Laboratories in The Gambia. As a founder member of the Wellcome Trust Centre for Human
Genetics since 1994 his research group has studied multiple genetic factors associated with resistance to malaria, tuberculosis,
bacterial pneumonia, sepsis and viral infections.
He has published over 500 research papers with an h-index of 112. He is a Fellow of the UK Academy of Medical Sciences
and of the Royal College of Physicians, an NIHR Senior Investigator and a Wellcome Trust Senior Investigator.
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Mon(2)-CIS10-2
Immunogenetic Factors that Impact the Course of HIV infection
1
Mary Carrington
1:Cancer and Inflammation Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer
Research, USA

Variation in the HLA class I genes has the greatest influence on outcome after HIV infection relative to the rest of the
genome. While allelic effects of these genes have been well-appreciated for decades, more recently it has become evident that
other polymorphisms within the region also contribute to HIV control, such as those involved in innate receptor recognition,
regulation of cell surface expression levels, and tapasin dependence. The killer immunoglobulin-like receptors (KIR) and the
leukocyte immunoglobulin-like receptors (LILR), which regulate effector cell functions through binding of certain groups of
HLA class I molecules, are also highly polymorphic, and variation in these genes in combination with that at the HLA loci
can have an impact on host defense against the virus. I will present data that emphasizes the multiple ways in which variation
within/around the HLA class I loci affects their interaction with other genes, and how these interactions in turn modulate
HIV control.
[Biography]
Dr. Mary Carrington is the Director of the Basic Science Program and a Senior Principal Scientist at the Frederick National
Laboratory for Cancer Research (FNLCR) where she heads the HLA Immunogenetics Laboratory in the Cancer and Inflam-
mation Program. Her primary research interests focus on the role of host genetics in cancer, autoimmunity and infectious
disease pathogenesis.
Dr. Carrington received her Ph.D. in Immunobiology from Iowa State University. Her postdoctoral studies took place in
the Departments of Immunology and Microbiology at Duke University and the University of North Carolina, after which she
joined the Immunology Department at Duke University as a faculty member. She moved to the National Cancer Institute at
Frederick (now the FNLCR) in 1989. She is a member of the Steering Committee of the Ragon Institute of MGH, MIT, and
Harvard, and a Visiting Professor at Harvard University. She is presently on sabbatical at Oxford University.
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Mon(2)-CIS10-3
Genetic Study of Leprosy in Chinese Population: Susceptibility and Treatment Re-
sponse
Jianjun Liu 1 ，Furen Zhang 2 ，Liu Hong 2 ，Astrid Irwanto 1
1:Human Genetics, Genome Institute of Singapore, Singapore、2:Shandong Provincial Institute of Dermatology and
Venereology, Shandong Academy of Medical Sciences, Jinan, China

Leprosy is a chronic infectious disease caused by intracellular pathogen Mycobacterium leprae. With about 200,000 new cases
being detected each year, leprosy remains to be a serious health problem in developing countries, including Asians. M leprae
mainly infects humans and cannot be cultured in vitro, which has greatly hindered research on M leprae and thus limited
biological understanding on leprosy development. Epidemiological studies as well as unusually low genomic diversity of M
leprae have, however, strongly suggested the importance of host genetics in leprosy development.
As a part of our Asian-centric research program on the genetics of complex diseases, we have been working on leprosy,
aiming to discover genetic variants that influence leprosy susceptibility and treatment response. We have performed a series
of the genetic studies of leprosy and discovered over a dozen of novel susceptibility loci/genes for leprosy (NEJM 2009,
Nature Genetics 2011 & 2015 and AJHG 2012). These novel susceptibility loci/genes have highlighted the important role
of NOD2-medicated innate and acquired immune responses as well as autophagy in leprosy development. Interestingly, our
studies have also revealed evidence of shared genetic susceptibility between autoimmune/inflammatory and infectious diseases.
Furthermore, we have also investigated the genetic basis of dapsone hypersensitivity syndrome (DHS). Dapsone is the primary
agent of the effective multidrug treatment for leprosy, and DHS is a severe adverse drug reaction (ADRs) induced by dapsone.
Our study has discovered HLA-B*13:01 as a highly sensitive and specific biomarker for DHS that can be used for clinical
screening to identify leprosy patients that are at high risk for DHS and should be excluded from dapsone-based treatment
(NEJM 2013). Our findings have clearly demonstrated that host genetics plays an important role in leprosy development and
treatment response.
[Biography]
Dr. Liu is currently the Deputy Director, Research Programs and Senior Group Leader, Human Genetics at the Genome
Institute of Singapore. Dr. Liu got his PhD on quantitative genetics at Duke University and did his postdoctoral training in
the genetics of psychiatric diseases at Columbia University. Dr. Liu’s main research interest is to understand the genetic basis
of human disease susceptibility and inheritance. Mainly focusing on complex disease phenotypes, his lab pursues collaborative
research to discover genetic variants that influence disease susceptibility, progression and treatment outcome by employing
both hypothesis-driven and hypothesis-free strategies for genetic analysis.
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Mon(2)-CIS10-4
Genomic approaches to hepatitis B virus related diseases
Katsushi Tokunaga 1 ，Hiromi Sawai 1 ，Nao Nishida 1,2
，Hiroko Miyadera 1,2
，Masaya Sugiyama 2 ，
Masashi Mizokami 2
1:Department of Human Genetics, The University of Tokyo Graduate School of Medicine, Japan、2:National Center
for Global Health and Medicine, Research Center for Hepatitis and Immunology

SNP-based genome-wide association studies (GWAS) have indicated that HLA-DPA1/DPB1 is the strongest susceptibility
region to chronic hepatitis B (CHB). Follow-up studies based on genotyping of HLA-DPA1 and HLA-DPB1 showed multiple
susceptibility and protective alleles to CHB in Japanese, Chinese, Korean, and Thai populations. Analysis on HLA-DPB1
genotypes or combinations of different alleles showed dominant effects of protective alleles to susceptibility alleles. HLA allele-
stratified analysis detected a new susceptibility gene. Moreover, we expanded HLA genotyping-based association analyses to
the other HLA class II genes, HLA-DQA1, DQB1 and DRB1 . Unexpectedly, some DRB1-DQA1-DQB1 haplotypes clearly
showed stronger associations than DPA1-DPB1 haplotypes. Thus the study provides an example that SNP-based GWAS
does not necessarily identify the primary susceptibility locus in the HLA region. Furthermore, our GWAS for hepatitis B
virus (HBV) related hepatocellular carcinoma identified a new protective allele in HLA class I , in addition to the previously
reported DPB1 allele. Binding assay of a series of Hepatitis B virus-derived peptides with various HLA-DP allele products
identified binding of certain peptides to susceptible or protective HLA-DP proteins. Our current study on interaction between
host (human) HLA alleles and sequence variants of pathogen (HBV) genome is also presented.
[Biography]
Professor Katsushi Tokunaga is the Chairman of Department of Human Genetics, Graduate School of Medicine, The University
of Tokyo since 1995. He received PhD at Graduate School of Science, The University of Tokyo in 1984. He has been working
on genome-wide search for susceptibility genes to various complex diseases including infectious diseases and other immune
mediated diseases, as well as drug response genes. He is a board member of several academic societies including Japan Society
of Human Genetics and Japanese Society of Histocompatibility and Immunogenetics. He is Editor-in-Chief of Human Genome
Variation and an Editorial Board member of several other international journals including Journal of Human Genetics and
Tissue Antigens.
(HP: http://www.humgenet.m.u-tokyo.ac.jp)
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Frontiers of Human Genomics
Tue., April 05, 2016 8:00-10:00 Annex 1 (1F)
Convener：Shinichi Morishita（Department of Computational Biology and Medical Sciences, Graduate School of Frontier
Sciences, the University of Tokyo, Japan）
Convener ：Jun Wang（iCarbonX, China）

In this session, we will hear from four prominent researchers exploring the frontiers of human genomics. Dr. Jun Wang
co-founded BGI and has published over 400 original papers in genomic sciences. Last year, he founded a new company,
ICarbonX, to establish a health-related big-omics data platform and to manage individual health more effectively. Dr.
Richard Durbin co-leads the 1,000 Genomes Project and is well-known for developing many computational sequence
analysis programs (e.g., HMMER, BWA, and GeneWise) and biological databases (e.g., WormBase, Pfam, and Ensembl).
Dr. Erez Lieberman-Aiden developed the Hi-C method for studying long-range interactions in a genome-wide manner.
Hi-C has been widely used to examine the entire three-dimensional structures of genomes, revealing important principles
of chromatin looping. Dr. Brian Piening works on the Human Microbiome Project with Dr. Michael Snyder; he analyzes
the dynamic aspects of microbiome-host omics during periods of human health and disease. We hope that this session
will provide a vision of the future for human genomics.
Tue(3)-CIS11-1
Million Genomes Ahead
1
Jun Wang
1:iCarbonX, China
Million Genomes Ahead
The achievement made by Human Genome Project and 1000 Genome project shows the power of the context and variation
catalogue of genetics. Those help to address information of variations related to diseases and support studies with better
references. Innumerable important discoveries have been found, promoting our knowledge from basic research to clinical
potential. However we further find more rare but largely existing variations have not but should be solved by much larger
data especially for resolving the difficult faced by personalized medicine and precise medicine. The advanced sequencing
technology we developed since merged with Complete Genomics now enable us to do ‘real’ 1000 dollars genome and enable
us to reach the scale of million genome per year in a more accurate, fast and cost efficient way.
We have announced million genome project two years ago and now we are more confident to reach to million scale in much
shorter plan. It is million genome level project but not just simply thousands times of 1000 genomes project. The project
will aim at clinical purpose driven genomic data accumulation and application. The initial 10,000 samples with impeccable
clinical and tracking records already been collected and shows it will be a solid foundation stone for foreseeable good prospect.
With thousands of refined individual genetic data from different ethnic groups, diseases study will be much more deeply and
comprehensively. From pathogenesis to pharmacokinetics, basis research could benefit with statistical significance. Risk
prediction, prevention, early diagnosis, precise medicine and prognostic caring will be ensured for better practice by ever most
sophisticated knowledge of individual diversity and cohort similarity.
[Biography]
Jun Wang is the Founder and CEO of iCarbonX. He is also Board Member of the BGI. He co-founded BGI in the 1999,
which is now widely recognized as one of world’s premier research facilities committed to excellence in genome sciences. Dr.
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Wang also holds a position as an Ole Rømer professor at the University of Copenhagen. He has authored 400+ peer-reviewed
original papers - of which 100+ are published in Cell, Nature (including Nature series), N Engl J Med., and Science (26 as
cover story). He has been recognized with an award from His Royal Highness Prince Foundation, Nature’s 10 - the year in
Science (2012); “Highly Cited Researchers (2013/2014/2015)” “The Hottest Scientific Researchers” (by Thomson Reuters),
“Rebels, leaders, innovators for the next 25 years” (by CNBC). His research focuses on genomics and related bioinformatics
analysis of complex diseases and agricultural crops, with the goal of developing applications using the genomic information.

Oct 27th 2015, WJ founded a new institute/company, iCarbonX, aiming to establish a health-related big Omics data platform,
to develop artificial intelligence engine to interpret and mine the data as well as to enable every individual to better manage
their health and defeat diseases.
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Tue(3)-CIS11-2
New human genome reference structures
1
Richard Durbin
1:Wellcome Trust Sanger Institute, UK

The current genome reference model is to have a linear exemplar chromosome sequence (“the reference sequence”), plus
possibly a catalogue of variant sites with alternative non-reference alleles (e.g. dbSNP), plus possibly a collection of haplotype
sequences given in terms of which variant at each site is present in which sequence (e.g. 1000 Genomes VCF). Analysis of
data from new individuals typically involves mapping to the single reference sequence, which can be relatively distant from
that of the sample, and rediscovery from scratch of many variant alleles already found in other samples and present in the
catalogue. In the last few years the Genome Reference Consortium has introduced ALT versions of regions of chromosomes
relatively distant from the primary chromosomes, but (a) these are not widely used, and (b) they only capture a small
fraction of the known diversity. Recently a number of approaches have been investigated to improve this situation, ranging
from graph references that include local variation in a more complex structure for mapping, to haplotype population models
that represent long range linkage disequilibrium structure. I will discuss recent progress on these, with respect to data
structures, algorithms, statistical interpretation, and their possible incorporation in new standards in the framework of the
Global Alliance for Genomics and Health.
[Biography]
Richard Durbin is a Senior Group Leader in Computational Genomics and Human Genetics at the Wellcome Trust Sanger
Institute in the United Kingdom, where he has been since its founding in 1992. He has played key roles in multiple genome
sequencing projects, including co-leading the 1000 Genomes Project. His current research is focused on studying human
genome variation and genome evolution and on methods for processing population scale whole genome sequencing data.
He has also made significant contributions to computational sequence analysis, including developing methods for sequence
alignment using Hidden Markov models and suffix array methods, and developing genomic databases including Pfam, Ensembl,
and TreeFam. Richard is an Honorary Professor in Computational Genomics at Cambridge University, a Member of EMBO
and a Fellow of the Royal Society.
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Tue(3)-CIS11-3
Reading and Writing Genomes in 3D: The CTCF code and how to hack it
1
Erez Lieberman Aiden
1:Molecular & Human Genetics, Baylor College of Medicine, USA

Stretched out from end-to-end, the human genome - a sequence of 3 billion chemical letters inscribed in a molecule called
DNA - is over 2 meters long. How does it fold?
In this talk, I describe our work developing ’Hi-C’ (Lieberman-Aiden et al., Science, 2009; Aiden, Science, 2011) and more
recently ’in-situ Hi-C’ (Rao & Huntley et al., Cell, 2014), which use proximity ligation to transform pairs of physically adjacent
DNA loci into chimeric DNA sequences. Sequencing a library of such chimeras makes it possible to create genome-wide maps
of physical contacts between pairs of loci, revealing features of genome folding in 3D.
Next, I will describe recent work using in situ Hi-C to construct haploid and diploid maps of nine cell types. The densest, in
human lymphoblastoid cells, contains 4.9 billion contacts, achieving 1 kb resolution. We find that genomes are partitioned
into contact domains (median length, 185 kb), which are associated with distinct patterns of histone marks and segregate
into six subcompartments. We identify ∼10,000 loops. These loops frequently link promoters and enhancers, correlate with
gene activation, and show conservation across cell types and species. Loop anchors typically occur at domain boundaries and
bind the protein CTCF. The CTCF motifs at loop anchors occur predominantly (>90%) in a convergent orientation, with
the asymmetric motifs "facing" one another.
Next, I will discuss the biophysical mechanism that underlies chromatin looping. Specifically, our data is consistent with the
formation of loops by extrusion (Sanborn & Rao et al., PNAS, 2015). In fact, in many cases, the local structure of Hi-C maps
may be predicted in silico based on patterns of CTCF binding and an extrusion-based model.
Finally, I will show that by modifying CTCF motifs using CRISPR, we can reliably add, move, and delete loops and domains.
Thus, it possible not only to "read" the genome’s 3D architecture, but also to write it.
[Biography]
Erez Lieberman Aiden received his PhD from Harvard and MIT in 2010. After several years at Harvard's Society of Fellows
and at Google as Visiting Faculty, he became Assistant Professor of Genetics at Baylor College of Medicine and of Computer
Science and Applied Mathematics at Rice University.
Dr. Aiden's inventions include the Hi-C method for three-dimensional DNA sequencing, which enables scientists to examine
how the two-meter long human genome folds up inside the tiny space of the cell nucleus. In 2014, his laboratory reported
the first comprehensive map of loops across the human genome, mapping their anchors with single-base-pair resolution. In
2015, his lab showed that these loops form by extrusion, and that it is possible to add and remove loops and domains in a
predictable fashion using targeted mutations as short as a single base pair.
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Tue(3)-CIS11-4
An ’omic checkup: Longitudinal multi-omics for personalized medicine
Brian D. Piening 1 ，Wenyu Zhou 1 ，Kevin P Contrepois 1 ，Gucci Urban 1 ，Shana Leopold 2 ，
Kimberly R Kukurba 1 ，Tracey P McLaughlin 1 ，George Weinstock 2 ，Michael P Snyder 1
1:Genetics, Stanford University, USA、2:The Jackson Laboratory for Genomic Medicine

While significant genetic and environmental risk factors are known that contribute to the development of Type 2 Diabetes
(T2D), overall our ability to predict which individuals will eventually develop T2D and when this will occur is woefully
inadequate. To better understand these factors, we present a longitudinal multi-omic personalized medicine pipeline for the
comprehensive molecular profiling of blood- and microbiome-based analytes that we apply to track the progression to T2D
in a cohort of 100 individuals over periods of health, illness and weight gain and loss. Multi-omic profiling (transcriptome,
DNA methylome, proteome, metabolome etc.) revealed significant differences in multiple ‘omes between prediabetics and
healthy controls at steady state, implicating pathways related to chronic inflammation and insulin regulation as well as novel
connections to T2D. A subset of participants were then placed on a short-term high caloric diet, followed by additional multi-
omic profiling. The dietary perturbation was associated with a wealth of biomolecular expression changes concomitant with
weight gain and spanning multiple ‘omes including the microbiome, and the omic response to weight gain differed between
prediabetics and healthy controls. In total, these large-scale longitudinal data offer a novel and comprehensive view of the
dysfunction in cellular networks associated with the progression to T2D and may offer new strategies for predicting and
preventing the disease.
[Biography]
Dr. Brian Piening is an NRSA Postdoctoral Fellow in Genetics at the Stanford University School of Medicine and Stanford
Center for Genomics and Personalized Medicine (USA). Dr. Piening is currently a fellow in the laboratory of Dr. Michael Sny-
der, and together their current work involves some of the most comprehensive molecular profiling of humans ever performed to
date with the goal of establishing paradigms for truly personalized medicine. Their platform, dubbed integrative Personalized
‘Omics Profiling (iPOP), combines state-of-the-art ‘omics measurements (genomics, transcriptomics, epigenomics, proteomics,
metabolomics, etc.) with bioinformatics tools to track millions of biomolecules over time from human patient samples. A
main focus of this approach is to better understand how individuals transition between healthy and disease states, with a
particular focus on transitions between healthy and unhealthy diets and the accompanying effects. As such, Drs. Piening
and Snyder are conducting an expansive longitudinal human study with the ultimate goal of mapping out the biomolecular
changes that accompany the development of metabolic diseases such as type 2 diabetes.
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Variations in Genome Structure
Tue., April 05, 2016 10:20-12:20 Annex 1 (1F)
Convener：Hiroki Kurahashi（Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health
Convener：Wigard P. Kloosterman（Dept. of Medical Genetics, Center for Molecular Medicine, University Medical Center

Structural genomic variations (SVs) form a relatively uncharted territory of genetic variations and include both copy
neutral rearrangement and copy number changes, such as deletions and duplications. SVs form a major driver of human
phenotypic variation and disease. Advances in next-generation sequencing have enabled the discovery of SVs at an
unprecedented scale in recent years. This has provided substantial insight into the mechanistic origin of SVs and has also
unveiled unexpected complexity of some SVs. Yet, the full spectrum and architecture of SVs will likely only become clear
with further improvements in sequencing technology and analysis tools.
This session will highlight our current knowledge on the frequencies and types of SVs in the human genome based on data
from population-scale sequencing projects. Another topic concerns the underlying mechanistic origin of SVs, both simple
changes as well as complex genomic rearrangements involving chromothripsis, Finally, latest insights into SV discovery
from third-generation sequencing methods will be presented, which provides an outlook into future developments in this
field.
Tue(3)-CIS12-1
Somatic mosaicism - How much of de novo is mitotic?
1,2
Pawel Stankiewicz
1:Molecular & Human Genetics, Baylor College of Medicine, USA、2:Institute of Mother and Child, Warsaw, Poland
Unlike recurrent genomic rearrangements occurring mainly via nonallelic homologous recombination (NAHR) between low-
copy repeats in meiosis, nonrecurrent rearrangements have been shown to arise during mitotic divisions by nonhomologous
end joining or DNA replication mechanisms involving template switching (e.g. MMBIR or FoSTeS). It has been estimated
that more than one mutation arises per mitotic division, resulting in somatic mosaicism. During the ~ 1016 mitotic cell
divisions required to generate an adult composed of approximately 1014 cells, mosaic mutations can go unnoticed, underlie
normal human variation or genetic disease, and may be transmitted to the next generation as constitutional variants, causing
unexpected intergenerational recurrences of genetic disorders with multiple affected children born to unaffected parents,
contrary to Mendelian expectations. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened
200 parents of children affected by genomic disorders due to rare deletion copy-number variants (CNVs) determined to be de
novo by clinical analysis of parental DNA. We found that an under-recognized and significant fraction of apparently de novo
CNVs are not meiotic in origin, but instead arise early in development during post-zygotic mitoses in the affected patients,
underscoring an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics.
Our probabilistic model of gametogenesis to consider parental mosaicism as a source of transmitted mutations predicts that
despite the fact that maternally transmitted mutations are the minority of alleles, a greater proportion of somatically mosaic
transmitting mothers are at increased risk of recurrence. I will review the influence of the developmental timing of mutations,
the mechanisms by which mutations arise, methods for detecting mosaic variants, and the risk of mosaic mutations being
passed on to the next generation.
[Biography]
Pawel Stankiewicz graduated Medical University of Warsaw, Poland in 1991. He received his scientific training in clinical
cytogenetics in the Department of Medical Genetics, Institute of Mother and Child in Warsaw (1994-2000), in the Institute
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of Human Genetics, University of Göttingen and in the Institute of Human Genetics and Medical Biology, University Halle-
Wittenberg, in Halle/Saale in Germany (1996-1997). He obtained PhD in 1999 and habilitation (D.Sc.) in 2006 from the
Institute of Mother and Child in Warsaw. Between 2000-2003, he was a postdoctoral fellow in Dr. James R. Lupski’s
laboratory in the Department of Molecular & Human Genetics at Baylor College of Medicine in Houston, Texas, where he
is now an Associate Professor. The main focus of his research are molecular mechanisms and phenotypic effects of genomic
rearrangements, somatic mosaicism, and pathogenetics of the FOXF1 locus in 16q24.1. He has been also responsible for the

design and clinical implementation of different versions of the clinical exon-targeted array comparative hybridization (aCGH).
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Tue(3)-CIS12-2
Palindrome-mediated recurrent translocations in humans
1
Hiroki Kurahashi
1:Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Japan

Gross chromosomal rearrangements, such as translocations, deletions or inversions, are often generated by illegitimate repair
between two DNA breakages at regions with nucleotide sequences that might potentially adopt a non-B DNA conformation.
One of the best-studied examples is the palindromic AT-rich repeat (PATRR), which induces recurrent constitutional translo-
cations in humans. The translocation-related PATRRs manifests high level of genomic instability and always located within
the gaps of human genome database. Cloned breakpoint sequences favor adopting a cruciform configuration in vitro. De novo
examples of the translocation are detected at a high frequency in sperm samples from normal healthy males, but not in other
somatic tissues. All of the de novo translocation cases originated from paternal chromosomes. In the PCR-based analysis of
the de novo translocation at single sperm level, both of the derivative chromosomes are always present in the same PCR tube.
We propose that the PATRR adopts a cruciform structure in post-meiotic spermatogenic cells, creating a common pathway
for recurrent translocations in humans.
[Biography]
1985, Graduated from Osaka University School of Medicine
1985-1991, Clinical Practice as a Pediatrician
1991-1998, Assistant Professor, Division of Clinical Genetics, Department of Medical Genetics, Biomedical Research Center,
Osaka University School of Medicine
1998-2001, Postdoctoral Fellow, Division of Human Genetics, The Children’s Hospital of Philadelphia
2001-2003, Assistant Professor, Division of Functional Genomics, Department of Post-Genomics and Diseases, Osaka Univer-
sity Graduate School of Medicine
2003-, Professor, Division of Molecular Genetics, Institute for comprehensive Medical Science, Fujita Health University
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Tue(3)-CIS12-3
Detection and interpretation of complex structural variations in human genomes
Wigard Kloosterman 1 ，Mirjam de Pagter 1 ，Mark van Roosmalen 1 ，Ivo Renkens 1 ，Annette Baas 1 ，
Ron Hochstenbach 1 ，Martin Poot 1 ，Edwin Cuppen 1 ，Ellen van Binsbergen 1 ，Lars van der Veken 1 ，
Lidia Larizza 2 ，Bjorn Menten 3 ，Sarah Vergult 3 ，Mike Talkowski 4 ，Vamsee Pillalamarri 4 ，
Harrison Brand 4 ，Ewart Kuijk 1 ，Jerome Korzelius 1 ，Marieke Simonis 1 ，Sebastiaan van Heesch 1 ，

Sjors Middelkamp 1 ，Genome of the Netherlands Consortium
1:Dept. of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, The Netherlands、
2:Laboratorio di Citogenetica Medica e Genetica Molecolare, Centro di Ricerche e Tecnologie Biomediche, IRCCS-
Istituto Auxologico Italiano、3:Center for Medical Genetics, Ghent University Hospital、4:Center for Human Genetic
Research, Massachusetts General Hospita
We are evaluating the occurrence of de novo genomic structural rearrangements, both in the healthy population and in pa-
tients with congenital diseases.
Within the Genome of the Netherlands project, we identified 332 validated de novo structural changes in whole genome
sequences of 250 families. Our data indicate a mutation rate of 2.94 indels (1-20bp) and 0.16 SVs (>20bp) per generation.
De novo structural changes affect on average 4.1kbp of genomic sequence and 29 coding bases per generation, which is 91 and
52 times more nucleotides than de novo substitutions, respectively. An excess of structural changes originated on paternal
haplotypes.
One class of complex genomic rearrangements - termed chromothripsis - has recently received much attention. Chromoth-
ripsis involves shattering of one or more chromosomes, followed by repair of the DNA damage and formation of new mosaic
chromosomes. We have characterized hundreds of breakpoint junctions from chromothripsis rearrangements, revealing insight
into break repair mechanisms, chromothripis origin and transmission to offspring. Furthermore, we have setup model systems
to characterize the cellular trigger for chromothripsis in somatic cells and germline.
To understand the phenotypic consequences of germline structural genomic variations, we have employed a molecular phe-
notyping approach on patient material. These experiments provide insight in the molecular determinants driving congenital
disease associated with chromosome rearrangements.
[Biography]
Wigard Kloosterman received his MSc in Biotechnology from the University of Groningen. In 2003, he started his PhD
project in the lab of Dr. Ronald Plasterk at the Hubrecht Institute (Utrecht), where he studied the expression and function
of microRNAs in embryonic development. Currently, he has a position as assistant professor at the department of Genetics
within the Center for Molecular Medicine at the University Medical Center Utrecht. The Kloosterman group focuses on
the role of structural genomic variation in human congenital disease and cancer. We have discovered that massive genomic
rearrangements, caused by chromothripsis, underlie congenital phenotypes. By making use of the latest developments in
sequencing technology, we have gained insights into the molecular mechanisms that cause germline chromothripsis. We are
further exploring model systems to study the chromothripsis process. In addition, we examine the molecular and phenotypic
consequences of chromosomal rearrangements by analyzing gene expression, epigenetic modifications and chromosome inter-
actions in patient cells or model systems with engineered rearrangements. Bioinformatic data analysis is key to our work and
we have developed several tools to detect and study (complex) structural genomic variation in genome sequencing data.
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Tue(3)-CIS12-4
Genome-first detection of variation with single-molecule sequencing
Mark J.P. Chaisson 1 ，Evan E Eichler 1 ，John Huddleston 1 ，David Gordon 1 ，Christopher M Hill 1 ，
Zev Kronenberg 1
1:Genome Sciences, University of Washington, USA

A common goal in human genetics is to establish a comprehensive catalog of variation. Considerable advances have been made
in discovering variation through population-scale high throughput sequencing (HTS). The dominant paradigm for detecting
variation using HTS is through comparing how short (150 base pair) reads differ from a reference genome. However, with
this approach it is difficult to detect certain types of variation, in particular structural variation. Advances in single-molecule
sequencing has enabled the sequencing of genomes with reads orders of magnitude longer than in conventional HTS. The
longer read lengths enable near complete de novo assembly of mammalian genomes and allow us to apply a “genome-first”
approach detecting variation where the sequence of a sample is completely determined and only then compared to a reference.
By applying this approach to a human hydatidiform mole CHM1, we are able to characterize variation from two base pair
indels up to hundreds of kilobases. We find that there has been a range of variation between 10 and 1000 base-pairs that
has gone undetected by past approaches based on HTS. We use the catalogue of variation detected in our CHM1 sample to
accurately genotype thousands of individuals sequenced by HTS. Additionally, we have sequenced and assembled the genome
of a western lowland gorilla using SMS, allowing us to detect structural variation across evolutionary time scales. An analysis
of the resolution of segmental duplication architecture in the CHM1 and gorilla genomes reveals that recent duplications over
50kbp in length are the remaining fragmented regions in SMS-based assemblies. With additional development to resolve such
duplication architecture, we envision a near-future when multiple population specific reference genomes are used to improve
the quality of variation in large scale HTS studies.
[Biography]
Mark Chaisson is a senior fellow in the Eichler lab at the University of Washington. He received his Ph.D. from the University
of California, San Diego, in 2008 under Pavel Pevzner, where he developed methods for de novo assembly of the first high-
throughput sequencing reads. He then joined Pacific Biosciences to develop methods for mapping single-molecule sequencing
(SMS) reads. He joined the lab of Dr. Evan Eichler to develop methods to detect genome architecture and structural variation,
primarily through de novo assembly and SMS.
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Complex Trait Diseases 1: Common Disease
Tue., April 05, 2016 8:00-10:00 Annex 2 (1F)
Convener：Michiaki Kubo（Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN,
Japan）
Convener ：Anne M. Bowcock（National Heart and Lung Institute, Imperial College, London, UK）

In the past ten years, widespread genomic mapping of factors contributing to complex traits have led to the identification
of thousands of loci, and some specific genes, that harbor non-coding variants that lead to genetic susceptibility. However,
how these factors lead to dysregulation of specific genes and pathways is still largely unknown; however, specific studies
are providing molecular insight into the biology of their complexity. Such studies exemplify two types of complexity:
first, their inheritance and second their biology. This session will use four exemplary study systems to demonstrate how
genetic advancements can lead to understanding disease pathophysiology.
Tue(3)-CIS13-1
Statistical Genetics for Autoimmune Diseases and Drug Discovery
1,2
Yukinori Okada
1:Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University; Laboratory for Statis-
tical Analysis, RIKEN Center for Integrative Medical Sciences, Japan、2:Laboratory for Statistical Analysis, RIKEN
Center for Integrative Medical Sciences
A major challenge in human genetics is to devise a systematic strategy to integrate disease genome BIG DATA with diverse
datasets to provide insight into disease pathogenesis and guide drug discovery. We propose that in silico approaches based on
Statistical Genetics can contribute to it, using large-scale genotype data of autoimmune diseases. We constructed an in silico
bioinformatics pipeline to systematically integrate the identified rheumatoid arthritis (RA) risk genetic loci with a variety
of biological, medical, and epidemiological databases (Okada et al. Nature 2014). Our pipeline demonstrated that RA risk
genetic loci are significantly enriched for genes that are the target of approved therapies currently used for RA treatment.
Our analysis further suggested that drugs approved for other disease indications may be repurposed for the treatment of RA
(e.g., CDK4/CDK6 inhibitors currently used for cancer treatments). Comprehensive integration of disease genome data with
microRNA (miRNA)-target gene networks showed significant enrichment of miRNA networks on the genetics of RA, pointing
biomarker miRNA candidates. We have recently developed a novel genetic analytical framework named “HLA imputation
method“, which can computationally estimate high resolution HLA gene polymorphisms. Comprehensive HLA gene analysis
by the HLA imputation method successfully elucidated risk biomarkers contributing to both onset and development of psoriasis
and Graves’ disease (Okada Y et al. Am J Hum Genet 2014, Okada Y et al. Nat Genet 2015). Together, our study provides
empirical evidence that Statistical Genetics can provide important information for human diseases, including novel therapeutic
targets and drug discovery, in the era of BIG DATA.
[Biography]
Yukinori Okada was born in Shizuoka in 1980. He graduated the University of Tokyo in 2005, and received Ph.D. from the
University of Tokyo in 2011. He worked as a research fellow at the Brigham and Women’s Hospital at Harvard Medical
School and the Broad institute. From 2013, he is a Tenure-track Junior Associate Professor at Tokyo Medical and Dental
University. He has multiple backgrounds as a rheumatologist, a statistician, and a bioinformatician. His research theme is
an elucidation of mechanism in which genetic variants of the populations affect human complex diseases. Through active
collaborative partnership among the researchers of the genetics, Dr. Okada enormously conducted genome-wide association
studies and identified a number of novel risk genetic loci. Dr. Okada also has experiences for analyzing genetic polymorphisms
in the major histocompatibility complex (MHC) region and HLA genes, which have substantial impacts on genetics of human
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diseases. His recent research interests include development of novel analytic methods of genetics and bioinformatics that
integrate Big Data obtained by the latest high-throughput technologies, such as next generation sequencing. Application of
his methods contributed to novel drug discovery, disease biomarker identifications, and personalized medicine.
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Tue(3)-CIS13-2
DRIVER GENES OF ORAL CANCER, ITS PROGRESSION AND METASTASIS
1
Partha P. Majumder
1:National Institute of Biomedical Genomics, India

Oral Cancer in India has clinical and epidemiological features that are markedly distinct from those found in Western
populations. Many putative environmental predisposing correlates are also very different.
I shall present the mutational landscape of oral cancer in India, and the genes that drive this cancer. I shall provide evidence
that the arachidonic acid metabolism pathway is significantly altered in oral cancer and mutations in genes on this pathway
increase the length of post-treatment disease-free survival. Our analysis of pre-cancerous lesion - leukoplakia - has revealed
the sequential accumulation of mutations from pre-cancer to cancer of the oral cavity. Finally, I shall provide evidence of
germline and somatic alterations that drive lymph node metastasis in oral cancer.
[Biography]
PARTHA P. MAJUMDER is the founding Director of the National Institute of Biomedical Genomics, Kalyani, West Bengal,
and a Professor in the Indian Statistical Institute, Kolkata. His major interests and contributions are on human genome
diversity, genetics of diseases and genetic epidemiology.
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Tue(3)-CIS13-3
Transcriptome landscape of chronic traumatic encephalopathy and Alzheimer disease
in human brains
1
Jeong-Sun Seo
1:Genomic Medicine Institute, Seoul National University, Korea

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder induced by repetitive head trauma
and is a cause of disability and death. Traumatic brain injury is known to involve complex cellular and molecular changes
but the mechanisms of neuronal damage in CTE remains elusive.To determine the transcriptome signatures linked to the
pathophysiology of CTE, we performed RNA sequencing and analysis on four regions of the brain from neuropathologically
verified CTE (n=6) and normal (n=7) subjects. Supervised hierarchical clustering and principal component
analysison the differentially expressed genes(DEGs) show distinct separation of CTE from control cases. Functional analysis
of DEGs using KEGG pathway annotations revealed that MAP Kinase pathways-, calcium signaling pathways-, and axon
guidance-related genes were significantly down regulated in CTE, exhibiting similar transcriptomic signatures to that of
Alzheimer’s disease (AD). Interestingly, we found down-regulation of neuronal serine/threonine protein phosphatases (PPs)
genes and reduced activity of PPs to be directly associated with the elevation of phosphorylated (p)-tau and tauopathy
in CTE. The altered expression of PPs provides an important pathological mechanism to deepen our understanding of
neurodegenerative condition in CTE that is overlapped with the tauopathy of AD. These findings provide important insights
into PPs-dependent disease pathogenesis and therapeutic approaches for CTE.
[Biography]
Dr. Seo received both his MD and PhD from Seoul National University, College of Medicine and subsequently, he spent his
time as a research fellow at Rockefeller University. He has been translating his knowledge of molecular biology to understand
the relationship between the genetic predispositions and diseases, and he has been relentlessly pursuing utilization of genomic
medicine for clinical applications.
Since 2001, he initiated his investigation of the human genome with the construction of the BAC clone map of a Korean
individual. He furthered his investigation with the whole genome sequencing and annotation of a single individual for
personalized medicine [2009, Nature]. He extended the scope of his research from a single individual to a population with
his research on the copy number variation and genomic and transcriptomic diversity in the Asian population. [2010 &2011,
Nature Genetics].
He has also applied the next-generation sequencing technology to not only discover a novel RET fusion gene. [2011, Genome
Research], but he also revealed the epigenomic roadmap by which induced pluripotent stem cells are reprogrammed [2014,
Nature Communcations]. He is currently concentrating his efforts with Dr.Mckee at Boston University to identify thegenomic
and transcriptomic signatures in neurodegenerative diseases such as chronic traumatic encephalopathy and Alzheimer’s disease.
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Tue(3)-CIS13-4
Genetic analysis of psoriasis and psoriatic arthritis
1
Anne M. Bowcock
1:National Heart and Lung Institute, Imperial College, London, UK

Psoriasis is a common inflammatory skin disease with complex genetics that affects 2-3% of the European population. GWAS
have revealed over 50 regions associated with psoriasis. Implicated genes span an array of functions that involve antigen
presentation (HLA-Cw6, ERAP1, ERAP2, MICA), the IL-23 axis (IL12Bp40, IL23Ap19, IL23R, JAK2, TYK2), T-cell
development and T-cells polarization (RUNX1, RUNX3, STAT3, TAGAP, IL4, IL13), innate immunity (CARD14, c-REL,
TRAF3IP2, DDX58, IFIH1), and negative regulators of immune responses (TNIP1, TNFAIP3, NFKBIA, ZC3H12C, IL36RN,
SOCS1). The contribution of some of these gene products to psoriatic disease has also been revealed in recent years through
targeting of key immune components, such as the Th17/IL-23 axis which has been highly successful in disease treatment. Fine-
mapping of the MHC has revealed an important role for all three HLA class I genes and a complex and heterogeneous pattern
of HLA associations between Caucasian and Chinese populations. Additional rare variants for psoriasis are being identified
through exome sequencing and an interrogation of the exome chip with large psoriatic cohorts. Through exome sequencing
we have identified gain of function mutations in the gene encoding caspase recruitment domain protein 14 (CARD14) that
are responsible for PSORS2 (psoriasis susceptibility locus 2). CARD14 encodes a nuclear factor of kappa light chain enhancer
in B cells (NF-kB) activator within skin epidermis and endothelial cells. We have proposed that, after a triggering event that
can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell
recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, a cycle which is
the hallmark of psoriasis. We are now investigating components of wild type and mutant CARD14-signalling with biochemical
approaches and the generation of Card14 mutant mice.
[Biography]
Anne Bowcock is Professor and Chair in Cancer Genomics at Imperial College London. She obtained a PhD from the
University of Witwatersrand in South Africa and was a postdoctoral fellow at Stanford University working with Professor
Luigi Cavalli-Sforza. She held faculty positions at the University of Texas Southwestern Medical Center at Dallas and
Washington University School of Medicine in Saint Louis. Among her research achievements are demonstrating the use of
DNA markers in reconstructing human evolution, identifying proteins interacting with the early onset breast cancer gene
BRCA1 and identifying a gene commonly mutated in highly metastatic uveal melanoma. She has studied the genetics of
psoriasis and psoriatic arthritis for over twenty years and her recent achievements in this field have been in identifying a
familiar form of psoriasis and psoriatic arthritis and functional consequences of the disease causing mutations. She is also
searching for additional rare and highly penetrant genetic changes that lead to psoriasis and psoriatic arthritis, their role in
disease susceptibility and ways of combatting their effects.
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Complex Trait Diseases 2: Autoimmune Diseases
Tue., April 05, 2016 10:20-12:20 Annex 2 (1F)
Convener：Kazuhiko Yamamoto（Department of Allergy and Rheumatology, Graduate School of Medicine, University of

Tokyo, Japan）
Convener：Soumya Raychaudhuri（Medicine, Harvard Medical School, Divisions of Genetics and Rheumatology, Brigham

and Women’s Hospital; Medical and Population Genetics, Broad Institute; Institute of Inflammation and Repair, Uni-
versity of Manchester; Department of Medicine, Karolinska Institutet, USA）
The majority of autoimmune diseases are complex genetic traits. Since early 1970s, HLA has been identified as the most
important genetic factor of many autoimmune diseases, but the precise roles of HLA have not yet clarified. Over the last
decade, genome-wide association studies (GWASs) have been employed to identify hundreds of non-HLA susceptibility
loci. Recently, extensive GWAS and meta-analyses have been performed for several autoimmune diseases, leading to the
discovery of >100 alleles for inflammatory bowel disease and rheumatoid arthritis. In order to promote our understanding
on the pathogeneses using our findings from genetic studies, it is vital to determine how disease associated variants function
to influence fundamental human immune processes. Integration of clinical information and functional immune data on
patients with genetic data has the potential to enable us the discovery of mechanistic clues. On the other hand, in
common autoimmune diseases, the driving alleles for the majority of these loci do not map to known coding regions of the
genome. Several studies suggest many autoimmune variants are enriched for expression quantitative trait loci (eQTL),
which influence the expression level of genes. Further, non-coding chromatin marks that identify regions of the genome
with regulatory potential, such as H3K4me3, have been found to localize genetic signals in critical cell types, and may be
useful for fine-mapping autoimmune disease loci and eQTL. Therefore, comprehensive integrative approach using such
information will unravel the fine mechanisms of complex trait autoimmune diseases. In this session, four speakers will
discuss several issues above.
Tue(3)-CIS14-1
Fine-mapping the HLA and other autoimmune loci
1,2,3,4,5
Soumya Raychaudhuri
1:Medicine, Harvard Medical School, Divisions of Genetics and Rheumatology, Brigham and Women’s Hospital; Med-
ical and Population Genetics, Broad Institute; Institute of Inflammation and Repair, University of Manchester; De-
partment of Medicine, Karolinska Institutet, USA、2:Divisions of Genetics and Rheumatology, Brigham and Women’s
Hospital、3:Medical and Population Genetics, Broad Institute、4:Institute of Inflammation and Repair, University of
Manchester、5:Department of Medicine, Karolinska Institutet
While genome wide associations studies have been remarkably effective in identifying common alleles for many autoimmune
diseases, in many instances we have not been able to easily pinpoint the causal alleles driving disease susceptibility. Link-
age disequilibrium and incomplete understanding of allelic function has made fine-mapping disease loci more difficult than
initially expected. Effectively overcoming this key challenge requires powerful non-coding annotations indicating cell-type
specific function, large patient cohorts, state-of-the-art statistical genetic strategies, and comprehensive interrogation of ge-
netic variation within the locus. Here we describe efforts to fine-map the MHC locus in rheumatoid arthritis, type I diabetes,
and psoriasis. For these diseases, and many others, this locus explains more heritability than all other loci throughout the
genome combined. Then we will go onto describe efforts to fine-map disease alleles in other loci, where power is more limited,
using complementary approaches integrating functional genomic data with genetic data.
[Biography]
Dr. Soumya Raychaudhuri is an Associate Professor at Harvard Medical School and at Brigham and Women’s Hospital. He
is also appointed as an Associate Member at the Broad Institute and a Professor in Genetics at the University of Manchester.
He matriculated into the Stanford University NIH funded MST program in 1997 after completing degrees in mathematics and
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biophysics at the University at Buffalo. In 2004, he completed both his medical training and his doctoral training in biomed-
ical informatics. After completing his clinical training in Internal Medicine, he joined the rheumatology fellowship training
program in 2006, and concurrently completed his postdoctoral fellowship training under Mark Daly at the Broad Institute.
Since starting his own group in 2010 at Harvard Medical School and Brigham and Women’s Hospital, his lab has focused on
finding and fine-mapping disease alleles and understanding their significance in immune-mediated diseases. He has focused on
multiple diseases including rheumatoid arthritis, type I diabetes, and tuberculosis infection. He has worked on fine-mapping

HLA loci, devising integrative statistical genetics strategies to identify causal variation by taking advantage of large-scale
epigenetic data, and integrating genetic data with functional genomics and data on human immunological phenotypes.
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Tue(3)-CIS14-2
GWAS and functional genomics of autoimmune diseases
1
Yuta Kochi
1:Laboratory for Autoimmune Diseases, IMS, RIKEN, Japan

Autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus are complex traits, where multiple
genetic and environmental components are involved in their etiology. Genome-wide association studies (GWAS) have discov-
ered many loci for autoimmune diseases, and some of them are shared among different diseases. However, GWAS can only
identify the disease-associated genomic regions, in most of which the responsible genes and their disease causing mechanisms
are largely unknown. Previous expression quantitative trait locus (eQTL) studies that examined association between genetic
variants and gene expression levels have suggested that majority of autoimmune disease loci are eQTLs. This indicates that
the cumulative effects of quantitative differences in risk genes leads to the onset of autoimmune diseases. In order to identify
disease-related eQTLs, with special focus on immune cells, we performed RNA-seq of freshly-isolated CD4+ T cells, CD8+ T
cells, B cell, monocytes and NK cells sorted from peripheral blood of Japanese healthy volunteers. We identified thousands
of eQTLs in each cell type, and some of them are cell-type specific. We jointly analyzed the data from the eQTL study and
GWAS for rheumatoid arthritis, which demonstrated over 60 % of rheumatoid arthritis loci were eQTLs in at least one cell
type. Furthermore, RNA-seq based transcriptomic analysis can also identify variants that are associated with changes in the
splicing ratio of target genes, so-called splicing QTL (sQTL). Our analysis showed substantial proportion of eQTLs can be
sub-categorized as splicing QTLs. Analysis of splice isoforms related to the disease should contribute to further understanding
the mechanism of human autoimmune diseases.
[Biography]
Yuta Kochi is a Deputy Team Leader at the Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences,
RIKEN, Japan. He graduated the University of Tokyo in 1999. After the residency programs in internal medicine and rheuma-
tology at the University of Tokyo Hospital, he received Ph.D. from the University of Tokyo in 2005. His research interests
are the genetic epidemiology of autoimmune diseases, especially for rheumatoid arthritis and systemic lupus erythematosus.
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Tue(3)-CIS14-3
Combining population and clinical biobanks to translate genetic variation into immune
function
1
Cisca Wijmenga
1:Genetics, University Medical Center Groningen, Netherlands

The immune system of modern populations has been shaped by past pathogenic infections. This evolutionary pressure results
in immune variation across modern humans and predisposition to immune-mediated diseases. The genes and pathways
contributing to biological variation in the immune system and the impact on health and diseases are only partly understood.
We investigate the impact of genetic variation on the human immune system by combining studies in general population
cohorts with studies in patients with autoimmune and infectious diseases. The diseases we focus on are celiac disease and
Candidemia, in combination with detailed functional genomics analysis in two population-based cohort studies (LifeLines
DEEP and 500FG). Genetic risk factors associated with celiac disease point to an important role for B cells. Furthermore,
wWe observed that susceptibility to both autoimmune and infectious disease caused by SNPs impacting cytokine responses.
[Biography]
Prof. Cisca Wijmenga has been Professor of Human Genetics at the University of Groningen and head of the Genetics
Department of the University Medical Center Groningen since 2007. The aim of her research is to understand the role that
genes play in the development of chronic diseases. Her research group focuses on the genetics of coeliac disease. Research led
by Wijmenga has discovered nearly 40 loci contributing to coeliac disease, several of which also cause other immune-related
disorders such as type 1 diabetes and rheumatoid arthritis. This knowledge is leading to new insights into the disease process,
with a prominent role for gene regulatory and non-coding RNA genes. She is employing functional genomics techniques to
further enhance our understanding by building regulatory gene networks in coeliac disease associated T cells and is testing
how risk variants perturb these networks. Besides she investigates the effect of the disease risk variants on intermediate
phenotypes such as cytokine production.
In November 2012 she received a prestigious ERC Advanced Grant for her research project on Celiac disease. In 2015 she
has been awarded a Spinoza Prize, also referred to as the 'Dutch Nobel Prize', for her research into complex genetic diseases.
Prof. Wijmenga is a member of the Royal Netherlands Academy of Arts and Sciences (KNAW).
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Tue(3)-CIS14-4
Transcriptome variation in human immunity
1,2
Barbara E. Stranger ，Towfique Raj 3 ，Meritxell Oliva 1,2
，Phillip De Jager 4,5,6
，Christophe Benoist 4,5
1:Section to Genetic Medicine, University of Chicago, USA、2:Institute for Genomics and Systems Biology, University of Chicago、3:Icahn
School of Medicine at Mount Sinai、4:Harvard Medical School、5:Broad Institute of Harvard and MIT、6:Brigham and Women’s Hospital

To extend our understanding of the genetic basis of human immune function and dysfunction, we performed an expression
quantitative trait locus (eQTL) study of purified CD4(+) T cells and monocytes, representing adaptive and innate immunity,
in a multi-ethnic cohort of 461 healthy individuals, as part of the Immunological (or ImmVar) Constortium. Context-specific
cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment
of candidate causal regulatory variants for disease-associated loci. We note an over-representation of T cell-specific eQTLs
among susceptibility alleles for autoimmune diseases and of monocyte-specific eQTLs among Alzheimer's and Parkinson's
disease variants. This polarization implicates specific immune cell types in these diseases and points to the need to identify
the cell-autonomous effects of disease susceptibility variants. We extend the analysis to investigate the effect of sex on the
transcriptome.
[Biography]
Dr. Barbara Stranger is an Assistant Professor of Medicine in the Section of Genetic Medicine, in the Department of Medicine
at the University of Chicago. She is also a Core Member of the Institute for Genomics and Systems Biology and Senior Fellow
in the Center for Data Intensive Science. She has a longstanding interest in understanding how genetic variation influences
molecular traits such as gene expression, and how these shape phenotypic variability. Her lab collects and analyzes large-scale
multi-dimensional human genomics data, particularly transcriptome data and genetic variation data, in the context of health
and disease.
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Therapy for Genetic Diseases
Tue., April 05, 2016 8:00-10:00 Room A (2F)
Convener：Eiji Nanba（Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University,
Japan）
Convener：Jeffery W. Kelly（Molecular And Experimental Medicine, The Scripps Research Institute; The Skaggs Institute

for Chemical Biology, The Scripps Research Institute, USA）
Most genetic disorders unfortunately cannot be cured. For a group of genetic disorders called inborn errors of metabolism,
which result from genetic mutations that disrupt the product of specific proteins or enzymes. Molecular understanding
on these diseases has been advanced during the last decades and leads to novel therapeutic agents. This session in the
Therapy for genetic diseases explores in depth many aspects of novel therapeutic approaches on the genetic metabolic
diseases as well as neurodegenerative diseases.
Tue(3)-CIS15-1
Understanding the Genetics and Biochemistry of the Transthyretin Amyloid Diseases
Afforded a Disease-Modifying Therapy, and Importantly, New Insights about Chaperone
Function
Jeffery W. Kelly 1,2 ，Xin Zhang 1 ，Benjamin I Leach 1 ，Regina M Murphy 3 ，Marcus Jaeger 1 ，
Peter E Wright 1,2
1:Molecular And Experimental Medicine, The Scripps Research Institute; The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, USA、2:The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 N. Torrey Pines Rd., La Jolla, CA 92037、3:Department of Chemical and Biological Engineering, University of
Wisconsin, Madison, Madison, WI 53706
The seminar will begin by covering the human genetic evidence that kinetically stabilizing transthyretin is sufficient to
ameliorate the transthyretin amyloidoses. This data, along with biochemical data, led to the development of small molecule
kinetic stabilizers that were refined by structure-based drug design. About six hundred kinetic stabilizers designed and
synthesized at Scripps allowed the formation of FoldRx Pharmaceuticals that translated this research and performed a
successful clinical trial that enabled approval of tafamidis by several regulatory agencies for the treatment of familial amyloid
polyneuropathy. Tafamidis dramatically slows, or in many patients, halts the progression of peripheral neuropathy over the
7 years of experience with tafamidis (patients remain stage 1 out of 4 disease stages). During the course of our research over
twenty years, we made some observations about transthyretin that do not align with our current understanding of protein
structure and energetics. While chaperone pathways are known to enhance cellular folding yield by reducing aggregation, they
are not expected to alter the structure or stability of folded proteins. We will present data supporting the hypothesis that
cellular folding by a transcriptionally reprogrammed proteostasis network alters the final conformations and kinetic stability
of folded transthyretin, even after rigorous purification. The reconstituted Hsp70-Hsp40-nucleotide exchange factor chaperone
pathway largely recapitulates this effect by altering side chain packing in the folded tetrameric structure, enhancing kinetic
stability and aggregation resistance, while also accelerating linked transthyretin folding and assembly. Thus, chaperones can
fine-tune both the folding pathway and the resulting structural ensemble - enhancing the conformational homogeneity and
kinetic stability of folded transthyretin, which has important implications for patients with aggregation-associated degenerative
diseases.
[Biography]
Jeffery W. Kelly, Ph.D., is the Lita Annenberg Hazen Professor of Chemistry in the Department of Chemistry and the
Chairman of the Department of Molecular and Experimental Medicine at the Scripps Research Institute. Kelly also served
as Vice President of Academic Affairs and Dean of Graduate Studies at Scripps for nearly a decade. His research is focused
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on uncovering protein folding principles and on understanding the etiology of protein misfolding and/or aggregation diseases
and using this information to develop novel therapeutic strategies. He has 300+ publications and has received several awards,
including The American Chemical Society Ralph F. Hirschmann Award in Peptide Chemistry (2012), The Biopolymers Murray
Goodman Memorial Prize (2012), The Protein Society Emil Thomas Kaiser Award (2011), The American Peptide Society
Rao Makineni Lectureship (Award; 2011), The American Peptide Society Vincent du Vigneaud Award (2008), The American
Chemical Society Arthur C. Cope Scholar Award (2001), State University of New York at Fredonia Alumni Distinguished

Achievement Award (2000), The Protein Society-Dupont Young Investigator Award (1999) and The Biophysical Society
National Lecturer (Award;1999). Kelly cofounded FoldRx Pharmaceuticals based on his discovery of Tafamidis-approved by
several regulatory agencies to treat familial amyloid polyneuropathy.
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Tue(3)-CIS15-2
AUTOPHAGY AND OTHER PATHWAYS THAT PROTECT AGAINST NEURODE-
GENERATION
1
David C. Rubinsztein
1:Cambridge Institute for Medical Research, University of Cambridge, UK

Intra cellular pro tein ag gre gation is a feature of many late-onset neuro degenerative dis eases, including Parkinson’s dis
ease, tauopathies, and poly glutamine expansion dis eases (like Huntington’s dis ease (HD)). Many of these mutant pro
teins, like that causing HD, cause dis ease via toxic gain-of-func tion mecha nisms. There fore, the factors regu lating their
clearance are crucial for under standing dis ease patho genesis and for de velop ing rational thera peutic strategies.
The two major in tra cellular pro tein degradation pathways are the ubiquitin-pro teasome system and (macro )auto phagy.
Autophagy is initiated by double-mem braned structures, which engulf portions of cyto plasm. The resulting auto phagosomes
ultimately fuse with lysosomes, where their contents are degraded.
I will briefly describe the basic bio logy of auto phagy before outlining its roles in neuro degene ration. We showed that the
auto phagy inducer, rapamycin, re duced the levels of mutant huntingtin and attenuated its toxicity in cells, and in Drosophila
and mouse HD models. We have ex tended the range of in tra cellular pro teinopathy substrates that are cleared by auto
phagy to other related neuro degenerative dis ease targets, like Parkinson’s dis ease. While auto phagy induction is pro
tective in models of various neuro degenerative dis eases, certain other conditions are as so ci ated with compro mised auto
phagy. I will dis cuss how two ge net ic variants in Parkinson’s dis ease and Alz heimer’s dis ease impact on auto phagosome
bio genesis.
Finally, I will describe two new pathways that protect against neurodegenerative disease models. One of these acts via
autophagy and the other is autophagy-independent.
[Biography]
David Rubinsztein did a BSc(Med) Hons and PhD at the University of Cape Town after his basic medical training and
housejobs. He came to Cambridge in 1993 as a senior registrar in Genetic Pathology. He was awarded a Glaxo Wellcome
Fellowship in 1997, a Wellcome Trust Senior Clinical Fellowship (2001, renewed in 2006) and a Wellcome Trust Principal
Research Fellowship in 2011. Rubinsztein was elected as a Fellow of the Academy of Medical Sciences (2004), Professor of
Molecular Neurogenetics (University of Cambridge, personal chair (2005)) and Spinoza Visiting Professorship (University
of Amsterdam (2009)). He was awarded the Graham Bull Prize for Clinical Science (Royal College of Physicians) in 2007
and was elected as a member of EMBO in 2011. In 2014 and 2015, he was selected as one of Thomson Reuters’ Highly
Cited Researchers (http://highlycited.com/). He is also deputy director of the Cambridge Institute for Medical Research and
Academic Lead of the Alzheimer’s Research UK Cambridge Drug Discovery Institute.
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Tue(3)-CIS15-3
Treatment of Friedreich’s ataxia and mitochondrial diseases
1
Jeanne Amiel
1:Institute Imagine and University Paris Descartes, Paris, France

TBA

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Tue(3)-CIS15-4
Chaperone therapy for lysosomal storage diseases
1
Katsumi Higaki
1:Research Center for Bioscience and Technology, Tottori University, Japan

A growing number of evidence suggests that misfolding of a mutant protein followed by its aggregation or premature degra-
dation in the endoplasmic reticulum is one of the main mechanisms that underlie many inherited neurodegenerative diseases,
including lysosomal storage diseases. Chemical or pharmacological chaperones are small molecules that bind to mutant en-
zyme proteins, correct their conformation and enhance their stability in the endoplasmic reticulum. A number of chaperone
compounds for lysosomal hydrolase enzymes have been identified in the last decade. They have gained attention because they
can be orally administrated, and also because they can penetrate the blood-brain barrier, presumably positive impact on the
quality of life of patients’ lives. In this talk, I describe identification and characterization of chaperone candidates mainly
for the treatment of GM1-gangliosidosis. I also discuss the future direction of this strategy targeting other lysosomal storage
diseases as well as protein misfolding diseases in general
[Biography]
Katsumi Higaki, PhD is an Associate Professor of Research Center for Bioscience and Technology at Tottori University
(Japan). He received his PhD degree in Life Sciences from Tottori University (Japan) in 2001. He trained as a postdoctoral
research fellow at the Institute of Human Nutrition, Columbia University (NY, USA) working on a yeast model of Niemann-
Pick type C disease. He then moved to the current position at the Research Center for Bioscience and Technology, Tottori
University (Japan) and started the research of GM1-gangliosidosis with Prof. Nanba and Prof. Suzuki. He has over 70
publications in peer-reviewed journals. His team is actively developing a chaperone therapy for GM1-gangliosidosis and other
lysosomal storage diseases.
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Gene Therapy
Tue., April 05, 2016 10:20-12:20 Room A (2F)
Convener：Keiya Ozawa（Division of Genetic Therapeutics, The Advanced Clinical Research Center, Institute of Medical
Convener ：Michel Sadelain（Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, USA）

Gene therapy research remained stagnant for many years due to serious side effects. However, clinical gene therapy has
been revived in Western countries, because a number of successful clinical trials have been reported recently. Currently,
lentiviral vectors and AAV (adeno-associated virus) vectors are mainly utilized for gene transfer into hematopoietic stem
cells and differentiated cells (neurons, muscles, retinal pigment epithelial cells, hepatocytes and so on), respectively. The
introduction of safe AAV vectors has expanded the target diseases of gene therapy. Regarding cancer gene therapy, there
has been increasing focus on engineered T cell therapy. Especially, CD19-targeted CAR (chimeric antigen receptor)-
expressing T cell gene therapy has achieved a great success in the treatment of relapsed/refractory B cell malignancies.
Promising technology for gene therapy in the near future is genome editing, and its clinical application has already started
for gene therapy of HIV infection and CAR gene therapy. Hereditary diseases will be the next target of genome editing
technology. These topics will be presented in this Gene Therapy session.
Tue(3)-CIS16-1
Haematopoietic stem cell- and liver-targeted gene therapy for hereditary disease
1,2
Ian E. Alexander
1:Gene Therapy Research Unit, Sydney Children’s Hospitals Network and Children’s Medical Research Institute;
University of Sydney Medical School, Australia、2:University of Sydney Medical School
Translating genetic knowledge and diagnostic power to therapeutic outcomes remains a formidable task in the genomic era.
Gene therapy has a significant role to play in addressing this challenge. The bone marrow and liver are particularly attractive
gene therapy targets, as mastery of the gene delivery challenges involved provides technological platforms for treating a wide
diversity of disease phenotypes. The earliest successes in the treatment of monogenic genetic disease where achieved over a
decade ago in the primary immune deficiencies, SCID-X1 and ADA-SCID, and involved ex vivo transduction of haematopoietic
stem cells using gamma-retroviral vectors. Lessons learnt, which have shaped the ongoing development of the field, include
the power of in vivo selection and the disease-specific risk of genotoxicity. More recently therapeutic success has been
reported in the liver targeting Haemophilia B following direct in vivo transduction of hepatocytes using systemic delivery of
adeno-associated virus-based vectors. Success across a broader spectrum of disease phenotypes in the liver, including many
cell autonomous diseases, however, awaits further improvements in gene delivery technology and development of preclinical
models that better predict vector performance in man. A common feature of contemporary successes in the bone marrow and
liver has been a gene delivery approach involving gene addition which is only effective in recessive phenotypes. The current
trajectory of the field is towards targeted genome editing approaches, which open the prospect of treating both dominant and
recessive phenotypes, that exploit user-targeted nucleases alone or in combination with co-delivery of a template for locus
specific homologous recombination. These approaches are already showing exciting promise in small animal models and are
on the cusp of clinical implementation. The presentation will expand on the points above placing the current state of the
field in historical context.
[Biography]
Professor Alexander is a physician/scientist within the Sydney Children’s Hospitals Network and Children’s Medical Research
Institute, Australia. He is a senior staff specialist in genetic metabolic disease and leads a research group focused on virus-
mediated gene transfer to the liver and haematopoietic compartment. He has established a translational research program
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and developed the specialised infrastructure and skill sets required to take promising novel therapies through to clinical
application. His team became the first in Australia to treat a genetic disease (SCID-X1) by gene therapy and are recognised
leaders in the establishment of this exciting field in Australia. Within Sydney Children’s Hospitals Network, which serves a
third of the entire paediatric population of Australia, he is currently leading the development of a major research initiative in
Genomics Rare Disease. He was the inaugural president of the Australasian Gene Therapy Society in 2001 and was Chair of
the NHMRC Cellular Therapies Advisory Committee. He is currently Chair of the International Committee of the American

Society of Gene and Cell Therapy and a member of the Viral Vector Committee. He is the Australasian Regional Editor
of Current Gene Therapy and Associate Editor for Human Gene Therapy and The Journal of Gene Medicine. In 2015 he
was appointed as a Fellow of the Australian Academy of Health and Medical Sciences and a Visiting Professor at University
College London.
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Tue(3)-CIS16-2
AAV (adeno-associated virus) vector-mediated gene therapy for hereditary and non-hereditory diseases
1
Keiya Ozawa
1:Division of Genetic Therapeutics, The Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Japan

AAV (adeno-associated virus) vectors are considered to be promising gene-delivery vehicles for gene therapy, because they are
derived from non-pathogenic virus, efficiently transduce non-dividing cells (e.g., neurons, muscles, retinal pigment epithelial
cells, hepatocytes and so on), and cause long-term transgene expression. Appropriate AAV serotypes are utilized depending on
the type of target cells; e.g., neurons are efficiently transduced with AAV2 vector, AAV1 vector is appropriate for muscles, and
AAV8 vector has been believed to be most efficient for hepatocytes. Among various target diseases for AAV vector-mediated
gene therapy, Parkinson's disease is one of the most promising candidates. AAV vector-mediated AADC (aromatic L-amino
acid decarboxylase; the enzyme converting L-DOPA to DA) gene transfer into striatum using a stereotactic apparatus in
combination with oral administration of L-DOPA was shown to be efficacious in phase I/II clinical trial (P.I.: Dr. Shin-
ichi Muramatsu). AAV-AADC vector injection was also effective in the treatment of AADC deficiency (P.I.: Dr. Takanori
Yamagata). Another appropriate target disease is Leber’s congenital amaurosis. Positive results of randomized, controlled
phase 3 clinical trial were recently reported. AAV8 vector can be utilized for gene therapy of hemophilia B by intravenous
injection (liver-mediated transduction), but a huge quantity of AAV vectors are needed to increase the serum Factor IX to
the therapeutic level. Another unsolved problem of intravenous injection is that inhibitory actions of pre-existing neutralizing
antibody against AAV vector capsids should be eliminated. One approach may be intravascular saline flushing before and
after AAV vector injection in order to avoid contact of vectors with neutralizing antibodies (P.I.: Dr. Yoichi Sakata). Finally,
intramuscular injection of AAV1 vectors would be useful for protein-supplement gene therapy.
[Biography]
Keiya Ozawa received his M.D. from University of Tokyo in 1977 and his Ph.D. from University of Tokyo in 1984. He studied
at the Clinical Hematology Branch, NHLBI, NIH, USA as a Fogarty Fellow (1985-87). He became Assistant Professor in
1987 and then Associate Professor in 1990 of The Institute of Medical Science, The University of Tokyo (IMSUT). In 1994
he became Professor of the Institute of Hematology, Jichi Medical School. He was Professor and Chairman of the Division of
Hematology, Department of Medicine (1998-2014) and Professor of the Division of Genetic Therapeutics, Center for Molecular
Medicine (1998-2014). He was Director of Center for Molecular Medicine, Jichi Medical University (2008-14). He was also
Professor of the Division of Immuno-Gene & Cell Therapy (Takara Bio), Jichi Medical University (2011-14). In 2014 he
became Director of IMSUT Hospital and Professor of the Division of Genetic Therapeutics, The Advanced Clinical Research
Center, IMSUT. He is also Director of Center for Gene & Cell Therapy (CGCT) of IMSUT. He continues to work at Jichi
Medical University as Visiting Professor. Dr. Ozawa has authored 450 original scientific articles and 55 reviews and book
chapters.
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Tue(3)-CIS16-3
Gene editing - From modeling diseases to treating patients
1
Toni Cathomen
1:Institute for Cell and Gene Therapy, Medical Center - University of Freiburg, Germany

Targeted genome editing with designer nucleases has heralded a new era in gene therapy. Genetic disorders, which have not
been amenable to conventional “gene addition” type gene therapy approaches, such as disorders with dominant inheritance
or diseases caused by mutations in tightly regulated genes, can now be treated by precise “gene surgery”. Moreover, designer
nuclease technology allows for novel genetic interventions to fight infectious diseases, including chronic viral infections. We
have developed highly specific designer nucleases based on transcription activator-like effector nucleases (TALENs) and the
clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system. In preclinical disease models we demonstrate
that TALENs and CRISPR-Cas9 nucleases can be employed to generate an immune system that is resistant to infection with
human immunodeficiency virus type 1 (HIV-1) or to correct primary immunodeficiencies. Strategies to translate these findings
into the clinic will be discussed.
[Biography]
Toni Cathomen is Professor and Director of the Institute for Cell and Gene Therapy at the Medical Center of the University
of Freiburg, Germany. The institute provides the Medical Center with blood and cell products as well as all transfusion and
transplantation related diagnostic services. Toni Cathomen received his PhD from the University of Zurich, Switzerland.
Before his appointment in Freiburg, he was a postdoctoral fellow at the Salk Institute in San Diego, USA, Assistant Professor
of Molecular Virology at Charité Medical School in Berlin, and Associate Professor of Experimental Hematology at Hannover
Medical School. Toni Cathomen’s main research goals are (i) to improve genome editing tools (incl. TALENs, CRISPR-Cas9)
for safe application in human stem cells, (ii) to develop disease models and cell therapies based on induced pluripotent stem
cells (iPSCs), and (iii) to translate cell and gene therapy efforts into the clinic.
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Tue(3)-CIS16-4
CAR Therapy: The CD19 Paradigm
1
Michel Sadelain
1:Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, USA

T cell engineering provides a means to rapidly generate therapeutic T cells of any specificity. In oncology, its purpose is to
generate potent immune responses that eradicate tumor cells and overcome immune barriers in the tumor microenvironment.
T cell engineering is predicated on the transduction of receptors and other molecules to redirect T cell specificity and
enhance T cell function. Chimeric antigen receptors (CARs) are synthetic receptors that mediate antigen recognition, T
cell activation, and, in the case of second generation CARs, costimulation. We demonstrated over a decade ago that human
T cells engineered with a CAR specific for CD19 eradicated B cell malignancies in mice, and were the first to report the
remarkable complete remission rate obtained with CD19-specific, second generation CARs in adults with chemorefractory,
relapsed acute lymphoblastic leukemia. Several groups, including ours, have extended these results to other B cell malignancies
including non-Hodgkin lymphoma, pediatric ALL and chronic lymphocytic leukemia. Novel T cell engineering modalities,
including auto- and trans-costimulation and combinatorial antigen recognition, hold the promise of further enhancing the
effectiveness of CAR therapy against a broad range of cancers.
[Biography]
Michel Sadelain, MD, PhD, is the Director of the Center for Cell Engineering and the incumbent of the Stephen and Barbara
Friedman Chair at Memorial Sloan Kettering Cancer Center. Dr. Sadelain's research focuses on human cell engineering and
cell therapy to treat cancer and hereditary blood disorders. His laboratory has made several seminal contributions to the field
of chimeric antigen receptors (CARs), from their conceptualization and optimization to their clinical translation for cancer
immunotherapy. In addition to second generation CARs, the Sadelain Laboratory developed artificial antigen presenting cells,
auto- and trans-costimulatory engineering strategies, combinatorial antigen recognition, and inhibitory CARs. His group was
the first to publish dramatic molecular remissions in patients with chemorefractory acute lymphoblastic leukemia following
treatment with CD19 CAR therapy.
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ELSI
Tue., April 05, 2016 8:00-10:00 Room E (1F)
Convener：Masayuki Yoshida（Department of Life Science and Bioethics, Tokyo Medical and Dental University, Japan）
Convener：Dina N. Paltoo（Genetics, Health and Society Program, Office of Science Policy/National Institute of Health,
USA）

Though future advances in genomic research require accessing and sharing of global genomic data, the sharing of such
data continues to raise concerns regarding how to protect genomic privacy. The difficulty in balancing the sharing and
protection genetic information is partially based on how the genomic data governance and management system or model
ensures that cutting edge genomic research is available with a reasonable control of research participant’s privacy. Current
approaches to overcome this issue are rather heterogeneous depending upon the region. Additionally, the responsibilities
of the researchers who access these data should also be considered.
In this workshop, we will learn of genomic data management practices and concerns from diverse geographic regions,
in an effort to discuss the practical solutions to confront the issue of sharing and potential risks in doing so. We hope
that this session will provide a meaningful vision to all stakeholders that ensures the promise of genetic research and its
application to medicine and health.
Tue(3)-CIS17-1
Patient Preferences for Governance of Use of Genomic Information in Research
1
Sandra S. Lee
1:Stanford Center for Biomedical Ethics, Stanford University, USA
Recent advances in genomic sequencing have created unique opportunities for research to improve patient care through sharing
of patient genomic data. Such efforts are evident in the emergence of the learning healthcare system, which aims to collect
personal genomic information towards evidence based decisionmaking and precision medicine. The paper draws upon studies
of diverse patient populations of patients in the U.S. and their preferences for governance of use of genomic information in
research, specifically preferences related to privacy, confidentiality, informed consent and oversight. This presentation will
focus on the shifting paradigms of protection of and access to genomic information and explore the need for new models of
governance that take into account the technical realities of de-identification, anonymization and data security and scientific
pressures for data sharing.
[Biography]
Sandra Soo-Jin Lee, Ph.D., is Senior Research Scholar at the Center for Biomedical Ethics and faculty in the Program in
Science, Technology and Society (STS) at Stanford University. She is a medical anthropologist whose research focuses on
the sociocultural dimensions and ethical issues of emerging technologies and their translation into clinical practice. Dr. Lee
has led studies on public understanding of research using clinical data and biological samples, concepts of race, culture and
human genetic variation, and citizen science, commercialization of biotechnology and entrepreneurship. Dr. Lee’s most recent
projects include Beyond Consent: Patient Preferences for Governance of Use of Clinical Samples and Data (NIH/NHGRI;
PI: Lee) and Social Networking and Personal Genomics: Implications for Health Research (NIH/NLM; PI: Lee), and she
is a Co-Investigator of NIH P50 Grant for the Stanford Center for Integrating Research in Genetics and Ethics (CIRGE)
(NIH/NHGRI; PI: Cho). Dr. Lee serves on the Scientific Advisory Board for the Kaiser Permanente National Biobank and
the NIH/NHGRI Coriell Consultation and Oversight Committee of the International Haplotype Map. She is Co-Chair of the
ELSI Affinity Group at the American Society for Bioethics and Humanities and is a member of the Social and Ethical Issues
in Research Study Section of the NIH Committee for Scientific Review
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Tue(3)-CIS17-2
Given a Voice: An Update on the Lacks Family-NIH Partnership on Use of HeLa
Genome Data
1
Dina N. Paltoo
1:Genetics, Health and Society Program, Office of Science Policy/National Institute of Health, USA

TBA
[Biography]
Dina Paltoo received a Ph.D. from Howard University in Physiology and Biophysics. After completing a postdoctoral fellow-
ship at the University of Medicine and Dentistry of New Jersey, she returned to Howard University in a research position and
was on faculty at Morgan State University. She then focused her research in molecular epidemiology as a Cancer Prevention
Fellow at the National Cancer Institute, earned a M.P.H. from the Johns Hopkins Bloomberg School of Public Health, and
served as a Program Director at the National Heart, Lung, and Blood Institute, where she initiated and managed research
programs in genomics and pharmacogenomics. Currently, Dr. Paltoo is the Director of the Genetics, Health, and Society
Program in the Office of Science Policy, Office of the Director, National Institutes of Health. Among other activities, Dr.
Paltoo’s Program manages NIH’s genomic data sharing policy, implementation, and oversight.
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Tue(3)-CIS17-3
ELSI practices and regulations for collaboration and public participation in personal genome research
1
Kazuto Kato
1:Biomedical Ethics and Public Policy, Osaka University, Japan

To promote genomic research and achieve effective implementation of genomic medicine, it is necessary to address ethical
issues and have good collaboration with patients and citizens. In this talk, I will pick up two areas that are important for
the promotion of genomic medicine. One is the emergence of new ethical issues such as incidental findings and protection of
genomic data. I will introduce how Japan has been addressing these issues. In particular, there are ongoing discussions as
to how the legislation regarding the personal data protection, that is being revised in Japan, should deal with genomic data.
The second area is how to facilitate the active participation of patients and citizens. Recently, there is a growing number of
projects which use the ICT technology to enable patients and citizens to enter their own health data to databases. These
patient and public centered activities have advantages over traditional methods of data collection. They also have many
challenges. I will describe the current state of the field and discuss implications of such activities for the future of genomic
medicine.
[Biography]
Kazuto Kato, PhD is Professor of Biomedical Ethics and Public Policy at the Graduate School of Medicine, Osaka University,
Japan. He is also a Project Professor of the Institute for Integrated Cell-Material Sciences (iCeMS) at Kyoto University. He
has a PhD degree in developmental biology from Kyoto University. After finishing postdoctoral research at the University of
Cambridge with Sir John Gurdon, he started to work in the interface between bioscience and society, particularly focusing
on ethical and social issues of genomics and stem cell research. He has been serving as a member of various international
projects/academic societies such as Committee on Ethics, Law and Society (CELS) of Human Genome Organization (HUGO),
ELSI group of the International HapMap Project, Ethics and Policy Committee of the ICGC (International Cancer Genome
Consortium), and Steering Committee of the Global Alliance for Genomics and Health. He is also a member of the international
network, ELSI 2.0. In 2010, he was appointed as a member of the Expert Panel on Bioethics of the Council for Science and
Technology Policy (CSTP) of the Cabinet Office, Japan. Since 2010 Professor Kato has been directing a research group,
the Research Unit for the ELSI of Genomics to carry out analysis of ethical, legal and social implications of human genome
research. Professor Kato is currently specializing in biomedical ethics, science communication and public policy of life sciences.
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Tue(3)-CIS17-4
Ethical theory and global challenges in the era of -omics and predictive medicine
1
Ruth F. Chadwick
1:Centre for Social Ethics and Policy, University of Manchester, UK

The future of medicine, it is said, is both predictive and personalised. What is meant by personalisation remains a matter of
dispute. The relatively recent move to use the word ’precision’ medicine has emphasised some interpretations at the expense
of others. Personalised precision medicine relies on increasing amounts of data of different kinds and from different sources.
These developments have the potential to require reconsideration of the physican-patient relationship, as both the demands
on professional judgment and patient expectations respond to the changing situation. Regarded in a global context, there
are also challenges for ethical theory in addressing these issues of professional ethics. This paper will consider the extent to
which global ethics can offer a principled way of thinking about them.
[Biography]
Professor Ruth Chadwick is Professor of Bioethics at the University of Manchester. From 2002-2013 she directed the ESRC
Centre for Economic and Social Aspects of Genomics (Cesagen). Cesagen was a dual site research centre funded for ten years
by the Economic and Social Research Council as a partnership between Lancaster and Cardiff Universities. Ruth co-edits
Bioethics and Life Sciences, Society and Policy and has served on the Council of the Human Genome Organisation, the Panel
of Eminent Ethical Experts of the Food and Agriculture Organisation of the United Nations (FAO), and the UK Advisory
Committee on Novel Foods and Processes (ACNFP). She is Fellow of the Academy of Social Sciences; of the Hastings Center,
New York; of the Royal Society of Arts; and of the Royal Society of Biology. In 2005 she won the World Technology Network
Award for Ethics and in 2014 she was elected Fellow of the Learned Society of Wales.
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Tue(3)-CIS17-5
Ethical and Policy Issues in Human Genome Editing and Germline Modifications
1,2
Xiaomei Zhai
1:Peking Union Medical College and Chinese Academy of Medical Sciences, China、2:Chinese Academy of Medical
Sciences

This paper discussed the ethical and Policy Issues in Human Genome Editing and Germline Modifications. After analyzing
the arguments against germline gene therapy (GGT), the conclusion is that the regulated research in GGT must not “Play
God”, violate the sanctity of life, open a Pandora Box leading to eugenics, and current generation does have a responsibility
of preventing serious diseases in future generations.
[Biography]
ZHAI Xiao-Mei, Ph.D, Dean & Professor,School of the Humanities & Social Sciences, Peking Union Medical College. Execu-
tive Director, Centre for Bioethics, Chinese Academy of Medical Sciences. The Fellow of Hastings Center.
She served as the member of Ethics Committee, HUGO and vice President of Asian Association of Bioethics, the member
for temporary expert group of WHO. Currently she serves as the member of National Committee of Experts on Medical
Ethics, the Member of National Advisory Committee of Experts on Public Health Policy, the Member of National Committee
of Expert on Human Organ Donation and Transplantation, the member of National Expert Committee for Chinese Bone
Marrow Bank, the Standing Director & Chair of Ethics Committee for Chinese Association of STD/AIDS Association. She
serves as the Chair of China Society of Bioethics affiliated to Society of Nature Dialectics China Association for Science and
Technology. She is Vice-Chair for ELSI Committee of China Genetics Society.
She is Deputy Editor of Chinese Medical Ethics, the member of Editorial Board of British Medical Journal (Chinese version),
the journal of Basic Medicine and Clinics, the journal Medicine and Philosophy, the journal of Chinese Medical Biotechnolo-
gies, the journal of Asian Bioethics Review and etc.
She has academic publications both in English and Chinese.
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Genetic Counseling/Education
Tue., April 05, 2016 10:20-12:20 Room E (1F)
Convener：Kristine Barlow-Stewart（Sydney Medical School, The University of Sydney; Royal North Shore Hospital,
Australia）
Convener ：Junko Yotsumoto（Natural Science Division, Faculty of Core Research, Ochanomizu University; Showa Uni-

versity, Japan）
Genetic counseling is defined as a communication process that aims to help people understand and adapt to the medical,
psychological and familial implications of genetic contributions to health conditions (Resta et al JGC, 2006). Necessary
for this process is the capacity of the practitioner to assess risk based on personal and/or family histories and/or ge-
netic/genomic test information. They also need to utilize education and counseling skills to promote understanding of the
condition and its inheritance, awareness of resources and adaptation to the risk or condition as well as informed choice
regarding testing, management and prevention strategies where available, and related research. The session will present
the experiences of genetic counselors from Japan, Australia, UK, USA and Malaysia in regard to some of these elements
in the process in the genomic era.
An overview of the training and roles of genetic counselors in Japan will be provided, illustrated by the challenges faced
when dealing with Variants of Unknown Significance (VUS) in BRCA testing.
Masters level training for genetic counselors is now available in Australia, Canada, China, Cuba, France, Israel, Japan,
Malaysia, the Netherlands, Norway, the Philippines, Saudi Arabia, South Africa, Spain, Sweden, Taiwan, United States
of America and the United Kingdom and their roles are expanding in many countries. However the rapid developments
in genomics have created a knowledge gap in genetic counselors who have not graduated recently and the strategies to
up-skill these practitioners in Australia and internationally will be reviewed. Similarly strategies to meet the genetics
education needs of health professionals faced with the increasing mainstreaming of genomic medicine will be discussed
as well as the resources available to promote education and decision-making of the community in regards to genetic and
genomic tests and their implications.
These implications increasingly facing practitioners in the genomic era include addressing the potential for incidental
findings and promoting informed choice in this regard as well as managing the return of such unexpected results. Ge-
nomic testing can be provided to those seeking a clinical service or to those taking part in research studies, and the views
and experience of those utilizing and providing the test in both of these settings will be reviewed.
In regard to the clinical setting, genetic counselors working in the Clinical Sequencing Exploratory Research Consortium
in the USA have developed recommendations in regard to best practice for facilitating informed consent in the pre-test
counseling session which will be presented.
In terms of expectations of research participants in regard to return of results, the responses of 6944 individuals (both
community and professionals) from 75 countries to a cross-sectional web-based survey will be presented.
However there are many additional challenges facing those practitioners in the implementation of genetic and genomic
medicine in non-Western middle and low income countries including overcoming health system, access, health and genetic
literacy, funding and cultural and psychosocial barriers. The experience of genetic counselors working in the field of
cancer genetics Malaysia will be used to illustrate the interventions which can be put in place to address some of these
barriers.
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Tue(3)-CIS18-1
Introduction and brief overview of genetic counselling in Japan - Role and training of
genetic counselors, and a topic, “Dealing with BRCA VUS in Japan”
1,2
Junko Yotsumoto
1:Natural Science Division, Faculty of Core Research, Ochanomizu University; Showa University, Japan、2:Showa
University

Japanese genetic counselors certification examination started in 2005 and is held every year. Now there are 182 certified
genetic counselors in Japan. Certified genetic counselors accredited by the Japan Society of Human Genetics and Japan
Society of Genetic Counseling. Both societies, and Japanese association for certified genetic counselors, serve as a valuable
site for education and training, for those who have achieved the qualification and also for those who are going forward with
their qualification process.
Recently, as Genomic medicine has grown more sophisticated and complicated, the problems that genetic counselor faces have
also become complicated. For example, recent studies indicate VUS results are challenging for clinicians and patients. Then,
I wish to introduce a topic,“dealing with BRCA VUS in Japan”.
In Japan, current practices regarding BRCA VUS results are unknown. To explore Japanese situation related to disclosing
BRCA VUS results, we are reporting the result of the Japanese HBOC consortium trial data.
This report utilizes a data of HBOC consortium trial survey, from 2009 to Aug 2015. We reviewed data from 827 breast
and/or ovarian cancer patients who had underwent BRCA1/2 testing, and the incidence of VUS among Japanese patients,
and their options, after having received BRCA VUS results.
The proportion of VUS was 6.6% (in 54 patients). Ten patients (38%) selected mastectomy, 14 patients (54%) selected
breast-conserving surgery, among 26 VUS patients who had received BRCA1/2 testing prior to surgery. And four patients
selected RRM and/or RRSO.
Japanese VUS rate is high, referring western database like Myriad. To improve this situation, there is a real need for national
database of HBOC. A misinterpreted VUS has the potential to lead to mismanagement of both the patient and their relatives.
We need to recognize the more importance of adequate pre-test counseling and the communication for VUS results.
[Biography]
Junko Yotsumoto is a genetic counselor, assistant professor and clinical genetic researcher in Division of Natural Science,
Faculty of Core research, at the Ochanomizu University in Tokyo, Japan.
Education
2009 Finished P.H.D program of Ochanomizu University
Degree
2006 Master of Science Ohanomizu University
2015 P.h.D Ochanomizu University
Work History
2014 Assistant professor, Ochanomizu University
2013 Genetic Counselor, Clinical Genetics Center of Showa University Hospital
2009 Genetic Counselor, Department of Obstetrics and Gynecology and Breast Center,
Showa University Hospital
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2009 Research assistant professor of Genetic Counseling program of Graduate school of Ochanomizu University
2007-2009 Clinical researcher, National Center for Child Health and Development
Academic/Professional Memberships and Other Professional Activities
Director of Japanese Association of Certified Genetic Counselors
Councilor of The Japan Society of Human Genetics, Councilor of Japanese Society for Genetic Counseling, Councilor of Japan
HBOC Consortium

Member of
ASCO American Society of Clinical Oncology (ASCO)
Japan Society of Human Genetics,Japanese Society for Genetic Counseling,Japan Society of Obstetrics and Gynecology,Japan
Society of Perinatal and Neonatal Medicine,Japan Society of Breast Cancer
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ICHG2016 242
Tue(3)-CIS18-2
Genetic Education Strategies to Enhance the Genetic Counselling process in the Ge-
nomic Era
1
Kristine K. Barlow-Stewart
1:Sydney Medical School, The University of Sydney; Royal North Shore Hospital, Australia

Genetic counselling in the 21st century faces many challenges including management of the consent process; obtaining,
interpreting and managing genomic results where there is limited evidence and conflicting interpretation of benefit and
value including incidental findings and variants of uncertain significance; and addressing the psychological impact of the
information on patients or their families. In recognition of the need for up-skilling currently practicing genetics clinicians to
meet these challenges a variety of genetics education strategies have been implemented internationally using web-based and
more traditional teaching. A review of these approaches will be presented. However with increasing mainstreaming of genetic
testing, the critical importance of education of non-genetics clinicians to the successful integration of genomics into health
care has been emphasised. Traditional educational approaches will not be successful with these time poor professionals and
strategies will need to focus on point of care tools and information. Facilitation of partnerships with genetic counsellors may
provide new models of care in the genomic era. At the same time it is essential that those utlising the genomic tests are
provided with information and resources that can support their decision-making and understanding. Such resources need to be
current and accessible and examples produced by the NSW (Australia) Centre for Genetics Education and other international
groups that have been shown to be effective will be reviewed. These resources are important especially in the pre-test and
consent setting but do not replace the essential communication component that underpins genetic counselling.
[Biography]
Associate Professor Kristine Barlow-Stewart, BSc (U.Syd), PhD (U.NSW), Genetic Counsellor (FHGSA) was one of the first
in Australia to be certified as a genetic counsellor in 1991. She was the Foundation Director of NSW Health’s Centre for
Genetics Education from1989-2012. In 2011 she established the Master of Genetic Counselling program for the University of
Sydney and is its current Director. Her teaching and research career has focussed on addressing the information and support
needs of the community, education and training needs of professionals and the psychosocial and ethical impact of the rapidly
developing field of genetic and genomics technologies. Kristine has contributed widely to development of policies in these
areas both State-wide and nationally.
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Tue(3)-CIS18-3
Genetic counselors’ experiences obtaining informed consent for genomic sequencing:
Lessons learned
1
Barbara A. Bernhardt
1:Translational Medicine and Human Genetics, University of Pennsylvania, USA

The Clinical Sequencing Exploratory Research (CSER) Consortium includes 20 US projects funded by the National Institutes
of Health to explore analytic validity, clinical validity, clinical utility, as well as ethical, legal and social considerations of
clinical sequencing. Consortium sites are recruiting about 5000 participants across diverse clinical settings (pediatric and
adult, symptomatic and healthy). Through research by and with genetic counselors in the CSER Consortium, recommenda-
tions have been made for best practices for conducting informed consent (IC) sessions. With experience, genetic counselors
have learned to tailor IC sessions based on individual participants’ needs, generally focusing on addressing misperceptions
and helping participants to develop realistic expectations about the number, types, limitations and implications of possible
results from sequencing. Challenges experienced by genetic counselors relate to ensuring sufficient understanding of informa-
tion so participants can make informed choices about undergoing sequencing and set preferences about return of incidental
findings, and on promoting autonomous decisions in the face of complicated on-going medical needs and family dynamics.
With experience, most genetic counselors spend only limited time discussing genomic principles or technological aspects of
sequencing, except for what is necessary for patients to understand how results are generated and interpreted. After gaining
experience reviewing, interpreting and returning results, genetic counselors have learned to conduct IC sessions using more
specific descriptions of possible results based on the kinds of conditions that are of concern to individual participants. Genetic
counselors have emphasized the need to create and evaluate educational materials and decision-support tools to supplement
pre-test genetic counseling. Other lessons learned by these experienced CSER genetic counselors will be discussed.
[Biography]
Barbara Bernhardt is a genetic counselor, Clinical Professor and social sciences researcher in the Division of Translational
Medicine and Human Genetics at the Perelman School of Medicine of the University of Pennsylvania. She was previously
on the faculty of the Johns Hopkins School of Medicine and the Bloomberg School of Public Health, where she served as
a core member of the Genetics and Public Policy Unit and as co-director of the Johns Hopkins/National Human Genome
Research Institute Genetic Counseling Graduate Training Program. For over three decades, Ms. Bernhardt has conducted
both qualitative and quantitative research exploring ethical and social issues relating to the diffusion of new genetic technolo-
gies, and the influence of the media, patients, providers, third party payers and clinical practice guidelines on the offering
and utilization of genomic tests and services. Her current research projects include an investigation of the impact of the
uncertainties of prenatal and pediatric microarray testing on patients and providers, and an evaluation of the offering of
whole exome sequencing to children. In her clinical work, Ms. Bernhardt has over 40 years of experience counseling patients
in the context of complex decision-making in prenatal, pediatric and adult genetic clinics.
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Tue(3)-CIS18-4
Engaging 7,000 people about the return of results from sequencing research
Anna Middleton 1 ，on behalf of the DDD study
1:Social Science and Ethics, Wellcome Genome Campus, UK

Whole genome/exome sequencing in a research setting offers an opportunity to return individual level results to research
participants about their current and potential future health. What do research participants expect of researchers with respect
to return of results? A cross-sectional, web-based survey investigated the attitudes of 6944 individuals from across 75 countries;
participants included 4961 members of the public, 533 genetic health professionals, 843 non-genetic health professionals and
607 genomic researchers. Treatability and perceived usefulness of the data were important with 98% personally interested
in receiving results about life-threatening conditions that were preventable. However, participants also indicated that they
would be interested in receiving other data, including uncertain results as well as raw sequence data. The most in favour
of this were genomic researchers and members of the public, the least in favour were genetic health professionals. Indeed
genetic health professionals consistently reported more conservative attitudes across most items compared to other participant
groups. This may be due to their appreciation of the complexities involved in translating genomic data in the clinic. There
is much anecdotal support in the literature for sharing results in a research setting, and our participants agreed with this
principle. However, they also thought that genomic researchers should be able to focus on answering their research question
without being forced to actively search for individual level results, potentially at the expense of their research.
[Biography]
Dr Anna Middleton has had two parallel careers - the first as a practicing genetic counsellor, the second as a senior social
scientist exploring the impact of genetic technology on people. She currently works at the Wellcome Trust Sanger Institute
in Cambridge, UK leading the social sciences work for the Wellcome Genome Campus. She is a previous vice-chair of the
Genetic Counsellor Registration Board (UK and ROI) and a current committee member of the Association of Genetic Nurses
and Counsellors. Together with genetic counselling colleagues she has co-written the core curriculum for training genetic
counsellors in the UK. She also co-designed the Genomic Practice for Genetic Counsellors Wellcome Trust course and is
module co-lead on the University of Cambridge MSt Genomic Medicine course. Anna has over 80 published peer review
papers, book chapters and invited conference presentations and has also edited two books on genetic counselling practice.
Follow Anna on Twitter at @genomethics.
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Tue(3)-CIS18-5
Genetic Counselling and hereditary testing in low and middle income Asian setting
1
Sook Yee Yoon
1:Familial Cancer, Cancer Research Malaysia, Malaysia

Malaysia is a middle-income multicultural country in Asia with a population of around 30 million. The experience of those
working in cancer genetics in Malaysia illustrates the challenges faced and the strategies implemented to overcome them.
It is estimated that up to 0.002% of the population (approximately 6,000 individuals) may potentially have an inherited BRCA
mutation. However, to date, less than 200 individuals have been identified, limiting the opportunities for decision-making
regarding their appropriate risk management options and early detection strategies for many thousands of women.
The majority of BRCA carriers in Asia currently do not have access to risk management because genetic counseling and
genetic testing is patchy and mostly inaccessible or unavailable. How do we improve access to genetic testing and genetic
counseling? How do we identify these barriers to access, such as the health systems, funding, cultural and psychosocial barriers
in these low and medium income society? Previous studies in Malaysia have shown that uptake of predictive testing is very
low (6%) even when cost and access to genetic testing and counselling is not an issue. We are beginning to understand some
of the issues surrounding the poor uptake and will present some of the intervention which can be put in place in a medium
resource country.
[Biography]
Ms Yoon Sook-Yee, a graduate from the University of Cambridge has been involved in the Malaysian Breast Cancer (MyBrCA)
research project in Cancer Research Malaysia since 2003. She is one of the two certified Genetic Counsellors in Malaysia and is
accredited by the Human Genetics Society Australasia (HGSA). She is currently the Head of the Familial Cancer Programme
in CRM. Her current focus is on hereditary breast and ovarian cancer patients and their families in Malaysia, with a research
interest in the psychosocial aspects of genetic testing and counselling in Malaysia.
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Psychiatric Genetics
Tue., April 05, 2016 8:00-10:00 Room B-1 (2F)
Convener：Norio Ozaki（Department of Psychiatry, Nagoya University Graduate School of Medicine, Japan）

Convener ：Joseph D. Buxbaum（Icahn School of Medicine at Mount Sinai, USA）

Psychiatric genetics explains the role of genes in mental disorders. The answers are not simple and the questions remain
numerous and complex, but the results are exciting and have the potential to transform the practice of psychiatry and
psychopharmacology. In this session the speakers will present the data about new paradigm for genes and psychiatry
that has recently emerged. That paradigm sees genes only as direct causes of mental disorders but also as direct causes of
undelaying molecular abnormalities that increase risk for onset of mental disorders. In other words, deleterious mutations
do not cause mental disorders but can bias brain circuits toward inefficient information processing, which may lead to
mental disorders under certain circumstances. It may be possible to identify critical genes to assess risk for mental illness
in individual patients and their families, and this may someday help guide treatment selection as well.
Tue(3)-CIS19-1
Rare and common variation in autism and associated neurodevelopment disorders
1
Joseph D. Buxbaum
1:Icahn School of Medicine at Mount Sinai, USA
TBA
[Biography]
Dr. Joseph D. Buxbaum is an American neuroscientist, autism researcher, and the director of both the Seaver Autism Center
at Mount Sinai School of Medicine, as well as the director of the Autism Genome Project there. Dr. Buxbaum is also, along
with Simon Baron-Cohen, the co-editor of the BioMed Central journal Molecular Autism, and is a member of the scientific
advisory board of the Autism Science Foundation. Dr. Buxbaum has a bachelor’s degree from Touro College, as well as an
MS and a PhD, both from the Weizmann Institute of Science. As director of the Autism Genome Project, Dr. Buxbaum
conducts research on the heritability of autism and how it may be possible to develop novel therapies for the disorder as
a result. Buxbaum has received recognition from the New York University Child Study Center in 2004, as well as from
the American College of Neuropsychopharmacology the following year, and from the Eden Institute Foundation in 2008 for
his "commitment and dedication to improving the quality of life in individuals with autism."
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Tue(3)-CIS19-2
Genetics of schizophrenia and bipolar disorder
1
Michael J. Owen
1:MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UK

The division of the functional psychoses into schizophrenia (SZ) and bipolar disorder (BD) has been preserved almost un-
changed since Kraepelin distinguished dementia praecox from manic-depressive insanity at the turn of the last century. The
underlying assumption that the two disorders reflected predominantly distinct underlying pathogenic processes was supported
by genetic epidemiology, which suggested high heritability of both conditions but minimal genetic overlap. This view has been
challenged by recent, large-scale family studies that have revealed evidence for a degree of shared inheritance. Recent genomic
studies have begun to reveal the genetic architecture of SZ and BD. GWAS have supported the more recent family studies
in providing evidence, that the two disorders share underlying common genetic risk alleles. In contrast studies of CNVs have
repeatedly shown that, while patients with SZ have an increased burden of large rare CNVs, in those with BD the burden
is actually lower than in controls. These observations, together with genetic findings in neurodevelopmental disorders such
as autism and intellectual disability and the lack of clear boundaries between diagnostic groups, support the view that these
conditions can be considered to occupy a gradient of neurodevelopmental impairment and that current diagnostic categories
may not be optimal for stratifying cases for research into aetiology and pathogenesis. Despite the fact that much of the
genetic risk remains unaccounted for at the DNA level, there are encouraging signs that the genes implicated converge onto
sets of plausible biological processes. In particular, the data point to defects of synaptic and dendritic function and implicate
mechanisms involved in brain plasticity that are important in development and in cognition. While these may not be the
only processes involved, they provide robust entry points for clinical and basic neuroscience research.
[Biography]
Mike Owen is Director of the Medical Research Council’s Centre for Neuropsychiatric Genetics and Genomics, and Head of
the Division of Psychological Medicine and Clinical Neurosciences in Cardiff University. He has researched the genetics and
genomics of a variety of psychiatric disorders since 1987 and has made notable contributions to the study of schizophrenia and
Alzheimer disease. He is interested in the impact of genetic findings on how psychiatric disorders are defined and the work
of his group has identified functionally related sets of proteins that are involved in a range of neurodevelopmental disorders
including schizophrenia. As well as continuing his work on psychiatric genetics, he is currently undertaking research aimed
at translating recent genetic findings into a greater understanding of disease mechanisms using a variety of neuroscience and
epidemiological approaches. He served on the Board of Directors of the International Society of Psychiatric Genetics (ISPG)
from 1993-2014 and was President from 2000-2005. He was awarded the Stromgren Medal for psychiatric research in 2011,
the Lieber Prize for schizophrenia research in 2012, the William K Warren Distinguished Investigator Award for schizophrenia
research in 2013, and the Lifetime Achievement Award of ISPG in 2015. He has published over 600 scientific papers and is a
Thompson Reuters Highly Cited Researcher. He was knighted for services to psychiatry and neuroscience in 2014.
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Tue(3)-CIS19-3
Shared Genetic Risk Across Psychiatric Disorders
Naomi R. Wray 1 ，Shared Genetic Risk Across Psychiatric Disorders
1:Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia

While it has long been recognised that psychiatric disorders are moderately to highly heritable, the degree to which genetic
variation is unique to individual disorders or shared across disorders has been less clear. In princi ple, family studies allow
quantification of the shared genetic etiology of disorders, but this requires collection of large samples of families recorded
for both disorders. National registries provide the best opportunity, but then shared environmental risk factors cannot be
excluded as contributing to increase shared risk based on measures of relatives. The era of genome-wide association studies has
heralded a new approach, in which independently collected case-control data can be used to estimate the genetic correlation
between disorders. These analyses have been applied to data sets of the common psychiatric disorders and show some expected
results (for example a high genetic correlation of 0.7 for schizophrenia/bipolar disorder and an important correlation of 0.4 for
Tourette’s/OCD) and some unexpected results (for example a correlation of 0.4 between schizophrenia and major depressive
disorder). A number of questions arise from these analyses and estimates: How to the estimates of genetic correlations from
common SNPs compare to the risk to relatives estimated from family studies? Could estimates of genetic correlation simply
reflect diagnostic misclassification? Can we differentiate pleiotropy (risk variants common to two disorders and present in all
individuals) from clinical heterogeneity (sharing of risk variants between one disorder and a subset of another disorder)? Can
we utilise data from correlated disorders in risk prediction models to achieve greater accuracy than possible from univariate
approaches. I will review the latest studies that explore shared genetic risk across psychiatric disorders based on studies of
both common and rare variants and I will provide some thoughts on how to interpret and utilise these results.
[Biography]
Naomi Wray is professor of statistical and psychiatric genetics at the Queensland Brain Institute of the University of Queens-
land, where she is co-director of the Centre for Neurogenetics and Statistical Genomics.
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Tue(3)-CIS19-4
Pharmacogenomics in Psychiatry
Masashi Ikeda 1 ，Nakao Iwata 1
1:Psychiatry, Fujita Health University School of Medicine, Japan

It is well established that genetic variants related to the pharmacogenetics (PGt) /pharmacogenomcis (PGx) traits have larger
effect size in comparison to variants associated with complex diseases. This indicates that, in general, risk variants could be
detected using relatively small samples. However, most of the PGx traits of the treatment response for the psychotropic agents
remains unidentified, therefore treatment strategy in psychiatric field still depends on trial and error process. Whereas, the risk
for the life-threatening side effect, such as Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) by antiepileptic
drugs, and agranulocytosis by clozapine has emerged by Genome-wide SNP and classical HLA analyses.
In this session, we will summarize the current scientific evidence in predicting treatment response and side effect by psy-
chotropic agents. Specifically, we will focus on the genetic risk for the side effect, and consider its potential clinical application.
[Biography]
Masashi Ikeda, MD, PhD, is Senior Lecturer at Department of Psychiatry, Fujita Health University School of Medicine. He
graduated from school of Medicine at Nagoya University (1999). After the clinical training of general medicine and psychiatry,
he started genetic research of schizophrenia, which is his main theme of PhD at Nagoya University (2005). Then he moved to
Cardiff University as a sponsored postdoctoral fellow (Sponsor: Japan Society for the Promotion of Science, host professors:
Prof. Michael O’Donovan and Prof. Mike Owen) for two years (2008-10) and finished genome-wide association study (GWAS)
of schizophrenia in a Japanese population. He came back to Japan in 2010 and now is conducting GWAS and re-sequencing
of psychiatric disorders.
He was awarded JSPN Award for Special Contributions to Psychiatric Research from Japanese Society of Psychiatry and
Neurology (2011), Paul Jansen Award from Japanese Society of Clinical Neuropsychopharmacology (2009), Butterfield Award
from Great Britain Sasawaka Foundation (2008) and Encouragement Prize from Japanese Society of Biological Psychiatry
(2015, 2006 and 2007).
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Neurogenetics and Neurodegeneration
Tue., April 05, 2016 10:20-12:20 Room B-1 (2F)
Convener：Tatsushi Toda（Division of Neurology, Kobe University Graduate School of Medicine, Japan）

Convener ：Bryan J. Traynor（Laboratory of Neurogenetics, National Institute on Aging, USA）

This symposium focuses on the major neurological diseases that are mostly sporadic but partially familial with a Mendelian
pattern of inheritance, including multiple system atrophy, Parkinson’s disease, amyotrophic lateral sclerosis, frontotem-
poral dementia, and mitochondrial diseases.
There is currently no cure or treatment for those intractable neurological diseases. While the genetic background of the
diseases has been partly revealed, much work remains to be done to find additional causative genes. A variety of ap-
proaches have been employed to identify these genes ranging from genome-wide association studies that examine common
variation to next generation sequencing that is ideal for identifying rare variants.
The groups presenting during this symposium lead the world in applying advanced genomic methods to the intractable
neurological disorders to identify genes. Through their analyses, they are aiming to unveil the pathogenesis of these
diseases and develop effective cures.
Tue(3)-CIS20-1
Molecular genetic basis of multiple system atrophy
Jun Mitsui 1 ，Takashi Matsukawa 1 ，Tsutomu Yasuda 1 ，Shoji Tsuji 1
1:Neurology, The University of Tokyo, Japan
Multiple system atrophy (MSA) is a neurodegenerative disease characterized clinically by autonomic failure in addition to
various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although MSA has been regarded as
a sporadic disease without familial occurrence, multiplex families with MSA including pathologically confirmed cases have
been described, suggesting that genetic factors underlie MSA. Recently, whole-genome sequence analysis in combination with
linkage analysis has revealed homozygous or compound heterozygous mutations in COQ2 in two of the six multiplex families
with MSA. COQ2 encodes parahydroxybenzoate-polyprenyl transferase, an essential enzyme responsible for the biosynthesis
of coenzyme Q10 (CoQ10). Indeed, CoQ10 levels in frozen brain tissues and lymphoblastoid cell lines from patients with
MSA carrying homozygous and compound heterozygous mutations were substantially lower than those in control subjects.
It was also demonstrated that functionally impaired variants of COQ2 were associated with a risk for developing MSA. A
metaanalysis of subsequent association studies demonstrated that carriers of V393A variant in COQ2 were associated with
patients with MSA (odds ratio 2.1 (95% confidence interval, 1.5 to 2.9); p< 0.0001).
Furthermore, we have been conducting a case-control study measuring the levels of CoQ10 in plasma from patients with MSA
and compared these levels to those of healthy controls, which revealed that the mean level of CoQ10 in patients with MSA
was significantly lower than that in control subjects. These findings strongly suggest that CoQ10 insufficiency is one of the
pathogenic mechanisms underlying MSA, and that other genetic factors might be involved in the CoQ10 insufficiency in MSA
patients who do not carry variants of COQ2 . Based on these findings, we are planning a clinical trial of supplementation
with CoQ10 in patients with MSA with and/or without COQ2 .
[Biography]
Education
Faculty of Medicine, The University of Tokyo M.D. 2001
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Graduate School of Medicine, The University of Tokyo Ph.D. 2010
Employment

2001-2002 Resident, Internal Medicine, The University of Tokyo Hospital
2002-2003 Resident, Internal Medicine, Mitsui Memorial Hospital
2003-2004 Neurology, The University of Tokyo Hospital
2004-2005 Neurology, Yokohama Rosai Hospital
2005-2006 Neurology, The University of Tokyo Hospital
2010- Project Research Associate, Department of Neurology, The University of Tokyo Hospital
2015- Research Associate, Department of Neurology, The University of Tokyo Hospital

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Tue(3)-CIS20-2
Genetics of Parkinson’s Disease
Tatsushi Toda 1 ，Wataru Satake 1
1:Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Japan

Parkinson’s disease (PD), one of the most common neurodegenerative diseases, is caused by multiple genetic and environmental
factors. ~ 14 disease causing genes have been identified for familial form of Parkinson’s disease (PD), studies of which indicate
a cell death pathway in dopaminergic neurons induced by defective protein degradation as a key molecular mechanism
underlying the pathogenesis of PD. Yet the majority of PD cases are sporadic, which is a multifactorial genetic disorder.
We performed genome-wide association study (GWAS) and two replication studies in a total of 2,011 PD cases and 18,381
controls from Japan. We identified a novel PD-susceptibility locus on 1q32 and designated this as PARK16 . BST1 also
showed a novel and strong association with PD. We detected a strong disease association at SNCA and LRRK2 on 12q12,
both causative genes for autosomal dominant parkinsonism. Now, large-scale meta-analysis of GWAS identifies total of ~
30 genes. Rare variants, less common yet associated with high risks for the disease onset, are also important, and Gaucher
disease mutations are proven to be a definite rare variant risk factor for PD.
To identify further common variant PD-risks, we performed Japanese 2nd SNP-GWAS that expanded our previous one. In
2nd GWAS using 1,948 cases and 28,990 controls, we identified a novel susceptibility locus with P <5 x 10-8 . Expression
level of a gene within the locus was reduced when the risk SNP exists. In a fly model, knockout of the gene worsened motor
function. Moreover, to search for further PD-risks in exonic areas, we performed exome sequencing of 755 PD patients.
Genetic variants with strong PD-risk did not exist within these 4 PD-loci, indicating that these 4 PD-loci will contribute to
this disease as common SNP variants. We will subsequently test association between whole exonic SNVs and PD to identify
novel PD-genes harboring rare-variant risks.
[Biography]
Dr. Tatsushi Toda is Professor and Chairman of Neurology, Kobe University Graduate School of Medicine. He graduated
from University of Tokyo in 1985 and entered into Department of Neurology, University of Tokyo. In 1996, he was appointed
as Associate professor of Institute of Medical Science, University of Tokyo. In 2000, he was appointed as Professor of Clinical
Genetics, Osaka University. From 2009, he holds the current position. He identified genes for Fukuyama muscular dystrophy,
muscle-eye-brain disease, and PD-susceptibility. His research interests include genetics of Parkinson's disease, neuromuscular
disorders, higher brain functions, and antisense therapy for Fukuyama muscular dystrophy. He has received Japanese Society
of Human Genetics Award, Japan Foundation for Aging and Health Award, Japanese Society of Neurology Award, Tokizane
Memorial Award, Asahi Award, and Award from Japanese Minister of Education, Culture, Sports, Science and Technology.
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Tue(3)-CIS20-3
Genetics of mitochondrial diseases
1,2
Patrick F. Chinnery
1:University of Cambridge, UK、2:MRC Mitochondrial Biology Unit

Mitochondrial diseases are primarily caused by a bioenergetic defect of adenosine triphosphate synthesis (ATP). ATP is
produced by the respiratory chain, which is a group of ~ 100 proteins arranged into five enzyme complexes with a dual
genetic origin. 13 peptides are synthesised from mtDNA present within the mitochondrion. The remainder are translated and
transcribed in the cytosol from nuclear gene transcripts. The cell nucleus codes for ~ 1500 proteins involved in the biogenesis
of mitochondria, including structural subunits, enzyme assembly factors, proteins involved in the maintenance and expression
of mitochondrial DNA, and proteins involved the organelle biogenesis, fusion and fission. As a consequence, mitochondrial
diseases can be caused by mutations in either mtDNA or nuclear DNA, and are therefore inherited down the maternal line,
or as an autosomal dominant, recessive or X-linked trait.
The investigation of mitochondrial disease has typically taken a systematic approach involving clinical evaluation followed
by biochemical analysis of mitochondrial function. However, next generation sequencing approaches have revolutionised the
diagnostic algorithm. There are, however, certain caveats. MtDNA mutations are often heteroplasmic, and the proportion
of mutated to mtDNA varies from patient to patient and tissue to tissue. As a result the causative genetic defect may not
be present in blood and thus go undetected. A further complication is the broad clinical heterogeneity that characterises
mitochondrial diseases. The lack of a tight genotype-phenotype relationship makes it challenging to directly ascribe causation
for a novel genetic defect, particularly for novel heterozygous variants. However, the growth of international databases
combining clinical and genetic data is helping to resolve this issue. This is, in part, being achieved through the Genomics
England 100,000 Genomes Project where mitochondrial disorders form a major clinical sub-group
[Biography]
Patrick Chinnery FMedSci is a clinical neurologist with a sub-specialist interest in neurogenetics. A Wellcome Trust Senior
Fellow in Clinical Science, he has been studying the molecular and biochemical basis of mitochondrial disorders for over
two decades. Until recently he was Director of the Institute of Genetic Medicine and NIHR Biomedical Research Centre
at Newcastle University. In 2015 he moved to the University of Cambridge as Professor of Neurology and Head of the
Department of Clinical Neurosciences. His research laboratory is within the MRC Mitochondrial Biology Unit. He is an NIHR
Senior Investigator (2010), was awarded the Foulkes Foundation Medal by the Academy of Medical Sciences (2011), and is
a corresponding fellow of the American Neurological Association. He jointly chairs the NIHR Rare Diseases Translational
Research Collaboration, and is Chair of the Uk MRC Neurosciences and Mental Health Board.
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Tue(3)-CIS20-4
Genomics of amyotrophic lateral sclerosis and frontotemporal dementia
1
Bryan J. Traynor
1:Laboratory of Neurogenetics, National Institute on Aging, USA

Amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease) is a fatal neurodegenerative disorder that leads to rapidly pro-
gressive paralysis and respiratory failure. ALS is the third most common neurodegenerative disease in the Western World,
and there are currently no effective therapies. Frontotemporal dementia (FTD) is the most common form of dementia in
the population under the age of 65. An overlap between these two clinically distinct neurological diseases has long been
recognized, but the molecular basis of this intersection was unknown.
In 2011, a hexanucleotide repeat expansion was identified as a major genetic cause of both ALS and FTD. This is the most
common genetic cause of both ALS and FTD identified to date, accounting for approximately 40% of all familial cases of ALS
and FTD in European and North American populations. Further, this mutation underlies about 8% of cases of sporadically
occurring ALS and FTD that lack a family history, representing the first time that a common genetic cause has been identified
for the sporadic form of these diseases. The same large hexanucleotide repeat expansion is found in ~ 1% of patients clinically
diagnosed with Alzheimer’s disease cases.
The discovery of the C9ORF72 hexanucleotide repeat expansion is a landmark discovery in our understanding of neurodegen-
erative disease. It has already greatly effected how these diseases are diagnosed, investigated and perceived, and it provides
a mechanistic link between two clinically distinct disorders, ALS and FTD. It also provides a distinct therapeutic target for
gene therapy efforts aimed at ameliorating the disease, and such efforts are already well underway.
[Biography]
Dr. Bryan Traynor, M.D., Ph.D., is an Irish neurologist currently working in the USA. He is a Senior Investigator at the
National Institute on Aging, and also adjunct faculty at Johns Hopkins University. Dr. Traynor is best known for his work
aimed at understanding the genetic etiology of ALS. He led the international consortium that identified pathogenic repeat
expansions in C9ORF72 as a common cause of ALS and FTD. He has over a 160 publications in professional journals, and
has received numerous awards for his work including the NIH Director’s award, the Derek Denny-Brown award, and both the
Sheila Essey award and the Potamkin Prize from the American Academy of Neurology.
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ICHG2016 255

NGS Dissecting Human Genetic Diseases
Wed., April 06, 2016 10:15-12:15 Annex 1 (1F)
Convener：Naomichi Matsumoto（Department of Human Genetics, Yokohama City University Graduate School of

Medicine, Japan）
Convener ：Xue Zhang（McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences & Peking

Next generation sequencers (NGSs) make a huge impact on human genetics researches. After the initial success of
identifying culprit mutations for Miller syndrome and Charcot-Marie-Tooth disease in 2010, whole exome sequencing
(WES) and whole genome sequencing (WGS) have become standard tools for investigation of genetic diseases in which
mutant genes are known or unknown. Now even clinical WES and WGS are available with affordable prices. In this
concurrent session, four speakers are invited from Asia, Middle East, North America and Europe to introduce you current
status of gene identification projects for human genetic diseases in the world.
Wed(4)-CIS21-1
Next Generation Sequencing dissecting human “genetic” diseases
1
Naomichi Matsumoto
1:Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan
Genome analysis in patients with genetic diseases has been developed and sophisticated together with technology advances.
The advent and frequent update of next generation sequencers (NGSs) can attain the appropriate accuracy for mutation
analysis and push genome analysis of human diseases into the new stages. We started NGS analysis in early 2009. To focus
on whole exome regions, we utilized exon capture methods such as SureSelect (Agilent). The current NGS protocol uses
100-108-bp pair-end reads and usually produces 6-7 Gb sequences (per one sample) could be enough for analysis of the whole
exome: 90 % of refseq coding regions are covered by 20 reads or more. Sequences are aligned by Novoalign, and nucleotide
changes are detected and annotated using GATK and ANNOVAR, respectively. More than 8000 exomes have been sequenced.
We have been successful in addressing culprit mutations in various Mendelian diseases as well as acquired diseases arising
from somatic mutations. During these researches, we witnessed high complexity of human genetic diseases due to genetic and
allelic heterogeneities. I will present some of our interesting data showing how NGS technologies brought us a new stage of
researches dissecting human genetic diseases.
[Biography]
[Name]
Naomichi Matsumoto
[Present Position]
Professor and Chair, Department of Human Genetics
[Institution]
Yokohama City University Granduate School of Medicine
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[Education]
Kyushu University School of Medicine, M.D., 1986
Nagasaki University Graduate School of Medical Science, Ph.D., 1997

[Career]
1986-1993: Obstetrics and Gynecology Practice at Kyushu University and related Hospitals
1997-2000: Postdoctoral Fellow and Research Associate at University of Chicago
2000-2003: Associate Professor at Department of Human Genetics, Nagasaki University Graduate School of Biomedical
Sciences
2003-present: Professor and Chair at Department of Human Genetics, Yokohama City University graduate School of Medicine
[Academic post]
2007-2012: Guest Professor at Central South University, Changsha, Hunan, China
Editorial Board: J Hum Genet (2007-) (Editor-in-Chief 2014-), Clin Genet (2005-), Am J Med Genet Part A (2008-), Hum
Genet (2015-)
[Research area]
Molecular genetics and cytogenetics
Mendelian diseases
Genome analysis technology
[Honors and awards]
2003 Japan Society of Human Genetics Award for Young Scientist
2011 Japan Society of Human Genetics Award
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Wed(4)-CIS21-2
Exome analysis of autosomal recessive disorders
1,2
Fowzan S. Alkuraya
1:Genetics, King Faisal Specialist Hospital and Research Center, Saudi Arabia、2:College of Medicine, Alfaisal Uni-
versity

Exome sequencing has now been established as a powerful tool to identify Mendelian mutations. In a country like Saudi
Arabia where consanguinity and large family size are the norm, autosomal recessive disorders dominate the genetic landscape.
Not only does this unique setup facilitate the discovery of autosomal recessive mutations, including those in novel genes,
but it can also provide valuable additional information. These include the opportunity to revisit disease-gene links in light
of asymptomatic individuals who are “knocked out” for the genes in question, the use of positional mapping to guide the
identification of mutations that are difficult otherwise to be picked up by exome sequencing, and calculating the theoretical
maximum yield of exome sequencing in the setting of autosomal recessive phenotypes. Also discussed in this presentation will
be some of the lessons learned from analyzing >1,500 exomes for various recessive Mendelian phenotypes.
[Biography]
Fowzan Alkuraya is a Professor of Human Genetics at Alfaisal University and a Senior Consultant and Principal Clinical
Scientist at King Faisal Specialist Hospital and Research Center. He graduated with first class honor and was the valedictorian
of his class at the College of Medicine, King Saud University, Riyadh, Saudi Arabia. He did a residency in pediatrics at
Georgetown University Hospital, followed by a fellowship in clinical genetics and another in molecular genetics at Harvard
Medical School. He also did a postdoctoral research fellowship in the area of developmental genetics in the lab of Prof.
Richard Maas at Harvard Medical School. He returned to Saudi Arabia in late 2007 to establish the Developmental Genetics
Lab at KFSHRC, which he still directs. He is an authority in the area of Mendelian genetics with more than 245 published
manuscripts that describe his lab’s discovery of more than 150 novel disease genes in humans. He is a frequently invited
speaker at local, regional and international conferences, on the editorial board of prominent human genetics journals, and the
recipient of numerous prestigious awards including William King Bowes Award in Medical Genetics and King Salman Award
for Disability Research.
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Wed(4)-CIS21-3
PhenoDB and GeneMatcher, solving unsolved whole exome data
1
Nara Lygia M. Sobreira
1:McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, USA

To address some of the unsolved whole exome data, we reanalyzed the WES data from 1063 samples for rare (MAF <1%)
functional variants (missense, nonsense, frameshift and splicing) in known imprinted genes, in the genes on pseudoautosomal
regions, genes that escape X-inactivation, and genes on chromosome Y. We found that the genes in the pseudoautosomal
regions are not captured by the Agilent SureSelect v4 baits that we used to sequence these samples. The analysis of variants
in the genes on chromosome Y identified 30 rare functional variants, the analysis of variants in the 246 genes with known
imprinting data identified 2,377 rare functional variants, and the analysis of genes that scape X-inactivation identified 785
rare functional variants. These variants are being further evaluated to define causality. To facilitate data sharing as well
as improve the search for patients or model organisms with variants in specific candidate genes we have also been adding
capabilities to GeneMatcher (www.genematcher.org). In GeneMatcher there is an option to match based upon OMIM
number, genomic location and, as of October 2015, on phenotypic features. As part of the Matchmaker Exchange (MME)
(http://matchmakerexchange.org/), we have also developed an Application Programing Interface (API) that was implemented
in August 2015 and allows the GeneMatcher users to submit their data to query PhenomeCentral and/or DECIPHER. The
user has the option of querying one or both databases by gene names, genomic location, OMIM number and/or phenotype
information; the match is done automatically with submitters receiving simultaneous email notification, and follow-up is at
the discretion of the submitters. As of February 2016, 3,979 genes were submitted by 1,149 individuals from 48 countries
and generated 1,706 matches that have enabled collaborations and the description of novel Mendelian phenotypes and novel
Mendelian genes like SPATA5 , HNRNPK and TELO2.
[Biography]
Dr. Sobreira graduated from the University of Pernambuco School of Medicine, then completed Clinical Genetics Residency
at Paulista School of Medicine (UNIFESP). In 2007 she started her PhD in Human Genetics at Johns Hopkins School of
Medicine followed by an one year postdoc and a two years Clinical Genetics Fellowship also at Johns Hopkins School of
Medicine. While at Johns Hopkins School of Medicine she worked with Dr. David Valle on using next generation sequencing
to elucidate the molecular basis of rare Mendelian phenotypes. During the last six years she has also worked with Dr. Ada
Hamosh as a Volunteer Contributor in OMIM where she is now Deputy Scientific Director for Phenotypes. At present, Dr.
Sobreira is an Assistant Professor of Pediatrics at Johns Hopkins School of Medicine with primary interest rare Mendelian
phenotypes and analysis of next generation sequencing. Dr. Sobreira clinical and research focus is on identifying the molecular
basis of phenotypes associated to enchondromatosis and understanding the physiopathology of these phenotypes to investigate
ways to treat them. She is also one of the creators of PhenoDB and GeneMatcher. A member of the American Society of
Human Genetics, Dr. Sobreira has published numerous peer-reviewed journal articles and has presented her work at national
and international meetings. Dr. Sobreira is member of the ClinGen Consortium acting at the ClinGen Actionability Working
Group and a member of the Matchmaker Exchange.
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Wed(4)-CIS21-4
Understanding the causes of inherited rare diseases
1
William Newman
1:Manchester Centre for Genomic Medicine, University of Manchester, UK

Next generation sequencing has transformed the identification of disease-causing genes underpinning rare inherited conditions.
In this talk I will share my experience of applying exome and genome sequencing to define a number of disorders including
urofacial syndrome, multiple meningiomas, Gorlin syndrome, Burn-McKeown syndrome and Heimler syndrome. I will
illustrate the different approaches that we have used, emphasise the importance of phenotyping, that success can be achieved
with a very small number of cases and the data can present some unexpected surprises. Further, I will show how the
emergent data has led in some disorders to improved clinical management
[Biography]
I am a clinician scientist in Genomic Medicine at the Manchesetr Centre for Genomic Medicine (http://www.manchester.ac.uk/research/
I trained in Manchester, UK and Toronto, Canada. I have used different technologies, including SNP arrays and next
generation sequencing to identify novel genes responsible for a number of rare inherited conditions. I have established a
Genome Clinic to use next generation sequencing to diagnose conditions that it was previously challenging to correctly
define. I am the current chair of the British Society of Genetic Medicine and lead the Manchester Centre for the 100,000
Genomes Project (http://www.genomicsengland.co.uk).
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Epigenetic Inheritance and Reprogramming in Biology and Disease
Wed., April 06, 2016 10:15-12:15 Annex 2 (1F)
Convener：Hiroyuki Sasaki（Medical Institute of Bioregulation, Kyushu University, Japan）

Convener ：Anne Ferguson-Smith（Department of Genetics, University of Cambridge, UK）

In this session, we discuss our latest knowledge regarding the regulation of the transcriptome and epigenome of human
tissues and cells, with a special reference to epigenetic reprogramming, trans-generational inheritance, and epigenetics-
related congenital disease. Fuchou Tang talks about the transcriptome and DNA methylome landscape of human germ
cells and pre-implantation embryos, providing insights into the critical features of the methylome of these tissues, as well
as its functional relationship with the regulation of gene expression and the repression of transposable elements. Hiroyuki
Sasaki presents data showing that human placenta retains some of the asymmetry of the methylome between the male
and female gametes, which results in placenta-specific imprinted genes unique to humans. Masayo Kagami’s work focuses
on imprinting-related disorders, especially those involving the imprinted genes on human chromosome 14, revealing the
mechanisms regulating the gene cluster and the genotype-phenotype relationship. Lastly, Anne Ferguson-Smith talks
about the effects of in utero undernourishment on the adult sperm methylome, which can be associated with metabolic
disease in offspring. We discuss the roles of epigenetic inheritance and reprogramming in human biology and disease.
Wed(4)-CIS22-1
Epigenetic regulation of gene expression network in human germline cells
1
Fuchou Tang
1:BIOPIC, College of Life Sciences, Peking University, China
Measuring gene expression in individual cells is crucial for understanding the gene regulatory network controlling human
embryonic development. We applied single-cell RNA -Seq analysis to human preimplantation embryos, primordial germ cells
(PGCs), and human embryonic stem cells (hESCs). We also systematically profiled the DNA methylome of human early
embryos from the zygotic stage through to post-implantation. We showed that the major wave of genome-wide demethylation
is complete at the 2-cell stage, contrary to previous observations in mice. Moreover, the demethylation of the paternal genome
was much faster than that of the maternal genome, and by the end of the zygotic stage the genome-wide methylation level in
male pronuclei was already lower than that in female pronuclei. Then we also showed that long interspersed nuclear elements
(LINEs) or short interspersed nuclear elements (SINEs) that were evolutionarily young are demethylated to a milder extent
compared to older elements in the same family and had higher abundance of transcripts, indicating that early embryos tend
to retain higher residual methylation at the evolutionarily younger and more active transposable elements. Furthermore, we
analyzed the DNA methylome of human PGCs and found global demethylation of their genomes. Approximately 10 to 11
weeks after gestation, the PGCs were nearly devoid of any DNA methylation, whereas the repeat elements still kept high
level of residual methylation. We also systematically analyzed the chromatin state during PGC development by NOME-seq
analysis. Our work provides insights of critical features of the transcriptome and DNA methylome landscapes of human early
embryos and primordial germ cells, as well as the functional significance of DNA methylome to regulation of gene expression
and repression of transposable elements.
[Biography]
Fuchou Tang received his Ph.D. degree from Peking University in 2003. He joined BIOPIC of Peking University as a group
leader in 2010. His lab focuses on studying gene regulation network in human early embryos. His lab demonstrated the proof
of principle for the MALBAC-based pre-implantation genomic screening in in vitro fertilization (IVF), which allowed accurate
and cost-effective selection of an oocyte free from aneuploidy, as well as Mendelian diseases associated alleles (Cell, 2013).
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Furthermore, his lab analysed the dynamics of gene expression network in human pre-implantation embryos at single-cell
and single-base resolution (Nature Structural & Molecular Biology, 2013). His lab also developed single cell DNA methylome
analysis technique (Genome Research, 2013) and analysed the dynamics of DNA methylome in human pre-implantation
embryos as well as primordial germ cells, which provides new insights into the critical features of the methylome of human
early embryos and primordial germ cells, as well as its functional relation to the regulation of gene expression and the
repression of transposable elements (Nature, 2014; Cell, 2015).
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Wed(4)-CIS22-2
Incomplete reprogramming of germline DNA methylation in the human placenta
Hiroyuki Sasaki 1 ，Hirotaka Hamada 2 ，Hiroaki Okae 2 ，Hidehiro Too 1 ，Hatsune Chiba 2 ，
Hitoshi Hiura 2 ，Kenjiro Shirane 1 ，Tetsuya Sato 1 ，Mikita Suyama 1 ，Nobuo Yaegashi 3 ，
Takahiro Arima 2
1:Medical Institute of Bioregulation, Kyushu University, Japan、2:Environment and Genome Research Center, Tohoku

University Graduate School of Medicine、3:Departments of Obstetrics and Gynecology, Tohoku University Graduate
School of Medicine
DNA methylation is globally reprogrammed after fertilization and as a result the parental genomes have similar DNA methy-
lation profiles after implantation except at the germline differentially methylated regions (gDMRs). We, and others, have
previously shown that there are a large number of transient gDMRs in human blastocysts, whose differential methylation is
lost in embryonic tissues after implantation. In this study, we performed genome-wide allelic DNA methylation analyses of
purified trophoblast cells from human placentas. Surprisingly, about one-third of the transient-in-embryo gDMRs maintained
their parent-of-origin-dependent allelic DNA methylation. RNA sequencing-based allelic expression analyses revealed that
some of the placenta-specific gDMRs were associated with novel imprinted genes. This approach also identified the first
examples of X-linked gDMRs. Comparisons of the data with those from other mammals revealed that genomic imprinting
in the placenta is highly variable. These findings highlight the incomplete reprogramming of germline DNA methylation
in the human placenta, which may be important for understanding normal placental development and the pathogenesis of
developmental disorders with imprinting effects.
[Biography]
Hiroyuki Sasaki is a Vice President of Kyushu University, the Director and a Distinguished Professor of Medical Institute
of Bioregulation, Kyushu University, Fukuoka, Japan. He graduated from Kyushu University Medical School in 1982 and
obtained his PhD in 1987. Dr Sasaki’s research focuses on the regulation of the mammalian epigenome in germ cells and
early embryos. He is particularly interested in DNA methylation and small RNA-based mechanisms and studies genomic
imprinting as a model system. He is the former President of the Japanese Society for Epigenetics and currently serves as
a board member of the Japan Society of Human Genetics, a Vice President of the Molecular Biology Society of Japan, a
member of the International Science Steering Committee of the International Human Epigenome Consortium. He received
the Japan Society of Human Genetics Award in 2009, the Genetics Society of Japan Kihara Award in 2012, and a Purple
Ribbon Medal of Honor in 2015.
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Wed(4)-CIS22-3
Kagami-Ogata syndrome: Clinically recognizable imprinting disorder caused by
upd(14)pat and related condition
Masayo Kagami 1 ，Tsutomu Ogata 1,2
1:Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Japan、

2:Department of Pediatrics, Hamamatsu University School of Medicine
Human chromosome 14q32.2 carries paternally expressed genes such as DLK1 and RTL1 and maternally expressed genes
such as MEG3 and RTL1as together with the germline-derived DLK1-MEG3 intergenic differentially methylated region (IG-
DMR) and the postfertilization-derived MEG3 -DMR. Consistent with this, paternal uniparental disomy 14 (upd(14)pat),
and epimutations and microdeletions affecting the IG-DMR and/or the MEG3 -DMR of maternal origin, result in a unique
phenotype characterized by facial abnormality, small bell-shaped thorax with
coat-hanger appearance of the ribs, abdominal wall defects, placentomegaly and polyhydramnios.
Recently, this clinically recognizable disorder has been named "Kagami-Ogata syndrome" (KOS) (OMIM 608149). Here,
we review the current knowledge about KOS. Important findings include: (1) upd(14)pat accounts for ~ two-thirds of
KOS patients, and epimutations and microdeletions are identified with as similar frequency; (2) the facial "Gestalt" and
the increased coat hanger angle constitute pathognomic features from infancy through childhood; (3) the hypomethylated
IG-DMR and MEG3 -DMR of maternal origin function as imprinting control centers in the placenta
and the body respectively, with a hierarchical interaction governed by the IG-DMR for the methylation pattern of the
MEG3 -DMR in the body; (4) RTL1 expression level becomes ~ 2.5 times increased in the absence of functional RTL1as-
encoded microRNAs that act as a trans-acting repressor for RTL1 ; and (5) excessive RTL1 expression constitutes the primary
underlying factor for the placental phenotypic development of KOS. Furthermore, we propose the clinical diagnostic criteria
and the f1ow chart for the molecular diagnosis.
[Biography]
Work experience
Dates: [2012-Present]
Name and address of employer: National Research Institute for Child Health and Development, Tokyo, Japan
Type of business or sector: Department of Molecular Endocrinology, Clinical Endocrine Reserch Division
Occupation or position held: Chief
Main activities and responsibilities: Group Head
Dates: [2010-2012]
Occupation or position held: Senior Investigator
Main activities and responsibilities: Research Fellow
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Dates: [2005-2010]
Occupation or position held: Postdoctoral Research Fellow
Main activities and responsibilities: Research Fellow

Dates: [1994-1999]
Name and address of employer: Department of Pediatrics, Hokkaido University School of Medicine (University Hospital,
Hakodategoryoukaku Hospital, Asahikawa City Hospital, Kushiro Red Cross Hospital and Nakashibetu Town Hospital)
Type of business or sector: Pediatrics
Main activities and responsibilities: Medical doctor
Education
Dates: [1999-2003]
Name and type of organisation providing education: Graduate School of Medicine, Hokkaido University, Sapporo, Japan
Principal subjects: Pediatrics
Title of qualification awarded: Ph. D
Dates: [1988-1994]
Name and type of organisation providing education: Asahikawa Medical University, Asahikawa, Japan
Principal subjects: Medicine
Title of qualification awarded: M.D.
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Wed(4)-CIS22-4
Establishment and maintenance of stable and variable epigenetic states in mammals
1
Anne Ferguson-Smith
1:Department of Genetics, University of Cambridge, UK

Animal models and epidemiological data indicate that phenotypes resulting from adverse environments can be transmit-
ted from one generation to another. Current dogma implicates epigenetic inheritance, but the precise mechanisms remain
difficult to determine. In an intergenerational developmental programming model affecting F2 mouse metabolism, we demon-
strated that the in utero nutritional environment of F1 embryos alters the DNA methylome of the F1 adult male sperm in a
locus-specific manner. However, differential methylation is not heritably transmitted to F2 tissues even though locus-specific
expression is perturbed. (Radford et al., Science 2014). Such environmental perturbation models offer challenges for under-
standing mechanisms of epigenetic inheritance across generations. We have therefore developed a novel murine genetic model
in order to understand fundamental properties of transgenerational epigenetic inheritance. This work will be presented.
[Biography]
Anne C. Ferguson-Smith is the Arthur Balfour Professor of Genetics at the University of Cambridge, UK, and is Head of the
Department of Genetics. She received her PhD from the Department of Biology at Yale University studying the functional
genomic organisation of mammalian Hox clusters. For the past two decades, her team has studied genomic imprinting in
development and disease, but more recently, their work has been focusing on the epigenetic control of genome function in a
wider context. Her current research focuses on three themes - stem cells and the epigenetic programme; genome-epigenome
interactions; and mammalian development, environment and disease. She is a Wellcome Trust Senior Investigator, an elected
member of EMBO and a Fellow of the UK Academy of Medical Sciences.
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Pharmacogenomics
Wed., April 06, 2016 10:15-12:15 Room A (2F)
Convener：Taisei Mushiroda（Research Group for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences,
Japan）
Convener ：Munir Pirmohamed（Department of Molecular and Clinical Pharmacology, University of Liverpool, UK）

Responses to drugs vary widely. Lack of efficacy of a drug can lead to inadequate control of disease and is a waste of
resources. Conversely, adverse drug reactions (ADRs) are frequent and often unpredictable. Many genetic polymorphisms
have been identified in genes that affect efficacy or risk of ADRs for various drugs. In USA, information on about 125
germline genomic biomarkers is available in US FDA-approved drug labels. In particular, US FDA strongly recommends
genotyping for polymorphisms in drug-metabolizing enzymes and HLA alleles prior to drug administration for several
drugs, such as eliglustat, nilotinib, pimozide, tetrabenazine, carbamazepine and lapatinib. One of the issues facing all of
us is implementation of an evidenced-based clinical practice using the genomic biomarkers. In order to establish PGx-
based individualization of drug therapy, the advantages of genomic biomarkers need to be demonstrated with respect to
clinical validity, clinical utility and pharmacoeconomics. In this session, lectures will be delivered by researchers in Asia,
Europe and Africa working on genomic biomarkers, from discovery to application to improve drug therapy.
Wed(4)-CIS23-1
Prediction of severe adverse drug reactions using pharmacogenomic biomarkers: Cur-
rent status and future prospects in Japan
Yoshiro Saito 1 ，Keiko Maekawa 1 ，Ryosuke Nakamura 1
1:Medicinal Safety Science, National Institute of Health Sciences, Japan
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions induced by
many drugs. In 2006, we started a case-control study to clarify the associations between genomic information including HLA
genotypes (and other SNPs) and the susceptibility of SJS/TEN in Japanese patients. First, we constructed a nation-wide case
collection network under the cooperation of the Japanese regulatory agencies (Ministry of Health, Labour and Welfare, and
Pharmaceuticals and Medical Devices Agency) and Federation of Pharmaceutical Manufacturers’ Association of Japan. For
the past 9 years, we have collected 244 definite and 41 probable cases diagnosed as SJS/TEN by dermatologists in our team. We
used allele frequencies of healthy Japanese population as a control. We have identified the following associations: HLA-B*58:01
for allopurinol cases, HLA-B*15:11 for carbamazepine cases, HLA-A*02:07 for zonisamide cases (collaboration with RIKEN),
HLA-B*51:01 for phenobarbital cases (collaboration with RIKEN), HLA-A*02:06 for cold-medicine cases (collaboration with
Kyoto Prefectural University of Medicine) and CYP2C9*3 for phenytoin cases (collaboration with Chang Gung Memorial
Hospital, Taiwan). In addition, Riken group clearly showed that HLA-A*31:01 was associated with carbamazepine-induced
cutaneous adverse reactions and our group was replicated this finding using SJS/TEN cases. By GWAS analysis using Illumina
Human DNA Analysis BeadChip, we found several SNPs strongly linked with HLA-B*58:01 or HLA-A*31:01 , which can
be used as surrogate markers for the HLA genotypes. We developed an easy and robust PCR-RFLP assay for genotyping
rs9263726, a SNP absolutely linked with HLA-B*58:01 and rs3869066 linked with HLA-A*31:01 in Japanese SJS/TEN
patients. Regulatory implementation of the pharmacogenomic results will be summarized and future prospects in Japan will
also be proposed in this presentation.
[Biography]
Yoshiro Saito, PhD
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Position: Director, Division of Medicinal Safety Science, National Institute of Health Sciences (NIHS), Ministry of Health,
Labour and Welfare (MHLW).
Visiting Professor, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan
Visiting Professor, Graduate School of Pharmaceutical Sciences, Teikyo Heisei University, Japan

Education
1989 M.Sc. (Pharmaceutical Sciences), Graduate Shool of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
1996 Ph.D. (Pharmaceutical Sciences), Graduate Shool of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Positions
1989 ~ 1998 Researcher, Division of Biochemistry and Immunochemistry, NIHS.
1998 ~ 2000 Post-Doctoral Fellow, Department of Biochemisty, Faculty of Medicine, University of Toronto, Toronto, ON,
Canada.
2000 ~ 2001 Senior Researcher, Division of Biochemistry and Immunochemistry, NIHS.
2001 ~ 2009 Section Chief, Division of Functional Biochemistry and Gnomics, NIHS.
2009 ~ 2010 Section Chief, Division of Medicinal Safety Science, NIHS.
2010 ~ current Director, Division of Medicinal Safety Science, NIHS
Original Papers: 167, Review: 36
Award:
2008 Award for Young Scientists (The Japanese Society of Immunotoxicology)
2009 Award for Young Scientists (The Japanese Society for the Study of Xenobiotics)
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Wed(4)-CIS23-2
Genomic Diversity of African populations and pharmacogenomics in the safe and effi-
cacious use of efavirenz in the treatment of HIV/AIDS
1
Collen Masimirembwa
1:African Institute of Biomedical Science and Technology, Zimbabwe

Background: Genomic studies in Caucasian and Asian populations have uncovered genetic variability of importance in disease
diagnosis and treatment. There is however little data on the genomic diversity of African populations and its implications for
medicine.Aim: To explore the genetic diversity of African populations and to investigate the pharmcogenetics of efavirenz in
the treatment of HIV/AIDS. Methods: Two thousand DNA samples from unrelated individuals belonging to 10 major African
ethnic groups, the Yoruba, Ibo and Hausa from Nigeria, the Kikuyu, Luo and Masaai from Kenya, the Shona, Ndebele and
San from Zimbabwe, and the Venda from South Africa. The samples were genotyped using the Illumina 600K SNP microarray
chip and for 20 SNPs in 6 important pharmacogenes (NAT-2, FMO, CYP2B6, CYP2D6, CYP2C19, GSTM) using standard
PCR. The data were analyzed using principal component analysis. The pharmacogenetics of efavirenz, were studied in a
cohort of 500 HIV/AIDS patients. A pharmacogenetics guided dosing algorithm was derived using pharmacometric modeling.
Cost-effective analysis (CEA) was done to assess the potential value of the algorithm in the use of efavirenz. Results and
Discussion: Population genotyping confirmed, with greater resolution, the genetic diversity of African populations compared
to Caucasian and Asian populations. The diversity and structure was also reproduced when analyzing genetic variants in
genes known to be important in drug safety and efficacy. The results of the efavirenz pharmacogenetics study showed that
the low activity CYP2B6*6 variant is more prevalent in African populations, which correlated with more patients having high
drug concentrations and higher incidences of CNS side effects. The pharmacogenetics guided dosing algorithm showed that
patients homozygous for the CYP2B6*6 required 200 mg/day of efavirenz compared to the standard dose of 600 mg/day. We
showed that 20% of Africans are homozygous for the CYP2B6*6.
[Biography]
Collen Masimirembwa is the founding President and Chief Scientific Officer of the African Institute of Biomedical Science and
Technology (AiBST). He is a biochemical pharmacologist trained at the University of Zimbabwe and the Karolinska Institute
in Sweden. After a postdoctoral fellowship at Uppsala University he joined AstraZeneca in Sweden where he worked as a
Principal Scientist in DMPK and Bioanalytical Chemistry for 10 years. He has made important innovative contributions
in drug metabolism and pharmacokinetics (PK) & pharmacogenetics (PGX) research and has published over 80 original
research papers in peer-reviewed journals. He has discovered genetic variants of drug metabolizing enzymes which are unique
to African populations and could have clinical implications in the safe use of medicines in these populations. To scale up
the conduct of genomics research in Africa, he has established a Biobank of African populations and cohorts of patients on
different treatment and treatment responses. Collen contributes to international research capacity and capability building
through membership of local and international organizations such as IUPHAR and is a Fellow of the Zimbabwe Academy
of Sciences and the African Academy of Sciences. He is an Honorary Professor at the University of Cape Town and at the
University of KwaZulu Natal in South Africa.
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Wed(4)-CIS23-3
Move Pharmacogenomics Discovery to Medical Practice
1,2
Yuan-Tsong Chen
1:Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Department of Pediatrics, Duke University,
Durham, NC, USA、2:Department of Pediatrics, Duke University, Durham, NC USA

Pharmacogenomics aims to investigate the genetic basis of inter-individual differences in drug responses, such as efficacy, dose
requirements and adverse events. Research in pharmacogenomics has grown over the past decade, evolving from a candidate-
gene approach to genome-wide association studies and next- generation sequencing. Genetic variations affect drug responses
can be divided into two types: acquired variants (i.e., somatic mutation in cancer) and inherited variants (i.e., germ-line
genetic variants). Somatic variants are frequently associated with the development or progression of cancer, and drugs have
been developed to target the specific mutations carried by the tumors, so called target therapy, which has recently been
adopted in clinic management of cancer. Germ-line variants of genes encoding drug-metabolizing enzymes, drug transporters,
drug targets, and human-leukocyte antigen (HLA) can affect individual response to medications. Because of the impact of
genetic variants on medication responses, how to give the “right drug” at the “right dose” for the “right patient” is a major
goal in the era of precision medicine. This presentation will focus on the pharmacogenomics of adverse drug reactions, the
underlying mechanisms and the potential use of genomic biomarkers in clinical practice for dose adjustment and the avoidance
of drug toxicity. Obstacles to the implementation of pharmacogenomics and the direction of future translational research will
also be discussed.
[Biography]
Professor Yuan-Tsong (Y-T) Chen received his MD degree from National Taiwan University and PhD from Columbia Univer-
sity. He is a Distinguished Research Fellow and Director Emeritus of the Institute of Biomedical Sciences, Academia Sinica,
Taiwan and also a tenured Professor of Pediatrics of Duke University.
Professor Chen is a physician/scientist, recognized for his work on human genetic disorders. His translational research leads to
the development of now standard therapies for two devastating inherited metabolic diseases: a simple and effective cornstarch
therapy for severe hypoglycemia in glycogen storage diseases and Myozyme  , a drug for a debilitating, progressive and often
fatal myopathy called Pompe disease.
Professor Chen has also identified the genetic basis of and developed DNA-based diagnosis for several major heritable dis-
eases, and more recently, his research focuses on the pharmacogenetics of adverse drug reactions and drug efficacy. His team
has discovered the genetic basis of Stevens-Johnson syndrome and toxic epidermal necrolysis, two of the most serious drug
hypersensitivity reactions. They have also identified gene variants associated with warfarin sensitivity and an algorithm for
warfarin dosage determination. By using genetic information to guide the choice of the drug and its dose, his research has
led to safer and more effective use of drugs. Professor Chen is an elected member of Academia Sinica and an elected member
of the World Academy of Sciences.
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Wed(4)-CIS23-4
Pharmacogenomics: The long journey from discovery to implementation
1
Munir Pirmohamed
1:Department of Molecular and Clinical Pharmacology, University of Liverpool, UK

Pharmacogenetics/genomics has been around for a long time: although this has led to many discoveries, i.e. associations
between phenotypes (drug efficacy and safety) and genotypes, translation of these discoveries into clinical practice has been
poor. Lack of robust evidence is cited as the main reason. In other clinical areas, the randomised controlled trial is often
regarded as the top of the evidence hierarchy, but very few trials have been undertaken in pharmacogenomics. Undertaking
a RCT for a pharmacogenomics phenotype is more complicated than undertaking a conventional RCT - apart from the
usual factors such as design, sample size, clinical outcome measures, and follow-up, additional factors such as how patients
will be genotyped, how genotype will affect drug dose/choice, whether it will be cost-effective, and how many patients will
need to be screened to identify those that fit with the inclusion criteria, all need to be considered. These additional factors
inevitably also make it much more expensive to undertake pharmacogenomics-based RCTs. An additional factor that needs
to be considered is the frequency of the phenotype, especially in the case of rare adverse events, where it may be impossible to
undertake a RCT or even a prospective cohort study. In order to improve the translation of laboratory findings into the clinic,
we need to consider different forms of evidence in a more intelligent, rather than purely relying on a hierarchy of evidence.
Implementation into clinical practice also requires a knowledge of the clinical pathways which may vary according to local and
regional healthcare differences, national healthcare models and of course internationally. Re-engineering of clinical pathways
is often necessary to ensure adoption of any innovation into the healthcare system.
[Biography]
Professor Sir Munir Pirmohamed is currently David Weatherall Chair in Medicine at the University of Liverpool, and a
Consultant Physician at the Royal Liverpool University Hospital. He is also the Associate Executive Pro Vice Chancellor
for Clinical Research for the Faculty of Health and Life Sciences. He also holds the only NHS Chair of Pharmacogenetics in
the UK, and is Director of the M.R.C. Centre for Drug Safety Sciences, and Director of the Wolfson Centre for Personalised
Medicine. He was awarded a Knights Bachelor in the Queen’s Birthday Honours list in 2015. He is also an inaugural NIHR
Senior Investigator, and Fellow of the Academy of Medical Sciences in the UK. He is also a Commissioner on Human Medicines.
His research focuses on personalised medicine in order to optimise drug efficacy and minimise toxicity, move discoveries from
the lab to the clinic, and from clinic to application. He has authored over 380 peer-reviewed publications, and has a H-index
of 78.
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The new world of RNA biology: Emerging roles of IncRNAs and RNA modifications
Wed., April 06, 2016 10:15-12:15 Room E (1F)
Convener：Yukio Kawahara（Department of RNA Biology and Neuroscience, Graduate School of Medicine, Osaka Uni-
versity, Japan）
Convener ：Marcel Dinger（Kinghorn Centre for Clinical Genomics (KCCG) and St Vincent’s Clinical School, Faculty of

The human genome contains about 20,000 protein-coding genes, similar in number and functional repertoire to those in
other animals, including nematodes. By contrast, the extent of non-coding DNA increases with increasing developmental
complexity, reaching 98.5% in humans. The vast majority of these sequences are differentially transcribed during develop-
ment to produce large numbers of short and long noncoding RNAs (lncRNAs) that are antisense, intergenic or intronic to
protein-coding loci. Unlike miRNAs, whose role in translational regulation is well established, the functions of lncRNAs,
which range from a few hundred bases to over 100 kb in length, are poorly understood. Some lncRNAs are components
of enigmatic subnuclear domains in mammals, but most are highly species- and cell-specific, and appear to be involved
in chromosomal organization and guidance of epigenetic processes to control transcription and splicing, thereby acting
as regulatory switches for development and organogenesis. Moreover, recent advances have shown that abundant editing
and many chemical modifications occur in RNA, termed the epi-transcriptome, which may play important roles in the
dynamic modulation of the RNA structure-function relationships, and hence epigenetic plasticity, especially in the brain.
This session will present the latest discoveries in the field of lncRNAs and RNA modifications, with important implications
for future studies in human genetics, developmental biology and neuroscience.
Wed(4)-CIS24-1
Journeys through Space and Time: Ultra High-Resolution Expression Profiling of Long
Noncoding RNAs
Marcel Dinger 1 ，Ira Deveson 1 ，Nenad Bartonicek 1 ，Simon A Hardwick 1 ，Marcel E Dinger 1 ，
Tim R Mercer 1
1:Kinghorn Centre for Clinical Genomics (KCCG) and St Vincent’s Clinical School, Faculty of Medicine, UNSW,
Australia
Long noncoding RNAs (lncRNAs) are increasingly recognized as having key regulatory roles in development and disease.
However, these regulatory molecules often have short half lives and are expressed only in specific tissues or cell types,
resulting in the poor representation of lncRNAs in transcriptomic datasets and limiting the ability to study their biological
function. Using novel detection and sampling approaches, we reveal a high-resolution spatiotemportal view of the long
noncoding transcriptome that challenges existing paradigms of genome function and provides new insights into their roles in
development and disease.
[Biography]
Marcel is the Head of Genome Informatics and Clinical Genomics at the Garvan Institute of Medical Research In Sydney
and conjoint Associate Professor at UNSW Australia. After completing his PhD in New Zealand in 2005, he was awarded a
Postdoctoral Fellowship to study the role of long noncoding RNAs in mammalian development and disease at The University
of Queensland. In 2012, he was recruited to the Garvan Institute, where he now leads a laboratory investigating the function
of noncoding regions of the genome.
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Wed(4)-CIS24-2
Primate-specific A-to-I RNA editing shapes the transcriptome
Marie Öhman 1 ，Chammiran Daniel 1 ，Gilad Silberberg 1
1:Dept. of Molecular Biosciences, The WennerGren Institute, Stockholm University, Sweden

RNA editing by adenosine deamination is a widespread phenomenon, particularly frequent in the human transcriptome. The
ADAR enzymes recognize double-stranded RNA and catalyze the deamination of adenosines to inosines (A-to-I). Since inosine
is structurally similar to guanosine (G), cellular processes such as splicing and translation recognize I as G. Primates are par-
ticularly prone to A-to-I editing, largely due to the presence of inverted Alu repeats and their ability to form double-stranded
structures. A surprisingly large fraction of the human transcriptome contains inverted Alu repeats, typically occurring in
introns and UTRs of protein coding genes. We show that inverted Alu repeats, expressed in the primate brain, induce site-
selective editing in cis on sites located several hundred nucleotides from the Alu elements. Furthermore, a computational
analysis, finds that site-selective editing often occurs close to edited Alu elements. These targets are poorly edited upon dele-
tion of the editing inducers, as well as in homologous transcripts from organisms lacking Alus. This is particularly frequent
in zinc-finger containing transcription factors. We specifically show that a site specific editing event with functional effects
changing the coding sequence of the Glioma-associated oncogene 1 (GLI1) is unique to humans and perhaps closely related
primates, due to proximate Alu inverted repeats. GLI1 act as a transcriptional effector in the Hedgehog (HH) signaling
pathway. We here propose a model whereby primate-specific editing is induced by adjacent Alu elements that function as
recruitment elements for the ADAR editing enzymes. The enrichment of site-selective editing with potentially functional con-
sequences on the expression of transcription factors indicates that editing contributes more profoundly to the transcriptomic
regulation and repertoire in primates than previously thought.
[Biography]
Professor Marie Öhman is born 1964. She defended her thesis in 1993 at Stockholm University, Sweden on analysis of regula-
tory RNA. Since then RNA biology has been the theme of her research. She did her postdoctoral work at University of Utah
under the supervision of Professor Brenda Bass working on RNA modifications. Returning to Stockholm as an independent
researcher she continued her work on RNA editing, focusing on adenosine to inosine (A-to-I) RNA editing in transcripts
expressed in the mammalian brain. In 2010 she became a full professor at Stockholm University. Her major contribution to
the field of A-to-I editing has lately been through high throughput analyses of editing during brain development. She and her
research group have shown that RNA editing increase during brain maturation both in transcripts involved in neurotrans-
mission and brain specific non-coding RNAs such as miRNA. In addition she has identified novel sites of editing in the major
inhibitory receptor GABA-A that regulates receptor assembly and in miR-381 regulating dendrite out growth in neurons.
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Wed(4)-CIS24-3
The expanding landscape of mRNA methylation
1
Gideon Rechavi
1:Cancer Research Center, Sheba Medical Center Tel Aviv University, Israel

Epigenetic regulation traditionally denoted modifications of DNA and proteins. Nowadays mRNA modifications joined the
arena of epigenetics in the new field of epitranscriptomics.
An extensive repertoire of modifications is known to underlie the versatile coding, structural and catalytic functions of RNA.
Until recently, most data regarding RNA modifications were the result of studies of the abundant rRNA and tRNA species
while the knowledge regarding mRNA was scarce.
The best example of epitranscriptomic regulation came from the study of N6-methyladenosine (m6 A), the most prevalent
internal modification in messenger RNA. We analyzed the human and mouse m6 A modification landscape using a novel
approach, m6 A-seq, based on antibody-mediated capture and next generation sequencing. We identify over 12,000 m6 A
sites characterized by a typical consensus in the transcripts of more than 7,000 human genes. Sites preferentially appear in
two distinct landmarks—around stop codons and within long internal exons—and are highly conserved between human and
mouse. A subset of stimulus-dependent, dynamically modulated sites was identified alluding to a fundamental role for m6 A
in regulation of gene expression.
We recently studied the functional role of m6 A decoration in early stages of embryonic stem cell development . We showed that
Mettl3, an N6-methyladenosine transferase, acts as a regulator for terminating murine naïve pluripotency. m6 A predominantly
reduces mRNA stability, including that of key naïve pluripotency-promoting transcripts. These findings highlight a critical
role for mRNA epigenetic modulation in vivo and identify regulatory modules that functionally influence naïve and primed
pluripotency in an opposing mode.
New modifications are now joining the expanding epitranscriptomic field.
[Biography]
Gideon Rechavi was born in Israel. He received an MD from Tel‑Aviv University in 1981 and PhD from the Weizmann
Institute of Science in 1987. He is board certified in Hematology, Pediatrics, and Pediatric Hematology-Oncology.
He is Professor of Hematology and holds the Djerassi Chair in Oncology, Tel Aviv University. In 1991-1996 served as head of
the Division of Hematology, Sackler School of Medicine. In 2001-2007 he served as head of the Tel Aviv University Cancer
Biology Research Center.
In 1992 he was appointed head of the Pediatric Hematology‑ Oncology and Bone Marrow Transplantation Department
and in 1999 he established the Cancer Genomics Unit, the leading Israeli center for medical genomics.
In 2003 he established the Sheba Cancer Research Center which he heads.
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He is a member of the European Academy of Cancer Sciences.
He has published more than 450 articles in Nature, Science, Nature Genetics, Nature Medicine, Nature Cell Biology, Nature
Biotechnology, Nature Structural and Molecular Biology, New England Journal of Medicine and the Lancet.

He has been awarded numerous prizes including the Kennedy award, the Stein award, the Seroussi Memorial Cancer Research
award, the Prize for Vision in Medicine and the Elkales Prize for Distinctive Scientist in Medicine.
In 2013 he received the EMET prize for Genetics and the Beutler award for Excellence in Genomic Medicine.
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Wed(4)-CIS24-4
Role of RNA modification in cognition and memory
1
Timothy Bredy
1:University of California Irvine, USA

RNA modification has emerged as a novel layer of epigenetic control over gene expression that is perfectly suited to serve as a
key post-transcriptional regulator in the fine-tuning of gene expression related to adaptation. One of the most prevalent and
widely conserved RNA modifications, N6-methyladenosine (m6A), has been shown to be both dynamic and reversible, and is
present in neurons. However, whether this epitranscriptomic mechanism is fundamental for the regulation of gene expression
underlying learning and memory, has not been explored in any detail. Using m6A capture followed by RNA sequencing,
we have discovered an experience-dependent redistribution of m6A in the prefrontal cortex of mice. This epigenetic mark
accumulates in specific regions of the transcriptome and early evidence suggests that it may dictate the fate of messenger
RNAs and/or mRNA stability. Importantly, we have also found that the RNA demethylase, FTO, contributes to the formation
and maintenance of fear-related memory Thus, our preliminary data demonstrate the dynamic nature of the epitranscriptome
and suggest that, like DNA methylation, m6A is involved in the regulation of genes directly related to learning and memory.
[Biography]
Dr. Timothy Bredy is currently Assistant Professor in the Department of Neurobiology and Behavior at the University of
California at Irvine, and maintains a laboratory at the Queensland Brain Institute, since 2009. Dr. Bredys research program
spans the fields of epigenetics, neuroscience, and neuropsychiatry, and his recent work in cognitive neuroepigenetics has been
influential in understanding and elucidating the molecular mechanisms of how environmental stimuli and experience translate
into long-term memories, and how this is related to neuropsychiatric disorders such as phobia, PTSD and the addictions.
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Databases and Data Sharing for Cross-border Genomics
Thu., April 07, 2016 12:45-14:45 Annex 1 (1F)
Convener：Yasukazu Nakamura（Genome Informatics Laboratory, National Institute of Genetics, Japan）

Convener ：Guy Cochrane（European Nucleotide Archive/European Bioinformatics Institute (EMBL-EBI), UK）

In this session, we address the existing and emerging infrastructure and practices that serve global genomics data sharing.
With speakers representing major bioinformatics data resources, a key knowledge organisation technology, a large-scale
national medical genomics programme and a global genomics data initiative, we will explore technical and human aspects
of databases and data sharing.
Thu(5)-CIS25-1
Data coordination in cross-border genomics: A very human challenges
1
Guy Cochrane
1:European Nucleotide Archive/European Bioinformatics institute (EMBL-EBI), UK
Two people can easily share and discuss simple data files by e-mail. Add in a few more people to this sharing, some high
volume data sets typical of modern genomics and the complexity and diversity of current genomics methods, and the case for
greater rigour and formality around the data sharing rapidly becomes compelling. While technical infrastructure to support
global sharing is an important part any formal data sharing system, human activities around the data sharing are also key but
often neglected. These activities are broad, relating for example to the development of standards for the description of shared
data, the configuration, support and use of the interfaces for data sharing and the value addition through curation of shared
data. In the talk, I will relate some of the experiences gained in the operation of EMBL-EBI’s European Nucleotide Archive,
the European component of the global public sequence data sharing system. I will focus in particular on this resource’s
emergence as a platform for sharing and collaborative working around‘live’sequence data and on the concept of‘structured
data sharing’ in which early organisation and description of data sets facilitate onward use and reuse.
[Biography]
Dr. Guy Cochrane heads the European Nucleotide Archive (ENA; http://www.ebi.ac.uk/ena), a platform for the management,
sharing, integration and dissemination of sequence data. ENA includes, on the technical side, core databasing infrastructure
for the rapid archiving of petabytes of sequence data, the Webin data submission/validation application used by several
thousands of data providers, and sophisticated data discovery and retrieval tools used by many times this number. On the
content side, ENA offers extensive public domain data from over a million species. With a background in cancer research
and 12 years of experience in bioinformatics services, he has driven numerous developments both within and beyond ENA,
notably leading the development of next generation sequence data infrastructure and comprehensive submission, archiving
and presentation services in the late 2000s. As part of the team that initially explored reference-based compression for
sequence data, Guy has led development work on the CRAM framework (http://www.ebi.ac.uk/ena/software/cram-toolkit),
now adopted by the Global Alliance for Genomics and Health. An active player in the sequence informatics community, he
involved deeply in standards development work, established and coordinated the popular‘Wellcome Trust Next Generation
Hinxton Retreat’ series of annual workshops (2008-2013) and was editor of the Nucleic Acids Research Databases Collection
(2008-2011).
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Thu(5)-CIS25-2
Genome graphs: A new kind of reference from human genetic variation
1,2
David Haussler
1:UC Santa Cruz Genomics Institute, University of California, Santa Cruz、2:Howard Hughes Medical Institute

Despite the worldwide explosion of genome data, genomics still relies on a single, arbitrary representative haploid reference
human genome for nearly all its analysis. This leads to reference allele bias—the tendency to over-report alleles present in the
reference and miss ones that are not. In fact, some variants simply cannot be described with respect to the reference genome;
these constitute the so-called dark matter of the genome.
An international project under the auspices of the Global Alliance for Genomics and Health, the Human Genome Variation
Map project, is creating a genome graph reference that will move the field beyond the current practice of using a linear haploid
reference genome plus independent variation catalogs such as dbSNP and various catalogs of structural variants. The ultimate
goal of the HGVM project is to replace the current snarl of isolated, incompatible reference human genetic variation data
with a single, fundamental object, formalized as a very large mathematical graph. Each common genetic variant will have a
standard name in the graph, preserved in perpetuity, even as new variations are added. Complex structural variations will be
handled in the same way as point variations, in contrast to the current piecemeal approach. We discuss initial experiments
by several groups indicating that such a structure can improve read mapping and variant calling, while reducing reference
allele bias. Ultimately such a structure could provide a better-defined standard for the representation of clinical genetic
variants, and offer a deeper understanding of human genetic variation and its association with phenotypes relevant to health
and disease.
[Biography]
David Haussler, Ph.D.
Investigator, Howard Hughes Medical Institute
Distinguished Professor, Biomolecular Engineering, University of California, Santa Cruz
Scientific Director, UC Santa Cruz Genomics Institute, University of California, Santa Cruz
David Haussler develops new statistical and algorithmic methods to explore the molecular function, evolution, and disease
process in the human genome, integrating comparative and high-throughput genomics data to study gene structure, function,
and regulation. As a collaborator on the international Human Genome Project, his team posted the first publicly available
computational assembly of the human genome sequence. His team subsequently developed the UCSC Genome Browser, a
web-based tool that is used extensively in biomedical research. He co-founded the Treehouse Childhood Cancer Project to
enable international comparison of childhood cancer genomes, and is a co-founder of the Global Alliance for Genomics and
Health (GA4GH), a coalition of the top research, health care, and disease advocacy organizations.
Haussler is a member of the National Academy of Sciences and the American Academy of Arts and Sciences and a fellow of
AAAS and AAAI. He has won a number of awards, including the 2014 Dan David Prize. 2011 Weldon Memorial prize for
application of mathematics and statistics to biology, 2009 ASHG Curt Stern Award in Human Genetics, and the ISCB 2008
Senior Scientist Accomplishment Award.
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Thu(5)-CIS25-3
The 100,000 Genome Project, UK
1
Mark Caulfield
1:William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, UK

The 100,000 Genomes project is using whole genome sequencing to bring diagnoses to patients with rare inherited disorders,
identify drivers to cancer and response to therapy and drivers to antimicrobial resistance in pathogens. This will transform
the capability and capacity of the NHS to apply genomic medicine for patient benefit. This programme will be carried out
in England requiring the NHS and third party providers to create new leading edge infrastructure and operational plans
for day to day NHS Practice. With NHS England we have created 13 NHS Genomic Medicine Centres across England to
enable generation of clinical data and sample flows from NHS patients with broad consent for whole genome sequencing
into our Genomics England Biorepository at the NIHR Biosample centre. We are creating one of the largest X Ten Next
Generation Sequencing Centres in the World at Hinxton with our partner Illumina. The value of this programme will be the
alignment of the highest fidelity and most comprehensive whole genome DNA sequence produced from patients to date with
high fidelity clinical data stored in pseudonymised format within a multi-petabyte data infrastructure. This will allow ongoing
refreshment from primary, secondary and tertiary NHS care to offer a picture of life-course health and disease progression for
participants. To drive up diagnoses for patients we have created the Genomics England Clinical Interpretation Partnership
where 2100 clinicians and scientists will work on pseudonymised builds to enhance value for patients. Alongside this significant
enhancement of NHS capability for utilisation of next generation sequencing in clinical care we will train with 530 person
years of Masters Training the next generation of clinicians and scientists to ensure that NHS capacity to harness Genomic
Medicine is the most advanced in the world.
[Biography]
Mark Caulfield graduated in Medicine in 1984 from the London Hospital Medical College and trained in Clinical Pharmacology
at St Bartholomew’s Hospital where he developed a research programme in molecular genetics of hypertension and clinical
research. In 2009 he won the Lily Prize of the British Pharmacology Society. In 2000 he established the Barts and The
London Genome Centre which now underpins over 40 programmes of research. Since 2008 he directs the Barts National
Institute for Health Research Cardiovascular Biomedical Research Unit. Mark was appointed Director of the William Harvey
Research Institute in 2002 and was elected a Fellow of the Academy of Medical Sciences in 2008. He led on fundraising towards
the £25m William Harvey Heart Centre which created a translational clinical research centre. Mark served on the NICE
Guideline Group for hypertension and leads the Joint UK Societies’ Working Group and Consensus on Renal Denervation
and was President of the British Hypertension Society (2009-2011). In 2013 he became an NIHR Senior Investigator and was
appointed as the Chief Scientist for Genomics England (NHS 100K Sequencing Project) 2013-2017.
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Thu(5)-CIS25-4
The Human Phenotype Ontology: A Resource for Clinical Data Sharing and Phenotype-
Driven Genomic Diagnostics
1,2,3,4
Peter N. Robinson
1:Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin; Free University Berlin;
Berlin-Brandenburg Center for Regenerative Therapy; Max Planck Institute for Molecular Genetics, Germany、2:Free

University Berlin、3:Berlin-Brandenburg Center for Regenerative Therapy、4:Max Planck Institute for Molecular Ge-
netics
The analysis of phenotype plays a key role in clinical practice and medical research but is difficult to „compute“ on. The
Human Phenotype Ontology (HPO) provides a standardized, controlled vocabulary that allows phenotypic information to be
described in an unambiguous fashion and has been adopted by a numerous groups including the NIH Undiagnosed Diseases
Program (UDP), the UK 100,000 Genomes Project, and the Genomic Matchmaking initiative of Global Alliance for Genomics
and Health (GA4GH). The HPO makes clinical data“computable”, and allow a shift from binary phenotype analysis (patient
cohort vs. control) to an analysis of phenotypic profiles that offers a foundation for computational approaches to integrating
clinical data in precision medicine. HPO-based algorithms integrate phenotype specificity, imprecision, noise and frequency to
identify matching diseases and patients. We have developed Exomiser to identify promising candidate genes in whole exome
sequencing WES studies by ranking candidate genes according to phenotypic similarity to human, mouse, and zebrafish
mutant phenotypes. Using simulated exomes and the NIH UDP patient cohort showed Exomiser ranked the causal variant
as the top hit in 97% of known disease-gene associations. Whole-genome sequencing (WGS) is providing new opportunities
and challenges by allowing variants in the non-coding genome to be analyzed in medical contexts. This has been regarded
as extremely challenging for non-coding point mutations. We have therefore developed a machine learning algorithm that
provides a pathogenicity score for each base of the non-coding genome, and extended the Exomiser to include an assessment
of regulatory regions. Simulations show an ability to rank the seeded causative variant in first place over an entire genome
in over 60% of cases. In this talk I will present a brief overview of the HPO and of these HPO-driven algorithms for genomic
diagnostics.
[Biography]
Peter Robinson studied Mathematics and Computer Science at Columbia University and Medicine at the University of
Pennsylvania. He completed training as a Pediatrician at the Charité University Hospital in Berlin, Germany. He is now
Professo for Medical Genomics at the Institute of Medical Genetics of the Charité and Professor of Bioinformatics at the Free
University of Berlin. His group developed the Human Phenotype Ontology (HPO), which is now an international standard for
computation over human disease that is used by the Sanger Institute, several NIH-funded groups including the Undiagnosed
Diseases Program, Genome Canada, the rare diseases section of the UK's 100,000 Genomes Project, and many others. The
group develops algorithms and software for the analysis of exome and genome sequences and has used whole-exome sequencing
and other methods to identify a number of novel disease genes, including CA8 , PIGV , PIGO, PGAP3, IL-21R, PIGT, and
PGAP2. The group supports a range of genomics research projects at the Charité including ChIP-seq, RNA-seq, T-cell
receptor profiling, and deep-sequencing analysis of DNA methylation,and have published algorithms for genomic analysis
such as ChIP-seq peak finding. The Robinson lab also has identifed secondary deleterious effects of a class of extracellular
matrix fragment containing the motif Gly-x-x-Pro-Gly in Marfan syndrome, and have used this finding to develop a novel
therapy in a mouse model of Marfan syndrome.
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Clinical Sequencing
Thu., April 07, 2016 12:45-14:45 Annex 2 (1F)
Convener：Kenjiro Kosaki（Center for Medical Genetics, Keio University School of Medicine, Japan）
Convener ：Leslie G. Biesecker（National Human Genome Research Institute, National Institute of Health, USA）

The first speaker in the session will be Professor Eric E. Schadt from Icahn School of Medicine at Mount Sinai. His twill
address the role of engaging patients in long-term relationships to enhance interpretation of genomic testing results. He
will also address frontiers of sequencing technology employing next generation sequencers.
The second speaker in the session will be Professor Veltman, from Radboud University in the Netherlands. He will discuss
approaches to the future unification of what is now a multimodal approach to molecular diagnosis. Severe intellectual
disability (ID) is an excellent model for this challenge because it is genetically and clinically highly heterogeneous. The
large number of genes involved in ID, plus the heterogeneity of the molecular lesions challenge us to push the frontiers
of sequencing technology to encompass the many lesions which range from substitutions to triplet repeats, to CNVs to
trisomy. Moving toward a single test platform is critical for cost efficiencies in the laboratory and the clinic.
The third speaker in the session will be Dr. Biesecker of the U.S. Genome Institute at the NIH. He will address some of the
conceptual shifts in approaching genetic testing and screening that need to be addressed and how these changes in clinical
testing mirror opportunities in clinical research. These concepts include the hypothesis-generating research design and in
clinical medicine genomic screening (opportunistic or primary). These two uses of next-generation sequencing (research
and clinical) are connected through secondary findings; which is the practice of opportunistic screening in the context of
clinically indicated sequencing.
The final speaker is Professor Kosaki of the Center for Medical Genetics, Keio University School of Medicine. He will
address how next-generation sequencing is entering the clinic from two clinical studies; medical exome analysis of singletons
and trios. By evaluating hundreds of cases with these two complementary approaches, this review will demonstrate both
the power of the approaches both to diagnose disease and for medical discovery, but also the critical need to develop novel
approaches to exome analysis, as exemplified by directed searches for retrotransposon and regulatory element mutational
events as a solution for currently unsolved cases.
Thu(5)-CIS26-1
A technology driven approach toward deriving high resolution human genome reference materials and
the future of niche NGS diagnostic assays
1
Robert Sebra
1:Department of Genetics, and Genomic Science,Icahn School of Medicine at Mount Sinai, New York, NY, USA
TBA
RESEARCH PROFILE
My interdisciplinary background spanning graduate school and industrial research experience includes strong expertise in
the fields of photopolymerization chemistry, surface bioconjugation techniques, lab-on-a-chip platforms, active biomaterials,
single-molecule detection assay development, and third-generation DNA sequencing. Previously, as a Staff Scientist at Pacific
Biosciences, I spearheaded various R&D projects aimed at developing a rapid-turnaround, single-molecule real-time (SMRT)
sequencing assay with long readlength. This increased readlength enables the identification of novel genomic alterations
critical for differentiating otherwise similar alleles and gDNA isolates. Some of the challenges associated with this research
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included correctly formulating the sequencing chemistry to overcome enzyme kinetic and photochemical barriers resulting in
a 100X increase in readlength and continuously troubleshooting complex, sometimes heterogeneous, genomic DNA samples
to provide more homogenous reads. I have demonstrated the capability to plan and rapidly execute SMRT sequencing
technology instrumental in the publication of recent NEJM papers investigating the Haitian cholera and German E. Coli
outbreak strains as well as various other publications in high impact journals. I have also collaborated with various genome
institutes on technology development programs that include hybrid assembly of long reads with other shorter read DNA

sequencing platforms such as Illumina Hi-Seq, Ion-Torrent and BioNano Genomics. Integration of these platforms has proven
fruitful in generating long, error-corrected reads necessary for various assembly algorithms to achieve low-contig, high N50
assemblies of novel genomes and for phasing large structural variants. Since establishing a Technology Development team
at ISMMS, I have enabled this integrated approach towards a variety of arenas, including infectious disease surveillance to
better understand genomic identity between community and hospital isolates by comprehensive characterization of microbial
isolates as well as initiated programs for better targeted approaches for human disease diagnostics that relate to cancer and
inherited disease.
IMPACT
The impact of establishing a technology presence at ISMMS is manifold. 1. Locally, we have developed expertise and
established a technology suite that enables the MSH community to discover, generate, and use common and niche genomic
information for creating the future of niche diagnostics in inherited, infectious, and somatic disease. The program is broad
and has helped to create a stronger foundation for generating higher resolution information. This data has been used for
pathogen surveillance, inherited disease diagnostics by developing panels like the Super Panel, and by creating an arsenal of
targeted cancer panels and technologies such as single cell isolation and sequencing methods. These resources are Institute
and community driven to enable a toolbox for enabling better R&D, clinical and patient information at Sinai. 2. Further, the
Technology Development initiative has led to a plethora of New York City and domestic external collaborations in infectious
disease, genomics, and beyond, facilitating collaborative grants and publications. 3. International collaborations have also
been on-going including early access technology development, infectious disease and outbreak surveillance and community
genomics efforts also resulting in collaborative publications and initiatives beyond those in the USA.
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Thu(5)-CIS26-2
Towards single-test genomics
1,2
Joris A. Veltman
1:Department of Human Genetics, Radboud University Medical Center; Department of Clinical Genetics, Maastricht
University Medical Centre, Maastricht, The Netherlands、2:Department of Clinical Genetics, Maastricht University
Medical Centre, Maastricht, The Netherlands

In my presentation I will discuss the development of genomic technologies and their application in clinical practice, using
intellectual disability as a model disorder.
The detection of genomic variation is revolutionized by the introduction of next generation sequencing approaches in clinical
genetics. There is a rapid move from single gene sequencing and karyotyping to exome and even genome sequencing as the
ultimate genetic test, allowing the detection of all genomic variation in a single experiment. Next to variation detection there
is the enormous challenge of interpreting all variation in the clinical context within individual patients and families. Large-
scale exome and genome sequencing has also shown us that each individual carries thousands of rare variations. This requires
an individualized interpretation of the genome, based on clinical and biological knowledge about the disorder. Importantly,
all of this needs to be done in a highly reproducible setting, with rapid turn-around times and for affordable prices, in order
to become relevant for clinical practice.
Severe intellectual disability (ID) is a genetic and clinically heterogeneous disorder that occurs mostly sporadic due to its effect
on fitness. In this presentation, I will describe our recent work on using both family-based exome and genome sequencing in
patients with severe ID. Our data indicate that de novo germline mutations may explain the majority of all patients with
severe ID. This has great implications for the diagnostic process of patients with ID and for estimating the recurrence risk
within families. Moreover, the detection of recurrent de novo mutations in genes as well as non-coding regulatory elements
gives an enormous boost to our understanding of the underlying biology of ID. Also I will discuss our progress with the
implementation of exome sequencing as a routine diagnostics test for genetically heterogeneous disorders and our plans to
implement genome sequencing in diagnostics.
[Biography]
I have been fascinated by the possibilities of genomics technologies to study the causes of human disease ever since these
technologies became available. In the last 8 years I have been using next generation sequencing technology to improve the
detection of all forms of genomic variation and study their role in human disease, using intellectual disability (ID) as a model
disease. In 2010 my group was the first to use this approach to successfully identify dominant de novo disease gene mutations
causing rare ID syndromes. Next, we pioneered exome sequencing in patient-parent trios to reliable identify de novo disease
gene mutations in common forms of ID. Following this success we implemented exome sequencing in routine diagnostics. In
our research we recently performed a first pilot study in which we studied de novo mutations using state-of-the-art genome
sequencing technology. We demonstrated for the first time that genome sequencing can identify the major causes of severe
ID, with de novo coding mutations explaining disease in 60% of cases. Application of this ultimate genetic test in our research
allows us to start understanding mutational processes and study mutations in the non-coding part of our genome. It is my
ambition as professor in translational genomics also to implement this genetic test as soon as possible into routine diagnostics,
albeit in a responsible manner.
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Thu(5)-CIS26-3
Hypothesis-generating research and predictive genomics
1
Leslie G. Biesecker
1:National Human Genome Research Institute, National Institute of Health, USA

Exome and genome sequencing (ES/GS) allow broad interrogation of genetic variants, irrespective or pretest risk or knowl-
edge. In research, this is the hypothesis-generating research design (HGRD) and in clinical medicine it is genomic screening
(opportunistic or primary). We piloted the HGRD approach using disease-specific and disease-agnostic approaches. The for-
mer included cancer susceptibility, malignant hyperthermia, and cardiomyopathy and malignant dysrhythmias. These have
good positive predictive value (PPV, >50%). We also piloted this in a genome-wide approach to loss of function variants,
showing that >3% of our cohort have a rare dominant disorder, many undiagnosed. We have also used the HGRD method to
test for gene-disease associations. We identify gene variants, then test the presence of the phenotype, measuring the validity of
the gene-disease association and penetrance. We piloted this to test the association of variants in MYO1A with deafness. The
analogous mode of clinical ES/GS sequencing in the US is primarily focused on the diagnosis of children with symptomatic
rare or undiagnosed diseases - tens to hundreds of thousands of such tests are estimated to be performed annually. The overall
yield of this testing is claimed to be 25-33%, but these assertions have not been critically evaluated. While clinical ES/GS
is useful and appropriate, the larger and more interesting question is whether, and if so how, to use ES/GS for predictive
medicine. In this mode of ES/GS, the testing would be routine and used to extract a range of predictive data - disease
susceptibility, pharmacogenetic variants, etc. to customize each individual’s lifetime medical care. These two uses of ES/GS
(research and clinical) are connected through secondary findings - which is the practice of opportunistic screening in the
context of clinically indicated sequencing. All of these issues are connected in research and clinical sequencing and will be
reviewed.
[Biography]
Dr. Biesecker is a clinical and molecular geneticist and Chief of the Medical Genomics and Metabolic Branch and Director of
the Physician-Scientist Development Program at the National Human Genome Research Institute of the National Institutes
of Health, which he joined in 1993. He uses genetic and genomic technologies to study the etiology of inherited disorders and
has published nearly 300 primary research articles, reviews, and chapters. He received his medical training at the Univ. of
Illinois, Pediatrics at the Univ. of Wisconsin, and Clinical and Molecular Genetics at the Univ. of Michigan. His laboratory
has elucidated the etiology and natural history of numerous diseases. In addition, he developed the ClinSeq  program, which
began clinical genomics research in 2006, before the widespread availability of next generation sequencing. He co-directs a
CLIA-certified molecular diagnostic laboratory within NHGRI.
Dr. Biesecker serves as an editor or board member for four biomedical journals, was a member of the board of directors for
the American Society of Human Genetics, is an advisor to the Illumina Corporation, and served on the advisory panels for
the World Trade Center and Hurricane Katrina victim identification efforts.
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Thu(5)-CIS26-4
Genome-scale sequencing in clinical settings
1
Kenjiro Kosaki
1:Center for Medical Genetics, Keio University School of Medicine, Japan

Genome-scale sequencing is being transformed into clinical practice. In the presentation, we will report the results from
two interrelated studies on the clinical use of genome-scale sequencing. Medical exome analysis (singletons): A cohort of
138 unselected and unrelated cases with suspected genetic diseases were analyzed at our university hospital with a capture
array designed to target the coding sequences of 4,813 known pathogenic genes. Molecular diagnosis was made in 56 cases
(40.5%). In 5 cases a new therapeutic intervention was suggested. In 3 cases an invasive investigation was deferred. In 5 cases
surveillance was started for known complications, while surveillance was stopped in 3 cases. Despite the clinical usefulness
of genome-scale sequencing as illustrated above, many cases remain unresolved. In order to better delineate such cases, we
incorporated an algorithm that detects exonic insertion of retrotransposons by using discordant read pairs and clipped reads:
Exonic insertion of the L1 retrotransposon at the CC2D2A locus was identified in a patient with Meckel-Gruber syndrome
phenotype. This approach was applicable in whole exome analysis as well. Whole exome analysis (trios): Our center functions
as both as clinical site and sequencing core of the Japan’s newly developed national undiagnosed diseases program,“Initiative
on Rare and Undiagnosed Diseases [IRUD]”. Our center completed clinical and molecular evaluation on ~ 150 cases without
clinical diagnosis and so far identified a few presumably new monogenic disorders: i) de novo CDC42 mutation leads to
thrombocytopenia, intellectual disability, lymphedema, and contracture of the fingers [MIM 616737: Takenouchi-Kosaki
syndrome]; ii) de novo PDGFRB mutation leads to a new form of overgrowth syndrome accompanied with scoliosis, skull
defects and fragile skin [MIM 616592: Kosaki Overgrowth syndrome]. In order to better delineate new disorders, systematic
case matching on a global scale is warranted.
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Effects of Genetic and Epigenetics, Geno-environmental Interactions on Healthy Aging and Longevity
Thu., April 07, 2016 12:45-14:45 Room A (2F)
Convener：Yi Zeng（Center for the Study of Aging and Human Development, Medical School of Duke University, Durham,
NC, USA; Center for Healthy Aging and Development Studies, National School of Development, Peking University,
Beijing, China, China/USA）

Convener ：Makoto Suzuki（Okinawa Research Center for Longevity Science, Japan）
While human lifespan is increasing and the number of elderly (especially oldest-old) is rapidly growing in almost all
countries in the world, is it possible to realize compression of morbidity, or at least dynamic equilibrium, rather than
expansion of disability? Why do some people survive to advanced ages with good health but others suffer severe disability
and morbidity? So far, there are not many good answers to these critical questions.
Various research have shown that genetics, epigenetics and gene-environment (GxE) interactions play crucial roles in
health and longevity, because environmental factors may activate or regulate gene expressions and functions, which
then influences health outcomes. Existing literature indicate that because of GxE interaction effects, the positive or
negative associations between environmental factors and health outcomes differ significantly among individuals with
different genotypes. Consequently, Genetic, epigenetic and gene-environment interaction studies can contribute to yield
significantly increased benefits and reduced costs of health promotion, programs which consider individuals’ genetic
profiles, and enable much more people to enjoy better health while lifespan is increasing. This is the goal of present
session and we intend to promote academic discussions on this important topic, and make contributions to improve the
quality of life for the elderly and all members of their families and entire society around the world.
Thu(5)-CIS27-1
Genetic studies of the oldest old: Somatic and germline variation
1
Eline Slagboom
1:Molecular Epidemiology Section, Department of Medical Statistics and Bioinfomatics, Leiden University Medical
Centre, The Netherlands
Despite the continuous increase in life expectancy in our societies, the diversity in health span is enormous, ranging from
unhealthy 60- to vital 90-year-olds and displays considerable gender effects (http://ec.europa.eu/health/indicators). Among
the many molecular profiles that associate with lifespan or healthspan, often representing pathways involved in regulating
energy metabolism and immunity, determinants can poorly be distinguished from biomarkers. Worldwide genetic approaches
to identify longevity determinants have pointed at a handful of loci. In addition to the most robust lifespan associated locus
of APOE, variation at 5q33.3 was found to associate to longevity. We report on phenotype associations with this locus and
ongoing analyses to disentangle its relevance. By whole genome sequencing of the oldest old in comparison to control subjects
we did not find consistent germ line variation related to longevity. We did observe, however, an accumulation of somatic
variation at loci known to be involved in clonal expansion of haematopoietic stem cellsand investigated the relation of such
accumulation and survival of the oldest old. Finally we investigated epigenetic changes in the ageing genome focusing not
on loci that represent DNA methylation clocks of chronological age but loci with increased variability arising as a function
of age. Profiles such as genome wide epigenetic and transcriptome changes may reflect signatures of early development as
lifespan determinants. Variability loci on the other hand may also indicate potential drivers of the loss of epigenetic control
that may contribute to lifespan regulation.
[Biography]
Professor P. Eline Slagboom is leading within the Leiden University Medical Center a group in molecular epidemiological
studies aimed at the identification of biomarkers and causal pathways for metabolic health, ageing and longevity. The section
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of Molecular Epidemiology is embedded in the department of Medical Statistics and Bioinformatics. Focus of the research in
the past 10 years is on genomic determinants (genetic, genomic, epigenetic), biomarker, functional genomic and intervention
studies of healthy/unhealthy aging and longevity in humans. Slagboom is PI of the Leiden Longevity Study, chair of the
Medical Research Profile on Aging at LUMC and has a leading role in large consortia within ageing research. She was
co-director of the Netherlands Consortium for Healthy Ageing, in the board of large scale EU collaborative research projects
(GEHA) and PI of a large scale collaborative EU project (IDEAL: Integrated research on DEvelopmental determinants of

Aging and Longevity). She is member of various boards and scientific bodies, among others member of the board of BBMRI
(Biobanking and Biomolecular Resources Research Infrastructure) and she leads the national efforts in metabolomics (25
cohorts) in BBMRI together with professors Boomsma and Van Duijn. Further she is chair of DUSRA - Dutch Society for
Research on Ageing and Section Editor of Aging Cell.
For the aforementioned activities see www.molepi.nl, www.ideal-ageing.eu and www.nvvvo.nl.
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Thu(5)-CIS27-2
Energy Sensing Genes and Longevity: Novel Findings from Multi-Ethic Populations
Bradley J. Willcox 1 ，D. Craig Willcox 1
1:Department of Geriatric Medicine / Department of Research, University of Hawaii / Kuakini Medical Center, USA

We prioritized 46 candidate genes from evolutionarily-conserved energy-sensing pathways in mice for study of their human
homologues in the Kuakini Honolulu Heart (HHP) cohort of long-lived men. Our goal was to assess their potential role in
longevity and healthspan phenotypes. These genes were chosen because they were found in mice to respond (with markedly
altered gene expression) to short term caloric restriction. An initial case: control study of over 400 centenarians (lived 95+
years) and equal numbers of birth cohort-matched controls (died average 78 years) revealed that 14 of these genes (including
repeat study of FOXO3) had at least one SNP associated with longevity (with 8 genes having 2+ SNP associations). Two genes
(EGFR and CTGF) had 3+ SNP associations and/or met additional validation criteria (corrected p < 0.01 for association with
longevity in case: control study; multiple SNPs in linkage disequilibrium from a defined gene locus; biological plausibility). We
are currently replicating these findings in other ethnic populations and assessing effects of genotype on healthspan phenotypes
in a longitudinal study. We report here the initial findings from this study. Supported by US NIH-NIA grants 2R01AG027060
and 1R01AG038707 and Kuakini Medical Center.
[Biography]
Bradley J. Willcox MD, MSc, FACP, is Professor and Director of Research at the Department of Geriatric Medicine, John
A. Burns School of Medicine, University of Hawaii, at the Kuakini Medical Center (KMC) Campus. He also is Principal
Investigator of the NIH-funded KMC Hawaii Lifespan Study and KMC Hawaii Healthspan Study, and co-Principal Investigator
of the Okinawa Centenarian Study.Dr. Willcox trained in Medicine at the University of Toronto, Internal Medicine at the
Mayo Clinic, and Geriatric Medicine at Harvard Medical School and is Board-certified in both Internal Medicine and Geriatric
Medicine.
Dr. Willcox is a frequent reviewer for major medical journals and is on the Editorial Board of the Journals of Gerontology,
the leading gerontological journal. Dr. Willcox is also on the Board of Scientific Counselors (BSC) for the U.S. National
Institute on Aging (NIA), which reviews all intramural NIA research programs.
He has been recognized with a Dorothy Dillon Eweson Award for Advances in Aging Research, the Henry Christian Award
from the American Federation for Medical Research, and a Director’s Citation from the Centers for Medicare and Medicaid
Services, among other honors. Dr. Willcox is also an author of a NY Times best-selling book on healthy aging, The Okinawa
Program, and his work has appeared in cover articles of Time Magazine, National Geographic, and on Oprah, Good Morning
America, NOVA Science, BBC, among other media.
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Thu(5)-CIS27-3
Meta-analysis of 4 genome-wide association studies identify new longevity genes
Paola Sebastiani 1 ，Nir Barzilai 2 ，Harold Bae 4 ，Annibale Puca 3 ，Gil Atzmon 2 ，
Anastasia Gurinovich 1 ，Thomas Perls 1
1:Department of Biostatistics, Boston University, USA、2:Albert Eistein University、3:University of Italy、4:Oregon
State University

Irreproducibility of results from genome wide association studies of extreme longevity may be the consequence of casual defi-
nitions of the phenotype. We conducted genome wide association studies of study participants surviving past the sex-specific
95th percentile of survival (according to birth cohort life tables). Participants were from the Long Life Family Study, the
New England Centenarian Study, the Longevity Gene Project that includes only Ashkenazi Jewish participants, and the
Southern Italian Centenarian Study, for a total of more than 2,000 long lived individuals and more than 6,000 controls.
Genetic associations of 2.2M SNPs were estimated using mixed effects Bayesian logistic regression adjusted for sex and top
principal components and results were combined through meta-analysis. In addition to the APOE locus that reached genome
wide significance (and negatively associated with longevity), several loci in chromosome 4, 6, 7, 12, reached strong statistical
significance. The analysis identified new candidate genes for extreme human longevity.
[Biography]
Paola Sebastiani is Professor of Biostatistics and Bioinformatics at Boston University. She works on the genetic and epidemi-
ology of extreme human longevity in collaborations with Thomas Perls (Director of the New England Centenarian Study, and
Principal Investigator of the Boston site of the Long Life Family Study). Paola Sebastiani used modern biostatistical methods
to characterize the compression of morbidity in the oldest old, and to identify genetic and non-genetic factors associated with
extreme human longevity.
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Thu(5)-CIS27-4
Associations of novel loci, pathway-specific polygenic scores and GxE interactions with
longevity and cognition in Han Chinese
Yi Zeng 1,2 ，Chao Nie 3 ，Huashuai Chen 1,4 ，Rui Ye 3 ，Xiaomin Liu 3 ，Zhihua Chen 3 ，
Konstantin Arbeev 5 ，Ting Ni 6 ，Kenneth C Land 5 ，Ze Yang 7 ，Jun Gu 8 ，Xiaoli Tian 9 ，
Junxia Min 10 ，Michael W Lutz 11 ，Elizabeth Hauser 12 ，James Vaupel 13 ，Huanming Yang 3,14
，

Anatoli Yashin 5
1:Center for the Study of Aging and Human Development, Medical School of Duke University USA; Center for
Healthy Aging and Development Studies, National School of Development, Peking University, Beijing, China、
2:Center for Healthy Aging and Development Studies, National School of Development, Peking University, Beijing,
China、3:BGI-Shenzhen, Shenzhen, China、4:Business School of Xiangtan University, Xiangtan, China、5:Population
Research Institute, Duke University, Durham, North Carolina, USA、6:State Key Laboratory of Genetics Engineering
& MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China、
7:National Institutes of Geriatrics, Beijing Hospital, Ministry of Health, Beijing, China.、8:School of Life Sciences,
Peking University, Beijing, China、9:Department of Human Population Genetics, Institute of Molecular Medicine,
Peking University, Beijing, China、10:The First Affiliated Hospital, Institute of Translational Medicine, School of
Medicine, Zhejiang University, Hangzhou, China、11:Department of Neurology, Medical Center, Duke University,
Durham, North Carolina, USA、12:Duke Molecular Physiology Institute, Medical Center, Duke University, Durham,
North Carolina, USA、13:Max Planck Institute for Demographic Research, Rostock, Germany、14:James D. Watson
Institute of Genome Sciences, Hangzhou, China
We recently completed a longevity genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the
largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated
in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-
wide significance (P<5.0 x10-8 ) and the rest with suggestive significance (P<3.65x10-5 ). Based on our collaborative analysis
with EU longevity genetics consortium and New England centenarians study, eight independent SNPs overlapped across Han
Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Our integrated analysis
indicates that four pathways (starch/sucrose, immunity, MAPK, calcium signaling) are highly associated with longevity
(P≤0.006) in Han Chinese, which are supported by findings in other human and animal studies. Our study suggests that
protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key
roles in human longevity.
As each SNP likely has very small effect and testing many single SNPs in gene-environment(GxE) interaction analysis is not
ideal, we employ polygenic risk scores(PRS) to summarize genetic effects among an ensemble of identified SNPs. However, the
use of a PRS summarizing all identified SNPs is problematic since potentially two different biological structures represented
by their component genes could produce the same PRS confounding the GxE analysis. To address this problem, based on
our prior research outlined above, we estimate pathway-specific PRS which summarize the SNPs of genes that occur in the
4 pathways(starch/sucrose, immunity, MAPK, calcium signaling) significantly associated with longevity. As an illustration,
we present the effects of the GxE interactions between PRS of starch/sucrose pathway and dietary factors on cognitive
impairment at advanced ages.
[Biography]
Yi Zeng, received PhD of Brass Free Univ in 1986 and had post-doc study at Princeton Univ in 1986-1987. He is a Professor
at Center for Study of Aging and Human Development and Geriatrics Division at School of Medicine of Duke Univ, Center
for Healthy Aging and Development Studies, National School of Development at Peking Univ, Distinguished Research Scholar
of the Max Planck Institute for Demographic Research, and a foreign member of the Royal Netherlands Academy of Arts and
Sciences. Up to Dec 2015, he had 146 articles in English published in U.S. and Europe including 106 articles in anonymously
peer-reviewed academic journals. He had 133 professional articles in Chinese and published in China including 102 articles
in anonymously peer-reviewed journals. He published 25 academic books, including 10 books in English published U.S. and
Europe. He was awarded 11 national academic prizes and 3 international academic prizes, such as the Dorothy Thomas Prize
of the Population Association of America, the Harold D. Lasswell Prize of Policy Sciences and Kluwer Academic Publishers,
the best paper Award of American Journal of Public Health, the Chinese national prizes for advancement of science and

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technology, the highest academic honor of Peking University: “Prize for Outstanding Contributions in Sciences” and the
“Chinese Population Prize (Science and Technology)”, jointly awarded by nine ministries and seven national non-governmental
associations in China.
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Current Aspects of Inborn Error of Metabolism
Thu., April 07, 2016 12:45-14:45 Room E (1F)
Convener：Shigeo Kure（Department of Pediatrics, Tohoku University School of Medicine, Japan）

Convener ：Wuh-Liang Hwu（Department of Pediatrics and Medical Genetics, National Taiwan University Hospital,
Taiwan）

This session includes four current topics in the study of inborn errors of metabolism (IEM), which will be presented by
four distinguished speakers. The presenting topics are mitochondrial diseases, IEMs of amino acid, IEMs of metals and
the gene therapy. First speaker, Dr Thorburn from Melbourne, has identified many causative genes for mitochondrial
disease by using next generation sequencing (NGS), and will present the latest genetic view of mitochondrial diseases.
Second speaker, Dr Blom from Heidelberg, is an expert of biochemical and genetic analysis of IEMs, especially one-
carbon metabolism. He will review the current topics of IEMs of amino acid, including recent progress in the study of
homocysteine metabolism. Third speaker, Dr Yoo from Seoul, will update genetic and metabolic pathogenesis of IEMs of
metals, especially of cupper metabolism including Wilson and Menkes diseases. Last speaker, Dr Hwu from Taipei, will
present the first successful gene therapy for aromatic acid decarboxylase (AADC) deficiency using adeno-associated virus
vector, which has amazingly ameliorated prognosis of patients with AADC. These four lectures would delineate various
aspects of current researches on IEM.
Thu(5)-CIS28-1
Novel mitochondrial diseases identified by NGS
1,2,3
David R. Thorburn
1:Genetics, Murdoch Childrens Research Institute; University of Melbourne, Dept of Paediatrics; Victorian Clinical
Genetics Services, Australia、2:University of Melbourne, Dept of Paediatrics、3:Victorian Clinical Genetics Services
The term “mitochondrial diseases” could potentially describe defects affecting any of the approximately 1200 proteins in the
known mitochondrial proteome but is usually restricted to disorders of oxidative phosphorylation (OXPHOS), which is how
I define it here. OXPHOS disorders are the most common group of inherited metabolic diseases, affecting at least 1 in 5000
births, but comprise over 200 different monogenic disorders, encoded on autosomes, the X chromosome or mitochondrial DNA
(mtDNA). Mechanistically, they comprise defects affecting subunits or assembly factors for individual OXPHOS complexes,
defects of mtDNA maintenance or expression, nucleotide synthesis or transport, membrane composition or dynamics and
other aspects of OXPHOS biogenesis and quality control. OXPHOS disorders show extreme clinical and genetic diversity.
For example, the most common OXPHOS disorder in children is Leigh syndrome, but this can be caused by mutations in
more than 75 genes (Lake et al., 2016, Ann.Neurol., in press). This complexity has driven the transition of Next Generation
DNA Sequencing (NGS) of mtDNA, gene panels or exomes from research into diagnostic practice. It has also enabled the
identification of more than 70 novel OXPHOS disease genes in the last 3 years. The largest category of novel disease genes
has been those involved in mtDNA transcription and translation but a wide range of other mechanisms have been described,
including processing or turnover of mitochondrial membrane lipids and proteins. It can sometimes be difficult to distinguish
between primary and secondary OXPHOS disorders and most studies of large cohorts of patients with suspected OXPHOS
disease have identified pathogenic mutations in genes associated with diseases not thought to be related to OXPHOS. I will
discuss the utility and limitations of these approaches, and our experience in molecular diagnosis in identifying mutations in
over 60 known and novel OXPHOS disease genes in over 300 children.
[Biography]
David Thorburn leads the Genetics Research Theme and Mitochondrial Research Group at Murdoch Childrens Research
Institute in Melbourne, Australia. He is also an Honorary Professorial Fellow in the University of Melbourne Department
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of Paediatrics. David did his PhD on erythrocyte metabolism, a postdoc on reticulocyte maturation and then decided
he preferred to work instead on cells that looked after their mitochondria better than the erythroid lineage. His research
focuses on inherited disorders of mitochondrial energy generation, which comprise more than 200 monogenic disorders. His
laboratory has acted as the Australasian referral centre for children suspected of mitochondrial disease for over 2 decades
and has diagnosed more than 600 patients. His research contributions include translating knowledge of mitochondrial DNA
genetics into reproductive options for families, defining diagnostic criteria & epidemiology and improving diagnosis & discovery

of novel “disease” genes through Next Generation DNA Sequencing. This has led to the identification and characterisation
of over 20 novel disease genes. Much of his current research focuses on human stem cell and mouse models of mitochondrial
disease, aimed at better understanding the pathophysiology of these disorders and trialling new treatment approaches.
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Thu(5)-CIS28-2
Current topics in inborn errors of amino acid metabolism
1
Henk Blom
1:Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and
Neonatology, University Medical Centre Freiburg, Netherlands

Inherited diseases of amino acid metabolism concern a major part of all inborn errors of metabolism. It includes
aminoacidemias, organic acidurias and many defects in vitamin or neurotransmitter metabolism. Amino acids are the
building blocks of all proteins and so essential to life. In general amino acids are degraded via transamination to generate
organic acids, which in complex pathways are converted to various intermediates of the citric acid cycle to produce energy.
The remaining nitrogen group needs to be removed in the urea cycle to prevent build up of the toxic compound ammonia.
After a short introduction to intermediary metabolism a few intriguing examples of inborn errors of amino acids will be
discussed, including:
Defects in methionine metabolism and epigenetic modifications
Novel treatment of Arg to Cys mutations
B6-dependent epilepsy
[Biography]
Henk Blom received his PhD in 1988 and was post-doc period at the Human Genetics Branch, NIH, USA. Next he was
employed at the Clinical Genetics Center Nijmegen, the Netherlands. In 2003 he was registered as Clinical Biochemical
Geneticist. In 2007 he was appointed at the Metabolic Unit at the VU University Medical Centre Amsterdam, the
Netherlands and in 2009 he became Professor in Biochemistry of Inherited Metabolic Diseases. Since 2014 he is head of the
Laboratory for Clinical Biochemistry and Metabolism, Center for Pediatrics and Adolescent Medicine University Hospital,
Freiburg, Germany.
His research concerns inborn errors of metabolism with special focus on inherited defects of homocysteine, methylation and
folate metabolism. Main contributions include the association of homocysteine with neural tube defects and cardiovascular
disease. He was the first to publish on of the MTHFR 677C>T (first identified genetic risk factor for neural tube defects)
and 1298A>C polymorphisms. He published on the molecular basis of homocystinurias, defects in folate metabolism and
the methionine methylation pathway, including methionine adenosyltransferase deficiency, including two new genetic defects:
dihydrofolate reductase deficiency and adenosine kinase deficiency.
He supervised as (co)promoter 30 PhD students and published over 350 papers in international journals resulting in an
H-index of 70.
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Thu(5)-CIS28-3
Clinical and molecular spectrum of Wilson disease (WD) patients with understanding
of molecular pathophysiology of WD in animal model, Long-Evans Cinnamon rats
1
Han-Wook Yoo
1:Pediatrics & Medical Genetics, Asan Medical Center Childrens Hospital, University of Ulsan College of Medicine,
Korea

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism. In the cohort of Wilson 365 unrelated Korean
WD families, presenting phenotypes were classified as hepatic (H1, H2), neurological (N1, N2, NX), and asymptomatic (ASx).
Presenting phenotypes were H1 (12.2%), H2 (42.4%), N1 (21.6%), N2 (0.4%), NX (0.4%), ASx (22.4%), and other (0.4%).
Liver cirrhosis was associated in 63% of N1 patients, similar as in H1+H2 patients (49%). On follow-up (average, 8.2±5.8
years), liver cirrhosis was rarest in ASx patients (4%). Decompensated cirrhosis was highest in H1 (48%). Sixty four ATP7B
mutations including 19 novel ATP7B mutations were identified in 85% of the 474 alleles. Yeast complementation and growth
curve assays demonstrated functional perturbation of the 19 novel missense mutants. Five major mutations, p.Arg778Leu
(38%), p.Asn1270Ser (10.0%), p.Ala874Val (9.4%), p.Leu1083Phe (5.4%), and p.Lys838SerfsX35 (4.8%), accounted for 68% of
the alleles. Also, we compared the serum proteome profiles of asymptomatic WD patients with those of normal control subjects
by two-dimensional electrophoresis (2-DE), tandem mass spectrometry (MS/MS) and Western blot analyses. The proteins,
C3, FB and α 2M, identified by using comparative proteome analysis are related to oxidative stress and inflammation. Using
Long-Evans Cinnamon (LEC) rats, the proteomic profiles of hepatic tissues and the cDNA expression profiles of brain tissues
of LEC rats were compared to the control rats in age-dependent manner. The hepatic proteins differentially expressed in
LEC rats are related to mitochondrial injuries or in oxidative stresses. The investigation of cDNA expression profiles of
brain tissues in LEC rats in age-dependent manner revealed the 178 genes differentially expressed in LEC rats: 68 genes
are involved in neuronal development and activities, 23 genes in inflammatory reactions, 33 genes in oxidative stress and
apoptotic conditions, and 4 genes in visual pathways.
[Biography]
Professor Yoo received his M.D., Ph.D. degrees from the College of Medicine, Seoul National University in 1979. He has
completed his clinical training as an internship and residency in 1983 and clinical fellowship in Pediatrics at Seoul National
University Children’s Hospital in 1986. He furthered his clinical and research training through a postdoctoral fellowship at
Division of Medical and Molecular Genetics, Department of Pediatrics, Mount Sinai Medical Center, New York, U.S.A. from
1989 through 1992, and certified as a clinical molecular geneticist by the American Board of Medical Genetics. In 1994, he
joined the faculty of University of Ulsan College of Medicine, Asan Medical Center. At present, he is serving as the director
of Medical Genetics Center at Asan Medical Center in Seoul, Korea.
Professor Yoo has published more than 200 articles in peer-reviewed international journals. He has received several awards
for his research and he is an active member of many international academic societies in the field of human genetics.
Professor Yoo’s main research interests focus on the characterization of molecular & functional defects in Mendelian genetic
disorders and development of new technology for DNA testing.
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Thu(5)-CIS28-4
Gene therapy for aromatic L-amino acid decarboxylase (AADC) deficiency
Wuh-Liang Hwu 1 ，Ni-Chung Lee 1 ，Yin-Hsiu Chien 1 ，Sheng-Hong Tseng 1 ，Shin-ichi Muramatsu 2 ，
Barry Byrne 3
1:Department of Pediatrics and Medical Genetics, National Taiwan University Hospital, Taiwan、2:Jichi Medical Uni-
versity、3:University of Florida

Aromatic l-amino acid decarboxylase (AADC) is an enzyme responsible for the final step of the synthesis of neurotransmitters
dopamine and serotonin. AADC deficiency is a rare genetic disorder causing motor and autonomic dysfunction and early
death in children. Taiwanese carry a high prevalence of AADC deficiency due to a founder mutation (IVS6+4A>T) in the
AADC gene. In the past few years, we conducted both a human gene therapy trial with local injection, and mouse studies
with wide spread vectors. A gene therapy with recombinant adeno-associated virus (AAV) serotype 2 CMV promoter-driven
human AADC (AAV2-hAADC) was conducted in 18 children with AADC deficiency since 2010. Clinical grade vector was
manufactured. Most patients had homozygous IVS6+4A>T mutations. PET signal intensity over putamen increased and
cerebrospinal fluid neurotransmitter levels rose in all treated patients currently completed the trial, and all treated improved
in their motor function . There is no virus-associated side effect, and currently no patient reveals a loss of treatment effect.
Currently, a phase I/II clinical trial is ongoing.
We also created an IVS6+4A>T knock-in mouse model of AADC (DdcKI mice). We first showed that gene therapy with direct
intraventricular injection of AAV9-CMV-hAADC (AAV9-AADC) at the neonatal stage can rescue the phenotype. We then
extended the treatment to systemic therapy on young mice. After intraperitoneal injection of 7-day-old mice with either AAV9-
CMV-hAADC (AAV9-AADC) or yfAAV9/3-Syn-I-mAADC (AAVN-AADC), the treated DdcKI mice showed improvements
in weight gain, survival, motor function, autonomic function, and behavior, but the effects of AAVN-AADC were superior.
Moreover, the AAV9-AADC-treated DdcKI mice exhibited slight hyperactivity. Under low magnification, AADC-positive cells
were found in the cortex of AAV9-AADC-treated mice. Therefore, mice with a neurotransmitter deficiency can be rescued at
a young age using systemic gene therapy, but a neuron-specific vector may be necessary.
[Biography]
Dr. Paul Hwu is a Professor in the Department of Pediatrics at the National Taiwan University Hospital (NTUH) in Taiwan.
Professor Hwu completed his medical and PhD degrees at the National Taiwan University. He completed his residency at
NTUH. He has done fellowship at the Department of Genetics at Johns Hopkins University, and he was also a Visiting
Scientist at the Department of Medical Genetics at the Mayo Clinic. He was the Department Head of Medical Genetics at
NTUH from 2006 to 2012, the President of the Taiwan Human Genetics Society from 1999 to 2002, and Board Member of
the Taiwan Foundation for Rare Disorders.
Professor Hwu set up the Newborn Screening Program for Pompe Disease in Taiwan, one of the first in the world, and has
dedicated much of his research and clinical effort in the diagnosis, management, and gene therapy for patients with rare
genetic diseases.
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[WS1] Workshop 1
Global Data Sharing in Human Genetics
Tue., April 05, 2016 13:50-15:20 Room A (2F)
Moderator：Sharon F. Terry（President and CEO / Genetic Alliance, USA）

Moderator ：Kazuto Kato（Graduate School of Medicine, Osaka University, Japan）
The issue of sharing human genetic data in any single country is filled with complexity. In a global context it is even
Workshop
more complicated, as culture, context, laws, regulations, directives, and customs vary greatly. For some countries, genetic
data can be simply used like other health data, and in others, it represents the essence of being human. Regardless
of a country’s oversight of the matter, individual and community sensibilities vary a great deal even within national
boundaries.
This workshop will provide a sampling of some of the issues relative to different countries and cultures. Kazuto Kato and
Sharon Terry will set the stage for this presentation with a short overview of the general issues related to sharing genetic
and genomic data. They will present this overview from policy, ethics, and consumer perspectives. Bartha Knoppers
will present on the work she has led for the Global Alliance for Genomes and Health (GA4GH). In this framework she
developed for the GA4GH, she details using a human rights framework to guide data sharing in the countries participating
in GA4GH. Victor Penchaszadeh will discuss north-south inequities in global sharing of genetic data. The Southern
Hemisphere generally is home to emerging nations who are less able to bear the same potential burdens as do citizens
of the Northern Hemisphere. It is not clear to what extent global sharing is actually global, and so Charles Rotimi will
describe his work in this area. Partha Majumder will present the point of view of individuals working in India and in
Asia in general.
Tue(3)-WS1-1
Global Genomic Data Sharing for Health: A Human Rights Approach
1
Bartha M. Knoppers
1:Human Genetics, McGill University, Centre of Genomics and Policy, Canada
The benefits of Big Data (spurred and reinforced by data sharing), include increasing knowledge on heterogeneous populations
from around the world, so as to detect patterns that are truly representative of risk and resistance to disease. But, current
ethics guidance framing such "sharing" may not have the political and legal clout needed to be equitable and enforceable. In
the normative hierarchy that ranges, from legally enforceable instruments, to declarations, to codes of conduct and guidelines,
whither secure international data sharing? Is the Framework for the Responsible Sharing of Genomic and Health-Related
Data of the Global Alliance for Genomics and Health sufficiently robust to include and protect both participants in research
and patients from around the world?
[Biography]
BARTHA MARIA KNOPPERS
Bartha Maria Knoppers, PhD (Comparative Medical Law), holds the Canada Research Chair in Law and Medicine (Tier 1:
2001 - ). Director of the Centre of Genomics and Policy, Faculty of Medicine, Human Genetics, McGill University she is the
founder of the Population Project in Genomics and Society (P3G) and CARTaGENE Quebec’s population biobank (30,000
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indiv.). Chair of the Ethics Working Party of the International Stem Cell Forum (2005- ); Co-Chair of the Sampling/ELSI
Committee of the 1000 Genomes Project (2007-2014); Scientific Steering Committee Member of the International Cancer
Genome Consortium (2009- ); Chair, Regulatory and Ethics Working Group - Co-Founder and Member, Transitional Steering
Committee of the Global Alliance for Genomics and Health. She holds four Doctorates Honoris Causa, is Fellow of the
American Association for the Advancement of Science, and of the Canadian Academy of Health Sciences; and Officer of the
Order of Canada and of Quebec. She received the “Prix Montreal In Vivo: Secteur des sciences de la vie et des technologies
de la santé” in 2012 and was named “Champion of Genetics” by the Canadian Gene Cure Foundation (2013). In 2014, she
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was named “Great Montrealer”, Scientific Sector, by the Board of Trade of Metropolitan Montreal, and in 2015 she received
the Medal Paul-André Crépeau for her work in comparative medical law (The Canadian Bar Association: Quebec).
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Tue(3)-WS1-2
North-South inequities in global sharing of human genetic data
Victor B. Penchaszadeh 1 ，Luis Justo 2,3
1:Latin American Bioethics Network, Argentina、2:Ministerio de Salud Neuquen, Argentina、3:Universidad Nacional del Comahue, Argentina
While health research is still largely financed by public funds, the medical applications of the knowledge generated is conducted
mostly by the pharmaceutical and biotech industries, in close alliance with researchers, undermining the common good through
Workshop
abusive patenting. The competition for profits creates the need for mega biobanks of human samples and associated clinical
data for “big data mining” and eventual development of profitable products. Private organizations with little public
accountability, representing industrial groups and researchers consortia are self-appointing themselves as “experts” to lobby
for the implementation of North-centered views, purported as “global consensus”, with only token representation of interests
from the developing world, which is a major source of samples and data but not part of strategic leadership. One of the
ethical casualties of this process is free informed consent (IC) for the use of samples and data. In effect, being IC a complex
and slow process (particularly considering need for re-consent), its ethical implementation would mean increased costs that
the industry prefers to avoid. Thus the current tendency for “broad informed consent”, in fact a blind authorization for
unspecified future uses to enhance the use of collected samples and data without new authorization. Furthermore, notions of
justice, common good and benefit sharing are disappearing from the discourse, displaced by the priority to protect privacy
and confidentiality, while the notion of “less than minimum” risk opens the door to “opt-out consent”. The asymmetry
of these initiatives in favor of powerful interests reflects North-South inequities in distribution of wealth and power, and will
increase global social inequalities. This must be countered by collective actions of governments, researchers and civil society
for the equitable application of genomics in health care.
[Biography]
Victor B. Penchaszadeh earned an MD from the University of Buenos Aires, Argentina (1964), a MSc in public health and
human genetics from The Johns Hopkins University (1971) and a Certificate in Bioethics and the Medical Humanities from
Columbia University (1996). After developing clinical genetic services in Argentina and Venezuela, he settled in the United
States, where he was, respectively, assistant, associate and full professor of pediatrics at Cornell University Medical College
(1981-1986), Mount Sinai School of Medicine (1986-1989) and Albert Einstein College of Medicine (1989-2002). He later joined
Columbia University School of Public Health (2002-2006) teaching epidemiology of genetic diseases. In 2007 he returned to
Argentina, where he teaches genetics, bioethics and public health. For many years he has been a consultant in bioethics and
genetics in public health to the Pan American Health Organization (PAHO/WHO) and served as president of it’s Advisory
Committee on Health Research (2004-2007). Since 2011 he is president of the Latin American and Caribbean Bioethics
Network UNESCO. He has been instrumental in applying forensic genetics in Argentina for the identification of children of
the disappeared by the military dictatorship, who were abducted and deprived of their identity. He has published extensively
on clinical genetics, public health genetics, ethical issues in genetics, bioethics of health research and genetics and human
rights.
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Tue(3)-WS1-3
How Global is "Global Data sharing"
1
Charles N. Rotimi
1:Center for Research on Genomics and Global Health, National Human Genome Research Institute, NIH, USA
The current lack of diversity and inequities in research capacity in genome science are arguably the most pressing ethnical
issues in global data sharing. International collaborations and data sharing in genomic science are now the norm. The benefits
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and impacts of these partnerships are obvious and expanding. However, not all scientists and communities are benefiting
from these global collaborations. African scientists and their communities have been excluded for several reasons including
limited local and international funding opportunities, lack of adequate infrastructure and shortage of African scientists with
genomic skills. Moreover, in the limited instances when African scientists have been invited to take part in international
collaborations they have done so as “second class” partners. Although some of these issues are beginning to be addressed by
funding agencies and scientists, it is clear that if not adequately resolved they have the potential to threaten and invariably
compromise international partnerships, including data sharing. In this presentation, I will discuss how the Human Heredity
and Health in Africa (H3Africa) initiative is addressing these issues including how local ethics review committees are challenged
by the complex issues surrounding “broad” data sharing given cultural beliefs and practices. I will also discuss how H3Africa
has negotiated fairness in genomics in resource-challenged settings.
[Biography]
Dr. Charles Rotimi, a genetic epidemiologist, is the Director of the Center for Research on Genomics and Global Health at
NIH. His lab conducts genomic and epidemiologic studies that explore the patterns and determinants of metabolic disorders
including diabetes, hypertension and obesity with particular emphasis on health disparities in African ancestry populations.
His lab gives particular attention to ways in which scientists document and describe the non-random pattern of human
genetic variation with respect to human history, notions of identity and disease risks in different populations. He is a
member of board of the American Society of Human Genetics, a member of the Executive and Scientific Committee for the
International Federation of Human Genetics Societies, member of Human Genome Organization (HUGO) council and the
founding president of the African Society of Human Genetics. Recently, he successfully led the establishment of the Human
Heredity and Health in Africa (H3Africa) initiative with over ＄ 76 million commitment from the NIH and Wellcome Trust.
H3Africa is revolutionizing genomic research across the African continent.
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Tue(3)-WS1-4
Sharing Big Data: A Personal Perspective from a Developing Nation
1
Partha Majumder
1:National Institute of Biomedical Genomics, India
With the increasing availability of massively-parallel sequencing platforms in the developing world, big data are being generated
both for diagnostic and research use. These data need to be appropriately stored and shared with researchers and clinicians
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across the world. India has developed a national data-sharing policy that is aligned to the general research goals of human
genetics. I shall briefly present an overview of the policy. However, there are technological and other challenges that must be
overcome for the policy to be adequately implemented in order to benefit researchers globally. I shall present an overview of
these challenges and a personal view of how some the challenges can be overcome in the short-term.
[Biography]
PARTHA P. MAJUMDER is the founding Director of the National Institute of Biomedical Genomics, Kalyani, West Bengal,
and a Professor in the Indian Statistical Institute, Kolkata. His major interests and contributions are on human genome
diversity, genetics of diseases and genetic epidemiology.
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[WS2.1] Workshop 2
Human Genetics in the Global Health Service: Genetics and Genomics in Developing Countries-Part 1
Wed., April 06, 2016 15:00-16:30 Room B-1 (2F)
In order to present genetic information of countries from the developing world, we started discussions in international
meetings, International Federation of Human Genetics Executive and Scientific Committee; Sub-Committee of Developing
Workshop
Countries; UNESCO; WHO; Latin American Network of Human Genetics (RELAGH); The Human Variome Project
(HVP); Global Alliance for Genomics and Health (GA4GH) among others, and proposed discussions about this matter.
Social, economic, religious, educational and legal aspects from different countries in our region and their importance on
the future development of Genetic Services have been considered. A research survey among geneticist from Developing
Countries was prepared and the results will be discussed in International Fora.
Some of our groups has led to the discovery of many potential genetic and genomic markers of disease susceptibility,
diagnosis, prognosis and follow up. Validation and integration of new molecular tools, including the new generation
of nucleic acid analysis methods, into clinical practice pose many significant challenges at several levels of health care
systems which need to be addressed.
Possible strategies and future actions for the improvement of the quality of genetic services will be discussed. Several
International initiatives currently aiming to consolidate technologies for genetic testing, aligned with the burden of disease
in these environments will be discussed.
It is hoped that our research work will provide a means to gather information before hand and a forum for discussion
concerning the practice of medical genetics and the importance of genetic education and the planning of effective medical
genetics programs in Global Health Services, for prevention of various genetic conditions in order to reduce their burden
on the health system.
The problems, needs and challenges will be discussed in this workshop.
Wed(4)-WS2.1-1
TBD
1
Jorge Sequeiros
1:Centro de Genética Preditiva e Preventiva - CGPP, Instituto de Biologia Molecular e Celular - IBMC, Portugal
TBA
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Wed(4)-WS2.1-1
Global Genetics Services in a University-affiliated Hospital in Madrid, Spain
1,2,3
Pablo Lapunzina
1:INGEMM-Instituto de Genética Médica y Molecular-, Hospital Universitario La Paz; IdiPAZ-Instituto de Investigación del Hospital Uni-
versitario La Paz; CIBERER-Centro de Investigación Biomédica en Red de Enfermedades Raras, Spain、2:IdiPAZ-Instituto de Investigación
del Hospital Universitario La Paz、3:CIBERER-Centro de Investigación Biomédica en Red de Enfermedades Raras
Genetic services in Spain suffer from a lack of formal structuring and integration, probably due to the fragmentation of the
Workshop
Public Health system into seventeen regional health Departments (corresponding to the 17 Autonomic Communities of the
political structure of the Nation). Diverse and heterogeneous quality and tests schemes, lack of reference systems and differing
Hospital regulations, have added to the overall disorganization and fragmentation of services.
In the regional Health system of Madrid, there are 37 Hospitals and 13 of them have Genetic Services (ranging from small
Centers with less than 5 people to large Institutes with more than 100 employees).
We have set up an Institute for Medical and Molecular Genetics in Madrid with the aim to structure, harmonize and improve
the overall quality of Genetics Services at an University-affiliated, tertiary Hospital in Madrid, Spain. We have integrated
in such Institute all the Genetic Services into a common structure. This integration has allowed the optimization of tests,
genetic counselling and clinical evaluation of a huge number of patients. We have included in the Institute all the clinical and
laboratory processes into a common one (cytogenetics, molecular genetics, pharmacogenetics, genomic tests such as arrayCGH
and SNParrays and NGS technologies, including bioinformatics).
Our Institute is a model for similar initiatives in developing countries and will provide appropriate support for their develop-
ment of similar Centers in Latin America and other countries.
In this Workshop, we will show the current processes we are applying, some similar initiatives of Spain, and the advantages
and disadvantages of this model of management of Genetic Services.
[Biography]
Prof. Pablo Lapunzina M.D., Ph.D.
Medical Degree and Ph.D. at the School of Medicine, University of Buenos Aires, Argentina. Master in Molecular Genetics,
Catholic University of Buenos Aires, Argentina. He is currently the Head of the Institute of Medical and Molecular Genetics
(INGEMM) at the Hospital Universitario La Paz, in Madrid, Spain and Professor of Clinical Genetics at the University San
Pablo CEU, Madrid, Spain. He is author of more than 200 scientific papers, has granted with more than 40 research projects
and has written several books and more than 100 book chapters. Lapunzina’s research is focused on Overgrowth Syndromes,
Genomic rearrangements and Genomic Services.
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Wed(4)-WS2.1-2
Genetic Services and Public Policies in Brazil
1,2 1
Ida Vanessa Doederlein Schwartz ，Lavinia Schuler-Faccini
1:Federal University of Rio Grande Do Sul, Brazil、2:BRAZILIAN MEDICAL GENETICS SOCIETY
Recently, Brazil underwent to several improvements in health conditions, which has been reflected in improved maternal-
child health indicators. However, under-five mortality due to congenital disorders, remained unchanged (5/1,000), becoming
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the second leading cause of infant mortality, surpassed only by perinatal causes. Although there were several initiatives to
include genetics in the Brazilian public health system, less than 30% of the total demand is presently met by existing genetic
services. Most clinical genetics centers are integrated with university and referral hospitals, predominantly concentrated in
the more developed regions of the country. In 2014, the “National Policy for Comprehensive Care of People Affected by Rare
Diseases within the SUS” was enacted, 80% of them of genetic etiology. SUS, or the Unified Health System in English, is the
Brazilian publicly funded health system, and may be used by anyone, and it covers preventive and curative care, at all levels of
complexity. Policies directed at providing access to orphan drugs for rare diseases are still either unclear in Brazil. Medicines
for some rare diseases are provided through specific programs. Finally, many rare diseases have no available treatment in
the country and are not included in any assistance programs. Patients with some of these diseases receive treatment only
after recourse to the courts. Also worthy of note is the absence of any defined policy on procedures for incorporation of new
health technologies in the field of genetic diseases. The lack of established, reproducible, and transparent technical criteria to
guide the incorporation process for rare disorders contributes to an unequal relationship between citizens and health system
managers. The complexity of the issue of allocation of resources for genetic diseases and drugs imposes a pressing need for
integrated approaches that combine aspects of (bio)ethics, law, the health sciences, and economics.
[Biography]
Ida Vanessa D. Schwartz graduated in 1994, starting residency in clinical genetics in 1995, a Masters in 1998 e a Ph.D.
in 2000 (this last post graduate course ended in 2004). Among the awards and recognition received, some stand out, such
as: L’OREAL/Brazilian Academy of Sciences for Women in Science (2007), and affiliation to the Brazilian Academy of
Sciences (2008). Currently, she is associate professor of the genetics department of the Universidade Federal do Rio Grande
do Sul; coordinator of the Inborn Metabolic Clinics at Medical Genetics Service-Hospital de Clínicas de Porto Alegre, Brazil;
coordinator of the Reference Center for Gaucher Disease, Rio Grande do Sul, Brazil; member of the Scientific Committee
of the Latin American Society of Inborn Errors of Metabolism; and the Brazilian Principal Investigator for the European
network and registry for homocystinurias and methylation defects (E-HOD).
Research and Professional Experience

1999-2000/2006-2007 - Adjunct Professor (Clinical Genetics Department, Fundação Faculdade Federal de Ciências Médicas
de Porto Alegre, Brazil)
2004-2005 - Clinical Geneticist (HCPA, Brazil)
2006 - Clinical Geneticist (Hospital Materno-Infantil Presidente Vargas, Porto Alegre, Brazil)2007- 2014 - Adjunct Professor
(Genetics Department, UFRGS, Brazil)
since 2015 - Associate Professor (Genetics Department, UFRGS, Brazil)
2015 - Post-Doctorate, University of Freiburg. Supervisor : Prof. Henk Blom (Germany)
Present position
Since 1998 - Member of the Brazilian Society of Medical Genetics
Since 2007 - Coordinator of the Inborn Metabolic Clinics at Medical Genetics Service of HCPA, Brazil
Since 2008 - Affiliate Member of the Brazilian Academy of Science
Since 2011 - Member of the Ethics Committee of UFRGS, Brazil
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Since 2013 - Member of the Scientific Committee of the Latin American Society of Inborn Errors of Metabolism Academy
Since 2015 - Associate Professor (Genetics Department, UFRGS, Brazil)
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Wed(4)-WS2.1-3
Genetics and Genomics in Mexico
1
Augusto Rojas-Martinez
1:Centro De Investigacion Y Desarrollo En Ciencias De La Salud, Universidad Autonoma De Nuevo Leon, Mexico
Mexico had a population of around 112.3 million inhabitants in 2010. The population growth remains positive (1.82%). The
life expectancy is of 75.6 years and the global mortality rate is 4.9/1000 inhab. Most of Mexico’s population is mestizo, but
Workshop
the country has 6.9 million of indigenous language speakers.
The main causes of death are cardiovascular diseases, diabetes and cancer, all these considered as complex diseases. The
infant mortality rate is 18.1% and it is leaded by perinatal associated illnesses (8° place in general mortality). About 9.9/1,000
newborns have congenital malformations involving the digestive apparatus, the central nervous system, chromosomopathies
and the heart. The health care for genetic diseases in children is covered by the major health programs like social security and
the“Seguro Popular”; but the actual access to genetics services is limited and concentrated in the largest cities. There are
several public and private laboratories for cytogenetics, biochemical analyses and molecular biology testing; but the access to
these services is limited. The national program for neonatal screening contemplates detection of congenital hypothyroidism
only; nevertheless, there are services that provide testing for other conditions.
There are 9 programs of residency in medical genetics and several graduate programs offered by the main Mexican universities.
There are 7 large centers for human genomics research. The practice of medical genetics is regulated by the Mexican Council
of Genetics which associates 210 specialists (534,762 inhab./geneticist). Regarding the legislation for genomics studies,
international collaborative studies on genomics in Mexican populations are regulated by the General Health Act.
[Biography]
Physician graduated at the Escuela Colombiana de Medicina (Bogota, Colombia). M.Sc. in Human Genetics, Universidad de
Guadalajara. D.Sc. in Molecular Biology, Universidad Autonoma de Nuevo Leon (UANL, Monterrey, Mexico). Postdoctoral
training, Center for Gene and Cell Therapy (Baylor College of Medicine, Houston, Texas). Full-time professor of the School
of Medicine and Unit Leader at Centro de Investigación y Desarrollo en Ciencias de la Salud, both at UANL. Member of the
Mexican System of Researchers and the Mexican Academy of Sciences. Past-president of the Mexican Association of Human
Genetics (AMGH) and the Latin American Network of Human Genetics (RELAGH). Research interests include gene and cell
therapy, genomics of monogenic and complex diseases, and cancer molecular biology.
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Wed(4)-WS2.1-4
How can genomics contribute to population health in developing countries? A public health perspective
from Latin America
1
Victor B. Penchaszadeh
1:Latin American Bioethics Network, Argentina
In Latin America, the region of the world with the highest degree of social and health inequality, the most important
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factors affecting population health are social determinants (social class, income, education, living and working conditions,
exposure to toxics, access to health care), while population genetic variability explains very little differentials in morbidity
and mortality. The prevalence of genetic diseases and birth defects in the region is similar to that of developed countries.
Health services transitioned from being fully funded by the state, to insurance-based privatized care, with the poor still
relying on state funded plans. Access to health care is highly inequitable, including clinical genetics and genetic counseling
services, which have developed very slowly and concentrated in urban centers and academic institutions. Some countries are
developing excellence centers for research in human molecular genetics, however neglecting important environmental and social
determinants and not being effective in improving access to innovations. Criminalization of abortion has so far effectively
undermined the development of prenatal genetic diagnosis. Genomic medicine technologies are being applied in the private
sector, catering to the affluent, for diagnosis and treatment of conditions that could possibly be better controlled by public
policies addressing social determinants and life styles. It is doubtful that genomic medicine alone can contribute significantly
to population health in a region where social inequality is as high and the average annual health care expenditure per capita
is less than USD 600, unless the following prerequisites are met: public policies addressing social determinants of health,
universal access to good quality health care, clinical genetics services and genetic counseling with equitable access, research
on prevalent neglected diseases and regulation ensuring that only technologies that prove to be cost-effective are used.
[Biography]
Victor B. Penchaszadeh earned an MD from the University of Buenos Aires, Argentina (1964), a MSc in public health and
human genetics from The Johns Hopkins University (1971) and a Certificate in Bioethics and the Medical Humanities from
Columbia University (1996). After developing clinical genetic services in Argentina and Venezuela, he settled in the United
States, where he was, respectively, assistant, associate and full professor of pediatrics at Cornell University Medical College
(1981-1986), Mount Sinai School of Medicine (1986-1989) and Albert Einstein College of Medicine (1989-2002). He later joined
Columbia University School of Public Health (2002-2006) teaching epidemiology of genetic diseases. In 2007 he returned to
Argentina, where he teaches genetics, bioethics and public health. For many years he has been a consultant in bioethics and
genetics in public health to the Pan American Health Organization (PAHO/WHO) and served as president of it’s Advisory
Committee on Health Research (2004-2007). Since 2011 he is president of the Latin American and Caribbean Bioethics
Network UNESCO. He has been instrumental in applying forensic genetics in Argentina for the identification of children of
the disappeared by the military dictatorship, who were abducted and deprived of their identity. He has published extensively
on clinical genetics, public health genetics, ethical issues in genetics, bioethics of health research and genetics and human
rights.
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Wed(4)-WS2.1-5
Human Genetics in the Global Health Service
Genetics and Genomics in Developing Countries
LATIN AMERICAN REGION
1
Aida B. Falcón de Vargas
1:Clinical Genetics Unit, Hospital Vargas de Caracas, Escuela de Medicina JM Vargas, Universidad Central de Venezuela. Hospital de
Clinicas Caracas, Venezuela
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The Latin American countries are culturally and economically unique, and these differences have been always reflected in the
access to information and to new technologies. Genetic Services have been in place in many of our countries for more than
60 years.
The ECLAM, continental network of professionals interested in prevention of birth defects, operates in Central and South
America, as well as Dominican Republic since 1990. Covers an important number of the neonatal population in the region
The Latin American Network of Human Genetics, RELAGH, constituted in Vienna, 2001, at the X International Congress
of Human Genetics, is a full member of the International Federation of Human Genetics.
José María Cantú (Mexico) was the first President and Roberto Giugliani (Brazil) the Coordinator. The web page is linked
to Federal University of Rio Grande do Sul, Brazil.
The Latin American School of Human and Medical Genetics (ELAG) prepare young researchers and professionals of Latin
America in genomic medicine and promotes an annually course since 2005, which have received near 900 students from 17
Latin American countries over the last 13 years.
Most of the Latin American Countries have Human Genetics Societies and periodically organize scientific meetings in the
field.
The situation of standard clinical, and specialized Medical Genetics, and supporting laboratory diagnostic (including molecular
and cytogenetic) services in some developing countries around the Continent is different. The historical, cultural and ethnic
aspects of each country need to be discussed. The frequency of specific disorders, genes and genetic variants associated with
inherited diseases is very variable between different countries of the region. .
Possible strategies and future actions for the improvement of the quality of genetic services in Latin American countries,
including new and affordable technologies, for patients who need access to such infrastructure, will be discussed.
[Biography]
MDUCV; Medical Genetic Specialty Hospital for Sick Children, Great Ormond Street Hospital, London; PhD Institute of
Child Health, University of London. Editorial board Venezuelan Genetics Society, Journal Venezuelan Medical Federation,
Journal Acta Científica Venezolana, Venezuelan Society Internal Medicine, Journal Medical Faculty, UCV, Genetic Memories
Venezuela Genetics Society, Journal FMV, Frontier Genetics.Venezuelan Genetics Society (past -President), Venezuelan
Society of Human Genetics (Current President), Hospital Vargas de Caracas Medical Society, Internal Medicine Venezuelan
Society, ASOVAC Venezuelan Science Society, Latin-American Network Human Genetics (Vice President and Current
President), Faculty member Latin American School of Human Genetics ELAGH; the International Genetics Association,
International Federation of Human Genetics (Executive Board and Scientific Member ); Dermatoglyphics International
Association, British Clinical Genetics Society, Clinical Pathology Venezuelan Society, European Genetics Society, American
Society of Human Genetics,American College of Medical Genetics; Clinical Genetics Colombian Society; Latin American
Network of Biological Dosimetry LDBNet; Human Variome Project HVP International Consortium Country Nodes member),
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Global Alliance for Genomics and Health GA4GH,Fellow of the American College of Physician-American Society of Internal
Medicine (fellow); American College of Medical Genetics.
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[WS2.2] Workshop 2
Human Genetics in the Global Health Service: Genetics and Genomics in Developing Countries-Part 2
Wed., April 06, 2016 16:45-18:15 Room B-1 (2F)

Moderator ：Raj Ramesar（MRC Human Genetics Research Unit, Division of Human Genetics, Institute of Infectious
Disease and Molecular Medicine, University of Cape Town and Affiliated Hospitals, South Africa）
Workshop
In order to present genetic information of countries from the developing world, we started discussions in international
meetings, International Federation of Human Genetics Executive and Scientific Committee; Sub-Committee of Developing
Countries; UNESCO; WHO; Latin American Network of Human Genetics (RELAGH); The Human Variome Project
(HVP); Global Alliance for Genomics and Health (GA4GH) among others, and proposed discussions about this matter.
Social, economic, religious, educational and legal aspects from different countries in our region and their importance on
the future development of Genetic Services have been considered. A research survey among geneticist from Developing
Countries was prepared and the results will be discussed in International Fora.
Some of our groups has led to the discovery of many potential genetic and genomic markers of disease susceptibility,
diagnosis, prognosis and follow up. Validation and integration of new molecular tools, including the new generation
of nucleic acid analysis methods, into clinical practice pose many significant challenges at several levels of health care
systems which need to be addressed.
Possible strategies and future actions for the improvement of the quality of genetic services will be discussed. Several
International initiatives currently aiming to consolidate technologies for genetic testing, aligned with the burden of disease
in these environments will be discussed.
It is hoped that our research work will provide a means to gather information before hand and a forum for discussion
concerning the practice of medical genetics and the importance of genetic education and the planning of effective medical
genetics programs in Global Health Services, for prevention of various genetic conditions in order to reduce their burden
on the health system.
The problems, needs and challenges will be discussed in this workshop.
Wed(4)-WS2.2-1
Genetic Services in Mainland China, Taiwan, Hong Kong and Macau
1
Stephen T.S. Lam
1:Faculty of Medicine, The Chinese University of Hong Kong, China
The Chinese are residing in all corners in the world. However, for this presentation on the development of genetic services
among Chinese, only those living in four discrete geographic areas will be discussed. These include Mainland China (with a
population over 1.355 billion), Taiwan (23.4 million), Hong Kong (7.07 million) and Macau (0.636 million). Chinese living
outside of these four places are generally referred to as Overseas Chinese, and has an estimated total of over 50 million.
Because of historical, geographical, epidemiological, economic, social and political reasons, the four major populations under
discussion have developed on different lines in terms of healthcare systems (including clinical and public health services); legal
regulations, policies and administrative functions; education and training of manpower; and research emphasis. In the field
of genetic and genomic services, for example, notable differences are evident in the family planning policies among the four
administrations. These have significant effect on the population demographies and result in variations in the approaches in
the provision of genetic services. Yet, all of them face the same problem of ageing population. Alternatively, the vastness of
Mainland China also has implications on the delivery of services, which tend to differ between the urban and rural healthcare
systems. Epidemiological differences are related to ethnicities and environmental factors, and interesting differences are
observed among the incidences and prevalences of genetic diseases in these populations . These differences account for
variations in the emphasis of healthcare delivery and research. Although these Chinese populations share many common
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values, there are also notable differences which account for the diversity of views related to ethic, legal and societal issues.
These major issues in the development of genetic services in these Chinese populations will be discussed.
[Biography]
Dr Stephen Lam was a MBBS graduate from the University of Hong Kong. Subsequently, he was trained in Paediatrics and
Clinical Genetics in Queen Elizabeth Hospital, Hong Kong and Guy's Hospital, London. For his research on Biochemical
Genetics and Cytogenetics, he was awarded Doctor of Medicine at the University of Hong Kong in 1988. He is now Fellow of
Workshop
Hong Kong College of Paediatricians, Fellow of Royal College of Physicians of Edinburgh, and Fellow of Hong Kong Academy
of Medicine. He was the Consultant Clinical Geneticist and Head of Clinical Genetic Service, Department of Health, Hong
Kong (1990-2015). His main clinical activities and research are in the diagnosis and prevention of genetic diseases and ethical,
legal and social issues in genetics. He has published more than 100 peer-reviewed articles and edited two books. He was the
Founding Chairman of the Hong Kong Society of Medical Genetics in 1987, a council member of the International Society
for Neonatal Screening, and a serving committee member of the Chinese Genetics Society. He is a Past President of the Asia
Pacific Society of Human Genetics (2011-12), and a Past President of the International Federation of Human Genetic Societies
(2012-14). He serves as editor of several international journals including Clinical Genetics, HUGO Journal, and Journal of
Community Genetics. He is an Honorary Professor of the Faculty of Medicine in the Chinese University of Hong Kong since
2012.
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Wed(4)-WS2.2-2
Evolution of Medical Genetics to Genomic Medicine Services: The Situation in South Africa
1
Raj Ramesar
1:MRC Human Genetics Research Unit, Division of Human Genetics, Institute of Infectious Disease and Molecular Medicine, University of
Cape Town and Affiliated Hospitals, South Africa
South Africa is a country of some 53 million people - with reasonably good infrastructure. Health care is provided to its citizens
Workshop
mostly through a public health care system comprised of clinics at primary or district level, to secondary hospitals, ultimately
to tertiary and quaternary hospitals - the latter are mostly attached to academic centres, which are not equally distributed,
geographically. Effectively, medical genetic services are provided through a range of general medical, paediatric and ob/gyn
facilities - however, specialist genetic services are available at only about five centres nationally, through approximately 10
specialist Medical Geneticists, 15 Genetic Counsellors, and a handful of Genetic Nurses. Diagnostic laboratory services are
provided within the network of the National Laboratory Health Services (NHLS). All of the genetic services (clinical and
laboratory) are based on a history of research into genetic disorders in our communities, and the development of relevant
genetic tests.
The majority of genetic services rely on patient or family- initiated contact (through a primary clinical referral) - such
patients/families are then consulted, diagnosed and managed, often within a team approach. Despite the clear shortage of
specialist medical genetic services, there is a clear need to revisit the role of the Medical Geneticists, Genetic Counsellors and
Genetic Nurses, in an environment where there is a clear need to educate and train other health care providers in the area
of genetic/genomic medicine. This situation is exacerbated by the unanticipated arrival of next generation technologies e.g.
whole exome sequencing, which is being offered to people with private health insurance, yet there is no workforce trained to
process and impart such information sensibly. This situation obviously exposes gaps in the education/training system, and
the lack of alignment between the public and private health care sectors. The role of an expanded training programme for
Genetic Counsellors is currently being explored in our environment.
[Biography]
Raj Ramesar is Professor and Head of the Division of Human Genetics at the University of Cape Town and its Affiliated
Hospitals in South Africa. This facility has wide-ranging clinical responsibilities from the quaternary and tertiary care levels,
to extensive rural outreach programmes, in addition to diagnostic and research capabilities. His interest is in using the
exciting developments in the field of genomic sciences to investigate human biodiversity. Africa offers the opportunity to use
population lineages in all of their richness towards identifying aspects of human biology, that have to do with both health
and disease.
As the Director of the MRC Human Genetics Research Unit, the emphasis of his research has been on disease susceptibility in
South African populations, progressing from the commonly recognised inherited diseases, to those that are more complex yet
more common and relevant to a large burden of disease. In this regard, he has been involved in researching Retinal Degenerative
diseases for the past 25 years - and has been working very closely with the lay support group: Retina South Africa, in terms
of developing and maintaining an active and translational research agenda. Furthermore, his most recent research enterprise
is embodied in a large scale project entitled:‘Human Diversity and Health’. As Director of the national Colorectal Cancer
Research Consortium his focus has been on the genetics of familial colorectal cancers, and the most effective translation of
laboratory findings to the field for optimum benefit of patients and their kin. In this regard, Raj recently received the (Vice
Chancellor’s) Alan Pifer Award for ‘outstanding research in cancer genetics which shows relevance to the advancement of
South Africa’s disadvantaged populations’. His most recent research involves whole exomic and whole genome sequencing for
disorders seen in South Africa, as well as investigating responses to drugs in Southern African populations. Apart from being
on the editorial board of several international journals, Raj serves as co-chair of the Scientific and Medical Advisory Board
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of Retina South Africa, he is on the Executive of the African Society for Human Genetics, and is the latter organisation’s
Liaison Officer to the International Federation of Human Genetics Societies. As Chair of the Local Organising Committee, he
organised the Joint Conference of the African and Southern African Societies in Cape Town (www.humangenetics2011.org).
Raj also led a successful bid to host the International Congress of Human Genetics in Cape Town in 2021. He serves on
several international advisory panels pertaining to genomic research, including that for: Human Heredity and Health: Africa
(or H3Africa).
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Wed(4)-WS2.2-3
Genetic Services in the Philippines
1,2,3
1:Department of Pediatrics, College of Medicine, University of the Philippines Manila; Institute of Human Genetics, National Institutes
of Health, University of the Philippines Manila; Philippine Genome Center, University of the Philippines System, Philippines、2:Institute
of Human Genetics, National Institutes of Health, University of the Philippines Manila、3:Philippine Genome Center, University of the
Philippines System
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The Philippines is a developing middle-income country in Southeast Asia with a population of 100M and annual births of 2M.
Delivery of medical genetic services remains to be a challenge in both private and public sectors. Infectious diseases are still in
the top ten causes of infant mortality and morbidity and as such, limited attention is given to congenital anomalies and other
genetic diseases. This is aggravated by the lack of geneticists and genetic counselors to serve the patients spread out in 7100
islands. Today, the Institute of Human Genetics at the National Institutes of Health, University of the Philippines Manila is
the largest provider of genetic services in the Philippines. It has the following units: clinical genetics unit, cytogenetics unit,
newborn screening center, molecular genetics unit and biochemical genetics unit. Its twin Institute is the Newborn Screening
Reference Center, NIH. The 2 institutes are instrumental in the policy development linked to genetics - the Newborn Screening
Act of 2004 and the recently passed Rare Disease Act that awaits the signature of the President of the Philippines. The 2
institutes supervise the implementation of the national newborn screening program and the operation of 14 satellite newborn
screening cum birth defects continuity clinics in the different parts of the country. In the last 5 years, government support for
genomic research has increased with the establishment of the Philippine Genome Center that offers core facilities (sequencing
and bioinformatics) and 5 research programs (health; agriculture; biodiversity; forensics & ethnicity; ethics, legal and social
issues). Genomic health researches focus on infectious diseases (dengue, H1N1, etc) and lifestyle diseases (cardiovascular
diseases, diabetes mellitus, etc). In response to the lack of geneticists, the Department of Pediatrics, College of Medicine
offers the Master of Science in Genetic Counseling to produce genetic counselors.
[Biography]
Academician of the National Academy of Science and Technology in 2008. Dr. Padilla is a pioneer in genetics in the
Philippines and the Asia Pacific region. In the Philippines, she is responsible for setting up the clinical genetic services and
the various genetic laboratories now housed at the Institute of Human Genetics - National Institutes of Health Philippines.
She is also responsible for setting up of national newborn screening services in the Philippines, currently available in 6000+
health facilities in the country. In the Asia Pacific region, she is part of the pioneering group that established the Asia
Pacific Society for Human Genetics and served as president in 2008-2010. Dr. Padilla is Council member of the Human
Genome Organization, an international organization of scientists from 69 countries. She is Vice President and Treasurer of
the International Society for Neonatal Screening. In 2010, she was appointed country representative to the InterAcademy
Medical Panel, a global network of more than 60 academies in the world. Dr Padilla has more than 100 publications. In the
area of policy making, she is responsible for the Newborn Screening Act of 2004 and the Rare Disease Act that was recently
passed into law.
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Wed(4)-WS2.2-4
Genetics and Genomics: The Collaboration between Belgium and The Democratic Republic of Congo
1
Thomy JL de Ravel
1:Centre for Human Genetics, University Hospitals Leuven, KU Leuven, Belgium
The University of Leuven taught human genetics and had human genetics laboratories in the early 1960’s in the capital of
the now-called Democratic Republic of the Congo (DRC). This activity dwindled soon thereafter and stopped altogether until
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the 21st century, when an active collaborative and supportive bond has been established between the University of Leuven
and the Universities of the DRC.
The Congolese Society of Human Genetics was recognized early in 2013 and organized the successful and well supported first
congress of human genetics in Kinshasa at the end of May 2013. The second such meeting took place in 2015.
In the last 5 years, a laboratory of human genetics has been established at the University of Kinshasa, and a Professor of
Human Genetics appointed to teach human genetics in the network of universities. Clinicians have been sent to Leuven to
gain experience in various aspects of the field, the first paediatrician obtaining his doctorate in the field of clinical genetics in
2015. There is presently a second paediatrician registered for a human genetics doctorate.
In the DRC, genetics clinics are being held at a number of cities at present, and some of the basic laboratory work being
carried out at their laboratory. The interaction and involvement between the two countries in this domain will be discussed.
[Biography]
Professor Thomy de Ravel received his M.D. from the University of the Witwatersrand in Johannesburg, South Africa, where
he thereafter specialized in both Paediatrics and Child Health, and in Clinical Genetics. After 10 years as coordinator of
the Clinical Genetics Services and also Head of the Cytogenetics laboratory, he moved to Leuven, Belgium. He read for
his PhD, this relating to the development of molecular karyotyping and interpretation of findings. He is presently Clinical
Geneticist and also Clinical Head of the Constitutional Cytogenetics facilities at the Centre for Human Genetics, University
Hospitals Leuven. His interest lies in the field of interpretation of the influence of a CNV in the expression of disorders,
in vitro fertilisation and pre-implantation diagnostics, and also clinical genetics in general. He is Board member, was the
Secretary, and has been President of the Belgium Society of Human Genetics the last 4 years, this being the Belgian HSV
node. He is also a Board member of the Belgian Paediatric Society.
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Wed(4)-WS2.2-5
Genetics and genomic in developing countries: the Malaysian experience
1
Zilfalil Alwi
1:Universiti Sains Malaysia, Malaysia
In Malaysia, knowledge revolution regarding the role of inheritance in health and disease has evolved over the last 20 years
through advances in human genetics field. The annual expenditure for ministry of health is 8.02% of the national budget and
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a sum of MYR 159,199,348 was allocated for research and technical support. Various genetic diseases are seen in its multi-
ethnic population which comprises of 50.4% Malays, 23.7% Chinese, 7.1% Indians, 11% indigenous and 7.8% of other ethnic
groups. Genetic disorders such as Thalassemia, Duchene Muscular Atrophy, Spinal Muscular Atrophy, G6PD deficiency,
orofacial Clefts, and Down syndrome are common in the country and an ethnic-specific molecular variation database has
been established for these diseases by the Malaysian Node of Human Variome Project (MyHVP). Medical genetic service
in Malaysia was introduced in 1994 and later in 1999, the first medical genetic services started in Kuala Lumpur Hospital
followed by Penang general hospital (for northern peninsular Malaysia), Johor Bahru (south peninsular Malaysia), and
Kuching general hospital (East Malaysia). Subsequently, 2 genetic centers were established at teaching hospitals; National
University of Malaysia (Kuala Lumpur) and Universiti Sains Malaysia (East Coast Peninsular Malaysia). Over the last 2
decades, the services gradually improved with the availability of genetic counselling, genetic testing and diagnosis. In addition,
a 4 year Master of Pathology (MPath) Medical Genetics training program was established in 2011 to train medical doctors
from Ministry of Health Malaysia in Medical Genetics. The genetic field advanced rapidly with government recognition and
support, increased funding, medical ethics guideline development and availability of support groups.
[Biography]
Professor Dr Zilfalil Bin Alwi started his medical career as a medical officer after completing his Bachelor of Medicine and
Bachelor of Surgery (MBBS) degree at University of Dacca. He joined Universiti Sains Malaysia (USM) School of Medical
Sciences as a Trainee Lecturer in 1994, and was later awarded the Master of Medicine (MMed) in Pediatrics from USM.
He then obtained his second Master degree (MSc) in Medical Genetics from University of Glasgow, United Kingdom and
then continued his studies at University of Aston, United Kingdom, where he was awarded Doctor of Philosophy (PhD) in
Pharmacogenetics.
His research interest includes genetics of childhood Spinal Muscular Atrophy (SMN genes & NAIP gene), population genomics
(genetic diversity of the Malay race) and genome wide studies on diseases common to the local population. He has published
more than 100 papers in international and local journals and presented more than 200 papers at local and international
conferences.
He is a member of the Pan-Asia SNP research consortium (PASNPI) which studies the genomic profile of the Asian population.
Professor Zilfalil is the founder and Head of the Malaysian Node of Human Variome Project (MyHVP).
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Wed(4)-WS2.2-6
GENOMIC CHALLENGES AND INITIATIVES IN THE FAST EMERGING ECONOMY OF INDIA- A
PARADIGM FOR THE DEVELOPING COUNTRIES
1,2,3 1,2
Dhavendra Kumar ，Dhavendra Dhavendra ，INDO-UK GENETIC EDUCATION FORUM
1:Institute of Cancer & Genetics Genetics, University Hospital of Wales, Cardiff, UK; Genomin Policy Unit, University of South Wales,
Pontypridd, UK; The Genome Medicine Foundation, Cardiff, UK、2:Genomic Policy Unit, University of South Wales, Pontypridd, UK、3:The
Genomic Medicine Foundation (UK), Cardiff
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The peoples of India (population ~ 1.2 billion) represent many socio-cultural beliefs and practices; diversity is unique for the
demographic landscape of India. Genomic variation data is available generated from the India Genome Variation project,
largely linked to Indo-European, Indo-Tibetan and tribal languages. Some genomic variation data exists linking peoples
inhabiting the Indian Ocean islands, South East Asia, Far East, Micronesia and Australasia.
Genetic disorders include birth defects-congenital developmental anomalies and early onset inherited metabolic and childhood
diseases) led by inherited hemoglobinopathies. Patchy and inconsistent data is available on genome sequencing in relation
to few complex disorders, for example oral cancer, type 2 diabetes mellitus & coronary artery disease. During the last 10
years, the emergence of many academic and private institutions and hospitals interested in fetal medicine/ prenatal diagnosis,
pediatric and young adults genetic diseases has led to wide public and media interest in genetic diseases. There is very
inconsistent genetic counseling support to both diagnostic genetic laboratories and genetic clinics largely based in the private
sector. However, during the last 5 years some interest in creating and encouraging genetic & genomic education and skills
base has led to post graduate teaching and training opportunities to for career genetic specialists or developing special interest
within the chosen specialty.
Apart from the health sector, there is visible interest and enthusiasm for harnessing advances in genome science and technol-
ogy in a number of innovative areas including development of new drugs, eco-genomics, nano-genomics, stem cell genomics
and bio-fuels/bio-engineering. There is tremendous scope for pharmaceutical and other biotechnology industrial sectors. As
the fast emerging economy of the developing world, India is well placed to harness gains of new technological advances and
revolution of genomics.
[Biography]
Professor Dhavendra Kumar, MD,DSc,FRCP,FRCPCH,FACMG, Consultant in Clinical Genetics,the University Hospital of
Wales,Cardiff University,UK. He served as an advisory member for WHO project on ‘Challenges of genomics for developing
countries’. Since 2010, he has served on the Council/ Co-Editor of the Human Genome Organization International (HUGO).
He works closely with the Human Variome Project and the Genomic Alliance for Global Health (GA4GH).
He has authored/edited ‘Genetic disorders of the Indian Subcontinent’, 2004; ‘Genomics and Clinical Medicine’,2008; ‘Prin-
ciples and Practice of Clinical Cardiovascular Genetics’,2010, ‘Oxford Specialist Handbook on Inherited Cardiac Disease’,
2011, ‘Oxford Genomics and Health in the Developing World’,2012 and ‘Oxford Genomic Medicine- Principles & Prac-
tice’,2014. He is the founding editor in chief for Applied and Translational Genomics, Genomic and Molecular Medicine,
Current Trends in Genomic Medicine and Cardiovascular Genetics & Genomics.
He is the Founder/Lead for the ‘Indo-UK Genetic Education Forum’; widely acclaimed for promoting and supporting ge-
netics/genomics teaching across India and the Indian subcontinent. He continues to work and engage in discussion and
collaboration for raising awareness and promoting genetics/ genomics for improved healthcare and socio-economic benefits in
the emerging economies of the developing world.
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[WS3] Workshop 3
Current Issues of Medical Genetics in Asia
Wed., April 06, 2016 15:00-16:30 Room C-2 (1F)
Moderator：Poh-San Lai（National University of Singapore, Singapore）

Moderator ：Jin-Sung Lee（Department of Clinical Genetics, Yonsei University College of Medicine, Korea）
Medical genetics has indisputably advanced our understanding of many disorders and identified many new genes and
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genetic conditions. In many developed countries, genomic medicine is providing clinicians with new tools and knowledge
to diagnose, treat and manage patients based on individual genetic profiles. In Asia, improvements in healthcare over the
decades have led to lower infant mortality rates and higher life expectancies. However, despite being home to more than
half of the world’s population and with six of the 10 largest nations in the Asia Pacific region, there are disparities among
different countries in Asia with regards to issues such equity and access to molecular genetic testing; scope of newborn and
population screening programs; adequacy of genetic services coverage under national healthcare systems; availability of
sufficient trained clinical geneticists and genetic counselors; extent of knowledge and understanding in new genetic testing
technologies like array CGH, non-invasive prenatal screening, next-gen sequencing, etc. among primary care providers
and specialists; regulatory control of genetic testing and the role of direct-to-consumer companies; challenges in genomic
medicine such as handling of incidental findings from NGS testing, barriers for clinical trials for genetic disorders, etc.
As precision medicine is poised to shift the way healthcare is managed and how patients are diagnosed and treated all
over the world, this workshop aims to promote dialogue in this area to better understand the issues faced and to explore
novel approaches to drive the practice of medical genetics in Asia. The audience will be invited to submit questions which
will be addressed by members of the Panel.
Wed(4)-WS3-1
Genomic Medicine and Medical Genetics Service in Vietnam
1
Vu Chi Dũng
1:Department of Medical Genetics, Metabolism and Endocrinology, National Hospital of Pediatrics, Hanoi, Vietnam
Vietnam is the easternmost country on the Indochina Peninsula in Southeast Asia. With an estimated 90 million inhabitants
as of 2013, it is the world’s 13th-most-populous country, and the eighth-most-populous Asian country. The overall quality of
health in Vietnam is good, as reflected by 2010 estimates of life expectancy (76.86 years) and infant mortality (14.8 per 1,000
live births in 2015 - General Statistics Office). Congenital anomalies accounted about 16% of causes of deaths in children under-
5 (Health profile 2013. WHO). The prevalence of birth defects combined ranges from a high of 60.9 to a low of 51.1 per 1000
live births in Vietnam. The number of children born with birth defects annually was 87 333 in Vietnam. The prevalence (per
1000 live births) of five common serious birth defects of genetic or partially genetic origin in Vietnam were: congenital heart
defects (7.9); neural tube defects (1.9); pathological hemoglobin disorders (0.9); Down syndrome (1.7) and G6PD deficiency
(2.1) (MOD - 2006). National registry and genotype databases are available for α and β Thalassemia; Duchenne muscular
dystrophy; spinal muscular dystrophy; congenital adrenal hyperplasia due to mutation of CYP21A2, CYP11B1 and HSD3B2
genes; congenital hyperinsulinism due to mutation of ABCC8, KCNJ11 and HNF4A genes; monogenic diabetes (neonatal
diabetes and MODY); osteogenesis imperfecta due to mutations COL1A1 and COL1A2 genes, haemophilia A; disorders of
sex developments due to mutations of AR, SRD5A2, and WT1 genes; some inborn errors of metabolism: beta-ketothiolase
deficiency due to mutation of T2 gene, urea cycle disorders due to mutations of OCT and ASS genes, maple syrup urine
disease due to mutations of BCKDHA, BCKDHB, and DBT, X-adrenoleukodystrophy due to mutations of ABCD1, citrine
deficiency, MPS I, MPS II, MPS IVA and MPS VI due to mutations of IDUA, IDS, GALNS and ARSB genes, respectively;
mitochondrial disorders and some cancers in children and adults. Further more, the c.1165A>G mutation in SBCAD is
very prevalent in “Hmong” minority (carrier freq. of 1:9). Clinical genetics service is available at the Northern referral
centre of Pediatrics - Vietnam National Children’s Hospital and provides services to the population of north VietNam (~
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30 million people) and for rare genetic diseases from whole country. Cytogenetic and molecular genetic testing for prenatal
and postnatal diagnosis is available in many centres of big cities. Newborn screening program was started in 1998 and there
are 7 newborn screening centres currently and provides screening for G6PD deficiency, congenital hypothyroidism, congenital
adrenal hyperplasia, hearing loss, congenital heart diseases and pilot for inborn errors of metabolism using MS/MS). Support
groups were organised for several genetics rare diseases.
[Biography]
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Dr. Vu Chi Dung is from Vietnam National Children’s Hospital and has extensive experience with Medical Genetics,
Inherited Metabolic Disease and Molecular Pediatric Endocrinology. He is now Head of Department of Medical Genetics,
Metabolism and Endocrinology, Vietnam National Children’s Hospital. He was pediatric resident in France at the Medical
Genetic Center of the Hospital Pediatrics of St. Antony, Catholic University of Lille and was research fellow for 3 years at the
Medical Genetics Division, Department of Pediatric, Saint Louis University, MO, USA. He was a fellow at Royal children’
s Hospital, Melbourne, Australia in Aug. 2001 and Mar. 2005 and Jul - Aug. 2010. He was awarded the Pfizer Overseas
Fellowship according to outstanding presentation for the Japanese Society for Inherited Metabolism Diseases in 2004. He
received a Travel Award to attend the 11th International Congress of Inborn Errors of Metabolism (ICIEM) in San Diego,
California, USA from 29 August through 02 September, 2009. He was granted Asian Investigator Award at the 53rd annual
meeting of the Japanese Society for Inherited Metabolic diseases and the 10th annual symposium of the Asian Society for
Inherited Metabolic diseases in November 24-26. 2011 in Chiba, Japan; The Award for Excellent Study of the joint meeting of
the 2nd Asian Congress for Inherited Metabolic Diseases (ACIMD) & the 12th Asian-European Workshop on Inborn Errors
of Metabolism in Seoul, Korea from April 1st to 4th, 2012. He is a reviewer and editorial board member for several scientific
journals.
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Wed(4)-WS3-2
National genetic screening and molecular testing program in Thailand
1
Suthat Fucharoen
1:Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Salaya Campus, Nakornpathom, Thailand
Thailand is the 51st-largest and 20th-most-populous country in the world with around 66 million people. About 75-95% of the
population is ethnically Tai with Thai Chinese 14% of the population, while Thais with partial Chinese ancestry comprise up
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to 40% of the population. Life expectancy in Thailand is seventy years. A universal health care system has been established
since 2002. Years of life lost, distributed by causes was 24% from communicable diseases, 55% from non-communicable
diseases, and 22% from injuries. 30-40% of the Thais are thalassemia carriers thus thalassemia control program was started
in 2003. There are 22 practicing clinical genetic units. Prenatal diagnosis for Mendelian diseases and preimplantation genetic
diagnosis (PGD) is available in both government and private hospitals. Although enzymatic assays of various enzymes were
desired, sufficient financial support is not available therefore most inherited metabolic disorders are diagnosed by molecular
testing. Cytogenetic services laboratories have become available throughout the country. Noninvasive prenatal fetal trisomy
testing as well as rapid noninvasive diagnostic methods for common aneuploidy is available. DNA testing was first done for
thalassemia and later for other Mendelian disorders. Pharmacogenetic testing for HLA-B*1502, which is a susceptibility allele
for Stevens-Johnson syndrome in-patients treated with carbamazepine is available. Cancer-related pharmacogenetic testing
for target therapy is also available in the country. Next generation sequencing technologies for research has been available for
the last few years with limited service because a deficiency in well-trained bioinformaticians. Since 1996 newborns screening for
congenital hypothyroidism and phenylketonuria was carried out but other neonatal screening for inborn errors of metabolisms
is not funded by National Health Security Office (NHSO). Birth Defects Registry was first developed in 2008 for five birth
defects namely Down syndrome, neural tube defects, cleft lip/palate, limb defects, and Duchene muscular dystrophy and for
the others in the last 3 years.
Genetic disease has a higher prevalence in Thailand. There are limitations such as inadequate budget, insufficient advanced
technologies and knowledgeable personnel in bioinformatics, and inefficient supporting systems. Thai physicians/scientists
are working in collaborations with foreign researchers throughout the world. This leads to better care of patients in Thailand
and migrants from neighboring countries.
[Biography]
Dr. Suthat Fuchareon is Professor Emeritus at the Institute of Molecular Biosciences, and Director of the Thalassemia
Research Center, Mahidol University, Nakornpathom, Thailand.
Dr. Fuchareon is internationally recognized for his work on thalassemia in Thailand and Southeast Asia. His scientific interests
encompass the spectrum of basic, translational, clinical and epidemiological research. Work from the Thalassemia Research
Center at Mahidol University has set the standard for defining the molecular genetics, genomics, and genotypic/phenotypic
correlations of thalassemic syndromes. His many publications include clinical trials on the use of inducers of fetal hemoglobin
and iron chelation, the use of MRI imaging for assessment of iron overload, as well as landmark epidemiologic studies defining
the genetic diversity and public health burden of these diseases.
Dr. Fuchareon has been the recipient of many honors, among them the Outstanding Researcher Award from the National
Research Council of Thailand, Outstanding Scientist Award from the Foundation for the Promotion of Science Award and
Technology under the Patronage of His Majesty the King of Thailand. Dr. Fuchareon had delivered the Berend Houwen
Lecture at the International Society for Laboratory Hematology in New Orleans on May 6, 2011

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Wed(4)-WS3-3
Medical genetics services in Malaysia: Challenges and the way forward
1
Meow-Keong Thong
1:Genetics and Metabolism Unit, Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
The first medical genetic service In Malaysia was introduced in 1995 at the University of Malaya Medical Centre. Two decades
later, medical genetic services were made available at 4 centers with genetic counseling, genetic testing and diagnosis as well
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as treatment for both paediatric and adult-onset inherited conditions. Prenatal diagnosis services and assisted reproductive
technologies are available at tertiary centres and private medical facilities. Outreach genetic services are being made available
in Penang, Sarawak and other centers.
Positive developments included governmental recognition of Clinical Genetics as a subspecialty in the National Specialist
Register, increased funding for genetics services, development of medical ethics guidelines and curricula and establishment of
support groups. However, the country lacked qualified genetic counselors. A genetic counseling course was started but due
to economic cutbacks, there are no posts created for genetic counselors. A pilot expanded newborn screening program was
completed but due to inadequate support and services in rural areas and smaller cities, the program had been postponed.
Other challenges encountered included limited resources and public awareness, unresolved ethical dilemmas pertaining to
psychosocial issues such as termination of pregnancy for birth defects, religious and cultural factors and inadequate genetic
health professionals. The high cost of genetics services and lack of insurance coverage coupled with the introduction of
recent genomics technologies, direct-to-consumer testing and new pharmaceutical products for rare diseases have added to the
current challenges. In the next decade, genomic counselling and mainstreaming of genetics service to the primary healthcare
system as well as increased research and training in genetics will increase. The evolving roles of the clinical geneticists and
genetics service will be subjected to further scrutiny and consolidation.
[Biography]
Dr THONG Meow-Keong is a Professor of Paediatrics and Consultant Clinical Geneticist at the University of Malaya Medical
Centre. He was a Fulbright scholar and a board-certified clinical geneticist by the Human Genetics Society of Australasia. He
established the first Genetics Clinic in 1995 and the Genetics & Metabolism Unit at the Department of Paediatrics, Faculty
of Medicine, University of Malaya. He has published over 60 peer-reviewed journal articles, authored 3 books, including the
Handbook of Hospital Paediatrics (2nd edition), Problem-based Learning in Medical Sciences and 10 book chapters, co-wrote
3 monographs and presented over 150 conference proceedings. He had won numerous research awards and worked with the
Ministry of Health Malaysia and WHO in developing counselling module for thalassemia and other paediatric disorders. His
current research interests included birth defects and genetic disorders, genetic counselling and inborn errors of metabolism.
He was the Head, Department of Paediatrics, University of Malaya from 2009-2011, the immediate past President of the Asia-
Pacific Society of Human Genetics and current President of the College of Paediatrics, Academy of Medicine of Malaysia;
Chair of the Clinical Genetics subspecialty, National Specialist Register, Vice-President of the Medical Genetics Society of
Malaysia and Advisor to the Malaysian Rare Disorders Society.

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Wed(4)-WS3-4
Genetic Testing in China
1
Xue Zhang
TBA
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Wed(4)-WS3-5
Basic and Expanded Newborn Screening: Setting the Stage for Low Income and Middle Income Countries
1,2,3
1:Department of Pediatrics,College of Medicine, University of the Philippines Manila; Institute of Human Genetics, National Institutes
of Health, University of the Philippines Manila; Newborn Screening Reference Center, National Institutes of Health, University of the
Philippines Manila, Philippines、2:Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila、3:Newborn
Screening Reference Center, National Institutes of Health, University of the Philippines Manila
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Newborn screening (NBS) is an important public health measure aimed at early identification and management of affected
newborns thereby lowering infant morbidity and mortality. It is a comprehensive system of education, screening, follow-up,
diagnosis, treatment/management, and evaluation that must be institutionalized and sustained within public health systems
often challenged by economic, political, and cultural considerations. Since its introduction by Dr. Guthrie in the ‘60s, there
have been major developments in the panel of disorders, screening technology, follow up protocols etc. NBS has become a
standard of health care in high-income countries. Low-income and middle-income countries have been challenged if newborn
screening must be a priority when there are more pressing health issues, i.e. control of death of infectious diseases and vaccine-
related diseases. It is the stand of the International Society for Neonatal Screening that all newborns in the world must be
given the opportunity to be saved from conditions that can be treated from birth. Developing countries face unique challenges
in implementing and expanding NBS that can be grouped into the following categories: 1) planning, 2) leadership; 3) medical
support; 4) technical support, 5) logistical support; 6) education; 7) protocol and policy development, 8) administration, 9)
evaluation, and 10) sustainability. This presentation reviews some of the experiences in overcoming implementation challenges
in developing newborn screening programs, and discusses model efforts aimed at encouraging increased newborn screening
through support networking and information exchange activities in the Asia Pacific. The Philippine program started 20 years
ago in 1996, initially with the basic panel of CH, CAH, Gal, PKU and HCY, and has recently expanded to 28 disorders. Just
when is a country ready?
[Biography]
Academician of the National Academy of Science and Technology in 2008. Dr. Padilla is a pioneer in genetics in the
Philippines and the Asia Pacific region. In the Philippines, she is responsible for setting up the clinical genetic services and
the various genetic laboratories now housed at the Institute of Human Genetics - National Institutes of Health Philippines.
She is also responsible for setting up of national newborn screening services in the Philippines, currently available in 6000+
health facilities in the country. In the Asia Pacific region, she is part of the pioneering group that established the Asia
Pacific Society for Human Genetics and served as president in 2008-2010. Dr. Padilla is Council member of the Human
Genome Organization, an international organization of scientists from 69 countries. She is Vice President and Treasurer of
the International Society for Neonatal Screening. In 2010, she was appointed country representative to the InterAcademy
Medical Panel, a global network of more than 60 academies in the world. Dr Padilla has more than 100 publications. In the
area of policy making, she is responsible for the Newborn Screening Act of 2004 and the Rare Disease Act that was recently
passed into law.
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Wed(4)-WS3-6
Clinical Genetics in Japan
1
Yoshimitsu Fukushima
1:Ex-President, The Japan Society of Human Genetics; Professor, Department of Medical Genetics, Shinshu University School of Medicine,
Japan
The Japan Society of Human Genetics (JSHG) was established in 1956, when the First International Congress of Human
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Genetics (ICHG) was held in Copenhagen. The Department of Human Genetics was first founded in Tokyo Medical and
Dental University in Japan also in 1956. Compared to the start of the basic research department, it took very long time
to start clinical genetics in Japan. The first clinical genetics division is founded in Kanagawa Children’s Medical Center
in 1971. Thereafter several children’ hospital established clinical genetics division . One of the reasons of the delay is
Japanese mentality for genetics. Many Japanese feel that genetic problems must result from somebody’s guilt. Even medical
professionals had wanted to avoid troubles concerning genetics. As the clinical genetics practice is necessary not only in the
field of birth defects or prenatal diagnosis, but also in clinical fields such as familial cancer, neurological diseases, deafness and
even other almost all medical fields, the first clinical division of university hospitals launched at Shinshu University Hospital in
1996． Subsequently, clinical genetics sections had been established in several University Hospitals, and the Japan’s National
Liaison Council for Clinical Sections of Medical Genetics was formed in 2003. Now, 111 institutions including all 80 university
hospitals join the Council. The Japan Society of Human Genetics (JSHG) is a scientific organization on behalf of Japan about
medical genetics and clinical genetics. The membership of the JSHG doubles in recent ten years, and it is more than 5,000.
The backgrounds of the member are a physician (pediatrician, Ob/Gyn, internist, surgeon, ENT, dermatologist, and so on),
a researcher (cytogeneticist, molecular geneticist, biochemical geneticist, ELSI and so on), a co-medical staff (nurse, midwife,
public health nurse, laboratory technologist) and a certified genetic counselor. Now, JSHG advocate the aim (Contribute to
the progress of science; Contribute to medical practice and welfare; Spreading proper knowledge of genetics by education;
Preventing genetic discrimination; Creating the society which each other respects assuming human variety) and are active
lively under the principle of genetics: “Genetics is the study of heredity and variation”.
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[WS4] Workshop 4
HUGO-PAPGI (Pan-Asian Population Genomics Initiative)
Wed., April 06, 2016 16:45-18:15 Room C-2 (1F)
Moderator：Sumio Sugono（Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University
of Tokyo, Japan）
Moderator ：Poh-San Lai（National University of Singapore, Singapore）
Workshop
The HUGO Pan-Asian Population Genomics Initiative (HUGO-PAPGI) is a collaborative international effort to sys-
tematically collect, analyse and understand the genetic diversity of the Asian populations. The main objective of this
consortium is to unravel patterns in genomic diversity modulating phenotypic traits and thus contribute to the baseline
data for understanding genomic diversity and healthcare interventions in this area. Additionally, it also aims to develop
a framework for exchange and sharing of resources, expertise and training between countries. HUGO-PAPGI had its
roots from the HUGO-HUGO Pan-Asian SNP consortium which had characterized genome-wide SNPs across 73 Asian
population groups in order to map human genetic diversity in Asia (Science, 11 Dec 2009:ol. 326, Issue 5959, pp. 1541-
1545, DOI: 10.1126/science.1177074). This workshop highlights work from PAPGI members in unraveling the geographic
structure of genetic variation across the continents and in searching for disease-associated genes.
Wed(4)-WS4-1
HUGO-PAPGI (Pan-Asian Population Genomics Initiative) update
1
Jong Bhak
1:Biomedical Engineering, UNIST, Korea
HUGO-PAPGI (Pan-Asian Population Genomics Initiative) is a volunteer based consortium to map the genomic diversity
of Pan Asia. This is the second phase of PASNP (Pan Asian SNP) consortium. The main difference between PAPGI and
PASNP is that PASNP used SNP chips while PAPGI uses whole genome sequences to map Asian genome diversity. Current
(2016) status of the project will be presented.
[Biography]
Jong Bhak is the director of TGI (The Genomics Institute), UNIST, Ulsan, Korea.
Jong Bhak served KOBIC as the director (Korean Bioinformation Center) from 2005 ~ 2009,
the national bioinformatics center of Korea.
He received his BSc. Honours in biochemistry from Aberdeen University in 1994 and his Ph.D. in BioInformatics
from Cambridge University in 1997.
His main research areas have been protein structure predictioin, sequence analysis, genome comparison,
DNA chip analysis, interactomics, variomics, and geromics (the omics study of aging).
He joined George Church lab at Harvard Medical School in 1998 as a postdoctoral researcher for DNA chip analyses.
He worked with Liisa Holm from 1999 until 2001. His main research interests have expanded to interactomics
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and [[network biology]]. In 2001, he joined MRC-DUNN as a group leader to research aging problems (geronto-genomics or
geromics) and mitochondrial functions.
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Wed(4)-WS4-2
Spatially explicit models and whole genome analysis for reconstructing the colonisation of Asia
Anders Eriksson 1,2 ，Kyusang Lee 3 ，Jong Bhak 3 ，Andrea Manica 2 ，Timothy Ravasi 1 ，
Pan-Asian Population Genomics Inititative (PAPGI)
1:Integrative Systems Biology Lab, Division of Biological and Environmental Sciences & Engineering, King Abdullah University of Science
and Technology, Saudi Arabia、2:Department of Zoology, University of Cambridge, UK、3:Department of Biomedical Engineering, Ulsan
National Institute of Science and Technology (UNIST), Korea
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The availability of next-generation sequencing data offers the possibility of asking sophisticated questions about how Asia was
populated by anatomically modern humans and subsequent population bottlenecks, migrations and admixtures. However,
the wealth of information available from complete genomes needs to be matched with clear, hypothesis driven approaches
that allow us to distinguish among the sometimes subtly different scenarios that have been proposed by anthropologists.
In this talk, I will present a new spatially explicit framework, informed by past climate and an ethnically diverse panel of
human high-quality whole genomes, for describing the colonisation of Asia. Simpler versions of this framework has been used
successfully to look at the out of Africa expansion of anatomically modern humans and their possibly hybridisation with
Neanderthal, and thus offer great promise in helping us unravel the details of the colonisation of the Asian continent. To
accommodate the complex history of Asia, we applied the MSMC tool to pairs of genomes in our panel to reconstruct the
signatures of common ancestry within and between populations through time, reflecting population bottlenecks and gene flow
between populations, and used a novel statistical analysis to identify the timing and extent of gene flow during population
splits and subsequent contacts. In addition to the main out-of-Africa bottleneck, we see events consistent with the expansion
of agriculture in Europe and East Asia, at approximately 10k and 4k years ago respectively. This information allowed us to
specify waves of migration in the spatially explicit model, and we validated our approach by comparing the pairwise empirical
cross-coalescent patterns from MSMC to the same patterns estimated directly from simulated gene genealogies in the spatial
model.
[Biography]
Anders Eriksson obtained his PhD from University of Gothenburg. He now has a postdoc shared between Andrea Manica’s
group at University of Cambridge and Timothy Ravasi’s group at King Abdullah University of Science and Technology
(KAUST). His recent work on human population genetics has focused on using past climate and spatially explicit models
to reconstruct the out-of-Africa expansion of anatomically modern humans. He has also worked on the effect of ancient
population structure on patterns of genetic similarity between human genomes and the Neanderthal, domestication of the
horse, and the spread of malaria.
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Wed(4)-WS4-3
Population structure and admixture history of East Asian populations
1
Shuhua Xu
1:CAS-MPG Partner Institute for Computational Biology (PICB), China
TBA
Workshop

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Wed(4)-WS4-4
Genomic analyses reveal insights into indigenous diversity and divergence in South East Asia
Maude Phipps 1 ，F Aghakhanian 1 ，R Naidu 1 ，A Manica 1 ，M Stoneking 1 ，Tang Kun 1 ，Zhao Hang 1 ，T Jinam 1 ，
P. Majumder 1 ，A Basu 1
1:Jeffrey Cheah School of Medicine & Health Sciences, Monash University Malaysia
Throughout the centuries, anthropological and linguistic investigations have informed our knowledge about Orang Asli (OA)
Workshop
indigenous tribes in South East Asia. In recent years, we were able to elucidate the paths of human migration & genetic
histories by high density SNP genotyping. Structural analyses indicated that Negritos, Senoi and Proto Malays are genetically
close to East Asian (EA) populations yet substantially distinct. We have demonstrated genetic affinity between Negritos in
Malaysia and the Andaman Islands. Formal admixture tests provided evidence of gene flow between Austro-Asiatic speaking
OAs and populations from South East Asia and South China suggesting a widespread presence of these people in SEA before
the Austronesian expansion. Elevated linkage disequilibrium (LD) and enriched homozygosity found in OAs reflect isolation
and bottlenecks experienced. Ne and LD estimates indicated that OAs diverged from East Asians during the late Pleistocene
(14.5 to 8 KYA). Negrito and Senoi populations show relatively low sizes with constant decrease over time. However, Proto-
Malay experienced a slight size increase approximately 500 generations ago. We estimated divergence between East Asians
and African ~ 84-88 KYA, and between European and African ~ 71 KYA assuming generation time of 25 year. European and
East Asians diverged from each other around 35-37 KYA. We estimated that OAs split from African, European and South
Asian around 68-71 KYA, 26-27 KYA and 18-22 KYA, respectively. These dates are in agreement with previous reports
on Out-of-Africa and East-West Eurasian divergence. Divergence time between Negrito, Senoi and Proto-Malay with CHB
were 17 KYA, 14.8 KYA and 8.5 KYA, respectively. Shortest divergence time was between Senoi and Proto-Malay estimated
at 6.4 KYA. Divergence between Andamanese and Malaysian Negrito may have occurred ~ 14.4. Preliminary analysis of
whole genome data indicates that selection in skeletal muscle, cardiac development and the immune response has occurred in
Negritos.
[Biography]
Maude’s early research at the University of Malaya, focused on the genetic basis of antibiotic resistance and virulence in
enterotoxigenic E. coli and S. typhi. She pursued doctoral work with Nabeel Affara at the Department of Pathology at the
University of Cambridge, UK, working closely with Eamonn Maher at Addenbrookes Hospital and Nigel Carter at the Sanger
Centre. Her work on the molecular genetics of Von Hippel Lindau disease and Chromosome 3p- syndrome resulted in the
physical mapping and identification of the VHL tumour suppressor gene.
After a brief postdoctoral stint, she returned to Malaysia to establish the first B. Biomed.Sc. program at the Faculty of
Medicine, University of Malaya. Whilst there, she developed an interest in systemic lupus erythematosus and was encouraged
to develop a local molecular HLA typing facility to support haematopeitic transplant programs in Malaysia. She obtained
a CICHE fellowship for specialist training with Ken Welsh and Mike Bunch at the Oxford Transplant Centre and later a
UNESCO Human Genome Fellowship at the University of Western Australia to learn MHC block matching and computational
analyses. She also trained briefly with Fred Hitchinson immunogenetics and histocompatibility faculty in Seattle.
Maude joined Monash University (Sunway Campus) in 2008 and is Professor of Human Molecular Genetics at the Jeffrey
School of Medicine and Heath Sciences, where she teaches medical, pharmacy and postgrad students. She continues to
pursue her passion in medical, population and evolutionary genomics. She also works closely with indigenous communities
in Malaysia. Maude is advisor to Stem Life Malaysia, founder member of Malaysian Bioethics Council, Co-Chair of Human
Genome Organization Pan Asia Population Genomics Consortium and a keen advocate of Bioethics Education in rapidly
developing countries. Her visiting positions and research collaborations with investigators in National Institute of Genetics
Japan, Universities of Oxford and Cambridge UK, Max Planck Institute Germany, University of Western Australia, the
HUGO Pan Asia Consortium, UCSF, UC Berkeley, Stanford University USA, etc have enriched her scientific, educational
and personal perspectives.‘Ancora Imparo’
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Wed(4)-WS4-5
Complete sequencing and characterization of three human genomes from Indian subcontinent
Harish Padh 1 ，Suhani Almal 2 ，Milee Agarwal 2 ，Sweta Patel 2 ，Shivangi Patel 2 ，JeHoon Jun 3 ，Jong Bhak 3,4
1:Sardar Patel University, India、2:B. V. Patel PERD Centre、3:Personal Genomics Institute, Genome Research Foundation,、4:Theragen
Bio Institute, TheragenEtex
The first draft of human reference genome and several other international-based consortia studies lacked of representation of
Workshop
DNA from Indian subcontinent accounting for 1/6 of world population in India alone.
It is well documented that Indian population is an amalgamation of repeated waves of human migration that have assimilated
together to form Indian population. In order to develop database for Indian population, we selected 3 Indian representatives;
one from Western part of India (male from Gujarat), female from South India and male from North East India (Mizoram).
This study gave us several insights in terms variant profiling, novel variants, variant annotation and their relation to health,
pharmacogenomic relevance and migration history of the individuals. One of the key achievements of our study is identification
and successful submission of more than 600,000 novel genetic variations to NCBI dbSNP database in the form of Indian-
specific variations.
Further, mitochondrial (mt) and Y-chromosome haplomap analysis revealed that male Gujarati male’s ancestry reached India
less than 15,000-20,000 years back and can be traced from Africa to middle-east region to Central-Eastern Europe to India by
land route, while South Indian women’s ancestry is first to arrive in Indian subcontinent about 70,000 years back perhaps by
sea route from Africa, while male from Mizoram revealed completely different migration pattern. From Africa his ancestors
have tracked to Middle-east, without entering Europe have gone to northern part of Asia to China-Korea and from there have
moved to Northeast region of India about 50,000 years back. The presentation will detail these findings and its correlation
with Asian Genomes analyzed thus far through PAPGI initiative.
Acknowledge: Financial support from Gujarat State Biotech Mission (GSBTM)
[Biography]
Prof. Harish Padh obtained his Ph.D. in Biochemistry from University of Delhi in 1978. From 1978 to 1995 for 17 years, he has
developed his academic career in USA at places like Temple University in Philadelphia, University of Chicago in Chicago and
Northwestern University in Evanston, Illinois. He was Assistant Director and Associate Professor at Northwestern University
for Biotechnology. In 1996 he returned to India and joined as Professor of Biochemistry at M. S. University of Baroda
and in 1999 he joined as Director of B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre in
Ahmedabad. In 2007, he also took responsibility as Project Director for NIPER, a Government of India’s Institution at
Ahmedabad.
He joined Sardar Patel University as Vice-Chancellor in July 2010 and continues as VC in his second term. His area of
research is Cell and Molecular Biology as applied to Health and Pharmaceutical Sciences. Prof. Padh has more than 170
research publications in reputed journals. He has more than 4000 citations; cumulative Impact Factor: 270; h-Index: 33;
i10-Index: 76. He is member of Governing Council of Gujarat Forensic Science University-Gandhinagar, Central University
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of Gujarat-Gandhinagar, Association of Indian Universities-New Delhi, Member of Court as well as Governing Council of
Indian Institute of Science - Bangalore.
Workshop
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Wed(4)-WS4-6
Search for disease-associated genes by ethnic specific SNP array and genome-wide imputation based on
large-scale whole-genome sequencing: Application to cold medicine related Stevens-Johnson syndrome
(CM-SJS) with severe ocular complications (SOC)
Katsushi Tokunaga 1 ，Mayumi Ueta 1,2 ，Hiromi Sawai 1 ，Yosuke Kawai 3 ，Chie Sotozono 4 ，Kaname Kojima 3 ，
Masao Nagasaki 3 ，Shigeru Kinoshita 2
1:Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Japan、2:Frontier Medical Science and Technology
for Ophthalmology, Kyoto Prefectural University of Medicine、3:Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku
Workshop
University、4:Ophthalmology, Kyoto Prefectural University of Medicine
An ethnic specific SNP array named Japonica has recently been developed (Kawai et al. 2015) based on whole-genome
sequences of 1,070 Japanese individuals (Nagasaki et al. 2015). It is expected that the whole-genome imputation with
Japonica array can increase the statistical power for detecting disease-associated variants. Thus we utilized the array for
GWAS on CM-SJS with SOC and compared with the results of our previous GWAS (Ueta et al. 2015). GWAS using Japonica
array was able to detect a larger number of candidate regions, and validation analysis with additional samples identified two
new susceptibility loci on Chromosomes 15 and 16. Moreover, interactive effects between the previously identified risk allele
HLA-A*02:06 and the newly detected risk variants were suggested. The present study confirmed the advantage of GWAS
using ethnic specific array with genome-wide imputation based on large-scale whole genome sequences, and contributes to
our understanding of genetic predisposition to CM-SJS with SOC.
[Biography]
Professor Katsushi Tokunaga is the Chairman of Department of Human Genetics, Graduate School of Medicine, The University
of Tokyo since 1995. He received PhD at Graduate School of Science, The University of Tokyo in 1984. He has been working
on genome-wide search for susceptibility genes to various complex diseases including infectious diseases and other immune
mediated diseases, as well as drug response genes. He is a board member of several academic societies including Japan Society
of Human Genetics and Japanese Society of Histocompatibility and Immunogenetics. He is Editor-in-Chief of Human Genome
Variation and an Editorial Board member of several other international journals including Journal of Human Genetics and
Tissue Antigens.
(HP: http://www.humgenet.m.u-tokyo.ac.jp)
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GA4GH, IRDiRC, and Matchmaker Exchange "IRDiRC and Matchmaker Exchange"
Wed., April 06, 2016 15:00-16:30 Annex 1 (1F)
Moderator：Paul Lasko（Former Chair of the IRDiRC Executive Committee; Department of Biology, McGill University,
Canada）
The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to promote international
collaboration and encourage the investment of more public and private research funds into the area of rare diseases.

IRDiRC teams up researchers and organizations investing in rare diseases research to achieve two main objectives by
the year 2020: to deliver 200 new therapies for rare diseases and means to diagnose most rare diseases. RDiRC now
encompasses 42 members from all over the world, who are funding bodies/organizations contributing towards IRDiRC
objectives, as well as invited patient advocacy group (EURORDIS, NORD, and the Genetic Alliance). Speakers in this
session will highlight recent developments in rare disease therapeutic development, and innovative approaches to patient
engagement. The session will also present novel approaches to the sharing of genomic data derived from patients, which
is essential to disease gene discovery and thus to diagnosing patients with diseases whose aetiology is not now known.
This initiative, Matchmaker Exchange has been developed jointly by IRDiRC and GA4GH.
The Matchmaker Exchange project was launched in October 2013 to address the challenge finding the genetic causes for
patients with rare disease. Finding just a single additional case with a deleterious variant in the same gene and overlapping
phenotype may provide sufficient evidence to identify the causative gene, but today, case data sits in isolated databases.
This involves a large and growing number of teams and projects working towards a federated platform (Exchange) to
facilitate the matching of cases with similar phenotypic and genotypic profiles (matchmaking) through standardized
application programming interfaces (APIs) and procedural conventions.
The Global Alliance for Genomics and Health was formed to help accelerate the potential of genomic medicine to
advance human health. It brings together over 385 leading institutions working in healthcare, research, disease advocacy,
life science, and information technology. The partners in the Global Alliance are working together to create a common
framework of harmonized approaches to enable the responsible, voluntary, and secure sharing of genomic and clinical
data. Engaging collaboratively with its stakeholders, the Global Alliance works to establish, broadly disseminate, and
advocate for the use of interoperable technical standards for managing and sharing genomic and clinical data.
Wed(4)-SFS1.1-1
IRDiRC in its fifth year: A progress report
1
Paul Lasko
1:Former Chair of the IRDiRC Executive Committee; Department of Biology, McGill University, Canada
TBA
[Biography]
Prof. Lasko received his A. B. from Harvard and his Ph. D. from the Massachusetts Institute of Technology, and joined
McGill in 1990 after a postdoctoral period at the University of Cambridge. Using the Drosophila system, Dr. Lasko’s
research concerns regulatory processes that control gene expression at the levels of mRNA stability or translation. He has
authored over 100 research papers in this area. Since 2010 Prof. Lasko has served as Scientific Director of the CIHR Institute
of Genetics. He oversees the Institute’s strategic research funding initiatives, many of which involve fostering international
partnerships. Dr. Lasko recently completed a three-year term as Chair of the Executive Committee of the International Rare
Diseases Research Consortium, a worldwide consortium of over 30 public and private research funders who collectively have
pledged over USD 1 billion for research in rare diseases. More information about this consortium is available at www.irdirc.org.
He was the recipient of the Prix Armand-Frappier from the Government of Québec in 2014.
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In the past Dr. Lasko worked extensively for the Human Frontiers of Science Program Organization (HFSPO), serving on
its program grant panel from 2001-2005, and then as one of two Canadian representatives on the Council of Scientists. He
chaired the HFSP Council of Scientists from 2007-2010. Dr. Lasko also served as President of the Genetics Society of Canada
from 2007-2010.
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Wed(4)-SFS1.1-2
The National Institutes of Health Undiagnosed Diseases Program and Undiagnosed Diseases Network
David R. Adams 1 ，Camilo Toro 1 ，Cynthia Tifft 1 ，William A Gahl 1
1:Uniagnosed Diseases Program, NIH, USA
The Undiagnosed Diseases Program (UDP) was established in 2008 with two goals: to make diagnoses for persons who
remained undiagnosed after extensive medical evaluation, and to pursue basic research into novel and rare diseases. The
program has been successful in terms of numbers of applicants, diagnoses and research findings. As a result, the Undiagnosed

Diseases Network (UDN) was established. The network comprises seven clinical sites (including the original NIH UDP), two
sequencing centers, a model organisms core, a metabolic core, a biorepository and a central coordination and data collecting
center. Although early in the process of seeing patients, the network has already shown innnovation in several areas including
the sharing of identifiable patient information and the utilization of a central IRB. The UDN is currently focusing on in-depth,
in-person participant phentyping, data sharing, and the application of diverse research techniques for making diagnosis and
understanding and novel diseases.
[Biography]
Dr. David Adams completed his Ph.D. in molecular biotechnology in 1998 under Maynard V. Olsen, and his M.D. in 2000. He
served as a pediatric resident and chief resident at the University of Maryland Medical Center from 2000 to 2004. Following
residency, he completed clinical genetics and clinical biochemical genetics training at the National Institutes of Health in
Bethesda, Maryland.
Dr Adams’s research interests include pigmentation disorders, bioinformatics and informatics. Working in the laboratory of
Dr William Gahl, he has conducted an oculocutaneous albinism natural history study since 2008, and is now investigating
the use of nitisinone in albinism treatment. Dr Adams was one of the founding members of the NIH Undiagnosed Diseases
Program, established in 2008. Within the UDP, he sees patients and runs the bioinformatics and informatics groups. In 2014,
he was designated as the Deputy Director of Clinical Genomics in the Office of the Clinical Director of the National Human
Genome Research Institute. Recently, Dr Adams has been involved in data sharing initiatives within the NIH Undiagnosed
Diseases Network and International Network.
Dr. Adams has authored or co-authored more than 40 papers and regularly presents at national and international meetings.
His current research efforts focus on finding potential disease-causing variants in genomic data that has been previously
unrevealing using standard clinical exome analysis methods.
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Wed(4)-SFS1.1-3
Japan Agency for Medical Research and Development (AMED), Rare/Intractable Disease Project, and
Initiative on Rare and Undiagnosed Diseases (IRUD)
1,2,3
Shigeki Kuzuhara
1:Suzuka University of Medical Science, Graduate School of Health Science, Japan、2:Professor Emeritus, Mie University School of Medicine、
3:Program Director, Practical Research Project for Rare/Intractable Diseases, Japan Agency for Medical Research and Development (AMED)
Japan Agency for Medical Research and Development (AMED) was founded in 2015 by the Government. Its mission is
to promote the medical research and development (R&D) by providing the researchers with integrated service on research

funds from 3 different Ministries and to facilitate and support R&D from basic to practical stages through improving and
maintaining the research environments. Its goal is to benefit “lives” of people, “biological life” and “quality of life”.
Rare/Intractable Disease Project, one of the 7 research projects of AMED is the successor of "the Action Program against
Intractable Diseases" established in 1972 by the Ministry of Health and Welfare of Japan to promote research and to aid
patients medically and financially. In 2015, the new law for rare/intractable diseases became effective, and more than 300
diseases have officially been acknowledged as legal rare/intractable diseases. Still remain, however, many patients suffering
from medically undiagnosed conditions and unprotected by the law.
To further promote R&D on these diseases, AMED launched a new research program, “Initiative on Rare and Undiagnosed
Diseases” (IRUD). IRUD is a national network which connects patients and medical experts. It consists of 3 major functional
modules of Diagnosis, Analysis and Data center. Diagnosis module at base hospitals consists of medical specialists of various
fields and analyses the findings of clinical examination and laboratory tests to make diagnosis. Analysis-module studies on
genes sent by Diagnosis modules. Data center-module develops the database of genes and clinical records for further studies
and domestic and international use.
The promising success of IRUD depends on the good collaboration of patients, their families, medical staff, and researchers
together with governmental supports. IRUD has resolved several ever-undiagnosed conditions, some of which have been
identified novel genetic diseases.
[Biography]
1970; Graduated from School of Medicine, the University of Tokyo and got licensed MD.
1982; PhD of Medicine, the University of Tokyo.
1970-77; Resident of Internal Medicine, Geriatrics and Neurology, the University of Tokyo Hospital
1977; Assistant professor, Department of Neurology, the University of Tsukuba
1983; Head, Department of Neurology, Tokyo Metropolitan Geriatric Hospital
1990; Professor and Chairman, Department of Neurology, Mie University School of Medicine.
2001; Director, Mie University Hospital.
2007-2010; Director, National Center of Neurology and Psychiatry Hospital.
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2007; President, the 49th Annual Meeting of Japanese Society of Neurology
2006-2010; President, Japanese Society of Neurology.
2010; Professor, Faculty of Health Science, Suzuka University of Medical Science.
2014; Dean, Graduate School of Health Science, and Professor of Neurology and Medicine, School of Nursing, Suzuka Uni-
versity of Medical Science

April 2014:Program Director/ Program Superviser, Project for Rare Intractable Diseases, Japan Agency for Medical Research
and Development
Major medical field and interest : Neurodegenerative diseases and Dementia, especially ALS and Parkinson’s disease, and
ALS/Parkinsonism-Dementia Complex of the Kii peninsula and Western Pacific
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Wed(4)-SFS1.1-4
New Trends and Novel Technologies in Orphan Drug Development
1
Carlo Incerti
1:Global Medical Affairs, Sanofi Genzyme, USA
Development of Orphan Drugs poses specific challenges linked with the rarity of conditions, natural history not fully known,
heterogeneity of clinical presentation, no validated biomarkers and diversity of approach among regulatory authorities. Apart
from addressing medical outcomes, development strategies today need to consider also patient access and early dialogues need

to be set up with key stakeholders (regulators and payers) to discuss demonstration of benefit. New clinical trial designs
and statistics need to be developed for these small populations, as challenges remain at the regulatory approval level because
these therapies are held to the same evidentiary standard as non-orphan drugs. New technologies are emerging, like gene
therapy and RNA silencing. Significant progress has been made in Gene Therapy R&D, with considerable number of academic
institutions and companies investing in this field. Another emerging technology is RNA interference, which is already at the
clinical stage of development. What worked in the past in Rare Disease development should be true for the future, i.e. know
the pathophysiology and natural history of the disease well, get the right stakeholders together (patients, clinical experts,
regulators, payers and industry), optimize health gains for each patient to create a sustainable access. In any case, it should
be remembered that Orphan Drug development is a life-time commitment.
[Biography]
Carlo Incerti, M.D. Head of Global Medical Affairs, Sanofi Genzyme
Dr. Incerti oversees Global Medical Affairs in the 4 Therapeutic Areas of Sanofi Genzyme: Oncology, Immunology, Multiple
Sclerosis, Rare Diseases. He is member of the Sanofi Genzyme Portfolio Management Committee, of the Research Leadership
Team, of the Executive Leadership Team, of the Operating Committee, of the Corporate Benefit/Risk Assessment Committee.
He is a Board Certified Endocrinologist, who started his career in the medical profession as a staff member and then as
Associate Professor at the Department of Endocrinology of Modena University Hospital in Italy. He joined Genzyme in
1992 and in his tenure he has been responsible for the development of all of the Genzyme products, with specific focus on
Lysosomal Storage Disorders. This development activities started with the successful approval in Europe of what is considered
the first pre-orphan drug (Cerezyme for Gaucher disease) and in the first officially approved orphan drug (Fabrazyme for
Fabry disease). He is currently President of EuropaBio, member of the Board of EBE (European Biotechnology Enterprises),
member of the Board of EFPIA (European Federation of Pharmaceutical Industries and Associations) and of the Governing
Board of IMI (Innovative Medicine Initiative), a Joint Undertaking between the EU Commission and EFPIA. He is a founding
member of the IRDiRC (International Rare Disease Research Consortium).
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Wed(4)-SFS1.1-5
If you are not at the table, you are on the menu
1
Sharon F. Terry
1:President and CEO / Genetic Alliance, USA
TBA

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Wed(4)-SFS1.1-6
IRDiRC-GA4GH Collaboration: Matchmaker Exchange - Linking International Datasets to １-Enable
Rare Disease Gene Discovery
1
Han G. Brunner
1:Radboud University Nijmegen Medical Centre, the Netherlands
TBA

[Biography]
Han Brunner trained as a clinical geneticist at Nijmegen University. In 1998 he was appointed full professor and head of the
department of Human Genetics at Nijmegen University Hospital. In 2014 he was also appointed chairman of the Department
of Clinical Genetics at Maastricht University Medical Center, in the Netherlands. He was elected member of the board of
directors of the Dutch, European (president in 2014-2015) and of the American Societies of Human Genetics. Han Brunner
was elected member of the Royal Netherlands Academy of Arts and Sciences in 2013, and of the Academia Europea in 2012.
He is a Knight in the Order of the Dutch Lion since 2013. He is a co-winner of the King Faisal International Prize in Medicine
2016, with Joris Veltman.
Han Brunner pursues the scientific understanding of the connections between clinical and molecular features of rare diseases,
including applications to patient care. He has pioneered the discovery of a large number of disease genes, and the application
of cutting-edge genomic technologies (genomic microarrays, exome sequencing, and whole genome sequencing) to discover
the causes of genetic diseases. Much of this work focuses on neurodevelopmental conditions such as intellectual disability
and abnormal behavior. A pertinent finding is that in non-consaguineous populations, the major cause for severe intellectual
disability lies in spontaneous mutations.
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Wed(4)-SFS1.1-7
IRDiRC-GA5GH Collaboration: Matchmaker Exchange -The Challenges and opportunities of connecting
different database
1
Nara Lygia M. Sobreira
1:John Hopkins University School of Medicine, USA
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GA9GH, IRDiRC, and Matchmaker Exchange "The Global Alliance for Genomics and Health"
Wed., April 06, 2016 16:45-18:15 Annex 1 (1F)
Moderator：Peter Goodhand（Global Alliance for Genomics and Health (Executive Director), Canada）
The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to promote international
collaboration and encourage the investment of more public and private research funds into the area of rare diseases.
IRDiRC teams up researchers and organizations investing in rare diseases research to achieve two main objectives by

the year 2020: to deliver 200 new therapies for rare diseases and means to diagnose most rare diseases. RDiRC now
encompasses 42 members from all over the world, who are funding bodies/organizations contributing towards IRDiRC
objectives, as well as invited patient advocacy group (EURORDIS, NORD, and the Genetic Alliance). Speakers in this
session will highlight recent developments in rare disease therapeutic development, and innovative approaches to patient
engagement. The session will also present novel approaches to the sharing of genomic data derived from patients, which
is essential to disease gene discovery and thus to diagnosing patients with diseases whose aetiology is not now known.
This initiative, Matchmaker Exchange has been developed jointly by IRDiRC and GA4GH.
The Matchmaker Exchange project was launched in October 2013 to address the challenge finding the genetic causes for
patients with rare disease. Finding just a single additional case with a deleterious variant in the same gene and overlapping
phenotype may provide sufficient evidence to identify the causative gene, but today, case data sits in isolated databases.
This involves a large and growing number of teams and projects working towards a federated platform (Exchange) to
facilitate the matching of cases with similar phenotypic and genotypic profiles (matchmaking) through standardized
application programming interfaces (APIs) and procedural conventions.
The Global Alliance for Genomics and Health was formed to help accelerate the potential of genomic medicine to
advance human health. It brings together over 385 leading institutions working in healthcare, research, disease advocacy,
life science, and information technology. The partners in the Global Alliance are working together to create a common
framework of harmonized approaches to enable the responsible, voluntary, and secure sharing of genomic and clinical
data. Engaging collaboratively with its stakeholders, the Global Alliance works to establish, broadly disseminate, and
advocate for the use of interoperable technical standards for managing and sharing genomic and clinical data.
Wed(4)-SFS1.2-1
-IRDiRC-GA4GH Collaboration- Automatable Discovery and Access Task Team
1
Clara Gaff
1:Melbourne Genomics Health Alliance, Australia
TBA
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Wed(4)-SFS1.2-2
-IRDiRC-GA4GH Collaboration- GA4GH Overview
1
Tom Hudson
1:Global Alliance for Genomics and Health (Chair, Steering Committee); Ontario Institute for Cancer Research, Canada
TBA

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Wed(4)-SFS1.2-3
-GA4GH Working Groups: Developing Tools and Solutions for Data Sharing- Clinical Genomic Data
Sharing
1
Kathryn North
1:Murdoch Childrens Research Institute, Australia
TBA
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Wed(4)-SFS1.2-4
-GA4GH Working Groups: Developing Tools and Solutions for Data Sharing- Family History Collection
1
Ingrid M. Winship
1:Royal Melbourne Hospital; University of Melbourne, Australia
TBA
[Biography]

Professor Ingrid Winship is the Chair of Adult Clinical Genetics at the University of Melbourne and the Executive Director
of Research for Melbourne Health.
Professor Winship has a wide range of clinical and research interests in inherited disorders, particularly those with adult
onset, including familial cancer, and where foreknowledge of genotype may influence clinical or lifestyle measures to create
positive patient outcomes. She has experience in gene discovery and in the translation of discovery into clinical practice.
She has also highlighted the societal implications with research into the ethical, legal, cultural and psychosocial domains of
genetic technology
Professor Winship is currently a member of the Victorian Cancer Agency, the Board of the Walter & Eliza Hall Institute, the
Peter Doherty Institute Council, the Steering Committee of the Melbourne Genomic Health Alliance and the Kinghorn Centre
for Clinical Genomics Strategic Advisory Board. She is also a member of the NHMRC Australian Health Ethics Committee.
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Wed(4)-SFS1.2-5
-GA4GH Working Groups: Developing Tools and Solutions for Data Sharing- Genomic Data Sharing
Enablers
1
David Haussler
1:University of California Santa Cruz, USA
TBA
[Biography]

David Haussler, Ph.D.
Investigator, Howard Hughes Medical Institute
Distinguished Professor, Biomolecular Engineering, University of California, Santa Cruz
Scientific Director, UC Santa Cruz Genomics Institute, University of California, Santa Cruz
David Haussler develops new statistical and algorithmic methods to explore the molecular function, evolution, and disease
process in the human genome, integrating comparative and high-throughput genomics data to study gene structure, function,
and regulation. As a collaborator on the international Human Genome Project, his team posted the first publicly available
computational assembly of the human genome sequence. His team subsequently developed the UCSC Genome Browser, a
web-based tool that is used extensively in biomedical research. He co-founded the Treehouse Childhood Cancer Project to
enable international comparison of childhood cancer genomes, and is a co-founder of the Global Alliance for Genomics and
Health (GA4GH), a coalition of the top research, health care, and disease advocacy organizations.
Haussler is a member of the National Academy of Sciences and the American Academy of Arts and Sciences and a fellow of
AAAS and AAAI. He has won a number of awards, including the 2014 Dan David Prize. 2011 Weldon Memorial prize for
application of mathematics and statistics to biology, 2009 ASHG Curt Stern Award in Human Genetics, and the ISCB 2008
Senior Scientist Accomplishment Award.
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Wed(4)-SFS1.2-6
-GA4GH Working Groups: Developing Tools and Solutions for Data Sharing- Regulatory and Ethics
Working Group
1
Kazuto Kato
1:Osaka University, Japan
TBA

[Biography]
Kazuto Kato, PhD is Professor of Biomedical Ethics and Public Policy at the Graduate School of Medicine, Osaka University,
Japan. He is also a Project Professor of the Institute for Integrated Cell-Material Sciences (iCeMS) at Kyoto University. He
has a PhD degree in developmental biology from Kyoto University. After finishing postdoctoral research at the University of
Cambridge with Sir John Gurdon, he started to work in the interface between bioscience and society, particularly focusing
on ethical and social issues of genomics and stem cell research. He has been serving as a member of various international
projects/academic societies such as Committee on Ethics, Law and Society (CELS) of Human Genome Organization (HUGO),
ELSI group of the International HapMap Project, Ethics and Policy Committee of the ICGC (International Cancer Genome
Consortium), and Steering Committee of the Global Alliance for Genomics and Health. He is also a member of the international
network, ELSI 2.0. In 2010, he was appointed as a member of the Expert Panel on Bioethics of the Council for Science and
Technology Policy (CSTP) of the Cabinet Office, Japan. Since 2010 Professor Kato has been directing a research group,
the Research Unit for the ELSI of Genomics to carry out analysis of ethical, legal and social implications of human genome
research. Professor Kato is currently specializing in biomedical ethics, science communication and public policy of life sciences.
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Wed(4)-SFS1.2-7
-GA4GH Demonstration Projects: Data Shared and Lessons Learned- The Beacon Project
1
Marc Fiume
1:DNAStack, Canada
TBA

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Wed(4)-SFS1.2-8
-GA4GH Demonstration Projects: Data Shared and Lessons Learned- Collaborative Ethics and Gover-
nance: From Data Sensitivity to Data Access
1
Stephanie Dyke
1:Centre of Genomics and Policy, McGill University, Canada
TBA
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Wed(4)-SFS1.2-9
-GA4GH Demonstration Projects: Data Shared and Lessons Learned- The BRCA Challenge
1
John Burn
1:Institute of Genetic Medicine Newcastle University Centre for Life, UK
TBA
[Biography]

Professor Sir John Burn MD FRCP FRCPE FRCPCH FRCOG FMedSci was born and trained in medicine in North East
England. He returned there in 1984 as its first consultant in clinical genetics and went on to become the professor of Clinical
Genetics at Newcastle University in 1991. After 30 years as the leader of a highly successful NHS service and Human Genetics
research institute he now combines his clinical and teaching role with being chief investigator of CAPP, the international
Cancer Prevention programme, genetics lead for the UK National Institute of Health Research, medical director of the
medical device company, QuantuMDx ltd., and co-chair of the Scientific Advisory Board of the Human Variome Project.
With his wife of 40 years, Linda, he has two children and four grandchildren and his favourite pastime is playing the drums.
He was knighted by Queen Elizabeth II in 2010 for services medicine and healthcare.
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Wed(4)-SFS1.2-10
-GA4GH Demonstration Projects: Data Shared and Lessons Learned- Public Access Variant Data: Lia-
bility?
1
Adrian Thorogood
1:Centre of Genomics and Policy, McGill University, Canada
TBA
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Genetics and Genomics in Diabetes and Metabolic Diseases
Wed., April 06, 2016 15:00-16:30 Annex 2 (1F)
Moderator：Mark I. McCarthy（OCDEM, University of Oxford, UK; Wellcome Trust Centre for Human Genetics, Uni-
versity of Oxford）
Moderator ：Takashi Kadowaki（Department of Diabetes and Metabolic Diseases, The University of Tokyo Hospital,
Japan）
Genome-wide association studies (GWAS) have identified more than 100 susceptibility loci for type 2 diabetes (T2D),

but most of them are still largely common loci across different ethnicities. In order to identify ethnicity-specific novel
susceptibility loci for T2D, it is important to employ much more SNPs using imputation with individuals from the 1000
Genomes Project as reference populations. It is also important to carry out
genome and exome sequencing in large cohorts, which enables characterization of the role of rare variation in complex
diseases. To assess whether a single variant at a locus contributes to disease risk, the statistical analysis framework is
relatively straightforward: compare the frequencies of alleles or genotypes at the site in relation to phenotype. To assess
whether multiple variants in the same gene contribute to disease, a much larger array of potential genetic models must
be considered, which has led to the development of numerous statistical methods for testing aggregate groups of variants
for association with disease. It is estimated that the human genome contains hundreds of thousands of enhancers, so
understanding these gene-regulatory elements is a crucial goal. About 85% of human DNA under evolutionary constraint
corresponds to non-protein-coding sequences, a sizeable fraction of which constitutes cis-regulatory elements. It is not
surprising, thus, that genetic variation within these regulatory sequences has the potential of resulting in phenotypic
variation and underlies the aetiology of human diseases. Genetic variation in distant enhancers has been linked to several
human Mendelian disorders. Importantly, a number of regulatory variants in enhancers emerging from GWAS hits have
been functionally characterized, and several insights have come out of these studies. Finaly, systematic approaches
for integrating the findings of genetic, biological and pharmacological studies could be useful for developing new T2D
treatments. In this session, most recent data on these issues will be presented.
Wed(4)-SFS2-1
Genetics in T2D
1
Torben Hansen
1:The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
TBA
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Wed(4)-SFS2-2
Regulatory Variants and Human Diseases
1
Marcelo Nobrega
1:University of Chicago, USA
TBA

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Wed(4)-SFS2-3
From p-values to proteins: understanding the biology of diabetes and diabetic complications using human
genetics and genomics
1,2
Mark I. McCarthy
1:OCDEM, University of Oxford, UK、2:Wellcome Trust Centre for Human Genetics, University of Oxford
The growing prevalence of type 2 diabetes highlights the limitations of available preventative options, and high rates of
diabetes complications attest to the inadequacies of current treatments. Novel therapeutic strategies need to be informed by

a more complete understanding of the molecular and physiological basis of disease, delivering validated interventional targets
and biomarkers to define disease risk, progression, and subtype.
My group, working within large global consortia, uses human genetics to deliver this understanding. Growing availability
of exome sequence and array data now delivers coding variant associations that can plug directly into functional studies.
However, the main repository of variant association for T2D remains ~ 100 common variant signals uncovered by GWAS,
most of which map outside coding sequence. We are implementing a multifaceted approach that combines genome-scale and
focused functional studies to unlock the biology within these loci.
We use fine-mapping to improve localisation of causal variants, and map these onto regulatory annotations from key tissues,
most notably the human islet. This provides a platform for identifying downstream transcripts through tissue-specific cis-eQTL
analyses and conformational capture. We combine these“regulatory variant” data with transcript level information to define
the best-supported transcripts in each GWAS region. Finally, we connect loci through analyses of protein-protein interaction,
co-expression and pathway data. These efforts are starting to bear fruit, with around one-third of GWAS signals now featuring
a well-supported priority transcript. We follow up these priority candidates through cellular, molecular, rodent and human
studies to consolidate mechanistic evidence. To build engagement, we are co-developing, via the Accelerating Medicines
Partnership, a dedicated T2D knowledge portal that facilitates access to these data for the wider research community.
[Biography]
Mark McCarthy is the Robert Turner Professor of Diabetes Medicine, based at both OCDEM and the Wellcome Trust Centre
for Human Genetics. Following medical training in Cambridge and London, a spell as an MRC Travelling Fellow at the
Whitehead Institute in Massachusetts, and 8 years at Imperial College, he moved to Oxford in 2002. His research group is
focused on the identification and characterisation of genetic variants influencing risk of type 2 diabetes and related traits:
they have been responsible for identification of many of the 100 or so signals of type 2 diabetes risk identified by genome wide
association studies, and have contributed to similar discoveries for obesity, birth weight, and continuous glycemic traits. His
research is now increasingly focused on using those discoveries to drive biological inference regarding the pathophysiology of
type 2 diabetes, and in developing these insights into novel translational opportunities.
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Wed(4)-SFS2-4
Type 2 Diabetes: From genes to therapies
1
Takashi Kadowaki
1:Department of Diabetes and Metabolic Diseases, The University of Tokyo Hospital, Japan
TBA
[Biography]

EDUCATION:
1978 M.D. Faculty of Medicine, The University of Tokyo
1997 Ph.D. (Medicine) The University of Tokyo
POSITIONS HOLD:
1978-1980 Resident in Internal Medicine, The University of Tokyo Hospital
1980-1986 Clinical Research Fellow, Diabetes Section, the Third Department of Internal Medicine, Faculty of Medicine, The
University of Tokyo
1986-1990 Visiting Fellow, Biochemistry and Molecular Pathophysiology Section, Diabetes Branch,
National Institute of Diabetes, Digestive, and Kidney, Disease, National Institutes of Health,
Bethesda, MD, U.S.A.
1990-2000 Chief, Diabetes Branch, Assistant Professor, the Third Department of Internal Medicine,
Faculty of Medicine, The University of Tokyo
2001-2003 Chief, Diabetes Branch, Associate Professor, the Department of Diabetes and Metabolic
Diseases, Graduate School of Medicine, The University of Tokyo
2003-present Professor and Chairman, the Department of Diabetes and Metabolic Diseases, Graduate
School of Medicine, The University of Tokyo
2004-2006 Advisor to the President of the University of Tokyo
2005-2010 Vice-director of The University of Tokyo Hospital
2008-present Chairman of the Board of Directors, The Japan Diabetes Society
2011-2015 Director of The University of Tokyo Hospital
2012-2015 Head of Translational Research Initiative, the University of Tokyo
SOCIETIES:
The Japan Diabetes Society (Chairman of the Board of Directors), The Japanese Society of Internal Medicine (Executive
Board Member, President of 113th Annual Meeting), The Japanese Association of Medical Sciences (Executive Board Mem-
ber), The Japan Endocrine Society (Executive Board Member), Japan Society for the Study of Obesity (Executive Board
Member), American Diabetes Association,
The Endocrine Society
HONORS AND FELLOWSHIPS:
Fogarty International Fellowship (1986-1990), Erwin von Baelz prize (2001), Academic Award of the Mochida Memorial Foun-
dation (2002), Hagedorn Award of the Japan Diabetes Society (2004),
Sankyo Takamine Memorial Award (2004), Medical Award of the Japan Medical Association (2007),
The Uehara Prize (2007), Awardee of a Medal with Purple Ribbon (2010), Takeda Medical Science Prize (2011), Japan
Endocrine Society Award (2012), Kroc Lecture in Diabetes, University of Chicago (2012), Japan Society for the Study of
Obesity Award (2013), Japan Academy Prize (2013),
Manpei Suzuki International Prize for Diabetes Research (2015)
EDITORIAL BOARD:
Diabetologia (Associate Editor, 2000-2002), Diabetes (Editorial Board, 2002-2005), J. Clin. Invest. (Editorial Board,
2002-2012), Endocrinology (Editorial Board, 2004-2007), Diabetes Care (Editorial Board, 2007-), The Journal of Clinical
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Endocrinology & Metabolism, (Editorial Board, 2007-), Cell Metabolism (Cell press) (Editorial Board, 2012-), Molecular
Metabolism (Regional Editor for Asia, 2012-)
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Genetics of Deafness
Wed., April 06, 2016 16:45-18:15 Annex 2 (1F)
Moderator：Shin-ichi Usami（Department of Otorhinolaryngology, Shinshu University School of Medicine, Japan）

Moderator ：Guy Van Camp（Department of Medical Genetics, University of Antwerp, Belgium）
Deafness is a disorder with high genetic heterogeneity; however, over the past two decades a good deal of progress has
been made in identifying many different genes responsible for similar phenotypes. The identification of deafness-causing

genes has been the most influential factor in the recent extensive advances in our knowledge of the biology of hearing. In
terms of clinical applications, the most remarkable aspect of these advances is that ENT clinicians can now make highly
accurate molecular diagnoses through the use of genetic testing, enabling a clearer understanding of the mechanisms
involved, more appropriate and precise treatment selection and greatly improved genetic counseling.
Genetic testing has accordingly become indispensable to the provision of personalized therapeutic intervention for deafness
patients. To date, approximately one hundred genes are estimated to cause non-syndromic hearing impairment, although
a number of these may result in similar phenotypes that entail no symptoms other than hearing loss. The question,
therefore, arises as to how can we reach a clear understanding of the responsible gene in individual patients. Conventional
one-by-one gene screening does not afford an efficient approach because it is too time- and cost- consuming.
The problem that remains is the large number of patients with deafness of unknown etiology. Recent high-throughput,
next-generation sequencing (NGS) technologies have revolutionized genome research as they can analyze a huge amount
of sequence data in a short time. The advent of NGS technologies has brought deafness research into a new era. Since
it is extremely efficient and cost-effective, comprehensive genetic analysis using NGS platforms has opened the door to
clinical applications, and diagnostic platforms using NGS technologies have been successful in identifying rare causative
mutations in relatively uncommon deafness genes.
In this session, four experts will present their most recent data on the genetics of deafness.
Wed(4)-SFS3-1
Massively parallel DNA sequencing for deafness applied to social health insurance-based genetic testing
Shin-ichi Usami 1 ，Shin-ya Nishio 1 ，Hideaki Moteki 1 ，Maiko Miyagawa 1 ，Kentaro Mori 1 ，Makoto Nagano 2 ，
Toshikazu Yamaguchi 2 ，The Deafness Gene Study Consortium
1:Department of Otorhinolaryngology, Shinshu University School of Medicine, Japan、2:Department of Clinical Genomics, Biomedical
Laboratories, Japan
Target exon resequencing using Massively Parallel DNA Sequencing (MPS) is a new and powerful strategy for the identification
of causative genes in rare Mendelian disorders such as deafness. Our recent data suggest that targeted exon sequencing of
selected genes using the MPS technology will enable the identification of rare responsible genes for individual patients with
deafness and improve molecular diagnosis in the clinical setting (Miyagawa et al., 2013, Nishio et al., 2015).
In Japan, genetic testing using Invader assay (46 known mutations in 13 known deafness genes) for deafness has been covered
by social health insurance since 2012.
To improve diagnostic rate, genetic testing using MPS for deafness was added to social health insurance-based genetic testing
as of August 2015.
Data obtained by social health insurance-based genetic testing suggests that targeted exon sequencing of selected genes using
the MPS technology followed by an appropriate filtering algorithm will enable the identification of rare responsible genes for
individual patients with deafness as well as improve molecular diagnosis. In addition, based on a large number of patients,
the present study clarified the molecular epidemiology of deafness in Japanese. GJB2 is the most prevalent causative gene,
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with 30-40% of cases of deafness being attributable to the major (commonly found; such as CDH23, SLC26A4, MYO15A,
COL11A2 ) gene mutations. The remaining cases of hearing loss result from various rare genes/mutations that have been
difficult to diagnose using a conventional one-by-one approach. In conclusion, target exon resequencing using MPS technology
appears to be a suitable method for the identification of common and rare causative genes for a highly heterogeneous monogenic
disease like hearing loss.
[Biography]
Prof. Usami graduated from Hirosaki University in 1981, and did his
residency training in the Dept. of Otorhinolaryngology at Hirosaki University Hospital. He spent one year doing basic research

at Baylor College of Medicine in 1986. He became Professor and Chairman of the Department of Otorhinolaryngology of
Shinshu University School of Medicine in 1999. He is a member of Oto-Rhino-Laryngological Society of Japan, CORLAS and
Barany Society. He is interested in various topics including genetics for deafness, cochlear implantation, space science, as well
as molecular phylogenetics of alpine butterflies. He has published nearly 200 peer reviewed articles in international scientific
journals. He is an Editorial board of Acta Otolaryngol, Audiological Medicine, Audiology & Neuro- Otology, Otology &
Neurotology.
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Wed(4)-SFS3-2
Diagnostic applications of deafness research in Europe
1
Guy Van Camp
1:Department of Medical Genetics, University of Antwerp, Belgium
Hearing loss is the most common sensorial disorder in children, with an incidence of 1 in 500 newborns. Most cases are caused
by mutations in a single gene. However, DNA diagnostics for hearing loss is challenging, since it is an extremely heterogeneous
trait. Although more than 50 causative genes have been identified for the nonsyndromic forms of hearing loss alone, diagnostic

application of the scientific progress has lagged behind. The reason for this is the cost: screening all the known causatives
genes for hearing loss in one patient with the current golden standard for DNA diagnostics, Sanger sequencing, would be
extremely expensive. Consequently, current routine DNA diagnostic testing for hearing loss is restricted to one or two of the
most common causative genes, which identifies the responsible gene in only 10-20% of cases. Recently several reports have
shown that “next generation DNA sequencing techniques” allow the simultaneous analysis of panels consisting of 50 or more
deafness genes at a reasonable cost. In addition, whole exome sequencing techniques offer the possibility to analyze all human
genes, and get a genetic diagnosis even for genes not present in these gene panels. It is to be expected that these new tests
will greatly improve DNA diagnostics over the next years.
[Biography]
Currently, Guy Van Camp’s main research interest is in the field of sensory genetics. Although work is done for different
forms of sensory diseases, the emphasis is on nonsyndromic hearing impairment. Large families are collected in Belgium
and The Netherlands, as well as in countries with high consanguinity rate such as Iran. These pedigrees are analyzed by
linkage analysis. Subsequently, the genes involved are identified by positional cloning. The laboratory was able to localize a
large number of deafness genes, and to identify several of them. Also complex genetic forms of hearing impairment are being
analyzed, including age-related hearing impairment, noise-induced hearing impairment and otosclerosis. The laboratory has
built substantial expertise in this field, and has collected large patient and family collections. The laboratory has been the
first to identify genes that are associated with these three complex forms of hearing impairment. Some of the genes that were
identified are being studied functionally, and mouse models are made for further analysis. One gene in particular, DFNA5, is
being studied in detail. This gene is responsible for autosomal dominant hearing impairment, but is also an important tumor
suppressor gene inactivated in various frequent forms of cancer.
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Wed(4)-SFS3-3
Genomics of Hereditary Deafness
1
Karen B. Avraham
1:Tel Aviv University, Israel
Our ability to perceive sound is facilitated by the inner ear, an elaborate structure with six sensory organs, which includes
the organ of Corti in the cochlea for hearing and the organs of the vestibular system for balance. The sensory organs contain
epithelial hair cells, the sites of mechanotransduction that facilitate the transformation of mechanical forces into electrical

signals. This extraordinary process allows humans to hear and enables communication, orientation and reaction to danger,
and the ability to listen to music. With over 360 million people suffering from hearing loss worldwide, over 50% of these cases
are predicted to be caused by inherited pathogenic variants. Hearing loss is genetically heterogeneous, with hundreds of genes
involved. Determining the etiology of hearing loss is crucial for clinical management, determining the prognosis of hearing
loss and other abnormalities and assessing the recurrence rate in family members. The use of isolated populations, such as
those of the Middle East, has had a strong influence on the discovery of deafness genes worldwide. We applied targeted
gene capture, along with massively parallel sequencing, of over 300 genes associated with deafness genes on unrelated families
of Israeli Jewish and Palestinian Arab origin. We identified variants that are candidates for deafness in our patients. For
unsolved families, a whole exome sequencing approach is being taken. Our epigenetic study of the mouse sensory epithelium is
revealing regulatory genomic regions that may harbor genetic or epigenetic mechanisms responsible for as-yet-unsolved forms
of human deafness. The auditory system, through the use of cell and cochlear cultures and mouse models for human deafness,
offers avenues for functional analysis to link variants to pathogenicity. Deciphering the genetic basis of hearing is leading to
the elucidation of mechanisms underlying the pathophysiology of deafness, with potential development of therapeutic options.
[Biography]
Prof. Avraham is Vice Dean and Professor at the Department of Human Molecular Genetics and Biochemistry at the Sackler
Faculty of Medicine at Tel Aviv University. Prof. Avraham has been awarded the Sir Bernard Katz Prize from the Humboldt
Foundation (Germany), the Bruno Memorial Prize from the Rothschild Foundation and the Teva Prize for Groundbreaking
Research in the Field of Rare Diseases. Funding in her laboratory includes from the National Institutes of Health, European
Commission, Human Frontiers, I-CORE, Israel Science Foundation and the US-Israel Binational Science Foundation. Prof.
Avraham has published 95 peer-reviewed manuscripts and 51 reviews and chapters. She has trained over 100 students in her
laboratory. Prof. Avraham is Council member of the European Molecular Biology Organization (EMBO), President of the
Israel Society for Auditory Research (ISAR), Chair of the Scientific Committee of Agir Pour L’audition (Acting for Hearing)
in France, President of the Federation of Israel Societies for Experimental Biology (FISEB/ILANIT), Council member of
the Human Genome Organization (HUGO), an elected member of the International Collegium Oto-Rhino-Laryngologicum
Amicitiae Sacrum (CORLAS), and past President of the Association for Research in Otolaryngology (ARO).
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Wed(4)-SFS3-4
Clinical applications of genetic studies for deafness
1,2
Chen-Chi Wu
1:Department of Otolaryngology, National Taiwan University Hospital; Department of Medical Genetics, National Taiwan University Hos-
pital, Taiwan、2:Department of Medical Genetics, National Taiwan University Hospital
Recent advancements in genetic medicine have revolutionized the clinical management of hearing-impaired patients in terms
of genetic diagnosis, genetic counseling, and treatment. Nowadays, comprehensive genetic examination for idiopathic sen-
sorineural hearing impairment (SNHI) can be achieved by using the massively parallel sequencing (MPS) technique. Using

a MPS panel which targets ~ 160 known deafness genes, we have increased the detection rates of causative mutations in
multiplex and simplex families with idiopathic SNHI to 67% and 50%, respectively. Precise genetic diagnoses facilitate genetic
counseling in these families and enable personalized medicine in the affected patients, such as predicting the outcomes with
cochlear implants before surgery. In a longitudinal observational study composed of >5000 newborns, our results revealed that
newborn genetic screening for common deafness mutations could compensate for the inherent limitations of newborn hearing
screening, and may be useful in identifying hearing-impaired children at an earlier age. The establishment of transgenic mouse
models provides insights into the pathogenesis of deafness mutations, and will be valuable in developing novel therapeutic
strategies accordingly. Our experience with regards to clinical implications of genetic studies for deafness will be presented.
[Biography]
Name: Chen-Chi Wu
Degree: MD, PhD
Birthday: Feb. 12, 1976
Current Position: Associate professor, Department of Otolaryngology
Institute: National Taiwan University College of Medicine
Country: Taiwan
E-mail: chenchiwu@ntuh.gov.tw
Education
1992-1999 Medical School: School of Medicine, National Taiwan University College of Medicine
2004-2010 PhD: Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine
2012-2013 Research fellow: Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School
Professional experience
2000-2004 Resident, Department of Otolaryngology, National Taiwan University Hospital
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2004- Attending Physician, Department of Otolaryngology, National Taiwan University Hospital
2006- Attending Physician, Department of Medical Genetics, National Taiwan University Hospital
Professional Societies
American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS): active member

Asia Pacific Symposium on Cochlear Implant and Related Sciences (APSCI): active member
Association for Research in Otolaryngology (ARO): active member
American Society of Human Genetics (ASHG): active member
Barany Society: active member
International Otopathology Society (a.k.a. The Schuknecht Society): active member
Politzer Society: active member
Major Interests
Dr. Wu’s clinical interest lies in otology, pediatric otorhinolaryngology and endoscopic ear surgery. His research interest
centers on the genetics of hearing impairment.
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Integration of Genomic Information and Electric Health Record Systems
Wed., April 06, 2016 15:00-16:30 Room A (2F)
Moderator：Catherine A. Wicklund（Center for Genetic Medicine, Northwestern University, USA）

Moderator ：Hiroshi Tanaka（Tokyo Medical and Dental University, Japan）
The integration of genomic information into electronic health records (EHRs) shows promise to advance the field of
precision medicine. We will present an overview of the current state of adoption of EHRs from select countries, identify

common barriers to successful integration, and describe promising early successes in both the United States (US) and
Japan.
Adoption rates of EHRs have steadily increased, often with significant government support. Despite these positive trends,
significant barriers to the meaningful use of EHRs include, poor usability, lack of data standardization and impaired in-
teroperability. These same issues impede progress in incorporating genomic information into EHRs. Compounding these
concerns are the ethical and legal implications of integration of genetic information into routine clinical care including
fear of discrimination and privacy violations, patient/provider education on how to utilize genomic information and equal
access to EHRs. We will highlight how data from EHRs have been used successfully to enable genomic studies and present
promising new directions.
As case examples, we will highlight four current initiatives. The Integrated Clinical Omics Database (iCOD), the To-
hoku Medical Megabank (TMM) project, the Electronic Medical Records and Genomics network (eMERGE) and the
Action Collaborative on Developing Guiding Principles for Integrating Genomic Information into the EHR Ecosystem
(DIGITizE).
Wed(4)-SFS4-1
1
Panelist：Catherine A. Wicklund
1:Center for Genetic Medicine, Northwestern University, USA
No Abstract
[Biography]
Ms. Wicklund is the Director of the Graduate Program in Genetic Counseling at Northwestern University and an Associate
Professor in the Department of Obstetrics and Gynecology. She has over 20 years of experience in clinical genetic counseling.
She served on the Board of Directors of the National Society of Genetic Counselors first as Region V Representative, then
as Secretary and was President in 2008. Currently she is a member of the Illinois Department of Public Health’s Genetic
and Metabolic Diseases Advisory Committee, the Advisory Committee on Hereditable Disorders in Newborns and Children,
the American Society of Human Genetics representative on the Scientific Program Committee of the 2016 International
Congress of Human Genetics and the NSGC representative on the Institute of Medicine Roundtable on Translating Genomic
Based Research for Health. Ms. Wicklund’s research interests include issues regarding whole genome/exome sequencing
and personalized medicine, psychosocial and counseling issues, and professional issues including workforce and access to and
delivery of genetic services. She is a co-investigator on the Electronic Medical Records and Genomics (eMERGE) Network,
which aims to bring personalized medicine into broader clinical use. She received her Master of Science degree in Genetic
Counseling from the University of Texas-Graduate School of Biomedical Sciences and is a diplomat of the American Board
of Genetic Counseling.
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Wed(4)-SFS4-2
1
Panelist：Hiroshi Tanaka
1:Tokyo Medical and Dental University, Japan
No Abstract

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Wed(4)-SFS4-3
1
Panelist：Abel Kho
1:Northwestern University, USA
No Abstract
[Biography]

Dr. Abel Kho is Associate Professor of Medicine and Preventive Medicine at Northwestern University and Director of
the Center for Health Information Partnerships (CHiP) within the Institute for Public Health and Medicine. His research
focuses on developing regional Electronic Health Record (EHR) enabled data sharing platforms for translational research,
epidemiologic studies, and quality improvement. Dr. Kho is co-PI and Informatics lead of the Chicago Area Patient Centered
Outcomes Research Network (CAPriCORN), one of the PCORI-funded Clinical Data Research Networks and also served as
Co-Chair of the Data Standards, Security and Network Infrastructure Task Force of PCORnet. As a member of the eMERGE
consortium (Electronic Medical Records and Genomics) he has developed EHR based phenotyping methods to enable high
throughput genetic studies. He maintains an active primary care practice which guides his role as PI of the Chicago Health IT
Regional Extension Center (www.chitrec.org), and in his role leading Illinois’ involvement in the CMS sponsored Great Lakes
Practice Transformation Network. He is the PI for the AHRQ funded Healthy Hearts in the Heartland consortium, which
aims to test the capacity of primary care practices in the Midwest to improve the ABCS of cardiovascular disease prevention:
Aspirin in high-risk individuals, Blood pressure control, Cholesterol management, and Smoking cessation.
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IGEN: Do they know what you think they know? Development and evaluation of health professional
education in genetics and genomics
Wed., April 06, 2016 16:45-18:15 Room A (2F)
Moderator：Vajira Dissanayake（Human Genetics Unit, Faculty of Medicine, University of Colombo, Sri Lanka）
Moderator ：Akihiro Sakurai（Department of Medical Genetics, Sapporo Medical University, Japan）
The proposed program will convene experts from the International Genetics Education Network (IGEN) in the needs
assessment, development and evaluation of genetics education for health professionals. The speakers will describe the

development of various educational programs and different approaches to assessing outcomes of interest in the targeted
populations.
The appropriate integration of genomics into routine practice has the potential to significantly impact patient care,
however, substantial barriers must be overcome. Internationally, health professionals, particularly primary care providers,
have acknowledged a gap in genetics knowledge and skills. A noted lack of confidence about their own genetics knowledge
has prevented physicians from having comprehensive discussions about it with their patients. Further, physicians may
order genetic testing that is inappropriate for the clinical situation and that they do not correctly interpret, potentially
leading to wasted healthcare resources and less than optimal patient outcomes. Physicians also have reported a lack of
understanding about when and how to make referrals for genetic counseling. Physicians have endorsed the need for more
training in areas such as genetic risk assessment, test ordering and interpretation, and counseling and some groups have
developed continuing education programs designed to address these topics.
Wed(4)-SFS5-1
How program evaluation can be applied to genomics education of health professionals
1
Sylvia Metcalfe
1:Genetics Education and Health Research, Genetics Theme; Murdoch Childrens Research Institute - The Royal Children’s Hospital, Aus-
tralia
This presentation will describe the importance of program evaluation in developing and evaluating education programs.
The focus will be on the first stages in developing programs, ie importance of working with and understanding the target
group, and in particular how needs assessments are critical in contributing to successful development of relevant content
and delivery. Needs assessments include mapping existing education and engaging the target group and key informants to
determine existing gaps, understanding and which content is relevant and perceived by the range of stakeholders, including
content experts. Examples will be discussed.
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Wed(4)-SFS5-2
Knowledge translation
1
June C. Carroll
1:Department of Family & Community Medicine, Mount Sinai Hospital, University of Toronto, Granovsky Gluskin Family Medicine Centre,
Canada
This presentation will discuss the development of point-of-care tools and resources in genomic medicine for primary care
providers based on needs assessments. Evaluation of these tools and dissemination strategies will also be discussed using
Canadian examples of primary care genomic medicine resources, knowledge translation strategies and evaluation.
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Wed(4)-SFS5-3
A national coordinated approach to workforce transformation
1
Michelle Bishop
1:Genomics Education Programme, Health Education England, Birmingham, UK
This presentation will outline how Health Education England’s Genomics Education Programme has implemented a co-
ordinated approach to workforce transformation in England. This approach includes upskilling the existing workforce (im-
plemented a multidisciplinary Masters in Genomics Education which is being delivered through a network of 9 universities

with 550 commissioned places for NHS staff; publishing online learning resources for specific clinical activities associated
with the 100,000 Genomes Project) and ensuring the future workforce is equipped to incorporate genomics into their practice
(development of training programs in emergent fields such as clinical bioinformatics and ensuring appropriate level of genomic
education in existing training pathways). Specific examples will be described.
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Wed(4)-SFS5-4
Telemedicine in the education of health professionals: Sickle cell disease as an exemplar
1
Kunal Sanghavi
1:McKusick-Nathans Institute of Genetic Medicine - Johns Hopkins University - School of Medicine, Baltimore, MD, USA; New York
Mid-Atlantic Consortium for Genetics and Newborn Screening Services (NYMAC), Baltimore, Maryland, USA
Challenges such as dearth of adequately trained health professionals and“medical home”, geographic and economic constraints,
and cultural barriers limit access to the care that is required to prevent morbidity and mortality. Telemedicine addresses these
challenges and can lead to long term benefits. This presentation will highlight successful examples of using telemedicine in the

education of health professionals including trainees, patient consultation and follow-up services, and public health programs.
Logistics of establishing telemedicine services, outreach efforts, and evaluation will be discussed using sickle cell disease as an
example.
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Wed(4)-SFS5-5
Application of evidence-based educational practices
1
Michael J. Dougherty
1:American Society of Human Genetics, USA
This presentation will discuss the impact of applying best practices of adult learning principles to the development of blended
educational program for primary care providers on cancer genomics. The Jackson Laboratory and the American Society
of Human Genetics developed, implemented, and evaluated the one-day workshop with 12 months of digital engagement in

multiple locations. Best practices will be discussed along with the short and long term outcomes of the program.
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Cardiac Genetics
Wed., April 06, 2016 15:00-16:30 Room E (1F)
Moderator：Julie McGaughran（Genetic Health Queensland, Australia）

Moderator ：Euan Ashley（Medicine/Cardiovascular Medicine and Genetics, Stanford University, USA）
Over recent years, there has been a significant increase in referrals to cardiac genetics clinics with an increase in the
availability of genetic testing. The ready availability of large-scale sequencing has led to improved definition of the

molecular cause of these conditions and the development of precision medicine. This should lead to improved diagnosis
and in turn improved therapeutics for these conditions.
In the interim, there continue to be challenges in understanding the molecular basis of these conditions and implementing
this technology into clinical practice in individuals and families.
This session will provide an overview of some of these current opportunities and challenges.
Wed(4)-SFS6-1
Cardiovascular Precision Medicine
1
Euan Ashley
1:Medicine/Cardiovascular Medicine and Genetics, Stanford University, USA
Inherited cardiovascular disease is being transformed by the ready availability of large scale sequencing. Increasingly, diseases
can be defined molecularly and therapeutics targeted at the underlying cause of disease. In this talk, I will give real world
examples of the application of cardiovascular precision medicine and provide a roadmap towards increasing the accuracy of
genetic diagnostics.
[Biography]
Euan Ashley is Associate Professor of Medicine and Genetics, Director of the Clinical Genomics Service, and Director of the
Center for Inherited Cardiovascular Disease at Stanford University. In 2010, he led the team that carried out the first clinical
interpretation of a human genome. In 2013, he was recognized by the White House OSTP for contributions to Personalized
Medicine. Currently, he serves as co-chair of the NIH Undiagnosed Diseases Network.
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Wed(4)-SFS6-2
Successes and Challenges from the Cardiac Genetics Clinic
1,2
Julie McGaughran
1:Genetic Health Queensland, Australia、2:University of Queensland School of Medicine
Over recent years, there has been a significant increase in referrals to cardiac genetics clinics with an increase in the availability
of genetic testing. In some areas, such as sudden unexpected death in the young, this has enabled family members to not only
have a diagnosis but to also be able to access genetic testing. However, it has become clear that cardiac genetics is a complex

area of clinical genetics as there can be great inter- and intra-familial variability in clinical presentation. In addition, the
increased use of large gene panels has demonstrated that mutations in particular genes can cause different cardiac conditions
in different families or apparent mutations are found in genes that do not match the phenotype. Interpretation of genetic
variants is also complex. A number of these challenges will be presented with clinical examples
[Biography]
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Wed(4)-SFS6-3
From Mendelian syndromes to blockbuster drugs: The PCSK9 story
1
Catherine Boileau
1:Institut National de la Santé et de la Recherche Médicale (INSERM) U698, Hôpital Bichat, France
TBA

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Wed(4)-SFS6-4
Genetics of long QT syndrome
1
Wataru Shimizu
1:Department of Cardiovascular Medicine, Nippon Medical School, Japan
Congenital long QT syndrome (LQTS) is a hereditary disorder characterized by a prolonged QT interval and trademark
arrhythmia of polymorphic ventricular tachycardia, known as Torsade de Pointes. Molecular genetic studies so identified
13 forms of congenital LQTS, which are caused by mutations in genes of ion channels or membrane adapter. The 3 major

genotypes, LQT1, LQT2 and LQT3 syndromes constitute more than 90 % of genotyped LQTS patients, and genotype-
phenotype correlation has been investigated in detail. Genotype-specific triggers for cardiac events are reported in the
3 genotypes due to differential sensitivity of each genotype to sympathetic stimulation. Genotype specific treatment and
management have been already introduced. More recently, mutation-site, type specific differences in clinical phenotype have
been reported. International registry suggested that LQT1 patients with transmembrane mutations in the KCNQ1 gene
had a greater risk of cardiac events, and had greater sensitivity to sympathetic stimulation than those with C-terminal
mutations. International registry also suggested that LQT2 patients with missense mutations located in the pore region
of the KCNH2 gene had the greatest risk for arrhythmic events than those with other mutations in other regions. These
data indicates a possibility for mutation-site specific management or treatment in each genotype. Since 2005, we started
Japanese Congenital LQTS Multicenter Registry. Until 2011, a total 1123 of congenital LQTS patients (LQT1, 2, 3) were
enrolled. In this lecture, the results of the Japanese registry will be presented. We also recently conducted whole-exome
sequencing analyses in genotype-negative, phenotype positive congenital LQTS, and revealed candidate pathogenic mutations
in calmodulin-interacting genes, suggesting an important role of calmodulin and its interacting proteins in the pathogenesis
of LQTS as LQT14.
[Biography]
EDUCATION: Hiroshima University School of Medicine, Japan M.D. Ph.D.
POSTDOCTORAL TRAINING AND PROFESSIONAL EXPERIENCE:
1985-87 Resident in Medicine, Hiroshima University
1987-90 Resident in Cardiology, National Cardiovascular Center (NCVC)
1990-91 Clinical Fellow, Hiroshima University
1992-2011 Clinical Staff, Division of Cardiology, NCVC
1996-98 Research Scientist, Masonic Medical Research Laboratory, Utica, NY
2011-2013 Director, Department of Cardiovascular Medicine, NCVC
2013-pres Professor and Chairman, Department of Cardiovascular Medicine, Nippon Medical School
PROFESSIONAL ACTIVITIES:
Memberships:
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Councilor, Japanese Society of Internal Medicine
Assistant of President, Japanese College of Cardiology
Director, Japanese Heart Rhythm Society (JHRS)
Treasurer, Asian-Pacific Heart Rhythm Society (APHRS)
HONORS AND SPECIAL AWARDS:

1992 First Prize, Kimura Eiichi Award, Japanese Society of Electrocardiology
1997 First Prize, YIA, Basic Research, NASPE
1998 Finalist, YIA, Physiology, Pharmacology, and Pathology, ACC
1999 First Prize, Jos Willems YIA, International Society for Computerized Electrocardiography,
2003 First Prize, 3rd Ikagaku-Ooyo Research Foundation Award, Japanese Society of Electrocardiology
2008 33rd Sato Award, Japan Heart Foundation, Japanese Circulation Society

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Genetics of Skin Diseases
Wed., April 06, 2016 16:45-18:15 Room E (1F)
Moderator：Masashi Akiyama（Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya,

Japan）
Moderator ：Vinzenz Oji（Department of Dermatology, University Hospital Münster, Münsterr, Germany）
Genodermatoses comprise an enormous spectrum of genetically caused diseases. Human skin - a large organ protecting
our body from various types of external stress - with its immune system, nerves, vessels and appendages, like nails,

hair, sweat glands etc., can be affected by mutations of any gene that is expressed in parts of the multifunctional organ.
Genodermatoses not only refer to monogenetic diseases and are rather seen as Mendelian as more than one gene might be
affected. A current internet search for “skin” in the OMIM database (www.ncbi.nlm.nih.gov/omim/) shows a number
of 3472 entries.
This workshop will provide an overview on major types of genodermatoses. It refers to clinical geneticists, dermatologists
and molecular biologists in order to provide an update on the current clinico-genetic approach for diagnosis. Through four
talks and following interactive discussions international experts will present the large group of disorders of cornification,
skin fragility, inflammatory and immune mediated skin diseases as well as vascular skin diseases. Their symptoms concern
the skin or other organ systems. Various forms of syndromic or non-syndromic diseases will be discussed. As such speakers
will focus on major disease types providing novel genetic insights into the large field of genodermatology.
Wed(4)-SFS7-1
Keratinization disorders
1
Vinzenz Oji
1:Department of Dermatology, University Hospital Münster, Münster, Germany
The majority of keratinization disorders are referred to as Mendelian disorders of cornification (MeDOC). This very broad
group is clinically characterized by hyperkeratosis or visible scaling or both. It comprises the ichthyoses, palmoplantar
keratodermas (PPKs) and miscellaneous disorders such as porokeratoses.
This talk is aimed at clinical geneticists as well as physician scientists, who have to make a clinico-genetic diagnosis and
are interested in understanding the pathophysiology of these fascinating disorders. To discuss novel findings on molecular
pathology and improve our current understanding of genotype-phenotype correlation, the presentation will be focused on the
generalized forms of MeDOC, i. e. the ichthyoses.
[Biography]
Career
1995-2002 Medical study Münster, Lille, Bangalore and Paris
2003 Dermatology residency
2004 MD thesis
2009 Board Certification Dermatology
2012 Habilitation Medical Faculty Münster
2013 Senior House Officer
Scientific activities
2000 Molecular studies Max-Delbrück-Centrum Berlin
2003 Network for Ichthyoses and Related Keratinization Disorders (NIRK)
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2009 Ichthyosis Consensus Conference (Sorèze)

2014 Funding by Medical Faculty Muenster and/or DFG
Memberships
Associated Editor (British Journal of Dermatolog)
European Society for Pediatric Dermatology (ESPD)
European Society for Dermatological Research (ESDR)
Arbeitsgemeinschaft Dermatologische Forschung (ADF)

Publications
- Oji V, et al. Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin
disease. Am J Hum Genet (2010)
- Oji V, et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus
Conference in Sorèze 2009. J Am Acad Dermatol (2010)
- Oji V, et al. Bathing suit ichthyosis is caused by transglutaminase-1 deficiency: evidence for a temperature sensitive
phenotype. Hum Mol Genet 15:3083-97 (2006)
- Oji V, Metze D, Traupe H. Mendelian Disorders of Cornifcation (MeDOC) In: Griffiths C, Barker J, Bleiker T, Chalmers
R, Creamer D (ed): Rook’s Textbook of Dermatology 9th edition: Blackwell Publishing Ltd, 2015 [in press]
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Wed(4)-SFS7-2
Mutational analysis of dystrophic epidermolysis bullosa
Eijiro Akasaka 1 ，Hajime Nakano 1 ，Daisuke Sawamura 1
1:Dermatology, Hirosaki University Graduate School of Medicine, Japan
Dystrophic epidermolysis bullosa (DEB) is an intractable genetic blistering disease in which the epithelial structure easily
separates from the underlying dermis. DEB is clinically characterized by mucocutaneous blistering in response to minor
trauma, followed by scarring and dystrophy of nails. While DEB occurs as either an autosomal dominant (DDEB) or

recessive (RDEB) fashion, both DDEB and RDEB are caused by mutations of COL7A1 encoding type VII collagen.
To date, we have detected COL7A1 mutations in 155 Japanese DEB families, including 65 DDEB and 90 RDEB. In this
session, we would like to present the summary of results of our COL7A1 mutational analysis. Even though the genotype-
phenotype relationship remains to be unclear, our study will provide further understanding of clinical and genetic features of
Japanese DEB patients.
On the other hand, screening for COL7A1 mutation with conventional methods with genomic DNA is time consuming and
need a large amount of labor, because COL7A1 is large and complex gene and human COL7A1 has no apparent hotspot
mutation. In addition, when splice site mutations are suspected in mutational analysis using genomic DNA, an additional
invasive skin biopsy is needed to obtain mRNA from fibroblasts or keratinocytes for detecting consequence of alternative
splicing.
In this study, we demonstrated that a small amount of COL7A1 mRNA was expressed in peripheral blood mononuclear
cells (PBMCs). We next examined whether mRNA obtained from PBMCs were available for detection of aberrant splicing of
COL7A1 . Mutational analysis using mRNA extracted from the PBMCs of DEB patients revealed that some mutations, which
seemed to be missense or nonsense mutations in analysis with genomic DNA, actually resulted in aberrant splicing. These
findings suggested that this approach may be useful for detection of accurate consequences of the mutations of COL7A1 .
[Biography]
Education
1997-2003 M.D. Hirosaki University Graduate School of Medicine
2005-2011 Ph.D. Hirosaki University Graduate School of Medicine
Professional Training and Employment
2003-2004 Resident, Hirosaki University Hospital
2004-2005 Resident, Aomori Prefectural Central Hospital
2005-2010 Medical Staff, Department of Dermatology, Hirosaki University Graduate School of Medicine, Hirosaki
2010-2011 Medical Staff, Dermatology, Aomori Prefectural Central Hospital, Aomori
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2011-present Assistant professor, Department of Dermatology, Hirosaki University Graduate School of Medicine

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Wed(4)-SFS7-3
Vascular malformations: From diagnosis to therapy
1,2,3
Miikka Vikkula
1:Human Molecular Genetics, de Duve Institute, Universite catholique de Louvain; Center for Vascular Anomalies, Division of Plastic
Surgery, Cliniques universitaires Saint Luc, Brussels; Walloon Excellence in Lifesciences and Biotechnology WELBIO, de Duve Institute,
Universite catholique de Louvain, Brussels, Belgium、2:Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques universitaires
Saint Luc, Brussels, Belgium、3:Walloon Excellence in Lifesciences and Biotechnology WELBIO, de Duve Institute, Universite catholique
de Louvain, Brussels, Belgium
Vascular anomalies are localized defects of the lymphatic or vascular system. They are most commonly cutaneous, but can

affect any body part. They are divided according to vessel type into arterial, capillary, venous, lymphatic and combined-
complex malformations (Wassef et al, Pediatrics 2015).
Based on familial inheritance of some vascular malformations, we have identified underlying inherited changes, including
in TIE2 (mucocutaneous venous malformations; VMCM), in glomulin (glomuvenous malformations; GVM), and RASA1
(capillary malformation-arteriovenous malformation; CM-AVM). These patients are typically characterized by small multifocal
lesions, which may increase in number with time. We explained this by Knudson’s double-hit theory and demonstrated somatic
second-hits (intragenic or chromosomal anomalies, including acquired uniparental isodisomy) in all three entities.
The frequency of somatic 2nd -hits made us study sporadic patients for somatic changes. We screened resected tissues from
>100 venous (VM), >70 lymphatic (LM) and >30 capillary (CM) malformations for mutations in candidate genes with high
sensitivity. We frequently pinpointed somatic activating mutations: in about 60% of VMs in TIE2 and in another 20% of VMs
in PIK3CA, in 80% of LMs in PIK3CA, in 50% of CMs in GNAQ, and in some combined-complex malformations representing
the syndromic forms, like the CLOVES syndrome, in PIK3CA. Therefore, somatic mutations are a common pathophysiologic
cause of sporadic vascular anomalies.
Many of the genetic mutations cause activation of the PI3K>AKT signaling pathway downstream of various receptor tyrosine
kinases. mTOR is one of the downstream target proteins, and it is commonly activated. Thus, mTOR inhibitors may be
useful in the treatment of some of these vascular anomalies. We have tested this in a clinical pilot study for refractory-to-
standard-care LMs, VMs and/or complex slow-flow vascular anomalies with encouraging results.
[Biography]
Prof Vikkula obtained his M.D. at the University of Helsinki in 1992 and his Ph.D. in molecular genetics, in 1993. He was a
Research Associate at Harvard Medical School 1993-1997, during which time he became interested in vascular and lymphatic
anomalies. With his wife, Prof Laurence Boon, Plastic Surgeon, Co-ordinator of the Vascular Anomaly Center, Brussels, the
couple discovered the gene for familial venous malformation in 1996, and since then many others. They settled in Brussels in
1997, where Dr Vikkula developed his own laboratory. He obtained a "docentship PhD" in 2000, and was nominated Assistant
Professor at the Faculty of Medicine in UCL. He is a member of the Directorate of the de Duve Institute since 2004, and a
full professor of Human Genetics since 2013. He has received numerous honours and awards; most recently, the Inbev-Baillet
Latour Clinical Prize in 2013. He is a Member of the Royal Belgian Academy of Medecine since 2012. Prof Vikkula is well
known internationally as a major contributor to the understanding of molecular basis of vascular anomalies and lymphedema
with >150 peer-reviewed pulications and nymerous chapters in major bio-medical text books.
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Wed(4)-SFS7-4
Genetic background of generalized pustular psoriasis
1
Kazumitsu Sugiura
1:Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Generalized pustular psoriasis (GPP), with acute, subacute, or occasionally chronic eruptions, is an uncommon variant of
psoriasis. Sterile pustulosis is the central feature of GPP. About a century after von Zumbusch first described a case of GPP
in 1910, the cause of the disease remains unknown. It was not considered a monogenic skin until Marrakchi et al. reported

the causative gene of familial GPP in 2011. Currently, two genes, IL36RN and CARD14 , which encode proteins secreted by
keratinocytes (KC) or KC-localized proteins, are thought to be the causative or susceptibility genes in GPP.
GPP often occurs in patients with existing or prior psoriasis vulgaris (PV;“GPP with PV”). However, GPP without a history
of PV (“GPP alone”) has also been reported. GPP onset occurs at any age. In 2013, my collaborators and I reported that
the majority of GPP alone cases are caused by recessive mutations in IL36RN . In contrast, only a few cases of GPP with
PV have recessive IL36RN mutations. We also reported recently that CARD14 p.Asp176His, a gain-of-function variant, is a
predisposing factor for GPP with PV; this variant is not associated with GPP alone in the Japanese population. These results
suggest that GPP alone is genetically different from GPP with PV. IL36RN mutations are also found in some patients with
impetigo herpetiformis, acute generalized exanthematous pustulosis, palmar-plantar pustulosis, and acrodermatitis continua
of hallopeau.
Currently, even individuals with heterozygous IL36RN mutations are considered susceptible to GPP. According to the Human
Genetic Variation Browser and a previous report, 1-4% of the citizens in Japan and China have a pathogenic heterozygous
IL36RN mutation. Thus, it is clinically important to analyze IL36RN mutations in patients with sterile pustulosis.
[Biography]
Kazumitsu Sugiura
Experience
Education
1988-1994 M.D. Nagoya University School of Medicine, Nagoya, Japan
1995-1999 Ph.D. Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Employment
1994-1995 Resident. Anjo Kosei Hospital, Anjo, Japan
1999-2001 Research Associate, Autoimmune Disease Center, Molecular Experimental Medicine, The Scripps Research Insti-
tute, La Jolla, CA, USA
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2001-2002 Research Associate, Department of Biochemistry II, Nagoya University Graduate School of Medicine, Nagoya,
Japan
2002-2003 Clinical Fellow, Department of Dermatology Nagoya University Hospital, Nagoya, Japan
2003-2004 Research Associate, Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
2004-2008 Assistant Professor, Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2008-2016 Associate Professor, Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
2016-present Professor and Chairman, Department of Dermatology, Fujita Health University, Toyoake, Japan
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Genetics of Eye Diseases
Wed., April 06, 2016 15:00-16:30 Room B-2 (2F)
Moderator：Takeshi Iwata（National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center,
Japan）
Moderator ：Rando Allikmets（Ophthalmology, Columbia University; Pathology & Cell Biology, Columbia University,
New York, USA）
It is known that approximately 80% of information our body receives comes as visual information. The visual system

include the anterior part of the eye (cornea, lens and vitreous body) and the posterior part of the eye (retina and optic
nerves). These components focus the incoming light to the retina, which transduces the light signal into neural signals
and passes through the optic nerves to central structures for more elaborate processing, integrating their information with
other sensory information. Any disease that interferes with the function of these components will cause loss of vision and
blindness, and each part of the visual system has specific susceptibilities to genetic background and age. Genetic factor
plays critical role for the onset of various eye diseases and for this reason, genetic research has been active in this field.
Number of leading genetics research such as the world first successful GWAS study on age-related macular degeneration
has been previously demonstrated. Over 250 genes has been associated with eye diseases and approximately 12,000 gene
mutations responsible for retinal diseases alone. In this session, four speakers will focus on critical eye diseases such as
retinitis pigmentosa, myopia, age-related macular degeneration and other hereditary retinal diseases and introduce the
cutting edge genetics analysis and diagnostics. Dr. Allikmets will speak about his recent work on retinitis pigmentosa,
one of the major inherited retinal disease. Dr. Zhang will present his recent work on myopia, a common eye problem
worldwide. Dr. Baird will speak about age-related macular degeneration, the major eye disease for elderly worldwide.
Dr. Iwata will describe the Japan consortium for hereditary retinal diseases.
Wed(4)-SFS8-1
Finding new genes for syndromic retinitis pigmentosa by next-generation sequencing
1,2 3,4 5,6 1
Rando Allikmets ，Carmen Ayuso ，Daniel F Schorderet ，Yajing Xie
1:Ophthalmology, Columbia University; Pathology & Cell Biology, Columbia University, New York, USA、2:Pathology & Cell Biology.
Columbia University, New York, USA、3:Genetics, Instituto de Investigacion Sanitaria-University Hospital Fundacion Jimenez Diaz (IIS-
FJD), Madrid, Spain、4:4Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Raras, ISCIII, Madrid, Spain、5:IRO - Institute
for Research in Ophthalmology, Sion, Switzerland、6:Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland
Retinitis pigmentosa (RP), a genetically heterogeneous group of retinopathies which occur in both non-syndromic and syn-
dromic forms, is caused by mutations in >100 genes. Although recent advances in next-generation sequencing have aided
in the discovery of novel RP genes, a number of the underlying contributing genes and loci remain to be identified. We
investigated three families who presented with syndromic RP, including facial dysmorphologies, brachydactyly, psychomotor
developmental delays recognized since early childhood, learning disabilities, and short stature. RP-associated ophthalmologi-
cal findings included salt-and-pepper retinopathy, attenuation of the arterioles and generalized rod-cone dysfunction resulting
in almost extinguished electroretinogram in most affected individuals. Some patients presented with atypical for RP features
including mottled macula at an early age and peripapillary sparing of the RPE. Whole exome sequencing (WES) data, queried
under a recessive model of inheritance, identified compound heterozygous stop mutations, p.R67* and p.R108*, in the retinol
dehydrogenase 11 (RDH11 ) gene, resulting in a non-functional protein, in all affected children of family 1. In families 2 and
3, homozygous deleterious mutations in the CWC27 gene which encodes for a spliceosome-associated protein, segregated with
the disease. Affected siblings in family 2 possessed a synonymous p.E165E variant which completely abolishes splicing. In
family 3 a homozygous protein-truncating p.E315* variant was present in affected children. In summary, deleterious muta-
tions in proteins with very different function, RDH11 and CWC27 , an important enzyme for retinoic acid metabolism and a
spliceosome-associated protein, cause very similar phenotypes of new syndromes with RP.
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[Biography]
Rando Allikmets, Ph.D., is the William and Donna Acquavella Professor at the Departments of Ophthalmology and Pathology
& Cell Biology, and Director of Research at the Harkness Eye Institute, Columbia University, New York. Before entering the
field of genetics of eye diseases, his main research interests were in human genome and cancer genetics, where he cloned and
characterized over 30 genes in the ATP-binding cassette (ABC) transporter superfamily, including several genes involved in
human inherited diseases. He determined that one of these genes, ABCA4 (ABCR), was responsible for Stargardt disease
and later characterized it as the first gene associated with age-related macular degeneration. Since then the main interest
of Dr. Allikmets’ research has been AMD genetics, where he and his colleagues have determined a major disease pathway,
involving two regulators of the alternative complement cascade, complement factor H and factor B. His other research interests

include designing high-tech diagnostic tools for eye diseases, finding new retinal disease genes, and therapeutic applications
for Stargardt disease and AMD.
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Wed(4)-SFS8-2
Genetic study on early onset high myopia: A story from whole exome sequencing on 298 probands
Qingjiong Zhang 1 ，Xueshan Xiao 1 ，Shiqiang Li 1 ，Jiali Li 1 ，Dan Jiang 1 ，Wenmin Sun 1
1:Zhongshan Ophthalmic Center, Sun Yat-sen University, China
High myopia are the most common causes of irreversible blindness due to its associated complications. Genetic factors have
been shown to play an important role in the development of high myopia. Both Mendelian and complex traits have been
suggested but many genetic studies on high myopia did not differentiate Mendelian trait from complex trait. Based on our

series studies on high myopia in the last two decades, most early onset high myopia should be considered to be transmitted as
Mendelian trait while most high myopia in teenage students associated with excessive near work are more likely to be complex
trait. In order to elucidate the genetic basis of Mendelian high myopia, whole exome analysis was conducted on genomic
DNA from 298 probands with early onset high myopia. Mutations in genes suggested to be associated with high myopia were
only detected in a few families. Comprehensive analysis of genes know to be responsible for other retinal diseases identified
potential pathogenic mutations in 34 of 234 genes in 71 of 298 (23.4%) probands. Comparative analysis between whole exome
sequencing data from the 298 probands and those from several cohorts with other diseases not only revealed several novel
candidate genes for Mendelian high myopia but also suggested a few unlikely causative genes reported to be responsible for
high myopia and other retinal diseases.
[Biography]
Professor Qingjiong Zhang is the Director of Eye Research Institute, Vice President of Zhongshan Ophthalmic Center, Sun
Yat-sen University. He also serves as the Deputy Director of the State Key Laboratory of Ophthalmology. He received his
medical education in Faculty of Clinical Medicine at Tongji Medical University (1980-1985) and his training in Ophthalmology
at Sun Yat-sen University of Medical Sciences (1985-1990). He became a full time staff of the Zhongshan Ophthalmic Center
(ZOC) in 1990, promoted as full professor in 1996, and is currently a consultant ophthalmologist for pediatric and genetic eye
diseases and a principal investigator for ophthalmic molecular genetics at ZOC. In 1993-1995, he studied on retinoblastoma
with Prof. Kensei Minoda at Teikyo University Ichihara Hospital, Japan as a Postdoctoral fellow. In 2001-2003, He learned
molecular basis of circadian rhythmicity in the retina with Prof. Joseph C. Besharse at Medical College of Wisconsin as a
Visiting Scientist. In 2013-2015, he received training on ophthalmic molecular genetics from Dr. J. Fielding Hejtmancik at
National Eye Institute, NIH, USA as a Research fellow. Prof. Zhang's major interest focuses on the identification of the
genetic defects for hereditary eye diseases and their associated phenotypes. He is now serving as a co-Editor-in-Chief for
Molecular Vision and AMPC member for ARVO.
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Wed(4)-SFS8-3
Investigating gene-gene interactions in AMD to better understand disease
Paul N. Baird 1 ，Adam Kowalczyk 2
1:Centre for Eye Research Australia, University of Melbourne, Australia、2:Centre for Neural Engineering, The University of Melbourne,
Parkville, Vic 3010, Australia
Identifying genes associated with common complex diseases through genome wide association studies (GWAS) has proven
particularly useful. However, the identified variants typically explain a limited amount of disease variance. In the case of
the progressive neurodegenerative disease of Age related macular degeneration (AMD), 52 common and rare genetic variants

have now been reported as explaining approximately half of its genetic variance. Uncovering the remaining sources of genetic
variance may come through exploring the role of gene-gene (epistatic) interactions at the genome level. Our ability to capture
such genetic interactions depends on the statistical methods and analyses used and the way in which these interactions are
defined by such methods. Currently used epistatic interactions are typically limited by the dimensionality of variables, where
investigations are limited to interactions at the single SNP-SNP level due to computational limitations, make broad statistical
assumptions of the data, or have a limited number of samples. The development of efficient data-mining techniques for
extraction of knowledge and predictive modelling for such studies constitutes one of the current major bottle-neck in the
analysis of GWAS data. To address this gap, we have developed a technique - genome-wide interaction study (GWIS) that
allows for the study of genetic interactions across the genome that when coupled with high-throughput computing technology,
allows for rapid interrogation of all genotyped markers in days rather than months.
[Biography]
Paul Baird obtained his PhD from the University of London and is currently head of the Ocular Genetics Unit at the Centre
for Eye Research (CERA) and Professorial Fellow in Ophthalmology, Department of Surgery at the University of Melbourne.
His research interests include investigating genetic causes of common eye diseases and shared disease mechanisms with a goal
of translating these into clinical practice. He has a particular interest in identifying novel gene pathways involved in response
to drug treatment, identifying novel genetic associations with disease, exploring the role of copy number and epigenetics in
disease, development of algorithms using machine learning to identify individuals likely to progress and develop disease, as
well as personalising treatment options for patients. He is a current recipient of a prestigious 5-year National Health and
Medical Research Council of Australia (NHMRC) Senior Research Fellowship. He has published over 150 journal articles in
top ranked journals including Nature Genetics, Nature Communications and Lancet and has established an expansive network
of both national and international collaborations. In particular he is actively involved in international consortia in age related
macular degeneration and myopia and co-chairs working groups in both of these consortia.
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Wed(4)-SFS8-4
Genes and molecular mechanisms of hereditary retinal diseases in Japanese population
1
Takeshi Iwata
1:National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Japan
Twenty-six ophthalmology departments and institutions in Japan were united as consortium to to obtain information of genes
responsible for hereditary retinal diseases in Japanese population. Over 800 pedigrees were collected with 36 different types
of hereditary retinal diseases. Blood or saliva samples were collected from each patients, parents and relatives and performed

whole exome sequence using Agilent SureSelect ver. 5/6 for exon capturing and Illumina HiSeq2500/4000 for next generation
sequencing at average of 100 reads. The sequence analysis was performed using super computers at the National Institute of
Genetics (Mishima, Japan) and the computers at Tokyo Medical Center (Tokyo, Japan). Approximately 14% of the pedigree
was identified with known mutations and 17% with novel mutation in known genes. Surprisingly 8% of the pedigree resulted
with mutation in novel gene. Each novel gene are cloned and characterized for abnormal function in cell or in animal eye.
Identified novel mutations and novel genes will be introduced at this talk.
[Biography]
Dr. Iwata graduated and received his Ph.D. from Meijo University in 1988 and immediately joined the National Eye Institute
(NEI), NIH as postdoctoral fellow. His first work was a linkage analysis of X-linked retinitis pigmentosa. He move to Bascom
Palmer Eye Institute with his supervisor and spent two years. In 1991, he returned to NEI to work on the transcriptional
regulation of aldose reductase and sorbitol dehydrogenase, one of the major pathways for diabetic retinopathy. He returned
to Japan in 1999 and move to current position in 2007. His research is focused on human retinal diseases to understand
the molecular and cellular mechanism of the disease onset. He has worked on normal tension glaucoma (NTG), age-related
macular degeneration (AMD) and number of hereditary retinal diseases. His research expands from identification of novel
disease causing genes to development of animal models and iPS cells for therapeutic development. His recent work on
identification of RP1L1 gene for occult macular dystrophy (Miyake’s Disease), OPTN gene for NTG and HTRA1 gene for
AMD is well known. He is now the project leader for the Japan Whole Exome Consortium for Hereditary Retinal Diseases.
Over 26 ophthalmology departments and institutions are involved in this project to collect phenotypic data and DNA samples.
He is now expanding this consortium to the Asian countries and established an Asian Eye Genetics Consortium (AEGC) to
share genetic information among Asian countries.
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Genetics of Skeletal Diseases
Wed., April 06, 2016 16:45-18:15 Room B-2 (2F)
Moderator：Shiro Ikegawa（Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Science,
Japan）
This session focuses on genetic studies on skeletal diseases (both monogenic and polygenic diseases) and invites active
researchers and doctors (all speakers have both MD. and PhD.) from various fields of medical science, including medical

genetics, orthopedics, regenerative medicine, and developmental biology. It is quite co-incidental that all speakers are
from East Asia (or rather it shows the high level of the region).
Prof. Zhang has been working on gene hunting of monogenic diseases. He talks on identification of disease genes for
monogenic skeletal diseases.
Prof. Jiang is a surgeon scientist working on bone and joint diseases from their etiology to treatment. He talks on the
association studies of polygenic bone and joint diseases (osteoarthritis, acetabular dysplasia, etc.).
Prof. Kitoh is also a surgeon scientist and has been working on skeletal dysplasia (monogenic disease of skeleton). He
talks on treatment strategies for short stature in skeletal dysplasias aiming for clinical application.
Prof. Tsumaki is working on the application of induced pluripotent stem cell (iPS) technologies to skeletal biology. He
talks on the use of iPS chondrocytes in the disease modeling of skeletal dysplasia, including his recent epoch-making
study on achondroplasia.
Wed(4)-SFS9-1
Phenotypic Variations in Congenital Limb Malformations
1
Xue Zhang
TBA

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Wed(4)-SFS9-2
The Genetic Research on OA: Goals and Challenges of the Translational Research
1
Qing Jiang
1:Joint Surgery, Drum Tower Hospital, China
OA is a genetic disease: OA: 50% heritability depending on the site. There are many eye-catching achievements in OA genetic
research. The main goals of genetic research on OA are

(1) To develop efficient diagnostics for risk and progression of OA and (2) to identify new targets for therapeutic interventions.
If view from the goals, The bridge is broken. Candidate gene studies have proposed over 100 genes as susceptible genes.
However, most of them have not later been reproduced in large meta-analysis studies. Mouse models have shown that
OA is initiated by production of proteases like matrix metalloproteinase-13 and a disintegrin and metalloproteinase with
thrombospondin motif-5. Trials applying the protease inhibitors for clinical use as a disease-modifying treatment have to date
been unsuccessful because of insufficient efficiency and adverse events.
How to get across the bridge from genetics to clinics?
Step one: Make a right diagnosis: the definitions of OA significantly influence the prevalence and association results.
Step two: Phenotyping is decided by us. Misdiagnosis and wrong phenotyping of cases and controls decreases the power of
P value.
Step three: To largen cases number and replication in different ethnics.
Step four: Select disease-free controls: the prevalence of radiographic knee OA(K/L>2) in the elderly was >30% and
prevalence of asymptomatic knee OA was 24-36% in all population. So-called healthy subjects without knee symptoms cases
as controls.
Finally, adjust by environment factors: Selection of case and control subjects with similar backgrounds is essential to minimize
selection bias which strongly influences the results in genetic studies.
[Biography]
Qing Jiang received his MD degree in Nanjing Medical University 1989, and PhD degree in Beijing Medical University in
1999. In 2008, he was appointed professor in Nanjing University and moved to Model Animal Research Center as Adjunct
Professor for genetic research on bone and joint disease.
Prof Jiang and his team are focusing on the search for susceptibility genes for osteoarthritis (OA). They together with Prof
Shiro Ikegawa (RIKEN) have been the discoverer of the role in OA susceptibility of polymorphisms in the GDF5 gene (Nat
Genet 39:529-33, 2007) and in the DVWA gene
(Nat Genet 40:994-8, 2008). They also detected ASPN D14 repeat was strongly associated with the age at onset and
pathology of OA in Han Chinese population. At the same time, they excluded LRCH1, IL1β, IL1RA, RHOB and TXNDC3
as susceptibility genes for OA by meta-analysis and global collaboration. In the global collaboration, EDG2, CALM were
excluded as the susceptibility genes of OA. Currently, HIF-2a was excluded as OA gene by Qing and his collaborators (Nat
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Med 2010, accepted). We have also worked in other common diseases related with bone and cartilage.
In development dysplasia of hip (DDH), they have identified that a susceptibility factor resides in a functional polymorphism
in GDF5
gene (Arthritis Res Ther. 2008). In 2009, they detected another promising gene associated with DDH and further functional
research was performed.
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Wed(4)-SFS9-3
Treatment strategies for short stature in achondroplasia
Hiroshi Kitoh 1 ，Kenichi Mishima 1 ，Masaki Matsushita 1
1:Orthopaedic Surgery, Nagoya University, Japan
Achondroplasia (ACH) is one of the most common skeletal dysplasias with short stature caused by gain-of-function mutations
in the FGFR3 gene. The limb lengthening is a therapeutic option to gain length, but the treatment is very tough for both
patients and physicians.

We have established a novel cell therapy using culture-expanded bone marrow cells (BMC) and platelet rich plasma (PRP)
during the limb lengthening to accelerate callus formation. We have performed this cell therapy in more than 130 bones since
2002. The clinical outcome of the limb lengthening in ACH was significantly improved by BMC and PRP transplantation.
The effectiveness of this therapy, however, was limited for skeletally mature patients due to limited osteoblastic differentiation
of BMC.
We tried to search clinically applicable drugs that promote the activity of Runx2, which plays a pivotal role in the differentiation
of mesenchymal cells to the osteoblastic lineages. By drug repositioning (DR) strategy, we found that a proton pump
inhibitor, lansoprazole, enhanced nuclear accumulation of Runx2, promoted expressions of various osteoblastic genes, and
induced osteoblastogenesis of human BMC. Systemic administration of lansoprazole to a rat femoral fracture model increased
osteoblastogenesis. Lansoprazole could be applicable for ex vivo culture to obtain better quality of BMC.
By DR strategy, we found that an antihistamine drug, meclozine, suppressed abnormally activated FGFR3 signaling in various
chondrocytic cells that were infected with human mutants. Meclozine increased the longitudinal growth of embryonic tibia
from ACH model mice in bone explant culture. Oral administration of meclozine increased the bone growth of growing ACH
mice as well as wild type mice. The plasma concentration of meclozine during treatment was within the range that has been
used in clinical settings. These results indicated potential clinical feasibility of meclozine for the improvement of short stature
in ACH.
[Biography]
Born 1964 in Japan
Higher education qualification: 1989 MD, Nagoya University
PhD degree: 2000 PhD in Orthopaedics, Nagoya University
Title: Extra pelvic ossification centers in thanatophoric dysplasia and platyspondylic lethal skeletal dysplasia-San Diego type
Specialist certification: 1996 Japanese Orthopaedic Surgeon Certificate
Present position: 2013- Associate Professor, Nagoya University
Previous positions:
2007-2013 Lecturer, Nagoya University
2002-2007 Assistant Professor, Nagoya University
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2000-2002 Medical Staff, Nagoya University
1996-2000 Senior Researcher, Aichi Human Service Center
1992-1995 Physician, Aichi Human Service Center
1990-1992 Physician, Fukuroi Municipal Hospital

1989-1990 Internship, Fukuroi Municipal Hospital
Visiting Scientist: 1997-1998 Cedars-Sinai Medical Center, Los Angeles
Society Memberships:
Japanese Orthopaedic Association Board member
Japanese Pediatric Orthopaedic Association Board member
Japanese Society for Bone and Mineral Research
Japanese Society for Regenerative Medicine
Japanese Society of Cartilage Metabolism
Clinical Subspeciality:
Pediatric Orthopaedic Surgery
Orthopaedic Genetics
Limb Reconstruction
Research Interest:
Genetics and Metabolic Bone Diseases
Bone and Cartilage Regeneration
Fracture Healing

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Wed(4)-SFS9-4
Use of induced pluripotent stem cell technologies in disease modeling of skeletal dysplasia
1
Noriyuki Tsumaki
1:Dept. of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Japan
Many causes of skeletal dysplasia are associated with gene mutations. Accordingly, mouse models have contributed enormously
to the understanding of skeletal dysplasia by allowing researchers to target specific genes and corresponding mutational effects.
However, differences between mice and humans mean observations from mouse models should be translated with caution when

studying the mechanisms driving human skeletal dysplasia. Human tissues affected by the disease, such as cartilage and bone,
are therefore sometimes more appropriate for study, but difficult to obtain from patients. In addition, chondrocytes are
difficult to expand or maintain in culture. However, the advent of induced pluripotent cells (iPSCs) is making it possible
to obtain chondrocytes and cartilage from which the pathomechanisms of skeletal dysplasia can be recapitulated in culture
dishes. iPSCs can be expanded almost infinitely and differentiated into any type of cells. Gain-of-function mutations in
fibroblast growth factor receptor 3 (FGFR3 ) result in a group of skeletal dysplasia known as FGFR3 chondrodysplasia,
which includes diseases such as thanatophoric dysplasia (TD) and achondroplasia (ACH). We converted skin fibroblasts from
TD and ACH patients into iPSCs and then differentiated the iPSCs toward chondrocytes to create cartilaginous tissue in
three-dimensional culture. Our method provided an unlimited number of chondrocytes / cartilage for study, because iPSCs
can be expanded infinitely. Importantly, we found that TD and ACH pathologies were recapitulated in the chondrogenically
differentiated patient-specific iPSCs. These results suggest that chondrogenically-differentiated iPSCs can be used to study
skeletal dysplasia pathomechanisms and drug discovery.
[Biography]
Noriyuki Tsumaki is currently Professor at the Center for iPS Cell Research and Application (CiRA), Kyoto University, Japan,
where he researches cartilage biology and pathology, and regeneration of cartilage using cell reprogramming technologies.
He earned his M.D. from Osaka University, Japan and joined the Department of Orthopaedic Surgery in Osaka University
in 1989. There he completed his Ph.D. in 1996 and soon after joined Yoshi Yamada’s laboratory at the National Institute of
Dental Research, NIH, USA as a visiting fellow. He returned to Osaka University as Assistant Professor in 1998 and there
became Associate Professor at the Department of Bone and Cartilage Biology in 2007. Noriyuki joined CiRA in 2011.
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Genetics of Kidney Diseases
Wed., April 06, 2016 15:00-16:30 Room C-1 (1F)
Moderator：Kazushige Hanaoka（Internal Medicine, Division of Nephrology and Hypertension, The Jikei University,
Kidney is composed of glomeruli, tubules, vessels, nerves and interstitial tissue. Various types of cells mutated in genetic
diseases behave abnormally and disrupt normal renal structure and function. There are many renal genetic diseases

caused by either single-gene defect or polygenic defects. Systemic genetic disorders influence kidneys as well. Based on
target genes affected and symptoms, renal genetic diseases are grouped to glomerular disease, renal cystic ciliopathies,
renal tubular disorders, and nephrolithiasis and congenital abnormalities of the kidney and urinary tract.
This workshop will start with an overview in renal genetic diseases, followed by presentation of topics in common three
diseases, Alport syndrome, Fabry nephropathy, and autosomal dominant polycystic kidney disease. These diseases are
found frequently in clinical nephrology all over the world and considered at high risk for progression to renal failure.
Recently discoveries of pathophysiology and molecular biology have brought new therapies to slow the course of the
diseases. In the workshop, international experts provide diagnosis, genetics, pathophysiology, current strategies of therapy
and future direction of curing renal genetic diseases.
Wed(4)-SFS10-1
Recent advancement of genetics and therapy in renal genetic diseases
1
Koichi Nakanishi
1:Pediatrics, Wakayama Medical University, Japan
Genetic kidney disease consists of monogenic glomerular diseases, renal cystic ciliopathies, renal tubular and metabolic
diseases, nephrolithiasis and congenital abnormalities of the kidney and urinary tract (CAKUT). Recent advancement of
mutation analyses has a high value in understanding of pathophysiology as well as diagnosis.
As an example, X-linked Alport syndrome (XLAS), one of major monogenic glomerular diseases, can be focused. It is a
progressive, hereditary nephropathy and caused by mutations in the COL4A5 gene encoding the type IV collagen α 5 chain
[α 5(IV)]. Complete absence of α 5(IV) in the renal basal membrane is considered a pathological characteristic in male
patients; however, positive α 5(IV) staining has been found in over 20% of patients. Detailed gene and α 5(IV) expression
combined analyses clarify the milder clinical manifestations and molecular characteristics of male XLAS patients expressing
the α 5(IV) chain. Another interesting finding is that variant frequency detected by next-generation sequencing (NGS) shows
a tendency between the variant allele frequency and disease severity in male XLAS patients with somatic mosaic variants in
COL4A5.
As to clinical routine treatments of XLAS male patients, retrospective registry data suggests that angiotensin-converting
enzyme inhibition delays end-stage renal failure and improves life expectancy. This observation emphasizes the importance
of early and accurate diagnosis of AS, including specific genotyping.
On the other hand, as for disease mechanism-specific treatments, clinical trials of exon-skipping and read-through therapies
have been started for monogenic glomerular diseases, such as Duchenne muscular dystrophy. This therapy can be expected
to be effective in AS.
Recently, a targeted NGS panel analysis shows that collagen IV mutations, including COL4A5, frequently underlie FSGS and
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should be considered, particularly with a positive family history. This study indicates a new clinical aspect of AS.
[Biography]
Education:
1983-1989 Kobe University School of Medicine, Kobe, Japan M.D.
1993-1995 Kobe University School of Medicine, Kobe, Japan Ph.D. Pediatrics

Previous Appointments and Positions:
1989-1990 Resident in Pediatrics, Kobe University, Kobe, Hyogo, Japan
1990-1990 Resident in Neonatology, Hyogo Children Hospital, Kobe, Hyogo, Japan
1990-1992 Medical Staff in Pediatrics, Takatsuki Hospital, Takatsuki, Osaka, Japan
1992-1993 Medical Staff in Pediatrics, Kumon Hospital, Kobe, Hyogo, Japan
1993-1998 Research Staff in Pediatric Nephrology, Kobe University, Kobe, Hyogo, Japan
1993-1995 Senior Resident in Pediatric Nephrology, Kobe University, Kobe, Hyogo, Japan
1995-1998 Medical Staff in Pediatrics, Head of division of Pediatric Nephrology, Kure-Kyosai Hospital, Kure, Hiroshima,
Japan
1998-2000 Research Associate in Pediatrics, Case Western Reserve University, Cleveland, OH, USA
Academic Background:
2000-2004 Instructor in Pediatrics, Head of division of Pediatric Nephrology, Wakayama Medical University
2004-present Senior Lecturer in Pediatrics, Head of division of Pediatric Nephrology, Wakayama Medical University
Area of specialization:
Pediatric and Developmental/Molecular Nephrology

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Wed(4)-SFS10-2
Genetics and pathophysiology in Fabry nephropathy
1
David G. Warnock
1:University of Alabama at Birmingham, USA
Fabry disease is a lysosomal disorder with mutations in the alpha-galactosidase A locus (GAL; OMIM#301500, Xq22.1).
The classical presentation in males includes acroparesthesias and angiokeratomas in the 1st or 2nd decade, with progressive
involvement of the heart, brain and kidneys, and death from renal failure in the 4th or 5th decade of life. Enzyme replacement

therapy (ERT) has changed the course of this disease.
There are over 1000 mutations in the GAL locus; including missense, nonsense, deletions/insertions or splicing variants. The
classic presentation is associated with nonsense mutations with extremely low residual enzyme. Mutations with significant
residual activity are increasing recognized, and are associated with non-classical presentations later in life as cardiac or renal
variants.
Affected males are more involved than affected females. Female offspring of affected males, carry the mutated paternal X allele,
but the phenotypic variation in females is striking. Approximately 15% of females have no significant clinical involvement,
even with classical truncation mutations, another 15% of females have serious multi-system involvement, and the remainder
have intermediate burden of disease. One explanation for this phenotypic variation in females is skewed X chromosomal
inactivation.
Phenotype-genotype correlations have been stymied by the realization that phenotypic variation can occur even with classical
mutations in males from the same pedigree. There are not any explanations for this variation, other than the usual notions
about“modifier” genes.
Recent studies in Autosomal Dominant Polycystic Kidney disease have described trans-acting effects between the 2 ADPKD
loci, and have described this as a possible source of phenotypic variation in ADPKD. Although speculative at this point, the
possibility of a second locus needs to be explored in Fabry disease, as a potential explanation for phenotypic variation in this
disorder.
[Biography]
Dr. David Warnock received a BA degree in 1966 from the University of California at Berkeley and received his MD degree
in 1970 from the University of California, San
Francisco. Following a fellowship at the NIH, his positions included Section Chief at the San Francisco VA Medical Center,
Director of Nephrology at the University of Alabama at Birmingham (UAB) from 1988 to 2008, and Director of the Office
of Human Research at UAB from 2005 to 2008. He served as the Marie K Ingalls Professor of Medicine and the Hilda B.
Anderson Endowed Professor in Nephrology at UAB, and became an Emeritus Professor of Medicine at UAB in October
2015.
Dr Warnock’s focus is on the genetic and environmental factors that contribute to hypertension and chronic kidney disease.
The spectrum extends from basic studies of salt and water transport systems to population-based studies of the prevalence of
CKD and the association with stroke and heart disease. Another focus is inherited disorders of renal function, with a current
emphasis on the renal manifestations of Fabry disease. Additional research interests include acid-base physiology, sodium
transport mechanisms, chronic kidney disease, diabetes and kidney disease, and inherited renal diseases.
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Wed(4)-SFS10-3
What Makes Tubules Turn Cystic?
1,2
Gregory Germino
1:National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health, USA; Johns Hopkins
School of Medicine, USA、2:Johns Hopkins School of Medicine, USA
Autosomal Dominant Polycystic Kidney Disease is the most common inherited renal disease, affecting ~ 1/1000 individuals
worldwide. Cysts increase in number and size over time, resulting in end stage kidney disease by the 5th to 6th decade in ~
50% of affected individuals. Mutations in PKD 1 cause 85% of cases while mutations in PKD2 account for the remainder.

PKD1 encodes Polycystin-1 (PC1), a >500kD glycoprotein while PC-2 encodes a TRP-like non-selective cation channel. The
proteins are thought to form a receptor-channel complex that responds to unknown signals in the extracellular environment.
Several lines of evidence suggest that cysts arise from previously normal tubules. My laboratory is interested in determining
the underlying mechanisms of this transformation. We know genetics play a key role. While the disease is inherited as an
autosomal dominant trait, studies from my lab and others indicate that it is recessive on a cellular level. Studies suggest that
cysts arise when the total functional activity of the two alleles of either PKD1 or PKD2 falls below an ill-defined threshold.
This most commonly arises as a result of acquired mutations in renal epithelial cells that have a germline mutation of either
locus, though rarely some individuals instead may have two germline, hypomorphic alleles whose combined activity falls below
the threshold. There also is evidence to suggest that the threshold may be different in different cell types and life stages.
Genetic modifiers are likely important in three steps of this process: determining the rate of somatic mutation, setting the
cystogenic threshold, and in downstream effector pathways. Studies suggest that non-genetic factors also may be important.
Our laboratory has recently shown that developmental status, sex and metabolic status are important determinants of PKD
severity. Finally, recent studies suggest that PKD mutant cells may undergo a metabolic switch, suggesting another avenue
for therapeutic targeting.
[Biography]
Dr. Germino is the Deputy Director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at
the National Institutes of Health and an Adjunct Professor of Medicine at Johns Hopkins School of Medicine. He also is a
Senior Investigator in the Kidney Disease Branch of the NIDDK Division of Intramural Research, where the main focus of
his research is on the molecular basis of renal cystic disease. Prior to joining NIDDK in 2009, he was Professor of Medicine
and Molecular Biology and Genetics at Johns Hopkins where he directed its Polycystic Kidney Disease Center. Dr. Germino
has served on the Scientific Advisory Board (SAB) of the Polycystic Kidney Research Foundation, was Chair of the SAB of
the Telethon Foundation of Italy, a Councilor of the American Society of Clinical Investigation, and a member of the Board
of Directors of Federation of American Societies for Experimental Biology. He has received multiple awards including an NIH
MERIT Award, induction into the Association of American Physicians, and the Lillian Jean Kaplan International Prize for
the Advancement in the Understanding of Polycystic Kidney Disease. He received his undergraduate degree in biology from
Loyola University of Chicago and his medical degree from the Pritzker School of Medicine at the University of Chicago. He
trained in internal medicine and nephrology at Yale, spent a research year at Oxford University, and was full time faculty at
Johns Hopkins from 1992-2009.
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Wed(4)-SFS10-4
Current strategies for curing autosomal dominant polycystic kidney disease (ADPKD)
1
Kazushige Hanaoka
1:Internal Medicine, Division of Nephrology and Hypertension, The Jikei University, School of Medicine, Japan
Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease caused by mutations in either PKD1 or
PKD2 . ADPKD is characterized by progressive formation of bilateral renal cysts, vascular abnormalities including intracranial
aneurysms, and diverticulosis of colon. Approximately 50% of individuals with ADPKD have end-stage renal disease (ESRD)

by age 60 years.
Over the past two decades, pathophysiology of ADPKD was elucidated in considerable detail. In ADPKD, mutated renal
tubular cells are the origin of cystic epithelial cells, and have characters such as abnormal cell proliferation, fluid secretion and
the disruption of controlling tubular diameter. Dysregulation of intracellular calcium and cyclic adenosine monophosphate
(cAMP) signaling plays an important role for cyst formation.
Outcomes from basic science research lead many clinical trials modifying life and food style and using drugs, such as V2
receptor antagonist, somatostatin, and mammalian target of rapamycin antagonist known to be effective in animal model.
Among those drugs, V2 receptor antagonist, tolvaptan, inhibits to increase total kidney volume and to decrease renal function
in ADPKD patients. The agent inhibits binding vasopressin to V2 receptor and producing cAMP in cystic epithelial cells,
followed by suppressing vasopressin-induced cell proliferation, chloride secretion, and cyst growth in ADPKD. Tolvaptan has
been approved in Japan, EU, and Canada. In Japan, over 1,800 ADPKD patients take tolvaptan since 2014. The new agent
among with therapies for common pathway of hypertension and renal failure is changing the strategies for curing ADPKD.
[Biography]
Dr. Hanaoka is Senior Lecturer of Department of Intenal Medicine at Jikei University, School of Medicine. The main focus
of his research is on investigating the pathophysiology and developing a new therapeutic strategy of autosomal dominant
polycystic kidney disease (ADPKD). He also conducts clinical nephrology as Clinical Director of Division of Nephrology and
Hypertension at Jikei Daisan Hospital, where he established Out-Patient Clinic of ADPKD patients for genetic counceling.
He received his medical degree from Nippon Medical School in 1987 and his degree of Doctor of philosophy from Jikei
University in 1993. While he was Graduate Student, he investigated renal physiology in tubules, especially in calcium
transport at Department of Pharmacology, Jichi Medical School. He joined Dr. Guggjno as a postdoctoral Research Fellow in
Department of Physiology, Johns Hopkins University in 1993. He worked as a National Kidney Foundation Fellowship from
1994 to 1996. He got promoted to Visiting Assistant Professor in 1997 and stayed until 2001. He investigated function of
PKD1 & PKD2 genes and mechanism of cyst formation in ADPKD. He trained in internal medicine and nephrology at Jikei
University Hospital. At present, he makes his best effort to provide genetic counseling to patients affected with renal genetic
diseases in Japan.
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UCSC Genome Browser - A platform for variant analysis
Wed., April 06, 2016 16:45-18:15 Room D (1F)
Moderator：Robert Kuhn（Center for Biomolecular Science & Engineering, Jack Baskin School of Engineering, University
of California Santa Cruz, USA）
The UCSC Genome Browser is widely used as a platform for visualizing genomic data of all sorts. In both the clinic and
the laboratory, the power of the Browser lies in the ability to combine user data (such as uploaded copy-number variants

or SNPs) with data resident on the Browser. Browser-resident data reflect the contributions from many sources including
both benign and pathogenic variants, regulatory regions, epigenomic data and comparative genomics. These resources,
combined all in one location, make the Browser and its tools a powerful platform for inquiry-driven data analysis.
By uploading data as Custom Tracks users may intersect their SNPs with dbSnp, HGMD and UniProt, and their CNVs
with large variant data from DECIPHER, OMIM and other resources. Data profiles can be created and saved for future
reference or for sharing with colleagues using the Saved Sessions utility.
The Variant Annotation Intergrator, a relatively new tool, takes input of SNPs and small indels and facilitates production
of reports of variants and their biochemical consequences such as missense, splice-junction, etc, as well as SIFT and
PolyPhen score, known regulatory sites and conservation score. The Table Browser allows export of lists of genes from
large CNVs. Finally, the Genome Browser-in-a-Box is a downloadable version of the Browser which can be used inside a
firewall for proprietary or sensitive data that cannot be uploaded to UCSC.

UCSC Genome Browser - A platform for variant analysis

The UCSC Genome Browser is widely used as a platform for visualizing genomic data of all sorts. In both the clinic and
the laboratory, the power of the Browser lies in the ability to combine user data (such as uploaded copy-number variants or
SNPs) with data resident on the Browser. Browser-resident data reflect the contributions from many sources including both
benign and pathogenic variants, regulatory regions, epigenomic data and comparative genomics. These resources, combined
all in one location, make the Browser and its tools a powerful platform for inquiry-driven data analysis.
By uploading data as Custom Tracks users may intersect their SNPs with dbSnp, HGMD and UniProt, and their CNVs with
large variant data from DECIPHER, OMIM and other resources. Data profiles can be created and saved for future reference
or for sharing with colleagues using the Saved Sessions utility.
The Variant Annotation Intergrator, a relatively new tool, takes input of SNPs and small indels and facilitates production of
reports of variants and their biochemical consequences such as missense, splice-junction, etc, as well as SIFT and PolyPhen
score, known regulatory sites and conservation score. The Table Browser allows export of lists of genes from large CNVs.
Finally, the Genome Browser-in-a-Box is a downloadable version of the Browser which can be used inside a firewall for
proprietary or sensitive data that cannot be uploaded to UCSC.
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Genetic Counseling 1
Wed., April 06, 2016 15:00-16:30 Sakura (1F)
Moderator：Anita Y. Kinney（Cancer Population Sciences, University of New Mexico Comprehensive Cancer Center,
USA）
Moderator ：Hironao Numabe（Genetic Counselling Course, Ochanomizu University, Japan）
Wed(4)-SFS12-1

Expanding Reach and Access to BRCA1/2 Counseling and Testing: One-year Follow-up Outcomes of a
Randomized Non-Inferiority Trial Comparing Telephone and In-Person Delivery
Anita Y Kinney 1 ，Barbara H Brumbach 1 ，Ji-Hyun Lee 1 ，Rufei Du 1 ，Wendy Kohlmann 2 ，Amanda Gammon 2
1:Cancer Population Sciences, University of New Mexico Comprehensive Cancer Center, USA、2:Huntsman Cancer Institute, University of
Utah, Salt Lake City, Utah
To meet the increased demand for genetic cancer susceptibility testing into routine clinical care, there is an urgent need to
enhance the accessibility and reach of such services while ensuring comparable care delivery outcomes. This randomized trial
compared one-year outcomes for telephone genetic counseling to in-person counseling among women at risk for hereditary
breast and/or ovarian cancer (HBOC) living in geographically diverse areas. Women who were at increased risk for HBOC
were randomized to in-person (n=495) or telephone genetic counseling (n=493). One-sided 97.5% confidence intervals (CIs)
were used to estimate the noninferiority effects of telephone counseling on one-year psychosocial, decision-making, and risk
management outcomes. A two-sided 95% CI was estimated for the difference in test uptake proportions. Telephone counseling
was noninferior to in-person counseling for all psychosocial and informed decision-making outcomes: Anxiety (difference
(d)=0.08, upper bound 97.5% CI=0.45), cancer-specific distress (d=0.66; upper bound 97.5% CI=2.28), perceived personal
control (d=0-0.01; lower bound 97.5% CI=0.06) and decisional conflict (d=0.12; upper bound 97.5% CI=2.03). Test uptake
was lower for telephone counseling (23.1%) than in-person counseling (29.7%: bootstrap difference = 9.4%; 95% CI=2.2% -
16.8%). Among mutation carriers, 50% received a prophylactic oophorectomy while 15% received a prophylactic mastectomy
in the year following testing. Although BRCA1/2 telephone counseling led to lower testing uptake, our findings provide
strong long-term evidence that telephone counseling for women at risk for BRCA1/2 mutations is not inferior to in-person
counseling with regard to fostering informed decision-making, minimizing adverse psychological reactions, and promoting
perceived personal control. Alternative care delivery approaches such as telephone risk communication can make genetic
services more widely accessible without sacrificing safety.
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Wed(4)-SFS12-2
Trend analysis of the cases received genetic counseling for HBOC in the Shinshu University Hospital
Asumi Iesato 1 ，Mayu Ono 1 ，Takaaki Oba 1 ，Yuko Fukushima 1 ，Tokiko Ito 1 ，Toshiharu Kanai 1 ，Kazuma Maeno 1 ，
Ken-ichi Ito 1 ，Emiko Kise 2 ，Masumi Ishikawa 2 ，Hiromi Yamashita 2 ，Kyoko Takano 2 ，Tomoki Kosho 2 ，
Yoshimitsu Fukushima 2 ，Tsuyoshi Miyamoto 3 ，Akiko Takatsu 3 ，Tanri Shiozawa 3
1:Division of Breast and Endocrine Surgery, Department of Surgery, Shinshu University School of Medicine, Japan、2:Department of Medical
Genetics, Shinshu University School of Medicine、3:Department of Obstetrics and Gynecology, Shinshu University School of Medicine
Introduction: In recent years, there is increasing interest in HBOC (hereditary breast and ovarian cancer) in Japan. In

the Shinshu university hospital, the department of medical genetics was established in 1996 and has been working on many
hereditary disorders. With regard to HBOC, we formed a team consisting of medical geneticists, breast surgeons, gynecologists
and genetic counselors in July 2014, and have had a regular meeting every other month. We have distributed an interview
sheet to the patients with breast or ovarian cancer with primary purpose of selecting the patients at high risk for HBOC since
September 2015. In the present study, we analyzed the trend of the cases who received genetic counseling for HBOC in our
hospital.
Patients: 46 clients (40 families) received genetic counseling for HBOC in the department of medical genetics in our hospital.
Result: The average age was 43.1 y.o. (11 ~ 71). All clients except one were female. 20 clients was referred by breast
surgeons, 3 were referred by gynecologists, 1 was referred by radiologist, 10 were from other hospital, and 12 had counseling
from their own motive. 29 clients were diagnosed as breast cancer, 3 were ovarian cancer, and 1 was peritoneal cancer. 16
clients were with no history of malignancy. 14 clients (30.4%) received BRCA1/2 genetic testing, and mutation was found in
3 clients (6.5%).6 of 23 clients (26.1%) received genetic testing from 1996 to 2011. On the other hand, 9 of 23 clients (39.1%)
received genetic testing from 2011 to 2015. In the former period, 11 clients had no referral by oncologists, while all expect
one client were referred to genetic counseling from clinicians.
Discussion: With the increased interest in HBOC, it is thought that the number of clients who wish to have genetic testing
will be increased. It will be necessary to create a system to pick up the people at high risk for HBOC and provide them
appropriate genetic counseling in medical care facilities.
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Wed(4)-SFS12-3
Genetic counselling for a case with breast cancer who underwent a whole-exome sequencing in a private
company
Yusuke Ebana 1 ，Hiroko Kohbata 1 ，Sayako Takahashi 1 ，Masayuki Yoshida 1
1:Life Science and Bioethics Research Center, Tokyo Medical and Dental University, Japan
With the rapid development of high-throughput sequencing, geneticists can encounter incidental findings in clinical exome and
genome sequencing. We experienced a case with breast cancer who underwent a whole-exome sequencing in a private company.

Hereditary breast and ovarian cancer syndrome (HBOC) is one of the familial cancer syndromes with the BRCA1/2 mutation.
Five to ten percent of patients with breast cancer have the genetic mutation, half of whom have the BRCA1/2 mutation. The
patient underwent whole-exome sequencing since she wanted to detect genetic errors and to inform the result of her sister.
Although she had no mutation in the BRCA1/2 , many members of her family affected gastric cancer. We investigated the
causal genes for gastric cancer and its preposition syndromes: CDH1 (gastric cancer, TP53 (Li-Fraumeni syndrome), APC
(familial adenomatous polyposis), MLH1 , MSH2 , MSH6 (Lynch syndrome), and PTEN (Cowden syndrome). We found 18
variants in these genes including synonymous ones. Among them, we focused on only the variant in MLH1 , rs63750447, with
“Damaging” in SIFT and Poly-Phen2, which has already been indicated as a colorectal cancer risk in the previous reports.
This information may help future medical management of other members of her family.
We experienced a case who underwent the whole-exome sequencing analysis for the breast cancer research and was identified
as a risk variant for colorectal cancer. Although it remains unknown that this variant could cause the onset of gastric cancer
in this family, our strategy might be applicable for the identification of variant/mutation in clinical practice.
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Wed(4)-SFS12-4
Exploring the return of precision oncology results and the implementation of genetic counselling in
Singapore
1,2,3
Yasmin M Bylstra ，Jyothi Thrivikraman 1 ，Tamra Lysaght 4 ，Patrick Tan 1,5
，POLARIS, Singapore
1:Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore、2:Inherited Cardiac Clinic, National University
Heart Centre, Singapore、3:Singapore Health Services, Singapore、4:Centre of Biomedical Ethics, National University of Singapore、5:Cancer
and Stem Biology, Duke-NUS Graduate Medical School, Singapore
The characterisation of gene mutations that drive tumour development has contributed vastly to the improvement of cancer

treatment. In identifying tumour specific mutations for precision oncology, germline DNA is also collected for comparative
analysis. As the identification of germline mutations is secondary to tumour testing for targeted treatment, the return of
germline findings and provision of genetic counselling has been extensively debated. However, clinical practice is shifting
towards a preference of routinely sequencing tumour tissue alone to reduce cost and simplify sample collection. This method
raises the question of how tumour testing contributes to the identification of germline mutations.
The laboratory at POLARIS, Singapore, has developed a panel of 93 genes associated with tumour development to guide
treatment for oncology patients which includes 29 genes associated with inherited syndromes. Genomic data of 130 colon
tumours was generated using this panel and analysed to determine if mutation origin could be identified. Although there
are many variables complicating origin identification, findings indicate that tumour testing can be suggestive of germline
predisposition. Yet, there is limited guidance around the return of tumour testing results regarding how this information
should be conveyed to patients and by whom.
To explore this further, the return of possible germline findings was discussed in semi-structured interviews with 27 cancer
patients and 11 oncology clinicians. This data was analysed qualitatively to describe the views and preferences that patients
and clinicians have towards receiving such results and discussing their implications outside cancer treatment. These findings,
in combination with tumour test data, will guide how consent is obtained from patients for precision oncology tests in
Singapore, the interpretation and reporting of tumour test results, and the involvement of genetic counselling to clarify test
implications.
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Wed(4)-SFS12-5
WISKOTT-ALDRICH SYNDROME: Genetic counseling issues in a large Malaysian family
Premala Muthukumarasamy 1 ，Meow Keong Thong 1 ，Rifhan Azwani Mazlan 1
1:Genetics and Metabolism Unit, Paediatric Department, University Malaya Medical Centre, Malaysia
Wiskott-Aldrich syndrome (WAS)(OMIM # 301000) is disorder of primary immunodeficiency characterized by recurrent

infections,microthrombocytopenia leading to recurrent bleeding,severe eczema,a high risk of malignancy and autoimmu-
nity.Treatment is supportive and the only available cure is allogeneic hematopoietic stem cell transplantation (HSCT).WAS

has an X-linked recessive inheritance pattern and is caused by a mutation in the WAS gene at Xp11.23-p11.22.We report
a large Malaysian pedigree with four individuals afflicted with WAS followed up over 15 years.The index case is a 69-year-
old lady with five male children who all died of recurrent bleeding and infections.Genetic counseling was provided.Her only
daughter had two children diagnosed with WAS, one who died in infancy and the other successfully treated with HSCT.The
family subsequently declined follow-up visits.
In 2015,our genetic service was re-contacted.The increased awareness of the X-linked inheritance pattern,the possibility of
obligate carriers amongst the female members of the family and unresolved maternal guilt led to a family consultation with
us.The issues discussed include the genetic guilt and anxiety of an obligate carrier, the possibility of skewed X-inactivation
resulting in a manifesting female with WAS,prenatal diagnosis and termination of pregnancy of an affected fetus as well as
the advantages and limitations of genetic testing.
We describe the assessment,genetic counseling and testing of the index case for WAS and subsequent targeted mutation
analysis of the consultand.With a known WAS mutation in this family, preimplantation genetic testing to avoid the birth of
a child with WAS could be offered. Whether the use of this test to bear a human leukocyte antigen (HLA)-matched donor
for HSCT as therapy for an affected child remains an ethical issue.Lastly,we highlight the importance of pre and post test
genetic counseling.
Key words: WAS, X-linked inheritance, gene sequencing, genetic counseling
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Wed(4)-SFS12-6
A review of reproductive decisions made by patients with vascular Ehlers-Danlos syndrome
1
Jessica M Bowen
1:Ehlers-Danlos Syndrome National Diagnostic Service, UK
Vascular Ehlers-Danlos syndrome (EDS) is an inherited disorder of connective tissue caused by mutations in COL3A1. The
major features include arterial or hollow organ rupture, extensive bruising, thin, translucent skin and characteristic facial
features as described in the Villefranche nosology. Patients who are diagnosed with vascular EDS before or during their

reproductive years have a number of decisions to make. Firstly, vascular EDS is an autosomal dominant condition and therefore
any offspring have a 50% risk of inheriting the condition. In addition to this, women with vascular EDS have substantial risks
associated with pregnancy itself. The risks include life-threatening complications of arterial dissection/rupture and uterine
rupture, as well as significant risks of third or fourth degree tears during labour.
The UK EDS national diagnostic service was set up in 2009 to aid the diagnosis of rare and complex EDS, and since being
established over 100 patients with confirmed vascular EDS have been seen. Over the last seven years the service has been
involved in discussing the options and risks when one partner has vascular EDS, and consequently we have overseen a number
of different reproductive decision making processes.
The aim in reviewing our experience was to identify factors that may influence the reproductive decisions made by both
women and men with vascular EDS, and to learn from the outcomes of those decisions. By sharing the results of this analysis
we hope to improve the understanding and management of this life threatening condition, and inform genetic counselling
practice.
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Genetic Counseling 2
Wed., April 06, 2016 16:45-18:15 Sakura (1F)
Moderator：Rosalind J. Hastings（CEQAS, Oxford University Hospitals NHS Foundation Trust, UK）

Moderator ：Shinji Kosugi（Department of Medical Ethics/Medical Genetics, Kyoto University School of Public Health,
Japan）
Wed(4)-SFS13-1

Genomic genetic counselling: same but different
Gemma Brett 1,2 ，Ivan Macciocca 1,2 ，Emma Creed 2,3
，Melissa Martyn 2 ，Nessie Mupfeki 2 ，Ella Wilkins 2,3
，
Clara Gaff 2 ，Melbourne Genomics Health Alliance
1:Victorian Clinical Genetics Services, Australia、2:Melbourne Genomics Health Alliance、3:Melbourne Health
New counselling issues may arise as new genomic tests become available in clinical settings, raising the question whether genetic
counsellors are appropriately equipped to manage these. The ability to deal with potential new issues will be paramount as
healthcare providers navigate the complexities of using genomic technologies to improve diagnosis and patient management.
The Melbourne Genomics Health Alliance, a collaboration between ten research and clinical organisations, has conducted
a demonstration project to emulate processes that would be involved in offering genomic sequencing in a clinical setting.
The purpose of the project was in part to determine the feasibility, performance and impact of genomic sequencing as a
‘first-line’ diagnostic tool in comparison to standard care. Whole exome sequencing with targeted analysis was offered to
five patient groups. All participants received pre- and post-test counselling by genetic counsellors and/or treating physicians,
and completed pre- and post-result disclosure surveys about their experience.
Using case examples, this presentation outlines counselling issues identified by genetic counsellors during the demonstration
project. Similarities and differences between issues encountered in genetic counselling for single gene tests versus genomic
tests will be presented, including managing uncertainty; storage and use of genomic data; incidental findings; and diagnosing
rare diseases where there are multiple differential diagnoses. Participant’s concerns captured in the pre-result survey and
their implications for genetic counselling will be discussed.

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Genetic counseling: when the east meets the west, can it be modeled?
1
Anne C Tsai
1:Pediatics/Genetics, University of Colorado School of Medicine, USA
Advances in technology have triggered a tsunami of Genetic data. Sciences are bringing together astonishing volumes of
information from the benches to the bedsides. Genetic counseling has become an inevitable process in medical practice. It is
not only required for rare, inherited diseases but also needed in plaining testing and treatment for common diseases, cancers

and even child birth. Medical providers recognize this necessity and many countries has initiated the genetic counseling
services modeling the western (North American) version. This commentary report summarizes 22 years of genetic counseling
dilemma and conflicts identified by an oriental clinical geneticist who practices mainly in the western society. While cultural,
ethnical and religious impacts for human activity have long been recognized; some of these influences and effects cannot be
avoided nor repaired. Therefore, modification and special strategies are required in the genetic counseling process.
Gender equality remains an issue despite the protection from law; it is still a culture burden in many eastern society.
Counseling X-link condition remains a difficult theme. The priority of judgement and mental activity for an individual is also
very different: the oriental people value relationship above reasoning and litigation therefore even if the brain is convinced by
the science, the mind is still full of guilt. The“incarnation” concept also cannot relive the blame from having a child with
a birth defect! “There is nothing I do to cause this but I must have done something in my previous life.” While autonomy
and informed decisions are valued by most western people, many oriental people look up to the providers for guidance and
paternalistic care. They rather take the direction relentlessly than making their own decision.
In conclusion, a health, effective and helpful counseling system cannot not be modeled or cloned into a different society, it
has to be customized.
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Wed(4)-SFS13-3
Comparison of two selection strategies based on genetic information when only small sample size is
available
Juan Wang 1 ，Ryo Yamada 1
1:Statistical Genetics, Center for Genomic Medicine, Graduate School of Medicine Kyoto University, Japan
Abstract: As the spread of an awareness of the benefits of use of personal genomics in predictive and precision medicine, many
genetic variants with or without other disease-related factors are going to be used to assist clinical decision in near future.
Personalization sometimes makes a size of people who are categorized in a same group very small and it makes unrealistic to

make a decision based on an observation of considerable number of samples sharing the same features. This kind of problem
is also found in the settings of very rare diseases including various Mendelian diseases, where no clinical trials are feasible. We
focused on this decision-making problem with limited sample size and investigated the effects of people’s decision strategy
on the overall benefits in the small populations. As an initial step for this problem, we defined two self-decision selection
strategies for binomial outcomes, both of which select one of two treatment deterministically with different index functions,
representing two types of individuals decision patterns; and both strategies used beta distribution as the posterior and the
first strategy was based on the expected success rate of it and the second on the probability that the beta distribution has
success rate more than or equal to a target one. We evaluated their effects of the two methods through exact probability
calculation for small sample sizes as well as identified potentially useful patterns for practical usage.
Keywords: Bernoulli process; strategy; medical decision-making; genetic marker
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External Quality Assessment of Genetic Counselling: experiences with the first pilot assessment
Rosalind J Hastings 1 ，Conny MA van Ravenswaaij 2 ，Christi J van Asperen 3 ，Els Dequerker 4 ，Lisbeth Tranebjaerg 5 ，
Livia Garavelli 6 ，Borut Peterlin 7
1:CEQAS, Oxford University Hospitals NHS Foundation Trust, UK、2:Dept. of Genetics, University Medical Centre, Groningen, The
Netherlands、3:Clinical Genetics, Leiden University, The Netherlands.、4:Biomedical Quality Assurance Research Unit, KU Leuven, Belgium、
5:Clinical Genetics, University of Copenhagen, Denmark、6:Dipartimentale di Genetica Clinica, IRCCS Arcispedale Santa Maria Nuova,
REGGIO EMILIA, Italy、7:Department of Genetics, Ljubljana University Medical Centre, Ljubljana
Quality assessment has long been associated with laboratory, but not clinical, services. To address this obvious gap, the

ESHG Genetic Services Quality Committee (GSQC) explored the needs for a European Quality Assessment (EQA) scheme
for genetic counselling. All European national societies of human genetics were surveyed using a web-based questionnaire.
All 15 participating countries expressed a need for an EQA for genetic counselling services.
A proposal for achieving an EQA for genetic counselling was launched at an European Society of Human Genetics (ESHG)
satellite symposium. The working group prepared four case scenarios in the fields of cardiogenetics, oncogenetics, monogenetic
disorders and dysmorphology. Each scenario started with a referral letter and consisted of multiple stages, to reflect an episode
of clinical care. At each stage more information was given and a number of questions presented. For each question, consensus
answers were obtained by the author of the case, a patient organisation and at least two other experts. A total of 16 genetic
centres from 11 countries participated in the pilot EQA and all answers were reviewed by two assessors per case. The whole
process was evaluated, both by the assessors and by the participating centres (post-pilot EQA questionnaire). The conclusion
was that an EQA for genetic counselling is feasible and highly educational. In order to further improve the process, a second
educational pilot EQA is being run by CEQAS with 43 genetic centres across 17 countries. The findings will be presented
and the EQA process will be demonstrated using one of the educational pilot cases.
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Wed(4)-SFS13-5
To assess knowledge and attitudes of Indian patients with inherited retinal disease (IRD) towards genetic
testing and counseling
Siddhita S. Nare 1 ，Radhika Krishnan 1 ，Sundaram Natarajan 1,2
，Govindasamy Kumaramanickavel 2
1:Research Department, Aditya Jyot Foundation for Twinkling Little Eyes, India、2:Aditya Jyot Eye Hospital
Introduction:
Genomic testing for IRD is becoming increasingly frequent and the potential of application of genomic technologies is rising

rapidly. New genetic testing approaches will deliver a dramatic change in the ability to diagnose and broaden the possibility
of genetic counseling. But less number of studies has been conducted to explore the patient’s knowledge and attitude towards
the genetic testing and counseling. The aim of this study was to investigate the attitude of patients in India with IRD towards
genetic testing and counseling and also to understand their knowledge. The views of patients with IRD are important to
build up models for the delivery of genetic services in ophthalmology.
Methodology:A pilot study was undertaken using a standardized questionnaire which includes multi-choce genetic knowledge
and attitude items.47 patients with IRD were interviewed for the understanding of their awareness and attitude towards the
genetic testing.Ethical approval was received from the Aditya Jyot Ethics Committee.
Result: Questionnaire was completed with 47 patients with inherited retinal diseases. The level of gnetic knowledge and
awareness was relatively low. Majority of patients i.e. 72% were unaware about this genetic testing and counseling. 64%
considered testing to be good and would readily undergo genetic testing. Most of the patients supported the provision of
diagnostic and predictive testing (88%) whereas 35% of patients were expecting to have some treatment benefit. The result
for the above was analyzed using Chi Square test for independence. It is significant at p < 0.05.
Conclusion:This study recorded the levels of patient’s understanding and attitudes to genetic testing and genetic counseling
for IRD which will further aid for evaluating the current demand for genetic counseling and testing. The results are helpful
in the development of a best practice model for the delivery of ophthalmic genetic services.
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Wed(4)-SFS13-6
"Living with Down Syndrome" -Systematic approach of a communication support tool for notification
of Down syndrome
Hiroko Kondo 1 ，Keiichi Matsuzaki 1 ，Shiho Ishigami 1 ，Yokohama Project Booklet Editorial Team
1:Yokohama Project, Japan
The diagnosis of Down syndrome is notified to parent or expectant parent by medical professionals. They are expected
to obtain specific knowledge on Down syndrome to raise babies with Down syndrome. However, knowing Down syndrome

itself is new to many of them as limited opportunities to understand Down syndrome in Japan. They are struggled with
understanding the notification and they start very beginning of life with Down syndrome in anxious feeling. In some cases,
parents face incorrect information by themselves.
We researched with questionnaire toward parents of babies and children with Down syndrome in Japan for the purpose of
understanding current notification and information access by parents and identifying improvement opportunities. The ques-
tionnaire was developed by adopting P.Kotler’s marketing approach. We have questioned the two themes; their information
acquisition of Down syndrome, and desirable notification and information access for them.
344 answers were gathered. Based upon the analysis, we identified that potential improvements would be possible both for
notification and post notification. Along with the questionnaire observation, we researched referable communication support
tool in the U.S. such as "Understanding a Down syndrome diagnosis" published by Lettercase org and interviewed the pub-
lisher on its distribution system. As the result, simple, update, balanced information from trusted channel is expected among
couples and parents from in the US case as same as the result from our questionnaire analysis.
Based on the two researches, requirements of a necessary communication tool are identified. A new booklet titled with ’Living
with Down syndrome’ in 40 pages is developed to cover requirements ’simple’, ’update’, ’well-balanced’, and ’trusted’.
The booklet is intended to be used as communication support tool at the timing of notification in medical institutions, public
sectors and public communities.
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Cancer Genetics 1
Wed., April 06, 2016 15:00-16:30 Room I (2F)
Moderator：Tomas Kirchhoff（NYU Cancer Institute, New York University School of Medicine, USA）
Moderator ：Mariko Eguchi（Department of Pediatrics, Ehime University Graduate School of Medicine, Japan）
Wed(4)-SFS14-1

Immunomodulatory expression quantitative trait loci (eQTLs) and their role in modulation of cutaneous
melanoma (CM) survival and immunotherapy response
Tomas Kirchhoff 1,2,3 ，Matjaz Vogelsang 1,2,3 ，Esma Ucisik-Akkaya 1,2,3
，Carlos N Martinez 1,2,3
，Richard Shapiro 4 ，
Anna C Pavlick 5,6 ，Michelle Krogsgaard 1,3,7 ，Iman Osman 1,2,5,6
1:Perlmutter Cancer Center, New York University School of Medicine, USA、2:Departments of Population Health and Environmental
Medicine, New York University School of Medicine、3:The Interdisciplinary Melanoma Cooperative Group, New York University School of
Medicine、4:Department of Surgery, New York University School of Medicine、5:Department of Medicine, New York University School of
Medicine、6:Ronald O. Perelman, Department of Dermatology, New York University、7:Department of Pathology, New York University
School of Medicine
Immunogenicity of CM impacts outcome and is an important surrogate of response to novel immunotherapies (IT). While
these treatments are reducing high CM mortality rates, >50% of IT-treated patients does not respond. As the host immunity
varies on individual level, it is strongly suggested that germline genetic variants in immune pathways modulate anti-tumor
capacities impacting CM prognosis and IT response. Here we propose a unique strategy suggesting that immune-specific
QTLs common in general population modulate survival and IT outcome in CM patients. We used whole-genome eQTL
data from 857 healthy female twins from Multiple Tissue Human Expression Resource and identified 385 SNPs significantly
associated with the expression of 268 immune-relevant genes. We tested 40 most significant immunomodulatory eQTLs using
Cox regression models, adjusted by demographic and clinical covariates, for their association with overall survival (OS) and
IT outcome in a prospective cohort of 1,221 CM patients, including a subset of 250 patients treated with anti-CTLA4 IT.
We discovered an interaction of two eQTLs (rs6695772 and rs6673928 controlling the expression of BATF3 and IL19, resp.)
associated with CM OS, reaching the significance level of clinical applicability (HR 1.92, 95% CI 1.43-2.60; P= 2.38e-5)
independent of clinicopathological markers. In addition, we have identified a novel eQTL associated with IT resistance for
rs2291299 in CCL5 chemokine locus (HR=1.5, 95% CI 1.07-2.15, p=1.47e-4), suggesting for the first time that the germline
genetic factors impact IT outcome. Our highly unique approach reveals novel and biologically relevant immunomodulatory
eQTL predictors of CM prognosis and IT response. The significantly enhanced combined effect of identified eQTLs suggests
the personalized utilization in a clinical setting, strongly indicating the promise of the proposed design for the discovery of
prognostic or IT-response germline predictors in other cancers.
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Wed(4)-SFS14-2
Identification of a lung cancer growth factor, LASEP1 as a serological and prognostic biomarker and a
therapeutic target
1,2
Atsushi Takano ，Yusuke Nakamura 3 ，Yataro Daigo 1,2
1:Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Japan、2:Departments
of Medical Oncology and Cancer Center, Shiga University of Medical Science、3:Department of Medicine and Surgery, University of Chicago
Lung cancer is the leading cause of cancer deaths in the world. The poor prognosis of lung cancer patients is largely a result
of the occult metastatic dissemination. Thus, the development of early cancer detection biomarker and new treatment is

required. This study aims to identify novel biomarkers or therapeutic targets for lung cancers. We used cDNA microarrays for
screening genes encoding transmembrane/secretory proteins that are up-regulated in lung cancers. As a result of this process,
we identified a secreted protein, LASEP1 (lung cancer-associated serum protein 1) as a candidate. Immunohistochemical
staining showed that LASEP1 expression was observed in 210 (56.1%) of 374 NSCLC (non-small cell lung cancer) that
had undergone curative surgery. High level of LASEP1 expression was associated with poor prognosis for NSCLC patients
(P<0.0001 by log-rank test). Multivariate analysis revealed that LASEP1 was an independent prognostic factor for NSCLC
patients. Serum LASEP1 levels were higher in NSCLC patients than in healthy volunteers. The proportion of serum LASEP1-
positive cases was 127 (38.6%) of 329 NSCLCs, while 4 (3.9%) of 102 healthy volunteers were falsely diagnosed. Furthermore,
lung cancer cells transfected with siRNAs for LASEP1 revealed a significant increase of apoptotic cells. In addition exogenous
LASEP1 expression enhanced the growth and the cell mobility in vitro. LASEP1 interacts with its 50-kDa receptor (LASEPR)
that is also important for cancer cell growth on the surface of cancer cells. Furthermore, the growth activity of the LASEP1-
positive cells was neutralized by addition of originally developed anti-LASEP1 monoclonal antibodies into their culture media,
and the systemic administration of the anti-LASEP1 antibody to tumor-implanted mice significantly suppressed tumor growth
without any adverse events.
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Wed(4)-SFS14-3
Germline variant analysis and ancestry inference of 2,153 high-depth whole genomes of patients afflicted
with diverse cancers
Francisco M De La Vega 1,2 ，Dai-Ying Wu 3 ，Suyash Shringarpure 1 ，Sebastian M Waszak 4 ，Sergei Iakhnin 4 ，
Tal Shmaya 3 ，Genevieve Wojcik 1 ，Christopher Gignoux 1 ，Jan Korbel 4 ，Carlos D Bustamante 1 ，
ICGC PCAWAG Network
1:Genetics, Stanford University, USA、2:TOMA Biosciences Inc., Foster City, CA USA、3:Annai Systems Inc., Carlsbad, CA, USA、4:EMBL,
Heidelberg, Germany
Numerous studies have shown a relationship between ancestry, penetrance of disease variants, and effectiveness of therapies.

Unfortunately, ethnicity is often not accurate or present in the metadata of cancer research cohorts and thus is ignored in
analysis. We aim to explore the relationship between ancestry, cancer etiology and outcomes analyzing 2,153 samples from
the TCGA and ICGC projects for which whole genome sequencing data of the germline is available. Samples were sequenced
with Illumina technology and realigned to the extended GRCh37 reference as part the ICGC PanCancer Analysis of Whole
Genomes Project. About 47% of variants are novel as compared with dbSNP and 1000 Genomes Project data. We used
a maximum likelihood method using a pre-selected set of 4,235 ancestry-informative-SNPs to assign continental ancestry
to each donor. For those individuals that appear recently admixed we apply the RFmix software, a fast discriminative
modeling approach, to identify ancestral chromosomal segments along the genome. Our results show that most donors are
from European or Asian descent in concordance with their source. However, some population diversity is found in particular
in the US cohorts. For example, in the US breast cancer cohort a third of donors are from African ancestry, which is relevant
given the prevalence of the triple-negative type of the disease in this population. Other ancestries, such as South-East Asian
and Native American, are present to a much lesser extent. We identified loss of functions (LoF) variants across cancer and
medically relevant genes stratified by ancestry. As cohort size increases a linear increase of LoF variant is observed without
saturation. Interestingly, 58% of cancer genes are found to be mutated in more than two tumor types, suggesting pleiotropic
effects. We highlight the need to recruit other populations for genomic studies to benefit all groups from the advances in
personalized medicine.
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Wed(4)-SFS14-4
Alternative splicing as biomarkers for DNA damage response: A novel mechanism of cancer progression
through a single-nucleotides binding/multi-functional protein, FIR
1,2,3
Kazuyuki Matsushita ，Kouichi Kitamura 2 ，Minako Beppu 1,2,3
，Motoi Nishimura 1,2,3
，Mamoru Satoh 4 ，
Fumio Nomura 3,4
1:Department of Molecular Diagnosis, Chiba University Graduate School of Medicine, Japan、2:Chiba University Hospital, Division
of Laboratory Medicine、3:Chiba University Hospital, Division of Clinical Genetics、4:Chiba University Hospital, Division of Mass
Spectrometric Laboratory Diagnosis
Alternative splicing is an important mechanism that links to transcription and contributes to protein diversity. Recent

studies revealed that DNA damage certainly alters RNA splicing and is frequently disturbed in cancers. FUSE-binding
protein (FBP)-interacting repressor (FIR; also known as PUF60 , a U2AF -related protein) is a transcriptional repressor of the
c-myc gene. A splice variant of FIR, FIR δ exon2 , that lacks exon2 in the transcriptional repressor domain, was increased
in cancers as a dominant-negative form of FIR. Recently, somatic mutations of the SF3B1 (SAP155 ) gene, a subunit of the
SF3B spliceosome complex, were found in myelodysplastic leukemia. The FIR proteins form a complex with SF3B1 , which
controls the splicing of FIR itself, of the cell-cycle gene p27kip1 . Bleomycin (BLM), a DNA damaging agent, reduces the
expression of SF3B1 and increases the production of FIR δ exon2 . The decrease of BLM-mediated SF3B1 may therefore
coordinate alternative splicing decisions to affect cell-cycle and apoptosis. In this study, FIR heterozygous knockout (FIR+/- )
was established as a dominant-negative model of FIR in the C57BL/6 mouse. FIR+/- mice showed an increased c-myc mRNA
expression level, particularly in peripheral blood, although FIR+/- mice had no apparent pathogenic phenotype. Therefore, an
increased c-myc mRNA expression level alone is not enough for leukemogenesis. Nevertheless, FIR+/- TP53 -/- mice generated
acute T-cell lymphoblastic leukemia with increased organ and/or bone marrow invasion. In conclusion, alternative splicing
of FIR, generating FIR δ exon2 , contributes to not only colorectal carcinogenesis but also leukemogenesis independent of
the c-Myc activation pathway. FIR haploinsufficiency accelerates cancer progression by inhibiting DNA repair response and
cell-cycle checkpoint, potentially disharmonizing transcription, RNA splicing and/or post-transcriptional mechanisms.
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Wed(4)-SFS14-5
Targeted Next-Generation Sequencing Identifies a Recurrent Mutation in MCPH1 Associating with
Breast Cancer Susceptibility
Katri Pylkas 1,2 ，Tuomo Mantere 1,2 ，Saila Kauppila 1 ，Mervi Grip 1 ，Arja Jukkola-Vuorinen 1 ，Anna Tervasmaki 1,2
，
Katrin Rapakko 2 ，Robert Winqvist 1,2
1:University of Oulu, Finland、2:Northern Finland Laboratory Centre NordLab Oulu
Breast cancer is strongly influenced by hereditary risk factors, a majority of which still remains unknown. Here, we performed a
targeted next-generation sequencing of 796 genes implicated in DNA repair in 189 Finnish breast cancer cases with indication

of hereditary disease susceptibility, and focused the analysis on protein truncating mutations. A recurrent heterozygous
truncation mutation was identified in early DNA damage response gene, MCPH1 , significantly associating with breast cancer
susceptibility both in familial (5/145, 3.4%, P = 0.003, OR 8.3) and unselected cases (16/1150, 1.4%, P = 0.016, OR 3.3).
A total of 21 mutation positive families were identified, of which one-third exhibited also brain tumors and/or sarcomas
(P = 0.0007). Mutation carriers exhibited significant increase in genomic instability assessed by cytogenetic analysis for
spontaneous chromosomal rearrangements in peripheral blood lymphocytes (P = 0.0007), suggesting an effect for MCPH1
haploinsufficiency on cancer susceptibility. Furthermore, 40% of the mutation carrier tumors exhibited loss of the wild-type
allele. These findings collectively provide strong evidence for MCHP1 being a novel breast cancer susceptibility gene. Several
other germline mutations in this gene are likely to explain familial breast cancer cases in other populations as well, thus
providing further tools for diagnostics and genetic counseling.
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Wed(4)-SFS14-6
HMGA2 as a potential molecular target in MLL-AF4 positive infant acute lymphoblastic leukemia
1,2
Mariko Eguchi ，Minenori Eguchi-Ishimae 1 ，Zhouying Wu 1 ，Wen Ming 1 ，Hidehiko Iwabuki 1 ，Hisamichi Tauchi 1 ，
Eiichi Ishii 1,2
1:Department of Pediatrics, Ehime University Graduate School of Medicine, Japan、2:Division of Medical Genetics, Ehime University Hospital
Infant acute lymphoblastic leukemia (ALL) are frequently characterised by chromosome translocations involving 11q23, re-
sulting in the rearrangement of the mixed-lineage leukemia (MLL) gene and subsequent generation of MLL fusion gene.
Amongst more than 50 fusion partner genes, fusion with AF4 is characteristically and commonly observed in infant ALL

representing a hallmark of poor prognosis. Although recent intensive chemotherapy progress has considerably improved ALL
treatment outcome, disease cure is often accompanied by undesirable long-term side effects, and efficient, less toxic molecular
targeting therapies have been anticipated. We previously reported that in infant ALL cells with MLL fusion, the microRNA
let-7b (MIRLET7B) is significantly downregulated by DNA hypermethylation of its promoter region. Here we examined the
expression of HMGA2, one of the oncogenes repressed by MIRLET7B, in leukemic cells obtained from 35 MLL-rearranged
infant ALL patients. As a result, HMGA2 is reversely upregulated in infant ALL leukemic cells, particularly in MLL-AF4
positive ALL. In addition to the suppression of MIRLET7B, MLL fusion proteins positively regulated the expression of
HMGA2 . Knockdown of HMGA2 by the specific siRNA suppressed the expression of endogenous HMGA2 and resulted in
suppression of cellular growth of MLL-AF4-positive leukemic cells. HMGA2 is one of the negative regulators of CDKN2A
gene which encodes the cyclin-dependent kinase inhibitor p16INK4A . The HMGA2 inhibitor netropsin, when combined with
demethylating agent 5-azacytidine, upregulated and sustained the expression of CDKN2A, which resulted in growth suppres-
sion of MLL-AF4 -expressing cell lines. This effect was more apparent compared to treatment with 5-azacytidine alone. These
results indicate that the MIRLET7B-HMGA2-CDKN2A axis plays an important role in cell proliferation of leukemic cells
and could be a possible target for molecular targeting therapy of infant ALL with MLL-AF4 .
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ICHG2016 417

Cancer Genetics 2
Wed., April 06, 2016 16:45-18:15 Room I (2F)
Moderator：Gong-Hong Wei（Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu,
Finland）
Moderator：Yoshinori Murakami（Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo,
Japan）

Wed(4)-SFS15-1
Towards systems understanding of prostate cancer GWAS discoveries
Gong-Hong Wei 1 ，Ping Gao 1 ，Yuehong Yang 1 ，Hang-Mao Lee 1 ，Ilaria Svezia 1 ，Qilai Huang 1
1:Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Finland
Prostate cancer is one of the leading causes of cancer death in men due to the development of metastatic castration-resistant
lethal disease while the underlying mechanisms are poorly defined. Prostate cancer has also been reported as one of the
most heritable diseases. Genetic heritable factors were estimated to account for over 40% of the risk. So far, genome-wide
association studies (GWAS) have identified substantial amount of single nucleotide polymorphisms (SNPs) that are associated
with predisposition for prostate cancer. However, biological effects of these SNPs remain poorly understood, particularly for
noncoding SNPs, hindering the translation of GWAS discoveries to the clinic for disease prediction and prognosis. We reasoned
that some noncoding SNPs may disrupt certain transcription factor (TF) binding sites and influence gene regulation, which
may lead to perturbation of gene expression programs that contribute to the initiation and development of prostate cancer.
TFs including androgen receptor, FOXA1 and HOXB13 are known to be implicated in the establishment of gene expression
programs for prostate cancer development. We performed genomic mapping of these TF binding sites to decipher their roles
in prostate cancer progression to high-grade disease. Meanwhile, we found that the prostate cancer risk-associated SNPs are
greatly enriched in the cistromes of these TFs and demonstrated an example of rs339331 impact on the expression of RFX6
that plays role in promoting prostate cancer cell growth and tumor progression (Nature Genetics 46:126-135, 2014). We next
expanded the project towards systems understanding of prostate cancer GWAS discoveries through mapping the binding sites
for over 100 distinct TFs and epigenome with chromatin marks such as H3K4me1/2/3 and H3K27ac. In combination with
available fine-mapping and eQTL data, we pinpointed potential causal regulatory SNPs and genes in the majority of prostate
cancer susceptibility loci discovered by GWASs.
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Wed(4)-SFS15-2
Population-based assessment of HOXB13 gene for prostate cancer risk, progression and survival of
Finnish men
Csilla Sipeky 1 ，Hannu-Pekka Schukov 1 ，Elina Kaikkonen 1 ，the PRACTICAL/ELLIPSE consortium 1 ，
Johanna Schleutker 1
1:Medical Biochemistry and Genetics, University of Turku, Finland
Aim: More than 100 PrCa susceptibility loci have been identified in the human genome, from which HOXB13 rs138213197
has been shown to have the highest risk effect in Nordic populations. Our aim was to evaluate the risk of HOXB13 G84E

combined with clinical parameters focusing on PrCa differentiation and prognosis. Materials&methods: To investigate the
role of the HOXB13 gene in the Finnish PrCa patients, we determined the frequency of G84E mutation in 2669 unselected
PrCa cases and 2423 controls. Genotyping was conducted using custom TaqMan SNP assay and sequencing. In statistical
analyses we used unconditional logistic, time-to-event, case-case association, survival analyses. Pathogenicity of missense
variants was investigated with in-silico prediction of Combined Annotation Dependent Depletion (CADD). Results: HOXB13
G84E is associated with 8.0-fold increased risk of PrCa (CI, 95% 5.0-12.8, p=7.69E-25). Evidence for association with even
higher risk of PrCa was found in patients with prior BPH diagnosis (OR, 12.6; CI, 95% 2.8-56.8, p=0.001). Additionally,
HOXB13 G84E carriers develop significantly earlier PrCa (HR, 1.9). In presence of HOXB13 mutation the risk to have
high PSA at diagnosis (>20 ng/mL) was 1.5-fold and to diagnose cancer in nodes (N stage) 4.1-fold higher compared to
controls. In general, HOXB13 mutation was associated with clinically diagnosed PrCa (OR, 1.6). A Kaplan-Meier analysis
suggested worse PrCa-specific prognosis for the HOXB13 G84E carriers, but not statistically significantly. In-silico prediction
underlined HOXB13 G84E variant to be deleterious with a scaled C-score of 22.7 indicating potentially causative mutation.
Conclusions: These findings reveal an increased cancer risk associated with the HOXB13 T allele carriers in the Finnish
population, which exerts a potential for targeted therapy in PrCa.
*List of participants in PRACTICAL/ELLIPSE consortium will be included in supplementary material. http://practical.ccge.medschl.cam.ac.uk/

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Wed(4)-SFS15-3
Whole exome sequencing identifies genomic drivers of local lymph node metastasis in oral cancer
Nidhan K Biswas 1 ，Subrata Das 1,3
，Rajiv Sarin 2 ，Sudhir Nair 2 ，Arindam Maitra 1,3
，Partha P. Majumder 1,3
1:Cancer Genomics Group, National Institute of Biomedical Genomics, India、2:Tata Memorial Center, ACTREC, Mumbai, India、3:National
Institute of Biomedical Genomics, Kalyani, India
Objectives: Oral squamous cell carcinoma (OSCC) is the 8th most common cancer in the world and a subtype affecting the
gingivo-buccal region (OSCC-GB) constitutes the major OSCC burden in India. Owing to late presentation and propensity
for regional lymph node metastasis (LN+), the disease-free and overall survival remain poor. We hypothesized that mutations

in specific genes or pathways promote regional lymph node metastasis.
Methods: Clinical, histopathological and treatment information, and samples (blood and tumour tissues) were collected
from OSCC-GB patients with informed consent. Presence (LN[+]; n=37) or absence (LN[-]; n=35) of regional lymph node
metastasis was identified by histopathological examination of neck dissection. Whole exome sequence data on two orthogonal
platforms (Illumina and Roche-GSFLX) were generated and analyzed using appropriate bioinformatic and statistical methods.
Results: Exome sequencing analysis in LN[+] and LN[-] patients revealed several genes significantly mutated in somatic and/or
germline in LN[+] patients, Specific hotspot somatic mutations in TP53 and CASP8 were found to be overrepresented only
in the LN[+] primary tumours. Rare loss of function (LOF) germline mutations in BRCA2 and FAT1 gene were found to be
enriched in the LN[+] tumours. Pathway analysis revealed that genes in TCA cycle, non-homologous DNA repair, Hedgehog
signalling, cell adhesion and tight junction pathways were significantly mutated in the LN[+] patients only. Some of these
pathways are known to promote metastasis in other cancers and targeted therapies are available. Patients with rare LOF
germline mutation in BRCA2 gene had shorter disease-free survival within the LN[+] subgroup of patients.
Conclusion: Rare germline mutations and somatic mutations in mutational hotspots of some cancer-related genes and path-
ways promote regional lymph node metastasis in oral cancer. These findings open new avenues for genomic risk categorization
and tailored treatment.
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Wed(4)-SFS15-4
Generation of high-quality DNA from formalin-fixed paraffin embedded tissue for clinical grade whole
genome sequencing: a Genomics England Pilot Study
Pauline Robbe 1 ，Shirley Henderson 1 ，Joanne Mason 1 ，Maite Cabes 1 ，Sara DC Ramos 1 ，Pavlos Antoniou 1 ，
Samantha JL Knight 2 ，Niko Popitsch 2 ，Alexander Kanapin 3 ，Anastasia Samsonova 3 ，Dimitris Vavoulis 1 ，
Jennifer Becq 4 ，Miao He 4 ，Mark Ross 4 ，Zoya Kingsbury 4 ，David Bentley 4 ，Matthew Parker 5 ，Jenny C Taylor 2,6 ，
Clare Verrill 7 ，Clare Turnbull 5,8 ，Anna Schuh 1 ，
The Genomics England Biomedical Research Centres of Imperial College London, Cambridge University Hospitals,
University College London Hospital, Royal Marsden Hospital, King’s College London
1:Oxford Molecular Diagnostics Centre, University of Oxford, Oxford, UK、2:Wellcome Trust Centre of Human Genetics, University of

Oxford, Oxford, UK、3:Molecular Oncology Laboratories, Department of Oncology, University of Oxford, Oxford, UK、4:Illumina Cambridge
Ltd., Chesterford Research Park, Saffron Walden, UK、5:Genomics England, Queen Mary University of London, London, UK、6:NIHR
Comprehensive Biomedical Research Centre, Oxford, UK、7:Cellular Pathology, John Radcliffe Hospital, Oxford University Hospitals NHS
Trust, Oxford, UK、8:Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
Whole genome sequencing (WGS) has redefined cancer genomics opening up new horizons for precision medicine. Translation
of such technologies into clinical cancer care however, presents practical barriers. Fresh-frozen (FF) tissues are optimal
for WGS but not always available for routine cancer diagnostics. Alternatively Formalin-fixed-paraffin-embedded (FFPE)
material is routinely available for all patients, but contains artefacts induced by the processing method.
The aim was to evaluate the current UK National Health Service histopathology and DNA extraction procedures for cancer
diagnostics and optimise them for WGS.
Our study from 5 UK centres included 150 cancer patients and seven tissue types. FF, FFPE and germline samples were
collected following routine diagnostic pathways. Different DNA extraction methods were compared and WGS was performed
on HiSeq2500, Illumina. QC metrics and somatic variants (SNV and CNV) were produced from a comprehensive bioinformatics
pipeline. Sequencing metrics were associated with tissue processing metadata by regression analysis.
Routine FFPE samples (n=70) from multiple UK centres revealed inferior coverage uniformity and sub-optimal variant
detection than matched FF. Further investigations by multivariate analysis of histopathology protocols and shallow WGS
metrics from 200 FFPE DNAs showed that unbuffered fixative, prolonged fixation and larger block size were associated with
shorter insert sizes and fewer mapped reads. FFPE DNA extraction conditions (Proteinase K lysis, deparaffinisation and
decrosslinking) were examined to identify parameters influencing quality of WGS. Newly optimised procedures were validated
in an independent cohort (n=20) by comparing results from pre- and post-optimised FFPE processes to those of matched FF.
We show that the current processes to generate FFPE material in routine diagnostics are not suited for WGS and define
FFPE tissue handling protocol modifications to improve WGS for clinical diagnostics.
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Wed(4)-SFS15-5
Dual roles of a cell adhesion molecule, CADM1, in human oncogenesis and its application to diagnosis
and treatment of cancer
Yoshinori Murakami 1 ，Takeshi Ito 1 ，Takehiro Tsuchiya 1,2
，Hideki Kuwano 1,2
，Yuki Kumagai 1 ，Kenji Tamura 3 ，
Atsushi Nakajima 2
1:Division of Molecular Pathology, Institute of Medical Sicence, The University of Tokyo, Japan、2:Department of Thoraci Surgery,
Graduate School of Medicine, The University of Tokyo、3:Division of Chemotherapy, National Cancer Research Center Hospital
Disruption of cell adhesion is a crucial step in invasion and metastasis of human cancer. An immunoglobulin superfamily cell

adhesion molecule, CADM1, is involved in the formation of an epithelial cell structure. CADM1 is frequently inactivated in
various cancers in advanced stages, suggesting its involvement in invasion and/or metastasis. We demonstrated that tras-
homophilic interaction of CADM1 activated PI3K to reorganize actin cytoskeleton. On the other hand, when cell adhesion
by CADM1 was disrupted, cells were induced to apoptosis, which was dependent on digestion of the cytoplasmic fragment of
CADM1 by caspase-7 as was observed in dependence receptors.. Here, we present spontaneous development of lung tumors
in Cadm1-/- mice. In addition, when Cadm1-/- mice were crossed with mutant K-ras knock-in mice, more invasive lung
adenocarcinoma were developed. We found that MET was activated and phosphorylated in these tumors. Furthermore,
we have previously shown that CADM1 inhibits HGF-induced epithelial-mesenchymal transition of MDCK cells. These
findings suggest that CADM1 might inhibit MET signaling. Thus, we examined whether CADM1 could modify the acquired
resistance of lung adenocarcinoma cells to EGFR-tyrosine kinase inhibitor (TKI) by MET overexpression. Both stable and
induced expression of CADM1 into a lung adenocarcinoma cell, HCC827GR5, successfully restored the sensitivity to EGFR-
TKI and suppressed the subcutaneous tumor formation in nude mice. These results suggest that CADM1 could provide a
molecular target to overcome the resistance to EGFR-TKI. In contrast, CADM1 is overexpressed in ATL or small cell lung
cancer (SCLC), providing a promising molecular marker for ATL and SCLC. Tissue- or cell context-dependent function of
CADM1 in tumor development as well as its application in diagnosis and treatment of specific cancer will be summarized.
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Wed(4)-SFS15-6
Rare mutations in base excision repair (BER) pathway genes implicated in breast cancer susceptibility
Ian Campbell 1 ，Na Li 1,2
，Ella Thompson 1 ，Simone Rowley 1 ，Paul James 1 ，Alison Trainer 1 ，Gillian Mitchell 1 ，
Lisa Devereux 1
1:Peter MacCallum Cancer Centre, Australia、2:Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology,
Wuhan, Hubei, China
Introduction: BRCA1 and BRCA2 mutations account for 20-25% of hereditary breast cancers and moderate penetrance genes
such as PALB2 account for a further 5-10%. However, in approximately half of the high risk families the causative genetic

factor remains unknown (BRCAx families). Identifying the full repertoire of breast cancer predisposition genes could have a
major and immediate impact on reducing breast cancer risk in these family members.
Methods: Up to 1325 candidate breast cancer predisposition genes, identified through exome sequencing of 69 BRCAx
families, were sequenced in index cases of up to 3,000 BRCAx families and 3,000 cancer-free women.
Results: Interim analysis of the data show that known (PALB2) or suspected (MRE11A) breast cancer genes are enriched
for the loss of function (LoF) mutations in families versus controls, and the top hit was the gene NTHL1 (9 cases versus 1
control, p=0.01). Significantly, one index case is homozygous for NTHL1 LoF mutation and had a history of multiple primary
cancers. Interestingly NTHL1 is a member of the genes encoding DNA glycosylases that recognize the DNA oxidative damage
which is an essential step in the base excision repair (BER) pathway. Thus we examined the BER pathway further, and a
strong pattern was found in the group of DNA glycosylases, represented by 12 genes in the capture design (NTHL1, OGG1,
APEX1, APEX2, NEIL1, NEIL2, NEIL3, MUTYH, MPG, ALKBH1, ALKBH2, ALKBH3): Among the 1,000 cases and
controls analysed to date, 32 LoF and 180 missense variants were detected in these genes in the cases versus 10 LoF and
139 missense changes in controls (p=0.0008 for LoF, p=0.0003 for all variants). Based on the overall distribution of variants
between cases and controls, the probability of selecting 12 genes with such enrichment from the 1325 genes screened was less
than 1 in 200.
Conclusions: Our data implicates rare mutations in BER pathway genes as moderate penetrance breast cancer susceptibility
alleles.
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ICHG2016 423

Clinical Genetics 1
Wed., April 06, 2016 15:00-16:30 Room J (2F)
Moderator：Eric Legius（Department of Human Genetics, University of Leuven, Belgium）

Moderator ：Tomoki Kosho（Department of Medical Genetics, Shinshu University School of Medicine, Japan）
Wed(4)-SFS16-1

NF1 mutation analysis in segmental neurofibromatosis. New diagnostic technique and implications for
genetic counseling
Eric Legius 1 ，Charlotte Bulteel 2 ，Petra De Haes 2 ，Ludwine Messiaen 3 ，Marie-Anne Morren 2 ，Kathleen Claes 4 ，
Suzanne Marcus 5 ，Raoul Heller 6
1:Department of Human Genetics, Catholic University of Leuven, Belgium、2:Clinical Department of Dermatology, University Hospital
Leuven, Belgium、3:Department of Genetics, University of Alabama at Birmingham, USA、4:Center for Medical Genetics, Ghent University
Hospital, Ghent, Belgium、5:Kompetenzzentrum fur Humangenetik, Regensburg, Germany、6:Institute of Human Genetics, University
Hospital, Cologne, Germany
Individuals with segmental neurofibromatosis show typical features of neurofibromatosis type 1 (NF1) in one or more segments
of the body. In most cases of segmental NF no NF1 mutation can be detected in peripheral blood leucocytes and prenatal
testing cannot be offered. Melanocytes and Schwann cells are affected by the segmental NF phenotype and should contain
the NF1 mutation if the gene is involved. To help counseling these individuals we set up a method in our diagnostic lab to
culture Schwann cells from neurofibromas and melanocytes from CALS. We investigated 14 individuals with segmental NF.
In 3/14 cases no result was obtained due to no or poor cell growth. In 8 cases we identified the responsible NF1 mutation.
No NF1 or SPRED1 mutation was found in the remaining 3 cases. Total NF1 gene deletions were seen in 4 cases and single-
or multi-exon deletions in 2 cases representing 75% of mosaic NF1 mutations. In typical NF1 patients we observe these
mutations only in 7%. In 14 of 18 separate cultures from these 8 individuals a neurofibroma or CALS specific second hit in
the NF1 gene was detected. We did not detect any of the NF1 mutations in peripheral blood leucocytes or in fibroblasts
from CALS or neurofibromas pointing towards the developing neural crest as the origin of the mosaic NF1 mutation. We
performed 5 times prenatal diagnosis in 3 patients with a normal result each time.
Segmental NF results mostly from a mosaic NF1 mutation that can be detected by sequencing and deletion testing of
melanocytes from CALS or Schwann cells from neurofibromas. NF1 gene deletions and exonic deletions are overrepresented
in segmental NF and are not easily detected by next generation sequencing techniques. It is important to study more than
one CALS and/or neurofibroma to distinguish between the mosaic NF1 mutation and second hits in NF1 . Prenatal diagnosis
can be offered if a mutation is detected.
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Wed(4)-SFS16-2
Pathophysiological investigation of Ehlers-Danlos syndrome caused by CHST14/D4ST1 deficiency using
iPS cells and knockout mice
Tomoki Kosho 1,2 ，Nana Tsumita 3,4 ，Chiaki Masuda 5 ，Takahiro Yoshizawa 6 ，Fengming Yue 7 ，Yuko Kasahara 5 ，
Shuji Mizumoto 8 ，Takuya Hirose 9 ，Masashi Uehara 10 ，Noriko Miyake 11 ，Ken-ichi Matsumoto 12 ，Yoshitsugu Aoki 4 ，
Shuhei Yamada 8 ，Kazushige Takehana 9 ，Jun Nakayama 13 ，Yoshihiro Nomura 3 ，Yoshimitsu Fukushima 1,2 ，
Atsushi Watanabe 5 ，Atsushi Hatamochi 14 ，Katsunori Sasaki 7 ，Takashi Okada 5 ，Japanese Consortium for DDEDS
1:Division of Clinical and Molecular Genetics, Shinshu University Hospital, Japan、2:Department of Medical Genetics, Shinshu University
School of Medicine、3:Scleroprotein and Leather Research Institute, Tokyo University of Agriculture and Technology, Faculty of Agriculture、
4:Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan、
5:Department of Biochemistry and Molecular Biology, Nippon Medical School、6:Division of Laboratory Animal Research, Research Center

for Human and Environmental Sciences, Shinshu University、7:Department of Histology and Embryology, Shinshu University School of
Medicine、8:Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University、9:Department of Veterinary Pathology, School of
Veterinary Medicine, Rakuno Gakuen University、10:Department of Orthopaedic Surgery, Shinshu University School of Medicine、11:De-
partment of Human Genetics, Yokohama City University Graduate School of Medicine、12:Department of Biosignaling and Radioisotope
Experiment, Interdisciplinary Center for Science Research, Organization for Research, Shimane University、13:Department of Molecular
Pathology, Shinshu University Graduate School of Medicine、14:Department of Dermatology, Dokkyo Medical University, School of Medicine
Carbohydrate sulfotransferase 14 (CHST14)/dermatan 4-O-sulfotransferase-1 (D4ST1) deficiency represents a specific form of

Ehlers-Danlos syndrome (EDS), characterized by multiple congenital malformations (craniofacial features, multiple congenital
contractures including adducted thumbs and talipes equinovarus) and progressive multisystem fragility-related complications
(skin hyperextensibility and fragility, recurrent dislocations and progressive talipes or spinal deformities, large subcutaneous
hematomas). Multisystem fragility is presumably caused by impaired assembly of collagen fibrils resulting from loss of
dermatan sulfate in the decorin glycosaminoglycan side chain that promotes electrostatic binding between collagen fibrils. In
view of developing future etiology-based therapy, we established models for the disorder including induced-pluripotent stem
cells (iPSCs) and knockout (Chst14 -/ - ) mice, and performed pathophysiological investigation. iPSCs were established from
cultured skin fibroblasts of three patients. After validating appropriate apoptosis, undifferentiation status, and pluripotency,
iPSCs were induced into neural progenitor cells, mature neurons, cardiomyocytes, and smooth muscle cells. Contraction of
induced smooth muscle cells was observed to be reduced, which might be related to large subcutaneous hematomas. Frozen
sperms from Chst14 +/- male mice were obtained from the Mutant Mouse Regional Resource Center. After reproducing
Chst14 +/- mice from the sperms, Chst14 -/ - mice were generated. The number of Chst14 -/ - mice were limited probably
because of perinatal lethality. Chst14 -/ - mice were observed to present craniofacial features, growth impairment, and spinal
and tail deformities. Further studies are necessary for understanding multisystem involvement with progressive nature of the
disorder, and for establishing therapeutic targets for etiology-based therapy such as AAV-mediated gene therapy.
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Wed(4)-SFS16-3
A child presenting distinct phenotype in severe alternating hemiplegia with a novel ATP1A3 mutation
Naoko Ishihara 1 ，Hidehito Inagaki 2 ，Misa Miyake 1 ，Yuya Ouchi 2 ，Tamae Ohye 2,3
，Makiko Tsutsumi 2 ，
Tetsushi Yoshikawa 1 ，Hiroki Kurahashi 2
1:Pediatrics, Fujita Health University School of Medicine, Japan、2:Molecular Genetics, Institute for Comprehensive Medical Science, Fujita
Health University、3:Clinical Hematology, Faculty of Medical Technology, Fujita Health University
Introduction: Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by
recurrent hemiplegic episodes and distinct neurological manifestations. Most frequent onset of this disease is in infancy or

early childhood with paroxysmal episodic neurological dysfunction. Here we present a case of extremely severe phenotype
and diagnosed as AHC by genetic analysis.
Subject: A 2-year-old boy who was born to nonconsanguineous parents with normal delivery, and transferred to NICU because
of respiratory failure at second day of birth. He also showed extreme hypotonia and frequent epileptic seizures. He needed
mechanical ventilation and tube feeding, tracheotomy and gastrostomy were performed then. His seizures were uncontrollable
with antiepileptic drugs. In spite of many examinations including chromosomal analysis and muscle biopsy, etiology of his
symptoms was remain unknown. He was transferred to our hospital at age of one year for further analysis.
Methods and Results: Whole exome sequencing analysis was performed for subject and his parents. First we filtered the data
with the known gene list for severe brain abnormality, but no candidate mutation was found. Then we filtered with de novo
mutation and found one heterozygous mutation of ATP1A3 (c.2736_2738CTTdel, p.Phe913del) and determined as causal
mutation of the disease.
Discussion: More than 70% of AHC is caused by heterozygous missense mutations of ATP1A3 . The mutation we found in
subject indicates one amino acid deletion. Phe913 is a residue which has high preservation in vertebrates, and the deletion
causes contracting of transmembrane domain. This is a first report as a cause of AHC. There is a report of p.Val919del
which place in a same transmembrane domain causes loss of function of ATP1 α 3, suggested our mutation also makes loss
of function. Further functional studies are recommended to clarify the relationship between the mutation and such distinct
phenotype.
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ICHG2016 426
Wed(4)-SFS16-4
Severe acne scar of the neck in pseudoxanthoma elasticum: Acne as a modifier?
Naoki Oiso 1 ，Yumi Okubo 2 ，Atsushi Utani 2 ，Akira Kawada 1
1:Department of Dermatology, Kinki University Faculty of Medicine, Japan、2:Department of Dermatology, Graduate School of Medicine,
Nagasaki University
Pseudoxanthoma elasticum (PXE) is an autosomal recessive genodermatosis caused by mutations in ABCC6. It is charac-
terized by generalized fragmentation and progressive calcification of elastic tissue in the dermis, blood vessels and Bruch’s
membrane of the eyes. No definitive genotype-phenotype correlations have been ascertained in PXE, indicating presence of

modifier genes and functions for environmental and life-style factors. We present a case of PXE with noticeable acne scar of
the neck. A 29-year-old Japanese man was referred to us with a 10-year history of the gradually progressing acne scars on the
neck. Physical examination revealed (i) asymptomatic yellowish papules on the nape, upper back, axillae, lower abdomen,
genital area and thighs, (ii) the acne scars with comedoes on the neck, and (iii) the gradually progressing periphery reddish
and adjacently pale-yellowish papules on the bilateral neck. Angioid streaks were detected by ophthalmological examination.
Cardiological abnormalities were not identified. We performed mutation analyses after ethical approval and signed informed
consent. We detected recurrent compound heterozygous c.1132 C>T, p.Q378X and c.4069 C>T, p.R1357W mutations in
ABCC6. Identification of genetic and environmental modifiers would be accompanied by accumulation of cases with uncom-
mon features. Our case indicates that the predisposed factors such as comedoes and acnes would be the modifier toward the
severe clinical characteristics of severe acne scar of the neck in PXE.
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ICHG2016 427
Wed(4)-SFS16-5
Clinical and demographic evaluation of a holoprosencephaly cohort from the Kyoto Collection of human
embryos
Yu Abe 1 ，Ariel F Martinez 1 ，Paul Kruszka 1 ，Erich Roessler 1 ，Shigehito Yamada 2 ，Maximilian Muenke 1
1:Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, USA、2:Congenital Anomaly Research
Center, Kyoto University Graduate School of Medicine
Holoprosencephaly (HPE) is a genetically and phenotypically heterogeneous disorder involving developmental defects of the
forebrain, midface, and limbs. HPE is a rare condition (1/10,000-20,000 newborns) but can be found as frequently as

1/250 conceptions, suggesting that most HPE embryos are incompatible with intrauterine life and eliminated by spontaneous
abortion during the first trimester of gestation. HPE can occur as part of another syndrome, or be caused by chromosomal
anomalies or discreet mutations affecting important developmental pathways. Over a dozen genes are known to be associated
with HPE, but currently only four genes (SHH , ZIC2 , SIX3 , and TGIF ) are routinely analyzed on a clinical basis.
Beginning in 1961, the Kyoto University in Japan has collected over 44,000 human conceptuses in collaboration with several
hundred domestic obstetricians. Within the Kyoto collection, over 200 cases of HPE have been identified, which represents the
largest single cohort of HPE specimens in the early organogenetic period. In this study, we present a comprehensive clinical
and demographic evaluation of this HPE cohort prior to genomic analysis. Phenotypic classification of HPE cases will help
dissect genetic contributions and better understand the genetic etiology of HPE and the biology of forebrain development.
Future research will involve 1) array CGH/SNP array to detect chromosomal anomalies and copy number variations; 2)
targeted-capture sequencing of important developmental genes and their regulatory regions; and 3) whole exome sequencing.
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ICHG2016 428
Wed(4)-SFS16-6
The Clinical Geneticist as an Expert Witness in Court
1
Michael A Patton
1:Medical Genetics, St Georges University of London, UK
The use of DNA in providing forensic evidence for the Courts is well established but the role of clinical geneticists in other
areas of Court work is perhaps not as well known. The author has acted as an Expert Witness in the UK Courts for over 20
years in addition to undertaking a busy schedule of clinical and academic work. The role of Expert Witness has fallen into

three areas. (1) Providing a defence in two high profile murder cases where the mothers of children who died from sudden
infant death syndrome were charged with the murder of their children (2) Family Court work with potential non accidental
injury and the possibility of predisposition to fractures. Also family court work to explain the impact of various genetic causes
of disability to the Court. (3) Medical negligence work in assessing the cause of complex motor and intellectual disability in
in children with perinatal asphyxia. This work also calls for estimates of life expectancy in cases with genetic disability. In
addition there have been some unusual cases. These have included a libel cases where a tabloid newspaper suggested that a
famous model was male rather than female and a case of a disabled child born after artificial insemination where the claim
was brought under the legislation for "Defective Product Liability" as no clinical negligence had taken place. There have also
been cases which were declined such as a murder case where the accused had 47XYY and a sexual assault where the defence
claimed it could not have taken place as the accussed had Klinefelter syndrome.
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ICHG2016 429

Clinical Genetics 2
Wed., April 06, 2016 16:45-18:15 Room J (2F)
Moderator：Richard H. Finnell（Dell Pediatric Research Institute, The University of Texas at Austin, USA）
Moderator ：Atsushi Watanabe（Division of Clinical Genetics„ Nippon Medical School Hospital, Japan）
Wed(4)-SFS17-1

Hypophosphatasia diagnosed during childhood in Japan
Atsushi Watanabe 1,2 ，Hanako Tajima 3 ，Seiko Nemoto 4 ，Motoko Sasaki 1 ，Maya Kawamura 2 ，Takashi Okada 2 ，
Takashi Shimada 1
1:Division of Clinical Genetics, Nippon Medical School Hospital, Japan、2:Department of Biochemistry and Molecular Biology, Nippon
Medical School、3:Department of Pediatrics, Nippon Medical School Hospital、4:Department of Pediatric Dentistry, Nihon University school
of Dentistry at Matsudo
Hypophosphatasia (HPP) is an inherited disorder characterized by defective bone mineralization and caused by mutations
in ALPL that encodes an isozyme of alkaline phosphatase, TNSALP. Clinically, HPP is heterogeneous and according to the
age of onset, six different forms can be distinguished. The perinatal (severe) type of HPP is one of major types of skeletal
dysplasia found in the prenatal period in Japan. Most frequent ALPL mutations in Japan are c.1559delT and p.F327L, which
cause severe and mild type of HPP. Recently, a bone targeted enzyme replacement therapy has been available since 2015 as
a new therapeutic option in HPP.
In six forms of HPP, two forms are diagnosed as HPP during childhood, childhood HPP and odonto type of HPP. In this
report, we introduced two forms of HPP diagnosed during childhood in Japan.
(case 1) 10-year-old boy, he had premature loss of teeth and short stature (80.1cm(-3.1 SD)started at the age of three. ALP 217
IU/L (normal range adjusted with age 500-1400) and urine PEA 1074 nmol/mgCr He had compound heterozygote mutations
(p.F327L/p.G339R) in ALPL. We diagnosed him as childhood HPP.
(case 2) 9-year-old boy, he had premature loss of teeth and no history of short stature (133cm) ALP:266 IU/L and urine PEA
849 nmol/mgCr. He had compound heterozygote mutations (1559delT/p.R136H) in ALPL. He had no symptom related bone
except tooth but had radiographic signs of knees with osteopenia. We diagnosed him as odonto type of HPP but think him
to need follow up to adulthood because of radiographic signs.
These two cases diagnosed as HPP during childhood had mutations of ALPL with both alleles, thus recessive type, whereas
major of childhood HPP and odonto type of HPP in US and Europe are diagnosed with dominant type. We need to examine
more between natural history and genotype of HPP in Japan.
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Wed(4)-SFS17-2
Withdrawn


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Wed(4)-SFS17-3
A missense mutation of the SLCO2A1 gene underlies a complete type of pachydermoperiostosis in 3
Japanese families
Hironori Niizeki 1 ，Maiko Matsuda 1 ，Kazuhiko Nakabayashi 2 ，Atsuhito Seki 3 ，Mikiko Miyasaka 4 ，Taiji Matsuo 5 ，
Shigeki Inui 6 ，Kazue Yoshida 1 ，Kenichiro Hata 2 ，Torayuki Okuyama 7
1:Dermatology, National Center for Child Health and Development, Japan、2:Reproductive Biology, National Research Institute for Child
Health and Development、3:Orthopedics, National Center for Child Health and Development、4:Radiology, National Center for Child Health
and Development、5:Endoscopy, Hiroshima University Hospital, Hiroshima、6:Regenerative Dermatology, Graduate School of Medicine,
Osaka University、7:Laboratory Medicine, National Center for Child Health and Development

Pachydermoperiostosis (PDP) is a rare genetic disease affecting the skin and bones. The major diagnostic criteria of the
complete type include finger clubbing, periostosis, pachydermia, and pachydermia of the scalp (cutis verticis gyrata, CVG),
which are absent in the incomplete type. A homozygous mutation in SLCO2A1 , encoding prostaglandin transporter (PGT),
causes PDP. The mutation results in insufficient degradation and increased tissue levels of prostaglandin E2, which contributes
to PDP pathogenesis. We previously reported that 50% of the alleles of 10 Japanese PDP patients with SLCO2A1 mutations
showed nonsense and splice site mutations. However, none of the patients with the complete type was compound heterozygous
for a missense (MM) mutation. We here report 3 cases of the complete type of PDP, which are all associated with MM
SLCO2A1 mutations.
The 3 male patients were referred to our hospital at the ages of 44 (case 1), 57 (case 2), and 33 (case 3). They had experienced
the triad of PDP symptoms with CVG. Case 1 experienced hair loss on the CVG region. Case 2 also had myelofibrosis and
small intestinal ulcers. In case 3, gastric endoscopy showed giant gastric rugae at the age of 32. Case 1 was homozygous for
c.664G>A, resulting in a glycine-to-arginine substitution at position 222 (p.G222R). Case 2 was homozygous for c.1682G>A,
resulting in an arginine-to-histidine substitution at position 561 (p.R561H). Case 3 had 2 mutations in exon 4: c.547G>A,
resulting in a glycine-to-arginine substitution at position 183 (p.G183R); and c.586G>A, resulting in an aspartic acid-to-
asparagine substitution at position 196 (p.D196N). These amino acid residues are highly conserved in human, mouse, chicken,
frog, and zebrafish. The p.R561H mutation is located in the highly conserved 11th transmembrane domain, which includes
critical amino acid residues for PGT activity. These results demonstrate that a MM mutation underlies the complete type as
well as incomplete type of PDP.
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Wed(4)-SFS17-4
Clinical and experimental evidence for OTX2 dosage sensitivity in individuals with Oculo-Auriculo-
Vertebral Spectrum
Tiong Yang Tan 1,2,3 ，Sue Price 4 ，Bernadette Hanna 5 ，Naomi Baker 2,3
，Joanna Roberts 6 ，Hani H Far 2 ，
Mai Raabus 2 ，Amber Boys 1 ，Peter G Farlie 2,3
1:Victorian Clinical Genetics Services, Australia、2:Murdoch Childrens Research Institute, Melbourne, Australia、3:Department of
Paediatrics, University of Melbourne, Melbourne, Australia、4:Clinical Genetics Department, Northampton General Hospital, Cliftonville,
Northampton, United Kingdom、5:Hunter Genetics, Waratah, NSW, Australia、6:Cytogenetics Laboratory, Churchill Hospital, Headington,
Oxford, United Kingdom

Goldenhar syndrome, hemifacial microsomia and Oculo-auriculo-vertebral spectrum (OAVS; OMIM 164210) are collectively
characterised by multiple congenital anomalies predominantly affecting the first and second branchial arches, including mi-
crotia, facial asymmetry, preauricular pits and tags, ocular colobomas and epibulbar dermoids. Malformations beyond the
craniofacial region affect the cardiovascular system, vertebrae, kidneys and urogenital tract. The manifestations can be
unilateral or bilateral, and most cases are sporadic, although affected siblings and dominant families have been reported.
Chromosomal anomalies are infrequently reported, but recurrent genetic abnormalities have not been consistently identified.
We report two unrelated families segregating a chromosome 14q22.3 microduplication and the OAVS phenotype in an auto-
somal dominant pattern. Using high resolution SNP microarray, we identified a 2 Mb microduplication in Family 1 and a
300 kb microduplication in Family 2. In Family 1, OTX2 and 13 other genes are duplicated, whereas in Family 2, OTX2 is
the only gene involved in the duplication. OTX2 is a transcription factor expressed in the telencephalon, diencephalon and
mesencephalon of developing vertebrate embryos. It is critical for eye and anterior neural tube development, and heterozygous
loss-of-function mutations cause ocular malformations including microphthalmia, anophthalmia and colobomas. We hypoth-
esised that increased dosage of OTX2 is the primary phenotypic determinant in our two OAVS families. We present findings
of experimental overexpression in chick embryos to replicate the increased dosage proposed to occur in these two families and
the implications of increased OTX2 dosage for craniofacial development.
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Wed(4)-SFS17-5
Mutations in Human Capicua Gene Found in Patients with Cerebral Folate Deficiency Syndrome and in
Patients with Spina Bifida
Richard H Finnell 1 ，Yunping Lei 1,2
1:Nutritional Sciences and Chemistry, The University of Texas at Austin, USA、2:Fudan University
Cerebral folate deficiency (CFD) syndrome is characterized by low concentration of 5-methyltetrahydrofolate (5-MTHF)
in cerebrospinal fluid, while folate levels in plasma and red blood cells are normal. CFD patients present with symptoms

including: developmental delay, ataxia, dyskinesias, spasticity, speech difficulties and epilepsy. Previously, mutations in several
folate pathway genes, including hFRa (folate receptor alpha), DHFR (dihydrofolate reductase), PCFT (proton coupled folate
transporter) and MTHFS (methenyltetrahydrofolate synthetase) have been identified in CFD patients.
In an effort to identify causal mutations for CFD, we performed whole exome sequencing analysis of DNA samples collected
from a CFD patient, her healthy sibling, and her biological parents. A de novo mutation in human Capicua gene (CIC ),
c.1057C>T (p.R353X), was identified in the patient. A second CFD patient was confirmed as a compound heterozygote of
two splice site variants of CIC gene, IVS1360+32G>AG and IVS3796-15C>CT. In addition, a missense mutation predicted
to be damaging, c.1738G>GT (p.G580GC) was identified in a 3rd CFD patient,
The CIC protein is a HMG-box transcriptional repressor. The DNA binding domain located at amino acid residues 200-268
binds the octomer sequence T(G/C)AATG(A/G)A. The mutation identified in the CFD patient, p.R353X, yields a truncated
protein which still contains the DNA binding domain (HMG box), therefore it is still able to bind to its targets. CIC target
binding octomer sequence has been found in the promoter regions of folate transport genes FOLR1 , PCFT , RFC1, and
DHFR, which is involved in folate metabolism.
CIC coding regions were also sequenced in 190 patients with spina bifida from California. Four missense mutations (p.S68P,
p.M379L, p.P484S, p.P896A) were identified.
Our findings suggest that human Capicua gene regulates folate transporter gene expression, and may play a role in the etiology
of CFD and NTDs.
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Wed(4)-SFS17-6
A New Subtype of Multiple-Synostoses Syndrome is caused by a Gain-of-Function Mutation in GDF6
that Enhances BMP Signaling during Skeletal Development
Jian Wang 1 ，Tingting Yu 1 ，Zhigang Wang 2 ，Satoshi Ohte 3 ，Ru-en Yao 1 ，Qinghua Zhang 4 ，James F Gusella 5 ，
Qihua Fu 1 ，Steven Pregizer 3 ，Vicki Rosen 3 ，Yiping Shen 1,6
1:Department of Medical Genetics, Shanghai Children Medical Center, Shanghai Jiaotong University School of Medicine, China、2:Depart-
ment of Pediatric Orthopedic, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine、3:Developmental
Biology, Harvard School of Dental Medicine、4:State Key laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University
School of Medicine、5:Molecular Neurogenetics Unit and Center for Human Genetic Research, Massachusetts General Hospital and Harvard
Medical School、6:Department of Laboratory Medicine, Boston Children’s Hospital

Multiple synostoses syndromes (SYNSs) are skeletal disorders characterized by multiple joint fusions that can affect digits,
wrists, ankles, elbows and spine. Three known types, SYNS1, SYNS2, and SYNS3 are caused by mutations in NOG, GDF5
and FGF9 , respectively. We have identified a fourth type, SYNS4, which predominantly affects carpal and tarsal bones, due
to a missense variant in GDF6 (Growth/Differentiation Factor 6). The variant (NM_001001557; c.1330T>C) fully segregates
with the SYNS4 phenotype (LOD > 7) in a large Chinese pedigree. It alters a highly conserved residue (NP_001001557.1;
p.Y444N) at the binding surface for BMPR type 1 receptors and for noggin, a natural antagonist. When wild-type and
mutant GDF6 were studied in vitro, mutant GDF6 was less inhibited by noggin and better able to induce chondrogenesis
than its wild-type counterpart. Thus excessive GDF6 signaling during skeletal development is another cause of multiple
synostoses. These findings open a new window on bone/cartilage development and further emphasize the critical importance
of the interplay among GDFs, BMPRs and antagonists in joint formation.
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ICHG2016 435

Complex Traits Disorders
Wed., April 06, 2016 15:00-16:30 Room K (2F)
Moderator：Jeffery M. Vance（John P. Hussman Institute for Human Genomics, University of Miami Miller School of
Medicine, USA）
Moderator ：Tatsushi Toda（Division of Neurology / Molecular Brain Science, Kobe University Graduate School of
Medicine, Japan）

Wed(4)-SFS18-1
Full Mitochondrial Genome Sequencing Reveals that the 12S rRNA Mitochondrial sub-unit is Involved
in Migraine Susceptibility in the Genetically Isolated Norfolk Island Population
Shani Stuart 1 ，Miles C Benton 1 ，David A Eccles 1 ，Cassie Albury 1 ，Heidi Sutherland 1 ，Larisa M Haupt 1 ，
Rod A Lea 1 ，Lyn R Griffiths 1
1:Genomics Research Centre, Queensland University of Technology, Australia
Migraine is a common neurological disorder, affecting approximately 12 % of the Australian population. This common
neurological disease poses a significant personal and economic burden, with current therapies only being effective for a
proportion of sufferers. The aim of this project was to conduct a complete mitochondrial genome scan to identify the full
spectrum of mtDNA variation in the Norfolk Island pedigree samples and to determine whether the variants are associated
with risk of migraine. Norfolk Island is a genetically isolated population and is useful for studying complex disease due to the
reduced genetic and environmental heterogeneity. Through full mitochondrial genome sequencing on the Ion Torrent platform,
3 homoplasmic and 11 heteroplasmic variants were identified to be significantly associated with migraine susceptibility in the
Norfolk Island population. Logistic regression analysis showed that a mitochondrial variant (p=0.0233) located within the
12S rRNA subunit is significantly associated with migraine. A Fisher’s exact test identified two rare variants associated with
migraine susceptibility, situated within the COX1 gene and NADH dehydrogenase. In order to comprehensively asses the role
of mitochondrial dysfunction in migraine susceptibility, Nuclear Encoded Mitochondrial Proteins (NEMPs) were investigated
in the Norfolk Island population and results were replicated in an Australian Caucasian outbred migraine case-control cohort.
In the discovery phase 16820 SNPs in 315 individuals from Norfolk Island were tested and it was found that 667 NEMP SNPs
were significantly associated with migraine. Of these, 21 SNPs significantly associated with migraine with p<0.0001 were
selected for replication in a large outbred migraine case-control cohort (544 cases, 584 controls). Replication analysis showed
that NEMPs are significantly associated with migraine susceptibility and that OXPHOS may be important for migraine
pathophysiology.
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ICHG2016 436
Wed(4)-SFS18-2
Genome-wide association meta-analysis of intracranial aneurysm identifies 8 previously unknown loci and
genes underlying the association
Katsuhito Yasuno 1 ，Yuwei Cheng 2 ，Murat Gunel 1,3
，International Intracranial Aneurysm Genetics Study Group
1:Neurosurgery, Yale University School of Medicine, USA、2:Computational Biology and Bioinformatics, Biological and Biomedical Sciences,
Yale University、3:Neurobiology and Genetics, Yale University School of Medicine
To date, genome-wide association studies (GWAS) of intracranial aneurysms (IAs) have been performed using 3 independent
cohorts. To increase the power to detect more loci that confer risk of developing IA, we assembled these 3 datasets, performed

whole-genome genotyping for newly collected samples in US, and established a replication cohort from UK. After quality
control, we had a total of 7,267 IA cases and 22,995 controls of European and Japanese. The discovery GWAS was performed
across > 8 million loci through imputation using 1000 genomes phase 1 reference haplotypes. The newly included GWAS
cohorts, as well as the replication data, increased the strength of association at 7 previously established IA risk loci (CDKN2B-
AS1, 5’-SOX17, 3’-SOX17, CNNM2, STARD13, between CTAGE1 and RBBP8, and EDNRA). We identified 8 previously
unknown loci at genome-wide significance level of 5 x 10-8 . Using the expression quantitative trait loci analysis data across 44
tissues from Genotype-Tissue Expression (GTEx) project and a Bayesian co-localization method developed by Giambartolomei
et al. (2014, PLoS Genet 10:e1004383), we were able to identify genes underlying the association with IA for relevant tissues.
In addition, using a Bayesian fine-mapping approach (Maller et al. 2012, Nat Genet 44:1294) with epigenomic data from
ENCODE and Roadmap projects, we derived a credible set of causal SNPs. Among these loci, several are shared with vascular
diseases, revealing common pathogenic pathways underlying the pathology of these disorders.
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Wed(4)-SFS18-3
ABC transporters confer risk in Parkinson Disease
Jeffery M. Vance 1,2 ，Karen Nuytemans 1 ，Lizmarie Maldonado 1 ，Krista John-Williams 1 ，Eden R Martin 1,2
，
Gary Beecham 1,2 ，William K Scott 1,2
1:John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, USA、2:Dr. John T Macdonald
Foundation Department of Human Genetics, University of Miami Miller School of Medicine
Recently, ABCA7 rare variants have been reported to represent risk factors for both Alzheimer Disease (AD) and Parkinson
Disease (PD). Interestingly, few additional studies have identified rare variants in ABC transporter genes in multiple complex

disorders (e.g. AD, bipolar disorder, Tangier disease). We set out to evaluate the overall contribution of rare variants in ABC
transporters to PD risk.
We performed whole exome sequencing (WES) in 396 unrelated cases and 222 controls and custom targeted sequencing
(CTS) of ~ 370 genes in 330 cases versus 166 controls. Two meta-analysis gene-based tests across WES and CTS data
were performed using SeqMeta on rare (MAF5%) nonsense, missense and splice (“functional”) variants and on all variants
weighted on functional CADD score. We performed four analyses evaluating enrichment in KEGG pathways using WebGestalt
(SeqMeta p-value cut-off 0.05) and GSEA. Single rare variant analyses were supplemented with WES data from the Parkinson
Progression Marker Initiative (PPMI).
We identified the ABC transporters pathway in the four pathway enrichment analyses at unadjusted significance level (p ~
0.005). This signal was driven by 5 to 19 genes depending on the analysis, such as ABCB4 , ABCB6 , ABCC4 and ABCD4 .
Single rare functional variants or variants with CADD>20 (especially those in the ATP binding domains) were mostly observed
in PD patients versus controls. Specifically, rare variant ABCB4 R590Q was found to be significantly associated with PD risk
when including both in-house and PPMI WES data (p=0.01).
Our data suggests that variants in the ABC transporters represent risk factors for PD; especially those located in the ATP
binding domains. We hypothesize these genes are strong candidate genes for PD and potentially other neurodegenerative
disorders. Additional analyses are ongoing to address the impact of the identified rare variants in the contributing genes to
PD.
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Wed(4)-SFS18-4
Exome Association study and 2nd SNP-GWAS of Parkinson’s disease in Japan
Wataru Satake 1 ，Yutaka Suzuki 2 ，Daichi Shigemizu 3 ，Atsushi Takahashi 3 ，Ken Yamamoto 4 ，Miho Murata 5 ，
Nobutaka Hattori 6 ，Tatsuhiko Tsunoda 3 ，Shoji Tsuji 7 ，Michiaki Kubo 3 ，Sumio Sugano 8 ，Naomichi Matsumoto 9 ，
Tatsushi Toda 1
1:Div Neurol/Mol Brain Sci, Kobe Univ, Japan、2:Dept Comput Biol, The Univ of Tokyo、3:Cen Integr Med Sci, RIKEN、4:Kurume Univ、
5:Dept Neurol, Natl Cen Hsp of Neurol and Psy、6:Dept Neurol, Juntendo Univ、7:Dept Neurol, The Univ of Tokyo、8:Dept Med Genome
Sci, The Univ of Tokyo、9:Dept Hum Genet, Yokohama City Univ
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases worldwide. The majority of cases show

sporadic onset, and 5-10% of cases show familial aggregation; that is, PD is a complex disorder caused by multiple genetic
risks. To identify genetic risks for PD, we performed a GWAS using Japanese samples, and identified four risk loci for PD
(PARK16 , BST1 , α-synuclein and LRRK2 ) with genome-wide significance (Satake et al, Nature Genet 2009). Association
signals between these four loci and PD have been also detected by Caucasian association studies (IPDGC, Lancet 2011; and
Lill et al, PLoS Genet 2012), indicating that these four loci are definite PD-risks common to both Asians and Caucasians. To
identify further common variant-risks for PD, we performed the second Japanese SNP-GWAS which expanded our previous
one. Using 1,948 cases and 28,990 controls, we identified a novel susceptibility locus with P <5 x 10-8 . Expression level of a
gene within the locus was reduced when the risk SNP exists. In a fly model, knockout of the gene worsened moter function.
Our genomic and in vivo model data show that this gene is a novel PD-risk. Moreover, in order to search for further PD-risks
in exonic areas, we performed whole exome sequencing of 755 PD patients using Sureselect and HiSeq2000/2500. Average
depth of our data was x 126, and 94.4 % of whole exon sequence was covered by >10 reads. Using data of 625 PD cases and
961 controls, we tested association between PD and exonic variants within the four PD-loci (PARK16 , BST1 , α-synuclein,
and LRRK2 ). We detected two nonsynonymous variants with moderate PD-risk (P ∼10-4 ) within LRRK2 . On the other
hand, we detected no nonsynonymous variants with moderate PD-risk within the other three PD-loci, suggesting that these
three PD-loci contribute to the disease as common variants. We will be testing association between whole exonic SNVs and
PD to identify novel PD-genes haboring rare-variant risks.
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ICHG2016 439
Wed(4)-SFS18-5
A multi-step approach identifies regions on chromosomes 3 and 17 as highly associated with Multiple
Sclerosis in Italian population
Melissa Sorosina 1 ，Nadia Barizzone 2,3 ，Ferdinando Clarelli 1 ，Santosh Anand 4 ，Sara Lupoli 5 ，Federica Esposito 1,6 ，
Eleonora Mangano 4 ，Roberta Bordoni 4 ，Vittorio Martinelli 6 ，Giancarlo Comi 6 ，Maurizio Leone 2 ，
Daniele Cusi 5 ，Nikolaos A Patsopoulos 7,8,9,10 ，Philip L De Jager 7,8,9,10 ，Gianluca De Bellis 4 ，Sandra D’Alfonso 3 ，
Filippo Martinelli Boneschi 1,6 ，PROGEMUS, PROGRESSO
1:Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele
Scientific Institute, Italy、2:Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara,
Italy、3:Department of Health Sciences, University of Eastern Piedmont, Novara, Italy、4:National Research Council of Italy, Institute for

Biomedical Technologies, segrate, Milano, Italy、5:Department of Health Sciences, University of Milan, Italy、6:Department of Neurology
and Neurorehabilitation, San Raffaele Scientific Institute, Milan, Italy、7:Ann Romney Center for Neurologic Diseases, Department of
Neurology, Brigham and Women’s Hospital, Boston, MA、8:Harvard Medical School, Boston, MA、9:Program for Medical and Population
Genetics, Broad Institute, Cambridge, MA、10:Program in Translational Neuropsychiatric Genomics, Institute for the Neurosciences,
Department of Neurology, Brigham and Women’s Hospital, Boston, MA
Multiple sclerosis (MS) is a complex disorder characterized by inflammatory and neurodegenerative mechanisms. Until now,
103 susceptibility genetic loci have been identified though genome-wide association studies (GWAS), which were enriched of
Caucasian populations of Northern European ancestry. In the present study we used a multi-step approach to identify the
most associated regions in the Italian continental population.
We performed a GWAS on an imputed cohort of 750 Italian MS patients and 1291 healthy controls (HC), and top associated
signals (p<0.001) have been meta-analysed with an imputation-based meta-analysis cohort of 20,512 cases and 19,145 HC
of European ancestry. 17 SNPs belonging to the top associated regions (p<5x10-7 , n=11) were tested in a second Italian
cohort (903 MS, 884 HC). This confirmed the association of two regions at Bonferroni threshold: region 1 on chromosome
17 and region 2 on chromosome 3. Next, we sequenced the two regions in an Italian cohort of additional 600 MS and 400
HC using a pooling approach. 201 signals in the region 1 and 12 in the region 2 were selected as associated; however, due to
the strong LD among them, we were unable to identify the causative signal, thus signals were tested by performing cis-eQTL
associations on blood and brain tissues according to Braineac, Scan, SNPExpress and GTEXPortal databases.
In region 1, a strong eQTL association was found with EFCAB13 in brain, and a less pronounced with TBKBP1 in
PBMCs/blood, suggesting a tissue-depending regulation. Region 2 did not show a clear function and needs to be better
explored.
Concluding, this is the larger association study performed in MS field on an Italian continental population. We confirmed
the regions on chromosomes 17 and 3 as highly associated and we better characterised the origin of the signals using a next-
generation sequencing approach. Moreover, we observed a tissue-dependent regulatory function of the first, opening questions
on its role in MS.
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Wed(4)-SFS18-6
Gene Discovery in Autism Using a Quantitative Autism Score
Michael Cuccaro 1,2 ，Sonija Luzi 2 ，Eden R Martin 1,2
，Holly N Cukier 1,2
，Anthony J Griswold 1,2
，John R Gilbert 1,2
，
John P Hussman 3 ，Margaret A Pericak-Vance 1,2
1:Dr. John. T. Macdonald Department of Human Genetics, University of Miami Miller School of Medicine, USA、2:John P. Hussman
Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL、3:Hussman Institute for Autism, Baltimore, MD,
USA
ASD is a multi-dimensional phenotype with varied social-communicative and behavioral features. We hypothesize that genetic
variants in ASD candidate genes will lead to an increased number of core autism features. To test this hypothesis, we developed

a quantitative autism score (QAS) based on core ASD features and examined its association to ASD candidate genes.
The QAS was derived from the ADI-R, a semi-structured informant interview for ASD. Using ADI-R items which consistently
distinguish ASD from non-ASD, a score was developed based on the total number of features present (range 0-25).
The QAS was calculated in 1118 ASD subjects (Hussman Institute for Human Genomics, Simons Simplex Collection) who
had DNA sequence data from a 17Mb custom capture covering 681 genes in regions identified by GWAS of ASD. Gene-based
and single-variant tests for association with the QAS as a quantitative trait were conducted with SKAT-O. Combinations of
synonymous, non-synonymous, and loss-of-function variants were investigated in different hypothesis tests.
We found significant association (meeting Bonferroni correction) for the gene CDH4 (p= 9.20E-06) when all exonic variants
were included in the gene-based test. CDH4, a neuronal cell adhesion molecule involved in brain segmentation and neuronal
outgrowth, is a member of the cadherin family of genes, which has been implicated in ASD. We also found a significant
association for the LGR5 gene when all exonic variants were included (p=3.59E-05) and when only missense variants were
included (p=7.67-05). LGR5 is known to be implicated in neuronal specification in the nervous system. Single-variant tests
within these two genes identified two synonymous variants in CDH4 and two variants (1 synonymous and 1 missense) in
LGR5 associated (p<0.05) with QAS. These genes are being further evaluated in three replication samples.
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ICHG2016 441

Molecular Basis of Mendelian Disorders
Wed., April 06, 2016 16:45-18:15 Room K (2F)
Moderator：Mark J. Cowley（Kinghorm Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney,
Australia）
Moderator ：Hirotomo Saitsu（Department of Biochemistry, Hamamatsu University School of Medicine, Japan）
Wed(4)-SFS19-1

Developing WGS as a First Line Diagnostic Test for Patients with Mendelian Disorders
Mark J Cowley 1,2 ，Lisa J Ewans 1,2 ，Amali Mallawaarachchi 1,5 ，Andre Minoche 1 ，Mark Pinese 1 ，
Kishore R Kumar 1,7 ，David Miller 1 ，Velimir Gayevskiy 1 ，Yvonne Hort 1 ，Ying Zhu 3 ，Clare Horvat 4 ，Diane Fatkin 4 ，
John Shine 1 ，Tim Furlong 5 ，John Christodoulou 6 ，Andreas Zankl 1,6 ，Carolyn E Sue 7 ，Tudor Groza 1 ，
Michael F Buckley 8 ，Tony Roscioli 1,2,9 ，Marcel E Dinger 1,2
1:Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Australia、2:St Vincent’s Clinical School, University of
New South Wales, Darlinghurst, NSW, Australia、3:Royal North Shore GOLD Service, Sydney, NSW, Australia、4:Victor Chang Cardiac
Research Institute, Darlinghurst, NSW, Australia、5:Renal Department, St Vincent’s Hospital, Darlinghurst, NSW, Australia、6:Children’s
Hospital, Westmead, NSW, Australia、7:Kolling Institute of Medical Research, North Sydney, NSW, Australia、8:SEALS laboratory, Prince
of Wales Hospital, Randwick, NSW, Australia、9:Department of Medical Genetics, Sydney Children’s Hospital, Randwick, NSW, Australia
Targeted sequencing (TS), whole exome sequencing (WES), and more recently, whole genome sequencing (WGS) have had a
remarkably rapid, and positive impact upon patient diagnosis. Diagnostic rates for patients with rare monogenic disorders
have risen to on average 25% using WES, and 40-73% using WGS. WGS is now cost competitive, driven by the Illumina
HiSeq X, and the promising potential of WGS as a comprehensive diagnostic test, we have been establishing the informatic
and clinical infrastructure to enable WGS-based genomic diagnosis, as a first-line diagnostic test. We have applied this to
a number of disease areas, including intellectual disability, epilepsy, dilated cardiomyopathy (DCM), autosomal dominant
polycystic kidney disease (ADPKD), skeletal, movement, mitochondrial and immune disorders. We aim to offer clinically
accredited WGS in early 2016.
By comparing the performance of WGS to WES or TS in a number of disorders, we find consistently that WGS offers higher
rates of callable bases, even in the bases targeted by the capture-probes. For example, in a targeted panel of 67 DCM genes,
sequenced to >200x average depth, only 90.7% of targeted bases were covered >20x, vs 95.5% by WGS at 30x depth, leading
to missed coding variants, and missed diagnoses. In ADPKD, we achieved a 50% diagnostic rate using WES, but an 86%
rate by WGS, in part due to coding variants with no coverage in WES, and the identification of two small deletions identified
only by WGS. The extremely high depth of coverage in mitochondrial DNA (typically >15,000x) by WGS permits extremely
sensitive assessment of mitochondrial mutations and heteroplasmy. WGS offers the sensitivity to detect structural variants
across the entire size range, although repeats longer than the read length remain challenging.
The broad-reaching utility of WGS as a first-line diagnostic test is particularly well suited to disorders where the rates of gene
discovery continue to climb, such as intellectual disability.
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Wed(4)-SFS19-2
Clinical efficiency of exome sequencing as a service for diagnosing hereditary diseases in Russia
Fedor A Konovalov 1,2 ，Ilya V Kanivets 1,2 ，Denis V Pyankov 1,2
，Oxana P Ryzhkova 1,2
，Irina A Akimova 1 ，
Elena L Dadali 1,2 ，Sergey A Korostelev 1,2
1:Genomed Ltd., Russia、2:Research Centre for Medical Genetics, Russia
Exome sequencing is becoming increasingly utilized in routine workup of mendelian cases in Russian clinical practice. From
April to October 2015 we performed NGS-based DNA analysis as a commercial service for 330 patients with suspected
mendelian disorders. For library preparation, we used Illumina TruSight One sequencing panel of 4813 genes (304 cases),

whole-exome enrichment (14 cases) and targeted panels (12 cases). Sequencing was done on Illumina NextSeq 500 instrument.
After calling and annotation, the variants were uploaded into a database-driven web interface for clinical analysis. In a typical
case, finding a causative mutation required a human expert to look manually through no more than 20-30 variants, pre-filtered
by biological criteria and cross-checked for presence in the other cases which helped to eliminate recurrent sequencing artifacts
and polymorphisms.
Among 330 cases, the definitive molecular diagnosis was obtained in 134 patients (41%), with another 87 patients (26%) hav-
ing a possible diagnosis based on variants of unknown significance with a need for additional evidence. Success rates differed
depending on indications and reached 88% in osteogenesis imperfecta (30 cases with definitive diagnosis out of 34); 61% in
primary myopathy (17/28 cases); 62% in motor and sensory neuropathy (8/13); 38% in epilepsy and various types of seizures
(32/85); 49% in neurodegenerative disorders (19/39); 14% in combined group of non-syndromic/syndromic mental retardation
(9/65). In addition to standard variant calls, the CNV analysis algorithm detected large imbalances in 11 cases, with 8 of
them explaining the phenotypes, including hereditary cancer syndrome (homozygous deletion in PMS2 gene, confirmed by
qPCR) and lissencephaly 1 (PAFAH1B1 deletion, confirmed by SNP microarray).
The incidental findings were reported in 8 cases and included dominant mutations responsible for hereditary cancer, cardy-
omyopathy, malignant hyperthermia, Long QT and Brugada syndromes.

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Wed(4)-SFS19-3
Gene Mapping in the Finnish National Collection of Balanced Translocations and Inversions
Teppo Varilo 1,3 ，Tiia Luukkonen 3,4 ，Minna Poyhonen 1 ，Kalle OJ Simola 5 ，Kristiina Aittomaki 1,4
，Jaakko Ignatius 6 ，
Aarno Palotie 1,2,8 ，Joseph Terwilliger 3,9,10 ，Riitta Salonen 7
1:Department of Medical Genetics, University of Helsinki, Finland、2:FIMM Institute for Molecular Medicine Finland, Helsinki, Finland、
3:National Institute for Health and Welfare, Helsinki, Finland、4:Dept. of Clinical Genetics, Helsinki University Central Hospital, Helsinki,
Finland、5:Dept. of Pediatrics, Tampere University Hospital, Tampere, Finland、6:Dept. of Clinical Genetics, Turku University Central
Hospital, Turku, Finland、7:Dept. of Medical Genetics, Norio-centre, Rinnekoti Foundation, Helsinki, Finland、8:Broad Institute of Harvard
and MIT, Cambridge, MA, United States、9:Columbia Genome Center, Columbia University, New York, NY, United States、10:New York
State Psychiatric Institute, New York, NY, United States

We have assembled a nationwide collection of all known carriers of reciprocal balanced translocations and inversions from
every Medical Genetics Department and Clinical Genetics Laboratory in Finland. Our database contains relevant medical
records of all available carriers to include all relatives carrying the same rearrangement identical by descent. To date we
have systematically examined 3016 carriers and their relatives, and gathered samples (n=124; DNA, RNA and cells). We are
collecting more biological samples, and linking our data to national comprehensive disease registers. We collaborate with the
International Breakpoint Mapping Consortium (Tommerup N et al. 2015 Cancer Genetics).
We use this collection as a valuable gene mapping tool, focusing on identification of the precise molecular location of the
chromosomal breakpoints, and correlating these to phenotypes. We investigate families, which appear to have a striking
correlation of a balanced translocation and an abnormal phenotype. In individuals from each pilot, we are performing stan-
dard cytogenetic analysis, copy number analysis (genotyping and aCGH), genome-wide paired-end sequencing, and capillary
sequencing with the objective of identifying the specific breakpoints and ruling out other potentially causative genetic fac-
tors. In our first gene-mapping pilot we identified a potential positional candidate gene for intracranial and aortic aneurysm
(Luukkonen T et al. 2012 JMG). Our second project is familial translocation t(1;12)(q43;q21.1), which truncates a CHRM3
GENCODE isoform in a family leading to stroke.
Our results demonstrate the feasibility of genome-wide paired-end sequencing for the characterization of balanced rearrange-
ments and identification of candidate genes in patients with potentially disease-associated chromosome rearrangements. This
unique registry will be of benefit to both researchers and clinicians by facilitating diagnostic purposes, genetic counseling,
and subsequent follow-up.
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Wed(4)-SFS19-4
Defining Genetic Causes of Hereditary Spastic Paraplegia with Whole Genome Sequencing
Kishore R Kumar 1,2 ，G. M. Wail 3 ，Mahesh Kamate 4 ，Andre E Minoche 1 ，Velimir Gayevskiy 1 ，Marcel E Dinger 1 ，
Tony Roscioli 1,5 ，Carolyn M Sue 2 ，Mark J Cowley 1
1:Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Australia、2:Kolling Institute of Medical Research, Royal
North Shore Hospital, University of Sydney, Australia、3:KLE Society Hospital, Belgaum, Karnataka, India、4:Department of Pediatrics,
JN Medical College, Belgaum, Karnataka, India、5:Department of Medical Genetics, Sydney Childrens Hospital, Randwick, Australia
Aim: The hereditary spastic paraplegias (HSPs) are a group of inherited disorders characterised by progressive lower limb
weakness and spasticity. There is a high degree of genetic heterogeneity with over 50 causative genes identified. The optimal

genetic testing strategy for HSP has yet to be resolved. We sought to identify a genetic diagnosis in HSP families from India
using WGS.
Methods: WGS was performed in 7 consanguineous and 2 non-consanguineous families with pure and complex forms of HSP
from Belgaum, India. We identified small variants using GATK HaplotypeCaller, copy number variants using CNVnator, and
structural variants using LUMPY. Using Seave, our variant filtration platform, variants were initially filtered using a panel
of known HSP genes, prevalence in healthy populations, functional impact, and the likely mode of inheritance.
Results: We identified likely pathogenic variants in 4 consanguineous families. This included a frameshift homozygous deletion
in CYP2U1 (c.782_785delTCTG) in one family and a homozygous donor splice site variant in DDHD2 (c.1125+1G>T) in
another family. In one pedigree we identified a novel in-frame homozygous deletion in PEX16 (c.995_997delTCT), a gene
known to cause a peroxisomal disorder (Zellweger spectrum disorder). Another family was compound heterozygyous for a
novel splice site variant (c.553-2A>G) and a known pathogenic mutation (p.R442Q) in GLB1 , the gene associated with
GM1 gangliosidosis. All variants were validated using Sanger, and ancillary investigations will be performed to confirm these
diagnoses.
Conclusion: We identified a probable genetic cause in 4 out of 9 families, including genes implicated in metabolic disorders
such as Zellweger spectrum disorder and GM1 gangliosidosis. Interestingly, no known HSP genes were affected by structural
or copy number variants. This study suggests that WGS is a useful tool for diagnosing HSP.
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Wed(4)-SFS19-5
Defective RNA metabolism is involved in Hereditary Spastic Paraplegia
Rebecca Schule 1,2 ，Jennifer Reichbauer 1 ，Beibei Chen 3 ，Angelos Skodras 1 ，Stephan Kotschote 4 ，Adriana Rebelo 2 ，
Alleene Strickland 2 ，Stephan Zuchner 2 ，Yang Xie 3 ，Michael Bonin 4 ，Ludger Schols 1 ，Andres Caballero Oteyza 1
1:Hertie Institute for Clinical Brain Research, University of Tubingen, Germany、2:Hussman Institute for Human Genomics, University of
Miami Miller School of Medicine, Miami, Florida、3:Department of Clinical Sciences UT Southwestern Medical Center, Dallas, TX、4:IMGM
Laboratories, Munich, Germany
Hereditary spastic paraplegias (HSPs) comprise a rare group of mendelian diseases. All 70 subtypes described they share
a common pathological phenotype: a distal upper motor neuron axonopathy. We have recently identified mutations in the

kinesin gene KIF1C to cause of autosomal recessive HSP. The physiological function of this microtubular motor remains
elusive.
Using affinity purification and mass spectrometry we discovered that KIF1C binds to several RNA-binding proteins. RNA
immunoprecipitation of KIF1C further revealed that KIF1C directly binds RNA. To identify bound RNA transcripts we
performed individual-nucleotide resolution UV crosslinking and immunoprecipitation (iCLIP), an RNASeq based technique
allowing the study of protein-RNA interactions with high positional resolution and specificity. Transcripts mapping to 441
individual genes were found to bind to KIF1C. Among these genes, several functional pathways were strongly over-represented,
including RNA/DNA binding, RNA splicing and RNA processing. The top hits however were RNA genes themselves, encoding
for noncoding-, micro-, or ribosomal RNA. We therefore suspected that ribosomes or ribosomal components might be a cargo
of KIF1C. To further validated this hypothesis we studied the localization of ribosomes in cells overexpressing either wildtype
or mutant KIF1C. While wildtype KIF1C strongly co-localizes with ribosomes at the tip of cellular processes of COS-7 cells,
overexpression of mutant KIF1C leads to a dramatic redistribution of ribosomes.
Taken together, our results provide strong evidence that KIF1C is involved in transport of ribosomes or ribosomal components.
Moreover, we for the first time implicated defective RNA metabolism in the pathogenesis of HSP and therefore reveal
parallels with the molecular pathology observed in amyotrophic lateral sclerosis and frontotemporal dementia, emphasizing
the importance of RNA metabolism for synaptic integrity in these diseases.
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Wed(4)-SFS19-6
The molecular genetic mechanism of Fahr’s disease and its prevention and treatment
Jing Yu Liu 1 ，Xuan Xu 1 ，Cheng Wang 1 ，Junyu Luo 2 ，Xixiang Ma 1 ，Hao Sun 1 ，Xue Zhang 3
1:Key Laboratory of Molecular Biophysics of the Ministry of Education, School of Life Science and Technology, Huazhong University of
Science and Technology, China、2:School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology、3:McKusick-Zhang Center
for Genetic Medicine and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of
Medical Sciences & Peking Union Medical College
Fahr’s disease is commonly called idiopathic basal ganglia calcification (IBGC, OMIM 213600). IBGC is an inheritable
neurodegenerative condition characterized by mineral deposits in the basal ganglia and other brain regions, movement disor-

ders, cognitive impairment and psychiatric signs. Calcification of the basal ganglia is observed in 1-20% of CT scans. Age at
onset of clinical symptoms is variable, from 2 to 60 years by degree of brain calcification. The IBGC was first reported by
Bamberger in 1850s. The pathogenesis of IBGCs was unknown before 2012. So far, no therapeutic drug has been developed
for the treatment of IBGC. Mutations in SLC20A2 gene were reported to account for 40% Fahr’s disease group, suggesting
it’s a major causative gene of Fahr’s disease. Mutants in SLC20A2 have been significantly impaired phosphate trans-
port activity in Xenopus laevis oocytes. By electrophysiology analysis, these mutants did not show significant Pi -induced
electrogenic activity. We established Slc20a2 knock in mice with the p.S602W mutation. Mice homozygous with p.S602W
developed brain calcification similar to human IBGC disease since 3 months old, and the number and volume of calcified
nodules increased with age. The Chinese herbal medicine formula SYM decoction and etidronate disodium (ED) were diluted
and added into the drinking water of 3-week-old homozygous Slc20a2 KI mice for 3, 4, 5, 6, 7 months, respectively. The
results showed the brain calcifications were not happened in Slc20a2 KI mice with drinking SYM before 5 mouths. Compared
with control groups, Slc20a2 KI mice by SYM treatment showed reduced brain calcification at 6 and 7 mouths of age. The
ED group showed the brain calcification similar to the control group. The SYM decoction produced preventive effect on the
formation of calcified nodules in IBGC model mice, which might be useful for the treatment of Fahr’s disease caused by
SLC20A2 mutations.
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ICHG2016 447

HVP (Sharing Human Variant Data Globally - Challenges and Opportunities for 2020)
Thu., April 07, 2016 12:45-14:45 Room B-1 (2F)
Moderator：Helen Robinson（Liason-World Health Organization / The Human Variome Project International Coordinating
Office / University of Melbourne, Australia）
This session will focus on recent developments and future challenges faced in the sharing of human genetic and genomic
information on variants to support clinical practice across the world. It will discuss issues in relation to current trends

in collecting, curating and interpreting global knowledge on variants. HVP has been instrumental in establishing several
key projects that are making significant progress in these areas and these projects will be used to report on progress in
the past two years. The session will also pay tribute to the work and vision of the late Professor Richard Cotton who
was the Funding Patron of HVP until his death in June 2015. Project-wide initiatives of HVP in haemoglobinopathies
and some cancers combine with those on gastrointestinal heredity tumours and cystic fibrosis, and form the basis of this
work on establishing international consortia to link and harmonise work being done in all parts of the world. The value
of accurate assignment of pathogenicity of variants in clinical practice is a challenge currently being addressed. The need
to form multi-disciplinary teams across all region of the world to build expertise in consistent interpretation based on
the best evidence will be described in this session. How to organize this engagement through a series of initiatives and
mechanisms will be described together with lessons learned and implications for the future. Examples include:
Breast cancer is a high profile disease. Understanding the impact of variants carried by patients is of great clinical
importance as it directs risk-reducing management strategies that improve survival such as screening and prophylactic
surgery and the choice of therapy after diagnosis. Unclassified variants area significant clinical problem that can be
addressed through the systematic collection and curation of key data that influencing clinical decision making;
An emphasis on Haemoglobinopathies aims to raise the profile of genomic medicine in low and middle income countries
and develop the capacity required for diagnosing, treating carriers in low and middle income countries by applying key
developments in human genomics to heamoglobinopathies. Tackling haemoglobinopathies is an ideal entry point for these
countries to develop the necessary infrastructure and expertise that can expand into other areas of health-service delivery.
Growth in the quality and quantity of curated inputs into internationally recognized genetic databases from low- and
middle-income countries requires the harmonization between countries in accordance with international best practice.
Ensuring that the storage, curation and sharing of the relevant DNA variation information is sustainable in the medium
and longer term is vital. Only by expanding and strengthening the international network of professionals, including
curators, researchers, clinicians, bioinformaticians, counsellors, patient groups and health bureaucrats can cost-effective
health care objectives be achieved.
Thu(5)-SFS20-1
TBD
1
Finlay Macrae
1:Department of Medicine, University of Melbourne, Australia
TBA
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Thu(5)-SFS20-1
What can be achieved on the African Continent by 2020?
1
Raj Ramesar
1:Division of Human Genetics, University of Cape Town, South Africa
TBA
[Biography]

Raj Ramesar is Professor and Head of the Division of Human Genetics at the University of Cape Town and its Affiliated
Hospitals in South Africa. This facility has wide-ranging clinical responsibilities from the quaternary and tertiary care levels,
to extensive rural outreach programmes, in addition to diagnostic and research capabilities. His interest is in using the
exciting developments in the field of genomic sciences to investigate human biodiversity. Africa offers the opportunity to use
population lineages in all of their richness towards identifying aspects of human biology, that have to do with both health
and disease.
As the Director of the MRC Human Genetics Research Unit, the emphasis of his research has been on disease susceptibility in
South African populations, progressing from the commonly recognised inherited diseases, to those that are more complex yet
more common and relevant to a large burden of disease. In this regard, he has been involved in researching Retinal Degenerative
diseases for the past 25 years - and has been working very closely with the lay support group: Retina South Africa, in terms
of developing and maintaining an active and translational research agenda. Furthermore, his most recent research enterprise
is embodied in a large scale project entitled:‘Human Diversity and Health’. As Director of the national Colorectal Cancer
Research Consortium his focus has been on the genetics of familial colorectal cancers, and the most effective translation of
laboratory findings to the field for optimum benefit of patients and their kin. In this regard, Raj recently received the (Vice
Chancellor’s) Alan Pifer Award for ‘outstanding research in cancer genetics which shows relevance to the advancement of
South Africa’s disadvantaged populations’. His most recent research involves whole exomic and whole genome sequencing for
disorders seen in South Africa, as well as investigating responses to drugs in Southern African populations. Apart from being
on the editorial board of several international journals, Raj serves as co-chair of the Scientific and Medical Advisory Board
of Retina South Africa, he is on the Executive of the African Society for Human Genetics, and is the latter organisation’s
Liaison Officer to the International Federation of Human Genetics Societies. As Chair of the Local Organising Committee, he
organised the Joint Conference of the African and Southern African Societies in Cape Town (www.humangenetics2011.org).
Raj also led a successful bid to host the International Congress of Human Genetics in Cape Town in 2021. He serves on
several international advisory panels pertaining to genomic research, including that for: Human Heredity and Health: Africa
(or H3Africa).
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ICHG2016 449
Thu(5)-SFS20-2
Human Variome Project and the Latin American region
1
Aida B. Falcón de Vargas
1:Clinical Genetics Unit, Hospital Vargas de Caracas, Escuela de Medicina JM Vargas, Universidad Central de Venezuela. Hospital de
Clinicas Caracas, Venezuela
The aim of the Human Variome Project is to ensure that all information on genetic variation can be collected, curated,
interpreted and shared freely and openly, and effectively integrated into routine clinical practice and in research work.
Professor Richard Cotton supported the attendance and active participation of scientists from developing countries to all

the HVP activities. As data collection and sharing is almost always subject to laws, regulations and best practice guidelines
operating at national levels, the Human Variome Project Global Collection Architecture proposes that much of the routine
data collection will be done through HVP Country Nodes, within the country and around the country. Until now, 80 Countries
have members of the Consortium and in the Latin American region, HVP countries members are Argentina, Brazil, Canada,
Chile, Colombia, Costa Rica, Ecuador, Guatemala, Mexico, and Venezuela. Country nodes have been established in 23
countries, and two of them, México and Venezuela are in the region. Some of our countries are working now in the two HVP
key projects, BRCA Challenge and Global Globin 2020. HVP has been instrumental in establishing key projects that are
aiming to make significant progress, and two major projects are BRCA Challenge and Global Globin 2020. BRCA 1 and
2 mutations underlie breast cancer disease in about 30% of multiple-case breast cancer families and in about 10% of early
on-set cases in groups of patients from some countries of our region and from many countries of the developed world. The
same situation is in other types of inherited cancers, and in complex disorders as diabetes miellitus type 2, coronary artery
disease, and in some contitions as haemoglobinopathies (beta thalassemia and sickle cell anemia). Gastrointestinal hereditary
tumours and cystic fibrosis are also part of the projects of the HVP in the Latin American region.
[Biography]
Professor Dr Zilfalil Bin Alwi started his medical career as a medical officer after completing his Bachelor of Medicine and
Bachelor of Surgery (MBBS) degree at University of Dacca. He joined Universiti Sains Malaysia (USM) School of Medical
Sciences as a Trainee Lecturer in 1994, and was later awarded the Master of Medicine (MMed) in Pediatrics from USM.
He then obtained his second Master degree (MSc) in Medical Genetics from University of Glasgow, United Kingdom and
then continued his studies at University of Aston, United Kingdom, where he was awarded Doctor of Philosophy (PhD) in
Pharmacogenetics.
His research interest includes genetics of childhood Spinal Muscular Atrophy (SMN genes & NAIP gene), population genomics
(genetic diversity of the Malay race) and genome wide studies on diseases common to the local population. He has published
more than 100 papers in international and local journals and presented more than 200 papers at local and international
conferences.
He is a member of the Pan-Asia SNP research consortium (PASNPI) which studies the genomic profile of the Asian population.
Professor Zilfalil is the founder and Head of the Malaysian Node of Human Variome Project (MyHVP).
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ICHG2016 450
Thu(5)-SFS20-3
Human Variome Project: The Global Globin 2020 Challenge (Southeast Asia)
1
Zilfalil Alwi
1:Universiti Sains Malaysia, Malaysia
Southeast Asia(SEA), consists of ten countries, Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, the Philippines,
Singapore, Thailand, and Vietnam, with a combined ethnically diversed population of about 400 million. Haemoglobinopathies
are divided into three broad groups: Thalassaemia, Hb variant and hereditary persistence of foetal Hb (HPFH). In SEA,

Thalassemia are the most common type of hemoglobinopathy. Alpha-thalassaemia, β-thalassaemia, haemoglobin (Hb) E and
Hb Constant Spring (CS) hemoglobinopathies are most prevalent. The gene frequencies of α-thalassaemia reached 30-40%
in northern Thailand and Laos, 4.5 % in Malaysia and 5% in the Philippines whereas β-thalassaemias vary between 1 and
9 %. Hb E hemoglobinopathy is the hallmark of SEA attaining a frequency of 50-60% in Thailand, Laos, and Cambodia.
Haemoglobin Constant Spring, the most common non-deletional α +-thalassaemia in SEA and β-thalassaemia mutations are
relatively population specific, each ethnic group has its own set of common mutants. Haemoglobinopathies causes significant
morbidity and mortality, especially in the region with weak health system, hence prevention and control of Thalassaemias
requires a well planned programme and education to raise the awareness of genetic risk in the population at large. The facilities
for laboratory diagnosis, including DNA analysis, HPLC and screening test for Thalassaemia are still lacking in some countries
like Loas and Combodia. In the absence of iron chelation, death from iron-induced heart failure occurs by mid-teenage years.
While oral iron chelators are available in some countries, it is very expensive. Developments in human genomics involving
the systematic collection and sharing of variation data to fighting haemoglobinopathies especially Thalassaemias are relavent
and applicable to SEA.
[Biography]
Professor Ingrid Winship is the Chair of Adult Clinical Genetics at the University of Melbourne and the Executive Director
of Research for Melbourne Health.
Professor Winship has a wide range of clinical and research interests in inherited disorders, particularly those with adult
onset, including familial cancer, and where foreknowledge of genotype may influence clinical or lifestyle measures to create
positive patient outcomes. She has experience in gene discovery and in the translation of discovery into clinical practice.
She has also highlighted the societal implications with research into the ethical, legal, cultural and psychosocial domains of
genetic technology
Professor Winship is currently a member of the Victorian Cancer Agency, the Board of the Walter & Eliza Hall Institute, the
Peter Doherty Institute Council, the Steering Committee of the Melbourne Genomic Health Alliance and the Kinghorn Centre
for Clinical Genomics Strategic Advisory Board. She is also a member of the NHMRC Australian Health Ethics Committee.
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Thu(5)-SFS20-4
The value of accurate assignment of pathogenicity of variants in clinical genetic practice
1,2
Ingrid M. Winship
1:University of Melbourne, Australia、2:Melbourne Health
The clinical validity and utility of many high penetrance gene mutations in adult onset genetic disorders is now beyond doubt.
It is of value to families to identify mutations in disease causing/ predisposing genes, in particular later onset disorders such
as the predisposition to breast, ovarian or colon cancer or to cardiomyopathy or sudden cardiac death. Diagnosis, prognosis

and management may be guided by the presence of a mutation. In a more preventive role, it is of benefit for at-risk, but
unaffected family members to know if a pathogenic mutation exists in the affected proband, to enable predictive testing. This
is the most accurate way of personalising risk assessment and consequently, to facilitate accurate evidence based strategies
for risk management. In transition from genetics to genomics, massively parallel sequencing allows many more genes to be
tested, including those which are of moderate penetrance. However, as more mutations are discovered, so are more variants
of uncertain significance (VUS). The use of pathogenic mutations is acknowledged; a VUS cannot be used to make clinical
decisions, particularly where interventions are irreversible. Variant calling is thus paramount to a clinical service. A key goal
of the Human Variome Project is determination of genetic variation across all disease related genes and populations. We
need accurate standards and effective means of assigning pathogenicity for genomics to reach its full potential in healthcare
delivery. Furthermore, there is the potential for serious clinical errors. The knowledge of existing mutations and the frequency
with which mutations have been associated with a phenotype is the cornerstone of this understanding. In the Australian
context, the population is increasingly heterogeneous, with the expectation that gene frequencies may differ as compared to
the developed Western Countries. This knowledge will serve to enhance healthcare services.
[Biography]
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Career Development Sessions: How to Write a Good Manuscript
Mon., April 04, 2016 14:00-15:30 Room D (1F)
Moderator：Eiji Nanba（Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori Uni-
versity, Japan）
Moderator ：Naomichi Matsumoto（Department of Human Genetics, Yokohama City University Graduate School of
Medicine, Japan）
It is evident that there is no simple answer to the long-asked question of fellows and junior faculty members: How can
we write good manuscripts?
Two distinguished physician-scientists, who have served as editors of medical genetics journals for many years, will give
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tips on how physicians can improve their writing skills. The session is intended to be interactive.
Mon(2)-ED1-1
How to Write a Scientific Paper
1
Maximilian Muenke
1:Chief, Medical Genetics Branch, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), and Director,
NIH Medical Genetics and Genomic Medicine Residency and Fellowship Programs, Bethesda, MD, USA
“If asked to name varieties of mental torture, most scientists would place writing at the top of the list.” Nobel Laureate
Arthur Kornberg
The purpose of this presentation is to make scientific writing a meaningful experience, to provide guidelines and suggestions
on the mechanics of writing and submitting a scientific paper. This presentation is based upon my professional experiences as
a physician scientist, as an editor of a peer-reviewed journal, and my encounters with“giants in the field”, like John M. Opitz,
John Carey, and Gary Schoenwolf. The presentation will also reflect noted books and other resources on writing biomedical
research papers.
Specifically, I will address and the learner will be able to list the elements of a scientific paper (IMRD: Introduction, Methods,
Results, Discussion), understand the role of each element, compose an outline for getting started, and to identify the best
resources for writing a paper. Writing a paper in the following order may make this process easier: Methods and Results
section first, followed by Introduction and Discussion, and Abstract last. The composition of each element benefits from the 6
C’s (Sullivan & Eggleston, 2006: “Editors, Writers, and Proofreaders ”): correct, consistent, compelling, clear, concise, and
context-based. Lastly, instruction manuals for correct grammar (Clark, 2011: “The Glamour of Grammar ”), style (Strunk
& White, 2000: “The Elements of Style ”; Zinsser, 2006: “On Writing Well ”), spelling and punctuation (Truss, 2006: “Eats,
Shoots & Leaves ”) will make writing scientific papers in English easier for the non-native speaker.
Getting started will become easier by being familiar with the elements and composition of a scientific paper. However, a
reference to two proverbs may ease the initiation of the task at hand: “A journey of a thousand miles begins with a single
step” (Lao Tzu, 6th century BCE), and “There is nothing to it, but to do it.” (present-day American proverb)
[Biography]
Dr. Max Muenke graduated from the Free University School of Medicine in Berlin in his native Germany. He then pursued
pediatric residency training at the Christian-Albrecht University in Kiel, Germany, followed by a research fellowship in the
Human Genetics Department at Yale University. He completed training in Clinical Genetics at the Children’s Hospital in
Philadelphia (CHOP) and the University of Pennsylvania (Penn). From 1990-2000 he was on the Penn faculty. Since 2000
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he serves as the Chief of the Medical Genetics Branch at the National Human Genome Research Institute (NHGRI) of the
National Institutes of Health (NIH). The focus of his research has been on the delineation and identification of the underlying
causes of craniofacial anomalies in humans. His lab made seminal discoveries in linking Sonic Hedgehog signaling to normal
and abnormal brain development in humans. His group identified several genes important in craniofacial disorders including
the most common craniosynostosis syndrome, now termed Muenke syndrome. More recently, he has focused on more common,
genetically complex disorders including Attention Deficit Hyperactivity Disorder, non-alcoholic fatty liver disease, rheumatic
heart disease, and congenital cardiac disease. Dr. Muenke is the Founding Editor-in-Chief of Molecular Genetics and Genomic
Medicine. He has been directing Medical Genetics Residency and Fellowship training for over two decades. Dr. Muenke is
passionate about training the next generation of leaders in the field of genetics and genomics and he finds the work with
patients and their families as one of the most rewarding aspects of his professional career.
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Mon(2)-ED1-2
How to write a scientific paper and a good piece of literary prose
1
Giovanni Neri
1:Institute of Medical Genetics, Università Cattolica del S. Cuore, Rome, Italy
The main concern when writing a science article is to be accurate and clear. Conciseness and consistency with writing rule
are also needed, but not always observed. I submit that a good science article should also be a good piece of literary prose,
capturing the attention of the reader and stimulating his/her curiosity. It is important for the reader to perceive a sense of
narrative, a story that develops from a beginning, where a question is posed, to an end, where the answer is given. Arguably,
one of the best pieces of medical literature ever written, where accurate science and compelling narrative mix in a perfect
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blend, is the description of hereditary chorea by George Huntington, published in 1872. Other notable examples will be
quoted, such as the description of the double helix by Watson and Crick. Elaborating on these texts, some guidelines will be
suggested on how to confection a product of similarly high quality.
[Biography]
Brief Chronology of Employment
1968 Assistant Professor, University of Perugia
1974 Assistant Professor, Institute of Human Genetics, Catholic University, Rome
1982 Associate Professor of Medical Genetics, Catholic University, Rome
1986 Full Professor of Medical Genetics, University of Chieti
1989-2013 Full Professor of Medical Genetics; Chairman of the Institute of Medical Genetics; Director of the Medical Genetics
Services, Policlinico """"""""A. Gemelli""""""""; Catholic University, Rome
2013-date Emeritus professor of Medical Genetics, Catholic University, Rome
2015-date Senior Scholar, Greenwood Genetic Center, Greenwood, S.C.
Scientific Activity:
Advisory Editor of“American Hournal of Medical Genetics”
Formerly, Section editor (Molecular and Cytogenetics) of“BMC Medical Genetics”
Editorial Board member of“BMC Medical Genomics” and of “Public Health Genomics”
Associate Editor of“BMC Research Notes”
Formerly, Section editor of“The Italian Journal of Cardiology”
Referee for the following journals: American Journal of Medical Genetics; American Journal of Human Genetics; European
Journal of Human Genetics; European Journal of Medical Genetics; Journal of Medical Genetics; Clinical Genetics; Human
Genetics; Nature Genetics; Science; Journal of the American Society of Nephrology; Italian Journal of Pediatrics; Inter-
national Journal of Developmental Biology; Neurology; Clinical Chemistry; European Journal of Pediatrics; Neuroscience
Letters; Human Molecular Genetics; Neurobiology of Disease; Molecular Psychiatry; BMJ Case Reports; Journal of Clinical
Investigation; Journal of Investigative Dermatology; Pediatrics; PLoS Genetics; Nature Reviews Endocrinology; Human Mu-
tation; Annals of Human Genetics, Neuroscience & Biobehavioral Reviews, Journal of Neurodevelopmental Disorders.
Referee for several international granting Agencies.
Author of more than 400 scientific papers, mostly published in international journals, indexed in Current Contents. Co-author
and/or contributor to several genetics books, including the textbook“Genetica Umana e Medica”, widely adopted by Italian
Medical Schools.
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Career Development Sessions: How to Develop an Academic Career
Mon., April 04, 2016 15:50-16:50 Room D (1F)
Moderator：Kenjiro Kosaki（Center for Medical Genetics, Keio University School of Medicine, Japan）
Moderator ：Shinji Saitoh（Department of Pediatrics and Neonatology, Nagoya City University, Japan）
Every senior scholar would agree with the classical Latin phrase, “Ars longa, vita brevis ” translated into English as
“Art is long, life is short”. Having said that, development of the careers of a young faculty is an unpredictable process,
especially in a rapidly emerging field like the field of medical genetics. There would appear to be no formula other than the
notorious “publish or perish” principle, which could make the process less unpredictable. Dr. Judith Hall, a prominent
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scientist and an enthusiastic educator, will give us helpful hints based on her own long scholarly career.
Mon(2)-ED2-1
Career Development Sessions: How to Develop Academic Career
1
Judith G. Hall
1:Professor Emerita of Pediatrics and Medical Genetics, University of British Columbia, Canada
Life can be thought of as having three major divisions: preparation, working life, and retirement. That is, of course, too
simplistic. However, rather than just talking about training, this presentation will try to cover the whole trajectory of an
academic career.
Within an academic career, there are four major roles: teaching, research, service, and administration, as well as seven
year cycles, including establishing self, focussing, taking on trainees, collaboration and networking, taking on administrative
leadership, reaching out internationally, and succession planning.
The talk will also cover personal lessons learned along the way.
[Biography]
Dr. Judith G. Hall is a Clinical Geneticist and Pediatrician. She trained at Wellesley College, the University of Washington
School of Medicine and Johns Hopkins Hospital. She is presently Professor Emerita of Pediatrics and Medical Genetics
at the University of British Columbia based at Children’s & Women’s Health Centre of British Columbia in Vancouver,
B.C., Canada. Her areas of research interest are human congenital anomalies, natural history of genetic disorders, and
non-traditional mechanisms of genetic disease.
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Case Studies in Clinical Genetics: Dysmorphology
Tue., April 05, 2016 8:00-10:00 Room D (1F)
Moderator：Nobuhiko Okamoto（Department of Medical Genetics, Osaka Medical Center and Research Institute for
Maternal and Child Health, Osaka, Japan）
Moderator ：Ritsuko K. Pooh（CRIFM Clinical Research Institute of Fetal Medicine PMC, Osaka, Japan）
It has been estimated that about 3% of neonates are born with congenital malformations that are responsible for 20-
30% of neonatal and 35% of infantile deaths. Dysmorphic syndromes are defined as the constellation of anomalies that
are observed in combination more frequently than they are estimated to occur together by chance. Every syndrome
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has its characteristic problems in growth, development, and behavior. Correct diagnosis and appropriate medical care is
important in these patients. Dysmorphology is the study of syndromes that constitute recognizable patterns of anomalies.
We will present educational cases. All attendants are encouraged to consider appropriate diagnosis together.
The prevalence of cerebral palsy has not decreased despite major improvements in clinical care in antenatal/neonatal
period as well as intrapartum period. The antepartum risk factors should include fetal brain maldevelopment and
intrauterine brain injuries, which are unclassifiable into congenital brain anomalies and may exist unconspicuously during
pregnancy and even after birth. Especially, neuronal migration disorder in utero should be responsible for postnatal
neurological impairment. Imaging technologies including 3D ultrasound have been remarkably improved and contributed
to prenatal evaluation of fetal central nervous system (CNS) development and assessment of CNS abnormalities in utero.
Migration takes place in the first and early-second trimesters and phenotype of migration in the cortex appears after 28
weeks. It has been believed that migration disorder such as lissencephaly cannot be detected before 28 weeks. However,
recent neuroimaging has enabled us to suspect migration disorder from early-second trimester. Fetal neurology has great
responsibility and an important role in perinatal medicine and a new field of fetal neuro-sono-genetics will be established.
Tue(3)-ED3-1
1
Presenter/Discussant：Nobuhiko Okamoto
1:Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan
No Abstract
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Tue(3)-ED3-2
1
Presenter/Discussant：Ritsuko K. Pooh
1:CRIFM Clinical Research Institute of Fetal Medicine PMC, Osaka, Japan
No Abstract
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Tue(3)-ED3-3
1
Presenter/Discussant：Louanne Hudgins
1:Stanford University and Lucile Packard Children’s Hospital, USA
No Abstract
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Case Studies in Clinical Genetics: Lysosomal Storage Disease
Tue., April 05, 2016 10:20-12:20 Room D (1F)
Moderator/Discussant for 1 and 2：Norio Sakai（Osaka University Graduate School of Medicine, Division of Health
Sciences, Japan）
Moderator/Discussant for 3 and 4 ：Han-Wook Yoo（Medical Genetics Center, Asan Medical Center, University of Ulsan
College of Medicine, Seoul, Korea）
Recent development of treatment for lysosomal storage disease (LSD) makes challenge for physical doctors who meet these
rare diseases. Establishment of enzyme replacement therapy and hematopoietic stem cell transplantation, development
of substrate reduction therapy and chaperone therapy are leading the change of prognosis of many LSDs. Physical doctor
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are expected to diagnose the patients precisely and promptly in order to start the effective treatment and supply the
important genetic counseling for the family.
In this session, we pick up four categories of disease within the LSDs. It includes mucopolysaccharidosis, Gaucher
disease, leukodystrophy (metachromatic leukodystrophy, Krabbe disease and adrenoleukodystrophy) and Fbry disease.
Case presenter shows the case history with clinical hints for diagnosis and the discussant picks up the points and asks
several questions to the audience. All attendants are expected to join the voting system to answer these questions. After
the voting, presenter answers the questions and talks next clinical scenario including treatment, genetic counseling or
prenatal diagnosis etc.
Audience should be involved in considering the best attitude of physical doctors in these setting. Organizers expect all
attendants participate positively to this program and hope effective discussion between the presenters and discussants.
Tue(3)-ED4-1
MPS
1
Motomichi Kosuga
1:Department of Clinical Laboratory Medicine, National Center for Child Health and Development, Japan
No Abstract
[Biography]
Dr.Motomichi Kosuga is a clinical geneticist and pediatrician. He is presently the chief of Division of Medical Genetics
at National Center for Child Health and Development in Tokyo, Japan. His main research interest is the inborn errors of
metabolism, particularly the lysosomal storage disorders.
Dr.Kosuga graduated from Niigata University, School of Medicine and received his MD degree in 1993. He did his pediatric
resident training and post-doctoral trainings at Keio University Hospital in Tokyo and obtained the PhD degrees at Keio
University, Graduate School of Medicine in 2001. He also did research fellowship at Department of Pediatrics, University of
California at Los Angeles (UCLA), USA from 2004 to 2008.
Dr. Kosuga is actively participating on the development of new treatments for LSDs, as investigator in several clinical trials
and also in basic research projects involving enzyme replacement therapy. He is a councilor member of Japanese Society
for Inherited Metabolic Diseases, Japanese Society of Lysosomal Storage Disorders, Japanese Society of Pompe Disease, and
Japanese Society of Mucopolysaccharidoses.
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Tue(3)-ED4-2
Gaucher
1
Han-Wook Yoo
1:Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
No Abstract
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Tue(3)-ED4-3
Luekodystrophy
1
Norio Sakai
1:Osaka University Graduate School of Medicine, division of Health Sciences, Japan
No Abstract
[Biography]
Dr. Sakai graduated from Dept. of Astronomy, Tokyo University, Tokyo, JAPAN in 1982 and the Osaka University Graduate
School of Medicine in 1987. He has completed his clinical training as a residency in 1990. He received PhD at the Osaka
University Graduate School of Medicine in 1994 with the paper for molecular cloning for Krabbe disease.
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He stayed as a Research Fellow at Dept. of Environmental Medicine, Res. Inst. Osaka Medical Center for Maternal and
Child Health, Osaka Japan for two years and moved to GSF-Institute for Mammalian Genetics, Germany.
He came back to Japan in 1998 to Dept. of Pediatrics, Osaka University School of Medicine and got the position of Assistant
Professor in 2005 and worked as Associate Professor from 2009. He leaded the clinical and research group for inborn error of
metabolic disease and medical genetics at Dept. of Pediatrics.
He has published more than 60 articles in peer-reviewed international journals. He has received several awards for his research
concerning molecular analysis for inborn errors metabolic diseases.
His clinical work focused on clinical treatment of lysosomal diseases with advanced method including enzyme replacement
therapy and hematopoietic cell transplantation. His recent research focused on disclosing the basic molecular pathology of
lysosomal diseases and developing the new treatment including chaperone therapy.
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Tue(3)-ED4-4
Fabry
1
Kimitoshi Nakamura
1:Department of Pediatrics, Kumamoto University, Japan
No Abstract
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Case Studies in Clinical Genetics: Cancer - Part 1: Genomic Medicine of Cancer on the Basis of the
Somatic Mutations / Part 2: Genetic Counseling of Breast Cancer
Tue., April 05, 2016 13:50-15:20 Room D (1F)
Moderator：Takashi Kohno（National Cancer Center Research Institute, Japan）

Moderator ：Yoshinori Murakami（Institute of Medical Science, The University of Tokyo, Japan）
Discussant for Part 1 ：Kuniko Sunami（National Cancer Research Center Hospital, Japan）
Discussant for Part 2 ：Seigo Nakamura（Department of Breast Surgical Oncology, Showa University School of Medicine,
Japan）
Discussant for Part 2 ：Chieko Tamura（Certified Genetic Counselor, Japan / USA; Medical Information & Genetic
Counseling Division, FMC Tokyo Clinic, Japan）
Discussant for Part 2 ：Masami Arai（Cancer Institute Hospital, Division of Clinical Genetic Oncology）
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This session will focus on two important themes in the clinical practice of cancer, decision making based on identification
of somatic mutations (part 1) and genetic counseling for familial cancer (part 2). The clinical information will be first
presented, followed by decisions/discussion based on clinical sequencing of tumor and cell-free DNAs by the discussant
and the audience. Latest information on somatic mutations in lung and other cancers and selection of therapeutic
ways, including the entry into clinical trials, will be presented. In the genetic counseling for breast cancer, the clinical
information of cases and their family history suggesting possible hereditary breast and ovarian cancer (HBOC) will be
first presented. Various issues on genetic counseling, including the genetic test and its possible application to prophylaxis
and treatment of cancer will be discussed.
Tue(3)-ED5-1
Part 1: Genomic Medicine of Cancer on the Basis of the Somatic Mutations
1
Takashi Kohno
1:National Cancer Center Research Institute, Japan
No Abstract
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Tue(3)-ED5-2
Part 1: Genomic Medicine of Cancer on the Basis of the Somatic Mutations
1
Sadakatsu Ikeda
1:Center for Personalized Cancer Therapy, University of California San Diego, Moores Cancer Center, USA
No Abstract
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Tue(3)-ED5-3
Part 2: Genetic Counseling of Breast Cancer
1
Yoshinori Murakami
1:Institute of Medical Science, The University of Tokyo, Japan
No Abstract
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Case Studies in Clinical Genetics: Neurology
Tue., April 05, 2016 15:40-17:10 Room D (1F)
Moderator：Thomas Gasser（German Center for Neurodegenerative Diseases (DZNE), Germany）

Moderator ：Hiroyuki Ishiura（The University of Tokyo, Japan）
Discussant ：Bing-wen Soong（Department of Neurology, National Yand-Ming University, Taipei, Taiwan）
Discussant ：Hiroshi Takashima（Neurology and Geriatrics, Kagoshima University, Japan）
Genetic analysis has often an important role in clinical neurology. We have to appropriately use sequence analysis
technologies for making a molecular diagnosis, appropriate management of patient care including molecular therapies,
and providing genetic counseling. In this program, three cases will be presented. After case presentations, presenters
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provide several choices on further clinical testing required, genetic diagnosis at the first glance, recommended methods
of genetic testing, and so on. Participants in the floor will make the online votes with their smartphones or laptop
computers. After experts’ discussion, presenters provide genetic diagnosis of the patients including an overview and an
update of the disease. The program is aimed mainly at neurologists or geneticists including beginners.
Please bring your own smartphones or laptop computers.
Tue(3)-ED6-1
1
Takashi Matsukawa
1:Department of Neurology, Graduate School of Medicine, The University of Tokyo, Japan
No Abstract
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Tue(3)-ED6-2
1
Masaki Tanaka
1:Department of Neurology, The University of Tokyo, Japan
No Abstract
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Tue(3)-ED6-3
1
Yoshio Sakiyama
1:Department of Neurology, Jichi Medical University, Saitama Medical Center, Japan
No Abstract
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Education of Genetics: Genetics Education for Undergraduate Medical Students in Asia
Thu., April 07, 2016 8:00-9:30 Room D (1F)
Moderator：Akihiro Sakurai（Sapporo Medical University, Japan）

Moderator ：Meow-Keong Thong（Genetics and Metabolism Unit, Department of Paediatrics, Faculty of Medicine, Uni-
versity of Malaya, Kuala Lumpur, Malaysia）
Until decades ago, clinical genetics remained one of the minor medical subspecialties which cover relatively narrow area
of clinical practice (mainly in pediatrics and obstetrics). In this century, however, accumulation of our knowledge in
genetic conditions and disorders as well as explosive technical advances of genetic analysis made genetic information
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fundamental and indispensable for wide range of clinical management. Accordingly, importance of genetics education for
medical professionals is growing more than ever. Meanwhile, public perception about issues related to genetics (such as
hereditary diseases and reproduction) are thought to be influenced by social, cultural and religious background of the
community, of which medical professionals should be aware.
In this session, we discuss genetics education for undergraduate medical students in Asia. Four speakers from Malaysia,
Philippines, India and Japan present current status and challenges in their countries. Participation of audience to
discussion is welcome.
Thu(5)-ED7-1
Problem-based learning in genetics education in a developing country
1
Meow-Keong Thong
1:Genetics and Metabolism Unit, Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Problem-based learning or PBL was introduced 40 years ago as an educational philosophy to instill the ideals of adult learning,
life-long learning and self-directed learning in the medical schools.
PBL is a student-centred learning that involves enquiry-based discussion triggered by a problem and facilitated by a tutor in
small groups. In a hybrid traditional-PBL curriculum where PBL runs parallel with conventional didactic teaching, there is
a concern that such curricular arrangement may produce undesirable learning behaviour. PBL was introduced in a gradual
manner into the first three years of a revised undergraduate integrated medical curriculum at the University of Malaya (UM)
in 1999/2000. By doing so, UM has attempted to move along the continuum from a teacher-centred lecture-based traditional
curriculum to a more student-centred PBL approach curriculum.
Self-administered questionnaires were distributed to preclinical students and clinical year students after completing their
respective final examination papers. The study compared the responses of nine cohorts of students (2001 to 2009) on
questions related to PBL. Students were asked to respond to each question based on their own experience using a 5-point
Likert scale. Across the board, progressively over the years, students from all the phases reported an improvement in their
critical thinking, integration of knowledge, appreciation of understanding rather than merely memorising facts, communication
skills, and braveness to counter-propose opinions. Written comments from the students also showed a shift from resistance
and outright call for the abolishment of PBL tutorials, to positive call to increase PBL tutorials.
Using the topic of genetics education, this paper will share the authors’ experience of integrating basic genetics sciences into
the hybrid curriculum and the roles of PBLs in clinical years, using scenarios in paediatrics that originated from patients with
genetics conditions.
[Biography]

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Thu(5)-ED7-2
Genetics education in Philippine medical schools
1
Maria Melanie Liberty B. Alcausin
1:Newborn Screening Reference Center, National Institutes of Health-University of the Philippines, Manila, Philippines
Medical education in the Philippines is a five-year program comprised of basic and clinical sciences including a one-year
clinical internship. There are more than 40 medical schools in the country with curricula using varied models: traditional
medical curriculum, problem-based learning, and organ-systems integration. In most schools, genetics education is briefly
introduced in the basic science subjects specifically biochemistry and anatomy. It is later discussed more extensively on the
background of clinical conditions and cases in pediatric modules and during clinical rotations. Given the important role of
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genetics in modern medicine, more attention to its standardized integration into the medical curriculum is needed to provide
aspiring physicians of a truly comprehensive medical education.
[Biography]
Dr. Maria Melanie Liberty Alcausin is the Director of the Philippine Newborn Screening Reference Center and a Research
Assistant Professor at the National Institutes of Health of the University of the Philippines-Manila. She is also a Clinical
Associate Professor at the Department of Pediatrics of the Philippine General Hospital (PGH). She is the program coordinator
of both the Masters in Genetic Counseling in the College of Medicine of the University of the Philippines and the Telegenetics
Referral System at the Institute of Human Genetics. She heads the Bisphosphonate Management Program for Osteogenesis
Imperfecta at the Philippine General Hospital. Dr Alcausin took her medical degree at the University of East-Ramon
Magsaysay Memorial Medical Center and did her pediatric residency and fellowship on clinical genetics at the UP-PGH. She
went on to have her fellowship on Skeletal Dysplasias and Bone and Mineral Medicine at the Children’s Hospital at Westmead
in Australia.

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Thu(5)-ED7-3
Integrating genetics in undergraduate curriculum - Indian perspective
1
Seema Kapoor
1:Department of Pediatrics, Maulana Azad Medical College, New Delhi, India
TBA
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Thu(5)-ED7-4
Genetic Education for Undergraduate Medical Students in Japan
1
Atsushi Watanabe
1:Division of Clinical Genetics, Nippon Medical School, Japan
Most of university hospitals in Japan have recently had the division of genetics services. But the role and position for
education of medical genetics is different among universities. When we deliver the concept of translation basic medicine
to clinical medicine, genetics and genomics education is important. To make educational program for medical genetics and
genomics, we need to imagine the area of medical genetics has been progressed after graduation from medical school. In
addition, before entering universities, the program for biology in high school does not contain human genetics (including
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human biology and inherited diseases) in Japan,. JAMS (the Japanese association of medical science) and JSHG (Japanese
society of Human Genetics) proposed ‘model core curriculum of medical genetics for undergraduate medical students’. This
model core curriculum includes not only molecular genetics but also clinical genetics. In my school, units for the molecular
genetics has been started from second year of medical school and units for the clinical genetics in forth year after taking
lectures of clinical medicine. Units for the clinical genetics include not only lectures from clinical geneticist but also PBL
(problem based learning), TBL (team-based learning) for discussion, role play of genetic counseling and speech from patient’s
association group. This presentation includes current issues about genetics education for undergraduate medical students and
introducing some education methods for medical genetics implimenting in Japan.
[Biography]
Atsushi WATANABE is the Head of Division, Division of Clinical Genetics and Division of Personalized Genetic Medicine at
Nippon Medical School Hospital,
He is also the vice chairman of education committee and chairman of pharmacogenetics committee in JSHG (Japanese Society
of Human Genetics) and chairman of editorial committee in Japanese Society of Genetic Counselling.
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Education of Genetics: Genetics Education for Public
Thu., April 07, 2016 9:45-11:15 Room D (1F)
Convener：Takahito Wada（Kyoto University, Japan）

Moderator ：Michael J. Dougherty（American Society of Human Genetics, USA）
In this session, we would discuss the vital issue of broadening our genetic education activities that are pressingly required
in society today, focusing on“What should we do to promote awareness of human genetics among young people, especially
pre-college students?”, and through this, we would also like to reconsider this increased role of genetic professionals.
The session consists of the five speakers from four countries, Australia, UK, USA, and Japan.
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Since 2003, when the complete human genome was sequenced, many new DNA sequencing techniques have been rapidly
identifying a lot of susceptibility genes for multifactorial common diseases, as well as for various genes of Mendelian
disease. These advances have the huge benefit to our medical care in the diagnosis and treatment of a wide range of
disorders. Actually, the President Obama proposed the new conception of“the Precision Medicine Initiative” in State of
the Union Address of 2015. On the other hand, for many ordinary people, increased knowledge or information on their
genes may present ethical dilemmas between life and treatment styles.
The WHO report in 2003, or“Review of Ethical Issues in Medical Genetics”, says that “The goals of medical genetics
can be optimally fulfilled only in the context of an educated, informed public. Education about human reproduction and
genetics should be part of the educational heritage of every person”, and “In the long run, genetics education for the
public can best be achieved through education IN SCHOOLS.”
We would expect your heated and fruitful discussion on the matter and will be able to find the right direction of our
future genetic study to be applied for.
Thu(5)-ED8-1
Educating the Public about Genetics: A Perspective from the U.S.
1
Michael J. Dougherty
1:American Society of Human Genetics, USA
The American public is interested in genetics but generally not well-informed. Museums and science centers featuring genetics
exhibits are popular, but they reach only a small fraction of the public, mostly young people. Thus, the most effective
institution for teaching genetics to large numbers of people continues to be the formal education system, which covers ages
5-18. Although topics related to reproduction begin in early grades, genetics is most commonly taught in secondary school,
and the U.S. has relied heavily on various “standards” to structure the content. Unfortunately, those standards do not
adequately address topics deemed essential by genetics experts, and a focus on high-stakes tests has eroded both the time
spent teaching science and the pedagogy used to teach it most effectively. This talk will review the state of genetics education
in U.S. secondary schools and discuss potential remedies to the current deficits.
[Biography]
Mike Dougherty is Director of Education for the American Society of Human Genetics (ASHG) and Associate Professor
Adjoint of Pediatrics at the University of Colorado School of Medicine. His work focuses on improving genetics education
for audiences ranging from high school students through post-graduate trainees and practicing health professionals, and he
leads research efforts to better understand the teaching and learning of genetics. Prior to joining ASHG, he spent nine years
on the biology faculty at Hampden-Sydney College in Virginia, where he taught genetics, molecular biology, biochemistry,
and introductory biology and conducted research on prion genetics. Dougherty has 20 years of formal genetics education
experience, which began when he joined the Biological Sciences Curriculum Study (BSCS) as a curriculum developer in 1993
and then eventually served as associate director. He has co-authored several textbooks and genetics curriculum modules.
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He earned his B.A. degree from the University of Colorado, Boulder, and a Ph.D. from the University of Massachusetts,
Amherst, in molecular biology and biochemistry. He has been Burroughs Wellcome Fellow in Alzheimer’s disease, Visiting
Senior Lecturer at the University of Kent, UK, and the McGavacks of Loudoun Chair in Biochemistry at Hampden-Sydney
College.
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Thu(5)-ED8-2
The Australian experience with genetics education for primary and high school students and current
challenges
1
Kristine Barlow-Stewart
1:Sydney Medical School Northern, University of Sydney, Australia
Genetics education for the public is necessarily a broad concept encompassing many “publics” and audiences, each requiring
their own strategies to promote engagement. School students and their teachers are two defined groups within a public that
can be specifically targeted. However two important factors influence the opportunities for genetics education with these
groups. First, the curriculum must require that genetics be taught at all stages. The presentation will review the work done
Educational Program
over the last 20 years in a number of Australian States by genetics professionals working with State Education Departments
to ensure that human genetics was in the science curriculum and the resources and activities that have been developed to
support the curriculum content. Timing of the genetics teaching is often linked to a broader activity that is occurring such as
the national fund-raising campaign called Jeans for Genes conducted by the Children’s Medical Research Institute. However
with developments in genomics it is essential that the curriculum requirements are updated and that requires sustained effort
and engagement with the process by genetics professionals. Second, data will be presented underscoring that teachers express
a lack of knowledge and confidence to teach genetics so that the students are engaged and appropriately informed. Teachers’
forums and workshops offered by a number of different Centres, Universities and Institutions up until a few years ago were
very successful in meeting that need. However, funding limitations and a focus on the education of health professionals in
genomics has meant that these forums and workshops have either ceased or are very limited, a situation which urgently
requires addressing if students are to be graduated with genomic awareness and understanding.
[Biography]
Associate Professor Kristine Barlow-Stewart, BSc (U.Syd), PhD (U.NSW), Genetic Counsellor (FHGSA) was one of the first
in Australia to be certified as a genetic counsellor in 1991. She was the Foundation Director of NSW Health’s Centre for
Genetics Education from1989-2012. In 2011 she established the Master of Genetic Counselling program for the University of
Sydney and is its current Director. Her teaching and research career has focussed on addressing the information and support
needs of the community, education and training needs of professionals and the psychosocial and ethical impact of the rapidly
developing field of genetic and genomics technologies. Kristine has contributed widely to development of policies in these
areas both State-wide and nationally.
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Thu(5)-ED8-3
The changing face of genomics learning and its drivers in the UK
Mat Hickman 1 ，Leah Holmes 2,3 ，Bella Starling 2,3
，Peter Finegold 4 ，Andrew Read 2 ，Helen Middleton-Price 2,3
，
Dian Donnai 2,3 ，Amy Sanders 1
1:Wellcome Trust, UK、2:Central Manchester NHS Trust、3:University of Manchester、4:Isinglass Consultancy Ltd
The Wellcome Trust has a long history of supporting genomics research, along with education initiatives and public engagement
with this research. In a field moving as quickly as genomics, it’s not surprising that it can be hard for young people and the
general public to keep up to date with the research and the conversation around it. We know that general understanding of
the term ‘human genome’ is low among the UK public (only 12% of adults and 11% of young people report a ‘good’ or
Educational Program
‘very good’ understanding), whereas familiarity with ‘DNA’ is much greater (48% and 60%, respectively).
In the late 2000s support from the Wellcome Trust led to ‘The Nowgen Schools Genomics Programme’ implementing change
for learners aged 14 to 18 across the UK. The Programme aimed to ‘narrow the gap between contemporary research and
classroom genetics’ and successfully advocated for more contemporary genetics in compulsory examinations. With these
changes in place, Wellcome continues to support the development of resources to help teachers address the new content in
the classroom.
More broadly, genomics brings with it ethical and societal questions (such as gene editing, and data and privacy issues) that
society needs to debate in an open and informed way with researchers, clinicians and policy makers to decide whether and
how genomics is used in healthcare. In the UK the 100,000 Genomes Project provides a useful ‘hook’ to engage the public
with genomics research. Over the coming months, we plan to initiate and support action with other key agencies in the UK
to improve public engagement, including with young people, to help address these issues.
[Biography]
Mat gained his PhD in Molecular Neuroscience from the University of Bristol in 2009, shortly before moving into public
engagement and science education. Drawing on his background in research, in 2011 he moved to 'Nowgen', a partnership
between The University of Manchester and Central Manchester NHS Trust, to work on developing genetics education across
the UK.
Having joined Wellcome in early 2014, Mat manages the Trust’s portfolio of work around informal science learning. This
includes a research programme, Science Learning+, which seeks to understand the value of informal science experiences;
working to increase the opportunities for school students to do authentic practical research projects; and oversight of work to
increase the opportunities available for young people from disadvantaged backgrounds to access, engage with and participate
in science.
Mat continues to be involved with issues concerning genomics education and engagement through the Wellcome Trust's various
projects in this area.
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Thu(5)-ED8-4
Genetic Education for Children: A Nagasaki University Initiative
Kanako Morifuji 1 ，Noriko Sasaki 1 ，Harumi Miyahara 1 ，Tadashi Matsumoto 2
1:Department of Nursing, Health Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan、2:Division of Developmental
Disability, the Misakaenosono Mutsumi Developmental, Medical and Welfare Center, Nagasaki, Japan
In recent years, social problems relating to undervaluing human life, such as juvenile crime and delinquency, have been
increasing. We recognize that each and every individual is different and believe it is necessary to begin studies at an early age
that will allow children to learn the importance of life and of valuing oneself and others. Accordingly, since 2004 we have been
conducting heredity education, targeting upper-grade elementary school students and their guardians in Nagasaki City. We
Educational Program
use the keywords “diversity” and “uniqueness,” which are the essence of genetics, as a means of conveying the sanctity of
life. This program takes from similar endeavors, such as Washington University’s genetics education program, and modifies
them in order to take Japanese culture and children’s interests into consideration. Through this program, children will learn
that some people have characteristics that others do not, that there are various combinations of characteristics (diversity),
and that no one has the same combination of characteristics (uniqueness) as they do. In this way, the children come to realize
that every individual’s life is important and precious.
[Biography]
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[YIA1] Young Investigator Awards Session 1

Tue., April 05, 2016 13:50-15:20 Annex 1 (1F)
Chair：Brunhilde Wirth（Institute of Human Genetics, University of Cologne, Germany）

Chair ：Stephen T.S. Lam（Faculty of Medicine, The Chinese University of Hong Kong, China）
Tue(3)-YIA1-1
Association between the literacy on genomics and health status; encouraging genomics education in
personalized preventive medicine era
Sho Nakamura 1,2 ，Hiroto Narimatsu 2,3 ，Kayoko Katayama 2 ，Ri Sho 3 ，Ryo Kawasaki 3 ，Akira Fukao 3 ，
Takashi Yoshioka 1 ，Takamasa Kayama 4

1:Department of Clinical Oncology, Yamagata University Faculty of Medicine, Japan、2:Cancer Prevention and Control Division, Kanagawa
Cancer Center Research Institute、3:Department of Public Health, Yamagata University Graduate School of Medical Science、4:Department
of Advanced Cancer Science, Yamagata University Faculty of Medicine
BACKGROUND Personalized preventive medicine applying genomic information is anticipated from the recent progress in
genomics. Personal literacy on genomics, which indicates individual’s ability to collect, critically interpret, and practically
use information concerning genomics, is necessary when applying genomic information to public health promotion. However,
improving individual’s genomic literacy by education is challenging, because substantial amount of knowledge on genetics and
genomics should be provided and properly understood. AIMS To determine association between the literacy on genomics and
health status, based on the hypothesis that person with lower genomic literacy are with poorer health status, who potentially
be benefited most by preventive interventions. METHODS Data from a population-based cohort study was used. Genomic
literacy score (GLS) (minimum/maximum score = 0/30) was calculated from 20 questionnaires based on the findings of prior
studies. Propensity score on GLS was calculated on age, sex, income, education, and eight questionnaires; propensity score
matched comparison on non-communicable diseases were performed between those with higher GLS (above median), and
lower GLS (below median). RESULTS GLS was available for 4,646 participants (men/women 1891/2755). Median of the
GLS was 12.4 (inter-quartile range 10.0-20.0). Odds ratio adjusted by age, sex, and income for approval of genomic studies
per point increase in GLS was 1.11 (95% confidence interval 1.09-1.12, P < 0.001). Propensity score matched analysis showed
that participants with higher GLS had 4.7% lower prevalence of hypertension than those who belonged to the lower GLS.
(P = 0.024) CONCLUSION GLS could be associated with the risk of non-communicable diseases, as hypertension observed
in this study, indicating that future intervention of health education should contain genetic and genomic issues, in the era
when genomics is applied in personalized preventive medicine.
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Tue(3)-YIA1-2
A molecular study on Stevens-Johnson syndrome patients with ocular manifestations
Sushil Kumari Sangwan 1 ，Arundhati Sharma 1 ，Namrata Sharma 2 ，Neena Khanna 3 ，Tushar Agarwal 2 ，
Rasik B Vajpayee 4
1:Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India、2:Dr. Rajendra Prasad Centre for Ophthalmic
Sciences, AIIMS, New Delhi、3:Department of Dermatology and Venerology, AIIMS, New Delhi、4:Center for Eye Research,University of
Melbourne, Australia
Purpose of study:
Stevens-Johnson syndrome (SJS) is a rare disorder of the skin and mucous membranes caused due to infectious agents and
inciting drugs leading to corneal damage and permanent visual loss. Role of MHC, Interleukins and apoptotic markers is
postulated in its predisposition. The study reports on correlation of molecular markers with severity grading and ocular

manifestations in these patients.
Material &Methods:
Two hundred subjects each, of SJS and controls were recruited for the study. DNA was isolated from blood samples followed
by PCR amplification and Sanger sequencing to screen interleukins IL4, IL4R and IL13 and sera were used to measure levels
of Granulysin and sFasL by ELISA.
Results:
The patients (122 males and 78 females) had a mean age of onset at 22.56 +10.50 yrs (Mean +SD). SJS patients were
categorized into mild (35%), moderate (23%) and severe (42%) on ocular grading. The main inciting drug was antipyretics
(59%) followed by antiepileptics (13.5%) and sulphonamides (4%). Screening of interleukins revealed IL-13 coding region A/G
polymorphism (rs20541) in 38%, IL-13 promoter region C/T change (rs1800925) in 28%, IL-4 T/C change (rs2243250) in 35%,
IL-4R A/G polymorphism (rs1801275) in 33% of the patients. Ocular complications were found to be significantly associated
with polymorphisms at IL-4 promoter region rs2243250 in trichiasis, IL-13 coding region rs20541 in mucocutaneous junction
involvement and IL-13 promoter region rs1800925 in conjunctival keratinisation. Raised levels of Granulysin (4.04+4.62
ng/ml) and sFasL (100.82 +98.12 pg/ml) were found in patients in comparison to controls (1.00+0.91 ng/ml; 3.69+3.00
pg/ml respectively).
Conclusion:
The study highlights the role of interleukins with ocular complications in SJS patients. Raised Granulysin and sFasL levels
are indicative of severity of the disease. These markers may be used to screen at risk individuals on the basis of their genotypic
profile.
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Tue(3)-YIA1-3
Investigation of Variants within Antipsychotic Pharmacogenes Associated with Treatment Outcome in
a South African First Episode Schizophrenia Cohort
Faatiemah Higgins 1 ，Britt I Drögemöller 5 ，Galen EB Wright 5 ，Lize Van der Merwe 3,4
，Bonga Chiliza 2 ，Laila Asmal 2 ，
Dana Niehaus 2 ，Robin Emsley 2 ，Louise Warnich 1
1:Genetics, Stellenbosch University, South Africa、2:Psychiatry, Stellenbosch University、3:Statistics, Stellenbosch University、4:Molecular
Biology and Human Genetics, Stellenbosch University、5:Paediatrics, University of British Columbia
Antipsychotic treatment of schizophrenia is often accompanied by distressing adverse effects and high relapse rates. Although
pharmacogenetic research has identified some promising candidate pharmacogenes, these remain poorly characterized in
South African (SA) populations. This study aimed at investigating variants within seven candidate pharmacogenes (COMT ,
CYP1A2 , CYP2D6 , DRD2 , DRD3 , HTR2A and SOD2 ) in a South African First Episode Schizophrenia (FES) cohort to

identify significant associations with antipsychotic treatment outcome.
A total of 33 variants were prioritized for genotyping using several genotyping assays in 103 FES patients. Mixed model for
repeated measures analyses were used to determine if any variants identified were associated with antipsychotic treatment
response, as measured by a change in PANSS scores over time from the twelve-month longitudinal PANSS scores. Inheritance
models to estimate the effect size (ES) of significant associations were assessed using 95% confidence intervals (CI).
Variants in COMT and DRD2 were significantly associated with changes in PANSS negative scores after twelve months.
Associations with improved treatment outcomes included COMT rs4633 [P=0.0080 (T allele), ES=-0.17 95% CI (-0.30 to
-0.04)], and DRD2 rs1799732 [P=0.0004 (-C vs CC), ES=-0.19 95% CI (-0.38 to 0.00)]. Undesirable treatment outcomes
were associated with COMT rs9332377 [P=0.0006 (T allele), ES=0.25 95% CI (0.11 to 0.39)], and DRD2 variants rs1799732
[P=0.0004 (– vs CC), ES=0.50 95% CI (0.15 to 0.86)] and rs1079597 [P=0.0020 (AA vs AG+GG), ES=0.93 95% CI (0.34 to
1.53)].
Several SNPs in COMT and DRD2 were identified to be involved in treatment response of negative symptoms. These results
serve as a platform for future antipsychotic pharmacogenetic studies within the SA context that could aid the optimization
of antipsychotic treatment in the uniquely diverse, but understudied populations.
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Tue(3)-YIA1-4
Biallelic truncating mutations in ALPK3 cause severe pediatric cardiomyopathy
Judith M.A. Verhagen 1 ，Rowida Almomani 2 ，Johanna C. Herkert 2 ，Erwin Brosens 1 ，Karin Y. van Spaendonck-Zwarts 2,3 ，
Angeliki Asimaki 4 ，Paul A. van der Zwaag 2 ，Ingrid M.E. Frohn-Mulder 5 ，Aida M. Bertoli-Avella 1,6 ，
Ludolf G. Boven 2 ，Marjon A. van Slegtenhorst 1 ，Jasper J. van der Smagt 7 ，Wilfred F.J. van IJcken 8 ，Bert Timmer 9 ，
Margriet van Stuijvenberg 10 ，Rob M. Verdijk 11 ，Jeffrey E. Saffitz 4 ，Frederik A. du Plessis 5 ，Michelle Michels 12 ，
Robert M.W. Hofstra 1 ，Richard J. Sinke 2
1:Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands, Netherlands、2:University of
Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands、3:Department of Clinical Genetics,
Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands、4:Department of Pathology, Harvard Medical School,
Beth Israel Deaconess Medical Center, Boston, USA、5:Department of Pediatric Cardiology, Erasmus University Medical Center, Rotterdam,
the Netherlands、6:Centogene AG, Rostock, Germany、7:Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The
Netherlands、8:Center for Biomics, Erasmus University Medical Center, Rotterdam, the Netherlands、9:University of Groningen, University
Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands、10:University of Groningen,
University Medical Center Groningen, Division of Neonatology, Beatrix Children’s Hospital, Groningen, the Netherlands、11:Department
of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands、12:Department of Cardiology, Erasmus University Medical

Center, Rotterdam, the Netherlands
Pediatric cardiomyopathies are a heterogeneous group of disorders characterized by structural and functional myocardial
abnormalities. Up to 40% of affected children die or undergo cardiac transplantation within five years of diagnosis. While the
understanding of the molecular basis of pediatric cardiomyopathy has greatly improved over the last two decades, in many
cases the underlying cause remains unknown.
Using homozygosity mapping and exome sequencing in two consanguineous families with idiopathic pediatric cardiomyopathy,
we identified homozygous truncating mutations in a new disease gene: alpha-kinase 3 (ALPK3 ). This gene encodes a nuclear
kinase that is essential for early differentiation of cardiomyocytes. A third family was identified upon cohort screening.
Patients with biallelic mutations presented with severe cardiomyopathy leading to early lethality or biventricular dysfunction
in childhood. Of note, some heterozygous family members showed adult-onset cardiomyopathy with atypically distributed
hypertrophy. We provide microscopic evidence of intercalated disc remodeling, as previously observed in Alpk3 knockout
mice.
In conclusion, biallelic truncating mutations in ALPK3 cause severe pediatric cardiomyopathy in humans. Further studies
are necessary to understand how dysregulation of the transcriptional regulatory network results in cardiomyopathy, and to
investigate the potential use of alpha-kinase-3 as a new drug target.
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Tue(3)-YIA1-5
Genetic association study identifies common variation in PHACTR1 to associate with fibromuscular
dysplasia
Nabila Bouatia-Naji 1,2,3 ，Soto Romuald Kiando 1,2,3 ，Nathan R Tucker 4 ，Cyrielle Treard 1,2,3 ，Luis J Castro-Vega 1,2,3 ，
Cristina Barlasina 8 ，Daniele Cusi 8 ，Pilar Galan 9 ，Jean-Philippe Empana 1,2,3 ，Xavier Jouven 1,2,3,10 ，Jeffrey W Olin 6 ，
Heather L Gornik 11 ，Pierre-Francois Plouin 12 ，Iftikhar J Kullo 7 ，David J Milan 4 ，Santhi K Ganesh 5 ，
Pierre Boutouyrie 1,2,3,13 ，Jason Kovacic 6 ，Xavier Jeunemaitre 1,2,3,14
1:Paris Cardiovacular Research Center, INSERM, France、2:INSERM UMR970, Paris, France、3:Faculty of medicine, Paris-Descartes
University, Sorbonne Paris Cite、4:Cardiovascular research Center, Massachusetts General Hospital, Charlestown, MA, USA、5:Department
of Internal Medicine and Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.、6:Zena and Michael A. Wiener
Cardiovascular Institute & Marie-Josee and Henry R. Kravis Center for Cardiovascular Health, Icahn School of Medicine at Mount Sinai,
New York, NY, USA、7:Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA、8:Dept.
of Health Sciences, Genomic and Bioinformatics Unit, School of Nephrology, University of Milano, Institute of Biomedical Technologies,
Italian National Centre of Research, Italy、9:Nutritional Epidemiology Research Group, Sorbonne-Paris-Cite, UMR University of Paris,
France、10:AP-HP, Department of Cardiology, Hopital Europeen Georges Pompidou, Paris, France、11:Cleveland Clinic Heart and Vascular
Institute, Cleveland, OH, USA.、12:AP-HP, Department of Hypertension, Hopital Europeen Georges Pompidou, Paris, France、13:AP-HP,

Department of Pharmacology, Hopital Europeen Georges Pompidou, Paris, France、14:AP-HP, Refferal Center for Rare Vascular Diseases,
Hopital Europeen Georges Pompidou, Paris, France
Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to arterial stenosis and aneurysm involving
mainly the renal and cerebrovascular arteries. FMD has higher prevalence in females (80-90%) and is associated with hyper-
tension and stroke. The pathophysiology of FMD is unclear and a genetic origin is suspected.
We performed a three-stage genetic association study in cases and controls of European ancestry. The discovery included
249 patients and 689 controls, in which we analyzed ~ 26K common variants (MAF>0.05) using an exome-chip array. We
followed-up 13 independent loci with suggestive association with FMD (P<10-4 ) in 393 cases and 2537 controls replicated
a signal on Chr6. Three additional case-control studies (all Ncases =512, Ncontrols =669) confirmed this association, with an
overall odds ratio of 1.39, 95% confidence interval=1.25-1.54, P=7.4×10-10 in a global sample of Ncases =1154, Ncontrols =3895.
The FMD risk variant is intronic to the phosphatase and actin regulator 1 gene (PHACTR1 ), involved in angiogenesis and
cell migration. PHACTR1 is a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analysis
of echotracking parameters of carotids from ~ 2,500 individuals indicates association between the FMD risk allele and higher
intima media thickness (P=3.9×10-5 ) and wall to lumen ratio (P=0.001). We show higher expression of PHACTR1 in FMD
risk allele carriers (N=100, P=0.02) in primary human fibroblasts. Antibodies detected PHACTR1 in paraffin-fixed sections of
FMD and healthy carotids. Finally, Phactr1 knockdown of zebrafish showed dilated vessels indicating impaired development
of vasculature.
Here we report the first risk locus for FMD with the largest genetic association study conducted so far. Our data reveal a com-
mon genetic variant at PHACTR1 supporting a complex genetic pattern of inheritance and indices of shared pathophysiology
between FMD and other cardiovascular and neurovascular diseases.
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Tue(3)-YIA1-6
Size-based molecular diagnostics using plasma DNA for noninvasive prenatal testing
Stephanie C. Y. Yu 1,2 ，K. C. Allen Chan 1,2 ，Yama W. L. Zheng 1,2 ，Peiyong Jiang 1,2 ，Gary J. W. Liao 1,2 ，
Hao Sun 1,2 ，Ranjit Akolekar 3 ，Tak Y. Leung 4 ，Attie T. J. I. Go 5 ，John M. G. van Vugt 5 ，Ryoko Minekawa 3 ，
Cees B. M. Oudejans 5 ，Kypros H. Nicolaides 3 ，Rossa W. K. Chiu 1,2 ，Y. M. Dennis Lo 1,2
1:Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong SAR, China,
Hong Kong、2:Centre for Research into Circulating Fetal Nucleic Acids, Li Ka Shing Institute of Health Sciences, The Chinese University of
Hong Kong, Shatin, NT, Hong Kong SAR, China、3:Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, London,
United Kingdom、4:Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin,
NT, Hong Kong SAR, China、5:Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
Noninvasive prenatal testing (NIPT) of fetal chromosomal aneuploidies using massively parallel sequencing (MPS) of cell-free
DNA in maternal plasma has become widely adopted in prenatal care. The current generation of NIPT tests is based on
counting plasma DNA molecules originating from different genomic regions. In this study, we introduced a different approach

that is based on the use of DNA fragment size as a diagnostic parameter.
The size-based analysis is built on the fact that plasma DNA molecules derived from the fetus have a shorter size distribution
than those derived from the mother. The presence of an extra dosage of shorter fetal-derived DNA in a pregnant woman
carrying a trisomy fetus would result in an increased proportion of short DNA from the trisomic chromosome. The reverse
would take place in cases of fetal monosomy. Hence, we performed maternal plasma DNA size analysis using paired-end MPS
and assessed the fetal chromosome dosage by detecting the increased or decreased proportion of short fragments from the
aneuploid chromosome in maternal plasma.
Using the size-based analysis, we detected fetal trisomy 21 and trisomy 18 with 100% sensitivity (T21: 36/36; T18: 27/27)
and 100% specificity (non-T21: 88/88; non-T18: 97/97). For trisomy 13, the sensitivity and specificity were 95.2% (20/21)
and 99% (102/103), respectively. For monosomy X, the sensitivity and specificity were both 100% (10/10 and 8/8).
In conclusion, we showed that maternal plasma DNA size analysis could be used for the detection of multiple types of fetal
chromosomal aneuploidies with high accuracy. Since the same set of sequencing data can be used for both the count- and
size-based analyses, one could actually combine the two types of analyses in interpreting the results of NIPT. This strategy
has the potential to improve the specificity of NIPT and that would be valuable if one wishes to expand the clinical spectrum
of NIPT, e.g. for subchromosomal copy number aberrations.
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ICHG2016 485
[YIA2] Young Investigator Awards Session 2

Tue., April 05, 2016 15:40-17:10 Annex 1 (1F)
Chair：Joris A. Veltman（Human Genetics, Radboud University Medical Centre, The Netherlands）

Chair：Naomichi Matsumoto（Department of Human Genetics, Yokohama City University Graduate School of Medicine,
Japan）
Tue(3)-YIA2-1
LAT2 transporter is involved in age-related hearing loss
Meritxell Espino Guarch 1,2,3 ，Mariona Font 2 ，Giorgia Girotto 1 ，Ekaitz Errasti 3 ，Clara Vilches 2 ，Silvia Murillo 4 ，
Paolo Gasparini 1 ，Manuel Palacin 3,5 ，Virginia Nunes 2,5

1:Experimental Genetics, Sidra Medical and Research Center, Qatar、2:Molecular Genetics Laboratory, Bellvitge Biomedical Research
Institute (IDIBELL), Barcelona, Spain、3:Institute of Research in Biomedicine (IRB), Barcelona, Spain、4:Unit 761, Center for Biomedical
Network Research on Rare Diseases (CIBERER), Madrid, Spain、5:Biochemistry and Molecular Biology Department, Barcelona University
(UB), Barcelona, Spain
LAT2 is a neutral amino acids transporter expressed in inner ear and classified as uncloned deafness-related human gene
although it remains to be illustrated the physiological as well as the pathological processes that involve it. Present work
demonstrates for the first time that the absence of LAT2 in cochlea triggers to hearing loss in mice and human LAT2
mutations correlate with an age-related hearing loss (ARHL) phenotype.
A null mouse model (Lat2-/- ) was generated and the absence of the transporter or any truncated form was confirmed. LAT2
transporter had been localized in stria vascularis and spiral limbus, both essential structures for proper auditory function.
Auditory Brainstem Response (ABR), an electrophysiological test, had been used to measure the integrity of hearing process.
Consistently with LAT2 location, results from ABR analysis confirmed that Lat2-/- mice suffer hypoacusia, a moderate
deafness. Interestingly, comparing ABR results between young Lat2-/- versus old wild type mice, those of C57Bl/6 strain that
suffer ARHL, showed similar pathological changes.
Concomitant with the phenotype observed in Lat2-/- mice, two different LAT2 missense mutations had been found in ARHL
patients. Both mutations are promising candidates to affect the transporter function due to its crucial location; V302I a
conserved amino acid in the inward-facing lid and T402M a group that could interact with the substrate in the binding site
(in vitro functional studies are in progress).
Characterization of Lat2-/- mice reveled how unbalanced amino acid content in cochlea could affect auditory system and proved
that LAT2 is involved in hearing mechanism. The finding of ARHL patients’ carriers of LAT2 mutation and forthcoming
functional studies are robust evidences that point out the significance of LAT2 in auditory system opening a new perspective
where amino acid transporters are new potential targets to unravel uncharacterized congenital deafness.
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Tue(3)-YIA2-2
Whole-genome sequencing of monozygotic twins discordant for schizophrenia
1,2
Yu Fan ，Jinsong Tang 3 ，Qun Xiang 1,2
，Hong LI 3 ，Yong-Gang Yao 1,2
，Xiaogang Chen 3
1:Kunming Institution of Zoology, Chinese Academy of Sciences, China、2:Kunming College of Life Science, University of Chinese Academy
of Sciences、3:Institute of Mental Health, the Second Xiangya Hospital, Central South University
Schizophrenia (SCZ) demonstrates a high heritability and familial clustering pattern, but the genetic causes remain only
partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows a
promise as a tool for identifying SCZ risk genes and unknown mutations in known loci. Deep (30X) WGS was performed
at BGI using the Illumina HiSeq platform in 8 families (32 samples). We applied forestDNM to detect de novo mutations
(DNMs) in trios and got 514 putative germline or somatic DNMs in 8 MZ twin pairs, and the DNM rate is 1.15 ~ 2.52×10-8
per generation. Most of DNMs detected were shared between the paired twins, only 40 DNMs were detected in only one twin

of pairs, including 21 DNMs identified in probands. Among the 21 DNMs, 14 DNMs were located in intron region, 1 DNMs
was located in the 5’upstream region, 6 DNMs were located in the intergenic region. One DNM from proband had a mutation
in intron of NXPH1 which located a potential autism risk loci. This DNM may cause some important function difference
in twins, even affect the risk of SCZ. There were 8 DNMs shared between twins, which were located in exon, including 7
missense SNPs and 1 synonymous SNPs. It’s worth mentioning that TTN and GCN1L1 were also been found by another
research of DNMs in SCZ and in autism. Moreover, we detected the potential correlation between the number of DNMs and
parents’ age at conception. We performed a conditional analysis of multiple regression models to separate the effect of the
father and/or mother. We observed a significant positive correlation (p-value=0.0086) between father age at conception and
the number of DNMs in the offspring, and whereas mother age at conception (p-value=0.9756) was not significant. Our WGS
for MZ twin pairs discordant for SCZ and their parents provides first hand data for us to estimate the mutation rate and to
identify the potential pathogenic mutation(s).
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ICHG2016 487
Tue(3)-YIA2-3
Towards clinical accreditation of structural variation calling from HiSeq X whole genome sequencing
data
Andre E Minoche 1 ，Greg B Peters 2 ，Velimir Gayevskiy 1 ，Mike Field 3 ，Claire Horvat 4 ，Andreas Zankl 2 ，
Diane Fatkin 4 ，Tony Roscioli 1 ，Marcel E Dinger 1 ，Mark J Cowley 1
1:Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Australia、2:Sydney Genome Diagnostics, Children’s
Hospital Westmead、3:NSW Health, Royal North Shore Hospital、4:Victor Chang Cardiac Research Institute
Genomic structural variation (SV) including copy number variation (CNV) underlies the etiology of many human genetic
disorders, and syndromes. Clinical microarrays have been the mainstay of diagnosing CNVs in patients; however, they are of
limited use in detecting inversions, translocations and small CNVs. The rapidly decreasing cost combined with the broad and
uniform depth of coverage from Illumina HiSeq X whole genome sequencing (WGS) data presents a unique opportunity to

improve detection of CNVs and SVs across the entire size gamut from a few nucleotides, to entire chromosomes, in a clinical
setting.
We developed a method that integrates SV calls from all three WGS evidence types (i.e. split reads, discordant reads and
read depth) assign various quality attributes and annotations, which enables us to obtain a comprehensive high confidence SV
call-set. By adding human population allele frequencies for SVs, we can distil down to rare disease causing variants. Further,
we developed a streamlined visualization procedure that allows the inspection of SV with their underlying evidence in genome
browsers.
With the aim of developing a clinically accredited SV calling test from WGS data, we performed extensive comparisons to
clinical microarrays (50 patients), NA12878 gold standards and determined Mendelian error rates using Illumina Platinum
CEU genomes.
We obtained a sensitivity and precision of up to 90% for deletions between 1 and 10 kb. Compared to microarrays currently
used in clinical genetic testing to detect copy number events >50kb, WGS detects ~ 25% more gold standard deletions.
Additionally, we detect ~ 4,000 CNVs below the resolution of microarrays as well as 144 balanced deletion duplication events,
50 inversions and ~ 1,000 additional breakpoints, which are often part of more complex rearrangements.
Here we present our findings from applying our method to 100 whole genomes from clinical samples, including a cohort of 44
dilated cardiomyopathy patients.
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ICHG2016 488
Tue(3)-YIA2-4
Thousands of novel translated open reading frames in humans inferred by ribosome footprint profiling
Anil Raj 1 ，Sidney H Wang 2 ，Heejung Shim 6 ，Arbel Harpak 4 ，Yang I Li 1 ，Brett Engelmann 2 ，Matthew Stephens 2,3
，
Yoav Gilad 2 ，Jonathan K Pritchard 1,4,5
1:Department of Genetics, Stanford University, USA、2:Department of Human Genetics, University of Chicago、3:Department of Statistics,
University of Chicago、4:Department of Biology, Stanford University、5:Howard Hughes Medical Institute、6:Department of Statistics, Purdue
University
Accurate annotations of protein coding regions are essential for understanding how genetic information is translated into
biological functions. The recent development of ribosome footprint profiling provides an important new tool for measuring
translation. In this work, we used hidden Markov models to analyze ribosome footprint data along with gene expression and
sequence information to accurately infer translated sequences. We applied our method to human lymphoblastoid cell lines
and identified 7,863 previously unannotated coding sequences, including 445 translated sequences in pseudogenes and 2,442

translated upstream open reading frames. We observed an enrichment of harringtonine-treated ribosome footprints at the
inferred initiation sites, validating many of the novel coding sequences. The novel sequences exhibit significant signatures of
purifying selection indicative of protein-coding function, both within the human lineage and across the vertebrate phylogeny,
suggesting that many of the novel sequences are functional. We observed that nearly 40% of bicistronic transcripts showed
significant negative correlation in the levels of translation of their two coding sequences, suggesting a key regulatory role for
these novel translated upstream open reading frames. Despite evidence for their functional importance, the novel peptide
sequences were detected by mass spectrometry at a lower rate than predicted based on data from annotated proteins, thus
suggesting that many of the novel peptide products may be relatively short-lived. Our work illustrates the value of ribosome
profiling for improving coding annotations, and significantly expands the set of known coding regions. The application of
our method to ribosome footprint data across cell types and organisms may prove useful in teasing apart functional and
evolutionary differences in gene expression between tissues and species.
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ICHG2016 489
Tue(3)-YIA2-5
Visualizing structural variation at the single cell level to explore human genome heterogeneity
Ashley D Sanders 1 ，Mark Hills 1 ，David Porubsky 3 ，Victor Guryev 3 ，Ester Falconer 1 ，Peter M Lansdorp 1,2,3
1:BC Cancer Agency, University of British Columbia, Canada、2:Division of Hematology, Department of Medicine, University of British
Columbia、3:European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen
Studies of genome heterogeneity and plasticity aim to resolve how genomic features underlie phenotypes and disease sus-
ceptibilities. Identifying genomic features that differ between individuals and cells can help uncover the functional variants
that drive specific biological outcomes. For this, single cell studies are paramount, as it becomes increasingly clear that the
contribution of rare but functional cellular subpopulations is important for disease prognosis, management and progression.
Until now, studying these associations has been challenged by our inability to map structural variants accurately and com-
prehensively. To overcome this, we employed the template strand sequencing method, Strand-seq, to preserve the structure

of individual homologues and visualize genomic variants in single cells. We used this method to rapidly discover, map and
genotype human polymorphisms with unprecedented resolution. This allowed us to explore the distribution and frequency of
structural variation in a heterogeneous cell population, identify several polymorphic domains in complex regions of the genome,
and locate rare alleles in the reference assembly. We then extended this analysis to comprehensively map the complete set of
inversions in an individual’s genome and define their unique invertome. We built comprehensive structural rearrangements
maps for two unrelated individuals to explore how sets of inversions can be used to predict ancestry and disease susceptibility.
We predict characterizing invertomes of patients will have important implications for population genetics and personalized
medicine. Finally, we generated a non-redundant, global reference of structural variants in the human genome and better
characterized their architectural features. Taken together, we describe a powerful new framework to study structural vari-
ation and genomic heterogeneity in single cell samples, whether from individuals for population studies, or tissue types for
biomarker discovery.
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ICHG2016 490
Tue(3)-YIA2-6
Genome-wide multi-phenotype analysis of rare variants boosts power for locus discovery and indicates
novel rare variant effects from a known common variant locus on omega fatty acids
Marika Kaakinen 1 ，Annique Claringbould 2 ，Reedik Magi 3 ，Krista Fischer 3 ，Mika Ala-Korpela 4,5,6
，
Marjo-Riitta Jarvelin 4,6,7,8 ，Andrew P. Morris 9 ，Inga Prokopenko 1
1:Genomics of Common Disease, Imperial College London, UK、2:Department of Genetics, University Medical Centre Groningen、3:Estonian
Genome Center, University of Tartu、4:Center for Life Course Epidemiology and Systems Medicine, University of Oulu、5:Computational
Medicine, School of Social and Community Medicine and the Medical Research Council Integrative Epidemiology Unit, University of Bristol、
6:Unit of Primary Care, Oulu University Hospital、7:Biocenter Oulu, University of Oulu、8:Department of Epidemiology and Biostatistics,
MRC-PHE Centre for Environment and Health, Imperial College London、9:Department of Biostatistics, University of Liverpool
Genome-wide association studies have been expanded to analysis of low-frequency and rare variants (MAF<5%, both denoted
by RVs). Power to detect RV association could also be increased by jointly analysing multiple correlated phenotypes. We
have developed a method and software for genome-wide Multi-phenotype Analysis of RVs (MARV), combining features from

both a RV burden test and multi-phenotype analysis. Specifically, the proportion of RVs at which an individual carries
minor alleles within a gene region is modelled on linear combinations of phenotypes. Our simulation studies show good
control of type I error rate and increased power over a univariate burden test under all tested scenarios. Using our method,
we investigated the contribution of RVs on omega fatty acids (FA), which are essential for various human body functions,
including building healthy cell membranes and maintaining brain and nerve performance. We used nuclear magnetic resonance
derived metabolites and 1000 Genomes imputed genetic data from the Northern Finland Birth Cohorts 1966 (NFBC1966,
N=4949) and 1986 (NFBC1986, N=3055). To avoid multicollinearity issues, we selected four FAs out of the available data
for joint genome-wide analysis: omega-3, -6, -7/9 and other polyunsaturated FAs. We identified statistically significant
(P<1.7x10-6 , Bonferroni correction for 30000 genes) signals on chromosome 11, with the strongest associations arising from
FADS1 (P=6.5x10-37 ) and FADS2 (P=1.3x10-25 ), which is a known common variant locus impacting lipid levels. All signals
were confirmed in NFBC1986. Single variant multi-phenotype analyses in NFBC1966 pointed to 11 variants with MAF
between 0.02 and 0.0495 (P<5.0x10-8 ), however, larger sample sizes are needed to refine the causal variant structure leading
to the detected effects. With our novel method, we have increased power both over single variant and single phenotype RV
burden test, allowing us to detect for the first time FADS1/FADS2 RV effects on FAs.
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ICHG2016 491

The Value of Pedigree Analysis and Genetic Counseling for Fabry Disease Management
Mon., April 04, 2016 12:20-13:20 Annex 1 (1F)
Chair：Norio Sakai（Professor, Division of Health Science, Osaka University Graduate School of Medicine）
Pedigree analysis is a targeted screening study with the family relatives of a new index case. In Fabry disease, in most of
the cases the mutation has been transmitted in the family throughout generations. So, when you find a new Fabry patient,
you find a new family with more patients. The availability of treatment options for patients and knowing that earlier
treatment has greater clinical benefit, makes pedigree analysis an important tool to give undiagnosed patient a confirmed
diagnosis at an earlier stage of the disease. In this talk I will show you our 13-year experience of work in pedigree analysis
for Fabry disease and how we were improving the approach to obtain better results. I will use real examples of the work
carried out with Fabry families we detected, along with the Pedigree Tool kit. I will present practical examples to show
and analyze how this work was done, along with correct and failed approaches.
Luncheon Seminar

The Value of Pedigree Analysis and Genetic Counseling for Fabry Disease Management
1
Paula Adriana Rozenfeld
1:IIFP (Institute for study of Immunology and Physiopathology) Facultad de Ciencias Exactas, Universidad Nacional de La Plata and
CONICET
No Abstract
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ICHG2016 492

Korean Hereditary Breast Cancer (KOHBRA) Study: Review and Future Perspectives
Mon., April 04, 2016 12:20-13:20 Annex 2 (1F)
Chair：Seigo Nakamura（Department of Breast Surgical Oncology, Showa University School of Medicine, Japan）
The KOHBRA study is a prospective multicenter cohort study from 38 major centers. The aims of the KOHBRA study is
to estimate the prevalence of BRCA1/2 mutations, to develop Korean BRCA mutation prediction model, to characterize
clinical phenotype and discover novel prognostic factors for BRCA associated BC, and to identify environmental and
genetic modifiers of BRCA1/2 mutation. Between May 2007 and July 2011, the KOHBRA study enrolled up to 2794
subjects and identified 651 mutation carriers. In this lecture, I will review the important findings from the KOHBRA
study and share the future perspectives of our study.
Luncheon Seminar

Korean Hereditary Breast Cancer (KOHBRA) Study: Review and Future Perspectives
1
Sung-Won Kim
1:Department of Surgery, Breast Care Center, Daerim St. Mary’s Hospital, Korea
No Abstract
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ICHG2016 493

Precision Oncology with IBM Watson
Mon., April 04, 2016 12:20-13:20 Room A (2F)
Chair：Yoichi Furukawa（Institute of Medical Science, University of Tokyo, Japan）
As genomics continues to become more affordable and clinically practical, there is increasing opportunity for bringing
therapies to the benefit of cancer patients in a highly precise manner, tailored to the patient’s genomic profile. However,
analyzing tumor genomic data including variants, copy number alterations, structural variants, and expression requires
considerable expertise and effort. In addition, expert based genomic analysis is not scalable, often leaves room for
improvement, and may lack objectivity. Watson Genomics (WG) addresses these issues by providing fast, comprehensive,
transparent, and objective report with up-to-date data in scalable manner. This talk will describe WG and provide a
summary of current status with major cancer centers.
Luncheon Seminar

Precision Oncology with IBM Watson
1
Takahiko Koyama
1:IBM T. J. Watson Research Center, USA
No Abstract
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ICHG2016 494

MaterniT™ GENOME”
Mon., April 04, 2016 12:20-13:20 Room E (1F)
Chair：Akihiko Sekizawa（Professor and Chairman, Department of Obstetrics and Gynecology, Showa University School
Since its inception in 2011, the list of conditions that can be detected through noninvasive prenatal testing (“NIPT”)
has continuously grown. Today it is estimated that standard NIPT detects around 80% of genetic conditions. To provide
the most scientifically advanced information available from an NIPT and close this information gap we have developed
MaterniT™ GENOME. This is the first NIPT that detects chromosomal aberrations and sub-chromosomal copy number
variations down to 7Mb in size. In this presentation we will show data from analytical and clinical validations studies, as
well as, showcase some interesting case studies.
Luncheon Seminar

MaterniT™ GENOME”
1
Mathias Ehrich
1:Senior Vice President, Research & Development, Sequenom, Inc., USA
No Abstract
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ICHG2016 495

Using Single Cell Genomics to Deconvolute Dynamic Biological Processes
Mon., April 04, 2016 12:20-13:20 Room B-1 (2F)
Chair：Naoya Hosono（Application Specialist, Fluidigm K.K.）
The quality of genomics data that can be acquired from single cells has rapidly improved over the last several years.
Making genomic measurements in single cells allows us to measure the diversity in magnitude and co-occurrence of
specific nucleic acid sequences in a population of cells. This enables the study of biological processes that exhibit high
levels of cell-to-cell variation in a population. Dr. Gawad will present how we can leverage single-cell genomics to
deconvolute dynamic biological processes using single-cell transcriptome sequencing to the measurements of mutations in
single leukemia cells underlying the mutation process and population genetic diversity.
Luncheon Seminar

Using Single Cell Genomics to Deconvolute Dynamic Biological Processes
1
Charles Gawad
1:Oncology Department, St. Jude Children’s Research Hospital
No Abstract
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ICHG2016 496

Addressing Unmet Medical Needs in Rare Hematological Diseases
Mon., April 04, 2016 12:20-13:20 Room D (1F)
Chair：Yoshikatsu Eto（Director, Advanced Clinical Research Center, Institute of Neurological Disorders / Tokyo Jikei
University School of Medicine, Tokyo, Japan）
Development of therapies for genetic rare disorders remains a challenge. Over 20 years ago Sanofi Genzyme developed
the first enzyme replacement therapy (ERT) for Gaucher disease. Since then other lysosomal storage diseases and inborn
errors of metabolism have had successful treatments developed. Enzyme replacement therapy, substrate reduction therapy
(SRT), as well as chaperone therapy and iRNA platforms have been investigated, and continue to be developed in the
rare genetic disease space. Here we present data on a new, investigational ERT being developed for the treatment of
nonneurological manifestations of acid sphingomyelidase deficiency (ASMD), as well as next generation ERT treatment
for Pompe disease, expanded development for SRT in sphingolipidoses, and iRNA technology for hematological and
Luncheon Seminar
neurovisceral diseases.

Addressing Unmet Medical Needs in Rare Hematological Diseases
1
Ana Cristina Scheidt Puga
1:Medical Director, Clinical Development Rare Diseases Sanofi Genzyme, USA
No Abstract
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ICHG2016 497

Asian Genome Project
Tue., April 05, 2016 12:40-13:40 Annex 2 (1F)
Chair：Trystan Whang（Macrogen APAC Manager）
Understanding of the unique genetic diversity of Asian population will leads to the insights into the biology of disease not
only in the Asian population that represent 40% of mankind but also to the insight to enable cures for all of mankind in
rare and inherited diseases, as well as complex diseases such as cancer, diabetes and neurological disorders.
Presenters will introduce key goals of the Asian population genomic study and elaborate their efforts in setting up a
standard for population genetic research and its applications to precision medicine for Asian patients.
Luncheon Seminar
1
Changhoon Kim
1:Macrogen, Inc., Korea
No Abstract
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ICHG2016 498

1
Ryo Yamada
1:Kyoto University, Japan
No Abstract
Luncheon Seminar

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ICHG2016 499

Unzipping the genome: How whole genome and transcriptome sequencing are transforming biology and
medicine
Tue., April 05, 2016 12:40-13:40 Room A (2F)
Chair：Hiroya Kumai（Marketing, Illumina K.K.）
Spiraling costs and exponential increases in output of massively parallel sequencing technology are having similarly trans-
formative impacts on both biological research and clinical practice. Intriguingly, genomics has also profoundly affected
the interplay between research and clinical activities, with an increasing synergy occurring between these traditionally
largely separate domains. Dr. Marcel Dinger from Garvan Institute will present on recent genomic-led advances in both
research, particularly with regard to deciphering the functions of the genome, and the clinic, where disease diagnosis and
screening are being transformed by genomic applications.
Luncheon Seminar

Unzipping the genome: How whole genome and transcriptome sequencing are transforming biology and
medicine
1
Marcel E. Dinger
1:Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia / St Vincent’s Clinical School, University of New South Wales,
Kensington NSW 2052, Australia
No Abstract
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ICHG2016 500

Ion PGM™ sequencing system for screening system of genetic skeletal muscle disorders
Tue., April 05, 2016 12:40-13:40 Room E (1F)
Chair：Hannah Viernes（Global Market Development, Next Generation Sequencing, Life Sciences Solutions）
We developed a screening system for rare skeletal muscle disorders using Ion PGM™ . We made four target-resequencing
panels each of which covers all exonic regions of genes reported to be causative for specific group of skeletal muscle
disorders; 1) muscular dystrophy, 2) congenital myopathy/congenital myasthenic syndrome, 3) metabolic myopathy, and
4) myopathy with protein aggregation/rimmed-vacuoles. Multiplex primer pools were designed using Ion AmpliSeq™
Designer software. We loaded ~ 6 samples to each Ion 318™ chip. We identified likely causative gene mutations in ~
28% of the patients. In conclusion, high-throughput sequencing technique is useful and effective for mutation screening
in genetic skeletal muscle disorders.
Luncheon Seminar

Ion PGM™ sequencing system for screening system of genetic skeletal muscle disorders
1
Satomi Mitsuhashi
1:Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP) /
Medical Genome Center, National Center of Neurology and Psychiatry (NCNP)
No Abstract
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ICHG2016 501

Biobank and Informatics for Cancer Project and Clinical Sequencing
Tue., April 05, 2016 12:40-13:40 Room B-1 (2F)
Chair：Seigo Nakamura（Director of Breast Center, Showa University Hospital, Japan）
Professor Muto will lecture about “Biobank and Informatics for Cancer Project and Clinical Sequencing”. He is one of
the world’s leading authorities on Cancer therapy based on Bioinformatics and OncoPrime. OncoPrime is a genetic test
that examines genetic change from over 200 drier mutation genes at a time.

Biobank and Informatics for Cancer Project and Clinical Sequencing
1
Luncheon Seminar
Manabu Muto
1:Department of Clinical oncology, Gradeuate School of Medicine, Kyoto University, Japan
No Abstract
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ICHG2016 502

Newborn Screening for Lysosomal Storage Disease
Tue., April 05, 2016 12:40-13:40 Room D (1F)
Chair：Fumio Endo（Department of Pediatrics, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University,
Japan）
Early detection of Lysosomal Storage Diseases (LSDs) can be important for patients/families and constitutes a major
rationale for instituting Newborn Screening (NBS). For several LSDs, it is clear that earlier initiation of therapy can make
a substantial difference in outcome. Testing from dried blood spots (DBS) is now possible in some countries/regions for
several LSDs using the same DBS. However, only few data are available that address sensitivity and specificity of these
assays. We will discuss in the seminar sharing the current situation of NBS for LSDs in the United States and Japan and
will find the future directions for better outcomes for the patients.
Luncheon Seminar

1
Kimitoshi Nakamura
1:Department of Pediatrics, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Japan
No Abstract
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ICHG2016 503

1
Joan Keutzer
1:Vice President and Head, Global Scientific Affairs, Sanofi Genzyme, USA
No Abstract
Luncheon Seminar

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ICHG2016 504

Insights about Reproductive Genetic Services Today and in The Future
Wed., April 06, 2016 12:30-13:30 Annex 2 (1F)
Chair：Shoji Okajima（President, LabCorp Japan）
The emergence of non-invasive prenatal testing (NIPT) made a significant impact on prenatal screening. NIPT began with
screening for trisomy 21 and has since expanded to other trisomies, sex chromosomes and even microdeletions/duplications.
In 2014, Integrated Genetics, launched informaSeqSM , our NIPT offering. In addition to informaSeq, we have been
providing traditional reproductive genetic testing services for decades. Additionally, Integrated Genetics has the largest
US commercial certified genetic counseling team that provides genetic counseling services for patients. Our presentation
will include our experiences in the changing US market and provide insights about reproductive genetic services today
and in the future.
Luncheon Seminar

1
Michael J. Sapeta
1:Vice President and General Manager, Integrated Genetics and CMBP Labcorp
No Abstract
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ICHG2016 505

1
Akihide Takatani
1:Genetic Coordinator, LabCorp Japan
No Abstract
Luncheon Seminar

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ICHG2016 506

Everything in One Assay: an Inescapable Approach
Wed., April 06, 2016 12:30-13:30 Room A (2F)
Chair：Heidi Kijenski（Global Marketing Director / Human and Reproductive Genetics / Agilent Technologies, Inc.）
WES has proved efficient to determine the molecular basis of diseases due to mutations in either known or new genes.
However, WES can be inefficient for the detection of CNVs that account for roughly 10% of monogenic disorders. We
present our research to address this inescapable requirement.

Everything in One Assay: an Inescapable Approach
1
Luncheon Seminar
Orsetta Zuffardi
1:Department of Molecular Medicine, University of Pavia and IRCCS Foundation Policlinico San Matteo, Pavia, Italy
No Abstract

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ICHG2016 507

Initiative on Rare and Undiagnosed Diseases (IRUD) in Japan
Wed., April 06, 2016 12:30-13:30 Room E (1F)
Chair：Kenjiro Kosaki（Keio University School of Medicine Center for Medical Genetics, Japan）
In 2015, the Japan Agency for Medical Research and Development (AMED) initiated and funded a research project
“Initiative on Rare and Undiagnosed Diseases (IRUD)”. The aims of IRUD are to establish nation-wide diagnostic
system for rare and undiagnosed diseases and to establish systematic database on those conditions. Expected outcome of
the project include installment of regional clinical centers for rare and undiagnosed diseases, feedback of analytical results
to patients for better clinical decision and medical care, discovery of novel disease entities and establishment of analytical
consortium and data sharing. Overview and current status of the IRUD project will be presented.
Luncheon Seminar

Initiative on Rare and Undiagnosed Diseases (IRUD) in Japan
1
Yoichi Matsubara
1:National Center for Child Health and Development, Japan
No Abstract
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ICHG2016 508

Mathematical Analyses on Disease Risk Prediction and Socio-Psychological Insights on Personal Genome
Services
Wed., April 06, 2016 12:30-13:30 Room B-1 (2F)
Chair：Naoyuki Kamatani（StaGen Co., Ltd.）
Recently, there is a growing demand for personalized medicine. However, a gold standard for accurately estimating
personal genetic risk has not yet been established. In this talk, we introduce our past studies on (1) how we can predict
our disease risk more precisely, (2) how we can interpret the results more appropriately and (3) how we can create new
values with personal genome information. We report our past studies on mathematical (statistical) analyses on disease
risk predictions, socio-physiological surveys with more than 4,000 Japanese individuals and quantified self (QS) and citizen
science projects for bringing us new insights on personalized medicine.
Luncheon Seminar

Mathematical Analyses on Disease Risk Prediction and Socio-Psychological Insights on Personal Genome
Services
1
Takashi Kido
1:RIKEN GENESIS CO., LTD.
No Abstract
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ICHG2016 509

Autosomal Dominant Polycystic Kidney Disease
Wed., April 06, 2016 12:30-13:30 Room D (1F)
Chair：Kazushige Hanaoka（Jikei University, Japan）
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder, affecting
1/1000-2000.
The development and proliferation of renal cysts lead to progressive renal enlargement and renal insufficiency. Approxi-
mately, 50% of patients with ADPKD progress to end-stage renal disease (ESRD) at a median age of 58 years.
Recently the mechanism of this disease is revealed by molecular biology, cell biology and metabolism. New therapy was
developed, and approved in Japan, Canada and EU.
At this seminar, the latest topics of pathophysiology and therapy in ADPKD will be presented.
Luncheon Seminar

1
Kazushige Hanaoka
1:Jikei University, Japan
No Abstract
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ICHG2016 510

1
Gregory G. Germino
1:National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health, USA; Johns Hopkins
School of Medicine, USA
No Abstract
Luncheon Seminar
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ICHG2016 511

-beginning of a new era of hereditary neurodegenerative disease therapy and genetic counseling-
Thu., April 07, 2016 11:30-12:30 Annex 1 (1F)
Chair：Tatsushi Toda（Division of Molecular Brain Science, Kobe University Graduate School of Medicine）
Hereditary ATTR amyloidosis is an autosomal dominant genetic disorder with systemic deposition of amyloid fibrils
induced by transthyretin (TTR) gene mutation. Mutations in TTR destabilize its native state tetrameric structure,
promoting TTR dissociation, misfolding and misassembly into amyloid fibrils. Recently, the clinical effects of TTR
tetramer stabilizers on hereditary ATTR amyloidosis were demonstrated in randomized clinical trials, and tafamidis has
been approved in more than 30 countries. Under these circumstances, early diagnosis, including predictive genetic testing,
will become increasingly important in ATTR amyloidosis. Recent research demonstrated that most neurodegenerative
disorders involve protein misfolding, in an analogous fashion to ATTR amyloidosis. It is expected that the newly developed
Luncheon Seminar
disease-modifying therapy for ATTR amyloidosis will open a new era of neurodegenerative disease therapy and genetic
counseling.

-beginning of a new era of hereditary neurodegenerative disease therapy and genetic counseling-
1
Yoshiki Sekijima
1:Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine
No Abstract
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ICHG2016 512

Six-layer Structure for Genomics: A Powerful Conceptual Framework Useful for a Comprehensive Un-
derstanding of Studies, Tests and Treatments in This Field...
Thu., April 07, 2016 11:30-12:30 Annex 2 (1F)
Chair：Matthew Levy（Affymetrix Inc.）
Although“genomics”is more broadly descriptive than“genetics”, it does not provide a satisfactory conceptual framework
that scientists can share. Here, I propose a 6-layer structure (life, species, population, family, individual, and finally cell)
that describes the entire scientific field for “genomics”. Each member of the upper layer comprises a set of members of
the lower layer. In each layer, we can define consistent partial orders of members based on genomic data which allows
logical and mathematical analyses. I will show that a comprehensive understanding of studies, tests and treatments in
this field is possible by the proposed 6-layer structure.
Luncheon Seminar

Six-layer Structure for Genomics: A Powerful Conceptual Framework Useful for a Comprehensive Un-
derstanding of Studies, Tests and Treatments in This Field, and for A Translation of The Results of
Genomic Studies to Medicine and Healthcare
1
Naoyuki Kamatani
1:Institute of Rheumatology, Tokyo Women’s Medical University, Japan
Session Title: Six-layer Structure for Genomics: A Powerful Conceptual Framework Useful for a Comprehensive Understanding
of Studies, Tests and Treatments in This Field, and for A Translation of The Results of Genomic Studies to Medicine and
Healthcare
No Abstract
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ICHG2016 513

Transforming the State of Genomic Biomarker Discovery and Diagnostic Testing with High-throughput
Long-read DNA Sequencing Technologies
Thu., April 07, 2016 11:30-12:30 Room A (2F)
Chair：William LaRochelle（Roche Sequencing Solutions）
Recent advances in the Pacific Biosciences SMRT technology have dramatically increased the sequencing throughput,
making it possible for the first time to tackle large-scale population-based studies using long-read sequencing. Beyond the
more general, we have developed high-grade clinical assays for routine genetic testing in complex gene regions associated
with disease, including long-range, high fidelity sequence capture in tandem with long-read sequencing in BRCA1/2
genes for assessing heritable cancer risk, CYP2D6 for more comprehensive assessment of response to a wide range of
drugs including tamoxifen, and the HLA region to more comprehensively characterize variation in HLA genes in support
of our novel vaccine development strategies for immunotherapy in different cancers currently in clinical trials.
Luncheon Seminar

Transforming the State of Genomic Biomarker Discovery and Diagnostic Testing with High-throughput
Long-read DNA Sequencing Technologies
1
Robert Sebra
1:Assistant Professor, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY
No Abstract
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ICHG2016 514

Update on the molecular genetics and pathogenesis of RASopathies
Thu., April 07, 2016 11:30-12:30 Room D (1F)
Chair：Yoichi Matsubara（Director of the Research Institute National Center for Child Health and Development）
RASopathies are a group of phenotypically overlapping syndromes caused by mutations that encode molecules of the
Ras/MAPK signaling pathway. These disorders include Noonan syndrome, Noonan syndrome with multiple lentigines,
Costello syndrome, cardio-facio-cutaneous (CFC) syndrome, neurofibromatosis type I, Legius syndrome and capillary
malformation-arteriovenous malformation. Recently, novel gene variants, including RIT1 , RRAS, RASA2 , A2ML1 , SOS2
and LZTR1 , have been shown to be associated with RASopathies. In addition, several mosaic RASopathies have been
identified, further expanding the disease spectrum. In this talk, molecular and phenotypic spectrum of germline/mosaic
RASopathies and our recent findings on knock-in mice of CFC syndrome will be presented.
Luncheon Seminar

Update on the molecular genetics and pathogenesis of RASopathies
1
Yoko Aoki
1:Professor of Department of Medical Genetics, Tohoku University School of Medicine
No Abstract
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Opening Ceremony
Mon., April 04, 2016 10:00-10:30 Main Hall (1F)


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Closing Ceremony
Thu., April 07, 2016 16:30-17:00 Main Hall (1F)


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Gala Dinner
Wed., April 06, 2016 19:00-21:00 Prince Hall at Kyoto Grand Prince Hotel

Gala Dinner

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Get-together
Sun., April 03, 2016 19:00-20:30 Garden and Banquet Hall Swan (1F)

Get-together

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Abstracts
Concurrent Oral Session

ICHG2016 520
[O1] Cancer Genetics 1

Mon., April 04, 2016 18:00-19:30 Annex 1 (1F)
Chair：Stephen E. Lincoln（Scientific Affairs, Invitae, USA）

Chair ：Yoichi Furukawa（Division of Clinical Genome Research, The Institute of Medical Science, The University of
Tokyo, Japan）
Mon(2)-O1-1
Monitoring Cancer Burden in Liquid Biopsies Utilizing Two Assays; Amplicon Sequencing and Global
Methylation Patterns to Characterize cfDNA
Matthew Hymes 1 ，Cassie Schumacher 1
1:Swift Biosciences, USA
Liquid biopsy is a non-invasive tool to assess cancer burden by examining the tumor-derived fraction of circulating, cell-
free DNA (cfDNA) from plasma. We have tested two assays to monitor cancer burden by examining cfDNA: a global
methylation sequencing assay and a targeted amplicon sequencing assay to identify mutations across 56 oncology related
genes. Genome-wide hypomethylation has been demonstrated as a surrogate biomarker for cancer and can detect cancer
independently of tumor-specific mutations. Amplicon-based detection of specific point mutations, however, provides a window
into tumorigenesis and potential therapeutic resistance. Amplicon sequencing costs are 10-times lower than methylation

sequencing with a faster turnaround time, but it is only effective if the cancer has a mutation covered by the panel. This
study utilizes both assays to probe the same diverse dataset as a means of characterizing their efficacy across a broad spectrum
of cancers. cfDNA was extracted from eight cancer patients and five normal controls. To monitor methylation status, whole
genome bisulfite sequencing was performed using 5 ng of bisulfite-converted cfDNA. A minimum threshold of greater than
three standard deviations below the methylation density of the normal controls in 1.1% of the genome analyzed was considered
significant as described by Lo et. al 2013. To detect tumor-specific mutations, 10 ng of cfDNA was used for the multiplexed
amplicon sequencing panel. Samples from both assays were sequenced on an Illumina MiSeq. When looking at a single time
point, we have demonstrated that each assay has varying utility based on cancer type and severity, thereby highlighting the
necessity to carefully consider these factors before choosing a characterization method. To further evaluate these techniques,
we will now apply them to a longitudinal study to follow mutation and hypomethylation status of cfDNA before, during, and
after treatment.
Mon(2)-O1-2
Evaluation of prediction models for Lynch Syndrome: Updating the PREMM1,2,6 model to identify PMS2
mutation carriers
Anne Goverde 1,2 ，Manon C.W. Spaander 2 ，Daan Nieboer 3 ，Ans M.W. van den Ouweland 1 ，Winand N.M. Dinjens 4 ，
Hendrikus J. Dubbink 4 ，Carli M. Tops 5 ，Marco J. Bruno 2 ，Robert M.W. Hofstra 1 ，Ewout W. Steyerberg 3 ，
Anja Wagner 1
1:Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, the Netherlands、2:Department of Gastroenterology
and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands、3:Department of Public Health, Erasmus MC,
University Medical Center Rotterdam, the Netherlands、4:Department of Pathology, Erasmus MC, University Medical Center Rotterdam,
the Netherlands、5:Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
Aim To evaluate the performance of two Lynch syndrome (LS) prediction models MMRpredict and PREMM1,2,6 .regarding
the identification of MMR-gene mutation carriers, especially PMS2 mutation carriers.
Methods In a retrospective, clinic-based cohort we calculated the probability of carrying a LS mutation according to MM-
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Rpredict and PREMM1,2,6 for each index patient. The area under the operator receiving characteristic curve (AUC) was
compared between MMRpredict and PREMM1,2,6 for LS patients in general and for the different MMR genes specifically.
Results Of the 927 index patients, 100 (11%) were diagnosed with LS; 23 MLH1, 20 MSH2, 41 MSH6 and 16 PMS2 mu-
tation carriers. Overall, PREMM1,2,6 had a slightly higher AUC than MMRpredict (AUC 0.75 vs. 0.72). Both prediction
models performed well for MLH1 and MSH2 mutation carriers (AUC 0.83 and 0.84 for PREMM1,2,6 and 0.78 and 0.80 for
MMRpredict). MMRpredict had poor discriminative power for MSH6 and PMS2 mutation carriers (AUC 0.66 and 0.67).
PREMM1,2,6 had a fair discriminative power for MSH6 mutation carriers (AUC 0.72), but failed to identify PMS2 mutation
carriers at all (AUC of 0.52). The only statistically significant difference between PMS2 mutation carriers and non-mutation
carriers was the proximal location of colorectal cancer (77% vs. 28%, p<0.001). By adding this variable to the PREMM1,2,6
model its performance considerably improved for PMS2 mutation carriers (AUC 0.69 vs. 0.50) and overall (AUC 0.81 vs.
0.75).
Conclusion MMRpredict and PREMM1,2,6 cannot adequately identify PMS2 mutation carriers. Adding location of colorectal
cancer to the PREMM1,2,6 model improves the performance of this model and should be validated in larger cohorts.
Mon(2)-O1-3
Rapid and comprehensive routine diagnostic approach for prognostic genetic markers in multiple myeloma

Jacqueline Schoumans 1 ，Sandrine Bougeon 1 ，Elodie David 1 ，Laurence Etter 1 ，Noemie Gesson 1 ，
Dominique Muehlematter 1
1:Medical Genetics, Centre Hospitalier Universitaire Vaudois CHUV, Switzerland
Multiple myeloma (MM) is a plasma cell (PC) malignancy characterized by clonal expansion of terminally differentiated B
cells in the bone marrow (BM). It is the second most common malignant blood disorder in the Caucasian population and
associated with complex genetic changes predicting patients’ outcome. Evaluation of genetic lesions is an important tool for
risk assessment and treatment monitoring.
Due to resolution and low proliferation activity of PC the detection of chromosomal aberrations by conventional karyotyping
has proven to have too strong limitations. Whilst molecular cytogenetic approaches such as SNP-array and iFISH performed
on PC enriched BM samples have shown that genomic alterations are present in more than 90% of the MM patients. Recent
studies demonstrated that disease evolution is associated with an accumulation of specific genome imbalances with important
prognostic values. Furthermore, one of the main genetic events in MM is the translocation of the immunoglobulin heavy
chain gene complex (IGH) with different chromosomes partners with the gene CCND1 at 11q13 being the most frequently
observed.
Due to the often small quantities of material available after PC enrichment, the assessment of the full MM genome for
prognostic markers including balanced translocations of the IGH gene can be challenging in a routine diagnostic setting. To
overcome this, we developed a sensitive and reliable analytical protocol allowing whole genome screening with low cell quan-
tities (minimum 5000 cells) using a combination of SNP-array and a tri-colour customized iFISH. This approach interrogates
genomic imbalances, CNLOH as well as IGH rearrangements with CCDN1 or other partner and allows rapid turnaround time
of analysis. Workflow, performance and analytical results will be presented and discussed.
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Mon(2)-O1-4
Clinical Validity and Actionability of Multigene NGS-Based Tests for Hereditary Cancers in a Large
Multi-Center Study
Stephen E Lincoln 1 ，Andrea J Desmond 2 ，Allison E Kurian 3 ，Shan Yang 1 ，Yuya Kobayashi 1 ，Aaron Solomon 1 ，
Swaroop Aradadhya 1 ，James M Ford 2 ，Leif W Ellisen 3
1:Invitae, USA、2:Massachusetts General Hospital, Boston, Massachusetts, USA、3:Stanford University Medical Center, Palo Alto,
California, USA
Clinical genetic testing is rapidly evolving with the introduction of next-generation sequencing (NGS) however questions
remain about these new tests. First, can NGS methods be deployed that deliver equal or improved performance vs. traditional
methods on the full spectrum of (often complex) disease causing variants? Second, do expanded NGS tests provide medical
benefits which outweigh the increased uncertainty that naturally follows from testing more genes in more patients?
In recently published work [Lincoln, JMD 2015; Desmond, JAMA Oncol 2015] we tested a large panel of cancer risk genes by
NGS in a representative cohort of over 1000 patients meeting current medical guidelines for BRCA1/2 testing. We find 100%
concordance with traditional methods on both sequence and copy-number alterations using a battery of 5 calling algorithms
and associated biochemistries. Using an interpretation system (Sherloc) based on ACMG 2015 guidelines and employing only
publicly available data, we find 99.8% concordance with BRCA1/2 classifications produced by a different laboratory that uses
a large proprietary database. Finally, we find that genetic test results beyond BRCA1/2 would often warrant consideration
of a change in screening or interventions for mutation-positive patients under current medical practice guidelines.

In ongoing studies, we find that challenging genes (e.g. PMS2) can be included with equally high performance using additional
biochemical and bioinformatic NGS methods. We also find demonstrated utility beyond the classical BRCA1/2 indications.
We conclude that expanded genetic testing by NGS has clinical validity and increases clinical actionability compared to
traditional tests.
Mon(2)-O1-5
The Mitochondrial Mutational Landscape of Human Cancer and its Impact on Cancer Progression
Sneha Grandhi 1 ，Colleen M Bosworth 1 ，Wesley J Maddox 1 ，Thomas LaFramboise 1
1:Genetics and Genome Sciences, Case Western Reserve University, USA
Despite their crucial role in cellular bioenergetics, mitochondria in cancer cells are often seen as bystanders to the tumorigenic
process. Mitochondria contain their own genome (mtDNA) which encodes key proteins involved in mitochondrial oxidative
phosphorylation, the primary source of ATP in normal cells. However, instead of utilizing mitochondria, cancer cells turn
to alternative sources of energy production such as aerobic glycolysis, even in the presence of oxygen. Although there is
an accumulation of somatic mtDNA mutations in cancer, the functional role of mitochondria in this altered metabolic state
is unclear. In particular, the importance of underlying selective processes that determine the cancer cell’s preference or
tolerance for acquiring protein-altering mtDNA mutations remains highly debated.
Preliminary analysis of TCGA whole-genome sequencing data from 2,048 cancer patients across 24 tumor types suggests that
normal cells predominantly show a strong negative selection against acquiring missense mtDNA variants, whereas tumor cells
are more tolerant of acquiring protein-altering changes to their mtDNA (relaxed negative selection). However, patients with
liver cancer show positive selection for missense mtDNA mutations in their normal liver tissues, suggesting that mitochondria
may play an important role in hepatocellular carcinoma. Additionally, our data shows severe depletion of overall mtDNA
content in the tumor cells of patients with liver, kidney, and muscle malignancies. Overall, results from this extensive pan-
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cancer analysis indicate the presence of variable tumor mtDNA content and selective pressures for missense mtDNA variants
based on tissue-type, suggesting a novel, tissue-specific role for mitochondria in cancer progression.
Mon(2)-O1-6
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[O2] Genetics/Genomics Education

Mon., April 04, 2016 18:00-19:30 Annex 2 (1F)
Chair：Brenda J. Wilson（School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Canada）
Chair ：Takahito Wada（Department of Medical Ethics and Medical Genetics, Kyoto University Graduate School of
Medicine, Japan）
Mon(2)-O2-1
Genomics and personalized medicine in primary care: a professional engagement study using theory-
informed approaches
Brenda J Wilson 1 ，Christina A Catley 2 ，Julian Little 1 ，Stuart G Nicholls 1 ，June C Carroll 3 ，Holly Etchegary 4 ，
Monica Taljaard 5 ，CIHR Emerging Team in Genomics in Screening
1:School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Canada、2:Clinical Epidemiology Program, Ottawa
Hospital Research Institute, Ottawa, ON, Canada、3:Department of Family & Community Medicine, Mount Sinai Hospital, University of
Toronto, Canada、4:Craig L Dobbin Centre for Genetics, Memorial University, NL, Canada、5:Centre for Practice Changing Research,
Ottawa Hospital Research Institute, Ottawa, On Canada
Background:
Studies consistently suggest that primary care professionals see great potential in genomics but hold reservations about its

utility for their own practice. New methods are required to understand how to design effective implementation strategies for
such emerging technologies. We developed and evaluated a deliberative workshop approach as a method to identify issues
salient to the successful adoption and implementation of genomics and personalized medicine in primary care.
Methods:
We developed a prototype professional engagement approach informed by Kirkpatrick’s educational hierarchy, relevant to
genomics as a new technology for the target group. It comprised a standardized background on genomics and personalized
medicine; hypothetical case studies reflecting the congruence between potential uses of genomics and current primary care
activities; pauses for facilitated deliberation/reflection; and embedded self-completion surveys. We recruited family physicians
and primary care nurses to participate the workshop delivered in-person or online.
Results:
Twenty physicians and 44 nurses participated (34 in-person, 30 online). Baseline analyses showed no differences by professional
group or workshop format in perceptions of genomics or assessments of clinical
utility. Pre-post quantitative comparisons indicated shifts to more positive judgments of likely utility for personalized medicine
in general, and for the systematic use of family history information (one of the case studies), but not for genomic profiling for
CRC risk or type 1 diabetes risk prediction (the other case studies). Dominant themes in qualitative analyses indicated both
positive and negative beliefs about the consequences of using genomics in practice, and perceived challenges with integration
into practice. We noted more extensive qualitative data from online than in-person participants.
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Mon(2)-O2-2
Supporting the workforce to deliver the 100,000 Genomes Project: the work of Health Education Eng-
land’s Genomics Education Programme
Michelle Bishop 1 ，Anneke Seller 1 ，Sue Hill 2 ，Val Davison 1 ，Genomics Education Programme
1:Genomics Education Programme, Health Education England, UK、2:Chief Scientific Officer, NHS England
England aims to become the first country to introduce genomic technologies across routine healthcare through the 100,000
Genomes Project. This ambitious project, to sequence 100,000 genomes from patients with rare inherited diseases or cancer,
is being delivered via a network of NHS Genomic Medicine Centres across England. Alongside the scientific and clinical
discoveries, this multifaceted programme provides a unique opportunity to embed genomic medicine into mainstream clinical
practice through a co-ordinated approach to workforce education and development. Health Education England’s Genomics
Education Programme was established to provide educational support to both staff delivering the Project, and to the current
and future NHS workforce to ensure a lasting legacy. The education and training needs of the workforce were determined
through a gap analysis with 9 resources identified to support the clinical and scientific activities across the Project pipeline.
These include resources specific to the Project protocol (e-learning on patient consent; eligibility tools; DNA extraction; sample
processing; data assurance; validation and clinical reporting of the results). Others have wider clinical applicability (MOOC
on whole genome sequencing (WGS); online tumour assessment for WGS competency training tool). Each resource has been
designed for multidisciplinary use, with clinical relevance and applicability assured through continuous engagement with NHS
staff throughout the development and implementation phases. Effectiveness is evaluated at two levels: acquisition of knowledge

and skills; and impact on clinical practice. Initial results show our resources meet participants’ educational and training needs
and provide practical information that can be incorporated into their clinical practice. This presentation will provide details
of our work in engaging NHS staff throughout this process and demonstrate evidence of workforce transformation.
Mon(2)-O2-3
Human Genetics: Medical and Societal Implications. A high school course on a medical school campus
Maurice Godfrey 1 ，Jaynie E Bird 2
1:Munroe Meyer Institute, University of Nebraska Medical Center, USA、2:Omaha Public Schools and University of Nebraska Medical Center
The University of Nebraska Medical Center (UNMC) High School Alliance is a partnership that includes 23 high schools from
twelve school districts in the Omaha, Nebraska area. The partnership was forged to increase the awareness of biomedical
careers in an effort to increase the pipeline of students choosing these careers. Over the first six years of this program more
than 30% of students have come from underrepresented minority groups; compared to an 18% minority population in the
Omaha area.
The Alliance program allows students to attend their home high schools in the morning and come to UNMC each afternoon for
an entire academic year. While at UNMC they are taught by Medical Center faculty. Courses include: Biomedical Research,
Infectious Disease, Art & Science of Decision Making, Community Health, Human Anatomy, Human Genetics, Pathology,
Study of Patient Care, and Pharmacy Science. Students also take part in numerous health science shadowing opportunities
both on and off the UNMC campus. To ensure that high school credit is received, a certified high school teacher assists in all
phases of the program. The Alliance was not designed to attract only the best and brightest. Requirements are modest and
student (as opposed to parent) interest is paramount.
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Here we report on the early evaluation and success of the Human Genetics: Medical and Societal Implications, a course taught
by medical school faculty to high school students. Student knowledge of genetics increased each year the course has been
taught. Interest in a career in genetics also increased. Students rarely thought about ELSI related issues prior to the course.
Hands-on modules that related molecular biology to genetics are engaging and among the most liked lessons. Mathematical
aspects of genetics are among the most difficult concepts for students. Nevertheless, many students expressed that they now
had the confidence and new knowledge that would enable them to pursue a career in the health sciences.
Mon(2)-O2-4
Impact of educational messages for parents about newborn screening: a randomized factorial survey
Beth K Potter 1 ，Brenda J Wilson 1 ，June C Carroll 2 ，Julian Little 1 ，David Castle 3 ，Pranesh Chakraborty 4 ，
Samantha Craigie 5 ，Holly Etchegary 6 ，Louise Lemyre 1 ，Fiona A Miller 2 ，George A Wells 1 ，
Jennifer Milburn 4 ，Keith Miller 1 ，Laure Tessier 1 ，Ruth R White 7 ，George Tawagi 8 ，Mark Walker 7 ，
CIHR Emerging Team in Genomics in Screening
1:University of Ottawa, Canada、2:University of Toronto、3:University of Victoria、4:Children’s Hospital of Eastern Ontario、5:McMaster
University、6:Memorial University、7:Ottawa Hospital Research Institute、8:The Ottawa Hospital
Background: Effective parental education about newborn screening (NBS) is important even where screening is mandated.
Potential benefits include promoting trust, mitigating anxiety, and emphasizing the importance of follow up where needed.
However, concerns are sometimes expressed that more comprehensive education may lead to parental anxiety and lower

acceptance rates. Published expert opinions suggest key NBS educational messages, but empirical evaluations are lacking.
Objectives: To measure the effect of specific educational messages on pregnant women’s decisional conflict about NBS.
Methods: Women were recruited from routine second trimester ultrasound clinics in Ottawa, Ontario. Using a factorial survey,
they were randomized to receive different combinations of messages: possibility of false positive/negative results; pain from
the heel-prick; possibility for results of uncertain clinical significance; storage/secondary use of bloodspots; and the nature of
parental consent. The primary outcome was the validated Decisional Conflict Scale (DCS) (1-100, higher scores indicating
higher decisional conflict). Secondary analyses explored associations with respondent characteristics, their understanding of
key messages, and cognitive burden.
Results: We received responses from 494 participants. The mean (95% CI) DCS score was 27 (25-29). Only one message was
independently associated with decisional conflict: recipients of the heel-prick pain message had lower DCS scores on average
than non-recipients (p<0.05). Specific knowledge questions were more likely to be answered correctly if the participant had
received the corresponding message. The mean DCS score declined significantly with increasing number of messages received
(test for linear trend, p<0.01).
Conclusions: The results suggest that providing information does not compromise NBS decision-making and may enhance it.
This study has high internal validity but needs to be replicated in more diverse populations.
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Mon(2)-O2-5
A psycho-educational intervention for people with a family history of depression for use in general
practice. Results from pilot testing
Kristine K Barlow-Stewart 1 ，Bettina Meiser 2 ，Michelle Peate 2 ，Charlene Levitan 2 ，Peter Schofield 3,4 ，
Lyndal Trevena 5 ，Timothy Dobbins 5 ，Helen Christensen 6 ，Kerry Sherman 7 ，Kate Dunlop 8 ，Philip Mitchell 9
1:Sydney Medical School Northern, University of Sydney, Australia、2:Psychosocial Research Group, Prince of Wales Clinical School,
UNSW, Sydney、3:Neuroscience Research Australia, Sydney、4:School of Medical Sciences, UNSW, Sydney、5:Sydney School of Public
Health, University of Sydney, Sydney、6:Black Dog Institute, Sydney、7:Centre for Emotional Health, Department of Psychology, Macquarie
University, Sydney、8:Centre for Genetics Education, NSW Health, Royal North Shore Hospital, St Leonards, Sydney、9:School of
Psychiatry, UNSW, Sydney
Background: No psycho-educational interventions are currently available that specifically target people with a family history
of depression. We developed and pilot-tested an online psycho-educational intervention (‘LINKS’). LINKS provides genetic
risk information and evidence-rated information on preventive strategies for depression and incorporates a risk assessment
tool and several videos using professional actors. Results from pilot-testing in the GP setting will be presented.
Methods: Sydney GP practices were broadly sampled to ensure heterogeneity and generalizability. The patient sample in-
cluded people with a family history of at least one first-degree relative with manic depressive (MDD) or bipolar disorder
(BD). Patients attending participating GP practices were invited to the study by letter by their GP. Patients were asked to
self-identify as having a first-degree degree relative with MDD or BD and then invited to access LINKS. Participants who
accessed LINKS completed purposively developed measures assessing satisfaction, relevance, emotional impact and perceived

improvement of understanding.
Results: 22 patients completed all questionnaires. 100% patients reported they were satisfied or very satisfied with LINKS.
85% reported they would recommend LINKS to others with a family history of depression. 73% reported that LINKS met
their expectations, and 23% that it exceeded their expectations.
Discussion: This novel psycho-educational intervention provides individuals with a family history of depression with informa-
tion on evidence-based strategies for the prevention of depression. In a subsequent cluster randomised controlled trial we will
test the hypothesis that LINKS will enable people to make appropriate lifestyle choices and implement behaviours designed
to reduce their risk for depression.
Mon(2)-O2-6
Exploring Australian public knowledge and understanding of DNA, genes and genetic testing in the era
of personal genomics
Bronwyn N Terrill 1 ，Jacqueline Savard 4 ，Chriselle Hickerton 2,3 ，Erin Turbitt 2,3 ，Ainsley J Newson 4 ，Clara L Gaff 5 ，
Kathleen Gray 2 ，Anna Middleton 6 ，Brenda J Wilson 7 ，Sylvia A Metcalfe 2,3
1:Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Australia、2:The University of Melbourne、3:Murdoch
Childrens Research Institute、4:The University of Sydney、5:The Walter and Eliza Hall Institute of Medical Research、6:Wellcome Trust
Sanger Institute、7:University of Ottawa
‘Next generation genomics’encompasses a ‘disruptive’technology enabling widely available personal genomic tests. Genomic
testing provides healthy individuals with access to their own genetic makeup for purposes that include ancestry, paternity,
sporting ability and health. It is anticipated that such testing will become routine and accessible to all Australians.
Focus groups were conducted as part of a multi-disciplinary project to explore Australians’ awareness and expectations
of personal genomic testing. Fifty-six members of the public participated in seven focus groups hosted over a two-month
period in 2015. Focus groups were split across three age groups: 18-25, 26-49 and 50 years and over. Transcripts were coded
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and themes generated with a specific focus on genetic literacy: whether participants demonstrated sufficient knowledge of
genomics principles to support informed decision-making.
Participants’ descriptions of DNA, genetics and genomics broadly reflected previously reported facets of genetics. They
were familiar with ideas of heredity, acknowledged the genetic influences on physical characteristics, and spoke about genetic
uniqueness. There was no clear consensus around the relative influence of genetics on health, mental health, behaviour, talent
or personality. In addition, participants were unfamiliar with the more visible academic terms direct-to-consumer testing and
personal genomics. Although discussions focused particularly on genetic influences using language that could be described as
highly deterministic, each group acknowledged the role of non-genetic factors such as diet, lifestyle and environment in the
development of specific characteristics.
The focus groups highlighted challenges of using terms such as personal genomics and direct-to-consumer testing in public
discussions and educational activities because many people are unfamiliar with their meaning.
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[O3] Prenatal, Perinatal and Reproductive Genetics 1

Mon., April 04, 2016 18:00-19:30 Room A (2F)
Chair：Lingqian Wu（State Key Laboratory of Medical Genetics, Central South University, China）
Chair ：Michiko Yamanaka（Dept. Clinical Genetics, St.Luke’s International Hospital, Japan）
Mon(2)-O3-1
Noninvasive Prenatal Testing and its Relevance to Clinical Practice: Update on Clinical Outcome Metrics
on Over 85,000 Cases
Sucheta Bhatt 1 ，Patricia A. Taneja 1 ，Holly Snyder 1 ，Eileen de Feo 1 ，Kristina M. Kruglyak 1 ，Meredith Halks-Miller 1 ，
Kirsten J. Curnow 1
1:Illumina, Redwood City, CA, USA
Objective: The verifi noninvasive prenatal test (NIPT) has been available through Illumina’s accredited clinical lab since
February 2012. In follow-up to Illumina’s first published clinical experience paper (Futch et al., 2013), this study highlights
continued efforts to provide clinically relevant metrics for chromosomes 21, 18, and 13.
Method: Outcome information (karyotype/birth outcome) was requested from providers for singleton samples reported as
aneuploidy detected (AD) or aneuploidy suspected (AS) for chromosomes 21, 18, or 13. Voluntary outcome reporting was

encouraged for all discordant outcomes.
Results: Of 86,658 cases, 85,298 (98.4%) met inclusion criteria for NIPT result reporting, 101 (0.1%) were cancelled for
technical reasons and 1,259 (1.5%) for administrative reasons. Average turnaround time was 3.3 business days. Of 85,298
reported cases, there were 2,142 (2.5%) positive results: 1,858 AD (2.2%) and 284 AS (0.3%). Informative clinical outcomes
were available for 851 (39.7%) positive cases. Of 85,298 reported samples, 108 (0.13%) AD cases were reported as putative
false positives; 15 (0.02%) false negatives were reported. The observed overall positive predictive value was 94.2% for AD
samples and 88.9% for AD/AS samples combined. The overall observed negative predictive value was >99.9%.
Conclusion: Since 2012, there have been improvements in turnaround time and cancellation rates, as well as a significant
decrease in the aneuploidy suspected results. Information about clinical performance of NIPT aids in appropriate pre- and
post-test counseling.
Mon(2)-O3-2
Non-invasive prenatal diagnosis for single gene disorders
1,2
Lingqian Wu ，Weigang Lv 2 ，Desheng Liang 1,2
，Yang Gao 3
1:State Key Laboratory of Medical Genetics, Central South University, China、2:Hunan Jiahui Genetics Hospital, Changsha, China、3:Berry
Genomics, Beijing, China
Objectives: Non-invasive prenatal testing (NIPT) for fetal single gene disorders that are caused by mutations remains an
analytical challenge. The aim of the study was to determine the reliability and accuracy of a new fetal genotyping assay
termed circulating single molecule amplification and re-sequencing technology (cSMART) for NIPT of single gene disorders.
Methods: In four prenatal programs for Wilson disease, phenylketonuria, hearing loss and β-thalassemia (n=4, n=23, n=32
and n=106 respectively), all couples at risk of having a affected child were offered invasive testing by Sanger sequencing of
fetal amniocytes. Stored plasma samples from these pregnancies were also analysed retrospectively by a 16-plex cSMART
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assay involving targeted primers for the different parental mutations and a set of SNPs with a high heterozygosity index for
fetal fraction confirmation. The percentage of mutant alleles/SNPs in the plasma samples determined by cSMART assay was
used to deduce fetal DNA fraction and assign fetal genotypes. Results: A total of 165 plasma samples from pregnancies at
risk for the related diseases were coded and blindly analyzed by cSMART assay at an independent sequencing facility. NIPT
identified 37 normal, 39 paternal carrier, 50 maternal carrier and 39 affected foetuses. All diagnoses were concordant with fetal
genotypes retrospectively determined by Sanger sequencing of amniocyte DNA. Correct fetal genotyping by cSMART assay
was achieved with fetal DNA fractions ranging from 5.71% to 26.8%. In addition, the cSMART assay also correctly assigned
the maternal genotypes and provided information on half the paternal genotypes. Conclusions: The cSMART assay is highly
sensitive and specific for fetal genotyping of maternal plasma samples from pregnancies at risk for single gene disorders. This
new assay has clinical potential for combined prenatal diagnosis and parental carrier testing for all known disease-specific
mutations during pregnancy.
Mon(2)-O3-3
Indication and detective rate of amniocentesis changed by the adoption of non-invasive prenatal genetic
testing
Rie Oi 1,2 ，Takahiro Yamashita 1 ，Yoshiharu Takeda 1 ，Setsuko Nakayama 3 ，Miki Hatakeyama 3 ，Takako Maruyama 3 ，
Hideki Sakamoto 1 ，Tomoko Adachi 1 ，Takashi Okai 1 ，Toshiro Kubota 2 ，Masao Nakabayashi 1
1:Obstetrics, Aiiku Hospital, Japan、2:Graduate School of Tokyo Medical and Dental University、3:Obstetrics, Aiiku Clinic

Objective: To compare the indication and detective rate of amniocentesis (AC) before and after the adoption of non-invasive
prenatal genetic testing (NIPT).
Methods: We divided the past several years into pre-NIPT period (April 2008 to March 2014) and NIPT period (April 2014
to July 2015). We investigated the population, indication and the results of AC performed before 22 weeks of gestation from
the chart.
Results: In the pre-NIPT period there were 9448 deliveries. During the period 667 AC was performed and the number
corresponded to 7.1% of the deliveries. Atypical karyotype including normal variant were detected in 51 cases (7.7% of AC);
30 cases of abnormal karyotypes and 21 cases of normal variants. Advanced maternal age (AMA) occupied 59.8% of the
indication. Abnormal ultrasound (US) findings including nuchal translucency occupied 3.9%. In the NIPT period there
were 2439 deliveries. The population of AC was 142 (corresponded to 5.8% of the deliveries). The detective rate of atypical
karyotype including normal variant significantly increased to 12.0% (17 cases; 9 abnormal karyotypes and 8 normal variants).
AC for the indication of AMA decreased to 41.4% and AC for US findings significantly increased to 16.6%. In regards of the
detective rate of each indication in the total period, the rate of abnormal karyotype was the following; 3.4% in AMA, 5.6%
in US, 3.4% in maternal serum screening (MSS) positive of over age 35, 3.0% in MSS positive of under age 35. Expectant
women underwent AC just for anxiety had no abnormal karyotypes. All of three AC for NIPT positive resulted in trisomies.
The detective rate of trisomy was 18.5% in US, 1.9% in AMA and 5.4% in MSS positive.
Conclusion: After the adoption of NIPT, AMA decreased and abmormal US findings increased for the reasons for AC. The
fact that the frequency of abnormal karyotype by AC developed after NIPT introduction may suggest that the expectant
women of AMA tend to choice NIPT.

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Mon(2)-O3-4
Development and validation of a novel whole genome sequencing pipeline for non-invasive prenatal
detection of fetal submicroscopic chromosome anomalies
1,2 1,2
Desheng Liang ，Lingqian Wu
1:State Key Laboratory of Medical Genetics, Central South University, China、2:Hunan Jiahui Genetics Hospital, Changsha, China
Objectives: Fetal copy number variations (CNVs) associated with clinically significant chromosome disease syndromes, occur
in approximately 1% of all pregnancies. To expand the clinical utility of non-invasive prenatal testing (NIPT) beyond common
chromosomal aneuploidies, the aim of the study was to determine the reliability and accuracy of a novel PCR free NIPT
pipeline specifically designed to detect and delineate fetal CNVs. Methods: Plasma DNA libraries were generated in a single
step using a combination of DNA modifying enzymes without PCR amplification and then directly subjected to massively
parallel sequencing on the HiSeq 2500 platform. Approximately 12-14 million uniquely and perfectly mapped 36 bp reads
were used for data analysis. An analysis pipeline based on PCA and HMM was used to identify CNVs. Results: We analysed
six archived plasma samples (10.6-52.0% FF) with known fetal CNVs previously detected by SNP array analysis of amniocyte
DNA. Three samples had single CNVs (2.59 Mb 22q11 del, 1.5 Mb 17q25.3 dup and 27 Mb 4p16.3 dup) and three samples
had terminal chromosome CNVs associated with unbalanced translocations t(4;9) (27 Mb p15.2 dup; 0.68 Mb q34 del),
t(2;16) (0.88 Mb p25 del; 16 Mb p13.1 dup) and t(11;22) (18.2 q25 Mb dup; 4.2 Mb q13 dup). In a blinded analysis, all
CNVs with sizes above 1Mb in the six samples were correctly identified. The analysis algorithm was then applied to 1526
prospective NIPT samples. Fetal CNVs from 35 samples were identified (positivity rate ~ 2.29%) and verified by invasive

prenatal diagnosis (karyotype/follow-up), along with 5 maternal CNVs. For fetal CNVs, the combined positive predictive
value was 91.4% and the false negative rate was zero. Conclusions: Our optimised PCR free whole genome sequencing
NIPT pipeline using relatively deep sequencing was reliable and accurate for detection of a range of fetal and maternal
microdeletion/microduplication CNVs varying in size and genomic location.
Mon(2)-O3-5
Informed Choice in Prenatal Genetic Testing: the Choice Between Non-invasive and Invasive Prenatal
Testing
Karin E.M. Diderich 1 ，Sanne L van der Steen 1 ，Iris Bakkeren 1 ，Maarten F.C.M. Knapen 2,3 ，Attie T Go 2 ，
Aad Tibben 4 ，Gosia M.I. Srebniak 1 ，Diane Van Opstal 1 ，Marike G Polak 5 ，Sam R Riedijk 1 ，Robert Jan Galjaard 1
1:Clinical Genetics, Erasmus MC, Netherlands、2:Department of Obstetrics and Prenatal Medicine, Erasmus MC、3:Foundation Prenatal
Screening Southwest Region of the Netherlands, Rotterdam、4:Department of Clinical Genetics, Leiden University Medical Centre, Leiden、
5:Institute of Psychology, Erasmus University Rotterdam
Introduction: In case of an increased risk for common aneuploidies at the first trimester combination test (ftCT), the majority
of the centres in the Netherlands offer further testing by non-invasive prenatal testing (NIPT) for trisomy 21, 18 and 13, or
invasive prenatal diagnosis (PND) with rapid aneuploidy detection (RAD) for common aneuploidies. In contrast, our centre
offers whole genome SNP array analysis at 0.5 Mb resolution, which has a broader scope compared to NIPT and RAD. This
study investigated whether pregnant women and their partners made informed choices between NIPT and array testing after
routine pre-test counselling.
Methods: In total, 263 women and 94 partners participated. Informed choice was defined as ‘a behaviourally implemented
choice that is attitude-consistent and based on sufficient knowledge’. It was measured with the Measure of Informed Choice
(van der Steen et al. 2015, manuscript in prep.).
Results: Eighty-seven percent chose for NIPT, 12% chose for invasive PND. Only a minority (26%) of the NIPT group made a
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completely informed choice (sufficient knowledge, consistent attitude), versus 85% of the participants who opted for invasive
PND. In the NIPT group, 60% of choices were based on sufficient knowledge, but were inconsistent with attitude, versus 32%
in the invasive PND group. Scrutinizing the attitudes, we found that 25% of women and partners choosing NIPT did prefer
broader testing, but were held back by the miscarriage risk of an invasive procedure.
Conclusion: Our results show that most women highly valued the avoidance of a miscarriage risk over invasive PND. Their
attitudes indicate they would prefer results comparable to whole genome testing, but ‘safely’, i.e. performed by NIPT. For
informed decision-making during counselling, we advocate more focus on attitude consistency as compared to only a strong
focus on knowledge.
Mon(2)-O3-6
Differences in the background factors and awareness of noninvasive prenatal testing between pregnancies
achieved with assisted reproductive technology and spontaneous pregnancy in Japan
Akimune Fukushima 1 ，Kayono Yamamoto 1 ，Yumiko Kobayashi 1 ，Tomoharu Tokutomi 1 ，Tomonobu Kanasugi 2 ，
Fumiharu Miura 2 ，NIPT consortium of Japan
1:Clnical Genetics, School of Medicine, Iwate Medical University, Japan、2:Obstetrics and Gynecology, School of Medicine, Iwate Medical
University
Objective: In Japan, the rate of pregnancies over 35 years is increasing due to changes in lifestyle and advances in assisted

reproductive technology (ART). We investigated the hypothesis that the background behind undergoing NIPT and the
awareness thereof differ between cases of pregnancy achieved with ART and those of spontaneous pregnancy. In addition to
that we divided ART experienced participants into two groups: an IVF/ICSI group and an ART group who have used other
techniques, as IVE/ICSI is considered more invasive than other ART technics for women. Methods: Using questionnaire
data from the NIPT Consortium (in 2013/4-2014/5), 8030 women were divided into three groups: an IVF/ICSI group (Group
I; n=2028), a group without IVF/ICSI-ART (Group A; n=1343) and a spontaneous pregnancy group (Group S; n=4659).
One-way ANOVA was used to assess associations between quantitative variables, complemented by multiple comparison.
Pairwise comparisons were performed after Kruskal-Wallis H. Pearson’s chi-square test was used to assess associations between
categorical variables, complemented by adjusted residual analysis. Results: The median age and mean rank of I, A and S
groups were 39 (4765.8), 38 (3596.4) and 38 (3809.7), respectively. The final academic background was scored according to
the 5 points Likert scale (3: junior college, 4: university etc.). I, A and S scored 3.46 (±0.92), 3.42 (±0.87) and 3.33 (±0.92),
respectively. The differences in S-A, S-I pairs were statistically significant (p<0.01). The median family income and mean
rank of I, A and S were 3 (4283.5), 3 (4074.7) and 3 (3765.1), respectively (p<0.05 in all pair groups). The point 3 representing
＄ 57,000-80,000 p/a. The rate of ’Having a family member with a genetic disease’ was greater than the expected value in S
and less in I (p<0.01). Conclusion: Our results suggested that participants with backgrounds in different gestational methods
had distinguishing features.
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[O4] Bioinformatics and Genomic Technology 1

Mon., April 04, 2016 18:00-19:30 Room E (1F)
Chair：Altuna Akalin（BIMSB, Max Delbrueck Center, Germany）

Chair ：Masao Nagasaki（Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku Uni-
versity, Japan）
Mon(2)-O4-1
A shared system for collating, storing, analysing and reporting clinical genomic data across ten indepen-
dent organisations: a demonstration evaluation
Clara L. Gaff 1 ，Natalie Thorne 1 ，Tim Bakker 1 ，David Hansen 2 ，Alicia Oshlack 3 ，Graham Taylor 4 ，Andrew Lonie 5 ，
Melissa Martyn 1,3 ，Ivan Macciocca 1,4 ，Paul James 5,6 ，William Wilson 2 ，Maureen Turner 7 ，Information Management,
Genomics & Bioinformatics and Clinical Interpretation & Reporting Advisory Groups;
VLSCI & Evaluation & Development teams, Advanced Users Group and the Alliance
1:Melbourne Genomics Health Alliance, Australia、2:Australian E-Health Research Centre, CSIRO, Australia、3:Murdoch Childrens Research
Institute, Vic, Australia、4:Victorian Clinical Genetics Services, Vic, Australia、5:University of Melbourne, Vic, Australia、6:Melbourne Health,
Vic, Australia、7:BioGrid Australia
Coordinated and concerted change is essential to address the many barriers across the health system which limit the avail-
ability and use of clinical genomic information. The Melbourne Genomics Health Alliance is simultaneously addressing these
challenges as it integrates genomics into care across ten independent healthcare, research and academic organisations. A key

objective is ensuring there is a shared system to support the use of clinical genomic information firstly for patient care and
secondly for research.
To develop robust systems acceptable for use in healthcare, a demonstration project was conducted and evaluated. This
entailed:
* developing a ‘proof of concept’ system across 3 accredited testing laboratories and 2 hospitals. This system comprises
policies, procedures, infrastructure and software applications;
* testing the system by providing whole exome sequencing to patients (n=315) with a germline or somatic condition;
Data sources used to evaluate the demonstration project included documentation of issues and improvements, patient surveys
(n>160) and interviews with professional participants including clinicians (n>28), bioinformaticians and diagnostic scientists
(n=14).
This project has established the feasibility of three diagnostic testing laboratories using a common bioinformatics pipeline,
variant curation database and data storage environment. The underpinning standards for data, curation and interpretation
have been agreed. Linkage of hospital, genomic data and patient entered data has been achieved. Consent policies and
procedures to provide access to clinical genomic data for research have been implemented. 93% of participants were willing
to allow access to their data for any form of research; 15 applications for research use have been received to date.
The system has been refined through stakeholder participation. Lessons learnt from the process evaluation for implementation
of a single state-wide genomics system will be presented.
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Mon(2)-O4-2
A systematic computational pipeline for mining high-confidence candidate mirSNPs in Hypertension-
implicated genes
Linda Koshy Vaidyan 1 ，Harikrishnan S 2 ，Raman Kutty V 3 ，Jissa V T 3 ，Jayakumaran A Nair 1 ，A Gangaprasad 1,4
，
G M Nair 1 ，P R Sudhakaran 1,5
1:Inter-University Centre for Genomics and Gene Technology, Department of Biotechnology, Kerala University, India、2:Department of
Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology、3:Achutha Menon Centre for Health Science Studies, Sree
Chitra Tirunal Institute for Medical Sciences and Technology、4:Deparment of Botany, University of Kerala、5:Department of Computational
Biology and Bioinformatics, University of Kerala
Discovery of microRNAs and its involvement in the epigenetic regulation of genes has expanded the possibilities of studying
disease aetiology and susceptibility from a new perspective. Polymorphisms in miRNA targets, also known as mirSNPs,
are a gold mine for molecular epidemiologists. Association studies involving mirSNPs in functionally important genes is a
novel strategy to elucidate the aetiological mechanisms in complex diseases like hypertension. Multiple algorithms are now
available that can predict the miRNA-mRNA targets, majority of which are based on the assumption that miRNAs bind to
highly conserved seed matches in the 3’UTR of target genes. The presence of single nucleotide polymorphisms (SNPs) in
the seed regions of miRNA recognition regions (MREs) in the 3’UTR of target mRNAs may either create, destroy or modify
the efficiency of miRNA binding by destabilizing the Watson-Crick base complementarity. Such regulatory polymorphisms in
disease-implicated candidate genes can lead to dysregulation of posttranscriptional gene expression in a heritable manner. The
recent application of next-generation sequencing (NGS) technology has enabled the discovery and typing of more mutations
with appreciable frequencies. While polymorphisms in miRNA genes themselves are relatively rare, mirSNPs in target genes

are more frequent. Such mirSNPs that have minor allele frequency >5% is preferable for population-based case-control studies.
In this study, we have formulated a streamlined approach to sift through available databases in a systematic manner using
existing bioinformatics tools to delineate a panel of high-confidence candidate mirSNPs in hypertension-implicated genes.
This panel, which consists of microRNAs, their predicted target genes and mirSNPs, can be used as a valuable reference point
for further functional validation. Such computational pipelines can be applied to other diseases as well that have integrated
data from well-established databases.
Mon(2)-O4-3
The BioOntological Relationship Graph (BORG) Database - a Novel Concept for Prioritizing Candidates
from High Throughput Genomics Studies
Junaid Gamieldien 1 ，Mahjoubeh Jalali Sefid Dashti 1
1:South African National Bioinformatics Institute, University of the Western Cape, South Africa
In all genomic studies, extant knowledge about a disease of interest and its general phenotypic presentation should be
holistically considered alongside gene functional annotations as a way to identify candidates that fulfill multiple criteria and
are therefore most likely to contribute to the disease of interest. While this approach is sound in principle, the sheer volume
of leads generated in modern high-throughput experiments, and the variety of independent knowledge sources that has to be
interrogated in an integrated manner makes it a very cumbersome task. In order to automate this process, we have developed
the BioOntological Relationship Graph (BORG) database, which assimilates and integrates multiple sources of genomic and
biomedical knowledge into a large on-disk semantic network, and is also able to learn rules about pathways, phenotypes and
gene functions associated with disease.
The system has proven especially useful in our NGS-based disease variant discovery studies. Using an intuitive semantic model
of a disease and graph-querying, it explores individual units of knowledge and relations between them to uncover non-obvious
yet biologically plausible and literature-supported associations between the candidate genes that bear functional variants and
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the disease of interest. The ‘guilt-by indirect-association’ approach discovers links that would likely have been missed when
consulting the literature or individual databases directly. We present the concept, how we develop a semantic model of a
disease, and how it is used to prioritise candidate variants. We also show an example of how the BORG system was used with
exome sequencing to solve a conundrum of a usually recessive Miyoshi myopathy/dysferlinopathy masquerading as autosomal
dominant in a South African family.
Mon(2)-O4-4
An automatic pipeline for analyzing sequencing data in families for disease studies
Ren-Hua Chung 1 ，Wei-Yun Tsai 1 ，Chen-Yu Kang 1 ，Po-Ju Yao 1 ，Hui-Ju Tsai 1,2,3
，Chia-Hsiang Chen 4,5
1:Institute of Population Health Sciences, National Health Research Institutes, Taiwan、2:Department of Public Health, China Medical
University, Taichung, Taiwan、3:Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA、4:De-
partment of Psychiatry, Chang Gung Memorial Hospital-Linkou, Gueishan, Taoyuan, Taiwan、5:Department and Graduate Institute of
Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
In disease studies, family-based designs have become an attractive approach to analyzing next-generation sequencing (NGS)
data for the identification of rare mutations enriched in families. Several family-based algorithms and tools are available
for analyzing sequencing data in families with disease. Integrating these resources into an automatic analysis pipeline will
significantly facilitate the analysis. However, current analysis pipelines for family data mostly focus on a specific function.
Therefore, a pipeline that can accommodate different analysis strategies for family-based analysis is desirable. We developed a

comprehensive analysis pipeline, FamPipe, which includes several family-specific analysis modules, including the identification
of shared chromosomal regions among affected family members, variant filtering assuming a disease model, imputation of
untyped variants, and linkage and association tests. A novel disease model identification algorithm is developed to classify
variants into different Mendelian disease models with high sensitivities and specificities in the presence of genotyping errors.
We applied FamPipe to an extended pedigree with whole exome sequencing data and identified two genetic variants in the
GBP5 and DPP4 genes with functional implications for bipolar disorder. The two variants are both missense mutations
with high probabilities (Polyphen2 probability of damaging > 0.9) of damaging and are in evolutionary conserved regions
(GERP score > 2), where the regions are shared by more than 70% of affected family members. FamPipe, which can be freely
downloaded at http://fampipe.sourceforge.net, will expedite the analyses of NGS data in families.
Mon(2)-O4-5
coalescentSTR: a statistical method that estimates repeat numbers for multiple samples from high-
throughput sequencing data by considering coalescent theory
Kaname Kojima 1 ，Yosuke Kawai 1 ，Naoki Nariai 2 ，Takahiro Mimori 1 ，Takanori Hasegawa 3 ，Masao Nagasaki 1
1:Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Japan、2:Institute of Genomic Medicine, University
of California, San Diego、3:Institute of Medical Science, University of Tokyo
Repeat number polymorphisms are known to associate with various disease phenotypes (e.g., the association of CAG repeat
stretch in the Huntingtin gene with Huntington’s disease). From high-throughput sequencing data, two types of approaches
are usually considered: approaches for the estimation of repeat numbers in short tandem repeat (STR) regions: counting
repeat patterns in sequence reads aligned to the region and paired-end read based approaches that consider the difference
between the insert size on aligned reads and its actual size. As the former approaches, lobSTR and RepeatSeq are available
as software tools and they can estimate repeat numbers accurately. However, the size of their target STR regions is limited
to the length of sequence reads. The latter approaches such as STRViper can handle STR regions longer than the length
of sequence reads although repeat numbers estimated with the latter approaches is less accurate than those with the former
approaches. In order to address this issue, we proposed a statistical approach called coalescentSTR, which estimate repeat
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numbers for multiple individuals from paired-end read distances with the consideration of their unobserved genealogy. The
genealogy is represented by coalescent trees sampled from phased genotypes around a target STR region with Markov chain
Monte Carlo. Because the change in repeat numbers in the genealogy is naturally considered in coalescentSTR, more accurate
estimation of repeat numbers is expected for STR regions longer than the length of reads. In this study, we compare the
performance of coalescentSTR, lobSTR, RepeatSeq, and STRViper by using simulation datasets and real exome datasets for
multiple HapMap JPT individuals analyzed in the 1000 Genomes Project.
Mon(2)-O4-6
A Statistical Exploration of How Multiple Enhancers Affect Traits Jointly
Yutaka Yasui 1 ，Evadnie Rampersaud 1 ，Guolian Kang 1 ，Jane Hankins 1 ，Jeremie Estepp 1 ，Shuoguo Wang 1 ，
Ruopeng Feng 1 ，Lance Palmer 1 ，Zhaoming Wang 1 ，Hideki Yanai 2 ，Leslie Robison 1 ，Jinghui Zhang 1 ，Gang Wu 1 ，
Katsushi Tokunaga 2 ，Mitchell J Weiss 1
1:St. Jude Children’s Research Hospital, USA、2:University of Tokyo
There is active research to determine the mechanisms by which non-coding SNPs identified by GWAS influence gene expression
and health-related traits. Emerging evidence suggest that many of these SNPs act by modulating the activity of cis regulatory
elements such as enhancers. Most genes are regulated by multiple enhancers, each of which may be altered by multiple SNPs.
In most cases currently, enhancer activity is only inferred by epigenetic signatures rather than proven by functional studies.

To understand how any gene is expressed, it is essential to identify comprehensively its cis regulatory elements and associated
SNPs, and define how these components act combinatorially to regulate transcription.
Our work is largely of statistical nature with two goals. First, we show mathematically the numerical mechanism by which
strong biological effects are masked to very small effects (characterized by marginal odds ratios close to 1.0) in GWAS analyses.
This mechanism is consistent to the concept that individual regulatory SNPs act combinatorially. Second, we illustrate the
use of a statistical tool to explore how multiple enhancers and associated SNPs affect a health-related trait of interest, given
a set of putative enhancers identified by GWAS SNP hits and/or bioinformatics analysis. Specifically, we explored how red
blood cell fetal hemoglobin (HbF) concentration, which reduces the clinical severity of sickle cell disease, is influenced by
multiple enhancers and associated SNPs, using Boolean logic regression. In 93 African American sickle cell disease patients,
we identified an epistasis involving 3 putative enhancer SNPs of a gene (MYB) and another involving 2 putative enhancer
SNPs of another gene (BCL11A) that act in a specific combinatorial fashion to increase HbF (23.6% vs. 10.9%, permutation-
test p=0.002). The finding is supported by bioinformatics evidence and will be validated with WGS data of new samples and
a functional study using HUDEP cells.
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[O5] Clinical Genetics and Dysmorphology 1

Mon., April 04, 2016 18:00-19:30 Room B-1 (2F)
Chair：Pornswan Wasant（Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Siriraj Hospital,
Mahidol University, Thailand）
Chair ：Kayoko Saito（Institute of Medical Genetics, Tokyo Women’s Medical University, Japan）
Mon(2)-O5-1
Heterozygous mutation of alpha 3 chain of collagen type IV (COL4A3 ) in a large Japanese pedigree
with autosomal dominant Alport syndrome showing a typical ultrastructural change in the glomerular
basement membrane (GBM) of the kidney
Hiroyuki Morita 1 ，Junko Takagi 1 ，Sho Hirase 1 ，Ayano Ito 2 ，Hirokazu Imai 2 ，Koji Kimata 3 ，Ichiro Naito 4 ，
Yoshifumi Ninomiya 5 ，Kazuo Otake 1
1:Division of Endocrinology and Metabolism, Department of Internal Medicine, Aichi Medical University School of Medicine, Japan、
2:Division of Nephrology and Rheumatology, Department of Internal Medicine, Aichi Medical University School of Medicine、3:Advanced
Medical Research, Aichi Medical University School of Medicine、4:Department of Human Morphology, Okayama University School of
Medicine、5:Department of Molecular Biology and Biochemistry, Okayama University School of Medicine
Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are major constituents of familial microscopic
hematuria of glomerular origin. Heterozygous mutation of alpha 3 or alpha 4 chain of collagen type IV (COL4A3 and

COL4A4 ) may cause either TBMN or autosomal dominant Alport syndrome (ADAS) that comprises 1% of the AS. However,
a clear genotype-phenotype correlation for TBMN or ADAS is currently unknown. Thus, identifying a novel mutation in
TBMN and AS, and clarifying clinicopathologic features of family members is important.
The proband was a 19 year-old man who was referred to our department for the evaluation of hematuria. He is a member
of a big family consisting of at least 32 individuals in which 11 members showed hematuria, and 2 members had end-stage
renal disease. Percutaneous biopsy was done on a kidney of the proband. Although light microscopic changes were minimal,
subsequent ultrastructural analysis demonstrated lamination of the glomerular basement membrane (GBM), a morphologic
hallmark of AS. Immunofluorescent findings for COL4A1, 2, 3, 4, 5, and 6 were compatible with those of ADAS. A direct
PCR-sequencing of all coding exons and intron/exon boundaries of COL4A3 and COL4A4 was performed. Genbank NM-
000091.3 was used to obtain the reference sequencing. A missense mutation, COL4A3 : c.2330G>A, which lead to COL4A3:
p.Gly777Asp, was found. This variant was not listed in the NHLBI Exome Variant database, and in silico predictions,
classified as a pathologic variant. The proband, his mother, his brother, his uncle, and his cousin were recruited to genetic
segregation study, which strongly indicated that COL4A3 : c.2330G>A caused hematuria.
In conclusion, this is the first Japanese ADAS pedigree to our knowledge, where a responsible mutation was identified, and
genotype-phenotype correlation was analyzed. Further genetic/epigenetic and clinical analyses may lead to identifying disease
suppressor gene of AS.
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Mon(2)-O5-2
Identification of a 21.7kb deletion of SLC25A13 gene causing untranscription of the affected allele:
Definite diagnosis of an infant with citrin deficiency by using a diversity of molecular tools
Qi-Qi Zheng 1 ，Zhan-Hui Zhang 2 ，Han-Shi Zeng 1 ，Wei-Xia Lin 1 ，Yuan-Zong Song 1
1:Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China、2:Core Laboratory, The First Affiliated
Hospital, Jinan University, Guangzhou, China
Background and aims: Citrin Deficiency arises from biallelic mutations of SLC25A13 gene. The analysis of SLC25A13 gene
and its expression products provided reliable evidences for the definite diagnosis of this disease. The purpose of the research
was to identify the biallelic mutations in the SLC25A13 gene of an infant suspected to be suffering from citrin deficiency.
Subjects and Methods: An infant as well as the parents were enrolled as the research subjects. Genomic DNA was extracted
from blood specimens and used for screening of four high-frequency SLC25A13 mutations. Following that, a diversity of
molecular tools, including direct DNA sequencing, cDNA cloning, SNP analysis and semi-quantitative PCR, were applied to
find out the obscure pathogenic mutation.
Results: Screening of the high-frequency mutations revealed t a paternally-inherited pathogenic mutation c.851_854del4
in the infant, but another mutation remained obscure. In addition, on cDNA cloning analysis, no SLC25A13 tran-
scripts of maternal origin could be detected, suggesting that the maternal allele was untranscribed due to the obscure
mutation. Finally, by means of SNP analysis and semi-quantitative PCR, a novel large maternally-inherited deletion

c.-3251_c.15+18443del21709bp was identified in the infant, which covered the whole 5’-UTR of the gene and probably
involved other regulatory sequence.
Conclusion: The infant was a compound heterozygote of the SLC25A13 mutations c.851_854del and c.-3251_c.15+
18443del21709bp, and thus citrin deficiency was definitely diagnosed. To the best of our knowledge, the 21.7kb deletion in
this study, which silenced the affected SLC25A13 allele of maternal origin, is the largest deletion in the SLC25A13 mutation
spectrum.
Mon(2)-O5-3
Unique biochemical alterations in patients with neonatal intrahepatic cholestasis caused by citrin defi-
ciency: A comparison with congenital biliary atresia and idiopathic infantile cholestasis
Wei-Xia Lin 1 ，Mei Deng 1 ，Li Guo 1 ，Feng-Ping Chen 2 ，Yuan-Zong Song 1
1:Department of Pediatrics, the First Affiliated Hospital, Jinan University, Guangzhou, China、2:Department of Laboratory Science, the
First Affiliated Hospital, Jinan University, Guangzhou, China
Objectives: This study aimed to compare the biochemical differences among Neonatal Intrahepatic Cholestasis caused by
Citrin Deficiency (NICCD), congenital biliary atresia (CBA) and idiopathic infantile cholestasis (IIC), exploring specific
biomarkers for NICCD diagnosis.
Methods: We retrospectively analyzed the records of 79 cholestatic patients under 6 months of age, encompassing 35 NICCD,
16 BA and 28 INC subjects, who were referred to our department from July 2005 to October 2015. Available biochemical
data at the first visit were investigated with one-way ANOVA and ROC curves analysis.
Results: Compared with CBA and IIC, the NICCD group had significantly lower serum levels of Copper (4.51±3.25 µmol/L
in NICCD vs 20.46±7.12 µmol/L in CBA and 13.86±7.36 µmol/L in IIC, P=0.000), Ceruloplasmin (Cp) [89.80(63.00,
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121.00)mg/L in NICCD vs 465.00(392.50, 580.00)mg/L in CBA and 350.00(232.50, 467.50)mg/L in IIC, P=0.000], to-
tal protein (TP) (51.61±6.63g/L in NICCD vs 56.97±5.12g/L in CBA and 57.52±5.34g/L in IIC, P=0.000), albumin
(ALB) (35.49±4.63g/L in NICCD vs 38.19±4.65g/L in CBA and 39.80±3.79g/L in IIC, P=0.001) and fibronectin (FN)
(153.47±32.32mg/L in NICCD vs 213.19±45.91mg/L in CBA and 178.21±38.80mg/L in IIC, P=0.000), as well as a higher
level of alpha fetoprotein (AFP) [96680.84(35873.55, 184715.1)ng/mL in NICCD vs 12931.10(4870.57, 27687.74)ng/mL in
CBA and 4148.30(328.60, 41224.00)ng/mL in IIC, P=0.000]. ROC analysis showed that serum TP, ALB, FN, AFP, Copper
and Cp were helpful in distinguishing NICCD from CBA and IIC. In particular, the diagnostic values of Copper and Cp
(with the cutoff of 7.15umol/L, 205g/L, area under curve 93.2%, 97.6%, the specificity of 87.5%, 94.3%, and the sensitivity
of 92.7%, 88.6%, respectively) were higher.
Conclusions: NICCD has unique serum biochemical alterations in comparison with BA and INC. The decreased Copper, Cp,
TP, ALB and FN as well as elevated AFP might be specific biomarkers differentiating NICCD from CBA and IIC.
Mon(2)-O5-4
The Common and Rare Variants of UGT1A1 in Neonatal Hyperbilirubinemia in Indonesian Population
Dewi A Wisnumurti 1 ，Yunia Sribudiani 2 ，Robert M Porsch 3 ，Ani M Maskoen 2 ，Sri E Rahayuningsih 4 ，Eni K Asni 5 ，
Frank Sleutels 6 ，Christel Kockx 6 ，Wilfred van Ijcken 6 ，Abdurachman Sukadi 7 ，Tri H Achmad 2
1:Neonatology Subdivision, Departement of Pediatric, Arifin Achmad General Hospital, Pekanbaru, Indonesia、2:Department of Biochemistry

and Molecular Biology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia、3:Department of Psychiatry, Li Ka Shing Faculty
of Medicine, The University of Hong Kong, Hong Kong、4:Cardiology Sub division, Department of Pediatric, Dr. Hasan Sadikin Hospital,
Bandung, Indonesia、5:Department of Biochemistry, Faculty of Medicine, Universitas Riau, Riau, Indonesia、6:Biomics Center, Erasmus
Medical Center, Rotterdam, The Netherlands、7:Neonatology Subdivision, Departement of Pediatric, Dr. Hasan Sadikin Hospital, Bandung,
Indonesia
Neonatal hyperbilirubinemia (NH) is a common finding in newborn babies in Asia, including in Indonesia. In severe cases, NH
may lead to morbidity caused by kernicterus. Genetic variations in UDP-Glucuronosyltransferase isof orm 1A1 (UGT1A1 )
have been known to be associated with NH, yet studies in different population gave conflicted results. This study aims to
identify common and rare variants of UGT1A1 involve in the development of NH in Deutromalays. We collected consecutively
116 cases and 116 controls and targeted-deep sequence the promoter, UTRs, exon-intron boundaries and exon regions of
U GT1A1 by using MiSeq from Illumina. We identified 513 and 438 variants with coverage ≥10 in cases and controls
respectively. Fourteen rare coding variants (MAF < 0.005) were identified in cases in controls. Four (p.A61T, p.H300R,
p.K407N and p.Y514N) and three (p.Y79X, p.A346V and p.T412S) rare novel variants were identified in cases and controls
respectively. The most identified variants in the promoter region for both cases and controls were heterozygous deletions
(TA6 /TA5 ) and insertion (TA6 /TA7 ) of TA sequence. While in the coding region, p.G71R was the most identified variant
with the odds ratio 1.4 (CI 95%, p = 0.35). However, none of those variants alone or in combination was associated with
NH. Although we did not identify any variant associated with NH in single variant analysis, by using haplotype analysis we
identified a haplotype consist of 3 UTRs SNPs (rs8330C>G, rs10929303C>T and rs1042640C>G) associated with NH (p <
0.05). This suggests that this haplotype is a risk-haplotype for NH in Deutromalays in Indonesia.
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Mon(2)-O5-5
Molecular Diagnosis of Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency by Analyzing
SLC25A13 Gene and Its Transcripts in Peripheral Blood Mononuclear Cells
Yuan-Zong Song 1 ，Zhan-Hui Zhang 2 ，Wei-Xia Lin 1 ，Qi-Qi Zheng 1 ，Man Mao 3 ，Ying Cheng 1 ，Han-Shi Zeng 1 ，
Shu-Tao Zhao 1 ，Feng-Ping Chen 3 ，Wang-Rong Wen 3
1:Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China、2:Core Laboratory, The
First Affiliated Hospital, Jinan University, Guangzhou, China、3:Department of Laboratory Science, The First Affiliated Hospital, Jinan
University, Guangzhou, China
Citrin deficiency (CD) is a mendelian disorder arising from biallelic mutations of SLC25A13 gene, and Neonatal In-
trahepatic Cholestasis caused by Citrin Deficiency (NICCD) is the major clinical CD phenotype at pediatric age. In
2006, we diagnosed the first patient with NICCD in mainland China, and by the end of 2015 October, 267 such patients
have been definitely diagnosed by our group. Besides PCR/PCR-RFLP and Sanger Sequencing, other molecular tools
such as SNP analysis, quantitative PCR, cDNA cloning and Western blotting by using peripheral blood mononuclear
cells were utilized to identify large deletion/insertions. For functional analysis of novel missense mutations, a yeast
model with abrogation of the homologous gene agc1 was applied. As the results, 41 SLC25A13 mutations/aberrant
transcripts were detected, including 10 ones that have not been described previously, including c.103A>G(p.M35V),
c.1381G>T(p.E461X), c.616-1G>C(r.755_756delAG), c.845_c.848+1delG, c.1706_1707delTA, c.933+1_c.933+2insCAGG,
c.-3251_c.15+18443del(r.0), c.329-1687_c.468+3865del(r.329_469del), c.1019_1177+893del(r.1019_1177del), and [c.329-
155_c.468+2351del2646;c.468+2392_c.468+2393ins23]. The SLC25A13 mutations in 6 alleles [6/(267×2)=1.1%] remained

to be identified.
Mon(2)-O5-6
GATA binding protein 2 (GATA2) mutation identified in a Japanese patient with adult-onset pulmonary
alveolar proteinosis
Ryushi Tazawa 1 ，Ryota Sato 2 ，Masayuki Ito 1 ，Amy P Hsu 3 ，Shinobu Akagawa 2 ，Yuko Ito 2 ，Jun Tohyama 1,4
，
Akira Hebisawa 2 ，Ken Ohta 2 ，Koh Nakata 1
1:Niigata University Medical and Dental Hospital, Japan、2:NHO Tokyo Hospital、3:National Institute of Allergy and Infectious Diseases,
NIH、4:NHO Nishi-Niigata Chuo Hospital
INTRODUCTION: Disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling causes PAP, a rare
lung disease characterized by the abnormal accumulation of surfactant material in the pulmonary alveoli, resulting in respi-
ratory failure. PAP is clinically divided into three forms: autoimmune, secondary, and hereditary PAP. Genetic defects in
the GM-CSF receptor genes CSF2RA and CSF2RB were recently associated with hereditary PAP. We describe here the first
Japanese case of adult-onset hereditary PAP with a mutated GATA2 gene. METHODS & RESULTS: The patient described
here is a 58-year-old Japanese female who was admitted to our hospital as her cough and sputum production worsened. The
computed tomography scan of the patient’s chest showed centrilobular, ground-glass opacities distributed mainly in the left
lower lung. Transbronchial lung biopsy revealed alveolitis. The symptoms and the opacities in her lung improved sponta-
neously; these findings led us to suspect hypersensitive pneumonitis. The patient had multiple recurrences that were treated
with corticosteroids successfully. She died of respiratory failure eleven years after the first documented episode. Autopsy
revealed the accumulation of amorphous materials in the pulmonary alveoli, leading to a diagnosis of pulmonary alveolar
proteinosis. The patient was negative for GM-CSF autoantibodies and had no underlying disease. DNA sequencing revealed
no mutation in the CSF2RA and CSF2RB genes. However, a heterozygous c.1192C>T change in exon 7 of the GATA2 gene
was observed that resulted in a p.R398W substitution. Notably, the patient demonstrated no history of monocyotpenia or
mycobacterium avium complex infection, both of which are often observed in GATA2 -mutated disorders. CONCLUSIONS:
This is the first Japanese report identifying a gene mutation in GATA2 that was associated with adult-onset PAP. The
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differential diagnosis of adult-onset PAP should include GATA2 deficiency, even in Japan.

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[O6] Complex Traits and Polygenic Disorders 1

Mon., April 04, 2016 18:00-19:30 Room B-2 (2F)
Chair：Margaret Pericak-Vance（John P. Hussman Institute for Human Genomics, University of Miami Miller School of
Medicine, USA）
Chair：Lin He（Human Neuropsychiatric Genetics Group of Shanghai Jiao Tong University & China Academy of Sciences,
China）
Mon(2)-O6-1
A novel regulatory variant of FADS1 determines binding of PATZ1 and is associated with metabolic and
inflammatory diseases
Claes Wadelius 1 ，Adam Ameur 1 ，Stefan Enroth 1 ，Madhusudhan Bysani 1 ，Helena Nord 1 ，Marco Cavalli 1 ，
Magnus Essand 1 ，Ulf Gyllensten 1 ，Gang Pan 1
1:Immunology, Genetics and Pathology, Uppsala University, Sweden
Background: The FADS region shows clear evidence of recent selection and may be associated to more diseases and traits
than any other outside of the HLA. The associations include the metabolic syndrome, fasting glucose, inflammatory bowel
disease, triglycerides, LDL and HDL cholesterol, brain development and many others. They were previously mapped to an
LD block with 28 known SNPs and we set out to identify the functional one.

Methods and results: We generated chromatin signals in liver tissue to define regulatory elements and tested SNPs in them
for allelic difference in luciferase assays. We found that all 28 SNPs could be explained by rs174557 located in an AluYe5
element in intron 1 of FADS1 , present in chimpanzee and human but no other species. The derived allele of rs174557, which
is the common variant in most populations, diminishes binding of PATZ1, a transcription factor (TF) conferring allele-specific
downregulation of FADS1. There are several ancestral alleles with lower activity. The regulatory element has three binding
sites for the TF SREBP1c, one for SP1, and one at the regulatory rs174557 for the repressor PATZ1. They were verified
in vitro and in cellular assays using ChIP and lentiviral over-expression of the TFs. The PATZ1 binding site overlaps with
the SP1 site. The competitive binding between the suppressive PATZ1 and the activating complex of SP1 and SREBP1c
determines the enhancer activity of this region, which regulates expression of FADS1.
Conclusions: The association of many diseases and traits to the FADS1 region can be explained by a multi-allelic polymorphism
in intron 1 of FADS1 bound by the repressor PATZ1 in competition with an activating complex. The results are interesting
from evolutionary and genetic perspectives and the gene variants may help explain why we react differently to modern diet
as compared to the diet in ancient times.
Mon(2)-O6-2
A meta-analysis of genome-wide association studies for diabetic nephropathy in Japanese patients with
type 2 diabetes
Makiko Taira 1 ，Minako Imamura 1 ，Atsushi Takahashi 2,4
，Yoichiro Kamatani 2 ，Michiaki Kubo 3 ，Shiro Maeda 1,5
1:Laboratory for Endocrinology, Metabolism and Kidney Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan、
2:Laboratory for Statistical Analysis, RIKEN, Center for Integrative Medical Sciences, Yokohama, Japan、3:Laboratory for Genotyping
Development, RIKEN, Center for Integrative Medical Sciences, Yokohama, Japan、4:Laboratory for Omics Informatics Omics Research Cen-
ter, National Cerebral And Cardiovascular Center, Osaka, Japan、5:Department of Advanced Genomic and Laboratory Medicine, Graduate
School of Medicine, University of the Ryukyus, Okinawa, Japan
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Background: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in Western countries as well as Japan.
Although several reports have shown that genetic factors play a pivotal role in the development and progression of DN,
worldwide efforts to identify susceptibility loci for DN have produced disappointing results. To explore novel genetic loci
associated with the susceptibility to DN, we performed a meta-analysis of genome-wide association studies (GWAS) for DN in
Japanese patients with type 2 diabetes. Methods: We divided Japanese patients with type 2 diabetes registered in BioBank
Japan, who had been analyzed in previously reported GWAS for type 2 diabetes (Set1: 9,343, Set2: 3,607), into 2 groups;
1) DN cases, defined as patients having overt nephropathy or end-stage renal disease, 2) controls, who did not have any
sign of DN and with diabetic retinopathy or with long duration of diabetes (≥ 5 years). We examined 2 independent case-
control groups (Study1; 2,380 DN cases and 5,238 controls, Study2; 429 DN cases and 358 controls) for ~ 7.5 million single
nucleotide polymorphisms (SNPs) from genotype imputation using 1000 genomes reference data (CHB+JPT). Results of the
2 GWAS were combined with an inverse variance method, and we selected candidate SNP loci (p-value<1.0x10-4 ) for further
analysis. Subsequently, we performed de novo genotyping for the candidate SNPs by Multiplex-PCR Invader assay in another
independent case-control group (Set3; 1,213 DN cases and 1,298 controls) and all association data (Set1, 2, 3) were combined
with a meta-analysis. Results: We identified that the association of 1 SNP locus reached a genome-wide significance level
(p =7.74×10-10 , odds ratio 1.23) and 10 SNP loci showed borderline association with DN (5×10-8 ≤p<5×10-7 ). Conclusion:
We have identified a novel locus for conferring susceptibility to DN, however, further studies using an independent cohort are
required to confirm the association of this locus with DN.

Mon(2)-O6-3
HETEROZYGOUS CONNEXIN50 MUTATION LOWERS BLOOD LIPIDS AND AFFECTS TRAN-
SCRIPTOME IN HEART AND KIDNEY IN A RAT MODEL
Ondrej Seda 1 ，Lucie Sedova 1 ，Frantisek Liska 1 ，Michaela Krupkova 1 ，Drahomira Krenova 1 ，Vladimir Kren 1
1:Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University in Prague, Czech Republic
We aimed to determine the metabolic and transcriptomic effects of heterozygous state of connexin50 gene (Gja8) mutation
L7Q that arose spontaneously in the spontaneously hypertensive inbred rat strain SHR/OlaIpcv, creating thus a coisogenic
rat strain SHR-Dca. Adult, standard chow-fed male rats of SHR/OlaIpcv, SHR-Dca(+/-) and SHR-Dca(-/-) strains were used
(n = 8/strain). The metabolic profile (including cholesterol and triglyceride blood concentration in 20 lipoprotein fractions,
glycerol level and chylomicron, VLDL, LDL and HDL particle sizes) was assessed by HPLC and Rat metabolic hormone
magnetic bead panel. We used Affymetrix GeneChip Rat Exon 1.0ST Array to assess the heart and renal transcriptome,
Ingenuity Pathway Analysis was used to identify the affected metabolic and signalling networks. In several parameters the
heterozygous animals exhibited either results similar to Gja8 -/- animals or even more pronounced when compared to SHR
(Gja8 +/+) as was the case for all 7 subfractions of HDL cholesterol (e.g. total HDL-cholesterol ANOVA p = 0.037, SHR:
31.9 +/- 0.9 vs. Gja8(+/-): 23.5 +/- 0.5 vs.Gja8(-/-): 26.7 +/- 2.6 mg/dl). No differences were found between the strains in
adiponectin or leptin levels. The transcriptome assessment in heart and kidney of both groups revealed series of functionally
potentially related genes that were differentially expressed in SHR vs. Gja8 +/- animals. After correction for multiple
comparison (FDR < 0.05) we have found that in the heart and kidney, 46 and 144 transcripts are upregulated in Gja8 +/- vs.
SHR (4 transcripts overlapping: Arrdc3, Ccr1, Igfbp1, Rassf4), respectively, and 106 and 161 transcripts are downregulated
(4 transcripts overlapping: Anln, Cyr61, Hist1h1a, Rnd3), respectively. We have identified crucial mechanistic networks
underlying the observed differences. We have shown that connexin50 mutation in heterozygous state affects significantly lipid
profile and heart and kidney transcritpomes.

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Mon(2)-O6-4
Gaining mechanistic insights at type 2 diabetes and glycemic trait association loci by integration with
human pancreatic islet transcriptome and regulatory information
Martijn van de Bunt 1,2 ，Robert G Legg 1 ，Jocelyn E Manning-Fox 3 ，Amy Barrett 1,2 ，Amanda J Bennett 1,2
，
Emmanouil T Dermitzakis 4,5,6 ，Patrick E MacDonald 3 ，Anna L Gloyn 1,2,7 ，Mark I McCarthy 1,2,7
1:Wellcome Trust Centre for Human Genetics, University of Oxford, UK、2:Oxford Centre for Diabetes, Endocrinology & Metabolism,
University of Oxford、3:Alberta Diabetes Institute, Li Ka Shing Centre, University of Alberta、4:Department of Genetic Medicine
and Development, University of Geneva、5:Institute for Genetics and Genomics in Geneva, University of Geneva、6:Swiss Institute of
Bioinformatics, Geneva、7:Oxford NIHR Biomedical Research Centre, University of Oxford
The intersection of genome-wide association analyses with physiological and functional data indicates that variants regulating
islet gene transcription influence type 2 diabetes (T2D) predisposition and glucose homeostasis. However, the specific genes
through which these regulatory variants act remain poorly characterized. To identify effector transcripts at association loci
for T2D and glycemic traits by integrating islet expression quantitative trait locus (eQTL) data with genetic and regulatory
state information. We generated eQTL data in 118 human islet samples using RNA-sequencing and high-density genotyping.
For 82 known common T2D association loci and 49 loci for glycemic traits, genetic data were integrated with islet eQTLs
and published islet regulatory state maps. Cis-exon-eQTL signals overlapped active islet chromatin signatures and were
coincident with established T2D and/or glycemic trait associations at 14 loci. These data provide an experimental link
between GWAS signals and biological candidates (e.g. DGKB and ADCY5 ), and implicate genes with no prior connection
to islet biology (e.g. WARS and ZMIZ1 ). We also determined whether any of the loci affected isoform usage of nearby
genes, and identified an additional mechanism at the G6PC2 locus. Here, the fasting glucose increasing G-allele of rs560887

significantly associated with higher levels of the full-length transcript (ENST00000375363; beta=0.56; permuted p= 1.3x10-3 ;
q= 0.04) and corresponding lower levels of the shorter isoform (ENST00000429379; beta= -0.46; permuted p= 0.03; q= 0.36).
These findings demonstrate how integrating human genetics with islet eQTL and chromatin information lead to a significant
advance in the mechanistic insights of T2D and glycemic trait association loci. We are currently combining RNA-seq data
on approximately 450 human islets generated by different laboratories around the world for further mechanistic inference at
T2D risk and glycemic trait loci.
Mon(2)-O6-5
Large scale exome array meta-analyses identify numerous novel common, low-frequency, and rare coding
variants associated with glycaemic traits
Hidetoshi Kitajima 1 ，Meta-Analyses of Glucose and Insulin-related traits Consortium
1:Wellcome Trust Centre for Human Genetics, University of Oxford, UK
Protein coding single nucleotide variants may facilitate more direct identification of effector transcripts and thus help with
biological inferences. To explore the role of coding variants in glycaemic traits, we investigated the association of 241,320
common (minor allele frequency (MAF) > 5%), low-frequency (MAF 1-5%), and rare (MAF < 1%) exome array variants
with fasting glucose (FG), fasting insulin (FI), 2-h glucose (2hGlu), and glycated hemoglobin (HbA1c) levels. We included
up to 144,060 non-diabetic individuals of European (N = 122,464), African American (N = 8,801), South Asian (N = 7,824),
East Asian (N = 2,644), and Hispanic (N = 2,327) ancestry from up to 66 studies. We combined single variant results
from linear mixed models by fixed-effect meta-analyses. Across the four traits, 125 loci harbored variants, either a coding
variant at exome-wide significance (P < 2.07x10-7 ) or a non-coding variant at genome-wide significance (P < 5x10-8 ), in
the combined-ancestry analyses. These included 41 novel loci; 12 for FG, 5 for FI, 19 for HbA1c, and 5 for 2hGlu. Among
the newly associated loci, missense variants showed most significant association in 16 loci: one low-frequency and five rare
variants. The rare variants included a variant in AKT2 (previously implicated in monogenic insulin resistance) associated
with FI levels (P50T, MAF = 0.2%, β = 0.020 log-pmol/l, P = 3.1x10-10 ), variants in ANKH and MAP3K15 associated
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with FG (ANKH : R187Q, MAF = 0.4%, β = -0.19 mmol/l, P = 5.7x10-10 ; MAP3K15 : G838S, MAF = 0.4%, β = -0.18
mmol/l, P = 1.4x10-11 ), and variants in HBB and AMPD3 associated with HbA1c (HBB: R31S, MAF = 0.02%, β = 0.26%,
P = 3.6x10-10 ; AMPD3 : V320L, MAF = 0.9%, β = 0.037%, P = 2.3x10-10 ). In conclusion, we identified coding variants
across the allele frequency spectrum in loci associated with glycaemic traits, which may provide novel biological insights into
the pathophysiology of diabetes.
Mon(2)-O6-6
Large-scale exome chip association analysis identifies novel type 2 diabetes susceptibility loci and high-
lights candidate effector genes
Anubha Mahajan 1 ，on behalf of the ExT2D Exome Chip Consortium, for PROMIS, CHARGE and T2D-GENES/GoT2D
1:WTCHG, University of Oxford, UK
To evaluate the contribution of coding variants to type 2 diabetes (T2D) risk, we combined exome array data from 56,597
cases and 176,024 controls from five ancestries (European, South Asian, African American, East Asian, and Hispanic). We
tested single variants for association with T2D, with/without body-mass index (BMI) adjustment, using a linear mixed model.
Variants with P<10-5 were taken forward for in silico replication in an additional 14,608 cases and 174,322 controls.
In the combined analysis of 421,551 samples, 62 coding variants, mapping to 34 loci, were associated with T2D at exome-wide

significance (P<5x10-7 ). All but 5 were common, with minor allele frequency (MAF)>5%. 21 variants were located outside
established T2D loci, including common variants in ZZEF1 (L1972P, P=7.8x10-12 ), POC5 (H36R, P=5.0x10-15 ), PNPLA3
(I148M, P=7.0x10-9 ), and a low-frequency variant (MAF=1% in Europeans) in FAM63A (Y285N, P=9.2x10-8 ). Of these,
POC5 maps to a known BMI locus and the PNPLA3 variant has been implicated in fatty liver disease. 12 variants in
established loci (SLC30A8 , MACF1 , GCKR, PPARG, KCNJ11-ABCC8 , and PAM-PPIP5K2 ) confirmed previous reports of
coding alleles that drive association signals. However, the 29 remaining variants have not been directly implicated in T2D, so
we investigated their relationship with previously reported non-coding lead SNPs through conditional analyses. At the CILP2
locus, TM6SF2 E167K (P=3.6x10-12 ) was indistinguishable from the previously reported lead SNP (Pcond =0.052), suggesting
that the association signal is mediated through this gene. Conversely, the association for GIPR E354Q (P=1.1x10-8 ) was not
eliminated after conditioning on the previously reported inter-genic lead SNP (Pcond =4.0x10-6 ), implying these signals to be
distinct.
Our results indicate that low-frequency and rare coding variants of large effect do not make a major contribution to T2D risk,
but implicate several novel genes in the pathogenesis of the disease.
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[O7] Molecular Basis of Mendelian Disorders 1

Mon., April 04, 2016 18:00-19:30 Room C-1 (1F)
Chair：John Christodoulou（Neurodevelopmental Genomics Research Unit, Murdoch Childrens Research Institute, Aus-
tralia）
Chair ：Mariko Taniguchi-Ikeda（Department of Pediatrics, Kobe University Graduate School of Medicine, Japan）
Mon(2)-O7-1
A Homozygous loss-of-function mutation in DNAJA3 causes Hereditary Motor and Sensory Neuropathy
with Spastic Paraplegia (HMSN type V)
Toshitaka Kawarai 1 ，Ryosuke Miyamoto 1 ，Yukiko Kuroda 2 ，Masatoshi Omoto 3 ，Morio Ueyama 4 ，
Nagahisa Murakami 1 ，Takahiro Furukawa 1 ，Ryosuke Oki 1 ，Atsuko Mori 1 ，Yusuke Osaki 1 ，Chimeglkham Banzrai 1 ，
Hiroyuki Nodera 1 ，Antonio Orlacchio 5,6 ，Akihiro Hashiguchi 7 ，Yujiro Higuchi 7 ，Hiroshi Takashima 7 ，
Takashi Kanda 3 ，Yuishin Izumi 1 ，Yoshitaka Nagai 4 ，Takao Mitsui 2 ，Ryuji Kaji 1
1:Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan、2:Department of Clinical
Research, Tokushima National Hospital, National Hospital Organization, Tokushima, Japan、3:Department of Neurology and Clinical
Neuroscience, Yamaguchi University Graduate School of Medicine、4:Department of Degenerative Neurological Diseases, National Institute
of Neuroscience, National Center of Neurology and Psychiatry、5:Laboratorio di Neurogenetica, CERC-IRCCS Santa Lucia, Rome, Italy、
6:Dipartimento di Medicina dei Sistemi, Universita di Roma Tor Vergata, Rome, Italy、7:Department of Neurology and Geriatrics,
Kagoshima University Graduate School of Medical and Dental Sciences
Objective: To identify a genetic cause for hereditary motor and sensory neuropathy with spastic paraplegia (HMSN type V).

Methods: We performed a clinico-genetical study in a Japanese family, in which two sibships are affected with HMSN type V,
including whole exome sequencing, bioinformatic analyses, pathological and ultrastructural study of biopsied nerve. Expression
level of DNAJA3 was evaluated using quantitative PCR in Rat neuronal tissues. Biological effect of homozygous variant,
p.Y95H in DNAJA3 gene, was evaluated by cell viability study in cultured cells. Suppression of endogenous Drosophila
DNAJA3 using RNAi was also performed to evaluate its effects on locomotive behaviour.
Results: Electrophysiological investigation revealed axonal degeneration in peripheral sensory and motor neurons. Electron
microscopic examination demonstrated abnormal mitochondrial morphology in the biopsied sural nerve. Genetic analyses
demonstrated a novel homozygous variant, p.Y95H, in DNAJA3 gene. The variant was not found in 618 control chromosomes
recruited in Japan and Italy, and is predicted to be damaging/deleterious or disease causing. Higher level of DNAJA3 was
also present in the nervous system, especially anterior horn, and lower level in hippocampus. Decreased viability in the
cells expressing mutant DNAJA3 was demonstrated under the conditioning of rotenone-induced oxidative stress. Reduced
expression of DNAJA3 showed reduced locomotor activity in Drosophila melanogaster.
Interpretation: DNAJA3, also known as Tid1 or mtHSP40, encodes a mitochondrial member of the DnaJ protein family, and
has been reported to play crucial roles in protein folding, degradation, and multimeric complex assembly through interaction
with heat shock protein 70. We demonstrated that mutated DNAJA3 is possibly associated with HMSN type V. Although
likely a rare cause HMSN type V, our findings indicate a critical role for DNAJA3 in motor neurons.
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Mon(2)-O7-2
Genetic profile for suspected dysferlinopathy identified by targeted next generation sequencing
Naoki Suzuki 1 ，Rumiko Izumi 1,2 ，Tetsuya Niihori 2 ，Toshiaki Takahashi 3 ，Maki Tateyama 4 ，Chigusa Watanabe 5 ，
Kazuma Sugie 6 ，Hirotaka Nakanishi 7 ，Gen Sobue 8 ，Masaaki Kato 1 ，Hiroshi Warita 1 ，Yoko Aoki 2 ，Masashi Aoki 1
1:Neurology, Tohoku University, Japan、2:Medical Genetics, Tohoku University、3:Department of Neurology, National Hospital Organization
Sendai-Nishitaga National Hospital、4:Departments of Neurology, Iwate National Hospital、5:Department of Neurology, Hiroshima-Nishi
medical center、6:Department of Neurology, Nara medical university、7:Department of Neurology, Nagoya University Graduate School of
Medicine、8:Research Division for Neurodegeneration and Dementia, Nagoya University Graduate School of Medicine
Objective: Dysferlin deficiency leads to two main phenotypes, limb girdle muscular dystrophy (LGMD) 2B and Miyoshi
myopathy, called dysferlinopathy. Our objective is to investigate the genetic causes of suspected dysferlinopathy and reveal
the genetic profile of myopathies with dysferlin deficiency.
Methods: Using next-generation sequencing, we analyzed 42 myopathy-associated genes, including DYSF, in 70 cases that
had been clinically or pathologically suspected with dysferlinopathy. Putative pathogenic mutations were confirmed by
Sanger sequencing. Copy number variations in DYSF were additionally investigated using multiplex ligation-dependent probe
amplification. We also analyzed the genetic profile of myopathies with dysferlin deficiency, including cases from a previous
cohort.
Results: We identified putative pathogenic mutations in up to 43 cases (61% of all investigated cases). Twenty-three cases
had DYSF mutations, including 6 novel mutations. The remaining 21 cases harbored putative pathogenic mutations in other

genes. We also investigated the genetic profile of 89 cases of myopathy with proven dysferlin deficiency, as indicated by muscle
specimen immunohistochemistry. This analysis showed that 69% had DYSF mutations (n = 61), 10% had CAPN3 mutations
(n = 9), 2% had CAV3 mutations (n = 2), 3% had mutations in other genes (in single cases), and 16% did not have any
identified mutations (n = 14).
Conclusions: The present study clarified the heterogeneous genetic profile of myopathies with dysferlin deficiency. Our results
demonstrate the importance of a comprehensive analysis of related genes in improving the genetic diagnosis of dysferlinopathy
as one of the most popular subtype in limb girdle muscular dystrophy. Unresolved diagnoses should be investigated using
whole genome or exome sequencing.
Mon(2)-O7-3
Plastin 3, a human protective modifier is highly upregulated in iPSC-derived motoneurons in asymp-
tomatic SMN1-deteted individuals and rescues spinal muscular atrophy in mice
Brunhilde Wirth 1 ，Miriam Peters 1 ，Ludwig Heesen 1,2 ，Seyyed Mohsen Hosseini Barkooie 1 ，Mihael Peitz 2,3
，
Anna Kaczmarek 1 ，Eva Janzen 1 ，Laura Torres Benito 1 ，Oliver Brüstle 2,3
1:Institute of Human Genetics, Institute of Genetics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany、
2:Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn and Hertie Foundation, Bonn, Germany、3:DZNE,
German Center for Neurodegenerative Diseases, Bonn, Germany
Spinal muscular atrophy (SMA) is a devastating motoneuron (MNs) disorder caused by functional loss of SMN1. Previously,
we identified Plastin 3 (PLS3) as a strong candidate protective modifier using transcriptome differential expression analysis
in SMA discordant families.
PLS3 was highly upregulated in lymphoblastoid cell lines of asymptomatic but not SMA siblings at both, RNA and protein
level. Instead fibroblast cell lines from both SMA and asymptomatic siblings showed similar PLS3 expression, suggesting
a tissue-specific regulation. To investigate whether PLS3 is upregulated in MNs, the primary affected cells in SMA, we
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generated induced pluripotent stem cells (iPSCs) from fibroblasts of three asymptomatic and three SMA III-affected siblings
and compared these to iPSCs from a SMA I patient and control individuals. After full characterization of pluripotency, small
molecule neural precursor cells (smNPCs) were generated from iPSCs. Next, MNs were differentiated from smNPCs and
characterized for any possible changes including survival, gem counts, protein and RNA expression of SMN and PLS3. Most
strikingly, PLS3 was highly upregulated only in MNs from asymptomatic siblings pinpointing a tissue-specific regulation.
Strong PLS3 accumulation in shaft and rim of growth cones in MN cultures from asymptomatic individuals implies an
important role in neuromuscular synapse formation and maintenance.
To finally address the PLS3 rescuing effect in SMA disorder, we generated PLS3 overexpressing mice, which were crossed
into a severe SMA mouse model. By applying low amounts of exon 7 inclusion SMN antisense oligonucleotides, we improved
the multi-organ dysfunction in these severe SMA mice and increased their survival from 14 to 28 days. Most importantly,
crossing the PLS3 transgene homozygously into these mice led to a robust increase of survival (>60% survived >180 days).
These combined data provide strong evidence for PLS3 as protecting modifier in humans and SMA mouse model.
Mon(2)-O7-4
Evaluating biomarkers and natural history of Fukuyama Congenital Muscular Dystrophy
Mariko Taniguchi-Ikeda 1,2 ，Risa Harada 3 ，Ai Unzaki 1 ，Tatsuya Nishii 4 ，Hiroyuki Awano 1 ，Lee Tomoko 5 ，
Yasuhiro Takeshima 5 ，Kazuhiro Kobayashi 2 ，Ichiro Morioka 1 ，Kazumoto Iijima 1 ，Tatsushi Toda 2

1:Department of Pediatrics, Kobe University Graduate School of Medicine, Japan、2:Department of Neurology/Molecular Brain Science,
Kobe University Graduate School of Medicine、3:Department of Rehabilitation,Kobe University Graduate School of Medicine、4:Department
of Radiology,Kobe University Graduate School of Medicine、5:Department of Pediatrics, Hyogo Medical College
Fukuyama type congenital muscular dystrophy (FCMD) is an autosomal recessive, severe childhood muscular dystrophy with
brain and eye involvement. FCMD is mainly caused by an ancestral insertion of 3-kb SVA type retrotransposal element
into the 3’ untranslated region of the causative gene, fukutin. Recently, we testified that pathogenic exon trapping by
SVA transposon cause splicing abnormality in FCMD. We also succeeded in optimizing antisense oligonucleotides therapy for
FCMD model mice and FCMD myoblasts. Since FCMD is an incurable disease, there has been no biomarkers for FCMD.
Moreover, there is few study on natural history of FCMD. There is a need to develop sensitive, non-invasive outcome measures
of FCMD patients that can be readily available to human clinical trials in the near future. To find specific serum biomarkers
and to comprehend natural history of FCMD patients, we collected serum and clinical data from patients. We tested on
serum biomarkers by measuring muscle specific microRNAs. Clinical data contains motor function score, muscle elastography
(supersonic shear imaging (SSI)), and whole body muscle computed tomography with ultralow level irradiation. As a result,
microRNA 206 (miR206), which is highly expressed in regenerating muscle fibers was significantly overexpressed in FCMD
patients compared to normal controls. Correlation coefficient of miR206 with serum CK level, serum creatinine level, and
motor function scores were also high. MiR 206 was especially high in FCMD patients with high muscle contents, suggesting
remaining sparing capacity of muscle regeneration. SSI showed significantly high elasticity in biceps brachii and brachial
muscle but not high in lower extremities in FCMD patients, compared to normal control, because of high content of fat
infiltration due to disuse of lower muscle. In conclusion, serum miR206 and SSI is a useful biomarker for monitoring the
muscle wasting progression and motor function level of FCMD.
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Mon(2)-O7-5
Mutation in hnRNPA1 causes isolated inclusion body myopathy in two families with multisystem pro-
teinopathy
Rumiko Izumi 1,2 ，Hitoshi Warita 1 ，Tetsuya Niihori 2 ，Toshiaki Takahashi 3 ，Maki Tateyama 1 ，Naoki Suzuki 1 ，
Ayumi Nishiyama 1,2 ，Matsuyuki Shirota 4 ，Ryo Funayama 5 ，Keiko Nakayama 5 ，Satomi Mitsuhashi 6 ，Ichizo Nishino 6 ，
Yoko Aoki 2 ，Masashi Aoki 1
1:the Department of Neurology, Tohoku University Graduate School of Medicine, Japan、2:the Departments of Medical Genetics, Tohoku
University Graduate School of Medicine、3:the Department of Neurology, National Hospital Organization Sendai-Nishitaga National
Hospital、4:the Division of Interdisciplinary Medical Science, United Centers for Advanced Research and Translational Medicine, Tohoku
University Graduate School of Medicine、5:the Division of Cell Proliferation, United Centers for Advanced Research and Translational
Medicine, Tohoku University Graduate School of Medicine、6:Department of Neuromuscular Research, National Institute of Neuroscience,
National Center of Neurology and Psychiatry (NCNP) and Department of Genome Medicine Development, Medical Genome Center, NCNP
Multisystem proteinopathy (MSP) is an inherited, pleiotropic degenerative disorder that can affect muscle, bone and/or the
nervous system. In 2013, novel missense mutations in the prion-like domain of hnRNPA1 and hnRNPA2B1 genes were
identified in patients with MSP which are now designated as MSP3 and MSP2, respectively. In this study, we performed
whole exome sequencing to identify the responsible genetic mutation of the Japanese family manifesting isolated inclusion
body myopathy (IBM) with autosomal dominant inheritance and identified a missense p.D314N mutation in hnRNPA1 , which
is also known to cause familial amyotrophic lateral sclerosis. The identical mutation was detected in another Japanese family
with isolated IBM by Sanger sequencing. Multiple immunohistochemical analyses in biopsied muscle specimens of the patient
with p.D314N mutation revealed the aberrant cytoplasmic aggregation of hnRNPA1 in close association with autophagosomes
and myonuclei. Furthermore, this accumulation was characterized by coaggregation with ubiquitin, sequestome-1/p62, valosin-

containing protein/p97, and a variety of RNA-binding proteins. This study expands the clinical phenotype of hnRNPA1 -linked
multisystem proteinopathy. Mutations in hnRNPA1 , and possibly hnRNPA2B1 , will be responsible for isolated IBM with
a pure muscular phenotype. Although the mechanisms underlying the selective skeletal muscle involvement remains to be
elucidated, these results suggest a broad sequestration of RBPs by the mutated hnRNPA1 .
Mon(2)-O7-6
Biophysical characteristics of GJB1 mutations and the correlation with clinical phenotypes of Charcot-
Marie-Tooth disease type X1
Yo-Tsen Liu 1,2 ，Pei-Chien Tsai 1,2,3 ，De-Ming Yang 4,5 ，Tai-Yu Chiu 4,5
，Yu-Ping Su 6 ，Yi-Chu Liao 1,2
，
Bing-Wen Soong 1,2,3 ，Kon-Ping Lin 1,2 ，Yi-Chung Lee 1,2,3
1:Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan、2:Department of Neurology, National
Yang-Ming University School of Medicine, Taipei, Taiwan、3:Brain Research Center, National Yang-Ming University, Taipei, Taiwan、
4:Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan、5:Biophotonics Interdisciplinary
Research Center, National Yang-Ming University, Taipei, Taiwan、6:Department of Psychiatry, Cathay General Hospital, Taipei, Taiwan
Objective Charcot-Marie-Tooth disease (CMT) type X1 (CMTX1) caused by mutations in the GJB1 gene is the second most
common form of CMT. GJB1 encodes the gap junction (GJ) beta-1 protein (GJB1), which is expressed by Schwann cells in
peripheral nerves to form GJs within the myelin sheath. How GJB1 mutants cause neuropathy is still not fully elucidated.
The aim of this study was to characterize the biophysical characteristics of the GJB1 mutants and their correlation with the
clinical features of patients with CMTX1.
Methods All patients with a validated GJB1 mutation were assessed by the Charcot-Marie-Tooth disease neuropathy score
version 2 (CMTNS V2). The impacts of the mutations on the biophysical functions of GJB1 were characterized by intracellular
localization, expression pattern and the GJ Ca2+ permeability.
Results Nineteen GJB1 mutations were identified in 24 patients with the clinical diagnosis of CMT. Six of the mutations are
first reported in patients with classic CMT: p.L6S, p.I20F, p.I101Rfs*8, p.F153L, p.R215P and p.D278V. Diverse pathological
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effects of the mutations were demonstrated, including reduced expression, intracellular mislocalization and altered GJ function.
The GJB1 mutations causing failure in GJB1 expression or loss of the GJ permeability were associated with earlier onset
and faster progression of the symptoms.
Conclusion This study demonstrated that altered expression, abnormal intercellular trafficking and impaired GJ functions
were the fundamentally biophysical dysfunctions of GJB1 mutations and the GJ function was closely correlated with the
disease onset and progression. Our results are helpful in further understanding of the mechanisms underlying CMTX1.
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[O8] Metabolic Disorders 1

Mon., April 04, 2016 18:00-19:30 Room C-2 (1F)
Chair：David Thorburn（Genetics Theme, Murdoch Childrens Research Institute, Australia）

Chair ：Akira Ohtake（Pediatrics, Saitama Medical University, Japan）
Mon(2)-O8-1
A mitochondrial tRNA modopathy due to QRSL1 mutations causes infantile mitochondrial disease
Nana Akiyama 1 ，Kei Murayama 2 ，Masaru Shimura 2 ，Takuya Fushimi 2 ，Keiko Ichimoto 2 ，Masato Mori 3 ，
Yoshihito Kishita 4 ，Yoshimi Tokuzawa 4 ，Masakazu Kohda 4 ，Tsutomu Suzuki 5 ，Yasushi Okazaki 3 ，Akira Ohtake 6
1:Clinical Genetics, Chiba Childrens Hospital, Japan、2:Department of Metabolism, Chiba Childrens Hospital、3:Department of
Pediatrics, Matsudo City Hospital、4:Research Center for Genomic Medicine, Saitama Medical University、5:Department of Chemistry and
Biotechnology, Graduate School of Engineering, University of Tokyo、6:Department of Pediatrics, Saitama Medical University
Background: Defects of tRNA modification (tRNA modopathy) are known as a cause of a variety of diseases. We present
two cases of infantile mitochondrial disease with pathogenic mutations in QRSL1 (hGatA) involved in Glu-tRNAGln amido-
transferase (Glu-Adt), which is composed of three subunits, hGatC, hGatA and hGatB.
Patients and methods: A girl (Pt250) suddenly suffered from hypoglycemia and lactic acidosis on day 1. Subsequently
tachypnea, hypertrophic cardiomyopathy, adrenal insufficiency and hearing loss appeared. She died of cardiac failure at 5

months. Another girl (Pt860) developed cyanosis and lactic acidosis on day 3. She died of interstitial pneumonia at 2 months.
We performed enzyme analysis, whole exome sequencing and their validation tests.
Results: The enzyme analysis showed combined respiratory chain deficiencies (I, III, and IV) in both cases. The whole
exome sequencing revealed Pt250 harbored a homozygous mutation and Pt860 harbored a compound heterozygous muta-
tion in QRSL1 . In vitro reconstitution of Gln-tRNAGln formation using recombinant hGatCAB showed strongly decreased
transamidation activity.
Conclusions: Our study is the first to demonstrate that QRSL1 mutations lead to a defect in the human mitochondrial
translation and are a cause of severe infantile mitochondrial disease.
Mon(2)-O8-2
CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutrope-
nia, Epilepsy, and Methylglutaconic Aciduria
Elsebet Ostergaard 1 ，Carol Saunders 2,3 ，Laurie Smith 3,4 ，Flemming Wibrand 1 ，Kirstine Ravn 1 ，Peter Bross 5 ，
Isabelle Thiffault 3 ，Mette Christensen 1 ，Andrea Atherton 4 ，Emily Farrow 3,4 ，Neil Miller 3 ，Stephen F Kingsmore 2,3,4
1:Clinical Genetics, Copenhagen University Hospital, Denmark、2:Department of Pathology and Laboratory Medicine, Children’s Mercy
Hospital, Kansas City, USA、3:Center for Pediatric Genomic Medicine, Children’s Mercy Hospital, Kansas City, USA、4:Department of
Pediatrics, Children’s Mercy Hospital, Kansas City, USA、5:Research Unit for Molecular Medicine, Aarhus University and Aarhus University
Hospital, Aarhus, Denmark
3-methylglutaconic aciduria (3-MGA-uria) is a nonspecific finding associated with mitochondrial dysfunction, including defects
of oxidative phosphorylation. 3-MGA-uria is classified into five groups, of which one, type IV, is genetically heterogeneous.
Here we report five children with a form of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression
during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood. Four of the individuals
were of Greenlandic descent, and one was North American, of Northern European and Asian descent. Through a combination
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of homozygosity mapping in the Greenlandic individuals and exome sequencing in the North American, we identified biallelic
variants in the caseinolytic peptidase B homolog (CLPB). The causative variants included one missense variant, c.803C>T
(p.Thr268Met), and two nonsense variants, c.961A>T (p.Lys321*) and c.1249C>T (p.Arg417*). The level of CLPB protein
was markedly decreased in fibroblasts and liver of affected individuals. CLPB is proposed to function as a mitochondrial
chaperone involved in disaggregation of misfolded proteins, resulting from stress such as heat denaturation.
Mon(2)-O8-3
A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain
complex deficiencies
Masakazu Kohda 1 ，Yoshimi Tokuzawa 1 ，Kishita Yoshihito 1 ，Yohsuke Moriyama 1,2 ，Yosuke Mizuno 1 ，
Tomoko Hirata 1 ，Yukiko Yatsuka 1 ，Yzumi Yamashita 1 ，Yutaka Nakachiy 1 ，Hidemasa Kato 1 ，Shunsuke Tamaru 3 ，
Hiromi Nyuzuki 1 ，Nurun Nahar Borna 1 ，Hiroko Harashima 4 ，Taro Yamazaki 4 ，Masato Mori 5 ，Kei Murayama 6 ，
Akira Ohtake 4 ，Yasushi Okazaki 1
1:Research Center for Genomic Medicine, Saitama Medical University, Japan、2:Department of Anatomy II and Cell Biology, Fujita Health
University School of Medicine、3:Department of Obstetrics and Gynecology, Saitama Medical University、4:Department of Pediatrics,
Saitama Medical University、5:Department of Pediatrics, Matsudo City Hospital、6:Department of Metabolism, Chiba Children’s Hospital
Mitochondrial disorders have the highest incidence among congenital metabolic disorders characterized by biochemical res-
piratory chain complex deficiencies. It occurs at a rate of 1 in 5,000 births, and has phenotypic and genetic heterogeneity.
Mutations in about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial dysfunction of energy production

and mitochondrial disorder. More than 250 genes that cause mitochondrial disorder have been reported to date. However
exact genetic diagnosis for patients still remained largely unknown. To reveal this heterogeneity, we performed compre-
hensive genomic analyses for 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies. The
approach includes whole mtDNA and exome analyses using high-throughput sequencing, and chromosomal aberration anal-
yses using high-density oligonucleotide arrays. We identified 37 novel mutations in known mitochondrial disease genes and
3 mitochondria-related genes (MRPS23 , QRSL1 , and PNPLA4 ) as novel causative genes. We also identified 2 genes known
to cause monogenic diseases (MECP2 and TNNI3 ) and 3 chromosomal aberrations (6q24.3-q25.1, 17p12, and 22q11.21) as
causes in this cohort. Our approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically
defined mitochondrial respiratory chain complex deficiencies in clinical settings. They also underscore clinical and genetic
heterogeneity and will improve patient care of this complex disorder.
Mon(2)-O8-4
Clinical, Molecular basis and Genetics of Hepatocerebral Mitochondrial DNA Depletion Syndrome in
Japan
Masaru Shimura 1 ，Kei Murayama 1 ，Takuya Fushimi 1 ，Makiko Tajika 1 ，Keiko Ichimoto 1 ，Masato Mori 2 ，
Yoshihito Kishita 3 ，Yoshimi Tokuzawa 3 ，Masakazu Kohda 3 ，Yasushi Okazaki 3 ，Akira Ohtake 4
1:Department of Metabolism, Chiba Children’s Hospital, Japan、2:Department of Pediatrics, Matsudo City Hospital、3:Research Center for
Genomic Medicine, Saitama Medical University、4:Department of Pediatrics, Saitama Medical University
Background: Mitcochondrial respiratory chain disorders (MRCDs) are the most frequent inherited metabolic diseases in
energy production caused by a defect of the nuclear or mitochondrial DNA. Mitochondrial hepatopathy accounts for 12% of
MRCDs in childhood (Ohtake et al. BBA 2014). Among them, Mitochondrial DNA Depletion Syndrome (MTDPS) is the
severest form of hepatopathy. The aim of our study is to clarify the clinical characteristics, molecular features and genetics
of MTDPS.
Methods: MRCDs were diagnosed using in vitro enzyme assay and BN-PAGE analysis. For MTDPS suspected cases in
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mitochondrial hepatopathy, mitochondrial DNA quantitation for nuclear DNA in liver were determined by quantitative
polymerase chain reaction. Subsequently, we performed Sanger Sequencing of some frequent causative genes and the whole
exome sequencing. We also measured oxygen consumption rate using their skin fibroblasts by microscale oxygraphy.
Results: 54 cases were diagnosed as mitochondrial hepatopathy. Among them, 18 cases from 16 families were diagnosed with
MTDPS. 13 cases (72%) died at the mean age of 8 month. Combined complex deficiency is the most common (59%), the
second is complex I deficiency. All liver samples showed decrease in enzyme activity, but all fibroblasts showed normal. We
identified causative gene mutations in 10 cases (MPV17 , DGUOK , POLG). Liver transplants were performed in 8 cases, 2
cases are alive. Oxygen consumption rate in skin fibroblasts of 6 cases was significantly lower than control.
Conclusion: Hepatocerebral MTDPS is one of the severe liver diseases in childhood. There is no evidence-based treatment
in mitochondrial disorder, and the mortality rate is especially high in MTDPS despite liver transplants. To make an early
correct diagnosis for MTDPS by combination with microscale oxygraphy, enzyme analysis and genetic test may improve the
prognosis and lead to develop new treatments.
Mon(2)-O8-5
Modulation of Mitochondrial Bioenergetics in Fibroblasts Derived From Patients With A3243G Mito-
chondrial DNA Mutation

1,2
Dar-Shong Lin ，Che-Sheng Ho 2 ，Hsuan-Liang Liu 3 ，Ming-Fu Chiang 4
1:Pediatric Genetics, Mackay Memorial Hospital, Taipei, Taiwan、2:Pediatric Neurology, Mackay Memorial Hospital, Taipei, Taiwan、3:De-
partment of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei, Taiwan、4:Neurosurgery, Mackay
Memorial Hospital, Taipei, Taiwan
Background: MELAS syndrome is most commonly caused by an A-to-G transition mutation at position 3243 of the mitochon-
drial DNA. A3243G mutation causes deficiency of respiratory chain complex I and IV resulting in impairment of oxidative
phosphorylation (OXPHOS) and mitochondria dynamics.
Objective: The present work evaluates the impact of OXPHOS defects on mitochondrial bioenergetics in fibroblasts from
MELAS patients with A3243G mutation.
Methods: ATP production was determined by chemiluminescent assay. Energy metabolism derived from OXPHOS, glycol-
ysis and fatty acid oxidation (FAO) was measured in adherent fibroblasts with a XF24 Extracellular Flux Analyzer. ATP
production was determined by chemiluminescent assay. Protein levels and molecular expression for bioenergetic function were
compared in control and mutant cells.
Results: Mutant cells showed remarkable decrease of OCR for basal, ATP production, proton leak, and maximum mitochon-
drial respiration. Furthermore, OCR for fatty acid oxidation were also significantly reduced in mutant cells compared to
control cells. In contrast, ECAR derived from glycolytic flux was significantly elevated in mutant cells. Analysis of molecular
expression revealed a significantly up-regulation of PGC1-alpha and UCP2, and down-regulation of TFAM and CPT-1 in
mutant cells. While protein levels of AMPK, Sirt-3 and phosphorylation of ACC-1and PDH were elevated, and CPT-1 were
decreased in mutant cells. Intringuingly, ATP production in mutant cells was severely reduced after inhibition of glycolysis.
Conclusion: The present study demonstrates that the A3243G mutation shifts bioenergetic production from impaired OX-
PHOS and reduced fatty acid oxidation to glycolytic flux in responding to the cellular function. The fibroblasts with A3243G
mutation synthesize the majority of their ATP by glycolysis. These findings may be of relevance for patient management
while unveiling novel therapeutic targets for mitochondrial disorders.
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Mon(2)-O8-6
Whole exome analysis of mitochondrial respiratory chain disorders: Prenatal genetic diagnosis
Taro Yamazaki 1 ，Hiroko Harashima 1 ，Yuichi Abe 1 ，Midori Taniguchi 2 ，Takuya Fushimi 2 ，Keiko Ichimoto 2 ，
Yukiko Yatsuka 3 ，Yoshihito Kishita 3 ，Yoshimi Tokuzawa 3 ，Tomoko Hirata 4 ，Masakazu Kohda 4 ，Yasushi Okazaki 3,4
，
Kei Murayama 2 ，Akira Ohtake 1
1:Pediatrics, Saitama Medical University, Japan、2:Metabolism, Chiba Children’s Hospital、3:Genomics and Systems Medicine, Research
Center for Genomic Medicine, Saitama Medical University、4:Translational Research, Research Center for Genomic Medicine, Saitama
Medical University
Mitochondrial disorders have the highest incidence among congenital metabolic diseases, and are thought to occur at a rate of
1 in 5000 births. About 25% of the diseases diagnosed as mitochondrial disorders in the field of pediatrics have mitochondrial
DNA abnormalities, while the rest occur due to defects in genes encoded in the nucleus. The most important function of the
mitochondria is biosynthesis of ATP. Mitochondrial disorders are nearly synonymous with mitochondrial respiratory chain

disorder (MRCD), as respiratory chain complexes serve a central role in ATP biosynthesis. Among patients in whom decreased
enzyme activity or complex formation abnormalities were seen biochemically, whole exome analyses were performed in those
with no known mitochondrial DNA abnormalities, and the obtained candidate causal genes were confirmed at the cellular
level by rescue experiment or other methods. After the careful genetic counseling, we planed prenatal genetic diagnosis
in 7 families whose propositus was a patient with clinically severe MRCD, namely, lethal infantile mitochondrial disorder
(LIMD) due to BOLA3 , ACAD9 , TUFM and QRSL1 , mitochondrial cardiomyopathy due to BOLA3 and Leigh disease due
to NDUFAF6 and BOLA3 . Among seven pregnancies in six families, five prenatal genetic testing were done. One fetus was
compound heterozygote as the proband. Four healthy babies were born, in which three were heterozygotes, and the last one
was homozygote of wild type. The other two mothers had miscarriages. In one patient, as fetal chorionic villi were confirmed
to be contaminated with maternal deciduas by the microsatellite assay, the re-examination using amniotic cells was done.
For severe and incurable MRCDs, prenatal genetic testing after the careful genetic counseling are essential as well as the
development of new drugs.
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[O9] Psychiatric Genetics, Neurogenetics and Neurodegeneration 1

Mon., April 04, 2016 18:00-19:30 Room I (2F)
Chair：Bing-Wen Soong（Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan）

Chair ：Hiroyuki Takashima（Department of Neurology and Geriatrick, Kagoshima University, Japan）
Mon(2)-O9-1
Target genes of transcriptional regulation by Dentatorubral-Pallidoluysian Atrophy protein (DRPLAp)
that acts as a transcriptional co-regulator
Keiko Hatano 1 ，Hidetoshi Date 1 ，Hiroyuki Ishiura 1 ，Jun Mitsui 1 ，Jun Goto 1,3
，Jun Yoshimura 2 ，Koichiro Doi 2 ，
Shinichi Morishita 2 ，Shoji Tsuji 1
1:Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan、2:Department of Computational Biology,
Graduate School of Frontier Sciences, The University of Tokyo, Chiba、3:Department of Neurology, International University of Health and
Welfare Mita Hospital, Tokyo
Backgrounds: Dentatorubral-Pallidoluysian atrophy (DRPLA) is an autosomal dominant ataxia caused by unstable expansion
of CAG repeats in the DRPLA gene (ATN1). Previous studies have shown that DRPLA protein (DRPLAp) functions as a
transcriptional co-regulator. Its target genes, however, remain unknown.

Purposes: To elucidate the physiological functions of DRPLAp based on determination of the target genes regulated by
wild-type DRPLAp and mutant DRPLAp.
Materials: Flp-In T-REx HEK293 cells stably expressing GFP-fused full-length human DRPLA cDNA (Q19 or Q88) under
the control by Tet (Tetracycline) -On/Off system were used.
Methods: RNA was extracted from the cells (Q19 or Q88) 24 hours after Tet-On or Tet-Off. Expression profiling analyses were
performed in four independent experiments. Strand-specific cDNA libraries were generated from ribosomal RNA-depleted
RNA with random primers. Paired-end RNA seq was performed using HiSeq 2500 and analyzed by Cufflinks2 and edgeR.
Comparisons between Q19 (On) and Q19 (Off) (Analysis 1) and between Q88 (On) and Q88 (Off) (Analysis 2) were performed.
Results: Transcriptional target genes were defined as differentially expressed genes (DEGs) obtained by both pipelines with
reproducibility confirmed by all 4 independent experiments. Analysis 1 revealed 9 up-regulated and 7 down-regulated genes,
and Analysis 2 revealed 11 up-regulated and 13 down-regulated genes. Total of 12 genes were considered to be common
changes by both Q19 and Q88, and total of 4 genes were considered to be changes by Q19. Four up-regulated and 8 down-
regulated genes were considered to be changes regulated by Q88, of which 8 genes are expressed in the brain based on GTEx
database and the 8 genes were validated by quantitative PCR.
Conclusions : We identified 8 genes regulated by Q19 or Q88 with reproducibility confirmed by 4 expression experiments.
Further studies using DRPLA mouse models as well as autopsied human brains will be needed to validate the 8 genes.
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Mon(2)-O9-2
Sigmar1 receptor: Genetics, clinical/subclinical investigations and animal and cell models characterisa-
tion to dissect the mechanisms of cell death leading to motor neuron disease
1
Hamid Azzedine
1:Institute of Neuropathology, Germany
SIGMAR1 is a chaperon membrane-associated protein involved in several cellular processes. In mitochondria, SIGMAR1 is
located at the interface between Endoplasmic Reticulum (ER) and mitochondria called Mitochondrial-Associated Membranes
(MAMs) and play an important role in calcium homeostasis.
Before NGS era, in 2 large consanguineous families with motor neuron disease inherited as a recessive trait, we first performed
a whole genome genotyping, and a large region of homozygosity was identified. Several genes in the region of interest were
sequenced. A truncated mutation was identified in SIGMAR1 gene. This is the first "Human knockout model" of SIGMAR1,
identified so far. These results were followed by the characterization of Sigmar1 KO mice which revealed muscle weakness,
axonal degeneration and motor neuron loss. In both human and animal tissues, we used electron and confocal microscopy
and other assays to investigate the biology of SIGMAR1 in health and disease. In primary motor neuron cultures, we
observed that pharmacological or genetic inactivation of SIGMAR1 led to motor neuron axonal degeneration followed by
cell death. Disruption of SIGMAR1 function in motor neurons disturbed ER-mitochondria contacts, affected intracellular
calcium signalling and was accompanied by activation of ER stress and defects in mitochondrial dynamics and transport.

Interestingly, the inhibition of mitochondrial fission was sufficient to induce mitochondria axonal transport defects as well as
axonal degeneration similar to the changes observed after SIGMAR1 inactivation or loss. Intracellular calcium scavenging
and ER stress inhibition were able to restore mitochondrial function and consequently prevent motor neuron degeneration.
These results uncover the cellular mechanisms underlying motor neuron degeneration mediated by loss of SIGMAR1 function,
provide therapeutically relevant insight into motor neuronal diseases and shed light on the corresponding human motor neuron
disease.
Mon(2)-O9-3
Identification of Long non-coding RNA as a Novel Susceptibility Gene for Non-Familial Hypokalemic
Periodic Paralysis by GWAS
I-Wen Song 1 ，Chih-Chien Sung 2 ，Chien-Hsiun Chen 1 ，Chih-Jen Cheng 2 ，Sung-Sen Yang 2 ，Yi-Chun Chou 1 ，
Jenn-Hwai Yang 1 ，Yuan-Tsong Chen 1 ，Shih-Hua Lin 2 ，Jer-Yuarn Wu 1
1:Institute of Biomedical Sciences, Academia Sinica, Taiwan、2:Division of Nephrology, Department of Medicine, Tri-Service General
Hospital, National Defense Medical Center, Taipei,Taiwan
Thyrotoxic periodic paralysis (TPP) and sporadic periodic paralysis (SPP) are life-threatening non-familial causes of hy-
pokalemic periodic paralysis (hypoKPP). Unlike the well-studied familial hypoKPP, the pathogenic mechanism of TPP and
SPP is largely unknown. Therefore, we aimed to identify susceptibility genes predisposing individuals to non-familial hypoKPP
and explore the potential pathogenic mechanisms. We enrolled non-familial hypoKPP patients not carrying mutations in pre-
viously reported hypoKPP causing genes (CACNA1S, SCN4A, KCNJ18, KCNJ2 ), and conducted genome-wide association
analyses comparing 77 TPP and 32 SPP patients with 1730 controls in a Han Chinese population in Taiwan. Replication
was performed using an independent Han Chinese cohort of 50 TPP, 22 SPP patients, and 376 controls. We identified four
SNPs located on chromosome 17q24.3 associated with both TPP and SPP reaching genome-wide significance (P < 9 × 10-8 ).
Among them, one SNP was mapped to CTD, a long intergenic non-coding RNA, and direct sequencing revealed an exon
variant highly associated with both TPP (P = 1.81 × 10-12 ; odds ratio= 3.22[95% CI 2.36-4.40]) and SPP (P = 8.6 × 10-12 ;
odds ratio= 5.4[95% CI 3.17-9.18]). Moreover, overexpression of normal allele in C2C12 skeletal muscle cell, but not risk allele,
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significantly decreased potassium channel. Higher steady state potassium channel mRNA was also detected in patient blood
sample. These indicated that risk-type CTD has lost the ability in regulating potassium channel expression. Altogether,
for the first time, we revealed a shared genetic predisposition factor between TPP and SPP. The miss-regulation of CTD on
potassium channel expression may result in paralysis attack in non-familial hypoKPP. These findings provide new insights
into the pathogenesis of non-familial hypoKPP.
Mon(2)-O9-4
Features of dysferlin mutations in Japan
Toshiaki Takahashi 1 ，Naoki Suzuki 2 ，Rumiko Izumi 2,3 ，Tetsuya Niihori 3 ，Chikako Yaginuma 4 ，Naoko Shimakura 2 ，
Hiroya Ono 2 ，Yasuko Shimosegawa 5 ，Sayaka Taniguchi 1 ，Hideki Oizumi 1 ，Hiroyasu Tanaka 1 ，Masaru Yoshioka 1,4 ，
Atsushi Takeda 1 ，Yoko Aoki 3 ，Masashi Aoki 1
1:Department of Neurology and Division of Clinical Research, National Hospital Organization Sendai-Nishitaga National Hospital, Japan、
2:Department of Neurology, Tohoku University School of Medicine、3:Department of Medical Genetics, Tohoku University School of Medicine、
4:Departments of Clinical Laboratory and Division of Clinical Research, National Hospital Organization Sendai-Nishitaga National Hospital、
5:Departments of Neurosurgery and Division of Clinical Research, National Hospital Organization Sendai-Nishitaga National Hospital
Dysferlinopathies are autosomal recessive muscular dystrophies caused by mutations in the dysferlin gene (DYSF ). It has 55
exons and 6,243 base pair nucleotides in an open reading frame predicted to encode 2,080 amino acids. Dysferlin deficiency
lead to two main phenotypes, Miyoshi muscular dystrophy (MMD) and limb girdle muscular dystrophy (LGMD) 2B. In ad-
dition, distal anterior compartment myopathy (DACM) was a rare phenotype of dysferlinopathy. We have screened Japanese

patients for DYSF mutations. Here we analyzed dysferlin gene mutational data.
Mutational analysis was performed by single-strand conformation polymorphism (SSCP) or targeted next-generation sequenc-
ing using a panel including DYSF . Putative pathogenic mutations were confirmed by Sanger sequencing.
We identified 73 different mutations in 177 families. Ninety two families carried homozygous mutations and 77 families car-
ried compound heterozygous mutations. In eight probands, we could identify mutations in only one allele. Mutations are
distributed along the entire length of the gene. There were 35 different truncating mutations, 25 different missense mutations,
and 13 different splice site mutations. The c.2997G>T (p.Trp999Cys) mutation was present in 77 alleles (22.3%), 41 alleles
(11.8%) for the c.1566C>G (p.Try522X) mutation, 24 alleles (6.9%) for the c.4497delT mutation, 21 alleles (6.1%) for the
c.3373delG mutation, 13 alleles (3.8%) for the c.6135G>A (p.Trp2045X) mutation, and ten alleles (2.9%) for the c.2974T>C
(p.Trp992Arg) mutation. Ninety five patients in whom mutations were identified in two alleles had MMD, 78 for LGMD2B,
one for DACM, and ten for hyper-CKemia. The c.2997G>T mutation had higher frequency in patients with LGMD2B than in
patients with MMD. Furthermore, there was only one patient with MMD who carried the homozygous c.2997G>T mutation.
The c.3373delG mutation was identified in only two patients with LGMD2B.
Mon(2)-O9-5
Mutations in CAPN1 Cause Autosomal Recessive Hereditary Spastic Paraplegia
Ziv Gan-Or 1 ，Naima Bouslam 2 ，Nazha Birouk 2 ，Alexandra Lissouba 3 ，Daniel Chambers 4 ，Julie Veriepe 3 ，
Alaura Androschuck 4 ，Ahmed Bouhouche 2 ，Ali Benomar 2 ，Mohamed Yahyaoui 2 ，Reda Ouazzani 2 ，Grace Yoon 5 ，
Nicolas Dupre 6 ，Oksana Suchowersky 7 ，Francois Bolduc 4 ，J Alex Parker 3 ，Patrick A Dion 1 ，Pierre Drapeau 3 ，
Guy A Rouleau 1 ，Bouchra O Bencheikh 1
1:McGill University, Canada、2:Centre Hospitalier Ibn Sina, University; Mohammed V Souissi, Rabat, Morocco、3:Centre de Recherche du
Centre Hospitalier de l’Universite; de Montreal (CRCHUM), Montreal, Quebec, Canada、4:Department of Pediatrics, Neuroscience and
Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada、5:Division of Neurology, Department of Pediatrics, University
of Toronto, The Hospital for Sick Children, Toronto, Canada、6:Division of Neurology, CHU de Quebec, and Faculty of Medicine, Laval
University, Quebec City, Quebec, Canada、7:Division of Neurology, University of Alberta, Edmonton, Alberta, Canada
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Hereditary Spastic Paraplegias (HSP) are a group of clinically and genetically heterogeneous diseases characterized by lower
limbs spasticity and weakness, with or without additional neurological symptoms. More than 70 genes and genetic loci have
been suggested in HSP, however many families remain genetically undiagnosed, implying that other genetic causes of HSP are
still to be identified. HSP can be inherited in an autosomal-dominant or -recessive, or X-linked manner. In the current study,
we analyzed three families with autosomal-recessive HSP, with a total of 9 affected individuals who were tested with whole
exome sequencing. Rare homozygous and compound heterozygous nonsense, missense, frame-shift and splice-site mutations in
the CAPN1 gene were identified in all patients, and sequencing in additional family members confirmed the co-segregation of
these mutations with the disease. CAPN1 encodes calpain 1, a protease that is widely expressed in the central nervous system.
Calpain 1 is involved in synaptic plasticity, synaptic restructuring and axon maturation and maintenance. Three models of
calpain 1 deficiency were further studied. In C. elegans, loss of calpain 1 function resulted in neuronal and axonal dysfunction
and degeneration. Similarly, loss-of-function for the Drosophila melanogaster orthologue calpain B caused locomotor defects
and axonal anomalies. Knockdown of calpain 1a, a CAPN1 orthologue in Danio rerio, resulted in abnormal branchiomotor
neurons migration and disorganized acetylated tubulin axonal networks in the brain. The identification of CAPN1 as an
HSP-causing gene expands our understanding of the disease causes and potential mechanisms.
Mon(2)-O9-6
Exome sequencing of singletons from individual families revealed a novel causative gene for autosomal
recessive hereditary spastic paraplegia

Hiroyuki Ishiura 1 ，Jun Mitsui 1 ，Haruo Shimazaki 2 ，Kishin Koh 3 ，Yuta Ichinose 3 ，Yuji Takahashi 4 ，Jun Goto 5 ，
Jun Yoshimura 6 ，Koichiro Doi 6 ，Shinichi Morishita 6 ，Hidenao Sasaki 7 ，Yoshihisa Takiyama 3 ，Shoji Tsuji 1 ，
JASPAC (Japan Spastic Paraplegia Research Consortium)
1:Department of Neurology, The University of Tokyo, Japan、2:Department of Neurology, Jichi Medical University、3:Department of
Neurology, Yamanashi University、4:Department of Neurology, National Center of Neurology and Psychiatry、5:Department of Neurology,
International University of Health and Welfare Mita Hospital、6:Department of Computational Science, Graduate School of Frontier
Sciences, The University of Tokyo、7:Department of Neurology, Hokkaido University
[Background] Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder characterized by spasticity and pyramidal
weakness of the lower limbs. Causative genes for 50-60% of autosomal recessive HSP (ARHSP) patients remain to be
elucidated. In the majority of the families, only a limited number of affected individuals is available for genetic studies. To
overcome this difficulty, we tried to identify novel causative gene for ARHSP combining exome sequence data of singletons
from individual families.
[Methods] One hundred and seven patients of undiagnosed HSP whose family histories were consistent with AR mode of
inheritance were enrolled. Nonsynonymous and splicing variants with minor allele frequencies <0.2% were selected from
exome data. We then searched for genes where multiple patients but no control subjects had biallelic rare variants.
[Results] We identified four families, where affected individuals shared biallelic rare variants in the same gene. Two families
have homozygous nonsense mutations and two families have the same homozygous missense mutation. The homozygous
nonsense variants strongly support loss-of-function mutations relevant to the disease. The missense variant is located in a
conserved catalytic domain and the haplotypes spanning 2.1 Mb flanking the variant were identical in the two families. The
clinical presentation of these four patients are characterized by ataxia or dysarthria in addition to spastic paraplegia. The
observation of the homogeneous clinical presentations of the patients in the four families further support the notion that the
gene is likely a novel causative gene for AR-HSP.
[Discussion] Through the search for genes with biallelic rare variants shared among singletons, we identified a novel putative
gene for ARHSP. The present study revealed that our study paradigm is efficient for identifying causative genes with AR
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inheritance even though only singletons from individual families are available for the analysis.

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[O10] Development
Mon., April 04, 2016 18:00-19:30 Room J (2F)
Chair：Andrew McCallion（McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine,
USA）
Chair ：Tadashi Kaname（Genome Medicine, National Center for Child Health and Developmen, Japan）
Mon(2)-O10-1
Fast and effective genome editing to study dominant de novo mutations: the Wdr45 mouse model for
BPAN
Caroline A. Biagosch 1,2 ，Svenja-Viola Hensler 1,2 ，Dirk Janik 3 ，Frauke Neff 3 ，Lore Becker 4,5
，Thomas Klopstock 4,5
，
Wolfgang Wurst 5,6 ，Thomas Meitinger 1,2 ，Holger Prokisch 1,2
1:Institute of Human Genetics, Technische Universitaet Muenchen, Germany、2:Institute of Human Genetics, Helmholtz Zentrum Muenchen,
Neuherberg, Germany、3:Institute of Pathology, Helmholtz Zentrum Muenchen, Germany、4:Department of Neurology, Friedrich-Baur-
Institute, Ludwig-Maximilians-University, Muenchen, Germany、5:Institute of Experimental Genetics, German Mouse Clinic, Neuherberg,
Germany、6:Institute of Developmental Genetics, Helmholtz Zentrum Muenchen, Neuherberg, Germany
Trio sequencing for intellectual disability delivers more and more potentially disease causing de novo DNA variants, emphasiz-
ing the need for an effective validation tool. We present an effective genome editing approach based on embryo microinjection
of TALENs (Transciption activator-like effector nucleases). We generated a mouse model for the X-linked dominant form of
NBIA (Neurodegeneration with Brain Iron Acculumation), caused by de novo loss-of-function mutations in WDR45 . The

course of this disease, known as BPAN (beta-propeller Protein-Associated Neurodegeneration), is two-staged with develop-
mental delay and intellectual disability in childhood and a second phase of rapid neurological deterioration characterized
by parkinsonism and dementia occurring in early adulthood with characteristic neuroimaging findings such as hypointense
signals in substantia nigra and globus pallidus. Microinjection of TALEN mRNA into oocytes resulted in 19% mutated
founders (5/26), 80% of which lead to frame-shift mutations. From the in situ design of TALENs, over in vitro testing in cell
culture to in vivo injection into embryo’s until the genotyping of founder mutants it took 4 months. The murine Knock-Out
proved to not necessarily be de novo; therefore we chose a mouse harboring a 20bp deletion in Exon 2 for further breeding.
Investigation of nine month old male brains (n=8) revealed numerous degenerated neurons and large axonal spheroids, clear
signs of neurodegeneration in medulla oblongata, cerebral cortex, thalamus and spinal cord of mutant animals only. A neu-
robehavioral screen of 21 animals at the age of one year showed motor impairment (Balance Beam, p=0.004; Inverted Grid,
p=0.018; Open-field, p=0.014), and an ageing cohort of 53 animals showed among others, genotype-specific signs of auditory
deterioration starting at the age of 6 months. Hence, the Wdr45 Knock-Out mouse resembles several characteristics of BPAN
providing a useful disease model.
Mon(2)-O10-2
Placental phenotypes of Chst14 -/- fetal mice: a model for vascular manifestations in Ehlers-Danlos
syndrome caused by CHST14/D4ST1 deficiency
Takahiro Yoshizawa 1 ，Shuji Mizumoto 2 ，Jun Nakayama 3 ，Takuya Hirose 4 ，Kazushige Takehana 4 ，Fengming Yue 5 ，
Nana Tsumita 6,7 ，Chiaki Masuda 8 ，Yuko Kasahara 8 ，Yuki Takahashi 9 ，Shin-ichi Takeda 7 ，Takashi Okada 8 ，
Kiyoshi Matsumoto 1 ，Tomoki Kosho 9
1:Division of Laboratory Animal Research, Research Center for Human and Environmental Sciences, Shinshu University, Japan、2:Depart-
ment of Pathobiochemistry, Faculty of Pharmacy, Meijo University、3:Department of Molecular Pathology, Shinshu University Graduate
School of Medicine、4:Department of Veterinary Pathology, School of Veterinary Medicine, Rakuno Gakuen University、5:Department of
Histology and Embryology, Shinshu University School of Medicine、6:Scleroprotein and Leather Research Institute, Tokyo University of
Agriculture and Technology, Faculty of Agriculture、7:Department of Molecular Therapy, National Institute of Neuroscience, National
Center of Neurology and Psychiatry、8:Department of Biochemistry and Molecular Biology, Nippon Medical School、9:Department of
Medical Genetics, Shinshu University School of Medicine
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Ehlers-Danlos syndrome (EDS) caused by CHST14/D4ST1 deficiency is a recently delineated disorder, also named as EDS,
musculocontractural type 1 (MIM#601776). It is clinically characterized by multiple congenital malformations (craniofacial
features, multiple congenital contractures including adducted thumbs and talipes equinovarus) and progressive fragility-related
manifestations (skin hyperextensibility and fragility, recurrent dislocations and progressive talipes or spinal deformities, large
subcutaneous hematomas). Multisystem fragility is presumably caused by impaired assembly of collagen fibrils resulting from
loss of dermatan sulfate in the decorin glycosaminoglycan side chain that promotes electrostatic binding between collagen
fibrils. Large subcutaneous hematomas, supposedly resulting from rupture of small arteries, are one of the most serious
complications accompanied by decreased ADL/QOL and potential lethality.
-/-
We evaluated Chst14 deleted mice (Chst14 ) as a model for the disorder, which were generated from sperms of Chst14 +/-
-/-
male mice obtained from the Mutant Mouse Regional Resource Center. Most Chst14 mice died during the perinatal
-/-
period and only limited number of adult mice were available. Therefore, we investigated placentae of Chst14 fetal mice,
+/- +/+ -/-
as compared with Chst14 or Chst14 fetal mice. The placentae of Chst14 fetal mice showed reduced weight,
alterations in vascular structure, and ischemic changes. Electron microscopy demonstrated abnormal structure of endothelial
-/-
cells and basal laminae. Dermatan sulfate was not detected in the placentae of Chst14 fetal mice.
These findings suggest that Chst14 gene would essential for placental vascular development in mice. Furthermore, placentae
-/-
of Chst14 fetal mice could be a useful model for vascular manifestations in the disorder especially large subcutaneous
hematomas.

Mon(2)-O10-3
Critical roles of Rdh10 in craniofacial development
1,2
Hiroshi Kurosaka ，Qi Wang 1 ，Takashi Yamashiro 1 ，Trainor Paul 2
1:Osaka University Graduate School of Dentistry, Japan、2:Stowers Institute for Medical Research
Retinoic acid signaling is well known to be widely involved in craniofacial development. Either loss or gain of function of
retinoic acid signaling during development could result in craniofacial abnormality such as cleft lip and/or palate. There
are various genes involved in retinoic acid metabolism including Retinol dehydrogenase 10 (Rdh10) which catalyzes the first
oxidative step in the metabolism of vitamin A to its active form retinoic acid. However the role of those genes in craniofacial
development is still elusive. Previously we reported Rdh10trex mutant mice which developed by our ENU mutagenesis screen
and have loss of function mutation in Rdh10 gene together with various craniofacial defect and significant reduction of retinoic
acid signaling. However, since the Rdh10trex mutant mice were embryonic lethal around E12.0, we couldn’t analyze the role
of Rdh10 on later stage craniofacial development. In this study we used Rdh10fx/fx mice crossed with a tamoxifen-inducible
CreERT2 line in order to excise Rdh10 gene at different developmental stages in mice to investigate temporal requirement
of retinoic acid signaling in craniofacial development. By excising Rdh10 at E7.5 from developing mice lead to cleft lip,
choanal atresia and secondary cleft palate at E15.5. Additionally, ectopic bone formation at anterior secondary palate could
be found which presumably part of the etiology of choanal atresia. From these results it is strongly suggested that retinoic
acid signaling controlled by Rdh10 is crucial during embryonic craniofacial development.
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Mon(2)-O10-4
Mutations in components of the endothelin 1-endothelin receptor type A signaling pathway cause
homeotic transformations of the first pharyngeal arch in humans
Jeanne Amiel 1 ，Chris Gordon 1 ，Yukiko Kurihara 2 ，Nicole Weaver 3 ，Roseli Maria Zechi-Ceide 4 ，Myriam Oufadem 1 ，
David Weaver 5 ，Howard Saal 3 ，Stanislas Lyonnet 1 ，Hiroki Kurihara 2
1:Institut Imagine, France、2:University of Tokyo、3:Cincinnati Children’s Hospital Medical Center、4:Hospital for Rehabilitation of Cran-
iofacial Anomalies, University of Sao Paulo、5:Indiana University School of Medicine
The first pharyngeal arch is an embryonic structure comprised of mandibular and maxillary prominences, which give rise to
the lower and upper jaws respectively. The endothelin 1 (EDN1)-endothelin receptor type A (EDNRA) signaling pathway
is essential for the establishment of mandibular identity in animal models. We have identified mutations in components of
this pathway in patients with rare craniofacial disorders. Auriculocondylar syndrome (ACS) is characterised by micrognathia,
condyle hypoplasia and question mark ear (QME). QME involves a defect in the fusion of the lobe and helix, and can occur as
an isolated anomaly. Recently, mutations in PLCB4 and GNAI3 were identified in ACS. Both genes are predicted to function
as intracellular effectors of the EDN1-EDNRA signaling pathway. By exome sequencing, mutations were also identified in
EDN1 in both ACS and isolated QME patients, suggesting that ACS and QME are a phenotypic continuum resulting from
impaired EDN1-EDNRA signaling. We have also identified de novo missense mutations in EDNRA in individuals with a
novel syndrome, mandibulofacial dysostosis with alopecia (MFDA). Most MFDA patients have an identical substitution in
EDNRA: p.Tyr129Phe. Tyr129 is known to determine the selective affinity of EDNRA for EDN1, its major physiological
ligand, and previous in vitro studies have shown that the p.Tyr129Phe mutation increases the affinity of EDNRA for EDN3,

its non-preferred ligand, by two orders of magnitude, suggesting a gain of function mutation. We will review the genetic and
phenotypic aspects of ACS and MFDA, and present data from new mouse models of these disorders. We suggest that ACS is
caused by loss of EDN1-EDNRA activity in the developing mandible, leading to a mandibular to maxillary transformation,
while MFDA represents the inverse transformation (maxillary to mandibular), due to ectopic activation of EDNRA in the
developing upper jaw.
Mon(2)-O10-5
Cell culture model for X-linked disorder: craniofrontonasal dysplasia and severe phenotype in female
Masanori Sugimoto 1 ，Hidehito Inagaki 1 ，Makiko Tsutsumi 1 ，Yoshikazu Inoue 2 ，Yoshihiro Taguchi 2 ，Hiroko Boda 3 ，
Masafumi Miyata 3 ，Takayuki Okumoto 2 ，Tetsushi Yoshikawa 3 ，Hiroki Kurahashi 1
1:Division of Molecular Genetics, ICMS, Fujita Health University, Japan、2:Department of Plastic and Reconstructive Surgery, Fujita Health
University、3:Department of Pediatrics, Fujita Health University
Craniofrontonasal syndrome (CFNS) is an X-linked craniofacial disorder, characterized by frontonasal dysplasia, craniofacial
asymmetry, craniosynostosis, and other extracranial manifestations. The phenotype shows paradoxically more severe in
heterozygous females than in hemizygous males. This unusual expression pattern of X-linked inheritance disease is likely to
be attributed to coexistence of mutant and normal cells mediated by the random X-inactivation in females. The mixed state
might disturb the normal developmental regulation, called cellular interference. The causative gene for CFNS is EFNB1 ,
encoding ephrin-B1, a transmembrane ligand of EPH receptor tyrosine kinase. The EFNB1 works for the cell-cell interaction,
migration and other developmental process through the kinase signaling. To explore the machinery of this cellular interference
observed in CFNS, we have made a cell culture model system with distinct cell lines each expressing either normal or mutant
EFNB1 ligand, or normal EPHB2 receptor ectopically. Addition of normal EFNB1 cells to the EPHB2 cells culture led to
a clump formation of EPHB2 cells. This formation was diminished when the mutant EFNB1 cells were added, and further
decreased by adding both mutant and normal EFNB1 cells simultaneously. This result suggests that the cellular interference
was seen in this culturing condition that mimic the mosaic state in CFNS females. To compare the migration speed of the
receptor cells toward the EFNB1 ligand cells, cell migration assays were carried out. The receptor cells migrated faster to
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the normal EFNB1 cells than to the mutant cells. The mixture of the normal and mutant ENFB1 lead to the intermediate
migration speed. These results suggest that the mosaic state in female patient is not simply explained by the reaction between
single ligand and receptor cells, and random X-inactivation at patchy distribution throughout the body, for example, may
cause the cellular interference in CFNS females.
Mon(2)-O10-6
MicroRNA in human induced pluripotent stem cells lineage specification
Lu Li 1 ，Shen Gu 2 ，Yick-Keung Suen 1 ，Hoi-Hung Cheung 1 ，Dan-dan Cao 1 ，Wai-Nok Law 1 ，Wai-Yee Chan 1
1:The Chinese University of Hong Kong - Chinese Academy of Sciences Guangzhou Institute of Biomedicine and Health Joint Laboratory
on Stem Cell and Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, China、
2:Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas, USA
Human induced pluripotent stem cells (hiPSC) have the potential to differentiate into all somatic cell types. Previous studies
suggest that the correlation of lineage specification of hiPSCs and miRNAs is high. With the increasing prevalence of renal
disease, renal development process and the renal regenerative strategies draw much attention. However, whether miRNAs are
key regulators in renal formation and associated diseases remains obscure.
To investigate the role of miRNAs in differentiation, we have established hiPSC differentiation platform for three germ layers,
namely, hepatocyte for endoderm, nephron progenitor for mesoderm, and neural progenitors for ectoderm, respectively.

Profiling of miRNA expression in samples collected from different time points during differentiation with microarrays allowed
vertical and horizontal comparisons among the three representative lineages of the three germ layers. A number of apparently
lineage-specific miRNAs were identified. A combination of target gene prediction and gene ontology enrichment analyses were
used to select candidate miRNAs, the expression of which was confirmed by qPCR. One of miRNAs, miR-105, was found to
decrease during nephron progenitor differentiation and was predicted to regulate PKD1 and PKD2, the pathogenic genes of
autosomal dominant polycystic kidney disease (ADPKD). To determine the role of miR-105 in renal formation, we extended
the differentiation of hiPSC to ureteric bud and collecting duct. The expression of miR-105 and PKD1/PKD2 was negatively
correlated during the process and the interaction between them was confirmed by luciferase reporter assay. In the future, a
gain- or loss-approach of miR-105 will be carried out for to confirm its effects on potential downstream pathway and to find
out how it affects renal specification and ADPKD pathogenesis.
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[O11] Cytogenetics
Mon., April 04, 2016 18:00-19:30 Room K (2F)
Chair：Ina E. Amarillo（Cytogenomics and Molecular Path Lab, Division of Lab and Genomic Medicine, Dept. of
Pathology and Immunology, Washington University in St. Louis School of Medicine, USA）
Chair ：Keiko Wakui（Medical Genetics, Shinshu University School of Medicine, Japan）
Mon(2)-O11-1
Finding Small Copy Number Variations (CNVs) and Regions of Homozygosity (ROH) Beneath the
Surface: A Retrospective Chromosome Microarray Analysis (CMA) and Genomic-Epigenomic Integration
in Disorders of Sex Development (DSD)
Ina E Amarillo 1,5 ，Vishwanathan Hucthagowder 1,5
，Isabelle Nievera 2 ，Drew Hagan 3 ，Jennifer Heeley 4 ，
Washington University in St Louis DSD Team
1:Pathology and Immunology, Washington University in St Louis School of Medicine, USA、2:University College in Washington University
in St Louis、3:Department of Developmental Biology, Washington University in St Louis School of Medicine、4:Department of Pediatrics,
Washington University in St Louis School of Medicine、5:Cytogenomics and Molecular Pathology Lab
Use of CMA has accumulated a wealth of CNV data. In many genetic disorders, including DSD, most CNVs are large and
tagged as variants of uncertain clinical significance with critical regions and causative genes yet to be identified. In clinical
CMA, CNVs or genes smaller than the set cutoff (e.g. 30-50 Kb) are unanalyzed, uncharacterized, and remain underrepresented

in existing databases and literature. We uncovered small CNVs from ~ 50 patients suspected of DSD using a customized
CMA track of ~ 334 genes related to sex development, ~ 60% of these genes were ≤50 Kb. Using 1 Kb as the detection limit,
12,719 CNVs (~ 52% losses, ~ 48% gains) were revealed and ~ 312 (2.5%; ~ 60% introns, ~ 36% exons) overlapped with
69 genes, ~ 94% were ≤50 Kb and ~ 60% were rare. Recurrent and overlapping CNVs and ROH involving 93 genes were
detected in ≥2 patients with similar clinical findings. In silico investigations revealed CNVs, genes, and regions with salient
genomic and epigenomic features; 5’, 3’, orphan CGI (44), transcription factor binding site (168), active transcription site
(27), enhancer (63), retro/transposon (220), functional region or domain (184), regulatory H3K27Ac peaks (103), segmental
duplication (13), haploinsufficiency (37), imprinting (33), and regulatory function via position effect (22). Comparing normal
fetal testis and ovary revealed distinct profiles of methylC-Seq (68 CNVs) and DNase hypersensitivity (DH) (128), as well
as RNA-Seq (74) and DH (136) between fetal and adult ovaries. This study highlights a gene-targeted and disease-specific
CMA approach that uncovers CNVs as small as 1 Kb that include relevant DSD genes, adding to the growing small CNV
data and narrowing the genomic gap. This genomic-epigenomic approach provides many avenues for downstream functional
studies and data from such integrated studies may improve the clinical diagnostic utility of CMA, as well as advance our
understanding of DSD and other complex genetic disorders.
Mon(2)-O11-2
Assessing copy number variants involving the ACMGG secondary finding genes in a clinical pediatric
population
Jinbo Fan 1 ，Surabhi Mulchandani 1 ，Matthew Dulik 1 ，Jinyun Chen 1 ，Adam Gleason 1 ，Pushkala Jayaraman 1 ，
Elaine Zackai 2 ，Mahdi Sarmady 1 ，Minjie Luo 1 ，Nancy Spinner 1 ，Laura Conlin 1
1:The Department of Pathology and Laboratory Medicine, The Childrens Hospital of Philadelphia, USA、2:Department of Pediatrics, The
Childrens Hospital of Philadelphia
Purpose: Unlike whole exome/genome sequencing, chromosomal microarray (CMA) testing is complicated by the fact that
one copy number variant (CNV) may harbor genes associated with the patient’s phenotype as well as genes associated with
a secondary finding. CMA is now the “first-tier” diagnostic test for individuals with developmental disabilities or congenital
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anomalies; however, the prevalence and significance CNVs that encompass or disrupt one of the 56 American College of
Medical Genetics and Genomics (ACMGG) secondary finding genes has not been systematically ascertained in a clinical
population referred for routine diagnostic chromosomal SNP array analysis.
Methods: We retrospectively compiled and reviewed 11,171 chromosomal SNP array cases from the Children’s Hospital of
Philadelphia Cytogenetics Laboratory. Only 32 of these 56 ACMGG genes have been associated with a loss of function (LOF)
mechanism, therefore eligible CNVs involving at least one of this subset of 32 genes were identified and analyzed to determine
if the CNV explained the patient’s reason for study.
Results: Out of 11,171 patients examined by chromosomal SNP array, only 29 patients (0.26%) had CNVs that were predicted
to result in a loss of function involving a deletion or intragenic duplication of one of the ACMGG genes with LOF mechanism.
These predicted LOF CNVs included 22 whole gene deletions, 4 partial gene deletions, and 3 intragenic gene duplications.
Among these CNVs, 21 patients’ clinical indications can also be explained by the CNVs. In total, only 8 of 11,171 (0.07%)
patients had a reportable secondary finding that was not associated with their reasons for study.
Conclusion: This study demonstrates CNVs involving the 56 ACMGG secondary findings genes can be identified in routine
chromosomal SNP array tests; however, the frequency of truly secondary findings (0.07%) is much lower than that reported
for whole exome sequencing (~ 1%).

Mon(2)-O11-3
Mechanistic Insight into Formation of Chromosomal Insertions
Shen Gu 1 ，Przemyslaw Szafranski 1 ，Zeynep H.C. Akdemir 1 ，Bo Yuan 1 ，Maria A. Magrina 3 ，Carlos A. Bacino 1,2,6 ，
Seema R. Lalani 1,2,6 ，Amy M. Breman 1,2 ，Janice L. Smith 1,2 ，Ankita Patel 1,2 ，Weimin Bi 1,2 ，Sau Wai Cheung 1,2 ，
Claudia M.B. Carvalho 1 ，James R. Lupski 1,4,5,6 ，Pawel Stankiewicz 1,2
1:Molecular and Human Genetics, Baylor College of Medicine, USA、2:Baylor Miraca Genetics Laboratories, Houston, TX、3:Medical
Specialties Unit From City Hall Sao Jose dos Campos, SP, Brazil、4:Department of Pediatrics, Baylor College of Medicine, Houston, TX、
5:Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX、6:Texas Children’s Hospital, Houston, TX
Chromosomal insertions are genomic rearrangements with a chromosome segment inserted into a non-homologous chromosome
or a different region on the same chromosome. Insertions, usually revealed through fluorescence in situ hybridization (FISH)
or chromosome analyses, constitute ~ 2% of nonrecurrent copy-number gains. Very little is known about the molecular
mechanisms of their formation. Chromothripsis-like chromoanasynthesis causes germline complex genomic rearrangements
(CGRs) observed in patients with congenital disorders. In contrast to the oscillation between two copy-number states (copy-
number neutral and deletion) seen in chromothripsis, frequent copy-number changes with interspersed regions containing
deletions/duplications/triplications are found in chromoanasynthesis; such events are usually restricted to one chromosome or
one chromosome arm. In this study, we identified 16 individuals with complex insertions among 56,000 individuals tested at
Baylor Miraca Genetics Laboratories using clinical array comparative genomic hybridization (aCGH) and FISH. Subsequently,
custom high-density aCGH was performed on 10 individuals with available DNA, and breakpoint junctions were fine-mapped
at nucleotide resolution by long-range PCR and DNA sequencing in 6 individuals. In addition, we analyzed 5 families with
apparently balanced insertion in one parent detected by FISH analysis and found that 3 parents had additional small CNVs
at one or both sides of the inserting fragments as well as at the inserted sites. We observed microhomologies and templated
insertions at the breakpoint junctions, resembling the breakpoint junction signatures found in CGRs generated through
replication-based mechanism(s). In conclusion, we propose that DNA replication errors could result in interchromosomal
complex insertions generated through chromoanasynthesis involving two or three chromosomes, and cause a significant fraction
of apparently balanced insertions harboring small flanking CNVs.
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Mon(2)-O11-4
Cytogenetic study of Ovotesticular Disorder of Sex Development (OT- DSD) among Egyptian DSD
patients
Mona K. Mekkawy 1 ，Inas M Mazen 1 ，Amal M Mohamed 1 ，Alaa K Kamel 1
1:Human Cytogenetics department, National Research Centre, Egypt
Ovotesticular disorder of sex development (OT-DSD) is a rare disorder of sexual differentiation characterized by the presence
of both testicular and ovarian tissues in the gonads of the same individual. Patients usually present at birth with ambiguous
genitalia, and the majority shows a 46,XX karyotype, with absence of the SRY gene sequence. We report on eight patients
with OT-DSD, who were referred to the Human Genetics and endocrinology Clinics, division of Human Genetics and Genome
Research, National Research Centre (NRC), Cairo, Egypt. The patients were selected from 540 DSD patients studied over
a period of 5 years (2010-2015). They constituted 5.7 % of the patients presenting with ambiguous genitalia. Five of the
patients were reared as males and three were reared as females. They had all underwent conventional cytogenetic and FISH
analysis, ultrasonography and laparoscopic assessment with gonadal histopathological examination. FISH on gonadal tissue
biopsies were also performed on two patients. Four patients had a 46,XX karyotype with a negative SRY gene signal, one
patient had a chimeric 46,XX/46,XY karyotype and three patients had unusual structural sex chromosomal abnormalities in
mosaic constitution, in the form of : 46,X,dic(X;Y)(p22.33; p11.32) [65]/45,X[23]/45,dic(X;Y) (p22.33;p11.32)[12] (in one male

patient) and 45,X/46,X,idic(Yq) (in two female patients). This study adds to the previous reports on this rare disorder and
extends the cytogenetic spectrum of OT-DSD patients. The study also elucidates the necessity for a comprehensive approach
to the accurate diagnosis of DSD patients.
Mon(2)-O11-5
Contribution of genomic copy number variations in prenatal oral clefts: a multi-center cohort study
Ye CAO 1,2 ，Zhihua LI 3 ，Jill Rosenfeld 4 ，Amber N. Pursley 5,6 ，Ankita Patel 5,6 ，Jin Huang 1 ，Huilin Wang 1,2
，
Xiaofang Sun 3 ，Tak Yeung Leung 1,2 ，Sau Wai Cheung 5,6 ，Richard Kwong Wai Choy 1,2,7
1:Department of Obstetrics and Gynecology, The Chinese University of Hong Kong, Hong Kong、2:Shenzhen Research Institute, The Chinese
University of Hong Kong, Shenzhen, China、3:Department of Obstetrics and Gynecology, Key laboratory of Reproduction and Genetics of
Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou、4:Signature Genomic
Laboratories, PerkinElmer, Inc., Spokane, Washington, USA、5:Department of Molecular and Human Genetics, Baylor College of Medicine,
Houston, TX, USA、6:Medical Genetics Laboratories, Baylor College of Medicine, Houston, TX, USA、7:Angsana Molecular & Diagnostics
Laboratory (HK) Ltd., Hong Kong
Purpose: We sought to investigate the utility of chromosomal microarray analysis (CMA) for prenatal diagnosis of oral clefts,
compared to traditional chromosome analysis, for improved prenatal genetic counseling and discovery of potential genotype-
oral cleft correlation.
Methods: This retrospective analysis includes 270 prenatal oral cleft cases with documented detailed ultrasound findings and
CMA results from four referral centers. Detection rates for pathogenic CNVs were calculated and compared with cases where
chromosome analysis was also performed.
Results: The overall detection rate for pathogenic CNVs by CMA was 14.8% (40/270), 7.2% in the nonsyndromic cases and
21.4% in the syndromic cases. Of the nonsyndromic cases with ultrasound soft markers, 20% (5/25) were identified with
pathogenic CNVs. CMA showed an improved detection rate of 15.3% (29/190) compared to 10.5% (20/190) for chromosome
analysis.
Conclusion: This study not only highlights the improved detection of chromosomal defects by CMA in prenatal oral clefts
but also deepens our understanding of oral clefts. The results suggest that CMA is highly recommended in prenatal invasive
genetic testing not only for syndromic oral cleft cases but also for nonsyndromic cases with soft markers. Candidate genes
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including CRKL, AKAP8, SYDE1, BRD4 are worthy of further investigation into their role in human palatogenesis.
Mon(2)-O11-6
Blood SNP-array can replace bone marrow SNP-array in Myelodysplastic Syndrome (MDS) and may be
used in place of Karyotype in some patients
Sarah Moore 1 ，Christopher N Hahn 1,2,3 ，Monika M Kutyna 4 ，Rosalie Kenyon 5 ，Rachel Fraser 1 ，Rakccha Chhetri 4 ，
Deepak Singhal 4 ，Ian Lewis 4 ，Peter Bardy 4 ，Luen B To 4 ，Hamish S Scott 1,3,6,7
1:Genetics and Molecular Pathology, SA Pathology, Australia、2:Centre for Cancer Biology, SA Pathology、3:School of Medicine, University
of Adelaide、4:Haematology Directorate, SA Pathology、5:Australian Cancer Research Foundation Cancer Genomics Facility、6:School of
Biological Sciences, University of Adelaide、7:School of Pharmacy and Medical Science, University of South Australia
Cytogenetic studies in MDS are performed to subtype disease, provide prognostic information and to guide patient manage-
ment or treatment. Since the genome may be unstable, and this can result in clonal evolution, repeat sampling is required.
Bone marrow (BM) metaphase cytogenetics is the gold standard for genetic studies of MDS, but the pitfalls of this method
include the discomfort it causes to patients because of the invasiveness of the procedure; failure because of lack of cell di-
vision or inadequate sample; lack of resolution and inability to identify copy-neutral loss of heterozygosity (LOH). These
difficulties have resulted in an abnormality rate of only 40% ~ 50%. BM SNP-microarray reveals abnormalities in 74% of
MDS cases because of no requirement for cell division, the increased resolution and the ability to identify LOH, but this
method still relies on a procedure that causes pain and discomfort to the patient. We trialled PB as a source of DNA for the

assessment of genetic abnormalities in MDS by SNP-array. Its collection is less invasive than BM sampling and removal of
the mononuclear cell (MNC) fraction, that consists mainly of lymphocytes, increases the sensitivity of the assay. DNA was
extracted from PB-granulocytes, PB-MNC and BM-MNC from 25 samples of 21 MDS cases and was used on the Affymetrix
CytoScanHD array platform. Karyotyping was performed contemporaneously on whole BM and 13/25 were abnormal. BM
SNP-microarray was concordant with karyotype and detected abnormalities in 4 samples with normal karyotype. All copy
number abnormalities detected in BM-cells were detectable in PB-granulocytes and MNC. PB-granulocytes generally showed
a higher clone size than PBMNC and unselected BM. Importantly, serial testing also showed that clonal evolution can be
detected on PB-granulocytes and MNC. These results demonstrate that the PB-granulocyte SNP-microarray is a suitable
alternative to BM SNP-array and may be superior to karyotyping in some patients.
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[O12] Statistical Genetics and Genetic Epidemiology 1

Mon., April 04, 2016 18:00-19:30 Room H (1F)
Chair：Suzanne M. Leal（Department of Molecular and Human Genetics, Baylor College of Medicine, USA）
Chair ：Taesung Park（Statistics, Seoul National University, Korea, South）
Mon(2)-O12-1
Collapsed Methylation Quantitative Trait Loci analysis for Low Frequency and Rare variants
Tom G Richardson 1 ，Hashem A Shihab 1 ，Gibran Hemani 1 ，Jie Zheng 1 ，Oliver Lyttleton 2 ，Wendy L McArdle 2 ，
Susan M Ring 2 ，Santiago Rodriguez 3 ，Colin Campbell 4 ，George Davey Smith 1 ，Caroline L Relton 1 ，
Nicholas J Timpson 1 ，Tom R Gaunt 1
1:MRC Integrative Epidemiology Unit, University of Bristol, UK、2:Avon Longitudinal Study of Parents and Children (ALSPAC), University
of Bristol、3:Bristol Genetic Epidemiology Laboratories, University of Bristol、4:Intelligent Systems Laboratory, University of Bristol
Background: Single variant approaches have been successful in identifying DNA methylation quantitative trait loci (mQTL),
although as with complex traits they lack statistical power to identify effects from rare genetic variants. We have undertaken
extensive analyses by collapsing regions of low frequency and rare variants together to identify association signals not detected
using single variant approaches.

Methods: We used repeated measurements of DNA methylation from five different life stages in human blood, taken from
the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Variants were collapsed across CpG islands and
their flanking regions to identify variants collectively associated with methylation. All analyses were undertaken using the
Sequence Kernel Association Test (SKAT) after applying two Minor Allele Frequency (MAF) cutoffs of 5% and 1% using
imputed genotype data.
Results: For loci where no individual variant mQTL was observed using a single variant approach, we identified 95 unique
regions where the combined effect of low frequency variants (MAF≤5%) provided strong evidence of association with methy-
lation. For loci where there was previous evidence of an individual variant mQTL from the single variant analysis, conditional
analyses identified a further 3 regions which provided evidence of association between multiple low frequency variants and
methylation levels. Effects were observed consistently across the life course, for offspring in the discovery analysis as well as
in an independent sample of mothers.
Conclusion: We have demonstrated the potential of this novel approach to mQTL analysis by analysing the combined effect
of multiple low frequency or rare variants. Future studies should benefit from applying this approach as a complementary
follow up to single variant analyses.
Mon(2)-O12-2
A statistical approach for testing cross-phenotype effects of rare variants
Michael P Epstein 1 ，Kelsy A Broadaway 1 ，David J Cutler 1 ，Richard Duncan 1 ，Jacob Moore 2 ，Erin B Ware 3 ，
Min A Jhun 3 ，Lawrence F Bielak 3 ，Wei Zhao 3 ，Jennifer Smith 3 ，Jennifer A Smith 3 ，Sharon Kardia 3 ，
Debashis Ghosh 4
1:Human Genetics, Emory University, USA、2:Evolution and Ecology, UC-Davis、3:Epidemiology, University of Michigan、4:Bioinformatics
and Informatics, Colorado School of Public Health
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Increasing empirical evidence suggests that many genetic variants influence multiple distinct phenotypes. When cross-
phenotype effects exist, multivariate association methods that model pleiotropy are often more powerful than univariate
methods that model each phenotype separately. While several statistical approaches exist for testing pleiotropy for common
variants, there is a lack of cross-phenotype tests for gene-based analysis of rare variants. In order to fill this important gap,
we introduce a new statistical model for cross-phenotype analysis of rare variants using a nonparametric, distance-covariance
approach that compares similarity in multivariate phenotypes to similarity in rare-variant genotypes across a gene. The ap-
proach can accomodate both binary and continuous phenotypes and further can adjust for covariates. Our approach yields a
closed-form test whose significance can be evaluated analytically, thereby improving computational efficiency and permitting
application on a genome-wide scale. We use simulated data to demonstrate that our method provides increased power over
competiting approaches. We also illustrate our approach using exome-chip data from the Genetic Epidemiology Network of
Arteriopathy.
Mon(2)-O12-3
Pitfalls in the development of statistical methods for rare variant association studies
Suzanne M Leal 1 ，Gao T Wang 1
1:Molecular and Human Genetics, Baylor College of Medicine, USA
Statistical analysis of rare variants (RVs) are often performed by grouping variants in a genomic region, usually a gene,

and testing for an association with a disease or quantitative trait. Group-based strategies can increase power compared to
analyzing individual RVs. Numerous group-based rare variant association (RVA) methods have been published. Rigorous
assessment of these methods in terms of type I & II errors using high quality empirical benchmarks and sequence data is
crucial before implementation; ignorance of this point in many method papers have resulted in biased conclusions. Here
we caution that development of RVA methods is subject to several potential pitfalls, including misuse of empirical genotype
data source for evaluation of power, under-representation of genetic architecture in simulation models at whole genome level,
and inappropriate modeling of protective variants. We demonstrate that 1.) sample size estimation for RVA study designs
can differ drastically due to differences in RV minor allele frequency (MAF) spectrum resulting from simulation of data
under various demographic models and resampling from sequence data and 2.) that the use of MAF from exome variant
databases for genotype simulation is flawed. We show that relative power of association methods are heavily influenced by
genetic context assessed rather than merely phenotypic models; a crucial point underappreciated in most method articles. We
also demonstrate that the impact of protective variants, if properly modeled, is minor compared to the impact of deleterious
variants and thus fixed effect burden tests should be preferred over variance component tests in practice. Our results highlight
the importance 1.) to perform sample size estimation and evaluation of RV methods only using simulated data with sufficiently
large samples whose properties are validated and 2.) that such analyses should be performed on a whole genome scale rather
than at genomic regions of choice.
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Mon(2)-O12-4
Pathway-based association tests for rare variants using hierarchical structures
Sungkyoung Choi 1 ，Sungyoung Lee 1 ，Heungsun Hwang 2 ，Taesung Park 1,3
1:Interdisciplinary Program in bioinformatics, Seoul National University, Korea, South、2:Department of Psychology, McGill University、
3:Department of Statistics Seoul National University
Recent advances in next generation sequencing (NGS) technologies have revolutionized association studies of human complex
diseases, which makes it possible for researchers to conduct rare variant association analysis. Pathway based analyses are well
known to be more powerful in association studies. Although several pathway based analysis methods have been proposed for
rare variants, they usually assume that the pathways are independent and do not consider the relationship across pathways
mainly caused by substantial overlapped genes. We propose a new pathway-based approach using hierarchical component of
collapsed rare variants to identify associations between a phenotype and entire pathways. To handle overlapping gene between
pathways, our approach uses ridge-regularized method assuming two penalties on both genes and pathways. Our approach
considers four types of tests: self-contained test (SC), Z-transformed self-contained test (SCZ), rank based permutation test
(RPT), and Z-transformed permutation test (ZPT), taking advantage of prior knowledge on existing relationships among
pathways. The proposed tests were evaluated with the Genetic Analysis Workshop 17 (GAW17) simulation data sets using
Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway data base, performing pathway analysis for the quantitative
risk trait. We find that SC and ZPT methods outperformed other methods in terms of empirical power. We also applied the
proposed tests for pathway analysis to the exome sequencing data of 1,000 Korean population for the phenotype of alanine

transaminase.
Mon(2)-O12-5
Increased power for detection of parent-of-origin effects via the use of haplotype estimation
Richard A. J. Howey 1 ，Chrysovalanto Mamasoula 1,2 ，Ana Töpf 1 ，Ron Nudel 3 ，Dianne F. Newbury 3 ，
Simon E. Fisher 4,5 ，Judith A. Goodship 1 ，Bernard D. Keavney 1,6 ，Heather J. Cordell 1
1:Institute of Genetic Medicine, Newcastle University, UK、2:Institute of Health and Society, Newcastle University、3:Wellcome Trust
Centre for Human Genetics, University of Oxford、4:Max Planck Institute for Psycholinguistics, Nijmegen、5:Donders Institute for Brain,
Cognition and Behaviour, Radboud University、6:Institute of Cardiovascular Sciences, University of Manchester
Parent-of-origin (or imprinting) effects relate to the situation where traits are influenced by the allele inherited from only
one parent, with the allele from the other parent having little or no effect. Given SNP genotype data from case/parent trios,
the parent-of-origin of each allele in the offspring can often be deduced unambiguously; however this is not true when all
three individuals are heterozygous. Most existing methods for investigating parent-of-origin effects operate on a SNP by SNP
basis and either perform some sort of “averaging” over the possible parental transmissions or else discard ambiguous trios.
If the correct parent-of-origin at a SNP could be determined, this would provide extra information and increase the power
to detect effects of imprinting. We propose making use of the surrounding SNP information, via haplotype estimation, to
improve estimation of parent-of-origin at a test SNP for case/parent trios, case/mother duos and case/father duos. This
extra information is then used in a multinomial modelling approach to estimate parent-of-origin effects at the test SNP.
We show through computer simulations that our approach has increased power over previous approaches, particularly when
the data consist only of duos. We apply our method to two real data sets and find a decrease in significance of p-values
in genomic regions previously thought to possibly harbour imprinting effects, thus weakening the evidence that such effects
actually exist in these regions, although some regions remained more significant than expected. Software is available at
www.staff.ncl.ac.uk/richard.howey/emim.
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Mon(2)-O12-6
FINEMAP: Ultrafast high-resolution fine-mapping using summary data from genome-wide association
studies
1,2
Christian Benner ，Chris Spencer 3 ，Samuli Ripatti 1,2,4
，Matti Pirinen 1
1:Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland、2:Department of Public Health, University
of Helsinki, Helsinki, Finland、3:Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK、4:Wellcome Trust Sanger
Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
Genome-Wide Association Studies (GWAS) have identified thousands of loci associated with complex diseases. A next crucial
step for fully exploiting the potential of GWAS is fine-mapping: to identify causal variants that can point to molecular mech-
anism behind the associations and, eventually, suggest targets for therapeutic interventions. Recently, fine-mapping methods
have been extended to use only GWAS summary data together with pairwise correlations of the variants (CAVIAR, PAINTOR
and CAVIARBF), which requires a high quality correlation estimate and accurate genotyping/imputation. Common to these
approaches is that they rely on computationally expensive exhaustive search restricting their use to only a few hundred
variants. Thus, new approaches are needed to handle the ever-increasing amount of variation captured by sequencing studies
as well as to scale up analyses to whole chromosomes or even to whole genomes. We introduce a freely available software
package FINEMAP that replaces the exhaustive search by an ultrafast stochastic search.
We illustrate FINEMAP with previously identified loci for Parkinson’s disease and high-density-lipoprotein cholesterol (HDL).
We show that FINEMAP (1) opens up completely new opportunities by, e.g., exploring a locus with 20,000 variants in less

than 90 seconds while exhaustive search would require more than 9,000 years, (2) provides similar accuracy to exhaustive
search when the latter can be completed, and (3) provides even higher accuracy when the latter must be restricted due
to computational reasons. By jointly modeling the whole locus, FINEMAP can identify more plausible combinations than
standard step-wise conditioning. For example, at 15q21/LIPC locus with at least a 3-SNP association pattern with HDL,
we suggest that a missense variant and a promoter polymorphism are likely to be causal whereas the variant with the lowest
P-value in single-SNP testing has less evidence than a regulatory variant correlated with it.
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Tue., April 05, 2016 13:50-15:20 Annex 2 (1F)
Chair：Stacey Edwards（Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Australia）
Chair ：Hiroyuki Aburatani（Research Center for Advanced Science and Technology, The University of Tokyo, Japan）
Tue(3)-O13-1
Non-random occurrence and early age of onset of diverse lymphoid cancers in families supports the
existence of genetic risk factors for multiple lymphoid cancers
1,2
Samantha Jones
1:Medical Genetics, University of British Columbia, Canada、2:Cancer Genetics, British Columbia Cancer Agency
Lymphoid cancers are a biologically diverse group of neoplasms, yet clustering of different lymphoproliferative disorders within
families has been observed, suggesting the existence of shared genetic risk factors. We have established a collection of 140
families with 2 or more members with lymphoid cancer. We hypothesized genetic factors which predispose to multiple types of
familial lymphoid cancers would have: 1) an earlier median age of onset, and 2) a different pattern of co-occurrence in families
than expected population frequencies. The median age at diagnosis corresponds to the 43rd , 32nd , 25th , and 25th percentile for
age of onset in Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), myeloma (MM) and chronic lymphocytic leukemia

(CLL) cases in these families, respectively. We also observed earlier age of onset in later generations, a phenomenon referred
to as anticipation. Apparent anticipation was seen in NHL (P <0.0001), HD (P <0.0001), CLL (P <0.0019) and all lymphoid
cancers together (P <0.0001).
Canadian population frequencies of HL, NHL, MM and CLL were used to derive expected frequencies for pairwise combinations
of lymphoid cancer types. Familial co-occurrences differed from those expected based on population frequencies (P <0.0001).
The difference is accentuated in families with more affected members (2 cases, P <0.0001; 3 cases, P <0.0001; 4 or more
cases, P <0.0001).
Non-random patterns of co-occurrence, and earlier age of onset of familial cases, underscore a difference between these familial
cases versus population cases, which are mainly sporadic. These observations support the idea that lymphoid cancer families
are not all collections of sporadic cases that arose in the same family by chance. These observations provide evidence for the
existence of inherited genetic factors that significantly increase the risk of developing lymphoid cancers, and justify the use
of family-based genomic methods to identify lymphoid cancer susceptibility genes.
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Tue(3)-O13-2
Targeted TET oxidase activity through methyl-CpG binding domain extensively suppresses cancer cell
proliferation
Shinichi Fukushige 1 ，Yasuhiko Mizuguchi 1 ，Kanchan Chakma 1 ，Yuriko Saiki 1 ，Akira Horii 1
1:Department of Molecular Pathology, Tohoku University School of Medicine, Japan
DNA demethylating agents are useful therapeutic drugs for human cancer; 5-aza-2’-deoxycytidine and 5-azacytidine for
myelodysplastic syndrome are good examples. They not only induce DNA demethylation but also have significant cytostatic
and cytotoxic effects. However, precise mechanisms for anticancer activity of these demethylating reagents have yet to be
established. Here we show that a fusion protein comprising the methyl-CpG binding domain (MBD) and the catalytic domain
of Ten-eleven translocation protein 1 (TET1-CD) globally demethylates and upregulates a number of methylated genes.
Human embryonic kidney cell line 293T expressing wild-type (wt) TET1 catalytic domain with MBD (MBD-TET1-CDwt)
frequently upregulated genes which contain CpG islands (CGIs) within ± 1,000-bp of the transcription start site (TSS).
Interestingly, 65% of genes upregulated 5-fold or more by MBD-TET1-CDwt were also reactivated after treatment with 5-
azacytidine, DNA demethylating agent. These results suggested a fact that gene reactivation by both methods was primarily
based on DNA demethylation. In order to examine growth inhibitory effects of DNA demethylation to cancer cells, we utilized
a tetracycline inducible system to regulate the expression of MBD-TET1-CDwt using a prostate cancer cell line. Induction of
MBD-TET1-CDwt demethylated and upregulated the glutathione S-transferase pi 1 (GSTP1 ), one of the hypermethylated
genes in prostate cancer. In accordance with reactivation of methylated genes, induction of MBD-TET1-CDwt extensively

suppressed the growth of LNCaP cells. Flow cytometry analysis showed decreased cells in S phase and increased cells in G1
phase by MBD-TET1-CDwt expression. Our present results clearly indicate that TET oxidase activity recruited at methyl-
CpG sites through MBD induces reactivation of hypermethylated genes by DNA demethylation, and that our methods allow
us to analyze the effects of global DNA demethylation in a wide variety of cancer cells.
Tue(3)-O13-3
Testing of Deletions or Excess Homozygosity for Head and Neck Cancer Association in Whole Genome
SNP Genotyping Studies
Chih-Chieh Wu 1 ，Sanjay Shete 2
1:College of Medicine, Department of Environmental and Occupational Health, National Cheng Kung University, Taiwan、2:Department of
Biostatistics, The University of Texas MD Anderson Cancer Center
Deletion copy number variations of DNA sequences are abundant and ubiquitous in the human genome and represent a variant
class that is often associated with disease. Compared with genome-wide association studies, few comprehensive studies of
copy number variation’s contribution to complex human disease susceptibility have been performed. Squamous cell cancer
of the head and neck includes cancers of the oral cavity (including the gums and tongue), pharynx, and larynx and is the
sixth most common malignancy worldwide. We performed genome-wide studies of association between deletions and head and
neck cancer using 500K SNPs. We extended the statistical method that we previously developed for detecting deletions or
excess homozygosity associated with complex disease in case-control studies, using SNPs in genome-wide association studies,
and that is based on logistic regression frame work, permitting to adjust for population structure. We used this method and
tested each contiguous SNP locus between the 1154 cases and 1542 controls in batch 1 and 1031 cases and 2965 controls in
batch 2 to detect deletion variants or excess homozygosity that influence susceptibility. Our method is designed to detect
statistically significant evidence of deletions or homozygosity at individual SNPs for SNP-by-SNP analysis at the first stage
and to combine the information among neighboring SNPs for cluster analysis at the second stage. We identified 65 SNPs of
p-value <= 10-4 with the most significant SNP of p-value = 1.38×10-6 in batch 1 and 23 SNPs with p-value < 5×10-8 in
batch 2. We are performing the cluster analysis, which is designed to further investigate the SNP-by-SNP analysis outcomes
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and detect aggregations of neighboring significant SNPs.
Tue(3)-O13-4
Five independent breast cancer risk variants at 6q25 display genotype-phenotype correlations and regulate
ESR1 and RMND1
Stacey Edwards 1 ，Alison Dunning 2 ，Kyriaki Michailidou 3 ，Karoline Kuchenbaecker 3 ，Deborah Thompson 3 ，
Juliet French 1 ，Jonathan Beesley 1 ，Catherine Healy 2 ，Siddhartha Kar 2 ，Richard Sallari 4 ，Elena Lopez-Knowles 5,6 ，
Mitch Dowsett 5,6 ，Paul Pharoah 2,3 ，Jacques Simard 7 ，Per Hall 8 ，Montserrat Garcia-Closas 9,10 ，Celine Vachon 11 ，
Georgia Chenevix-Trench 1 ，Antonis Antoniou 3 ，Douglas Easton 2,3
1:QIMR Berghofer Medical Research Institute, Australia、2:Department of Oncology, University of Cambridge, UK、3:Department of
Public Health and Primary Care, University of Cambridge, UK、4:Computer Science and Artificial Intelligence Laboratory, Massachusetts
Institute of Technology, Cambridge, MA, USA、5:Breast Cancer Research, Breakthrough Breast Cancer Research Centre, UK、6:Academic
Biochemistry, Royal Marsden Hospital, UK、7:Centre Hospitalier Universitaire de Québec Research Center, Laval University, Canada、
8:Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden、9:Division of Cancer Studies, Breakthrough Breast
Cancer Research Centre, Institute of Cancer Research, UK、10:Division of Genetics and Epidemiology, Institute of Cancer Research, UK、
11:Department of Health Sciences Research, Mayo Clinic, Rochester, USA
Single nucleotide polymorphisms (SNPs) at 6q25 are associated with breast cancer susceptibility, risk for BRCA1 mutation
carriers and breast density. To date, however, attempts to identify the causal SNPs underlying the associations have been
inconclusive. Here, we analysed 3872 SNPs across the 6q25 locus in 118,816 subjects from three consortia and found evidence
for five independent sets of correlated, highly trait associated variants (iCHAVs). At all five sites, the minor allele of the
candidate SNPs increased risks of ER- tumors and, with one exception, all are more strongly associated with risk of developing

ER- than ER+ tumor-subtypes. We also identified associations with mammographic density, human ERB2 tumor status and
with high-grade breast cancer. The strongest candidate causal SNPs within each iCHAV lay in cis-regulatory elements and
chromosome conformation capture assays confirmed they physically interact with the promoters of ESR1, RMND1, C6orf211
and CCDC170 . Allele-specific expression analyses identified significant associations between iCHAV1-3 SNPs and the allelic
ratio of ESR1 and RMND1 transcripts. Furthermore, IHC in 150 normal breast samples showed iCHAV1 risk alleles to
be associated with reduced ER levels. Reporter assays demonstrated that cis-elements within iCHAVs 1,2,4 and 5 act as
transcriptional enhancers and one element within iCHAV3 acts as a silencer. Consistent with expression analyses, constructs
including the risk alleles decreased ESR1 and RMND1 promoter activity. This study provides definitive evidence for genetic
control of both major breast tumour subtypes by genetic variants in the 6q25 locus. We also provide the first evidence of
genetic risk factors for developing two rarer classes of tumor: the ER-/PR-/HER2+ subtype and ER+/high-grade tumors.
Our functional data implicate ESR1 as the main target gene driving the associations, and highlights the potential importance
of ER in establishing both ER- and ER+ breast cancer.
Tue(3)-O13-5
Breast cancer pedigree exome sequencing reveals inherited RAD52 truncation mutation implicated in
breast cancer susceptibility
1,2
Helio A Costa ，Martin Sikora 3 ，Kedar Hastak 2 ，James M Ford 2 ，Louise C Laurent 4 ，Carlos D Bustamante 2
1:Genetics, Stanford University, USA、2:Stanford University School of Medicine, Department of Genetics, Stanford, CA, USA、3:Natu-
ral History Museum of Denmark, Centre for GeoGenetics, Copenhagen, Denmark、4:University of California, San Diego, Department of
Reproductive Medicine, La Jolla, CA, USA
BRCA1/2 mutations have been the most exhaustively elucidated mechanism for inherited breast cancer cause, however only an
estimated 25% of cases are atributable to mutations in these two genes. We have sequenced the exomes of a non-BRCA breast
cancer pedigree and have identified a shared truncation mutation in the RAD52 protein. We have performed cellular based
assays to functionally characterize this truncation mutation and demonstrate it results in the mis-localization of RAD52
during double strand break repair. This observation gives credence to the growing body of work regarding the complex
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involvement of RAD52 in breast cancer etiology and progression, and suggests that genetic background can modulate the
effect of common or perceived ”benign” mutations among different populations.
Tue(3)-O13-6
High miR-30d expression associates with improved breast cancer survival
Maral Jamshidi 1 ，Rainer Fagerholm 1 ，Sippy Kaur 1 ，Sofia Khan 1 ，Eliisa Ollikainen 1 ，Johanna Kiiski 1 ，
Kristiina Aittomaki 1 ，Paivi Heikkila 1 ，Ralf Butzow 1 ，Carl Blomqvist 1 ，Heli Nevanlinna 1
1:University of Helsinki and Helsinki University Hospital, Finland
Altered miRNA expression may contribute to initiation and progression of breast cancer. Several miRNAs have been identified
to associate with the pathogenesis of breast cancer and can be classified as oncomirs, tumor-suppressors, pro-metastatic or
metastasis-supressors. MicroRNAs (miRNAs) expression analysis presents an attractive approach to identify novel prognostic
and drug response indicators. miR-30d has been shown to associate with induced cell proliferation and reduced apoptosis in
ovarian cancer, and in a metastatic breast cancer cell line (MDA-MB-231). Here, we have applied miRNA in situ hybridization
to study the expression of miR-30d in an extensive series of human breast cancer tumors (n=1,238) for association with
tumor clinical and pathological characteristics, patient survival, and treatment outcome. We found that while high miR-
30d expression is a marker of aggressive tumors as such, it associates with better breast cancer survival especially in the
subgroups of patients with HER2 positivity (HR 0.30, 95% CI 0.1-0.6, p= 0.003), highly proliferating tumors (HR 0.35, 95%

CI 0.2-0.6, p= 0.0003), and chemotherapy treatment (HR 0.51, 95% CI 0.2-0.9, p= 0.028). In multivariate analysis adjusting
for conventional prognostic factors, high miR-30d expression was found as a predictor of better breast cancer prognosis (p=
0.0006, HR 0.49, 95%CI 0.3 to 0.7). The results obtained from this study suggest that altered expression of miR-30d may
associate with the prognosis and treatment outcome in breast cancer patients. Further studies are required to validate the
prognostic and predictive potential of miR-30d expression in breast cancer.
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Tue., April 05, 2016 15:40-17:10 Annex 2 (1F)
Chair：Denise A.S. Batista（Department of Pathology, Johns Hopkins University, USA）

Chair ：Seigo Nakamura（Division of Breast Surgical Oncology, Showa University, Japan）
Tue(3)-O14-1
Clinical analysis of founder mutations of BRCA1 and BRCA2 in the Japanese population
Reiko Yoshida 1 ，Shiro Yokoyama 1 ，Chie Watanabe 2 ，Mayuko Inuzuka 1 ，Junko Yotsumoto 4 ，Masami Arai 3 ，
Seigo Nakamura 1 ，The registration committee of The Japanese HBOC consortium
1:Breast center, Showa University, Japan、2:Sophia University, Faculty of Human Sciences、3:Cancer Institute Hospital, Division of Clinical
Genetic Oncology、4:Ochanomizu University, Natural Science Division, Faculty of Core Research
(Background) Hereditary breast and ovarian cancer (HBOC) is a high-penetrance inherited disease, and founder mutations
have been reported from each local area. There are some reports of founder mutations of HBOC from breast cancer patients
in the Japanese population, but those data remain limited. The Japanese HBOC consortium was established in 2012, and
trial registration has been provided by registration committee members. Using the Japanese HBOC consortium registration
data, we report the clinical characteristics of breast cancer bearing the L63X (307T>A, c.188T>A) mutation, which is one
of the BRCA1 founder mutations in the Japanese population.

(Methods) Data on 827 affected breast cancer patients (88 BRCA1 carriers, 76 BRCA2 carriers, 1 carrier of both BRCA1
and BRCA2 , 54 variant of uncertain significance and 608 non-carriers) were registered by the Japanese HBOC consortium
through August 2015. Of 56 independent mutations of BRCA1 , the L63X mutation was detected in 26 patients. In evaluating
the age of breast cancer onset, pathological features, clinical features, and family history of these patients, we observed a
significant difference between those with the L63X mutation, other BRCA1 mutations, and BRCA2 mutations using χ2 test
analysis.
(Results) There were no significant differences in the age of onset between the L63X mutation, other BRCA1 mutations, and
BRCA2 mutations (40.3 vs. 40.4 vs. 41.6 years). The proportion of triple negative breast cancer patients was 88.9% in the
L63X mutation carriers, 72.5% in other BRCA1 mutation carriers and 26.8% in BRCA2 mutations (p<.001). There were no
significant differences in pathological features, bilateral breast cancer incidence, or family history of breast cancers.
(Conclusions) The clinical characteristics of breast cancer in patients with the L63X mutation might be no different from
other BRCA1 or BRCA2 mutations, except regarding the subtype of the resultant cancer.
Tue(3)-O14-2
Exome sequencing reveals new potential markers of therapy efficacy and safe cancellation of targeted
therapy in patients with chronic myeloid leukemia
Sergey I Kutsev 1,2 ，Svetlana A Smirnikhina 1 ，Elmira P Adilgereeva 1 ，Ekaterina Y Chelysheva 3 ，Oleg A Shukhov 3 ，
Anna G Turkina 3 ，Alexander V. Lavrov 1,2
1:Laboratory of Mutagenesis, Research Center for Medical Genetics, Russia、2:Russian National Research Medical University、3:National
Research Center for Hematology
Chronic myeloid leukemia is a clonal oncohematological disease characterized by translocation t(9;22) which results in forma-
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tion of chimeric tyrosine-kinase BCR-ABL. Targeted inhibitors (TKI) of BCR-ABL are very effective. But there’re ~ 20% of
patients with low efficacy of TKI. Only 40% of patients with excellent response to TKI keep remission after therapy cessation.
We performed whole exome sequencing (WES) in CML patients in order to find molecular markers of therapy efficacy and
stability of remission.
We estimated response to TKI therapy at 6 mths after beginning therapy according to ELN 2013 criteria and stability of deep
molecular response during 24 months after stopping TKI therapy (failures have BCR-ABL expression level over 0.1%IS ).
We selected 4 patients with optimal response (BCR-ABL <1% and 0% of Ph+ cells) and 4 patients with therapy inefficacy
(BCR-ABL >1% or Ph+ > 10%); 3 patients with stable remission and 3 patients with relapse. We extracted DNA from
blood of these patients taken at diagnosis when ~ 100% of blood cells are leukemic (for estimation of TKI efficacy) and
during deep molecular remission (for estimation of remission stability). We found ~ 30K SNV and/or indels in each sample.
We filtered variants common in one group of patients and absent in the opposite group and annotated them using VEP tool.
Missense variants with SIFT/PolyPhen scores were selected and confirmed by Sanger sequencing. These variants were found
in genes associated with cancer development: ANKRD35, DNAH9, MAGEC1, TOX3, THSD1, MORN2, PTCRA (groups of
different TKI efficacy); and CYP1B1, ALPK2, IRF1, PARP9 (groups with relapse/remission). The latter were verified in a
small group of patients with TKI cessation and demonstrated their high sensitivity (77%), specificity (86%), positive (85%)
and negative (79%) predictive values.

In conclusion we revealed variants which may become prognostic factors for better therapy of CML and relapse prediction
after TKI cessation.
Tue(3)-O14-3
Next-generation sequencing to analyze ABL1 tyrosine kinase domain mutations in targeted therapeutic
chronic myelogenic leukemia patients
Chinh Q Duong 1 ，Hang T Pham 1 ，Trang T Nguyen 1 ，Hoang C Tran 1 ，Tuong Q Le 1 ，Khanh Q Bach 1 ，
Tri A Nguyen 1
1:Department of Genetics and Molecular Biology, National Institute of Haematology and Blood Transfusion, Vietnam
Background: Although imatinib, as tyrosine kinase inhibitor, has been firmly established and used in frontline therapy for
chronic myelogenic leukemia patients (CML), there are 33% of patients recorded to develope drug resistance in chronic phase
and higher in acceleration phase. This partially driven by mutations appeared in the tyrosine kinase domain (TKD) within
the ABL1 of the BCR/ABL1 fusion gene. Here, we utilized next generation sequencing (NGS), as a new tool for routine
analyses of drug resistance CML patients. Methods: 102 CML patients were contributed to this study, including not treated
(9), treated and response to imatinib (16), partially response (7 ) and do not response to treatment (70). RNA from bone
marrow samples were extracted, cDNA synthesized, TKD gene fragments were cloned and followed by Illumina’s Nextera
XT DNA library preparation. DNA libraries were sequenced using Illumina MiSeq sequencer and data was analyzed with
MiSeq Reporter (Illumina), IGV (Broad Institute) and CLC Genomic Workbench (CLC Bio). The sequencing results were
randomly confirmed by AB3500 Genetic Analyzer. Results: The sequencing runs had minimum 93% of QC30, and filtered
nucleotide variations had minimum read depth of 3300. Overall, we found 35% patients (of the no-response group) carrying
point mutations within TKD gene region, which is similar to other studies. No mutations found in other groups. In this
study 64% of mutations similar to data published by Soverini, 2011, and 67% samples having more than one mutation in the
TKD region. The data showed that several new nucleotide variations have been indentified in the drug-resistance patients.
Conclusions: Mutation analysis in drug resistance CML patients can be analyzed using NGS, due to its high sensitivity,
accuracy and throughput. Our study also revealed some new nucleotide variations that needed to be further investigated for
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their frequency and role in CML.
Tue(3)-O14-4
Increasing diagnostic yield: Addition of next generation sequencing panel to chromosome microarray
and karyotype in myeloid leukemia
Denise A.S. Batista 1 ，Elizabeth Wohler 2 ，Kerry Powell 2 ，Victoria Stinnett 2 ，Yi Ning 1
1:Pathology, Johns Hopkins University School of Medicine, USA、2:Pathology, Johns Hopkins Hospital
Genetic biomarkers are used in hematologic malignancies to improve diagnosis and prognosis as well as predict response to
targeted therapies. The implementation of chromosome microarray (CMA) has improved our ability to detect copy number
changes below the level of resolution of microscopy and enabled detection of copy neutral loss of heterozygosity. From
January to June 2015 we performed SNP based CMA in 88 bone marrow or peripheral blood specimens from patients with a
presumptive diagnosis of AML, myelodysplasia and myeloproliferative disorders. Abnormalities were detected in 55 specimens
for a diagnostic yield of 62.5% (55/88). Among the 55 cases with abnormal CMA, 56.4% (31/55) had an abnormal karyotype,
18.2% (10/55) had a normal karyotype, and in 14/55 (25.5%) no karyotype was performed. A normal CMA was observed in
33 specimens and of these 4 (12.1%) had an abnormal karyotype, 18 (54.5%) had a normal karyotype, and in 11 (33.3%) a
karyotype was not performed. Taking into account the abnormalities detected by karyotype and/or CMA the diagnostic yield
was 67.0% (59/88).To ascertain whether the detection of disease biomarkers could be improved, we performed targeted next

generation sequencing (NGS) of 54 genes known to be tumor suppressors or oncogenic hotspots in myeloid leukemia. For a
pilot project we selected specimens from 7 individuals with AML or myelodysplasia who had a normal CMA and normal/not
performed karyotype. Oncogenic mutations were detected in 6/7 (85.7%) individuals. In total 9 mutations were identified
among the 6 individuals within the genes NPM1, FLT3, KRAS, U2AF1 and IDH2. The presence of these mutations can
be used for further risk stratification and treatment plan coordination/design. The addition of targeted NGS allowed for an
increase in our diagnostic yield of genetic biomarkers from 67.0% to 73.9%. Our data shows that the use of CMA and NGS
within this group of leukemia greatly improves diagnostic yield and risk stratification.
Tue(3)-O14-5
The Effects Of JAK2V617F, MPL and CALR Mutations On Diagnosis, Classification, Frequency, Lab-
oratory Results and Clinical Status In Myeloproliferative Neoplasms
Hatice Akar 1 ，Deniz Torun 1 ，Yusuf Tunca 1
1:Medical Genetics, Gulhane Military Medical Academy, Turkey
Introduction
We investigated the mutation profiles of Calreticulin (CALR), Janus kinase 2 (JAK2) and Myeloproliferative leukemia virus
oncogenes (MPL) and their clinical and laboratory characteristics in a cohort of Turkish MPN patients.
Methods
A total of 168 MPN patients (78 polycythemia vera [PV], 79 essential throm bocythemia [ET], and 11 primary myelofibrosis
[PMF] cases) were included in the study. JAK2V617F mutation was analyzed by real time Taqman PCR; while CALR and
MPL mutations were identified by bi-directional Sanger sequencing.
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Results
JAK2V617F was the most frequent mutation (70,8%). None had MPL W515K/L mutations. C ALR mutations were detected
in 12,7% of ET and 9,1% of PMF patients, which accounted for 43,47% and 25% of ET and PMF patients without JAK2 or
MPL mutations, respectively. CALR and MPL mutations were not found in PV. A total of six types of mutation were de-
tected, among which, c.1092_1143del (36,4%) and c.1100_1145del (18,2%) and c.1154_1155ins TTGTC (18,2%) were found
to be the most common.
CALR mutants were associated with lower hematocrit, lower red blood cell count and higher platelet counts than the
JAK2 V617F mutants. JAK2V617F mutants were male and had splenomegali when compared to JAK2V617F negatives.
c.1099-1150del (type1) mutant CALR patients had higher white blood cell counts and c.1154_1155ins TTGTC (type 2) mu-
tant patients were older than all types of CALR mutants. c.1100_1145del patients had higher hemotocrit level, hemoglobin
level, red blood cell counts and platelet counts when compared to c.1099-1150del and c.1154_1155ins TTGTC patients.
Conclusion
This study which held in Turkey have same CALR mutations molecular profile with the other studies worldwide. A novel

CALR mutation (c.1100_1145del) in ET patient was found. Larger prospective studies need to be designed to establish the
impact of the new mutations in contributing to disease phenotype and prognostic outcome of patients.
Tue(3)-O14-6
Germline variants in pediatric leukemia detected by next generation sequence
Akira Shimada 1 ，Hiromu Narasaki 1 ，Takae Hanada 1 ，Ritsuo Nisiuchi 2
1:Pediatrics, Okayama University Hospital, Japan、2:Pediatrics, Kouchi Medical Center
Introduction)Recently, we performed the target amplicon sequencing using customized panel containing about 150 genes
related to the leukemogenesis by next generation sequence (NGS). At that time, we analyzed the dual samples from the
first diagnosis and complete remission (CR), simultaneously, to find the somatic mutations, however, some patients had the
variants in the diagnostic and CR samples, simultaneously. We checked these variants in several database and excluded SNPs
but some variants which seemed missense mutation still existed. Now we found the germline variants of BCOR, MLL, MLH1,
and KRAS in pediatric leukemia patients.
Case 1) Three months old female was diagnosed as having acute myeloid leukemia (AML)-M5 with MLL-AF10 chimera
and she was treated with chemotherapy followed by cord blood stem cell transplantation. We found BCOR p.G1056E. This
mutation was confirmed by Sanger sequence in oral mucosa in this patient and also in his father.
Case 2) Congenital AML patient was successfully treated by AML- chemotherapy and survived for more than 10 years. We
found MLL p.Q3170E.
Case 3) Three years old boy was diagnosed as having acute lymphoblastic leukemia (ALL) with TEL-AML1 chimera and
treated with chemotherapy and achieved CR. However, he showed extra medullary relapse after 6 years later from the end of
chemotherapy. We found MLH1 germline variant.
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Case 4) Six years old female was diagnosed AML-M2 with inv(16). She was treated with AML-chemotherapy and survived
for more than 5 years. She had KRAS p.G12D.
Discussion) BCOR, MLL and MLH1 genes are estimated to cause Oculofaciocardiodental syndrome, Wiedemann-Steiner
syndrome and Lynch syndrome, respectively. Some of the causative genes for the rare inheritance syndrome such as RAS and
PTPN11 also had the pivotal role in pediatric leukemia, therefore, to find the genetic variants in pediatric leukemia seems to
be very important at the cancer susceptibility in the NGS era.
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Tue., April 05, 2016 15:40-17:10 Room A (2F)
Chair：Marieke Joosten（Clinical Genetics, Erasmus MC, Rotterdam, Netherlands）

Chair ：Takahiro Yamada（Department of Obstetrics, Hokkaido University Graduate School of Medicine, Japan）
Tue(3)-O15-1
A case report of management including perinatal genetic counseling for May Hegglin Anomaly in preg-
nancy that low platelets counts made the opportunity to diagnose
Yuka Yamashita 1 ，Rei Matsuura 1 ，Yoshie Oikawa 2 ，Shoko Hamada 1 ，Hirotugu Ariizumi 3 ，Kei Odawara 1 ，
Maya Koyano 1 ，Shogo Nishii 1 ，Tsutomu Muramoto 1 ，Shin Takenaka 1 ，Ken Nakayama 1 ，Kaori Matsumoto 1 ，
Mitsuyoshi Ichihara 1 ，Yasushi Sasaki 1 ，Nahoko Shiroto 4 ，Ryu Matsuoka 4 ，Kouichi Ogawa 1 ，Shinji Kunishima 5 ，
Akihiko Sekizawa 3
1:Department of Obstetrics and Gynecology, Showa University Fujigaoka Hospital, Japan、2:Department of Clinical Laboratory, Showa
University Fujigaoka Hospital、3:Department of Hematology, Showa University Fujigaoka Hospital、4:Department of Obstetrics and
Gynecology, Showa University Hospital、5:Department of Hemostasis and Thrombosis,Clinical Research Center, National Hospital
Organization Nagoya Medical Center
May Hegglin Anomaly (MHA) is a typical hereditary disorder characterized by a thrombocytopenia, giant platelets and
sometimes accompanied by nephritis, cataract and difficulty in hearing. MHA is a rare genetic disorder, caused by mutations
in a MYH9 gene located on chromosome 22q12-13 and encoding non-muscle myosin heavy chain class IIA. MHA is developed

in autosomal dominant manner whereas thirty percent is de novo mutation. We recently experiences a pregnant woman with
MHA.
Case report
A 35-years-old primipara woman was referred at 7 weeks of gestation.
She had family history of thrombocytopenia and difficulty in hearing, and she had bilateral sensorineural hearing loss and
had been pointed out the low platelets counts . At 1st trimester, routine antenatal blood test showed 6.1×104 /ml of platelets.
And we consulted a hematologist for investigation. We diagnosed MHA due to giant platelets and Dohle inclusion bodies
which were showed in her blood smear whereas both bleeding time and thrombocytic agglutinability test were normal. Her
pregnancy progressed without trouble except diagnosed gestational diabetes mellitus (GDM).
In genetic counseling, we informed the parents that their baby would have the possibility of MHA from the heredity form
and we would need investigate the baby carefully after birth. We also consulted pediatricians about this patient and tried
to share information. We performed caesarian section because of breech presentation at 37 weeks of gestation. A healthy
2760g male infant was delivered. Thrombocytopenia, abnormality in hearing test and abnormal bleeding complication was
not found. He was followed carefully and we are waiting for mother ｀ s result of genetic testing.
MHA is a rare genetic disorder but we have to discriminate from idiopathic thrombocytopenia if we meet patients showing low
platelet counts. It is important to have a joint management by otolaryngologist, ophthalmologist, hematologist, nephrologist
and obstetrician.
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Tue(3)-O15-2
Uniparental disomy (UPD) 14 diagnosed by SNP microarray at 16 week amniotic fluid showed distinctive
ultrasonic finding from early 2nd trimester; a case report
1,2
Norio Shinozuka ，Sena Eda 2 ，Akinori Taguchi 1,2
，Hiroshi Seto 1 ，Shoji Okajima 3
1:OBGYN, Seto Hospital, Japan、2:Clin. Genetics, Seto Hospital、3:LabCorp Japan
[Introduction] UPD 14 paternal has known to show unique phenotype, however, the cases antenatally diagnosed were much
less common.
[Case] A 40-year-old primigravid woman who got pregnant with IVF /ICSI was referred for prenatal diagnosis at 11w0d. The
1st trimester detailed ultrasonography (dUS), NIPT and other option were proposed by genetic counseling. Specific findings
of dUS at 12w0d were as follows; Increased NT 4.78mm, Nasal bone existed, somewhat flat facial profile with presence of nasal
bone, reverse flow of ductus venosus. Omphalocele like belly. NIPT was chosen for the 1st step of genetic diagnosis, however,
the result ware negative (low risk). At 2nd dUS at 14w3d, Nuchal translucency (NT) was 4.49mm. Neck to upper chest
subcutaneous thickness was observed . Omphalocele like belly/ muscle belly hypoplasia and flat facial profile with saddle
nose were observed Thorax to Abdominal circumference (TC/AC) was 0.66. 3D ultrasound showed relatively small chest with
large belly and distinctive finding of whole body disproportion was visually recognized. Based on these, UPD 14 paternal was
suspected as a the most possible diseases. To clarify fetal disease, karyotyping with additional SNP microarray analysis were
carried out at 16w3d. At amniocentasis, in addition to above findings, hydroamnios, large head (BPD +2.4SD), TC -0.7SD,

TC/AC 0.70 were observed. RevealSM SNP microarray (LabCorp) showed complete allele homozygosity on chromosome 14.
Karyotype was normal 46XY. Through genetic counseling, the termination of pregnancy was chosen at 19w0d. As fetal
specific finding indicated paternal origin, following microsatellite analysis using parental blood samples proved paternal UPD.
[Discussion] 1st to early 2nd Trimester dUS findings are important for prenatal diagnosis. The case with fatal structural
anomaly who confirmed negative NIPT, the microarray analysis should be next step examination to apply for prenatal
diagnosis.
Tue(3)-O15-3
Prenatal whole genome SNP array diagnosis: relevance of incidental findings in pregnancies with and
without ultrasound anomalies
Marieke Joosten 1 ，Karin EM Diderich 1 ，Diane Van Opstal 1 ，Lutgarde CP Govaerts 1 ，Sam R Riedijk 1 ，
Krista Prinsen 2 ，Femke AT de Vries 1 ，Robert-Jan H Galjaard 1 ，Malgorzata I Srebniak 1
1:Clinical Genetics, Erasmus MC, Netherlands、2:Gynaecology and Obstetrics, Erasmus MC
Background: We routinely perform SNP array analysis as a first-tier test for all prenatal indications. As compared to
karyotyping, array detects more clinically relevant anomalies, including pathogenic aberrations that are not related to the
indication. The chance of detecting these so called incidental findings, or more accurately defined: unexpected diagnoses, is
one of the reasons that the use of whole genome array in prenatal diagnosis is controversial. We will show the relevance of
detecting such unexpected diagnoses in the fetus, based on the nature, prevalence, counseling and outcome of the affected
pregnancies.
Methods: In January 2010 - August 2015 3,783 patients were referred for prenatal SNP array testing (Illumina): 1,980
pregnancies with and 1,803 without ultrasound anomalies. All unexpected diagnoses were discussed in a multidisciplinary
team consisting of laboratory specialists and clinical geneticists before disclosure. All patients received pre- and post-test
counseling. Psychological help was available if required.
Results: In 1:200 (19/3,783) cases an unexpected diagnosis was found. This concerned 7 in 1980 pregnancies with and 12 in
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1803 pregnancies without ultrasound abnormalities. Twelve out of 19 were severe early-onset untreatable diseases. In 11/12
severe cases (e.g. Duchenne muscular dystrophy, Angelman syndrome) the unexpected diagnosis was helpful either for the
couples in making a decision about the course of their pregnancy, or for perinatal management. No severe late-onset diseases
were detected in our cohort.
Conclusion: We will show that in the majority (11/19) the so called unexpected diagnosis was relevant for counseling and
pregnancy management. This adds another reason to the known recommendations to use SNP array for all prenatal indica-
tions.
Tue(3)-O15-4
Postnatal and prenatal diagnosis for neonatal intrahepatic cholestasis caused by citrin deficiency
Nguyen T.M Huong 1 ，Nguyen P.A Hoa 2 ，Ngo D Ngoc 1 ，Nguyen T.P Mai 1 ，Ly T.T Ha 1 ，Ngo M Tien 1 ，Le T Hai 1,2
，
Vu D Quang 1
1:Human Genetics Department, National Hospital of Pediatrics, Vietnam、2:Hepatology Department
Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) which resulted from mutation in SLC25A13 gene can
present transient intrahepatic cholestasis, prolong jaundice, chronic liver disease and so on.
This study aimed to identify mutations of SLC25A13 for 695 NICCD and 46 siblings of patients with NICCD caused by

Citrin deficiency and prenatal diagnosis for 10 pregnancies with high risk of Citrin deficiency.
Detection 4 common mutation termed as 851del4, IVS6+5G>A, 1638ins23, IVS16ins3kb of SLC25A13 gene by PCR/RFLP
and confirm by directly sequencing. The NICCD parents who had fetus then enrolled in DNA testing for the carrier. Prenatal
diagnosis for their fetus were performed following by amniocentesis and amniocyte cultured.
In posnatal group, 25,3% (176/695) patients have identified mutations. Among them, 94 patients were homozygote of mutation
851del4, 66 patients were 851del4 heterozygote, 5 patients were compound heterozygote of mutation [1638ins23+851del4],
1 patients was heterozygote of single mutation [IVS6+5G>A+851del4] and 1 patients were homozygote of mutation
IVS6+5G>A, 6 patients were compound heterozygote of mutation [851del4+IVS16ins3kb]; 1 patients was homozygote of
mutation IVS16ins3kb. 851del4 was the major mutation type, accounting for 76,3% in mutant allele, followed by c.1638ins23
(1,5%), IVS16ins3kb (1.8%), and IVS6+5G>A (0,9%); In the prenatal group, out of 10 couple enrolled DNA testing before
doing prenatal diagnosis, 2 (20%) fathers and 1 (10%) mother revealed that they were homozygous mutation without any
clinical figure and the others (80%; 90% repectively) were carrier. Among 4 pregnancies having prenatal diagnosis, 2 (50%)
fetuses were homozygote, 1(25%) fetus was heterozygote and the remaining (25%) was normal.
851del4 was the most most prevalent in Vietnamese NICCD patients. Citrin deficiency prenatal diagnosis might open a novel
area of clinical management for citrin deficiency in Viet Nam.
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Tue(3)-O15-5
Prenatal Counseling and Diagnosis of Gaucher Disease In Egypt: 15 Years Experience
Ahmed A.L. Aboulnasr 1 ，Ekram A.M. Fateen 2
1:Obstetrics and Gynecology, Faculty of Medicine, Cairo University, Egypt、2:Biochemical Genetics Department, National Research Centre,
Cairo,Egypt
Objective : Prenatal counseling(PC) and diagnosis(PD) of Gaucher disease (GD) in pregnants with previous affected sibling
(s).
Subjects and Methods : Prenatal counseling was done in 97 pregnancies among 70 females from June 2000 to October
2015. One female was counseled in four pregnancies, 6 females in 3 pregnancies and 12 females in 2 pregnancies . Positive
consanguinity found in 62 (88.57%) couples.
chorionic villus sampling (CVS) was done between 11-12 weeks gestational age in 73 pregnancies among 56 females. 4 females
had CVS in 3 pregnancies and 9 females in 2 pregnancies. Beta- glucocerebrosidase activity was measured in chorionic villi
Results : 73 (75.26%) of 97 counseled pregnancies proceeded to CVS. 24 (24.74%) were not subjected to CVS. 12 did not
show up at scheduled time, 4 already came late for PD, 4 had missed abortion, 2 had spontaneous abortion, one had induced
abortion before PD and one refused.
In 69 cases, enough chorionic villi were retrieved and beta- glucocerebrosidase activity was measured . 51 (73.91%) of the 69
cases had normal beta-glucocerebrosidase activity and 18 (26.09%) had low activity denoting affected fetus. In 4 cases, we

could not retrieve enough chorionic villi.
Conclusions : In spite of the presence of enzyme replacement therapy for GD, it is not effective for all types in addition to
high cost and variable response. So, our responsibility in prenatal counseling is to offer early diagnosis by CVS, as one of the
options, to the pregnant/couple
Tue(3)-O15-6
Serious complex-heart disease is hardly predicted by prenatal genetic screening
Mika Saito 1 ，Taku Ishii 1 ，Yuuji Hamamichi 1 ，Akio Inage 1 ，Yuuki Nakamoto 1 ，Tomomi Ueda 1 ，Satoshi Yazaki 1 ，
Tadahiro Yoshikawa 1 ，Ryo Suzuki 2 ，Yoshinori Maeda 2 ，Ikuno Kawabata 2 ，Atsushi Yoshida 2 ，Shinji Katsuragi 2 ，
Gengi Satomi 3
1:Pediatric Cardiology, Sakakibara Heart Institute, Japan、2:Obstetric and gynecology, Sakakibara Heart Institute、3:Satomi Clinic
Introduction:
Approximately 25% of patients with congenital heart disease (CHD) have genetic abnormality including multifactorial genetic
disease. NIPT has been available in Japan since April 2013, and research has shown this to reduce prenatal invasive testing.
On the other hand, a Japanese consortium reported 15 pregnant women with negative NIPT results had babies with CHD
(0.9%). Our institute started obstetric and fetal clinic in June 2014, where many severe CHD cases with or without increased
nuchal translucency were sent to undertake diagnosis.
Method:
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We reviewed 65 examinations diagnosed CHD and deliveries between June 2014 and October 2015, excluding fetuses sent to
other hospitals due to other problems.
Result:
The age at first examination ranged from 17 to 41 years (median 31 years). Nine cases (13.8%) underwent prenatal early
screening including NT scan; seven (10.8%) infertility treatment. Of these 9 cases, 4 accessed NIPT, 2 chose amniocentesis
and 1 underwent CVS, all of which showed normal karyotype. One of the latter 3 with invasive tests was revealed to have
46XX, add(1)(p36.2) or del(1)(p36.2). Also, 4 of the total cases were diagnosed as trisomy 21, and 3 as 22q11.2 deletion after
birth. As for CHD diagnosis by fetal echo, 28 (43.1%) were serious complex-heart anomalies for which Fontan-type surgery
would be planned: single ventricle (10), left hypoplastic heart (8), and asplenia (10). Seven of the 28 patients died after first
surgery. However, there was no correlation between maternal age and severity.
Conclusion:
Many of our cases diagnosed by prenatal echo had complex heart anomalies, one fourth of which died eventually after stage I
palliation. Grade of severity had no relation to abnormality in genetic testing before birth. Echo would still be a fundamental
diagnostic modality in fetal cardiology, even if NIPT was widely distributed. Furthermore, it is important to correctly detect
CHD prenatally to predict prognosis and also to treat them.
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Tue., April 05, 2016 13:50-15:20 Room E (1F)
Chair：Elizabeth Hauser（Duke Molecular Physiology Institute, Duke University, USA）

Chair：Tatsuhiko Tsunoda（Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and
Dental University, Japan）
Tue(3)-O16-1
Coding and non-coding transcriptomic landscape of human brain: preliminary analysis of RNA sequencing
data
Chao Chen 1 ，Yan Xia 1 ，Chuan Jiao 1 ，Amber Thomas 2 ，Yongjun Wang 3 ，Lijun Cheng 3 ，Xiyao Long 3 ，
Miguel Brown 2 ，Jason Grundstad 2 ，Annie Shieh 2 ，Kevin P. White 2 ，Chunyu Liu 3
1:The State Key Lab of Medical Genetics, Central South University, Changsha, China、2:Institute for Genomics and Systems Biology, the
University of Chicago, Chicago, USA、3:Department of Psychiatry, University of Illinois at Chicago, Chicago, USA
Brain gene expression and its regulation are fundamental biology for understanding neuropsychiatric disorders. So far, most
published RNA-seq data have come from polyA-based (PA) libraries, which capture primarily protein-coding mRNAs. How-
ever, many non-coding RNAs regulate mRNA expression and may play important roles in disease etiology or pathology.
In our PsychENCODE study, we have sequenced 223 European frontal cortex samples using Ribo Zero (RZ) libraries. Nine of

them were also sequenced using PA library for comparison. We found that 17,394 genes were detected in both libraries, and
their expression levels were highly correlated (Spearman correlation r=0.88, p<2.2e-16). However, this correlation is weaker
than that of pairs of random two samples within each library, indicating the technical variation between the two platforms is
larger.
In the top 100 highly expressed genes in RZ data, 85 were ncRNAs. Interestingly, some of those top expression ncRNAs
clustered in several genomic regions, including three regions in 15q11.2, a region associated with Autism Spectrum Disorder.
We also examined several groups of genes for their expression levels and variabilities, such as 11 housekeeping genes, 16 clock
genes,18 mitochondrial genes, 318 transcriptional factors, 64 mTOR pathway genes and 17 RNU6 genes. The house-keeping
genes in general have relatively low variability, except RNU6 genes, though they were commonly used for normalization in
mRNA profiling.
The preliminary analyses of our RNA-seq data proved the importance of RZ library sequencing. RZ library captured expres-
sions of many genes that are missed by PA library, particularly ncRNAs. We also discovered a few genomic regions, including
one on 15q11.2, carrying extremely highly expressed ncRNAs. The biological functions and clinical implications remain to
be investigated. Lastly, our data confirmed that house-keeping genes are suitable for being used as normalization controls
except RNU6 genes.
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Tue(3)-O16-2
Pleiotropic landscape of anthropometry inferred from 359 novel and 297 established loci discovered in
270,000 individuals
Xia Shen 1,2 ，Zheng Ning 1 ，Yakov Tsepilov 4,5,6 ，Xiao Wang 10 ，Peter K. Joshi 2 ，Masoud Shirali 2 ，Blair H. Smith 2,7
，
Lynne J. Hocking 2,8 ，Sandosh Padmanabhan 2,9 ，Caroline Hayward 2 ，David J. Porteous 2 ，James F. Wilson 2 ，
Yudi Pawitan 1 ，Chris S. Haley 2 ，Yurii S. Aulchenko 2,3,4,5 ，Generation Scotland
1:Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden、2:University of Edinburgh、3:PolyOmica、4:Novosibirsk State
University、5:Institute of Cytology and Genetics SB RAS、6:Helmholtz Zentrum Munchen - German Research Center for Environmental
Health、7:University of Dundee、8:University of Aberdeen、9:University of Glasgow、10:Stockholm University
Anthropometric traits are globally relevant risk factors for disease, including obesity. Many genetic variants have been
associated with anthropometric measurements, but they explain little trait variation of the traits. Joint-modeling of multiple
traits may boost discovery power and enhance understanding of pleiotropic genetic architecture. Here, we develop and perform
a fast and powerful multi-trait meta-GWAS analysis and replicate the findings in two independent cohorts of Generation
Scotland and the large UK Biobank. Using results from the GIANT meta-GWAS of 270,000 individuals, we discovered
359 novel loci significantly associated with six anthropometric traits, which doubled the number of established loci for
anthropometric measurements. The “overeating gene” GRM5 was the strongest novel locus. The novel variants had an
enriched rediscovery rate in the replication cohorts and emphasize the value of combining multiple correlated phenotypes in
genomic studies. Together with the established loci, we provide important new insights into pleiotropic mechanisms and the
fullest pleiotropic landscape network to date underlying anthropometry.

Tue(3)-O16-3
From Paris to Kyoto or from Dermatoglyphics to Exome Sequencing
Regina M. Zambrano 1 ，Yves Lacassie 1
1:Department of Pediatrics, Louisiana State University Health Sciences Center and Children’s Hospital of New Orleans, USA
I have been fortunate to attend all the ICHG meetings since 1971 with the exception of Jerusalem in 1981. During those
45 years practicing genetics, I have watched important changes in the way clinical geneticists practice the speciality. In this
presentation I will review how clinicians have been systematically and progressively replacing the art and science of clinical
evaluation by the performance of laboratory testing. Although new tests, especially microarrays and exome sequencing, allow
us to finish the diagnostic odyssey in many unknown cases, if we select the kind of testing after a detailed and comprehensive
clinical evaluation, including a thorough history and full and meticulous examination especially of face and hands including
dermatoglyphics, the diagnostic yield is much better. I will illustrate how clinical evaluation allows us to establish many
diagnoses and often to predict years in advance the possible etiology; discuss the improvement in diagnosis since the advent
of chromosomal banding which was a huge milestone in 1971 in Paris, and finally I will review the current classification of
diagnostic problems that unquestionnably are present and affect the whole international community.
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Tue(3)-O16-4
QTR1: An Enhanaced, Population-Centric Reference Genome Based on GRCh37 to Facilitate Precision
Medicine in Qatar and the Middle East
Khalid Fakhro 1,2 ，Michelle Staudt 3 ，Amal Robay 2 ，Charbel Abi-Khalil 2 ，Ramin Badii 4 ，Ajayeb Al-Nabet 4 ，
Jason Mezey 3,5 ，Ronald Crystal 3 ，Juan Rodriguez-Flores 3
1:Translational Medicine, Sidra Medical Research Center, Qatar、2:Weill Cornell Medical College in Qatar、3:Weill Cornell Medical College
in New York、4:Hamad Medical Corporation、5:Cornell University
Precision medicine will ultimately depend on the quality and speed of genome interpretation, tailored to individuals in the
context of their native populations. In order to facilitate precision medicine in the Middle East, a population-specific reference
genome for Qatari Arabs (QTR1) was constructed by incorporating allele frequency data from sequencing of 1,158 Qataris,
(~ 0.5% of the population) into the standard reference genome (GRCh37). The new QTR1 reference was tested by alignment
of an independent Qatari individual sequenced on four platforms to both it and GRCh37, and demonstrated a reduction
in genotype calling errors when employing QTR1. Further, aligning reads from an “n+1” individual from each of the 3
Qatari genetic subpopulations, to QTR1 reduced the number of variants identified as the "minor allele" in the exome by 14%
and genome by 23% compared with GRCh37. This is a significant reduction in the number of sites that would usually be
considered variants and require time and resources to annotate and interpret. For example, when considering 2,330 variant
alleles linked to disease or pharmacogenetics, 295 (12.6%) have the GRCh37 minor allele as the major alleles in QTR1 and
are therefore unlikely to be deleterious. Conversely, 26 of them had deleterious variant allele frequencies higher in Qataris
than the rest of the world, including for diseases with known high incidence in Qatar such as homocystinuria, cystic fibrosis

and arterial tortuosity. Importantly for personalized medicine in this population, only a minority of all discovered mutations
presented here are currently on the national newborn screening panels. The QTR1 genome and analysis software developed
for personalized genome interpretation in this population are provided as open access tools for precision medicine in Qatar
and genetically related Arab populations.
Tue(3)-O16-5
HOT or not: redefining the origin of high-occupancy target regions
Altuna Akalin 1 ，Katarzyna Wreczycka 1 ，Vedran Franke 1 ，Bora Uyar 1 ，Ricardo Wurmus 1
1:BIMSB, Max Delbrueck Center, Germany
High-occupancy target (HOT) regions are segments of the genome with unusual enrichment of transcription factor binding
sites. These regions are observed in multiple species and thought to have biological importance due to high density of
transcription factor occupancy. Furthermore, they coincide with house-keeping gene promoters and the associated genes
are stably expressed across multiple cell types. Despite these features, HOT regions are solemly defined using ChIP-seq
experiments and shown to lack canonical motifs for transcription factors thought to be bound there. Although, ChIP-seq
experiments are the golden standard for finding genome-wide binding sites of a protein, they are not noise free. Here, we
show that these regions are likely to be ChIP-seq artifacts and they are similar to previously proposed ｀ hyper-ChIPpable
regions ｀. Using ChIP-seq data sets for knocked-out transcription factors, we demonstrate enrichment of the knocked-out
factors on HOT regions. We observe sequence characteristics and genomic features that are unique to HOT regions that are
in turn statistically associated with the artificial ChIP-seq enrichment. Furthermore, we propose strategies to deal with such
artifacts for future ChIP-seq studies.
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Tue(3)-O16-6
Short inversion detection by splitting and re-aligning poorly mapped and unmapped next-generation
sequencing reads
Ruoyan Chen 1 ，Yan Zhang 1 ，Wanling Yang 1
1:Paediatrics and Adolescent Medicine, The University of Hong Kong, China
Rapid development of sequencing technology has enabled routinely discovery of deletions and insertions. However, unlike these
two kinds of structural variation, characterization of inversions is left behind. Summary of public databases and researches
shows that little short inversions smaller than 500bp have been detected for now. One explanation is that in contrast to small
insertions and deletions, which are considered by gap alignment and recorded in primary mapping files, inversions short enough
to interrupt alignment probably result in poorly mapped or unmapped reads, which are mostly left out of consideration for
structural variation detection by existing methods. And as a result, the majority of signals of short inversions are overlooked.
Here, we introduce SRinversion, a framework that tries to re-use those poorly mapped or unmapped reads by splitting and
re-aligning them for inversion detection, and in this way improve the resolution of inversion detection to less than 10bp.
Comparison with previous structural variation detection methods using simulated data indicates that SRinversion performs
the best among these methods when inversion size is smaller than 100bp. The method was also tested on two chromosomes
(chr1 and chr21) of a high-coverage parent-child trio (NA12878, NA12891, and NA12892) from 1000 genomes project. In
total, 262, 42, 38 inversions with length smaller than 1kb are detected on daughter (NA12878), father (NA12891), and mother

(NA12892), respectively. After excluding ones within repeat regions or fail assembly, 5 inversions were selected to perform
PCR for all three samples. And except for one region that failed the experiment, all of them are validated.
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Tue., April 05, 2016 15:40-17:10 Room E (1F)
Chair：Davide Cittaro（Center for Translational Genomics and Bioinformatics, San Raffaele Hospital, Italy）
Chair ：Zhaoming Wang（Department of Computational Biology, St. Jude Children’s Research Hospital, USA）
Tue(3)-O17-1
Imputation of KIR types from SNP variation data
Damjan Vukcevic 1,2 ，James A. Traherne 3,4 ，Sigrid Næss 5,6 ，Eva Ellinghaus 7 ，Yoichiro Kamatani 8,9 ，
Alexander Dilthey 10 ，Mark Lathrop 8,11 ，Tom H. Karlsen 5,12 ，Andre Franke 7 ，Miriam Moffatt 13 ，William Cookson 13
，
John Trowsdale 3,4 ，Gil McVean 10 ，Stephen Sawcer 14 ，Stephen Leslie 1,2
1:Statistical Genetics, Murdoch Childrens Research Institute, Australia、2:School of Mathematics and Statistics, University of Melbourne,
Australia、3:Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK、4:Division of Immunology, Department of
Pathology, University of Cambridge, Cambridge, UK、5:Research Institute of Internal Medicine, Department of Cancer Medicine, Surgery
and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway、6:Norwegian PSC Research Center, Division of Cancer, Surgery
and Transplantation, Oslo University Hospital, Oslo, Norway、7:Institute of Clinical Molecular Biology, Christian-Albrechts-University
of Kiel, Schittenhelmstr, Germany、8:Fondation Jean Dausset-CEPH, Paris, France、9:RIKEN Center for Integrative Medical Sciences,
Kanagawa, Japan、10:Wellcome Trust Centre for Human Genetics, University of Oxford, UK、11:McGill University and Génome Québec
Innovation Centre, Montreal, Canada、12:K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo,
Oslo, Norway、13:National Heart and Lung Institute, Imperial College London, Royal Brompton Campus, UK、14:Department of Clinical
Neurosciences, University of Cambridge, Cambridge, UK
Large population studies of immune system genes are essential for characterizing their role in diseases. Of key interest are

genes encoding the killer-cell immunoglobulin-like receptors (KIRs), which have known and hypothesised roles in autoimmune
diseases, resistance to viruses, reproductive conditions and cancer. These genes are highly polymorphic, making typing
expensive and time-consuming. Consequently, despite their importance, KIRs have been little-studied in large cohorts. This
parallels the case of the human leukocyte antigen (HLA) genes, whose proteins are known to interact with KIR and have
been implicated in many autoimmune conditions.
Statistical imputation methods developed for other complex loci (e.g. HLA), based on single nucleotide polymorphism (SNP)
data, provide an inexpensive high-throughput alternative to direct laboratory typing of these loci and have enabled important
findings for many diseases. Here we present KIR*IMP, the first imputation method developed for KIR.
To develop our method, we assembled a reference dataset of almost 500 accurately phased haplotypes typed for KIR gene copy
number and at 305 SNPs covering 400kb around the KIR genes. We used a separate dataset derived from 1,300 individuals
to validate our method.
We show that KIR*IMP is highly accurate, to a level that is more than adequate for association studies. For imputing
KIR copy number, we achieve greater than 98% accuracy for the majority of KIR loci, at least 95% accuracy for half the
remaining loci, and better than 90% for the rest. KIR haplotypes can also be imputed with high accuracy. For example, a
standard classification of KIR haplotypes is into two broad groups (named A and B) based on their biological function; we
can distinguish these with 98.5% accuracy.
The high accuracy of KIR*IMP allows for the first time the study of KIRs in large cohorts, enabling detailed investigation of
the role of KIRs in human disease.
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Tue(3)-O17-2
Diagnostic Role of Exome Sequencing in Immune Deficiency Disorders
Steven E Brenner 1 ，Aashish N Adhikari 1 ，Jay P Patel 2 ，Alice Y Chan 3 ，Divya Punwani 3 ，Haopeng Wang 3 ，
Antonia Kwan 3 ，Theresa A Kadlecek 3 ，Morton J Cowan 3 ，Marianne Mollenauer 3 ，John Kuriyan 1 ，Shu Man Fu 4 ，
Uma Sunderam 5 ，Sadhna Rana 5 ，Ajithavalli Chellappan 5 ，Kunal Kundu 5 ，Arend Mulder 6 ，Frans HJ Claas 6 ，
Joseph A Church 7 ，Arthur Weiss 3 ，Richard Gatti 8 ，Jennifer Puck3 , Rajgopal Srinivasan5
1:University of California, Berkeley, USA、2:Children’s Hospital of Los Angeles、3:University of California, San Francisco、4:University of
Virginia School of Medicine、5:Innovation Labs, Tata Consultancy Services、6:Leiden University Medical Centre、7:University of Southern
California、8:University of California, Los Angeles
We developed an analysis protocol for individual genome interpretation and used its distinctive features to diagnose numerous
clinical cases. We applied the protocol to exomes from newborn patients with undiagnosed primary immune disorders. To
yield high quality sets of possible causative variants, we used multiple callers with multisample calling and integrated variant
annotation, variant filtering, and gene prioritization.
In two unrelated infant immunodeficient girls with no diagnoses, we discovered compound heterozygous variants in the ATM
gene for both the infants offering a very early diagnosis of Ataxia Telangiectasia (AT) which allowed for avoidance of undue
irradiation and live vaccinations.
In another case, the affected siblings had early onset bullous phempigoid, a chronic autoimmune disorder. Our analysis revealed
compound heterozygous mutations in ZAP70, a gene associated with profound primary immunodeficiency, the opposite

phenotype. Cellular immunological studies indicated that one variant was hypomorphic and the other was hyperactive.
These combined to yield a novel presentation, adding to the existing phenotype repertoire of ZAP70 in humans.
We also discovered variants in PRKDC occurring after the genomically-encoded stop codon, since we correctly identified a
premature stop codon in the stop codon resulting from a single base deletion. Our protocol has been similarly revealing in
other SCID and CID cases including Nijmegen Breakage Syndrome, which highlight unique features of the analysis framework
that facilitate genetic discovery. These help provide crucial information to offer prompt appropriate treatment, family genetic
counseling, and avoidance of diagnostic odyssey.
Tue(3)-O17-3
Using patterns of somatic mutations in cancer to predict disease genes
Davide Cittaro 1 ，Dejan Lazarevic 1 ，Paolo Provero 2
1:Center for Translational Genomics and Bioinformatics, San Raffaele Hospital, Italy、2:University of Turin, Dept. of Molecular Biotechnology
and Life Sciences, Torino, Italy
Many recent studies show that genes associated to genetic diseases often are found recurrently mutated, at the somatic level,
in cancer. These observations could in principle be useful in understanding the origin of both genetic diseases and cancer.
However they are currently anecdotal in nature. We systematically explored this issue by asking whether patterns of recurrent
somatic mutations in cancer can be used to predict the involvement of genes in genetic diseases. We built a logistic model
that uses cancer somatic mutation data from COSMIC to predict the involvement of genes in genetic diseases as reported in
the ClinVar database. The model achieves a significant predictive power (AUC = 0.65, P < 2.2e-16); pattern of recurrent
mutations in tumors of soft tissues and large intestine are especially informative about involvement in genetic disease.
We then built separate logistic models for each term of the Disease Ontology (DO), keeping the whole COSMIC dataset as
regressors, to predict the involvement of genes in diseases as annotated in the DO. AUC values higher than 0.8 can be obtained
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for several DO terms, including gastritis, allergic asthma and migraine. The results can be summarized in a bipartite network
where each disease is connected to the cancer types (histology or anatomical site, as defined in COSMIC) whose patterns of
somatic mutations are significantly informative.
Since, to our knowledge, data about somatic mutations in cancer are not currently used for the task of prioritizing the results
of NGS-based screenings or GWAS studies, our results can be used to improve the identification of causal mutations in genetic
diseases. More generally, they provide new insight in the origin of both genetic diseases and cancer.
Tue(3)-O17-4
Telomere Length and Accelerated Aging in Adult Survivors of Childhood Cancer: a report from the St.
Jude Lifetime Cohort
Zhaoming Wang 1 ，Yutaka Yasui 1 ，Kirsten K Ness 1 ，Carmen L Wilson 1 ，DeoKumar Srivastava 1 ，Michael Rusch 1 ，
Andrew Thrasher 1 ，Melissa M Hudson 1 ，Jinghui Zhang 1 ，Leslie L Robison 1
1:St. Jude Children’s Research Hospital, USA
Telomere length (TL) is a marker for cellular aging. However, its association with actual aging is debated. We evaluated TL
and its association with the frailty phenotype (low lean muscle mass, weakness, slow walking speed, low energy expenditure,
fatigue) in long-term survivors of childhood cancer potentially at risk for accelerated aging because of cancer therapies

received in childhood. Deep coverage (~ 30x) whole genome sequencing (WGS) data were generated for 547 childhood cancer
survivors (mean age [yrs]: 32.9 (18.7-60.0); mean follow-up [yrs]: 25.6 (12.1-48.3)). TL was estimated and found to be
normally distributed (mean = 6.47 kilobases; standard deviation = 1.33; range (2.40-11.2)). The mean attrition rate per year
was 52 base pairs (bp), which is higher than the average rate of 30 bp reported for the general population, and differed by
primary cancer diagnosis: (neuroblastoma 96 bp (95% CI 56-136), acute lymphoid leukemia 70 bp (95% CI 46-93), Hodgkin’
s lymphoma 59 bp (95% CI 20-99), brain tumor 46 bp (95% CI 22-115), Wilms’ tumor 41 bp (95% CI 9-74)).
A combined outcome of pre-frailty and frailty conditions had a prevalence of 23.3% (19.6% pre-frailty, 3.7% frailty). After
adjusting for age at sample collection, sex, race, smoking, and DNA extraction lab/batches, TL was significantly associated
with low lean muscle mass (LLMM) (P=0.0001; beta=-0.15) with a stronger association in males (beta=-0.17) than females
(beta=-0.13). TL was also significantly associated with binary or continuous measurement for fatigue (P=0.013; P=0.036
respectively) when restricted to adults younger than 35 years old.
Telomere attrition was faster among childhood cancer survivors than reported population values and rates varied by cancer
diagnosis. These preliminary data suggest an association between TL and an aging phenotype among childhood cancer
survivors. Analyses will be expanded when WGS data becomes available for an additional 2500 participants.
Tue(3)-O17-5
CentoMD  , the largest variant database for rare diseases
1
Daniel Trujillano
1:Centogene AG, Germany
Our ability to discover genetic variation in a patient is running far ahead of our ability to interpret it. Databases with
accurate description of the relationship between the variants and the phenotype become the critical step in the interpretation
clinical genetic diagnostics, since these enable a proper classification of “variants of unknown significance” in the context
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of rare diseases. Here we introduce CentoMD  , the largest variant database with clinical descriptions with main focus on
rare diseases. CentoMD  is browser based software that supports a comprehensive and curated repository of genetic and
clinical information based on patient’s diagnosis. It aids medically trained professionals in the evaluation of the genetic
variants that have been identified in their own patients. This enhances the validity of the genetic analytical workflow and
aids the clinician in evaluating treatment options for patients with hereditary diseases. It correlates the clinical information
of consented patients and probands of different ethnical background with a large dataset of genetic variants and biomarkers
(when available).
Tue(3)-O17-6
Patient Archive: An integrated solution for deep phenotyping of clinical cases
Tudor Groza 1,2 ，Mark Cowley 1,2 ，Tony Roscioli 1,2 ，Gareth Baynam 3,4,5,6,7 ，Hugh Dawkins 5 ，Melissa Haendel 8 ，
Chris Mungall 9 ，Nicole Washington 9 ，Damian Smedley 10 ，Peter N Robinson 11,12,13,14 ，Marcel Dinger 1,2 ，
Andreas Zankl 1,15,16
1:Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Australia、2:St Vicent’s Clinical School, Faculty of
Medicine, University of New South Wales, Australia、3:School of Paediatrics and Child Health, University of Western Australia, Perth,
Australia、4:Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Australia、5:Office of Population Health
Genomics, Public Health and Clinical Services Division, Department of Health, Perth, Australia、6:Genetic Services of Western Australia,
King Edward Memorial Hospital, Perth, Australia、7:Telethon Kids Institute, Perth, Australia、8:Department of Medical Informatics and
Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, USA、9:Division of Environmental Genomics and Systems
Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA、10:Skarnes Faculty Group, Wellcome Trust Sanger Institute, UK、
11:Institute for Medical and Human Genetics, Charite-Universitaetsmedizin Berlin, Germany、12:Max Planck Institute for Molecular Ge-
netics, Berlin, Germany、13:Berlin Center for Regenerative Therapies (BCRT), Charite-Universitaetsmedizin Berlin, Germany、14:Institute

for Bioinformatics, Department of Mathematics and Computer Science, Freie Universitaet Berlin, Germany、15:Academic Department of
Medical Genetics, The Children’s Hospital at Westmead, Sydney, Australia、16:Discipline of Genetic Medicine, Sydney Medical School,
University of Sydney, Australia
Phenotype is fundamentally important to identifying the etiology of rare disorders, in particular in the era of genome scale
sequencing. The interpretation and prioritization of millions of variants per patient, together with the incomplete linking of
detailed phenotypic terms to genomic variants, is currently the major limitation to achieving an accurate and timely clinical
diagnosis.
Patient Archive (PA) is an integrated platform, part of the Monarch Initiative, which enables deep phenotyping to provide a
translational bridge from genome-scale biology to a patient-centered view on human disease pathogenesis. PA realizes precise
phenotype capture through automatic extraction of Human Phenotype Ontology concepts from free text clinical summaries
and the description of uploaded images. Using semantic similarity matching algorithms, the resulting phenotype profile
empowers applications such as variant prioritization and patient matching against known diseases, or other patients. PA
integrates the Monarch phenotype sufficiency score to provide a measure to determine the uniqueness and specificity of a
patient profile, and the Exomiser, to enable exome variant prioritization by combining pathogenicity, frequency and cross-
species phenotype data. Patients in PA can be shared and discussed with other clinicians via fine-grained individual or group
level access control. Furthermore, the GA4GH MatchMaker Exchange Program is fully implemented, thus enabling patient
matchmaking in a seamless manner.
The detailed phenotype profile achievable in PA, combined with the corresponding clinical genomic data, has an enormous
potential to accelerate the identification of disease aetiology, facilitate disorder stratification and inform prognosis. The
platform enables the translation of genomic technologies into clinical practice, is freely available and has been successfully
deployed in clinical settings - such as the Dept. of Health, Govt. of Western Australia.
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Tue., April 05, 2016 13:50-15:20 Room B-1 (2F)
Chair：Kimihiko Oishi（Genetics and Genomic Sciences, Pediatrics, Icahn School of Medicine at Mount Sinai, USA）
Chair：Nobuhiko Okamoto（Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal
and Child Health, Izumi, Osaka, Japan）
Tue(3)-O18-1
XRCC4, a novel gene associated with Seckel syndrome and increased genomic instability
Nadine Rosin 1,2,3 ，Nursel H. Elcioglu 4 ，Filippo Beleggia 1,2,3 ，Pinar Isgueven 5 ，Janine Altmueller 1,6 ，Holger Thiele 6 ，
Katharina Steindl 7 ，Pascal Joset 7 ，Anita Rauch 7 ，Peter Nuernberg 2,3,6 ，Bernd Wollnik 1,2,3,8 ，Goekhan Yigit 1,2,3
1:Institute of Human Genetics, University of Cologne, Cologne, Germany、2:Center for Molecular Medicine Cologne (CMMC), University of
Cologne, Cologne, Germany、3:Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University
of Cologne, Cologne, Germany、4:Department of Pediatric Genetics, Marmara University School of Medicine, Istanbul, Turkey、5:Department
of Pediatric Endocrinology, Sakarya University Medical Faculty, Sakarya, Turkey、6:Cologne Center for Genomics, University of Cologne,
Cologne, Germany、7:Institute of Medical Genetics, University of Zurich, Zurich-Schlieren, Switzerland、8:Institute of Human Genetics,
University Medical Center Goettingen, Goettingen, Germany
DNA double strand breaks (DSBs) are highly toxic lesions, which, if not properly repaired, can give rise to genomic instability.
Non-homologous end-joining (NHEJ), a well-orchestrated, multistep process involving numerous proteins essential for cell
viability, represents one major pathway to repair DSBs in mammalian cells. To date, mutations in different NHEJ components

have been described in microcephalic syndromes characterized by clinical features including short stature, facial dysmorphism,
and immune dysfunction. By using whole-exome sequencing (WES) we now identified a homozygous mutation, c.482G>A,
in the XRCC4 gene encoding a crucial component of the NHEJ pathway, in three affected siblings of a consanguineous
Turkish family. Moreover, we found one additional patient of Swiss origin carrying the compound heterozygous mutations
c.25delG (p.His9Thrfs*8) and c.823C>T (p.Arg275*) in XRCC4 . Affected individuals showed typical clinical features of
Seckel syndrome, which is characterized by facial dysmorphism, severe microcephaly, intellectual disability, short stature, but
no recognizable immunological phenotype. Our data showed that the c.482G>A mutation affects the last nucleotide of exon
4, resulting in altered splicing of XRCC4 pre-mRNA thereby causing a reduction of full length protein and most likely loss of
XRCC4 function. Moreover, we observed on cellular level that XRCC4 deficiency leads to hypersensitivity to DSB-inducing
agents and defective DSB repair, which results in increased cell death after exposure to genotoxic agents. Taken together, our
data provide evidence that autosomal recessive mutations in XRCC4 induce increased genomic instability and cause Seckel
syndrome defined by typical facial dysmorphism, primary microcephaly, and short stature.
Tue(3)-O18-2
Systematic Cellular Disease Models Reveal Synergistic Interactions of Trisomy 21 and GATA1 Mutations
in Hematopoietic Abnormalities
Kimihiko Banno 1 ，Yasuji Kitabatake 1 ，Sayaka Omori 1 ，Keiichi Ozono 1
1:Department of Pediatirics, Graduate School of Medicine, Osaka University, Japan
Chromosomal aneuploidy and specific gene mutations have been recognized as early hallmarks of many oncogenic processes.
However, the net effect of these abnormalities has not been demonstrated clearly, which is typically exemplified by transient
myeloproliferative disorder (TMD) in Down syndrome (DS), a preleukemic condition caused by trisomy 21 and somatic GATA1
mutations. Here, we constructed systematic cellular disease models using human induced pluripotent stem cells (iPSCs) and
genome-editing technologies (TALENs and CRISPR/Cas9). Multiple iPSC lines based on the chromosome 21 copy number
(disomy, Di; or trisomy, Tri) and variations due to GATA1 mutation (no mutation, GATA1wt; short-form mutation, GATA1s;
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and knockout mutation, GATA1KO) were established, including targeted partial trisomy 21 iPSCs in which a 4-Mb segment
(a part of Down Syndrome Critical Region; DSCR) was artificially deleted from an extra copy of chromosome 21. Fourteen
types (and more than 40 clones) of hiPSCs were generated and subjected to hematopoietic differentiation to explore the
molecular mechanisms underlying multistep leukemogenesis. Constitutive trisomy 21 as a first step significantly accelerated
the endothelial-to-hematopoietic transition (EHT) process through the stimulatory action of RUNX1, leading to an enhanced
multilineage differentiation. Acquisition of the GATA1s mutation, a second step observed in TMD, perturbed differentiation
of erythrocytes and megakaryocytes in a lineage-dependent manner. In addition, trisomy 21 upregulated GATA1s expression
upon aberrant activation of the transcriptional network, giving rise to excessive generation of abnormal megakaryoblasts. We
succeeded to isolate the 4-Mb critical region for hematopoietic defects in DS and identified three genes, RUNX1, ETS2, and
ERG, as key molecules involved in an interconnected regulatory network. These results demonstrate synergistic effects of
aneuploidy and a specific gene mutation on the leukemogenesis.
Tue(3)-O18-3
Novel MCA/ID syndrome with ASH1L mutation
Nobuhiko Okamoto 1 ，Fuyuki Miya 2,3 ，Kenichi Nishioka 4 ，Hidenobu Soejima 4 ，Tatsuhiko Tsunoda 2,3
，
Mitsuhiro Kato 5 ，Shinji Saitoh 6 ，Mami Yamasaki 7 ，Yonehiro Kanemura 8,9 ，Kenjiro Kosaki 10
1:Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Japan、2:Department
of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University、3:Laboratory for Medical Science
Mathematics, Center for Integrative Medical Sciences, RIKEN、4:Division of Molecular Genetics and Epigenetics, Department of Biomolec-

ular Sciences, Faculty of Medicine, Saga University、5:Department of Pediatrics, Showa University School of Medicine、6:Department
of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences、7:Department of Pediatric Neurosurgery,
Takatsuki General Hospital、8:Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National
Hospital Organization、9:Department of Neurosurgery, Osaka National Hospital, National Hospital Organization、10:Center for Medical
Genetics, Keio University School of Medicine
INTRODUCTION:Mutations of genes involved in epigenetic modification, such as DNA methyltransferases, MBD proteins,
histone deacetylases, histone methylases and defects in chromatin remodeling are associated with various multiple congenital
anomaly (MCA)/ intellectual disability (ID) syndromes. Absent, small, or homeotic discs 1-like (ASH1L) catalyzes H3K36
methylation and plays important roles in development. De Rubeis et al. (Nature 2015) identified autosomal genes associated
with autism spectrum disorders. ASH1L was supposed to be involved in ID in their report. We report a boy with novel
MCA/ID syndrome with a novel mutation in the ASH1L gene.
CLINICAL REPORT : The 4-year-old male was the fourth child of healthy and non-consanguineous Japanese parents. He was
hypotonic and his developmental milestones were delayed. At 4 years, he showed axial hypotonia and could not sit of crawl.
He showed severe ID. He showed dysmorphic features including hypertelorism, low set ears, a flat nasal bridge, short upturned
nose, short philtrum, open mouth, high arched palate and down-turned corners of the mouth. Horizontal nystagmus and
sensorineural deafness of left ear was noted. His height was 94cm (-1.8SD), weight was 10 kg (-2SD) and OFC 44cm (-3.9SD).
CT scan of cervical spine revealed congenital fusion of C2 and C3. Brain MRI revealed markedly delayed myelination of
cerebral white matter.
METHODS : With the approval of the institutional ethics committee, the samples were analyzed using whole-exome sequence.
We planned a proband-parent trio approach.
RESULTS : A novel mutation in the ASH1L(c.G8356C:p.A2786P) was identified. This mutation was de novo and predicted
to be pathogenic by in silico analysis.
DISCUSSION : We identified a novel mutation in ASH1L in a patient with severe ID, growth failure, microcephaly, char-
acteristic facial features, myelination delay and skeletal abnormalities. We suggest that ASH1L abnormalities may cause a
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novel MCA/ID syndrome.
Tue(3)-O18-4
Novel Splicing Mutation in the ASXL3 gene causing Bainbridge-Ropers Syndrome
Ikumi Hori 1 ，Fuyuki Miya 2 ，Kei Ohashi 1 ，Yutaka Negishi 1 ，Ayako Hattori 1 ，Naoki Ando 1 ，Nobuhiko Okamoto 3 ，
Mitsuhiro Kato 4 ，Tatsuhiko Tsunoda 2 ，Mami Yamasaki 5 ，Yonehiro Kanemura 6,8 ，Kenjiro Kosaki 7 ，Shinji Saitoh 1
1:Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan、2:Laboratory for
Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan、3:Department of Medical Genetics, Osaka
Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan、4:Department of Pediatrics, Showa University School
of Medicine, Tokyo, Japan、5:Department of Neurosurgery, Takatsuki General Hospital, Osaka, Japan、6:Division of Regenerative Medicine
and Department of Neurosurgery, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan、
7:Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan、8:Department of Neurosurgery, Osaka National Hospital,
National Hospital Organization, Osaka, Japan
Bainbridge-Roper syndrome (BRPS: OMIM #615485) is a newly appreciated syndrome characterized by severe developmental
delay, feeding problems, short stature, ulnar deviation of the hands, characteristic facies including arched eyebrows, and
anteverted nares. BRPS is caused by a heterozygous mutation in the additional sex combs-like 3 (ASXL3 ) gene. All reported
potential pathogenic mutations in ASXL3 have been either frameshifting or truncating. We herein report on a case of BRPS
carrying a heterozygous de novo splicing mutation in the ASXL3 gene. The proband is a 5-year-old Japanese girl with no

family history. The girl was born by vaginal delivery in 38th gestational weeks without any perinatal abnormalities. At
birth she had a weight of 2430g(-0.9SD) and OFC 30.5cm(-1.8SD). After birth she showed feeding difficulty and failure to
thrive. Feeding difficulties gradually improved, but developmental delay became apparent. She has shown abnormal sleep
pattern since her infancy. She showed prominent forehead, thick eyebrows, long-lashed eyes, exotropia, depressed nasal ridge,
thin upper lip, hirsutism, deep palmar creases, and small hand and feet. Head MRI and G-banding chromosome analysis
were normal. We performed whole exome sequencing on the proband and her parents, and identified a heterozygous single
nucleotide substitution (c.3039+1G>A) in the invariant ‘GT’ splice donor site 3’ of exon 11, which is absent in her parents,
indicating that the mutation arose de novo. The mutation is predicted to remove the exon 11 which would create a frameshift
and truncate the protein. Reported disease causing mutations in ASXL3 are located mostly in the first half of the exon
11, which is analogous to that in ASXL1 where mutations resulting in Bohring-Opitz syndrome (BOS) occur. Our findings
further support that the exon 11 in ASXL3 is functionally important, and truncating mutations in the exon would give rise
to BRPS which is distinct but overlapping with BOS.
Tue(3)-O18-5
Further characterization of Coffin-Siris syndrome caused by a novel variant in SMARCB1
Kimihiko Oishi 1 ，Lisa Karger 1 ，Noriko Miyake 2 ，Lakshmi Mehta 1 ，Naomichi Matsumoto 2
1:Pediatrics, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, USA、2:Human Genetics, Yokohama City University
Graduate School of Medicine
Coffin-Siris syndrome (CSS) is a rare genetic disorder with core features including, microcephaly, short fifth digits with
hypoplastic nails, hypotonia, feeding difficulties, coarse facial features and intellectual disabilities. Whole exome sequencing
(WES) has demonstrated mutations in BAF complex genes in CSS. Due to its genetic heterogeneity and a wide variety
of clinical symptoms, diagnosis of CSS and identification of disease-causing mutations is challenging. We report an infant
born at full term with prenatally diagnosed IUGR to non-consanguineous parents. He was first evaluated at birth for
prenatal growth deficiency, hypotonia, microcephaly and dysmorphic features including low-set ears, contracted fifth digits
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with hypoplastic nails, hypoplasia of distal phalanx, bilateral inguinal hernia and undescended testes. He later developed
coarse facial features prompting the diagnosis of CSS. His clinical course during infancy was complicated by feeding difficulties,
necrotizing enterocolitis and intestinal malrotation, which required Ladd’s procedure at the age of 2 months. Developmental
delays were severe. He also had episodes of pneumonia and urinary tract infection. At the age of 26 months, he developed
subacute bowel obstruction, and died of septic shock. To confirm the clinical diagnosis, we performed WES using genomic
DNA from the patient and his parents that identified a de novo heterozygous variant, c.1060A>G:p.K354E, in exon 8 of
the SMARCB1 gene, which encodes a subunit of the BAF complex proteins with roles including chromatin remodeling. The
affected amino acid, lysine, is located in a mutation hot spot in SMARCB1 and is highly conserved between species, suggesting
this variant is disease-causing. SMARCB1 mutations account for less than 10% of cases of CSS. This patient illustrates many
of the common findings of CSS, with the more severe disease course associated with SMARCB1 mutations and with the
unusual complication of intestinal malrotation.
Tue(3)-O18-6
Broadening the phenotypic spectrum of ANKRD11 -related syndrome [S1] [S1] 62 characters <255
characters
Satoko Miyatake 1 ，Nobuhiko Okamoto 2 ，Zornitza Stark 3 ，Yoshinori Tsurusaki 1,4
，Mitsuko Nakashima 1 ，
Hirotomo Saitsu 1 ，Noriko Miyake 1 ，Akira Ohtake 5 ，Naomichi Matsumoto 1
1:Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan、2:Department of Medical Genetics,

Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan、3:Victorian Clinical Genetics Service, Murdoch
Childrens Research Institute, Victoria, Australia、4:Kanagawa Childrens’s Medical Center, Clinical Research Institute, Yokohama, Japan、
5:Department of Pediatrics, Faculty of Medicine, Saitama Medical University, Saitama, Japan
KBG syndrome is one of intellectual disability/multiple congenital anomaly syndromes, following autosomal dominant in-
heritance. KBG syndrome is characterized by developmental delay with various neurological involvements, macrodontia of
the upper central incisors, characteristic facial dysmorphism, and skeletal anomalies. Mutations in ANKRD11 cause this
syndrome. Here we present five individuals from four pedigrees with ANKRD11 mutations identified by whole exome se-
quencing. Four of the five were apparently affected and admitted to the clinic, given the clinical diagnosis which varied:
typical KBG syndrome, Coffin-Siris Syndrome (CSS) in two individuals, intellectual disability with infantile spasm. Clinical
re-evaluation revealed that three of the five individuals with ANKRD11 mutation fulfilled the diagnostic criteria for KBG
syndrome. Delayed bone age, macrodontia and speech delay were frequently observed along with round/triangular face and
hypertelorism. In patients suspected as CSS, known features for CSS such as brachy-clinodactyly of the 5th finger, sandal gap,
coarse face, upturned nose with broad base, wide mouth, synophrys and long eyelashes were observed. Lipoma of the corpus
callosum was identified in a patient by brain MRI, which might be a previously unknown complication of KBG syndrome.
This study revealed the broader phenotype of ANKRD11 -related syndrome, implying that patients with this syndrome might
exist in the wide spectrum of intellectual disability.
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Tue., April 05, 2016 15:40-17:10 Room B-1 (2F)
Chair：Susan H. Blanton（Dr. John T. Macdonald Department of Human Genetics, University of Miami, USA）
Chair ：Hiroki Kurahashi（Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health
Tue(3)-O19-1
An unique case of a mosaic genome-wide uniparental isodisomy in a newborn with Beckwith-Wiedemann
syndrome
Lars T. van der Veken 1 ，PFR Hochstenbach 1 ，A.A. Verrijn Stuart 2 ，J.C. Giltay 1 ，S.M.J. Hopman 1
1:Dept of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands, Netherlands、2:Dept. of Endocrinology, University Medical
Center Utrecht, Utrecht, The Netherlands
Mosaicism for a cell line in which all chromosome pairs consists of two identical copies derived from only one of the parents,
a so called genome-wide uniparental isodisomy (gwUPiD) is a rare phenomenon.
We report on a newborn presenting with clinical characteristics of Beckwith-Wiedemann syndrome (BWS), birth weight 2610g
(~ P80), facial dysmorphisms including ear lobe creases and nevus flammeus, umbilical hernia, diastastis recti, hepatomegaly

and hypoglycemia due to hyperinsulinism.
Beckwith Wiedemann syndrome (OMIM#130650) is characterized by prenatal and postnatal overgrowth, hemihyperplasia,
macroglossia and an increased frequency of embryonic tumors. In 60-70% of the patients, an epigenetic error at either the
H19DMR (imprinting control region, ICR1) or KvDMR (ICR2), controlling the appropriate allelic expression of the paternal
IGF2 and maternal CDKN1C genes, causes the clinical phenotype. In 10-15% of cases, the cause is presence of two paternally
derived copies of chromosome region 11p15, a so called paternal uniparental disomy (UPD) 11p15. A small percentage of
cases are caused by maternal translocations/inversions or paternal duplications (2-3%) or mutation in CDKN1C (5-7%).
To confirm clinical diagnosis, a methylation test was performed which showed hypermethylation of H19DMR, corresponding
to a paternal UPD 11p. To exclude a chromosomal rearrangement, karyotyping and SNP-array analysis (Illumina CytoSNP-
850k) were performed on DNA isolated from peripheral blood. SNP-array showed a gwUPiD in a high percentage of cells
(>95%). No additional clinically relevant copy number alterations were observed and karyotyping showed a normal female
karyotype. Since only mosaicism for gwUPiD can be compatible with life we decided to perform additional SNP-array analysis
on saliva derived DNA, which showed normal biparental contribution without any indication for the presence of gwUPiD cells.
In conclusion, we present a rare case of BWS in a newborn caused by mosaic gwUPiD.
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Tue(3)-O19-2
The comprehensive genetic analysis of congenital anomalies of the kidney and urinary tract (CAKUT)
in Japan
Naoya Morisada 1,2 ，Akemi Shono 2 ，Mariko Taniguchi-Ikeda 2 ，Kandai Nozu 2 ，Koichi Kamei 3 ，Kenji Ishikura 3 ，
Shuichi Ito 4 ，Ryojiro Tanaka 5 ，Hisahide Nishio 1 ，Kazumoto Iijima 2
1:Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Japan、2:Department
of Pediatrics, Kobe University Graduate School of Medicine、3:Division of Nephrology and Rheumatology, National Center for Child Health
and Development、4:Department of Pediatrics, Yokohama City University Graduate School of Medicine、5:Department of Nephrology,
Hyogo Prefectural Kobe Children’s Hospital
Purpose: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of end-stage renal
disease in childhood over the world. More than 20 genes associated with CAKUT so far have been reported, the comprehensive
analysis method has, however, not yet been established. Methods: This study was approved by the Institutional Review Board
of Kobe University Graduate School of Medicine, and samples and clinical data were collected from patients with CAKUT and
nephronophthisis related to ciliopathy (NPHP-RC), which is difficult to be distinguished from CAKUT clinically. Genomic
DNAs were extracted from patient-derived peripheral blood mononuclear cells and were used in the following experiments:
direct sequencing, multiplex ligation-dependent probe amplification (MLPA) analysis, array comparative genome hybridization
(aCGH) analysis and/or next-generation sequencing (NGS). Results: We examined 281 patients of 254 families, resulting in
124 patients of 112 families were non-syndromic CAKUT (NSC) and 157 patients of 138 families were syndromic CAKUT
(SC). We identified the responsible genes in 86 patients from 69 families, and of which detection rates in NSC and SC families
were 15.2% and 37.7%, respectively. The most common responsible genes found in this cohort were PAX2 and EYA1 (13

families each), and the following responsible genes were also detected such as HNF1B, NPHP1 , OFD1 , WDR19 , CHD7,
UMOD, RET, EP300 and SALL1 . aCGH which is useful to reveal the responsible chromosomal lesion allowed detecting
copy number variations such as 22q11.2 microdeletion, 16q microdeletion and 17q microduplication in 10 patients of CAKUT.
Furthermore, some responsible genes such as GATA3 , SDCCAG8 and WDR35 were identified by using NGS. Conclusions:
This is the first nation-wide genetic study for CAKUT and NPHP-RC in Japan, leading to the establishment of the screening
platform for CAKUT based on the comprehensive genetic analysis.
Tue(3)-O19-3
MOLECULAR DIAGNOSIS OF RWANDAN CHILDREN WITH UNEXPLAINED INTELLECTUAL DIS-
ABILITY/NEURODEVELOPMENTAL DELAY BY a-CGH AND WHOLE EXOME SEQUENCING
Leon Mutesa 1 ，Annette Uwineza 1,2
，Jean Hubert Caberg 2 ，Vincent Bours 2
1:Human Genetics, University of Rwanda, Rwanda、2:Human Genetics, University of Liege, Belgium
Intellectual disability (ID) is described by significant limitations in both intellectual functioning and adaptive behavior that
begin before the age of 18 years. The present study aimed at analyzing the potential pathogenic genomic imbalance in
Rwandan children with unexplained intellectual disability (ID) and/or developmental delay (DD) and its association with
phenotypes.
Array CGH was performed in 50 rwandan patients with ID/DD associated with multiple congenital anomalies (MCA).
Furthermore, whole exome sequencing using Hiseq2000 was performed in three families: two consanguineous and one non-
consanguineous. Homozygosity mapping previously performed in consanguineous families, allowed to identify large regions of
loss of heterozygoty.
G-band karyotyping of peripheral blood cells showed no abnormalities in the 50 children. The results of the array-CGH
revealed that 13 patients (26%) genomic CNVs. Six patients had CNVs associated with known syndromes including William-
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Beuren syndrome, deletion 22q11.21, duplication 7q23.11, deletion 8p23.1, and deletion 17q21.31; whereas 7 patients presented
rare genomic imbalances. The whole exome sequencing allowed identifying mutation in the PEX13 gene responsible of a mild
peroxisomal biogenesis disorder in a consanguineous family and a dominant mutation in EFTUD2 gene responsible of the
mandibulofacial dysostosis syndrome Guion-Almeida type (MFDGA) in another family.
This research highlights the contribution of genetic factors in the etiology of DD/IDD and MCA, especially the implication
of chromosomal abnormalities with an array-CGH detection high rate of 26%. The WES showed a great clinical utility in
diagnosis of ultra-rare neurodevelopmental diseases. As Africa, is still facing the challenge that there are no available data
about genomic studies it seems possible that the identified novel variants could be commonly frequent in that population.
Tue(3)-O19-4
Screening of copy number variants in 450 Japanese subjects presenting with intellectual disability (ID)
and multiple congenital anomalies (MCA) by SNP array unveiling rare small variants and PPFIA2 as a
novel candidate gene for ID
Daniela T. Uehara 1 ，Shin Hayashi 1,2,3
，Yoshio Makita 4 ，Akira Hata 5 ，Issei Imoto 6 ，Johji Inazawa 1,2,7
1:Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Japan、2:Hard Tissue Genome
Research Center, Tokyo Medical and Dental University, Tokyo, Japan、3:Department of Neurobiology, Yale University School of Medicine,
New Haven, Connecticut, USA、4:Education Center, Asahikawa Medical College, Asahikawa, Japan、5:Department of Public Health, Chiba
University Graduate School of Medicine, Chiba, Japan、6:Department of Human Genetics, Institute of Biomedical Sciences, Tokushima

University Graduate School, Tokushima, Japan、7:Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan
Intellectual disability (ID) is a heterogeneous condition affecting 1-3% of the population, often associated with other clinical
findings referred to as multiple congenital anomalies (MCA). The genetic cause remains largely unknown for a significant
proportion of the cases. With the aim of identifying the genetic factors behind those conditions in the Japanese population,
we have investigated 645 subjects presenting with ID/MCA using multiple types of microarrays. First, we performed a
two-stage screening using two in-house bacterial artificial chromosome (BAC)-based arrays, which allowed the identification
of pathogenic copy number variants (CNVs) in 133 cases (20.6%). Next, we performed a third screening in 450 negative
cases using a single nucleotide polymorphism (SNP) arrays platform to identify causative CNVs undetected in the previous
screenings. Rare pathogenic CNVs were found in 22 subjects (4.9%), in which 19 CNVs were located in regions where clinical
significance had been previously established. Among the 22 cases, we highlight a de novo heterozygous deletion revealing a
novel candidate gene, PPFIA2 , to explain ID. The deletion has an estimated size of 186 kb and is in-frame, encompassing
three exons of PPFIA2 , a region where benign variants have not been described so far. PPFIA2 , or Liprin-α 2, is solely
expressed in brain and interacts with the MALS-CASK-Mint1 complex in the prenasyptic zone. This interaction occurs
through the direct binding of PPFIA2 to CASK, a known X-linked ID gene whose heterozygous aberrations are known to
cause ID and microcephaly with pontine and cerebellar hypoplasia in females. Analysis of copy-neutral loss of heterozygosity
(CNLOH) detected one case in which the CNLOH regions seem to be significant. The SNP array detected a modest fraction
of small causative CNVs, which is explained by the fact that the majority of causative CNVs have larger sizes, and those had
been mostly identified in the two previous screenings.
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Tue(3)-O19-5
Family-based association analysis of whole exome sequencing data identifies evidence for major role of
focal adhesion pathway
1,2
Susan H. Blanton ，Steven Lang 2 ，Paul Dillingham 2 ，Jacqueline T. Hecht 3
1:Department of Human Genetics, University of Miami, USA、2:John P. Hussman Institute for Human Genomics, University of Miami、
3:University of Texas Health Medical School and School of Dentistry
Nonsyndromic cleft lip/palate (NSCLP) is a common birth defect, with a birth prevalence of approximately 1/1000. Family
and twin studies provide strong evidence for a genetic component to NSCLP. Empiric recurrence risk estimates are consistent
with multifactorial inheritance and a sex influenced threshold. This suggests that the etiology involves multiple genes in
an individual interacting with the environment. Moreover, it is likely that that the genetic risk profile varies even within
families. Association studies have identified several candidate pathways, including those involving HOX and WNT genes. We
conducted whole exome sequencing (WES) on 35 of our multiplex nonHispanic White families that contained 2-6 affected
individuals. Rather than focusing on individual variants within families, we took a global approach and employed a gene based
association analysis using F-SKAT including sex as a covariate. F-SKAT is designed for association studies of dichotomous
phenotypes in families under a generalized linear mixed model. Several genes met genome-wide significance (p<2.2E-06),
including LRP6, a candidate gene identified in our zebrafish studies. KEGG pathway analysis of genes with p<0.05 using
Webgestalt identified the focal adhesion pathway as the most significant pathway (3.84E-09). This is a biologically plausible
pathway which interacts directly with other pathways that contain candidate genes from our other studies, e.g. the Wnt
signaling pathway.

Tue(3)-O19-6
Clinical utility of next generation sequencing for undiagnosed syndromic disorder in pediatric patients
with short stature or overgrowth
Yoo-Mi Kim 1 ，Yun-Jin Lee 1 ，Jae Hong Park 1 ，Hyoung Doo Lee 1 ，Chong Kun Cheon 1 ，Su-Young Kim 1 ，
Gu-Hwan Kim 2 ，Han-Wook Yoo 2 ，Eun Hae Cho 3 ，Ja-Hyun Jang 3
1:pediatrics, Pusan National University Children’s hospital, Korea, South、2:Medical Genetics Center, Asan Medical Center, University of
Ulsan College of Medicine, Seoul, Korea、3:Green Cross Laboratories, Green Corss Genome
Purpose: Next generation sequencing is effective for multiple gene screening. This study was for detecting causative gene in
Korean pediatric patients with short stature or overgrowth using exome sequencing. Methods: The study included 12 patients
with short stature and one patient showing overgrowth from 11 unrelated families. In short stature group, the mean height
SDS was -3.1 SDS and five patients were born with small for gestational age. All of them were failed to detect genetic cause
using single gene sequencing or karyotyping. Informed consent was obtained from their parents. Diagnostic exome sequencing
(DES) was performed using Nextseq (illumina) and trusight panel capturing 4813 genes and 62,000 exons. Clinical features,
laboratory and radiologic finding, and neurodevelopmental state were reviewed, respectively.Results: We identified a genetic
cause of short stature in six patients and a one patient with overgrowth and hypotonia using DES. Two patients suspected with
Noonan syndrome were diagnosed with Coffin-Lowry syndrome and trichorhinophalangeal (TRP) syndrome, respectively. A
Coffin-Lowry syndrome patient had also congenital glaucoma and genetic testing revealed not only a p.Arg112* of RPS6KA3
but also compound heterozygote mutations of CYP1B1 for congenital glaucoma. A TRP syndrome patient had a novel
mutation p.Lys779Glufs*26 of TRPS1 . Two siblings showing severe short stature, senile face, protosis, brachydactyly, and
recurrent hepatic failure had compound heterozygote mutations for novel splicing and p.R1914H of NBAS. Other two siblings
with microotia and dysmorphic face were diagnosed with Meier-Gorlin syndrome and had compound heterozygote mutations
for novel splicing and p.Arg462Gln of CDT1 . Conclusions: We identified five different diseases from seven patients of 11
families (overall detection rate: 45.5%) using DES. Our data contribute to a better understanding for the genetic causes of
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growth disorder and DES application in pediatrics.

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Tue., April 05, 2016 13:50-15:20 Room B-2 (2F)
Chair：Guillaume Lettre（Department of Medicine, Montreal Heart Institute and Université de Montréal, Canada）
Chair：Toshihiro Tanaka（Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental
Tue(3)-O20-1
Imputation analysis using reference panel of 1,070 Japanese individuals (1KJPN) and in silico / in vitro
functional analyses identified functional variants for primary biliary cirrhosis (PBC) susceptibility
Yuki Hitomi 1,11 ，Kaname Kojima 2,3,11 ，Minae Kawashima 1,4 ，Yosuke Kawai 2,3 ，Nao Nishida 1,5
，Yoshihiro Aiba 6 ，
Michio Yasunami 7 ，Masao Nagasaki 2,3,8 ，Minoru Nakamura 6,9,10 ，Katsushi Tokunaga 1
1:Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Japan、2:Department of Integrative Genomics,
Tohoku Medical Megabank Organization, Tohoku University、3:Graduate School of Medicine, Tohoku University、4:Japan Science and
Technology Agency (JST)、5:The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine、6:Clin-
ical Research Center, National Hospital Organization, Nagasaki Medical Center、7:Department of Clinical Medicine, Institute of Tropical
Medicine, Nagasaki University、8:Graduate School of Information Sciences, Tohoku University、9:Department of Hepatology, Nagasaki Uni-
versity Graduate School of Biomedical Sciences、10:Headquarters of PBC Research in NHOSLJ, Clinical Research Center, National Hospital
Organization Nagasaki Medical Center、11:These authors contributed equally to this work
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease caused by autoimmune destruction of intrahepatic small
bile ducts, eventually leading to liver cirrhosis and hepatic failure. POU2AF1 , IKZF3 , NFKB1 , and two other genes were

recently identified as the novel susceptibility genes for Japanese PBC patients by our genome-wide association study (GWAS).
However, causal variants in these genes and their molecular mechanisms for the disease - susceptibility to PBC have not been
clarified.
In the present study, in order to identify the causal variants in each of PBC susceptibility genes, SNP imputation analysis
was carried out using reference panel of 1,070 Japanese individuals (1KJPN) and genotype data from our previous GWAS
(Affymetrix Axiom ASI 1 array). Among the SNPs which showed a genome-wide significant association (P < 5.0 x 10-8 )
by the SNP imputation analysis, candidate functional SNPs that potentially regulate the gene expression efficiencies were
selected by in silico analysis based on Regulome DB. Causal variants for disease susceptibility were identified by in vitro
functional analysis (Luciferase assay and EMSA) using human bile duct cell line HuCCT1 and human T cell line Jurkat.
Additionally, e-QTL data from GTEX-portal database supported the regulations of expression efficiencies by these functional
variants (P < 1.0 x 10-4 ).
These results suggested that imputation analysis and in silico / in vitro functional analysis could identify causal variants of
disease susceptibility genes detected by GWAS. This study illustrated a systematic methodology to identify primary disease
causal variants from a pool of suggestive SNP associations, and this may eventually contribute to novel diagnostic and
therapeutic methods for PBC.
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Tue(3)-O20-2
The Latent Low Rank Model to Colocalize Genetic Risk Variants in Multiple GWAS
Jin Liu 1 ，Can Yang 2
1:Center of Quantitative Medicine, Duke NUS Graduate Medical School, Singapore、2:Hong Kong Baptist University
To date, more than one thousand genome-wide association studies (GWAS) have been completely. Due to the polygenic
architecture of complex diseases, identification of risk single-nucleotide polymorphism (SNP) markers remains challenging.
Until recently, most of conventional statistical methods only investigate one GWAS data set of one trait/disease at a time.
To model the genetic correlation among complex diseases (formally known as "pleiotropy”), GPA [Chung et al., 2014] and
EPS used ｀｀ four-group model" for two GWAS. The model complexity of parameter space grows exponentially as the
number of GWAS increases. Here, we proposed LLR, the Latent Low Rank model to jointly analyze multiple GWAS. LLR
uses a latent variable Z to indicate the null and non-null states as a ｀｀ two-group model" for each trait meanwhile the
prior probability of the latent variable Z is modulated by a low-rank matrix X which is constrained by the nuclear norm.
To estimate parameters in the corresponding penalized complete-data log-likelihood of LLR, we showed the penalized EM
algorithm based on EM and accelerated proximal gradient (APG) algorithms as the benchmark. To improve its efficiency,
we developed a extreme efficient path algorithm — EM boosting. EM boosting algorithm updates parameters in the M-step
using the forward stagewise procedure [Tibshirani,2014] and is capable of building up a whole path efficiently. We compared
the similarity of the two algorithms using a synthetic dataset and used synthetic datasets to show that LLR greatly improved
the power of identification of risk markers by extensive simulation study. We applied LLR to jointly analyze p-values for 19

traits.
Tue(3)-O20-3
Leveraging Characteristics of Common Genetic Variants to Improve Power of Gene Discovery in Genome-
wide Association Study of Neuroticism
Min-Tzu Lo 1 ，Yunpeng Wang 1,2 ，Chun-Chieh Fan 1,3 ，Olav Smeland 2 ，Aree Witoelar 2 ，Andrew Schork 1,3 ，
Wesley K. Thompson 5 ，23andMe co-authors 7 ，Srdjan Djurovic 2,4 ，Ole A. Andreassen 2 ，Anders M. Dale 1,5,6 ，
Chi-Hua Chen 1
1:Department of Radiology, Multimodal Imaging Laboratory, University of California, San Diego, USA、2:NORMENT, KG Jebsen Centre
for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University
Hospital, Oslo, Norway、3:Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA、4:Department of
Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway、5:Department of Psychiatry, University of California,
San Diego, La Jolla, CA, USA、6:Department of Neurosciences, University of California San Diego, CA, USA、7:23andMe
Neuroticism is one of Big Five domains for personality trait, characterized by emotional instability and is associated with
various mental and physical illnesses suggesting its great significance for the public health. Given neuroticism with prediction
ability to psychiatric disorders and comorbidity among them, it implied that the genetic mechanisms linking neuroticism to
those disorders might be complex and multiple. Neuroticism is heritable and its heritability has been estimated to range from
25% to 56% based on twin and family studies. However, based on large-scale genome-wide association studies (GWAS), few
significant genes are reported for neuroticism. It has been shown that SNPs are not exchangeable and certain genic categories
like 5’UTR and exon have greater genetic effects. We propose to use prior-information approach to increase power to detect
common genetic variants associated with neuroticism by incorporating characteristics of single nucleotide polymorphisms
(SNPs) including genic annotations, total linkage disequilibrium scores and heterozygosity. Based on SNP characteristics, we
used a logistic regression model to construct relative enrichment score (RES) for each SNP. Using stratified Q-Q plots, SNPs
stratified by RES showed differential enrichment levels reflected by greater departure from the null as RES increased. We
then estimated false discovery rate (FDR) for each SNP by fitting the Q-Q curve in each RES stratum using a mixture of
Weibull and chi-square distributions. Applying this approach to the GWAS summary statistics of neuroticism in the 23andMe
cohort, a total of 32 independent significant SNPs were identified, compared with 12 independent significant SNPs identified
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using unstratified FDR method without inclusion of any prior information (FDR < 0.05). In addition, GWAS (with threshold
of p-value < 5*10-8 ) only detected 6 independent significant SNPs. These findings provide new insight into the molecular
biology of neuroticism.
Tue(3)-O20-4
Dominant Genetic Variation and Missing Heritability for Human Complex Traits - Insights from Twin
versus Genome-wide Common SNP Models
Xu Chen 1 ，Ralf Kuja-Halkola 1 ，Iffat Rahman 2 ，Johannes Arpegard 3,4 ，Alexander Viktorin 1 ，Robert Karlsson 1 ，
Sara Hagg 1 ，Per Svensson 3,4 ，Nancy L Pedersen 1 ，Patrik K.E Magnusson 1
1:Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden、2:Institute of Environmental Medicine, Karolinska
Institutet、3:Department of Medicine-Solna, Karolinska Institutet、4:Department of Emergency Medicine, Karolinska University Hospital
Objective: To further illuminate the potential role of dominant genetic variation in the “missing heritability” debate.
Methods: We investigated the additive (narrow-sense heritability, h2) and dominant (δ 2) genetic variance for eighteen
human complex traits. Within the same study base (10682 Swedish twins), we calculated and compared the estimates
from classic twin-based structural equation model with SNP-based genomic-relatedness-matrix restricted maximum likelihood
[GREML(d)] method.

Results: Contributions of δ 2 were evident for fourteen traits in twin models (average δ 2twin=0.25, range 0.14 to 0.49),
two of which also displayed significant δ 2 in the GREMLd analyses (triglycerides δ 2SNP=0.28 and waist circumference δ
2SNP=0.19). On average, the proportion of h2SNP/h2twin was 70% for ADE-fitted traits (for which the best fitting model
included additive, dominant genetic and unique environmental components), and 31% for AE-fitted traits (for which the
best fitting model included additive genetic and unique environmental components). Independent evidence for contribution
from shared environment, also in ADE fitted traits was obtained from self-reported within-pair contact frequency and age at
separation.
Conclusions: Despite additive genetics appear to constitute the bulk of genetic influences for most complex traits; dominant
genetic variation may often be masked by shared environment in twin and family studies, and may therefore have a more
prominent role than what family based estimates often suggest. The risk of erroneously attributing all inherited genetic
influences (additive and dominant) to the h2 in too small twin studies may also lead to exaggerated“missing heritability”
(the proportion of h2 that remains unexplained by SNPs).
Tue(3)-O20-5
Withdrawn

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Tue(3)-O20-6
The role of rare and low-frequency coding variants in adult height, a classic polygenic human trait
Guillaume Lettre 1 ，Eirini Marouli 2 ，Mariaelisa Graff 3 ，Carolina Medina-Gomez 4 ，Ken Sin Lo 1 ，Claudia Schurmann 5 ，
Kevin Lu 5 ，Nancy Heard-Costa 6 ，Joel N. Hirschhorn 7,8 ，Ruth J.F. Loos 5 ，Timothy M. Frayling 9 ，
Fernando Rivadeneira 4 ，Panos Deloukas 2 ，GIANT Consortium
1:Medicine, Universite de Montreal, Montreal. Canada、2:Queen Mary University of London, London、3:University of North Carolina at
Chapel Hill, Chapel Hill, USA、4:Erasmus Medical Center, Rotterdam, The Netherlands、5:Icahn School of Medicine at Mount Sinai, New
York, USA、6:Boston University School of Medicine, Boston, USA、7:Broad Institute, Cambridge, USA、8:Childrens Hospital Boston,
Boston, USA、9:University of Exeter, Exeter, UK
Human height is a highly heritable, polygenic trait. GWAS have identified 423 loci (697 SNPs) associated with adult height
variation. The majority of these variants are common (MAF>5%). To what extent rare (MAF<1%) and low-frequency
(1<MAF≤ 5%) variants also influence adult height remains an open question. To empirically explore what role rare/low-
frequency variants may play in the architecture of complex human traits, we used an exome array to test the association
between ~ 245,000 coding variants and adult height in >450,000 individuals. We combined single-variant tests and conditional
analyses to identify 561 variants that are independently associated with height (P<2x10-7 ), of which 76 fall within new loci.
In an independent sample of >58,000 individuals, we strongly replicated these results (P<2.2x10-16 for concordance of effect
sizes). We found 31 rare and 56 low-frequency coding height variants. We observed the largest effect sizes for two rare missense
variants in CRISPLD2 (MAF=0.08%, P=2.9x10-14 ) and IHH (MAF=0.08%, P=1.3x10-14 ), where heterozygous carriers were
~ 2 cm shorter, compared to common variants that had mean effect sizes 10-times smaller. Focusing on non-synonymous
variants with MAF <5%, we used gene-based tests to identify12 genes at known (FLNB, CCDC3 , B4GALNT3 ) and novel loci

(CSAD, NOX4 , UGGT2 ), with robust statistical evidence for multiple variants contributing to the association signal. NOX4
encodes an enzyme that produces reactive oxygen species, a biological pathway that has not been linked to human growth.
Interestingly, Nox4 -/- mice displayed higher bone density and reduced numbers of osteoclasts. In conclusion, our findings
confirmed the hypothesis that a large number of rare and low-frequency coding variants contribute to adult height. They also
imply that studies with hundreds of thousands of individuals are key to discover rare/low-frequency variants implicated in
other complex human diseases and traits.
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Tue., April 05, 2016 15:40-17:10 Room B-2 (2F)
Chair：Swapan K. Nath（Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, USA）
Chair ：Katsushi Tokunaga（Department of Human Genetics, University of Tokyo, Graduate School of Medicine, Japan）
Tue(3)-O21-1
Gene-based analysis of regulatory variants identifies P2RY14 as a new asthma risk gene
Manuel AR Ferreira 1 ，Rhiannon Werder 2 ，Melanie Matheson 3 ，Jennie Hui 4,10 ，Joyce Tung 5 ，Svetlana Baltic 6 ，
Peter Le Souef 7 ，Joseph Powell 8 ，Grant Montgomery 1 ，Colin Robertson 9 ，Alan James 4,10,11,12 ，Philip Thompson 6 ，
Nicholas Martin 1 ，John Hopper 3 ，David Hinds 5 ，Simon Phipps 2 ，Australian Asthma Genetics Consortium
1:QIMR Berghofer Medical Research Institute, Australia、2:School of Biomedical Sciences, University of Queensland, Brisbane, Australia、
3:Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia、4:PathWest Laboratory Medicine
of Western Australia (WA), Nedlands, Australia、5:23andMe, Inc., Mountain View, California, USA、6:Institute for Respiratory Health,
University of WA, Perth, Australia、7:School of Paediatrics and Child Health, Princess Margaret Hospital for Children, Perth, Australia、
8:The Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia、9:Respiratory Medicine, Murdoch Childrens
Research Institute, Melbourne, Australia、10:Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth,
Australia、11:School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia、12:Department of Pulmonary
Physiology and Sleep Medicine, West Australian Sleep Disorders Research Institute, Nedlands, Australia
Background. Hundreds of genetic variants are thought to contribute to asthma risk through modulation of gene expression.
Most of these risk genes remain unknown.

Aims. To (1) develop a gene-based approach that tests the association between a disease and variants that influence gene
expression (eSNPs), and that is applicable to GWAS summary statistics; and (2) use this approach to identify novel asthma
risk genes.
Methods. We collated results from GWAS of gene expression to identify a set of independent eSNPs for each of 16,098
genes. A gene-based test was then developed to aggregate observed association results across independent eSNPs of a gene.
Simulations that take into account linkage disequilibrium between SNPs were used to correct the gene-based P-value for
multiple gene testing. This approach, which is implemented in the freely available software EUGENE, was applied to a
published asthma GWAS (N=20,776).
Results. After accounting for multiple testing, 30 genes had a significant association with asthma. For most, the gene-based
test was orders of magnitude more significant than the single most asthma-associated eSNP in that gene. Of these 30 genes,
five were not located near established risk variants for asthma and so represent putative novel risk genes. These included
P2RY14, a G coupled-protein receptor activated by UDP-glucose, for which the association replicated in an independent
study. P2RY14 expression in blood was (i) increased in asthmatics; and (ii) associated with worse lung function in obese
asthmatics, who are predicted to have high UDP-glucose levels. In a mouse model of asthma, P2RY14 was expressed in airway
epithelial cells and up-regulated after allergen challenge. Mice challenged with UDP-glucose had increased IL-33 levels and
eosinophil numbers in bronchoalveolar lavage fluid.
Conclusion. Using a novel gene-based approach followed by functional studies, we identified P2RY14 as a risk gene that might
underlie obesity-associated asthma.
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Tue(3)-O21-2
Association analysis of the HLA-DRB1 locus in Immune-mediated necrotizing myopathy
Yuko Ohnuki 1 ，Shingo Suzuki 1 ，Atsuko Shigenari 1 ，Shigeaki Suzuki 2 ，Ichizo Nishino 3 ，Takashi Shiina 1
1:Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine,
Japan、2:Department of Neurology, Keio University School of Medicine、3:Department of Neuromuscular Research, National Institute of
Neuroscience, National Center of Neurology and Psychiatry
Immune-mediated necrotizing myopathy (IMNM) is a newly recognized subgroup of inflammatory myopathies, which also
includes polymyositis, dermatomyositis and sporadic inclusion body myositis. IMNM is characterized by the subacute onset
of symmetrical proximal limb weakness clinically and distinguished from the other myopathies by the absence of prominent
inflammatory infiltrates in histopathologically. The diagnosis of IMNM basically relies on the muscle biopsy. In previous
studies, anti-SRP (signal recognition particle) antibody was the most frequent etiology of IMNM and anti-HMGCR (3-
hydroxy-3-methylglutaryl-coenzyme A reductase) antibody which HMGCR is the pharmacologic target of the statins was the
second. These two are associated with IMNM but not specific. It is yearned to detect new indicators for definite diagnosis and
clarify the pathogenesis of IMNM. Many autoimmune diseases are genetically associated with particular alleles of the human
leukocyte antigen (HLA) loci, but association between IMNM and HLA alleles is unknown. In this study, we genotyped the
HLA-DRB1 locus in IMNM patients and elucidated genetically association of HLA-DRB1 polymorphisms and IMNM. The
HLA-DRB1 locus was genotyped by the sequence based typing (SBT) or the PCR-SSOP method using 53 IMNM patients
and 400 healthy controls. As a consequence, among the 106 alleles detected, three DRB1 types, DR4 (OR=4.39, P=3.37E-05),
DR8 (OR=2.69, P=3.98E-04) and DR14 (OR=1.93, P=4.80E-02), were significantly associated with IMNM by Pearson’s chi-

square and Fisher exact tests after Bonferroni correction. Of them, DR4 was significantly lower frequency in IMNM patients
than controls. This tendency shows the exact opposite of DR4 associated autoimmune diseases with inflammation such as
rheumatoid arthritis and Crohn disease, suggesting that IMNM has a unique immune response to generate autoantibodies.
Tue(3)-O21-3
The high comorbidity of inflammatory bowel disease in primary sclerosing cholangitis is only partly
explained by shared genetic risk factors
Sun-Gou Ji 1 ，Brian D Juran 2 ，Konstantinos N Lazaridis 2 ，Carl A Anderson 1 ，International PSC Study Group
1:Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK、2:Center for Basic Research in Digestive Diseases,
Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America
Primary sclerosing cholangitis (PSC) is an inflammatory disorder of the bile ducts and approximately 75% of patients have
comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC to date, using
a combined discovery and replication cohort of 4,796 PSC cases and 19,955 population controls, and identified four novel
genome-wide significant loci. The most associated SNP in the UBASH3A locus lies within the splice consensus sequence of
the 10th intron of UBASH3A and is a known eQTL and splice-QTL of UBASH3A. Re-analysis of the gEUVADIS RNA-seq
data showed that the PSC protective allele (C) is associated with increased expression of the 10th intron, which is predicted
to cause nonsense-mediated mRNA decay. This SNP is also significantly associated with the risk of rheumatoid arthritis and
celiac disease suggesting UBASH3A inhibition has therapeutic potential in several immune-mediated disorders. In order to
understand the genetic contribution to the high comorbidity of IBD in PSC patients, genetic comparisons were conducted
between our PSC cohort and 44,589 IBD cases and 55,747 controls ascertained by the International IBD Genetics Consortium.
These sets of analyses demonstrated that PSC is genetically more related to ulcerative colitis (UC) than Crohn’s disease
(CD). Furthermore, of the twelve loci with strong evidence of association with both PSC and IBD, at least four contain
different causal variants in the two diseases. We also show that the genome-wide genetic correlation between PSC and UC
is insufficient to explain the observed comorbidity under a liability threshold model. In summary, our study has identified
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four novel loci associated with PSC, identified a potential therapeutic target for a number of immune-mediated diseases and
shown that shared genetic risk factors alone do not explain the high comorbidity of IBD in PSC patients.
Tue(3)-O21-4
Genotyping of relapsing polychondritis for classical HLA genes identified novel susceptibility HLA alleles
and distinct genetic characteristics from other rheumatic diseases
Chikashi Terao 1,2,3,4 ，Hajime Yoshifuji 3 ，Yoshihisa Yamano 5 ，Hiroto Kojima 6 ，Kimiko Yurugi 7 ，Yasuo Miura 7 ，
Taira Maekawa 7 ，Hiroshi Handa 8 ，Koichiro Ohmura 3 ，Hiroh Saji 6 ，Tsuneyo Mimori 3 ，Fumihiko Matsuda 2
1:Division of Rheumatology, Immunology, and Allergy and Division of Genetics, Brigham and Women’s Hospital, USA、2:Center for
Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan、3:Department of Rheumatology and Clinical Immunology,
Kyoto University Graduate School of Medicine, Kyoto, Japan、4:Center for the Promotion of Interdisciplinary Education and Research,
Kyoto University, Kyoto, Japan、5:Department of Rare Diseases Research, Institute of Medical Science, St. Marianna University School of
Medicine, Kanagawa, Japan、6:HLA Laboratory, Kyoto, Japan、7:Department of Transfusion Medicine and Cell Therapy, Kyoto University
Hospital, Kyoto, Japan、8:Division of Respiratory and Infectious Diseases, Department of Internal Medicine, St. Marianna University
School of Medicine, Kanagawa, Japan
Relapsing polychondritis (RP) is a rare autoimmune disease with unknown etiology and mechanisms, characterized by sys-
temic inflammation of the cartilage. RP develops with other rheumatic diseases in some occasions. Overlapping of RP
and Behçet disease is known as MAGIC syndrome. A previous genetic study for RP in German population reported that
HLA-DRB1*04 is associated with RP, but the following genetic studies failed to replicate the finding. Uncovering the genetic
background of RP would deepen our understanding of the pathophysiology of RP and show its distinct genetic characteristics

from other rheumatic diseases.
Here, we recruited a total of 102 patients with RP and 1,000 healthy subjects for a two-staged genetic association study and
genotyped for six HLA classical loci. This study is the biggest genetic study of RP ever. We found that HLA-DRB1*16:02,
HLA-DQB1*05:02, and HLA-B*67:01, which are in linkage disequilibrium (LD) to some extent with each other, were asso-
ciated with RP (p=1.9x10-6 , 1.4x10-5 , and 0.00024, respectively). Amino acid (AA) residue at position 57 in HLA-DQB1,
the most significant position in type I diabetes mellitus, showed the strongest association among AA residues. HLA-DR4,
a known susceptibility allele in Germans, showed a suggestive association (p=0.067). We did not observe any associations
between the three HLA alleles and clinical phenotypes. Representative susceptibility HLA alleles to rheumatoid arthritis,
systemic lupus erythematosus, Behçet disease and Takayasu arteritis did not show enrichment in RP in spite of sufficient
statistical power in the current study.
In conclusion, HLA-DRB1*16:02, HLA-DQB1*05:02, and HLA-B*67:01, in LD with each other, are associated with suscep-
tibility to RP. Importance of HLA-class II loci in RP susceptibility is suggested. RP is considered to be a genetically distinct
disease from other rheumatic diseases.
Tue(3)-O21-5
Fine-mapping analysis of TNFSF15 across leprosy, Crohn’s disease and primary biliary cirrhosis
Astrid Irwanto 1 ，Yonghu Sun 4 ，Yuki Hitomi 2 ，Licht Toyooka 2 ，Hyunchul Choi 3 ，Furen Zhang 4,5
，Kyuyoung Song 3 ，
Katsushi Tokunaga 2 ，Jianjun Liu 1 ，Anand Kumar Andiappan 6 ，Olaf Rotzschke 6
1:Human Genetics, Genome Institute of Singapore, Singapore、2:Department of Human Genetics, Graduate School of Medicine, The Uni-
versity of Tokyo, Tokyo, Japan、3:Departement of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul,
Korea、4:Shandong Provincial Key Laboratory for Dermatovenereology, Jinan, China、5:Shandong Provincial Institute of Dermatology and
Venereology, Shandong Academy of Medical Sciences, Jinan, China、6:Singapore Immunology Network, Agency for Science, Technology and
Research, Singapore
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There have been multiple discoveries of disease associations within 9q32 locus, including autoimmune diseases such as Crohn’
s disease (CD) and primary biliary cirrhosis (PBC) as well as infectious disease like leprosy. This suggests a pleiotropic
effect of 9q32 on disease development, but it is still unclear which gene it affects and whether diverse disease associations are
driven by the same or different causal variants. We performed a systematic fine-mapping analysis to address this question
in three large disease datasets of leprosy (9,619 cases and 12,896 controls of Chinese), CD (1,576 cases and 3,013 controls of
Koreans) and PBC (1,594 cases and 1,529 controls of Japanese). We identified two independent genetic susceptibility variants
strongly tagged by rs6478108 and rs4979462, both with evidence surpassing genome-wide significance. Both of them play
important role in CD and leprosy, whereas only one of them influences the development of PBC. Interestingly these SNPs play
an opposite effect between leprosy and CD/PBC. Further comprehensive functional annotation of all the disease associated
SNPs within 9q32 show strong eQTL effect of rs6478109, a SNP perfectly tagged by rs6478108, on TNFSF15 expression in
whole blood, particularly monocytes and no other eQTL effects observed in the region. We also see strong evidence for the
regulatory functionality of rs6478109 and rs4979462 in a cell/tissue-specific fashion. Our study suggests a diverse function of
TNFSF15 in immunity, gastrointestinal cells and epithelial/connective tissues, and further demonstrated that high expression
of TNFSF15 provides protective effect again infection such as leprosy, but increase the risk for immune and inflammatory
diseases.
Tue(3)-O21-6
High-density genotyping of immune-related loci and follow-up genetic association study identified ten

novel SLE susceptibility genes in individuals with Asian ancestry
Swapan K. Nath 1 ，Celi Sun 1 ，Julio Molineros 1 ，Loren Looger 2 ，Xu-Jie Zhou 3 ，Kwangwoo Kim 4 ，Yukinori Okada 5 ，
Yuta Kochi 6 ，Kazuhiko Yamamoto 7 ，Nan Shen 8 ，John Harley 9 ，Kek Heng 10 ，Hong Zhang 3 ，Sang-Cheol Bae 4
1:Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, USA、2:Howard Hughes Medical Institute,
Janelia Research Campus, Ashburn, VA, USA、3:Renal Division, Peking University First Hospital, Peking University Institute of Nephrology,
Key Laboratory of Renal Disease, Beijing、4:Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul,
Korea、5:Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan、6:Laboratory for Autoim-
mune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan、7:Laboratory for Autoimmune Diseases, Center for
Integrative Medical Sciences, RIKEN, Yokohama, Japan、8:Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and
Shanghai Jiaotong University School of Medicine, Shanghai, China、9:Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA、
10:Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. To identify novel SLE
susceptibility locus and to better localize previously known SLE susceptibility loci, we conducted an ImmunoChip-based tar-
geted fine-mapping using 2,645 SLE cases and 8,541 unrelated population-matched controls from 3 discovery cohorts (Korean,
Han-Chinese and Malaysian-Chinese). We identified 578 associated regions (P<5x10-3 ), and performed an imputation-based
association followed by conditional analysis and Bayesians-based functional localization to detect most likely functional vari-
ants. We replicated 20 previously known SLE loci passing the genome-wide significance (P< 5x10-8 ). We then followed up
16 novel loci with PDiscovery-meta <5x10-5 in three replication cohorts: one Japanese, and two independent Han-Chinese from
Beijing and Shanghai. Combined analyses with 4,492 SLE cases and 12,675 controls from 6 independent cohorts, we detected
10 novel SLE loci with Pmeta < 5x10-8 , and 6 novel suggestive loci. Among the novel loci, the most significant was GTF2IRD1-
GTF2I at 7q11.23 (rs73366469, Pmeta =3.75x10-117 , OR=2.38), followed by DEF6 , IL12B, TCF7 , TERT, CD226 , PCNXL3 ,
RASGRP1, SYNGR1 and SIGLEC6 . Surprisingly, the GTF2IRD1-GTF2I signal is much stronger than human leukocyte
antigen (HLA) locus (P=2.48x10-37 , OR=1.65). We localized the most likely functional variants for each locus by analyzing
epigenetic marks and gene regulation data: e.g. alteration of conserved promoters, enhancers and transcription factor binding
sites. Ten putative variants are known to alter cis- or trans-gene expression. Enrichment analysis of cell type-specific ex-
pression highlights the importance of these loci in B- and T-cell biology. Together with previously known loci, the explained
heritability of SLE increases to 24%. Novel loci share functional and ontological characteristics with previously reported loci,
and are possible drug targets for SLE therapeutics.
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Tue., April 05, 2016 13:50-15:20 Room C-1 (1F)
Chair：Tiong Yang Tan（Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, Aus-
tralia / Department of Paediatrics, University of Melbourne, Melbourne, Australia / Department of Paediatrics and
Adolescent Medicine, University of Hong Kong, Hong Kong）
Chair ：Fuki Marie Hisama（Division of Medical Genetics, Department of Medicine, University of Washington, USA）
Tue(3)-O22-1
Novel mutations in ZNF335 broaden the phenotypic spectrum including less severe microcephaly and
survivability into childhood
Tiong Yang Tan 1,2,3 ，Maie Walsh 1,2 ，Naomi Baker 1,2,3 ，Mai Raabus 2 ，Andrew J Kornberg 3,4
，David Tickell 3,5,6
，
Natasha J Brown 1,7 ，Lavinia Gordon 2,8 ，Peter G Farlie 2,3
1:Victorian Clinical Genetics Services, Australia、2:Murdoch Childrens Research Institute, Melbourne, Australia、3:Department of
Paediatrics, University of Melbourne, Melbourne, Australia、4:Neurology Department, Royal Childrens Hospital, Parkville, Australia、
5:Ballarat Health Services, Ballarat, Australia、6:Deakin University, Melbourne, Australia、7:Department of Clinical Genetics, Austin
Health, Heidelberg, Australia、8:Australian Genome Research Facility, Walter and Eliza Hall Institute, Parkville, Australia
Microcephaly is causally heterogeneous and characterised by a head circumference (HC) <3rd centile, or >2 standard de-
viations below the mean for age, gender and ethnicity. Reduction in brain volume and intellectual deficit are usual, and
pathogenesis ranges from genetic to environmental factors affecting developmental influences on brain size. Primary autoso-

mal recessive non-syndromic microcephalies are caused by homozygous or compound heterozygous mutations in a growing
list of genes known to be important in complex cellular processes that control brain growth. ZNF335 is one such gene
identified in 2012 (PMID 23178126) as the basis of a severe primary microcephaly phenotype (MCPH10; OMIM 615095)
characterised by severe microcephaly (-9SD) and death before age 1 year. The ensuing functional characterisation identified
a link between chromatin-remodelling complex involving H3K4 methyltransferases and the known neuronal progenitor cell
master regulator REST. Only one highly consanguineous family has been reported to date. We have identified by WES novel
compound heterozygous mutations in ZNF335 in a 5-year-old boy to healthy non-consanguineous Caucasian parents, who
are carriers of one mutation each. The proband has congenital microcephaly, and at age 51/2 years, his HC is 47.5cm (1.5
cm< 3rd centile). He has global developmental delay, with absent speech and no unassisted walking. He has poor sleep, but
no seizures, abnormal respiration, dystonia or hand stereotypies. SNP microarray, Fragile X molecular analysis, metabolic
investigations, Angelman methylation studies and UBE3A sequencing were normal. Brain MRI demonstrated reduced brain
volume, but normal structures. We present mRNA data on fibroblast-derived cell lines from the proband and both parents,
demonstrating pathogenicity of the novel ZNF335 mutations. Our work highlights the finding that ZNF335 mutations can
also be associated with a milder microcephaly and survivability into childhood.
Tue(3)-O22-2
ADCY5 -Related Dyskinesia is Likely Under-recognized: Genotype-Phenotype Correlations and Broaden-
ing the Spectrum
Fuki Marie Hisama 1,4 ，Dong-Hui Chen 1 ，Jennifer R Friedman 2 ，Aurelie Meneret 3 ，Emmanuel Roze 3 ，
Thomas D Bird 1,4 ，Wendy H Raskind 1
1:Medical Genetics/Medicine, Univ of Washington, USA、2:Departments of Neurosciences and Pediatrics, University of California, San
Diego、3:Departements de Neurologie et de Genetique, Hopital de la Pitie Salpetriere、4:Department of Neurology, Univ of Washington
Introduction: In 2001, we described Familial Dyskinesia with Facial Myokymia as a novel movement disorder, and reported
a causative mutation in adenylate cyclase 5 (ADCY5 ) in 2014. Since then, we identified new cases, whose manifestations
markedly broaden the phenotypic spectrum.
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Objective: To investigate the clinical spectrum and genotype-phenotype relationship of ADCY5 -related dyskinesia in over 50
new and previously reported cases, the largest cohort to date.
Methods: We analyzed ADCY5 in patients with choreiform and/or dystonic movements by exome or targeted sequencing.
Mosaicism was identified or confirmed by allele-specific amplification.
Results: We identified pathogenic ADCY5 variants in three new families and 13 sporadic cases, which produce a mixed
hyperkinetic disorder that includes dystonia, chorea and myoclonus, often with facial involvement. The movements may be
painful and show episodic worsening on a fluctuating background. Many patients have axial hypotonia. In two unrelated
families, a p.A726T mutation causes a mild disorder of prominent facial and hand dystonia and chorea. Myokymia could
not be confirmed by EMG. Recurrent pathogenic variants p.R418W or p.R418Q produce a moderate to severe disorder with
axial hypotonia, limb hypertonia, paroxysmal nocturnal and/or diurnal dyskinesia, chorea, myoclonus, and occasional facial
dyskinesia. Somatic mosaicism appears to result in a milder phenotype, in some cases with near resolution in later adulthood.
Conclusions: ADCY5 -related dyskinesia is a childhood-onset disorder with a wide range of hyperkinetic abnormal movements.
It is likely under-recognized, as 3 unrelated families and 3 sporadic cases, one family and 8 sporadic cases, and 2 sporadic
cases were identified from three centers respectively. Genotype-specific correlations and mosaicism influence the phenotypic
variability. Recurrent mutations suggest particular functional importance of residues 418 and 726 in disease pathogenesis.

Tue(3)-O22-3
Mutations in HACE1 cause an autosomal-recessive neurodevelopmental disorder
Ronja Hollstein 1 ，David A. Perry 2 ，Lisa Nalbach 1 ，Clare V. Logan 2 ，Tim M. Strom 3,4 ，Verity L. Hartill 2,5 ，
Ian M. Carr 2 ，Georg C. Korenke 6 ，Sandeep Uppal 2 ，Mushtaq Ahmed 5 ，Thomas Wieland 4 ，Alexander F. Markham 2 ，
Christopher P. Bennett 5 ，Gabriele Gillessen-Kaesbach 7 ，Eamonn G. Sheridan 2,5 ，David T. Bonthron 2,5 ，
Frank J. Kaiser 1
1:Section for Functional Genetics at the Institute of Human Genetics, Universitaet zu Luebeck, Germany、2:Section of Genetics, School of
Medicine, University of Leeds, UK、3:Institute of Human Genetics, Technische Universitaet Muenchen, Munich, Germany、4:Institute of
Human Genetics, Helmholtz Zentrum Muenchen, Neuherberg, Germany、5:Yorkshire Regional Genetics Service, Leeds, UK、6:Zentrum fuer
Kinder- und Jugendmedizin, Neuropaediatrie, Klinikum Oldenburg, Oldenburg, Germany、7:Institut fuer Humangenetik, Universitaet zu
Luebeck, Germany
Intellectual disability (ID) is characterized by the impairment of general mental abilities associated with defects in adaptive
function. Many patients with ID exhibit additional clinical features or symptoms, such as speech delay, motor abnormalities
or epilepsy. ID affects about 2-3% of the general population and with recent advancements in genetic technology, the number
of genes known to be involved in ID is increasing rapidly. Here, we describe two families in which eight individuals displayed
a variable neurodevelopmental phenotype with ID, spasticity and abnormal gait. Because of the consanguinity in one family,
and sibling recurrences in the other, an autosomal recessive inheritance was suspected. Autozygosity mapping followed
by candidate gene sequencing and exome sequencing were used to identify loss of function mutations in HACE1 . In the
consanguineous family, a homozygous mutation p.R219* predicted a truncated HACE1 protein entirely lacking its catalytic
domain. In the other family, compound heterozygosity for nonsense mutation p.R748* and a 20-nt insertion interrupting the
catalytic HECT domain was present; Western analysis of patient cells revealed an absence of detectable HACE1 protein.
HACE1 encodes for an E3 ubiquitin ligase, which provides proteosomal degradation of its substrates by polyubiquitylation.
Known target proteins of HACE1 are small Rab- and Rho GTPases, including RAC1. Previous studies showed that mice
with constitutive active RAC1 show a similar symptoms as the patients. In addition to its E3 ligase activity, functional
investigations have indicated an E3-independent role of HACE1 in repressing the transcriptional activity of retinoic acid
receptors (RARs).
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By ongoing functional investigations, we could detect increased levels of active RAC1 protein levels and upregulation of RARb
expression in patient cells indicating alterations in E3-dependent as well as independent pathways of HACE1.
Tue(3)-O22-4
Severe CNS involvement in WWOX mutations: Description of five new cases
Amal M Alhashem 1 ，Saad Alsahwan 1 ，Fowzan S Alkuraya 2 ，Abdulla M Alhashem 1 ，Giulio Zuccoli 4 ，
Satyanarayana Gedela 3
1:Pediatrics, Prince Sultan Military Medical City, Saudi Arabia、2:King Faisal Specialist Hospital and Research Center、3:Nationwide
Children Hospital、4:Children Hospital of Pittsburgh of UPMC, University of Pittsburgh
Recently, mutations in WWOX have been identified in the setting of central nervous system (CNS) disorders, highlighting a
previously unrevealed role of this gene in the normal development and function of the CNS. In this report, we add five patients
from two seemingly unrelated families presenting with a primarily neurological phenotype. All the children were product of
consanguineous marriages. Whole exome sequencing revealed the same homozygous mutation (NM_016373.3:c.606-1G>A)
of WWOX in all five patients. All patients and carriers in the family share the same haplotype indicating the families
are in fact related to one another. The clinical presentation included progressive microcephaly, early onset of spasticity in
the first 3 months of life, intractable epilepsy, severe failure to thrive, and profound developmental delay. Retinopathy was
observed in two patients. All five patients died before their third birthday. Neuroimaging showed extensive neurodegeneration

characterized by periventricular white matter volume loss and atrophy of the corpus callosum. Additional degeneration
selectively affecting the mediodorsal nucleus of the thalamus was observed in one patient. Our findings in five new patients
affected by WWOX mutation with early infantile phenotype confirm the features of the disease represented by early infantile
epileptic encephalopathy. We suggest that neuroimaging in these patients reveals a characteristic pattern of neurodegeneration
in which the cerebellum is spared that could help with early diagnosis in the appropriate clinical setting.
Tue(3)-O22-5
Genetic studies on a Portuguese Parkinson disease patient cohort
Gabriel Miltenberger-Miltenyi 1 ，Leonor Guedes 2 ，Tiago Soeiro 2 ，Marcos Gomes 1 ，Joaquim J Ferreira 2 ，
Tiago F Outeiro 3
1:Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal、2:Neurology Department, Hospital de Santa
Maria - Centro Hospitalar Lisboa Norte, Lisbon、3:Department of NeuroDegeneration and Restaurative Research, University Medical
Center Goettingen
Introduction: Genetic studies of Parkinson’s disease (PD) have revealed a number of loci conferring high or lower risk for PD.
However, the relationships between the identified genes and the relevant pathways are still not fully understood. Mutations in
GBA1 were recognized as one of the most prevalent risk factors for sporadic and familial parkinsonism. Deficiency in GBA1,
which encodes the lysosomal enzyme glucocerebrosidase, gives rise to Gaucher disease, the most common lysosomal storage
disorder which manifests with variable phenotypic abnormalities.
Methods: 415 PD patients of our center were clinically and genetically characterized. Mutation screening was carried out
for the LRRK2 gene and for the GBA1 gene. Subsequently, we analyzed 66 patients divided in three groups (19 LRRK2
positive, 37 GBA1 positive and 10 non-mutated) for the Chitotriosidase enzyme activity in serum.
Results: 19 of the 415 patients carried mutation in the LRRK2 gene. We found three different variants, of which the most
common mutation p.Gly2019Ser was found in 16 patients. 37/415 patients showed exonic variants in the GBA1 gene (8.9%).
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We found 16 different GBA1 mutations and describe a novel mutation. One patient had mutations in homozygous state and
two patients carried compound heterozygous mutations. No patients shared mutations in both LRRK2 and GBA1 genes. The
chitotriosidase enzyme activity did not show any significant changes in the LRRK2 positive or the GBA1 positive group when
compared with the non-mutated patients. The clinical characteristics, e.g. age-at-onset of the symptoms, were comparable
in the different groups.
Conclusion: We analyzed the frequency of LRRK2 and GBA1 mutation carriers in a large number of Portuguese PD patients.
We described 39 pathogenic GBA1 mutations, including a novel mutation, as potential risk factors for PD.
Tue(3)-O22-6
Neuron-specific Cul4b knockout mice recapture the cognitive impairment phenotype in human X-linked
mental retardation patients
Baichun Jiang 1 ，Wei Zhao 1 ，Shuqian Zhang 1 ，Huili Hu 1 ，Changshun Shao 1 ，Yaoqin Gong 1
1:Department of Genetics, School of Medicine, Shandong University, China
Mutations in CUL4B gene are one of the most common causes of X-linked mental retardation. Although the E3 ubiquitin ligase
complex formed by CUL4B (CRL4B) is known to target substrates for proteolysis or to coordinate with PRC2 complex in
promoting H3K27 trimethylation and transcriptional repression, how CUL4B dysfunction causes mental retardation remains

unclear. Global knockout of Cul4b in mice leads to embryonic lethality due to defect in the development of extra-embryonic
tissues. Here we report that mice lacking expression of Cul4b in nervous system (Cul4bNestin-Cre ) are impaired in spatial
learning and memory. Strikingly, we show that CUL4B represses the expression of GFAP in neural progenitor cells (NPCs)
during brain development. Moreover, the increased generation of GFAP+ cells from Cul4b-null NPCs was mediated by an
upregulation of prostaglandin D2 synthase PTGDS. The increased GFAP expression can be attenuated by pharmacological
inhibition of the PTGDS enzymatic activity or by shRNA-mediated knockdown of Ptgds. On the other hand, exogenously
added PTGDS could promote the generation of GFAP+ cells from wild-type NPCs. We also observed that Ptgds is targeted
and repressed by the CUL4B/PRC2 complex. To further determine the cell type responsible for the impaired spatial learning
and memory in Cul4bNestin-Cre mice, we characterized two lines of mice that lack expression of Cul4b in neurons (Cul4bNse-Cre )
and in astrocytes (Cul4bGfap-Cre ), respectively. We observed that learning and memory were impaired in Cul4bNse-Cre mice,
but not in the Cul4bGfap-Cre line, suggesting that the impairment in spatial learning and memory in Cul4bNestin-Cre mice was
due to the lack of Cul4b in neurons but not in astrocytes. Together, our results demonstrate a critical role of CUL4B in the
differentiation of neural progenitor cells and in neuronal function, and provide a potential model for human X-linked mental
retardation.
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Tue., April 05, 2016 15:40-17:10 Room C-1 (1F)
Chair：Claude Ferec（Director of the INSERM UMR1078 “Genetic, Functional Genomic & Biotechnologies”, INSERM,
Brest University, Brest Hospital, France）
Chair：Noriko Miyake（Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan）
Tue(3)-O23-1
The utility of medical exome-based virtual gene panel in the molecular diagnosis of genetically hetero-
geneous sensorineural hearing loss
Qiaoning Guan 1 ，Kajia Cao 1 ，Zhiqian Fan 1 ，Ian Slack 2 ，Sawona Biswas 2 ，Sarah Noon 2 ，Matthew Dulik 1 ，
Elizabeth DeChene 1 ，Mahdi Sarmady 1 ，Zhenming Yu 1 ，Surabhi Mulchandani 1 ，Jin Yun Chen 1 ，
Elizabeth Denenberg 1 ，Jinbo Fan 1 ，Jorune Balciuniene 1 ，Avni Santani 1 ，Ian Krantz 2 ，Nancy Spinner 1 ，
Laura Conlin 1 ，Minjie Luo 1
1:Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, USA、2:Division of Human Genetics, Children’s Hospital of
Philadelphia
Inherited hearing loss (HL) is characterized by impressive clinical and genetic heterogeneity, making it challenging for diag-
nostic labs to keep abreast of the unfolding discoveries using targeted gene panels. We developed a whole exome sequencing
(WES) based-virtual panel for the diagnosis of HL in the pediatric population. A hierarchical strategy was implemented

for cost- and time-efficiency. Cases negative for GJB2/GJB6 and MT-RNR1 sequencing mutations were pursued for the
identification of genetic etiology by interpreting 111 curated genes as an exome slice. The majority of the genes are associated
with non-syndromic HL (NSHL), as evidenced by published segregation and/or functional data. Some genes are associated
with syndromic HL (SHL) but may initially present as NSHL. At the sequencing depth of 150X, more than 95% of the genes
are covered at >20X for at least 95% of the coding and splicing regions. Gaps were filled in by standard- or long-range PCR
followed by Sanger sequencing. The bioinformatics pipeline was optimized and validated by using 10 samples with known
NSHL gene mutations. To test the utility of this virtual panel in the diagnosis of patients with SHL, we also analyzed 18
patients with HL as one of the clinical indications for WES test. The diagnostic rate was 11% (2/18) when only the genes
included in the virtual panel were analyzed, but was increased to 28% (5/18) when the test was reflexed to the whole exome.
Six cases (33%) were found to carry a heterozygous pathogenic variant in autosomal recessive NSHL genes. The remaining
7 cases were either negative (22%) or inconclusive (16%). Further complementary tests, including SNP array and family
studies, are needed to establish the genetic diagnosis for these cases. We concluded that the WES-based virtual panel has
advantages compared to the targeted gene panel for the diagnosis of genetically heterogeneous disorders such as HL, given
the ability for reflex to WES at no additional sequencing cost
Tue(3)-O23-2
Targeted screening of 187 genes involved in ocular development increases mutation detection rate by
10 % in individuals with anophthalmia-microphthalmia spectrum
1,2,3,6 4,5,6 1,2,3
Nicolas Chassaing ，Nicola Ragge ，Patrick Calvas
1:Medical Genetics, CHU Toulouse, France、2:Inserm U1056、3:EA-4555, Universite Toulouse III、4:School of Life Sciences, Oxford Brookes
University, Oxford, UK、5:Clinical Genetics Unit, Birmingham Women s Hospital, Birmingham, UK、6:These authors contributed equally
to this work
Anophthalmia/Microphthalmia (AM) are severe ocular developmental anomalies with a prevalence of about 1/10,000. Nu-
merous genes have been implicated in either nonsyndromic or syndromic forms of AM. Apart from the SOX2 gene, which
is involved in about 15 % of severe AM cases, other genes are individually implicated in only a small percentage of cases.
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Despite extensive screening of major AM genes in two cohorts of AM patients (150 patients in the French cohort, 320 in the
UK cohort), ~ 75% of AM patients remained undiagnosed (consistent with published data).
In order to increase diagnosis rate, we screened a cohort of 96 AM patients without an identified genetic cause using targeted
high throughput sequencing of a panel of 187 known or candidate AM genes. These patients had been previously had Sanger
sequencing of individual genes (e.g. SOX2, OTX2, BMP4, FOXE3, BMP7, STRA6, RAX, VSX2 ). We identified causal
mutations in known genes in 10 out of the 96 patients (BCOR [2 patients], CHD7 , FOXE3 , GJA8 , MFRP, PAX6 , PITX3
[2 patients], and TENM3 ). These genes were not previously screened in our patients because (i) some of them are rarely
involved in AM and are not studied routinely, and/or (ii) phenotypes of the mutated patients were unusual regarding the
involved gene. High throughput sequencing result analysis also allowed us to identify a deletion encompassing the SOX2 gene
in one patient.
Taken together, this targeting sequencing approach allowed identification of causative genetic defects in 11/96 previously
undiagnosed patients, thus demonstrating the power of such an approach for diagnosis. In addition, we were able to confirm
the proposed role of one gene (TENM3 ) previously reported in only one AM family, and to extend the phenotypic spectrum
associated with mutations in known genes.
Tue(3)-O23-3

The p.S178L mutation in TBC1D24 lead to dominant, non-syndromic hearing impairment through a
gain-of-function mechanism
Tao Yang 1 ，Luping Zhang 1 ，Linxiang Hu 1 ，Xiuhong Pang 1 ，Penghui Chen 1 ，Hao Wu 1
1:Xinhua Hospital, Shanghai Jiaotong University School of Medicine, China
Mutations in TBC1D24 have been linked to a variety of epileptic syndromes and recently to syndromic deafness DOORS
syndrome and non-syndromic deafness DFNB86. All TBC1D24 mutations reported previously were inherited in the recessive
mode and resulted in congenital, severe-to-profound deafness. By linkage analysis of a dominant Chinese Han family segregated
with late-onset, progressive and non-syndromic hearing impairment, we identified a 2.07 Mb candidate region on chromosome
16p13.3 that contains TBC1D24. Whole-exome sequencing identified a heterozygous p.Ser178Leu variant of TBC1D24 as the
only candidate mutation segregating with the hearing impairment within the family. In perinatal and adult mouse cochlea,
expression of Tbc1d24 was detected in the spiral ganglion neurons, implying of an important function of TBC1D24 in this
region. Interestingly, the p.Ser178Leu mutation of TBC1D24 has been subsequently reported as the cause of a Caucasian
family with similar dominant, non-syndromic hearing impairment, suggesting that it is probably a hot-spot mutation with
a rather consistent phenotype. Since all truncating mutations of TBC1D24 were phenotypically normal in heterozygosis,
we speculated that the dominantly inherited p.Ser178Leu mutation most likely cause the non-syndromic hearing impairment
through a gain-of-function mechanism. This hypothesis were supported by our in vitro study in which exogenous expression of
wild type and p.S178L mutant TBC1D24 both provoked the extension and the branching of the mouse cortical neurons, while
the latter produced a much stronger effect. A p.S178L knock-in mouse model has been generated to further characterized the
pathogenic mechanism of this specific mutation in TBC1D24 .
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Tue(3)-O23-4
Submicroscopic deletions at 13q32.1 cause congenital microcoria
Lucas Fares Taie 1 ，Sylvie Gerber 1 ，Akihiko Tawara 2 ，Arturo Ramirez-Miranda 3 ，Jean-Yves Douet 4 ，
Hannah Verdin 5 ，Juan C Zenteno 3 ，Hiroyuki Kondo 2 ，Bruno Passet 6 ，Ken Yamamoto 7 ，Masaru Iwai 8 ，
Toshihiro Tanaka 9 ，Yusuke Nakamura 10 ，Wataru Kimura 11 ，Arnold Munnich 1 ，Elfride De Baere 5 ，
Isabelle Raymond-Letron 4 ，Josseline Kaplan 1 ，Patrick Calvas 12 ，Olivier Roche 13 ，Jean-Michel Rozet 1
1:Imagine - Institute of Genetic Diseases, France、2:University of Occupational & Environmental Health, Kitakyushu, Japan、3:Instituto de
Oftalmologia Conde de Valenciana. UNAM, Mexico City, Mexico、4:Veterinary School of Toulouse, University of Toulouse, France、5:Center
for Medical Genetics, Ghent University, Belgium、6:Institut Nationale de la Recherche Agronomique, Jouy-en-Josas, France、7:Institute of
Bioregulation, Kyushu University, Fukuoka, Japan、8:Ehime University Graduate School of Medicine, Japan、9:Graduate School of Medical
and Dental Sciences, Tokyo Medical and Dental University, Japan、10:University of Chicago, USA、11:Kimura Eye Clinic, Kure, Japan、
12:Hopital Purpan, Toulouse, France、13:IHU Necker-Enfants Malades, University Paris-Descartes, Paris, France
Congenital microcoria (MCOR) is a rare autosomal dominant disorder characterized by inability of the iris to dilate owing to
absence of dilator pupillae muscle. In addition, the miotic iris is thin and the stroma and iridocorneal angle are abnormal.
High myopia and glaucoma are frequently associated with this condition. By using whole-genome oligonucleotide array CGH,
we have identified deletions at 13q32.1 segregating with MCOR in six families originating from France, Japan and Mexico.
Breakpoint sequence analyses showed nonrecurrent deletions in 5/6 families. The deletions varied from 35 Kbp to 80 Kbp in
size, but invariably encompassed only two genes: TGDS encoding the TDP-glucose 4,6-dehydratase and GPR180 encoding
the G protein-coupled receptor 180. Unlike TGDS which has no known function in muscle cells, GPR180 is involved in the
regulation of smooth muscle cell growth. The identification of a null GPR180 mutation segregating over two generations with
iridocorneal angle dysgenesis can be regarded as a MCOR endophenotype. It cannot be excluded that full range of MCOR

symptoms are due to both the loss of GPR180 function and to that of elements that regulate the expression of neighboring
genes by position effect. Two genes involved in eye development are located close to the MCOR region, DCT , which encodes
the dopachrome tautomerase, and SOX21 which encodes SRY-related high-mobility-group box 21. Mice knocked-out for dct
or sox21 have no ocular symptoms consistent with MCOR, however, it cannot be excluded that over-expression could lead
to all or part of the MCOR phenotype. To assess this hypothesis, we are generating cellular and mouse models harboring the
minimal deletion found in MCOR patients using the CRISPR-Cas9 system. The identification of the molecular mechanisms
underlying this disease should provide further insights into the development of the anterior chamber of the eye, whose anomalies
are an important cause of visual loss due to glaucoma.
Tue(3)-O23-5
Biallelic NUP107 mutations cause early childhood-onset steroid resistant Nephrotic syndrome
Noriko Miyake 1 ，Hiroyasu Tsukaguchi 2 ，Eriko Koshimizu 1 ，Akemi Shono 3 ，Satoko Matsunaga 4 ，Masaaki Shiina 5 ，
Yasuhiro Mimura 6 ，Shintaro Imamura 7 ，Tomonori Hirose 8 ，Koji Okudela 9 ，Hae Il Cheong 10,11,12 ，Kenichi Ohashi 9 ，
Naoko Imamoto 6 ，Akihide Ryo 4 ，Kazuhiro Ogata 5 ，Kazumoto Iijima 3 ，Naomichi Matsumoto 1
1:Department of Human Genetics, Yokohama City University, Japan、2:Second Department of Internal Medicine, Kansai Medical Univer-
sity、3:Department of Pediatrics, Kobe University Graduate School of Medicine、4:Department of Microbiology, Yokohama City University
Graduate School of Medicine、5:Department of Biochemistry, Yokohama City University Graduate School of Medicine、6:Cellular Dynamics
Laboratory, RIKEN、7:National Research Institute of Fisheries Science、8:Department of Molecular Biology, Yokohama City University
Graduate School of Medicine、9:Department of Pathology, Yokohama City University Graduate School of Medicine、10:Department of Pedi-
atrics, Seoul National University Childrens Hospital、11:Research Coordination Center for Rare Diseases, Seoul National University Hospital、
12:Kidney Research Institute, Medical Research Center, Seoul National University College of Medicine
Nephrotic syndrome is a renal disorder caused by disruption of the glomerular filtration barrier, resulting in massive protein-
uria, hypoalbuminemia, and dyslipidemia. Idiopathic NS occurs in 16/100,000 children, and most of them respond well to
steroids, but 10-20% of affected children showed steroid-resistant (SRNS). Here, we report on biallelic NUP107 mutations
in nine affected individuals from five unrelated families who showed early-onset SRNS. Seven of nine affected individuals
had compound heterozygous mutation of one truncating mutation (c.1079_1083del or c.969+1G>A) and commonly sheared
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missense mutation (c.2492A>C), and they all developed nephrotic syndrome from 2 to 3 years of age and progressed to
end stage renal disease until 10 years old. The rest of two patients in one family had compound heterozygous mutation
of two missense mutation (c.469G>T and c.2492A>C) and showed milder phenotype with later onset (10 to 11 years old).
At least five affected individuals underwent renal transplants with no recurrence of SRNS to date, which suggest that the
renal transplant is the proper treatment for SRNS with NUP107 mutation at present. NUP107 encodes Nucleoporin 107kDa
(NUP107) which is a component of the nuclear pore complex (NPC) embedded in the nuclear envelope and play central func-
tions in nucleocytoplasmic transport, nuclear framework and gene regulation. NUP107 is ubiquitously expressed, including
in glomerular podocytes. Three of four NUP107 mutations detected in the affected individuals hampered NUP107 binding
to NUP133 (nucleoporin 133kDa) and NUP107 incorporation into NPCs in vitro. NUP107 knockdown zebrafish generated
by morpholino oligonucleotides displayed hypoplastic glomerulus structures and abnormal podocyte foot processes, which
could recapitulate the pathological renal changes observed in the SRNS individuals with NUP107 mutations. A series of our
experiments indicate that biallelic NUP107 mutations cause early childhood-onset SRNS.
Tue(3)-O23-6
Genic and allelic variability in polycystic kidney disease :impact in the erea of precision medicine
Claude Ferec 1 ，Marie-Pierre Audrezet 1 ，Emilie Cornec-LeGall 1,2
，Yannick Le Meur 2 ，Jian-Min Chen 1
1:Inserm/university, France、2:Service de Nephrologie University/Hospita

Two genes, PKD1 and PKD2 are responsible of the Autosomal Dominant Polycystic Kydney Disease (ADPKD).The disorder
occurs in 1/400 to 1/1000 individuals worlwide .ADPKD is characterized by the progressive development and expansion of
fluids -filled cysts developped from renal epithelial cells and typically leads to End Stage Renal Disease (ESRD )in late midle
age.
In the past twenty years we have performed mutation analysis of the coding sequence of the 46 exons of PKD1 and of PKD2
by sanger sequencing completed by large rearrangements analysis.
The ADPKD Mutation Data base (http //pkdb.mayo .edu /) has registred 1454 distinct pathogenic variants among those
we have reported more than 200mutations. (Audrezet et al, 2012 ) (Cornec-le Gall, 2013). Our current overall pathogenic
mutation detection rate is 90% in more than 1200 pedigrees (The Genkyst cohort) ; 86% of mutations were found in PKD1
and 14% in PKD2.
The phenotype is hightly variable in ADPKD and the age of onset has been used as a quantifiable trait to study geno-
type/phenotype relationships. In our cohort of patients .We have confirmed that PKD1 is a more severe disease that PKD2,
as exemplified by a 20 years difference in ESRD occurrence (Cornec-Le Gall, JASN, 2013) . Moreover we have shown an
allelic influence and found that the type of mutation displays a strong correlation with renal survival .The median age at
onset of ESRD was 55.6 years for carriers of truncating mutation and 67.9 years for carriers with a non truncating mutation .
We have shown also that hypomorphic alleles in PKD1 are involved in the prenatal presentation of ADPKD (Audrezet et
al, 2015). We have proposed that the genetic score based on the gene responsible (PKD1or PKD2) and the type of PKD1
mutations could be improved by including clinical data and this score ie the PRO-PKD score will help clinicians to delineate
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patients who should be treated as targeted therapies are on the way.(Cornec-Le Gall et al, 2015)

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Tue., April 05, 2016 13:50-15:20 Room C-2 (1F)
Chair：William K. Scott（Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman
Institute for Human Genomics, University of Miami, USA）
Chair ：Takeshi Ikeuchi（Molecular Genetics, Brain Research Institute, Niigata University, Japan）
Tue(3)-O24-1
Genome-wide interaction study of Parkinson disease and vitamin D deficiency implicates autoimmunity
pathways
William K. Scott 1,2 ，Lizmarie Maldonado 1 ，Gary W. Beecham 1,2 ，Eden R. Martin 1,2 ，Marian L. Evatt 3 ，
James C. Ritchie 4 ，Jonathan L. Haines 5 ，Cyrus P. Zabetian 6,7 ，Haydeh Payami 8,9 ，Margaret A. Pericak-Vance 1,2
，
Jeffery M. Vance 1,2 ，Liyong Wang 1,2
1:John P. Hussman Institute for Human Genomics, University of Miami, USA、2:Dr. John T. Macdonald Foundation Department of Human
Genetics, University of Miami、3:Department of Neurology, Emory University、4:Department of Pathology, Emory University、5:Department
of Epidemiology and Biostatistics and Institute for Computational Biology, Case Western Reserve University、6:Veterans Affairs Puget
Sound Health Care System、7:Department of Neurology, University of Washington、8:Departments of Neurology and Genetics, University
of Alabama-Birmingham、9:HudsonAlpha Institute for Biotechnology
Parkinson disease (PD) is a complex disease with many known genetic and environmental risk factors. While these explain
part of the risk of PD the remainder is likely composed of rare variants, epistasis, and gene-environment (GxE) interactions.

Vitamin D deficiency (VDD; plasma concentration <20 ng/mL) is reproducibly associated with increased PD risk. To identify
new loci we conducted a genome-wide interaction study (GWIS) with VDD in two datasets: 1) 477 PD cases, 430 controls and
2) 482 PD cases, 412 controls. Both were imputed to 5.3 M single nucleotide polymorphisms (SNP) using the 1000Genomes
reference panel. VDD was associated with PD in both datasets (OR=2.7, p<0.0001; OR=1.9, p=0.009). For GWIS, two
logistic regression models were generated in each dataset: a full model with SNP allele dosage, VDD, SNP-VDD interaction,
and covariates (sex, age, sampling season), and a restricted model of VDD and covariates. Meta-analysis of 2-df joint tests
of SNP main effect and GxE interaction was conducted across both datasets using JMA in METAL. The only genome-wide
significant result (p<5x10-8 ) was for SNP main effects in known PD gene SNCA. Three other loci had results with p<10-6 .
Two were due to main effects (known PD gene MAPT and a novel locus on 20q13 between MIR548AG2 and LOC100506470 ).
The third, in LOC401188 on 5q11, resulted primarily from GxE. To assess clustering of significant results in pathways, we
selected 465 genes having >=1 SNP with JMA p<0.05 (corrected for number of SNPs in the gene). WebGestalt analysis of
overrepresentation in KEGG pathways identified significant enrichment of these genes in the graft-versus-host-disease pathway
(FDR-corrected p<0.05). Notably, in this pathway, rs45620941 in the CD28 gene was associated with PD only in the VDD
subset (OR=1.8, 95% CI (1.2-2.6)). These results are consistent with the role vitamin D plays in immune response and our
prior results associating PD with SNPs in the HLA class II region.
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Tue(3)-O24-2
ABCA7 Frameshift Deletion Associated with Alzheimer’s Disease in African Americans
Holly N Cukier 1,2 ，Brian W Kunkle 1 ，Badri N Vardarajan 3 ，Sophie Rolati 1 ，Kara L Hamilton-Nelson 1 ，
Patrice L Whitehead 1 ，Derek Van Booven 1 ，Rosalyn Lang 4 ，Derek M Dykxhoorn 1,5 ，Lindsay A Farrer 6 ，
Michael L Cuccaro 1,5 ，Jeffery M Vance 1,2,5 ，John R Gilbert 1,5 ，Gary W Beecham 1,5 ，Eden R Martin 1,5 ，
Regina M Carney 1,5 ，Richard Mayeux 1,5 ，Gerard Schellenberg 7 ，Goldie S Byrd 4 ，Jonathan L Haines 8 ，
Margaret A Pericak-Vance 1,2,5 ，Alzheimer’s Disease Genetics Consortium (ADGC)
1:John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, USA、2:Department of Neurology,
University of Miami Miller School of Medicine、3:Taub Institute for Research on Alzheimer Disease and the Aging Brain, Gertrude
H. Sergievsky Center, Departments of Neurology, Psychiatry, and Epidemiology, Columbia University、4:Department of Biology, North
Carolina A&T State University、5:Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller
School of Medicine、6:Departments of Medicine, Neurology, Ophthalmology, Genetics & Genomics, Epidemiology, and Biostatistics, Boston
University、7:Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine、8:Department
of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University School of Medicine
The ATP-binding cassette, sub-family A (ABC1), member 7 (ABCA7 ) gene has been implicated as a risk factor in Alzheimer’
s disease (AD) in both African American (AA) and non-Hispanic white (NHW) populations, each with distinct polymorphisms
of differing effect sizes. The effect in AA is significantly higher, comparable to that found in NHW for APOE e4 . While there
are reports of rare, loss-of-function alterations in ABCA7 in NHW, the underlying damaging variant(s) in AA is unknown. We
performed custom capture sequencing of a 150 kb region encompassing the ABCA7 region on 40 AA individuals with AD and
37 AA controls, all carrying the AA risk allele (rs115550680). A 44 base pair deletion (rs142076058) was identified in all 77 risk
genotype carriers, showing that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed
in a large dataset (531 cases, 527 controls) and, following adjustments for age, sex, and APOE status, was significantly

associated with disease (p=0.0002, OR=2.13 [95% CI:1.42-3.20]). An independent dataset replicated the association (447
cases, 880 controls, p=0.0117, OR=1.65 [95% CI:1.12-2.44]), and joint analysis increased the significance (p=1.414x10-5 ,
OR=1.81 [95% CI:1.38-2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of
our NHW cohort. Whole exome sequencing of multiplex, Caribbean Hispanic families identified the deletion co-segregating
with disease in a large sibship. Reverse transcription-PCR from RNA extracted from the blood of AA individuals with and
without the deletion demonstrated that the deleted allele produces a stable, detectable RNA strand. The deletion falls in the
14th exon of ABCA7 and is predicted to result in a frameshift and truncating mutation (p.Arg578Alafs) that could interfere
with protein function. This ABCA7 deletion could represent an ethnic-specific, pathogenic alteration in Alzheimer’s disease.
Tue(3)-O24-3
Structural variants and neurodegenerative diseases in aging: regulatory and causality consequences
Ornit Chiba-Falek 1 ，Michael W Lutz 1 ，Robert Saul 2 ，Lidia Tagliafierro 1 ，Allen D Roses 1,3
1:Neurology, Duke University, USA、2:Polymorphic DNA Technologies, Alameda, CA, USA、3:Zinfandel Pharmaceuticals, Chapel Hill, NC,
USA
GWAS identified many loci associated with neurodegenerative disease, however the precise causal genetic variants and the
molecular mechanisms underlying those genetic associations remain largely unknown. In GWAS of human complex diseases,
SNPs have taken the spotlight while Structural Variants (SVs) such as, short tandem repeats (STRs), homopolymers and
indels, were underrepresented, mainly due to GWAS platforms that enabled high density SNP genotyping and the difficulties
to accurately sequence long contiguous genomic sequence using most of the current next-generation sequencing technologies.
Recently, there has been increased support for the idea that SVs, rather than SNPs, may be responsible for many human
complex traits. We aim to identify noncoding SVs within loci in the genome that have been associated with neurodegenerative
diseases in the spectrum of Alzheimer’s (AD)-Parkinson’s (PD) that are likely to be causal, and characterize their molecular
mechanism of action. We employ bioinformatics tools including a novel software (dbSV) to prioritize candidate SVs, followed
by association analyses of candidate SVs with neurodegenerative diseases and neuropathological phenotypes and, mRNA
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studies to evaluate the cis-effects of disease-risk SVs on gene expression in human brain tissues and neurons isolated by laser
capture microdissection (LCM) from disease-affected and healthy donors. Discoveries that demonstrate the key role of SVs
will be discussed, including a SV in the TOMM40-APOE region in relation to AD, and SVs in SNCA gene in the context
of PD and Lewy body pathology. Experiments using iPSCs and genome-editing technologies to validate and modulate the
regulatory effect of the putative causal/functional SVs, and computational analysis coupled with transcription factors-DNA
binding experiments to identify trans factors are underway. Our research has underscored the importance of noncoding SVs
in the etiology of neurodegenerative diseases in aging.
Tue(3)-O24-4
Novel candidate genes for early-onset Alzheimer disease identified using whole-exome sequencing
Gary W Beecham 1 ，Brian W Kunkle 1 ，Badri Vardarajan 2 ，Patrice L Whitehead 1 ，Sophie Rolati 1 ，Eden R Martin 1 ，
John R Gilbert 1 ，Richard P Mayeux 2 ，Jonathan L Haines 3 ，Margaret A Pericak-Vance 1
1:John P Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, USA、2:Taub Institute of Research on
Alzheimer’s Disease, Columbia University、3:Institute for Computational Biology, Case Western Reserve University
BACKGROUND: Known mutations in APP, PSEN1 and PSEN2 account for ~ 11% of early onset Alzheimer’s disease
(EOAD), leaving the majority of EOAD’s genetic risk unexplained. METHODS: To search for novel variants contributing to
EOAD risk we performed whole-exome sequencing (WES) in 50 Caucasian EOAD cases screened negative for APP, PSEN1 ,

and PSEN2 . Variants were filtered for functional, damaging rare variants (MAF<0.1%), as well as genotype quality (GQ>20),
read depth (>5), and VQSLOD Score (>0). Variants were then filtered for nonsynonymous or splice site variants present in
2+ individual cases, and having a Combined Annotation Dependent Depletion (CADD) score in the top 10% of all variants.
Surviving variants were assessed for protein-protein interaction with known EOAD genes (APP, PSEN1, PSEN2, GRN ,
MAPT ) using STRINGdb. RESULTS: We identified 51 rare, damaging variants in 46 genes in two or more EOAD cases.
Gene network analysis of these 46 genes with known EOAD genes identified three candidate genes: HSPG2 (interacts with
GRN and APP), CLSTN1 (interacts with PSEN1 and APP), and DOCK3 (interacts with PSEN1 and PSEN2). Specifically,
five cases (2 pairs of cases with a shared variant and a fifth case with a different variant) have rare, damaging variation in
HSPG2, a gene in a known AD susceptibility region that is potentially involved in amyloidogenesis and tau aggregation. Four
cases (2 pairs of cases with a shared variant) have a variant in DOCK3 , a gene shown to regulate amyloid-β secretion, and
associated with neurofibrillary tangles in AD brains. Several other cases have shared variants in CLSTN1. Disruption of
calsyntenin-1-associated axonal transport of APP by mutations in CLSTN1, a known APP interactor, has been identified as
a potential pathogenic mechanism of AD. CONCLUSION: This studiy identified three novel loci linked to EOAD risk. These
genes are being investigated in additional datasets for further association with AD.
Tue(3)-O24-5
Transethnic Genome-Wide Meta-Analysis for Alzheimer Disease identifies Novel Genes
Gyungah R Jun 1,2 ，Jaeyoon Chung 1 ，Giuseppe Tosto 3 ，Badri Vardarajan 3 ，Christiane Reitz 3 ，
Kathryn L Lunetta 4 ，Jennifer Manly 3 ，Goldie Byrd 5 ，Jonathan L Haines 6 ，Margaret A Pericak-Vance 7 ，
Ryozo Kuwano 8 ，Richard Mayeux 3 ，Gerard D Schellenberg 9 ，Lindsay A Farrer 1,3,10,11,12 ，
The Alzheimer’s Disease Genetics Consortium
1:Medicine, Boston University, USA、2:Integrated Neurogenetics, Eisai Inc、3:Neurology, Columbia University、4:Biostatistics, Boston
University、5:Biology, North Carolina A&T State University、6:Epidemiology and Biostatistics, Case Western Reserve University、7:The
John P. Hussman Institute for Human Genomics, University of Miami、8:Molecular Genetics, Brain Research Institute, Niigata University、
9:Pathology and Laboratory Medicine, University of Pennsylvania、10:Ophthalmology, Boston University、11:Epidemiology, Boston
University、12:Neurology, Boston University
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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and a global health issue. However, unique or common
genetic predispositions affecting different ethnic populations are still unknown. Transethnic meta-analysis using previously
published genome-wide association (GWA) studies for late-onset Alzheimer’s disease (AD) assembled by the Alzheimer Disease
Genetics Consortium (ADGC) were conducted for main effect of a single nucleotide polymorphism (SNP) and interaction
effect between a SNP and APOE ϵ4 status using the total sample in Stage 1. In addition, we examined genetic risk factors
for AD across the genome in APOE ε 4+ and ε 4- subgroups. A total sample in Stage 1 comprised with European Ancestry
(11,751 cases and 14,569 controls), African American (2,106 cases and 2,877 controls), Japanese (686 cases and 1,159 controls),
and Israeli-Arab (51 cases and 64 controls) cohorts. We conducted SNP-based and gene-based transethnic meta-analysis in
Stage 1. SNPs with p<10-5 and genes with p<10-3 from novel loci were further evaluated using the previously published GWA
study from the International Genomics of Alzheimer’s Project (IGAP) in Stage 2. Genome-wide significant (GWS) SNPs
(p<5.4x10-8 ) from the combined set of the stages 1 and 2 were identified with main effects from HBEGF (best p=7.1x10-9 ),
USP6NL (best p=3.0x10-8 ), and BZRAP1 (best p=4.4x10-8 ), and with interaction effect from NFIC (best p=1.5x10-9 ).
These association signals were incorporated from multiple ethnic groups and stronger in the APOE ε 4- subgroup than in
the APOE ε 4+ subgroup. We also identified three novel GWS genes (p<2.7x10-6 ) from main effects using the total sample
from the combined set (gene-based p value: KLF7 =7.5x10-7 , CIDEC =4.8x10-7 , TPBG=1.8x10-6 ). This study suggests that
the transethnic meta-analysis can detect novel AD susceptibility genes whose effects are either independent of or influenced
by APOE genotype.

Tue(3)-O24-6
CFH variants affect structural and functional brain changes and genetic risk of Alzheimer’s disease
Deng-Feng Zhang 1,6 ，Jin Li 2 ，Huan Wu 3 ，Yue Cui 2 ，Rui Bi 1,6 ，He-Jiang Zhou 1 ，Hui-Zhen Wang 1 ，
Chen Zhang 4 ，Dong Wang 1 ，Qing-Peng Kong 3 ，Tao Li 5 ，Yiru Fang 4 ，Tianzi Jiang 2,7 ，Yong-Gang Yao 1,6,7
，
Alzheimer’s Disease Neuroimaging Initiative (ADNI)
1:Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences,
China、2:Brainnetome Center and National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences,
Beijing, China、3:State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences,
Kunming, Yunnan, China、4:Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of
Medicine, Shanghai, China、5:The Mental Health Center & Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu,
Sichuan, China、6:Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China、7:CAS Center
for Excellence in Brain Science, Chinese Academy of Sciences, Shanghai, China
The immune response is highly active in Alzheimer’s disease (AD). Identification of genetic risk contributed by immune
genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In
this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort,
followed by a multiple-stage study focusing on Complement Factor H (CFH ) gene. Effects of the risk SNPs on AD-related
neuroimaging endophenotypes were evaluated through Magnetic Resonance Imaging (MRI) scan, and the effects on AD
cerebrospinal fluid biomarkers (CSF) and CFH expression changes were measured in aged and AD brain tissues and AD
cellular models. Our results showed that the AD-associated top immune genes reported in Europeans (CR1 , CD33 , CLU and
TREML2 ) have weak effects in Chinese, whilst CFH showed strong effects. In particular, rs1061170 (P meta =5.0x10-4 ) and
rs800292 (P meta = 1.3x10-5 ) showed robust associations with AD, which were confirmed in multiple world-wide sample sets
(4317 cases and 16795 controls). Rs1061170 (P = 2.5x10-3 ) and rs800292 (P = 4.7x10-4 ) risk-allele carriers have an increased
entorhinal thickness in their young age and a higher atrophy rate as the disease progress. Rs800292 risk-allele carriers have
higher CSF tau and A β levels and severe cognitive decline. CFH expression level, which was affected by the risk-alleles,
was increased in AD brains and cellular models. These comprehensive analyses suggested that CFH is an important immune
factor in AD and affects multiple pathological changes in early life and during disease progress.
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Tue., April 05, 2016 15:40-17:10 Room C-2 (1F)
Chair：Dong Hwan Lee（Soon Chun Hyang University Hospital, Korea, South）

Chair ：Naoko Iwasaki（Diabetes Center, Institute of Medical Genetics, Tokyo Women’s Medical University, Japan）
Tue(3)-O25-1
Prevalence of MODY subtype and clinical characteristics in patients with early onset diabetes in Japanese
1,2,3
Naoko Iwasaki ，Miho Takizawa 1 ，Makiko Ogata 1 ，Risa Ide 1 ，Yasuko Uchigata 1 ，Kayoko Saito 1,2,3
1:Diabetes Center, Tokyo Women’s Medical University, Japan、2:Institute of Medical Genetics, Tokyo Women’s Medical University、3:Institute
of Integrated Medical Science, Tokyo Women’s Medical University
Aim: Maturity onset diabetes of the young (MODY) is a subtype of diabetes mellitus characterized by Mendelian inheritance
and early onset of diabetes. Prevalence of MODY is reported to be 1 to 5 % among diabetes in Caucasian. At least 13 genes
responsible for MODY have been identified, and MODY 1, 2, 3, and 5 are the most prevalent. However, little is known about
prevalence of those MODY in Japan. The aim of this study was to elucidate the prevalence of each type of MODY and clinical
phenotype for providing an accurate measure for genetic testing in subjects with early onset diabetes.
Methods: The subjects were those diagnosed with diabetes before 30 years of age, regardless of family history of diabetes,

negative for auto-antibody and participated from 1992 to March 2014. Genotyping was performed by direct sequencing of
MODY1 (HNF4A), 2 (GCK ), 3(HNF1A), and 5(HNF1B) genes and WFS1 according to the clinical presentations. If no
causative mutation was found in these genes, Multiplex Ligation dependent Probe Amplification assay was performed to
screen genomic rearrangements.
Results: Two hundred and seventy-six patients (M/F: 141/135, age at diagnosis 19.2±6.3 years) were studied. Among them,
39 subjects (14.1%) were found to have mutations: 3 subjects in MODY1 (7.7%), 3 subjects in MODY2 (7.7%), 18 subjects in
MODY3 (46.1%) and 13 subjects in MODY5 (33.3%). In addition, we identified mutations in WFS1 in two cases of clinically
diagnosed with Wolfram syndrome (5.1%). Subjects with mutations had a lower body mass index (BMI), and were diagnosed
at younger age compared to those without mutations. Moreover, 29.8% of the subjects with a maximum BMI <30 had a
mutation in one of those genes tested.
Conclusion: Subjects diagnosed with diabetes under 30 years of age who did not have autoantibodies and had a maximum
BMI < 30, were more likely to have MODY.
Tue(3)-O25-2
Relationship between haplotype diversity of the HLA-G gene with type 1 diabetes mellitus and its
expression pattern on dendritic cells DC-10
Rafael de Albuquerque 1 ，Norma Lucena 2 ，Eduardo Donadi 1 ，Celso Mendes-Junior 1 ，Silvia Gregori 3
1:USP, Brazil、2:Fiocruz、3:TIGET
Type 1diabetes (T1D) is a multifactorial autoimmune disease with genetic, immunological, metabolic and environmental
factors, characterized by the destruction of pancreatic cells mediated by humoral and cellular mechanisms. The main function
of the HLA-G molecule is the inhibition of NK cells and cytotoxic T cells (CTL) by interacting with inhibitory receptors found
on these cells. Considering that association studies show evidence of involvement of the HLA-G gene with susceptibility to
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T1D and that HLA-G is expressed in normal baseline level in pancreatic β-cells, increased HLA-G expression in individuals
with the disease could be potentially beneficial. In this study, we sought to evaluate, through sequencing, 77 previously
identified polymorphic sites in the 5’URR, coding and 3’UTR regions of HLA-G gene of Brazilian diabetic patients (n = 120),
compared to healthy controls (n = 100) previously typified by our group. Additionaly, haplotypes from healthy Italian
subjects (n = 40) were identified and related to the expression of membrane bound molecule on tolerogenic dendritic cell
(DC-10). Trying to understand the mechanisms of control of HLA-G expression, DC-10, tolerogenic dendritic cells derived
from monocytes differentiated in vitro by IL-4 and IL-10, were used as a model. DC-10 express, among other molecules,
HLA-G, ILT-4 and high IL-10 levels, inducing Tr1 cells. The possibility of immunomodulation by membrane-bound HLA-G
expression on DC-10, which in turn could stimulate the production of regulatory T cells which would prevent the destruction
of the pancreatic β-cells by the immune system, would be of great therapeutic value for T1D. Our results show that, despite
the recognized role of the 5’URR and 3’UTR regions in the control of HLA-G gene expression, the coding region is highly
relevant in this context.
Tue(3)-O25-3
Protein tyrosine phosphatase 1B (PTP1B) gene polymorphism is associated with obesity and resistance
to weight reduction therapy in the Japanese
Noriko Satoh-Asahara 1 ，Hajime Yamakage 1 ，Masashi Tanaka 1 ，Shinya Masuda 1 ，Kazuya Muranaka 1 ，
Akira Shimatsu 1 ，Kikuko Hotta 2 ，Yoshihiro Miyamoto 3 ，Hiroko Morisaki 4 ，Takayuki Morisaki 4

1:Division of Diabetic Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan、2:Medical Center
for Translational Research, Osaka University Hospital、3:Department of Preventive Cardiology, National Cerebral and Cardiovascular
Center、4:Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute
[Aim] We aim to identify genetic factors that associate with the onset and response to the treatment of obesity in the Japanese.
[Methods] All protocols were approved by the ethics committees of Kyoto Medical Center. We conducted case-control and
cohort studies using obese patients and control subjects (general population), targeting 712 SNPs in the candidate genes of
obesity and type 2 diabetes. After two-stage screening of the case-control association study, we determined 5 SNPs in the 5
genes were associated with obesity. Among these genes, we focused on the protein tyrosine phosphatase 1B (PTP1B) gene,
which have been reported to be associated with insulin and leptin resistance, and conducted a prospective study to elucidate
the effect of SNPs (rs3787348 and rs6067484) in the PTP1B on the weight reduction therapy. We used additive model and
adjusted with gender and age for the statistical analyses. [Results] In 447 obese patients (male/female: 196/251, age: 50
±15, BMI: 32 ± 6 kg/m2), the minor allele frequencies of PTP1B gene were 45.5 % in rs3787348 and 9.1 % in rs6067484,
respectively. T-allele of rs3787348 significantly associated with increased BMI (G/G, 31 ± 1; G/T, 32 ± 1; T/T, 33 ± 1,
P = 0.041). No significant association was observed in rs6067484. After 3-month weight reduction therapy, patients with
G-allele in rs3787348 showed significant decrease of body weight, BMI, waist circumference (WC), and total cholesterol (TC)
(decrease of BW: G/G, -5.1 ± 0.5; G/T, -4.1 ± 0.2; T/T, -3.1 ± 0.3. decrease of BMI: G/G, -1.9 ± 0.2; G/T, -1.5 ± 0.1;
T/T, -1.2 ± 0.1; decrease of WC: G/G, -5.2 ± 0.7; G/T, -4.1 ± 0.4; T/T, -2.9±0.4; decrease of TC:G/G, -17 ± 3; G/T, -13
± 2; T/T, -8 ± 2, P < 0.05). [Conclusion] SNP rs3787348 in the PTP1B was shown to be related to obesity and resistance
to weight reduction therapy.
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Tue(3)-O25-4
The Incidence of Congenital Hypothyroidism and Study of Endorine Disruptors in Korea
Dong Hwan Lee 1 ，Ken Suzuki 2
1:Department of Pediatrics, Soonchunhyang University Hospital, Korea, South、2:Deparmtnet of Neonatal Screening, Tokyo Health Service
Association
Congenital hypothyroidism (CH) is the most frequent congenital endocrine disorder. The purpose of the present study was
to determine the incidence of CH in South Korea from 1997 to 2014. Newborn screening for CH was based on measuring
neonatal thyroid stimulating hormone (TSH) using a 20 mU/l cutoff until 12/2010, 10 mU/l thereafter. During the study
period, there were 7,515,832 live births screened for CH. Primary CH was detected in 2,848 newborns, with incidence of
1:2,942. The prevalence per 10,000 of CH was gradually increased (1.8 in 1997, 3.32 in 2006, 7.89 in 2012, 8.02 in 2014) in
Korea. The prevalence per 10,000 of CH in Japan was increased similarly (1.25 in 1980, 2.6 in 1992, 4.31 in 1999, 5.25 in
2008, 5.81 in 2013). We studied to concentrations of endocrine disruptors and their correlations with thyroid hormones, were
investigated in sera from infants with congenital hypothyroidism, healthy infants, and their mothers. Significant correlations
were found between these groups in t-Octyl Phenol, n-Nonyl-Phenol, Phthalic acid, Mono-(2-ethylhexyl) phthalate. There
was significant correlations with t-Octyl Phenol levels and TSH levels of infants with congenital hypothyroidism at diagnosis.
The results of comparative analysis of residential environmental factors were significant difference (p=0.009), 10.7% (patients
with congenital hypothyroidism) and 2.1% (normal healthy group) in factory area.

Tue(3)-O25-5
Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period
through puberty
Yoshihiro Maruo 1 ，Keisuke Nagasaki 2 ，Katsuyuki Matsui 1 ，Yu Mimura 1 ，Asami Mori 1 ，Maki Fukami 3
1:Pediatrics, Shiga University of Medical Sicence, Japan、2:Pediatrics, Niigata University、3:Molecular Endocrinology, National Research
Institute for Child Health and Development
Objective: We previously reported that biallelic mutations in dual oxidase 2 (DUOX2 ) cause transient hypothyroidism. Since
then, many cases with DUOX2 mutations have been reported. However, the clinical features and prognosis of individuals
with DUOX2 defects have not been clarified.
Objective: We investigated the prognosis of patients with congenital hypothyroidism (CH) due to DUOX2 mutations.
Patients: Twenty-five patients were identified by a neonatal screening program and included seven familial cases. Their serum
thyroid stimulating hormone (TSH) values ranged from 18.9 to 734.6 mU/L. Twenty-two of the patients had low serum free
T4 (fT4) levels (0.17-1.1 ng/dL). Twenty-four of the patients were treated with l-thyroxine.
Methods: We analyzed the DUOX2 , thyroid peroxidase, Na+/I- symporter, and dual oxidase maturation factor 2 genes of
these 25 patients by PCR-amplified direct sequencing. An additional 11 genes were analyzed in 11 of the 25 patients using
next-generation sequencing.
Results: All patients had biallelic DUOX2 mutations, and seven novel alleles were detected. Fourteen of the patients were
able to discontinue replacement therapy, and seven were receiving reduced l-thyroxine doses. Normalization of thyroglobulin
lagged several years behind the completion of treatment. Two patients showed permanent hypothyroidism. Except for one
case of a learning disability, growth and psychomotor development were normal.
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Conclusion: The prognosis of Japanese patients with DUOX2 defects was usually transient CH. Delayed improvement of
thyroglobulin indicates that these patients have subclinical hypothyroidism. Hypothyroidism did not recur in patients during
the study period (up to 18 years old).
Tue(3)-O25-6
Biallelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Rhab-
domyolysis, Cardiac Arrhythmias, and Progressive Neurodegeneration
Laura S Kremer 1 ，Felix Distelmaier 2 ，Bader Alhaddad 3 ，Maja Hempel 4 ，Arcangela Iuso 3 ，Clemens Kuepper 5 ，
Chris Muehlhausen 6 ，Reka Kovacs-Nagy 3 ，Robin Satanofskij 3 ，Elisabeth Graf 1 ，Riccardo Berutti 3 ，
Gertrud Eckstein 3 ，Richard Durbin 7 ，Sascha Sauer 8 ，Georg F Hoffmann 7 ，Tim M Strom 1,3 ，Rene Santer 6 ，
Thomas Meitinger 1,3 ，Thomas Klopstock 5 ，Holger Prokisch 1,3 ，Tobias B Haack 1,3
1:Institute of Human Genetics, Helmholtz Zentrum Muenchen, Neuherberg, Germany、2:Department of General Pediatrics, University
Childrens Hospital, Heinrich-Heine-University Duesseldorf, Germany、3:Institute of Human Genetics, Technische Universitaet Muenchen,
Germany、4:Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany、5:Department of Neurology,
Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany、6:Department of Pediatrics, University Medical Center
Hamburg-Eppendorf, Hamburg, Germany、7:Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom、8:CU Systems
Medicine, University of Wuerzburg, Wuerzburg, Germany
Molecular diagnosis of mitochondrial disorders is complicated by their extreme clinical and genetic heterogeneity. Using
exome sequencing, we identified three different biallelic truncating mutations in TANGO2 in three unrelated individuals with
infancy-onset episodic metabolic crises characterized by encephalopathy, hypoglycemia, rhabdomyolysis, arrhythmias, and

laboratory findings suggestive of a defect in mitochondrial fatty acid oxidation. Over the course of the disease all individuals
developed global brain atrophy with cognitive impairment and pyramidal signs. TANGO2 encodes transport and Golgi
organisation 2, a protein with a putative function in redistribution of Golgi membranes into the endoplasmic reticulum in
drosophila and a confirmed mitochondrial localisation in mice. Studies in mutant fibroblasts showed evidence of a functional
defect in mitochondrial β-oxidation. Our results establish TANGO2 deficiency as a clinically recognizable cause of pediatric
disease with multi-organ involvement.
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[O26] Clinical Genetic Testing 1

Tue., April 05, 2016 13:50-15:20 Room I (2F)
Chair：Ian G. Campbell（Peter MacCallum Cancer Centre, University of Melbourne, Australia）

Chair ：Shin-ichi Usami（Department of Otorhinolaryngology, Shinshu University School of Medicine, Japan）
Tue(3)-O26-1
Mutation spectrum of Japanese Lynch syndrome patients diagnosed by universal tumor screening for
colorectal cancer
Kiwamu Akagi 1 ，Miho Kakuta 1 ，Akemi Takahashi 1 ，Tetsuhiko Tachikawa 1 ，Gou Yamamoto 1 ，Yoshiko Arai 1 ，
Shiho Kobayasi 1 ，Kenji Fujiyoshi 1,3 ，Yoshito Akagi 3 ，Takashi Takenoya 1,2 ，Yoji Nishimura 2 ，Yoshiyuki Kawashima 2 ，
Hirohiko Sakamoto 2
1:Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Japan、2:Digestive Surgery, Saitama Cancer Center、3:Surgery,
Kurume University
<Background & Aims> Lynch syndrome is caused by germline mutations in the mismatch repair (MMR) genes; MLH1,
MSH2, MSH6 and PMS2 and most common hereditary cancer syndrome, which account for about 1-4% of the total colorec-
tal cancer. However, little is known about the frequency and distribution of mutations in MMR in Asians. The aim of this
study is to investigete the mutational spectrum of Lynch syndrome in Japan.

<Methods> The present study was conducted on 2124 consecutive primary colorectal cancers at the Saitama Cancer Center
from July 1999 to December 2013. Paired specimens of tumors and normal mucosa were collected from surgically resected
colorectal cancer (CRC) and were screened by testing of microsatellite instability (MSI). MSI-high cases were investigated
the clinical and molecular features, such as personal and family cancer history and pathological findings, immunohistochem-
istry(IHC) for MMR proteins, methylation status of MLH1 promoter and BRAF mutation of colorectal tumor and germline
mutation analysis of the MLH1, MSH2 , MSH6 and PMS2 by Sanger sequence and MLPA.
<Results> Of the 2124 CRCs, 123(5.8%) were MSI-H and 58(47%) were detected hypermethylation of MLH1 promoter.
Germline mutation analysis revealed 27(22%) MMR gene mutation carriers, 5 in MLH1, 10 in MSH2 , 10 in MSH6 and 2 in
PMS2 . The results of IHC pattern were well concordant with pathogenic mutations. Pathogenic mutation detection rate for
total CRC patients was 1.3% and for total MSI-H CRC patients was 22%.
<Conclusions> The germline mutation rate in MMR genes was at least 1.3% for total CRC cases in Japan. The MSH6
pathogenic mutation rate in causal MMR genes was 37%, which is very high than that of previously reported.
Tue(3)-O26-2
Breast and Ovarian cancer prevention: Is it time for population screening for BRCA1 and BRCA2
mutations?
Ian G Campbell 1 ，Ella Thompson 1 ，Simone Rowley 1 ，Mary_Anne Young 1 ，Alison Trainer 1 ，Na Li 1 ，Lisa Devereux 1 ，
Gillian Mitchell 1 ，Paul James 1 ，Lifepool
1:Research DIvision, Peter MacCallum Cancer Centre, Australia
Germline mutations in BRCA1 and BRCA2 confer high lifetime risk of breast and ovarian cancer but importantly these risks
are not irreversible. Identification of asymptomatic carriers could significantly reduce the incidence of these diseases. The
traditional model of familial breast and ovarian cancer practice involves ascertaining high-risk individuals based on family
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history. In general, the family is first identified because one member develops cancer and because of high-risk indicators, is
referred to a Familial Cancer Centre. However, more than 50% of women who carry a BRCA1/2 mutation may not have a
family history of cancer in a close relative. Momentum toward genetic screening of the asymptomatic population is growing
but there remain some significant unknowns. For example it is unclear what is the true frequency of actionable mutations
in the general western population and the extent to which the public would accept such screening, particularly for those
individuals identified with an actionable mutation in the absence of an overt family history. As a first step toward population
based BRCA gene screening, we are sequencing the entire coding region of 18 known and proposed HBOC genes in 4,000
cancer-free Australian women recruited from the lifepool study (www.lifepool.org), which is a cohort of women attending the
Australian population, based mammographic screening program. To date, data from 1,997 women has identified 17 with
actionable mutations in BRCA1 (4 mutations), BRCA2 (9 mutations) or PALB2 (4 mutations). All 17 women subsequently
accepted an invitation to attend a Familial Cancer Centre and then proceeded to formal clinical genetic testing. In addition
4 women had pathogenic mutations in BRIP1 . Our unique pilot data directly demonstrates a population carrier frequency
of ~ 1% for pathogenic mutations in these recognized high risk breast and/or ovarian cancer genes and that such testing is
well accepted by the screened population.
Tue(3)-O26-3
Differences of Clinical Characteristics among Heterozygous Familial Hypercholesterolemia Based on Ge-
netic Diagnosis

Atsushi Nohara 1 ，Masa-aki Kawashiri 2 ，Hayato Tada 2 ，Mie Yoshida 1 ，Mika Mori 2 ，Chiaki Nakanishi 2 ，
Kunimasa Yagi 3 ，Akihiro Inazu 4 ，Takeshi Kobayashi 1 ，Masakazu Yamagishi 2 ，Hiroshi Mabuchi 1 ，
The Hokuriku FH Study Group
1:Department of Advanced Research in Community Medicine, Kanazawa University Graduate School of Medical Sciences, Japan、
2:Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences、3:Medical Education Research
Center, Kanazawa University Graduate School of Medical Sciences、4:Division of Health Sciences, Kanazawa University Graduate School
of Medical Sciences
Familial hypercholesterolemia (FH) is “underdiagnosed and undertreated” and a very common inherited disease. Genetic
diagnosis is helpful for improving their diagnosis rate. Proprotein convertase subtilisin kexin type 9 (PCSK9) gene is the third
causal gene of FH, and is now an emerging therapeutic target. We have found Gain-of-function mutation E32K in PCSK9
gene is common in Japanese FH.
Methods: A total of 940 clinically diagnosed FH heterozygotes were investigated for LDLR, PCSK9, and APOB gene. High-
resolution melting (HRM) method followed by Sanger sequence were used for point mutation, and multiplex ligation-dependent
probe amplification methods were applied for large rearrangements in LDLR. Fasting lipid levels without lipid-lowering drugs
were analyzed.
Results: LDLR mutations were identified in 732 patients (78%) and 10% of them were large rearrangements. PCSK9 E32K
mutation was identified in 56 patients (6%). No APOB mutations causing FH were identified, and 143 patients showed no
known FH-gene mutations. LDLR mutation carriers showed significantly higher LDL-C (LDLR 268±73, PCSK9 198±82,
No mutation 198±65 mg/dL, p<0.001) and higher apoB (183±51, 130±49, 148±42 mg/dL, p<0.001) compared with other
two groups. On the other hand, PCSK9 and No mutation group had higher TG compared with LDLR mutations (126±94,
150±84, 145±74 mg/dL, p<0.05 in log-transformed TG). Hypertriglyceridemia was common in PCSK9 mutation (25%, 41%,
36%, p<0.01). HDL-C was higher in No mutation group (47±15, 51±51, 55±27 mg/dL, p<0.01). Achilles tendon xanthoma
was more frequent in LDLR mutations.
Results: PCSK9 gain-of-function mutation E32K showed mild LDL-C elevation, but with frequent hypertriglyceridemia
compared with LDLR mutation carriers, and sometimes lacked xanthomas. Genetic diagnosis should be more important for
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PCSK9 mutation carriers.
Tue(3)-O26-4
Target resequencing of neuromuscular disease-related genes using next-generation sequencing for patients
with undiagnosed early-onset neuromuscular disorders
1,2 1,3
Yuri Kitamura ，Eri Kondo ，Mari Urano 1 ，Ryoko Aoki 1 ，Kayoko Saito 1,2
1:Institute of Medical Genetics, Tokyo Women’s Medical University, Japan、2:Affiliated Field of Medical Genetics, Division of Biomedical
Engineering and Science, Graduate School of Tokyo Women’s Medical University Tokyo、3:Imperial Gift Foundation AIIKU Maternal and
Child Health Center, AIIKU, Clinic Department of Pediatrics
Neuromuscular disorders are clinically and genetically heterogeneous, these disorders exhibit broadly overlapping clinical
features. Progress in molecular genetics has led to the identification of numerous causative genes for neuromuscular disorders,
but diagnosis employing Sanger sequencing remains labor-intensive and expensive due to the genes being large, overlapping
genotypes and phenotypes, and the existence of multiple genes related to a single phenotype. Recently, the advent of next-
generation sequencing (NGS) has allowed several related genes to be efficiently examined concurrently. Thus, we used NGS for
target resequencing of 74 neuromuscular disease-related genes from 42 patients with undiagnosed early-onset neuromuscular
disorders; the patients were classified based on clinical diagnosis into muscular dystrophy (MD), congenital myopathy (CM),
and spinal muscular atrophy (SMA) groups (20, 17, and 5 patients). Causative genes were identified in 21/42 (50%) patients:
MD group, 12/20 (60%) patients (7, congenital muscular dystrophy; 2, Becker muscular dystrophy (BMD); 3, limb-girdle

muscular dystrophy); CM group, 9/17 (52.9%) patients (5, nemaline myopathy; 1 each, centronuclear myopathy, congenital
fiber-type disproportion, myosin storage myopathy, and congenital myasthenic syndrome(CMS)); SMA group, 0/5 patients.
1 patient was found to have concurrent BMD and Fukuyama-type congenital muscular dystrophy. In 11/21 patients who
received a definitive diagnosis, the diagnosis did not require muscle biopsy. Thus, for patients with suspected neuromuscular
disorders, whose causative mutations are not identifiable with conventional genetic testing alone, the combination of the
conventional approach with NGS-based target resequencing is a potentially powerful tool for making a definitive diagnosis.
Accurate molecular-genetic diagnosis facilitates providing appropriate genetic counseling and effective therapy such as CMS.
Tue(3)-O26-5
Deafness gene variations in a 1,120 nonsyndromic hearing loss cohort: Molecular epidemiology and
deafness mutation spectrum of patients in Japan
Shin-ya Nishio 1 ，Shin-ichi Usami 1
1:Department of Otorhinolaryngology, Shinshu University School of Medicine, Japan
Objectives: To elucidate the molecular epidemiology of hearing loss in a large number of Japanese patients analyzed using
massively parallel DNA sequencing (MPS) of target genes.
Methods: We performed MPS of target genes using the Ion PGM system with the Ion AmpliSeq and HiSeq 2000 systems
using SureSelect in 1,389 samples (1,120 nonsyndromic hearing loss cases and 269 normal hearing controls). We filtered the
variants identified using allele frequencies in a large number of controls and 12 predication program scores.
Results: We identified 8,376 kinds of variants in the 1,389 samples, and 409,835 total variants were detected. After filtering
the variants, we selected 2,631 kinds of candidate variants. The number of GJB2 mutations was exceptionally high among
these variants, followed by those in CDH23, SLC26A4, MYO15A, COL11A2, MYO7A, and OTOF.
Conclusions: We performed a large number of MPS analyses and clarified the genetic background of Japanese patients with
hearing loss. This dataset will be a powerful tool to discover rare causative gene mutations in highly heterogeneous monogenic
diseases and reveals the genetic epidemiology of deafness.
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Tue(3)-O26-6
Improved Performance of Whole Genome Sequencing detects a SYNGAP1 Mutation in siblings with
Epilepsy with Myoclonic-Atonic seizures and photosensitivity
Mark J Cowley 1,2 ，Yu-Chi Liu 3 ，Karen L Oliver 3,5 ，Gemma Carvill 4 ，Candace Myers 4 ，Velimir Gayevskiy 1 ，
Marin Delatycki 6 ，Ying Zhu 7 ，Kevin Ying 1 ，David Miller 1 ，Paula Morris 1 ，Aaron L Statham 1 ，Heather Mefford 4 ，
Michael F Buckley 8 ，Samuel F Berkovic 5,6 ，Melanie Bahlo 3 ，Ingrid E Scheffer 5,6,9,10 ，Marcel E Dinger 1,2 ，
Tony Roscioli 1,2,11
1:Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Australia、2:St Vincents Clinical School, University of New
South Wales, Darlinghurst, Australia、3:Population Health and Immunity Division, Walter and Eliza Hall Institute, Melbourne, Australia、
4:University of Washington Department of Pediatrics, Genome Sciences, Seattle, USA、5:Epilepsy Research Centre, Department of Medicine,
University of Melbourne, Austin Health, Heidelberg, Australia、6:Austin Health, Melbourne, Australia、7:Department of Medical Genetics,
Royal North Shore Hospital、8:SEALS laboratory, Prince of Wales Hospital, Randwick, NSW, Australia、9:Florey Institute, Melbourne,
Australia、10:Department of Paediatrics, University of Melbourne, Royal Childrens Hospital, Australia、11:Department of Medical Genetics,
Sydney Childrens Hospital, NSW, Australia
We report whole genome sequencing (WGS) results in a non-consanguineous family of Ashkenazi-Jewish descent with two
sisters with epilepsy with myoclonic-atonic seizures and photosensitivity. They were investigated with targeted sequencing
of known epilepsy genes using Molecular Inversion Probes (MIPs), followed by Whole Exome Sequencing (WES), with no
aetiology identified by either technology. WGS using HiSeq X identified a 13-bp heterozygous duplication in SYNGAP1
(chr6:g.33400507_33400519dup) which was only present in both children, consistent with inheritance from a gonadal mosaic
parent. Heterozygous mutations in SYNGAP1 are consistent with the epileptic encephalopathy phenotype. We present an
analysis of the events that confounded this molecular diagnosis.

The reads containing the duplication were unmapped in the MIPs data using BWA v0.5.9, which is likely due to the large
duplication at the end of the 101bp read. By increasing the gap extension parameter (-e=20) we were able to detect the
mutation within the previously unmapped reads. The WES analysis used the hg19 reference genome, which contains 7
alternative MHC haplotypes. One of these contains SYNGAP1 , resulting in two identical copies in the reference genome, and
most reads having a mapping quality of 0. Mapping the WES reads to GRCh37 or with BWA-MEM v0.7.12 to GRCh38,
which supports alternate haplotypes, revealed the mutation. In the WGS analysis, the longer 150bp reads, and the use of
BWA-MEM v0.7.10 with the GRCh37d5 reference genome allowed the reads to map appropriately, and led ultimately to the
identification of the duplication.
This case study highlights that technical confounders can lead to missed diagnoses, and that the appropriate aligner for the
reference genome should be used. We propose that alternative analysis pipelines, and/or WGS should be performed where a
diagnosis has not been achieved using targeted sequencing and that all forms of possible inheritance should be considered.
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Tue., April 05, 2016 15:40-17:10 Room I (2F)
Chair：Michael Buckley（Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, Australia）
Chair ：Toshiyuki Yamamoto（lnstitute for lntegrated Medical Sciences, Tokyo Women’s Medical University, Japan）
Tue(3)-O27-1
The use of custom-designed NGS panels and CGH array for population-specific clinical testing
Filip Zembol 1 ，Filip Lhota 1 ，Bara Honysova 1 ，Leona Cerna 1 ，David Stejskal 1 ，Marie Trkova 2 ，Monika Koudova 1 ，
Martina Bittoova 1 ，Martina Putzova 1
1:Laboratory of molecular genetics, Gennet, Czech Republic、2:Laboratory of Clinical Cytology
With large data sets generated by new methods of next-generation sequencing (NGS), the need of proper bioinformatic data
analysis and handling is as crucial as the final clinical interpretation. For these purposes we have implied two custom-designed
NGS panels and a complementary CGH array into our clinical testing portfolio.
First is a Haloplex-based sequence capture“Carrier test” panel, which comprises 1052 known pathogenic SNVs in 202 genes
responsible for autosomal recessive hereditary disorders including various metabolic diseases, congenital syndromes, infertility
or drug intolerance. This panel can be used for determination of mutation carriers of manifested disease, gamete donation

screening or specific individuals undergoing an IVF. The second NGS panel, CZECANCA (designed at Inst. of Biochemistry
and Exp. oncology, Charles University) targets 212 cancer susceptibility and candidate genes based on the genetic variability
of Czech cancer patients. For the detection of CNVs in the most important 22 genes of this panel we have designed a CGH
array (CZECArray, CZEch Cancer Array CGH) to be used as a complementary method replacing MLPA analysis.
We have developed a bioinformatic pipeline for both NGS and CGH array data, locally build up Ensembl database and
own database for clinical reporting of relevant annotated data. The pipeline produces fastq and bam statistics output with
filtration possibilities on a user friendly interface. It has two possible alignments with automatic choice of superior alignment
and realignment around Indels with different score matrix parameters. Annotated data is filtrated by parameters of clinical
significance such as population frequencies and phenotype impact. Results and settings of this structure were validated by
direct sequencing. The last step of bioinformatics pipeline is own standalone clinical database, with number of statistical
options, searching options and reports.
Tue(3)-O27-2
aCGH ANALYSIS AND ITS IMPLICATIONS IN THE CASE OF A r(X) CHROMOSOME; ADVAN-
TAGES IN AN ERA OF DIAGNOSTIC ODISSEY
Ciprian D. Ion 1 ，Georgeta Cardos 2 ，Lucian Oprea 2 ，Viorica Radoi 1,2
1:Medical Genetics, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania、2:Synevo Central Laboratory, Cytogenetics,
Chiajna, Ilfov County, Romania
Ring chromosomes are rare structural aberrations with a frequency ranging from 1/27,000 to 1/62,000 in the postnatal setting.
We report a case with an unbalanced 46 chromosome complement encompassing a ring X, in a 2-year-old girl ascertained
through a Turner phenotype. High resolution chromosome analysis revealed the ring in a mosaic state of approximately 40%;
FISH with CEP X probe confirmed the percentage of cells with the ring, while FISH with SRY excluded the existence of a
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line harbouring a Y chromosome.
Array CGH described a sizeable terminal deletion spanning genes that escape X inactivation like SHOX, STS, NLGN4X ,
plus a possible gene disruption in GPC3 (glypican 3), a tumor suppressor gene with implications later on for the patient’s
course, increasing her risk for Wilms tumor.
Microarray was a potent and valuable method in analysis of our case of a ring X chromosome. There are some general
preconceptions about the molecular karyotype that are not always the rule. In our case it has been shown to have given
precise architectural information about a classical mechanism for the X ring formation, to provide an objective results
interpretation, including good mosaicism characterization; these data were not supplied nonetheless by the high resolution
chromosome analysis.
Concerning the clinical aspect, we were able to predict a milder Turner phenotype, with definite features like short stature,
cubitus valgus, and mild neurocognitive impairment. Fertility may be potential, given the large size of the ring, with a
possible transmission of the r(X) to her future daughters. Clinical features are the joint consequence of both the dynamic
mosaicism, and the size of the terminal deletions in the r(X) replacing a potential normal gonosome, of particular interest
being the preservation of the XIST gene in the rearranged chromosome.

Tue(3)-O27-3
Childhood-onset peripheral neuropathy: gene panel or whole exome?
Maie I Walsh 1 ，Katrina Bell 1 ，Belinda Chong 1 ，Gemma R Brett 1,2 ，Paul A James 3 ，Natalie P Thorn 1,2,4 ，
Alicia Oshlack 1,4 ，Simon Sadedin 1 ，Peter Georgeson 4 ，Ivan Maccocia 1 ，Clara Gaff 2,4 ，Eppie M Yiu 1,5 ，
Zornitza Stark 1 ，Monique M Ryan 1,4,5 ，Melbourne Genomics Health Alliance
1:Clinical Genetics, Murdoch Childrens Research Institute, Melbourne, Australia、2:Melbourne Genomics Health Alliance, Melbourne,
Australia、3:Royal Melbourne Hospital, Melbourne, Australia、4:University of Melbourne, Australia、5:Royal Childrens Hospital, Melbourne,
Australia
Purpose
To compare the diagnostic yield of a virtual gene panel and of whole exome sequencing (WES) in children with a presumed
genetic peripheral neuropathy.
Methods
Singleton WES was performed in a cohort of patients recruited though a single paediatric tertiary centre between February
2014 and August 2015. Initial analysis was restricted to an evidence-based gene list of 55 genes associated with peripheral
neuropathies and related disorders. Patients with uninformative results or a result that only explained part of their phenotype
underwent further analysis of the remainder of the WES data.
Results
Twenty-five patients with chronic peripheral neuropathy presenting in childhood were recruited (age range 3-29 years, average
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12 years). Eighteen patients had an isolated neuropathy phenotype, whereas 7 patients had additional systemic features such
as congenital anomalies and intellectual disability. Of the 25 enrolled patients, 6 received a molecular diagnosis through the
initial targeted analysis of 55 neuropathy genes (24%). A further five patients received a diagnosis following the analysis
of untargeted exome data, increasing the overall diagnostic yield to 44%. An additional two patients received a diagnosis
through SNP microarray identifying pathogenic copy number variants not detected by WES.
Conclusions
This study provides evidence that whole exome sequencing is superior to a targeted gene panel in paediatric patients presenting
with a presumed genetic peripheral neuropathy. It also outlines an approach to the reanalysis of data from patients in whom
a diagnosis is not reached following initial analysis, and reinforces the importance of microarray as a first-tier test in this
cohort of patients.
Tue(3)-O27-4
Australian Renal Gene Panels: A National Program of Diagnostic Gene Panels For Multiple Renal
Phenotypes Utilising Massively Parallel Sequencing With Multi-Disciplinary Team Reporting
Hugh J McCarthy 1,2,3 ，Amali C Mallawaarachchi 1 ，Gladys Ho 4 ，Katherine Holman 4 ，Chirag Patel 5 ，Jeff Fletcher 6 ，
Stephen I Alexander 2,3 ，Bruce Bennetts 4 ，Andrew J Mallett 7,8,9

1:Department of Clinical Genetics, The Children’s Hospital at Westmead, Australia、2:Department of Paediatric Nephrology, The Children’s
at Westmead, Sydney, Australia、3:Centre for Kidney Research, University of Sydney, Sydney, Australia、4:Department of Molecular Genetics,
The Children’s Hospital at Westmead, Sydney, Australia、5:Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane,
Australia、6:Department of Paediatrics, The Canberra Hospital, Canberra, Australia、7:Kidney Health Service and Conjoint Kidney Research
Laboratory, Royal Brisbane and Women’s Hospital, Brisbane, Australia、8:Centre for Kidney Disease Research, The University of Queensland,
Brisbane, Australia、9:Centre for Rare Diseases Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane,
Australia
Chronic Kidney Disease has a genetic aetiology in 50% and 10% of paediatric and adult cohorts respectively. Most conditions
have Mendelian inheritance but genetic heterogeneity. Phenotypic prediction of genes is poor and testing a panel of potential
genes most appropriate.
The Molecular Genetics Department of The Children’s Hospital at Westmead. Australia, is an accredited diagnostic laboratory
with a history of nephrogenetic diagnostics and panels utilizing massively parallel sequencing.
A renal genetics team was formed ensuring representation from molecular and clinical genetics and nephrology (adult and
paediatric). The team designed the gene panels and request forms (for complete phenotypic information capture). Where the
phenotype is unclear, prior discussion between the referrer and the renal genetics team ensures the most appropriate panel is
tested.
Sequencing is undertaken using Illumina Tru Sight One targeted capture and a HiSeq-series platform. Bioinformatic analysis
is restricted to genes of interest. Reportable pathogenic and likely pathogenic variants are confirmed using Sanger sequencing.
Over 120 patients from 6 Australian states have undergone sequencing for genes within one of 12 subpanels grouped into
Glomerular; Tubular; Cystic; CAKUT (congenital anomalies of the kidney and urinary tract) and complement dysregulopathy
panels with a 40% positive result rate to date. Variants classified as pathogenic, likely pathogenic and of uncertain significance
are reported. Where interpretation is difficult, additional consultation and review is provided.
In nephrology, phenotyping is difficult. Diagnostic panels of genes provide a mechanism to confirm diagnosis as the majority
of renal genes can be sequenced using targeted exome sequencing. Review by a multi-disciplinary team has provided a useful
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method for interpretation. This team also provides a conduit between referring and laboratory teams, optimising testing,
reporting and clinical utility.
Tue(3)-O27-5
Evaluating Whole-Genome Sequencing as a General Purpose Genetic Screen
Mark Pinese 1 ，Marcel E Dinger 1,2
，Mark J Cowley 1,2
1:Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Australia、2:St Vincent’s Clinical School, Faculty of Medicine,
UNSW Australia
Diagnostic laboratories have enthusiastically adopted targeted sequencing (TS, eg Illumina TruSight One) or whole exome
sequencing (WES) as general-purpose screens for genetic disorders, with diagnostic yields of ~ 25%. Whole-genome sequencing
(WGS) is an emerging technology which promises improved coverage over WES or TS, but whether this translates to better
screen sensitivity has not been established. To address this, we examined the diagnostic utility of WGS, by comparing variant
detection performance and sequencing coverage between WGS at 30X depth, WES at 123X depth, and TS at 78X depth. We
report gene coverage as >95% of bases sequenced to >10X depth, across a curated catalogue of disorder-gene associations.
Despite a lower average coverage, WGS had superior minimum coverage to WES and TS across the whole coding genome,
and was more sensitive to gold-standard NA12878 variants (99.9% WGS vs 95.5% TS). WGS provided sufficient coverage

over 96% of disorder-related genes, whereas WES only covered 82%, and TS 72%. Overall, for the 149 disorders considered, a
30X WGS-based screen would provide complete gene set coverage for 72% of disorders, versus 24% for WES, and 26% for TS.
Notably, only WGS provided sufficient coverage for genetically heterogeneous disorders like epilepsy, intellectual disability,
and cardiomyopathy.
WGS provides the best coverage and variant detection sensitivity across genes associated with genetic disorders. Although
WGS was superior overall, for a small number of disorders it was not the most efficient technology, and so we created a
web tool that compares technology performance for user-defined gene sets. If a single cover-all diagnostic screen is required,
the superior performance of WGS across the majority of genes makes it the best single choice, particularly for heterogenous
disorders where the target gene list may be very large, or subject to change over time (eg intellectual disability).
Tue(3)-O27-6
Clinical Exome in Consanguineous Population Provides Higher Detection Rate
Abdul Ali Zada 1 ，Majid Alfadhel 2 ，Soha Tashkandi 1 ，Saud Alsahli 2 ，Iram Alluhaydan 2 ，Fuad Almutairi 2 ，
Ali Alothaim 2 ，Seham Alameer 3 ，Eissa Faqeeh 1 ，Ali Alasmari 1 ，Abdulaziz Alsamman 1 ，Abdulaziz Alghamdi 4 ，
Amal Alhashem 4 ，Amir Babiker 5 ，Sarar Mohamed 5 ，Wafaa Eyaid 2 ，Ahmed Alfares 2,6
1:King Fahad Medical City, Saudi Arabia、2:King Abdulaziz Medical City, National Guard Hospital, Riyadh, Saudi Arabia、3:King Khaled
National Guard Hospital, Jeddah, Saudi Arabia、4:Prince Sultan Military Medical City, Riyadh, Saudi Arabia、5:King Saud University
Medical City and College of Medicine, Riyadh, Saudi Arabia、6:Qassim University, Qassim, Saudi Arabia
Whole-Exome Sequencing (WES) is a diagnostic method to identify molecular defects in patients with suspected genetic
disorders. The reported diagnostic rate of WES ranges from 25-35%. In Saudi Arabia, the overall estimated consanguinity
rate is 58%, the most frequent of which are first-cousin marriages (28%). Thus, we examined the effectiveness of WES in a ho-
mogenous population from consanguineous unions. METHODS: This is a multicenter study with data from five centers across
the Kingdom of Saudi Arabia. Clinical reports of 452 WES between 2011 and 2015 were reviewed. Testing was performed
in CLIA or CAP accredited laboratories. All the reported results were reviewed again by the treating physician and major
changes in the classifications of some of the reports have been made based on the additional clinical information normally
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not available to the testing laboratory. RESULTS: We present data on 452 probands with a wide range of phenotypes for
whom treating physicians ordered WES. We identified a highly likely disease-causing variant in 218 probands, achieving a
48% molecular diagnostic rate. Among the 452 families, 324 (72%) families were consanguineous and 128 (28%) were not
consanguineous or the status is unknown. The diagnostic rate increased to 52% in consanguineous unions but dropping to 39%
in non-consanguineous unions. Sixty-five percent of positive cases were harboring homozygous variants in consanguineous
families with autosomal recessive disorder. Ten positive reported results were reclassified by the treating geneticist (four
inconclusive and six negative), and 18 inconclusive reported results were reclassified (13 positive and five negative). CON-
CLUSIONS: WES identified an underlying genetic defect in 48% of patients with possible genetic conditions, reaching 52%
in consanguineous unions. It is assumed that this higher hit rate is in large part due to the simplified variant interpretation
and classification in consanguineous unions.
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[O28] Epigenetics 1
Tue., April 05, 2016 13:50-15:20 Room J (2F)
Chair：Andrea Riccio（CNR, Institute of Genetics and Biophysics, Italy）

Chair ：Kenichiro Hata（Department of Maternal Fetal Biology, National Research Institute for Child Health and Devel-
opment, Japan）
Tue(3)-O28-1
Identification of genetic determinants of monocyte epigenetic plasticity across differing innate immune
stimuli
Benjamin Fairfax 1 ，Evelyn Lau 1 ，Esther Ng 1 ，Sara Danielli 1 ，Seiko Makino 1 ，Julian Knight 1
1:Wellcome Trust Centre for Human Genetics, University of Oxford, UK
Monocytes are innately active myeloid derived cells that are responsible for much of the early cytokine release during in-
flammation and can differentiate into long-lived macrophages. DNA methylation forms an epigenetically encoded mechanism
that can have profound transcriptional consequences. Whereas the methylation of DNA at cytosine residues was envisaged
to be relatively stable in a particular cell type, evidence is accruing that conversely it is highly plastic. Given that the
genetics of monocyte gene expression are dependent upon the environmental context, we sought to explore how inflammatory
stimuli modified monocyte genomic DNA methylation using paired Illumina 450K arrays and sequencing approaches. We

observe widespread but highly specific changes in the DNA methylation profile at >1000 CpGs (FDR <1e-3) after exposure
to various inflammatory stimuli. We find the TLR4 agonist lipopolysaccharide (LPS) has both shared and specific effects
when compared to the TLR1/2 agonist Pam3CysK4 and IFN gamma. We subsequently have proceeded to describe these
effects on a population basis from a specifically recruited cohort of 192 healthy volunteers of European ancestry, comparing
the methylation profile of naive monocytes with that of moncytes exposed to LPS for 24h. We observe that ~ 500 dynamic
CpGs are dependent upon cis SNPs (FDR<0.05). Integrating these data with expression and eQTL data further enhances
our understanding of the mechanisms whereby genetic diversity impacts upon the epigenetics and gene expression of the
innate immune system. These findings have relevance to our understanding of the genetic control of monocyte inflammatory
responses and role across various disease states.
Tue(3)-O28-2
Novel epigenetic loci associated with Beckwith Wiedemann Syndrome
Izabela Krzyzewska 1 ，Marielle Alders 1 ，Saskia M. Maas 2 ，Faisal I. Rezwan 3 ，Karin van der Lip 1 ，
Adri N. Mul 1 ，Andrea Venema 1 ，Deborah Mackay 3 ，Marcel M.A.M. Mannens 1 ，Peter Henneman 1 ，
Novel epigenetic loci associated with Beckwith Wiedemann Syndrome
1:Clinical Genetics, Academic Medical Center, Netherlands、2:Department of Pediatrics, Academic medical Center, Amsterdam, the
Netherlands、3:Faculty of Medicine, University of Southampton, Southampton, UK
Beckwith Wiedemann Syndrome (BWS) is an overgrowth disorder. Most BWS cases show various genetic and epigenetic
aberrations in the imprinted region on chromosome 11p15.5. However, 20% of BWS cases cannot be explained by indels
and/or DNA-methylation aberrations of this locus. The aim of this study was to reveal new epigenetic loci explaining BWS
cases without epimutations of the 11p15.5 locus.
We collected DNA samples from 37 BWS patients (criteria of DeBaun) without any known defects in the methylome according
to our diagnostics workflow (KCNQ1OT1 , H19 ). As positive control group we used 5 patients (HIL) with known alterations
of the methylation level in BWS loci. Negative controls involved 26 healthy subjects. DNA was extracted from whole blood.
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DNA methylation levels of patients and controls were analyzed using the DNA-methylation 450K array of Illumina. General
differences including all cases vs. all controls were analyzed using the R package IMA. Single case vs. control analysis was
performed using the recently developed R method of Rezwan et al (Epigenetics, 2015).
450K array qc analysis, based on control probes and detection P-value showed no bad quality arrays. No significant differen-
tially methylated probes or regions were detected in the general analysis. Single case vs. control statistical analysis using the
method of Rezwan et al showed 5 altered methylation regions in one of the 37 BWS diagnosed patients. These differentially
methylated regions were also moderately disrupted in the positive control HIL patients but did not involve the critical BWS
locus (KCNQ1OT1 , H19). The genes situated in these 5 disrupted regions perfectly fit an overgrowth phenotype as described
in earlier reports.
Our study suggests that the 5 regions in which we found DNA-methylation alterations may be considered as new epigenetic
loci for BWS susceptibility. Additional studies of these loci have to be performed before including them in an extended
diagnostic package for BWS.
Tue(3)-O28-3
Genome-Wide DNA Methylation and Gene Expression Analyses in Blood and Dermal Fibroblasts from
Twin Pairs Discordant for Systemic Sclerosis Reveals Distinct Signatures Between Disease Subsets

Paula S Ramos 1 ，Thomas A Medsger Jr 2 ，Carol A Feghali-Bostwick 1
1:Medical University of South Carolina, USA、2:University of Pittsburgh
The reasons underlying the wide variation in disease heterogeneity in systemic sclerosis (SSc) remain unknown. This analysis
was conducted to characterize (a) DNA methylation profiles of whole blood and dermal fibroblasts in twins discordant for
SSc, and (b) differentially expressed genes in dermal fibroblasts of twins discordant for SSc.
Methylation was assessed on 470,000 CpGs using genomic DNA isolated from 1) whole blood from 20 twin pairs discordant for
limited cutaneous SSc (lcSSc) and 10 twin pairs discordant for diffuse cutaneous SSc (dcSSc), and 2) skin fibroblasts from 5
twin pairs discordant for lcSSc and 7 twin pairs discordant for dcSSc. Gene expression was assessed on total RNA from these
skin fibroblasts on 47,000 transcripts. An efficiency analysis was performed with caGEDA to determine best normalization
and to test for differential methylation/expression between unaffected and affected twins. Ingenuity Pathway Analysis was
used for pathway analysis.
Dramatic DNA methylation differences were observed both between tissues and disease subsets, with very limited overlap.
Despite the enrichment of different pathways and biological functions in each tissue and disease subset, most of these pathways
can be placed into broader categories implicating an overall involvement of cancer functions. Gene expression data from
fibroblasts revealed 20% of genes shared between disease subsets. There were common and unique pathways enriched in
disease subsets, also implicating an involvement of cancer functions. There were no genes simultaneously differentially
methylated and expressed in either disease subset.
The distinct methylation patterns observed in blood and fibroblasts between lcSSc and dcSSc suggest that subset-specific
epigenetic signatures may be, at least in part, responsible for the clinical heterogeneity of the disease. These data also support
a role for DNA methylation differences in mediating susceptibility to SSc.
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Tue(3)-O28-4
Deletion of the Williams syndrome region in human and mouse causes systemic, genome-wide changes
in DNA methylation
Emma Strong 1 ，Rajat Singhania 2 ，Daniel De Carvalho 2 ，Luis A Perez-Jurado 3,4,5
，Victoria Campuzano 3,4,5
，
Lucy R Osborne 1,6
1:Molecular Genetics, University of Toronto, Toronto, Canada、2:Princess Margaret Cancer Centre, University Health Network, Toronto,
Canada、3:Genetics Unit, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain、4:Hospital
del Mar Research Institute (IMIM), Barcelona, Spain、5:Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER),
Barcelona, Spain、6:Department of Medicine, University of Toronto, Toronto, Canada
Williams syndrome (WS) is a developmental disorder caused by deletion of ~ 25 genes on chromosome 7q11.23, whilst the
reciprocal duplication (Dup7) results in a distinct syndrome. Both disorders present with an array of cognitive and behavioural
phenotypes. Several genes at 7q11.23 have been linked with epigenetic regulation, and we recently identified striking genome-
wide, symmetrical changes in DNA methylation in peripheral blood from children with WS and Dup7. These differentially
methylated (DM) positions were enriched in many pathways associated with neurodevelopment.
Based on our initial findings we hypothesized that similar genome-wide changes in DNA methylation would be present in
other tissues and thus we extended our analyses to a tissue more relevant to the cognitive and behavioural features of WS
and Dup7. We used reduced representation bisulfite sequencing (RRBS) to identify genome-wide DM loci in DNA from the
cortex of nine week old mice with a hemizygous deletion of the WS syntenic region (Gtf2i to Fkbp6 ), compared to wild type
mice. DM loci were enriched for many neuronal pathways (using GREAT), including terms relating to neural development

and neurotransmitter transport and release. Direct comparison of the human and mouse data was difficult since different
platforms were used, but it is clear that DM loci in mouse cortex span several autism spectrum disorder-associated genes,
including Shank3, which was DM in our original study.
Our identification of genome-wide changes in DNA methylation in blood and brain in humans and mice with WS suggests
that aberrant DNA methylation is likely a systemic feature in WS and Dup7, and that epigenomic effects may underlie many
of the neurological features of these disorders. We are currently focusing on assessing DNA methylation profiles of individuals
with atypical deletions and duplications of 7q11.23 to help unravel the underlying molecular mechanisms of aberrant DNA
methylation in these disorders.
Tue(3)-O28-5
The zinc-finger protein ZFP57 controls imprinted and non-imprinted genes through different types of
cis-acting regulatory elements
Andrea Riccio 1,2 ，Vincenzo Riso 1,2 ，Marco Cammisa 1,2 ，Harpreet Kukreja 1,2 ，Zahra Anvar 1,2
，Shraddha Lad 1 ，
Annalisa Fico 1 ，Angela Sparago 1,2 ，Claudia Angelini 3 ，Grimaldi Grimaldi 1
1:CNR, Institute of Genetics and Biophysics, Italy、2:2nd University of Naples, DiSTABiF, Caserta、3:Istituto per le Applicazioni del
Calcolo Mauro Picone (IAC), CNR, Napoli
Maintenance of imprinting in early embryogenesis is critical for normal development and altered imprinting results in human
diseases and cancer. The zinc finger protein ZFP57 is necessary for maintaining repressive epigenetic marks at Imprinting
Control Regions (ICRs) and ZFP57 deficiency causes mid-gestation lethality in the mouse and imprinting disorder in humans.
High-throughput analyses of new and reported gene knock-outs showed that ZFP57 plays a broader role in the control of
cis-acting regulatory elements in undifferentiated embryonic stem cells (ESCs). In absence of ZFP57, we find complete and
extensive loss of tri-methylation of lysine 9 of histone H3 (H3K9me3) and mCpG paralleled by increase of tri-methylation of
lysine 4 of histone H3 (H3K4me3) at all ICRs. A larger number of ZFP57 target sites whose imprinting is mostly unknown show
H3K9me3 loss as well, but undergo moderate DNA hypomethylation which is paralleled by acquisition of mono-methylation
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of lysine 4 of histone H3 (H3K4me1). We find that the different H3K4me1/H3K4me3 ratio of ICR and non-ICR ZFP57 target
sites is not simply a consequence of their mCpG level, but these active marks appear as specific features of these loci that
are repressed by ZFP57 in undifferentiated ESCs. Furthermore, ZFP57 loss results in activation of nearby genes at both
imprinted and non-imprinted target sites. These data support a model in which ZFP57 recruits heterochromatin marks to
prevent activation of promoters at imprinted loci, and tissue-specific enhancers at non-imprinted loci in undifferentiated ESCs.
These results are relevant for understanding molecular mechanisms and phenotypes associated with imprinting disorders.
Tue(3)-O28-6
RNF12 is essential for X-inactivation in female mouse embryonic stem cells, is required for female mouse
development, and might be a target for future therapies to treat X-linked disorders in females: evidence
from a mouse knockout model
1,2 2
Stefan Barakat ，Joost Gribnau
1:MRC Centre for Regenerative Medicine, University of Edinburgh, UK、2:Erasmus MC-University Medical Center, Rotterdam
X-inactivation (XCI) is a crucial mechanism which equalizes X-linked gene-dosage between both sexes. In mice, a first wave
of imprinted XCI (iXCI) occurs during cleavage stages of embryonic development, followed by X-reactivation (XCR) at the
pre-implantation blastocyst, and subsequent random XCI (rXCI) in the post-implantation epiblast. rXCI can be simulated in
differentiating mouse ES cells. We have previously shown that the X-encoded RNF12 protein act as a dosage-sensitive XCI-

activator (PMID:19945382, PMID:21298085, PMID:24613346). When RNF12 becomes up-regulated during differentiation,
it targets the pluripotency factor Rex1 for proteasomal degradation (PMID:22596162). As Rex1 is a repressor of the non-
coding Xist RNA, which is crucial for initiating chromosome-wide gene-silencing, down-regulation of Rex1 by RNF12 allows
female-specific Xist-expression and XCI-initiation in a stochastic manner (PMID:20083102). Here we present the generation
and analysis of a novel Rnf12 knockout mouse model, and provide evidence that RNF12 is also crucial for iXCI and rXCI in
vivo. Whereas Rnf12 -/Y males are viable, Rnf12 -/- female mice fail to undergo XCI leading to post-implantation lethality.
Rnf12 -/+ animals inheriting the maternal knockout allele are lethal due to silencing of the paternal Rnf12 allele upon iXCI.
In addition, RNF12 stored in the oocyte and produced de novo from both the maternal and paternal X-chromosome influence
XCI kinetics in pre-implantation embryos. Rnf12 +/- females inheriting the paternal knockout allele are healthy but show an
XCI-defect, with adult cells displaying XCR. Bi-allelic expression of X-linked transcripts is observed in various tissues, but is
compensated by an XCI-independent form of dosage compensation. This peculiar finding, together with our recent results on
XCR in human iPS cells (PMID: 25640760), opens a new area of research which might lead to novel approaches for treating
X-linked diseases, such as Rett syndrome, in females.
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[O29] Epigenetics 2
Tue., April 05, 2016 15:40-17:10 Room J (2F)
Chair：Hiroyuki Sasaki（Division of Epigenomic and Development, Department of Molecular Genetics, Medical Institute
of Bioregulation, Kyushu University, Japan）
Chair ：Melanie A. Carless（Genetics, Texas Biomedical Research Institute, USA）
Tue(3)-O29-1
Longitudinal changes in DNA methylation influence type 2 diabetes
Melanie A Carless 1 ，Jack W Kent 1 ，Hemant Kulkarni 2 ，Michael C Mahaney 2 ，Anthony G Comuzzie 1 ，John B 2
1:Genetics, Texas Biomedical Research Institute, USA、2:South Texas Diabetes and Obesity Institute
We recently conducted an epigenome-wide study investigating the effect of DNA methylation on diabetes, identifying signifi-
cant associations between DNA methylation levels at 53 CpG sites and liability to type 2 diabetes (T2D), fasting blood glucose
and insulin resistance. In order to investigate whether these genes might play a role in the onset of disease, we took advantage
of the longitudinal design of our study and assessed DNA methylation levels in 250 individuals at two different time-points,
collected approximately five years apart. We conducted pyrosequencing analysis on seven genetic regions (ABCG1 , CALHM1 ,
CPT1A, LOXL2 , SOCS3 , SREBF1 , TXNIP; each encompassing between 2-5 CpG sites) that were significantly associated
with T2D in our initial study. We used a polygenic regression framework within SOLAR to identify associations between

differences in methylation across the two visits and differences in fasting glucose, insulin resistance and T2D. Applying a
Bonferroni correction (based on the number of genetic regions assessed, p<7.14x10-3 ), we identified significant associations
between methylation differences in candidate regions and differences in diabetes-related traits, including: TXNIP and fasting
glucose and T2D (p=8.39x10-7 , and 4.97x10-6 , respectively); and LOXL2 and fasting glucose (p=5.38x10-3 ). Our pyrose-
quencing studies indicate that DNA methylation may play a role in longitudinal changes in quantitative diabetes-related
traits and TXNIP in particular, may be involved in progression towards diabetes. We are currently conducting an epigenome-
wide study, using Illumina HumanMethylation450 BeadChip arrays to identify additional candidate genes that may serve as
markers for early detection of type 2 diabetes.
Tue(3)-O29-2
Genome-wide and targeted analysis of DNA methylation in disease discordant amyotrophic lateral scle-
rosis (ALS) cohorts
Kelly L Williams 1 ，Beben Benyamin 2 ，Emily P McCann 1 ，Anjali K Henders 2 ，Sonia Shah 2 ，Dominic B Rowe 1 ，
Garth A Nicholson 1 ，Naomi Wray 2 ，Ian P Blair 1
1:Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia、2:Queensland Brain Institute, University of Queensland,
Brisbane, Australia
Amyotrophic lateral sclerosis (ALS) is a late-onset fatal disorder characterised by progressive degeneration of upper and lower
motor neurons. Mutations in just two genes, C9ORF72 and SOD1 , account for more than half of Australian hereditary
ALS cases. Substantial variation is seen in age of onset and progression of disease, including among patients with identical
gene mutations. Comorbidity with frontotemporal dementia (FTD) is frequently observed, especially in patients with the
C9ORF72 repeat expansion. The absence of a clear genotype-phenotype correlation provides strong evidence for the role of
highly penetrant modifying factors, including epigenetic changes, in disease onset and progression. Discovery of modifiers will
provide insight into the phenotypic discordance, highlight dysfunctional disease pathways, and offer potential targets to delay
onset or progression of ALS/FTD.
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We are examining both genome-wide and gene-specific DNA methylation in a large cohort of ALS and/or FTD families
with C9ORF72 repeat expansions or SOD1 mutations. The discovery cohort comprises 315 individuals from 84 families,
including patients with ALS and/or FTD, pre-symptomatic individuals (i.e. carry a disease-causing mutation but currently
unaffected) and controls. gDNA samples have undergone genome-wide methylation quantitation using the Illumina Human-
Methylation450K BeadChip. An EpiTYPER assay determined quantitative methylation of the SOD1 and C9ORF72 CpG
islands.
Initial analysis shows a substantially higher level of C9ORF72 -CpG island methylation in the single“pure FTD” patient.
Genome-wide analysis has identified a highly significant differentially methylated CpG site (p=5x10-9 ) in C9ORF72 cases
compared to controls. The CpG site falls within the promotor region of a gene encoding an RNA-binding protein, relevant to
disease since RNA processing dysfunction is one of the two major pathogenic mechanisms implicated in ALS.
Tue(3)-O29-3
Genome-wide analysis of neuron specific DNA methylation in Alzheimer’s disease
Tatsuo Mano 1 ，Kenichi Nagata 2 ，Shigeo Murayama 3 ，Takaomi C. Saido 2 ，Shoji Tsuji 1 ，Atsushi Iwata 1,4
1:Department of Neurology, Graduate School of Medicine, The University of Tokyo, Japan、2:Laboratory for Proteolytic Neuroscience,
RIKEN BSI、3:Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital、4:Japan Science and Technology Agency, PRESTO

In Alzheimer’s disease, deposition of amyloid beta and phosphorylated tau has been shown to be the cardinal features.
However, it remains to be elucidated how these features are related to deterioration of neuronal function and what kinds
of other molecules play an important role in pathogenesis. To elucidate a novel pathogenic pathway in neuronal cells, we
performed epigenome-wide analysis of neuron specific DNA methylation with Illumina’s Infinium 450k DNA methylation
Beadchip system. We used 30 Alzheimer’s disease brain samples and 30 age-matched healthy control brain samples. Brain
tissues from inferior temporal gyrus were minced and, neuronal and non-neuronal nuclei were separated by FACS (fluorescence
activated cell sorting) with anti-NeuN antibody. Genomic DNA was extracted and analyzed with Infinium 450k DNA
methylation Beadchip. We found 316 differentially methylated probes (DMPs), and extracted 10 differentially methylated
regions (DMRs) from these DMPs. These DMRs were related to 10 genes and 3 DMRs were in CpG islands of the promoter
regions. We validated these DNA methylation changes of 3 genes by pyrosequencing. We also analyzed DNA methylation
levels of these 3 gene regions of genomic DNA from whole blood cells in Alzheimer’s disease and from neuronal cells in Lewy
body disease, which revealed these methylation changes observed in neuronal cells in Alzheimer’s disease brain were disease
specific and brain specific. RT-qPCR and immunohistochemistry revealed that two genes were differentially expressed at
mRNA and protein levels. Overexpression of APP with the Swedish mutation (KM670/671NL) induced up-regulation of one
of these genes in vitro and Alzheimer’s disease model mouse. Our study showed for the importance of neuron specific DNA
methylation analysis in finding a novel mechanism of neurodegenerative disease.
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Tue(3)-O29-4
Metabolomic changes fine-map the DNA methylation signature of cigarette smoking
1,2
Yan V. Sun ，Yunfeng Huang 1 ，Qin Hui 1 ，Douglas Walker 3 ，Dean Jones 3 ，Jack Goldberg 4 ，Viola Vaccarino 1
1:Department of Epidemiology, Rollins School of Public Health, Emory University, USA、2:Department of Biomedical Informatics, Emory
University School of Medicine, Atlanta, GA, USA、3:Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School
of Medicine, Atlanta, GA, USA、4:Vietnam Era Twin Registry and Department of Epidemiology, University of Washington School of Public
Health, Seattle, WA, USA
Cigarette smoking is a major risk factor of human diseases including cancer and cardiovascular disease. Smoking-related
metabolic changes have revealed its biochemical effects in human body. Additionally, epigenetics including DNA methylation
(DNAm) plays an important role in the regulation of gene expression and the protection of genome integrity. Several
studies have shown that smoking modifies DNAm levels. However, the role of multiple smoking-related metabolites in
modifying DNAm has not been thoroughly investigated. We conducted an epigenome-wide association study (EWAS) of 11
smoking related metabolites, including nicotine and cotinine, in 180 adult male twins to fine-map the relationship between
smoking-related metabolites and DNAm levels. Adjusted for age, relatedness, batch effect and cell type heterogeneity, we
identified three, three, four and 46 CpG sites significantly associated (FDR corrected p<0.05) with 13-C cotinine, cotinine,
5-Hydroxycotinine and N-Acetylpyrrolidine, respectively. No significant association was identified for the other 7 smoking-
related metabolites. Additionally, we compared the association results between DNAm and smoking-related metabolites to
that between DNAm and self-reported smoking status, and observed both consistent and inconsistent epigenetic associations
with smoking status and metabolites. These detailed epigenetic associations with smoking-related traits may help to further

understand specific pathways causing DNAm changes provide insights in the smoking-related health risks mediated by DNAm.
More importantly, the integrative metabolome-epigenome approach can be extended to investigate other risk factors and
human disease, and can provide a comprehensive and complementary understanding of the molecular systems linking risk
factors, multiple molecular layers and the disease traits.
Tue(3)-O29-5
Deciphering the role of DNA methylation in SLE pathogenesis through integrative analysis of different
types of genomic data
Mengbiao Guo 1 ，Tingyou Wang 1 ，Wanling Yang 1
1:University of Hong Kong, China
Although genetic studies of systemic lupus erythematosus (SLE) over the past decade has yielded many insights, missing
heritability still exist and epigenetics has been proposed to account for the missing heritability. Genome-wide DNA hypo-
methylation in patients compared with healthy individuals is a hallmark of SLE, but studies on methylation in SLE have
focused on differentially methylated sites only. In-depth analysis of methylation is needed to address the possible mechanisms
of SLE pathogenesis. Using genome-wide DNA methylation data (Illumina 450k) of B cell, T cell and monocytes, we identified
a large set of differentially methylated regions (DMRs). Large proportion of DMRs were shared among these 3 cell types,
with T cells hosting the largest number of DMRs. We found very consistent DMR patterns among groups of known SLE
susceptibility genes such as IRF7, ETS1 and CD247. Especially interesting among these genes are ones that exhibit immune
cell type specific histone marks, such as BLK and CD247. We correlated by cell type DMRs with gene expression and found
high consistency. For approximately 100 upregulated genes, 40 of them correspond to hypo-methylation, with only 1 or 2 to
hyper-methylation which may suggest other mechanisms of expression regulation. With the goal of finding clusters of TFs
that are present in the DMRs, we performed biclustering of genomic regions and 165 TFs who have binding sites (TFBSs)
in top DMRs. We found one bicluster (26 TFs x 78 DMRs) that shows dense presence of TFBSs and significant enrichment
of immune-related TFs (14 out 26 TFs, p-value = 0.005828). Additionally, GWAS association signals (SNPs) and expression
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quantitative trait loci (eQTLs) also tend to co-occur within DMRs. Preliminary results of protein-protein interaction (PPI)
of genes near DMRs showed itself to be another promising direction of analysis. Overall, DNA methylation analysis serves a
promising method to probe SLE pathogenesis.
Tue(3)-O29-6
DNA methylation profiling of Crohn’s disease in peripheral blood and CD14+ cells in women
Andrew Y.F. Li Yim 1,4 ，Jing Zhao 2 ，Nicolette N.W. Duijvis 2 ，Wouter J. de Jonge 2 ，Menno P.J. de Winther 3 ，
Adri N. Mul 1 ，Marcel M.A.M. Mannens 1 ，Anje A. te Velde 2 ，Peter Henneman 1
1:Clinical Genetics, Academic Medical Center, Netherlands、2:Tytgat Institute for Live & Intestinal Research, Academic Medical Center,
Amsterdam, The Netherlands、3:Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands、4:Department of
Epigenetics, GlaxoSmithKline, Stevenage, United Kingdom
Crohn’s disease (CD) is a complex chronic disorder and is characterized by inflammation in distinct parts of the gastrointestinal
tract with symptoms including diarrhea, fever, abdominal pain, weight loss and anemia. While numerous genome-wide
association studies (GWAS) have identified CD-associated loci, common variants explain only 20% of the estimated heritability.
A growing body of literature suggests that additional factors such as diet, the gut-microbiome and the epigenome play an
important role in the development and progression of CD. In this study we sought to elucidate the effects of CD on the DNA
methylome of peripheral blood and CD14+ monocytes obtained from adult women using the Illumina HumanMethylation
450k BeadChip. Targets of interest were confirmed through amplicon (MiSEQ) sequencing. Our analysis in peripheral

blood implicated 4,509 significantly differentially methylated positions (DMPs; corrected P < 0.05) blood with a maximum
methylation difference of 20%. Gene ontology (GO) analysis on significant DMPs revealed enrichment in pathways associated
to immune response, wounding and response to molecules of bacterial origin (corrected P < 0.05). In addition to DMPs, we
searched for differentially methylated regions (DMRs), which we defined as groups of four or more consecutive DMPs. In total
we report eight DMRs with notable DMRs found upstream of genes responsible for immunoregulation and genes that code for
long non-coding RNAs. Next, we sought to establish which leukocyte in the peripheral blood is responsible for the differential
methylation. Preliminary analysis of the methylome in CD14+ cells yields neither significant DMPs nor significant DMRs
when comparing CD patients versus healthy controls. We are currently in the process of comparing our results with other
datasets obtained from previous studies as well as methylation data obtained from pro- and anti-inflammatory macrophages
(unpublished data).
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[O30] Genome structure, variation and function 1

Tue., April 05, 2016 13:50-15:20 Room K (2F)
Chair：Andrew H. Sinclair（Deputy Director, Murdoch Children’s Research Institute, Melbourne, Australia）

Chair ：Itsuro Inoue（Division of Human Genetics, National Institute of Genetics, Japan）
Tue(3)-O30-1
Mechanism of transcriptome abnormalies in Cornelia de Lange syndrome: Disturbance of trnascriptional
elongation
1,2
Kazuhiro Akiyama ，Masashige Bando 1 ，Ian D Krantz 3 ，Kosuke Izumi 1,3
，Katsuhiko Shirahige 1
1:Research Center for Epigenetic Disease, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Japan、2:Japan Society
for the Promotion of Science、3:Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Cornerlia de Lange Syndrome (CdLS) is characterized by facial dysmorphisms, intellectual disabilities, growth retardation
and limb anomalies. CdLS is mainly caused by NIPBL, cohesin regulatory factor. Unique transcriptome pattern is seen in
CdLS, and genome-wide distribution alterations of AFF4, a component of super elongation complex (SEC) was implicated
as a molecular basis of such unique transcriptome. SEC controls transcriptional elongation reaction and contributes to the
gene expression regulation during embryogenesis.

In order to reveal transcriptional regulatory mechanism governed by NIPBL, we performed transcriptome analyses using
genome-edited NIPBL mutant cell lines and CdLS sample. RNA-seq revealed that highly expressed genes were down-regulated,
and lowly expressed genes were up-regulated in NIPBL mutant cell line and CdLS. Next, we evaluated the profile of nascent
RNA, which is actively transcribed RNA. Nascent RNA-seq of NIPBL mutant line revealed the presence of aberrant tran-
scriptional elongation, suggesting that altered transcriptional elongation underlies transcriptome abnormalities of CdLS.
To understand how transcriptional elongation process is controlled by NIPBL, we utilized in vitro pre-initiation complex
(PIC) and SEC assembly systems. Transcription reconstitution system revealed that NIPBL was recruited to the gene coding
region, under transcriptional activation condition that recapitulates NIPBL genomic binding pattern in vivo. In addition,
elongation inhibitors caused NIPBL accumulation on gene promoter region, and NIPBL depletion inhibited the recruitment of
SEC components. These findings indicate NIPBL contributes to the stability of SEC-binding to the genome and adjustment
of transcriptional elongation step.
Collectively, in vivo and in vitro data strongly suggest NIPBL controls gene transcription via governing transcriptional elon-
gation step, and transcriptome alteration of CdLS is caused by dysregulation of transcriptional elongation.
Tue(3)-O30-2
Comprehensive analyses of the regulatory sequences derived from human endogenous retroviruses
Jumpei Ito 1 ，Shiro Yamada 1 ，Ryota Sugimoto 1 ，Hirofumi Nakaoka 1 ，Ituro Inoue 1,2
1:Human Genetics, National Institute of Genetics, Japan、2:The Graduate University For Advanced Studies (SOKENDAI)
Human genome contains 500 families, 700,000 copies of human endogenous retroviruses (HERVs) comprising 8% of total
genome. Although all HERV copies were already inactivated by accumulations of the deleterious mutations, transcriptional
regulatory sequences of HERVs (HERV cis-elements) still retain their activities on promoters, enhancers, and insulators.
Recently, importance of the HERV cis-elements on host transcriptional network was repeatedly discussed, however, the
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fundamental information, such as what kinds of cis-elements each HERV family has, is still unclear. Here, we comprehensively
identified and analyzed HERV cis-elements that were commonly observed among HERV copies belonging to one particular
HERV family, termed HERV conserved cis-elements, using data sets of ENCODE and Roadmap Epigenomics. In order
to identify HERV conserved cis-elements, we first extracted the overlapped regions between HERV and TFBS from ChIP-
Seq and multiply aligned them. Subsequently, we identified the conserved cis-elements that present the same positions of
multiply aligned sequences. As the results, various HERV conserved cis-elements were identified in germ cells (SOX2, OCT4
and NANOG), hematopoietic cells (PU.1, TAL1 and GATA2), and ubiquitously observed CTCF. A comparison between
phylogenetic relationship of intra-HERV family and presence or absence of conserved cis-elements revealed some cis-elements
were gained or lost during the HERV endogenizing periods. After all, abundant HERV copies belonging to a certain family
have a particular set of cis-elements, and so they can coordinately affect on the host transcriptional network. This study
provides fundamental information to elucidate HERVs functions on the host transcriptional network and insights into the
evolutions of HERVs or their ancestral retroviruses in terms of the regulatory sequences.
Tue(3)-O30-3
RNA splicing is a primary link between genetic variation and disease
Yang I Li 1 ，Bryce van de Geijn 2 ，Anil Raj 1 ，David Knowles 1 ，Allegra Petti 3 ，David Golan 1 ，Yoav Gilad 2 ，
Jonathan K Pritchard 1,4
1:Stanford University, USA、2:University of Chicago、3:Washington University in St. Louis、4:Howard Hughes Medical Institute, Stanford

University
Noncoding genetic variants play a central role in both the etiology of diseases and the evolution of novel traits in humans,
yet the exact mechanism by which most variants act remain largely unknown. I will present an evaluation of inter-individual
variation in gene regulation using newly and previously collected molecular data from a population sample of Yoruba lym-
phoblastoid cell lines. I will first show that variation in gene transcription rates nearly always result in concordant changes
in protein expression levels. Our results support two widely assumed primary mechanisms that mediate the effect of genetic
variants on complex traits: chromatin-based mechanisms and mechanisms that control gene expression co- or post- transcrip-
tionally. I will then present how we used a novel method to detect variation in intronic splicing and identified over a thousand
genetic loci at 10% false discovery rate that affect mRNA splicing (sQTLs). Most sQTLs had little or no detectable effect on
overall gene expression and function through distinct mechanisms, indicating that mRNA splicing is a third primary target of
common genetic variation. We also found that variation in mRNA splicing contribute significantly to several complex traits
and, for certain diseases, show stronger effects than variants that control gene expression levels. RNA splicing therefore links
common genetic variation to complex disease risk.
Tue(3)-O30-4
Global patterns of copy number variation in humans from a population-based analysis
1,2
Jean Monlong ，Caroline Meloche 3 ，Guy Rouleau 4 ，Patrick Cossette 3 ，Simon Girard 1,2
，Guillaume Bourque 1,2
1:Human Genetics, McGill University, Montreal, Canada、2:McGill University and Genome Quebec Innovation Center, Montreal, Canada、
3:Centre de Recherche du Centre Hospitalier de l’Universite de Montreal, Notre Dame Hospital, University of Montreal, Montreal, Quebec,
Canada、4:Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada
Copy number variants (CNVs) are known to affect a large portion of the human genome and have been implicated in many
diseases. Although whole-genome sequencing holds the promise of facilitating the systematic identification of CNVs and of
other types of structural variants, existing analytical methods suffer from limited sensitivity and specificity.
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Here we show that this is due to the non-uniformity of read coverage, even after intra-sample normalization, and that this
issue is exacerbated in specific regions of the genome. To improve on this, we propose PopSV, a new analytical method that
uses multiple samples to control for technical variation and enables the robust detection of CNVs throughout the genome. We
show that PopSV is able to detect 50% more variants than previous methods, including variants in regions of low-mappability,
with an accuracy of about 90%.
Applying PopSV to 640 human whole genomes, we demonstrate that CNVs affect on average 7.3 million DNA bases in each
individual. This represents a 22% increase compared with previous estimates, which can be explained in part by the fact
that regions of low-mappability, that are frequently concealed, harbor 9.8 times more CNVs than the rest of the genome.
Specifically, we observe that CNVs are found more than expected near centromeres and telomeres, in segmental duplications,
in specific types of satellite repeats and in some of the most recent families of transposable elements such as L1-Hs and SVAs.
Although CNVs are found to be depleted in protein-coding genes, we identify 7242 genes with at least one exonic CNV, 326
of which hosted exonic CNVs in low-mappability regions. Similarly, 2261 trait- and disease-associated loci are observed to
overlap at least one CNV. In summary, our results provide the most comprehensive map of CNVs across the human genome
to date and highlight the broad potential impact of this type of genetic variation including in regions that are frequently
ignored.
Tue(3)-O30-5

Identification and analysis of two novel enhancers of human SOX9: Implications for Disorders of Sex
Development
Andrew H Sinclair 1 ，Thomas Ohnesorg 1 ，Jacqueline Tan 1 ，Jo Bowles 2 ，Peter Koopman 2 ，Vincent Harley 3
1:Molecular Development, Murdoch Children’s Research Institute, Australia、2:Institute for Molecular Bioscience, Queensland、3:Hudson
Institute of Medical Research, Victoria
Disorders of Sex Development (DSDs) encompass a wide spectrum of conditions and often manifest with atypical gonads
or genitalia. The cause is often a flaw in the network of gene regulation responsible for development of testes or ovaries.
The majority of DSD patients cannot be given an accurate diagnosis, which severely comprises their clinical management.
While mutations in coding regions of gonad genes have been important in understanding the etiology of DSD little attention
has focussed on the regulatory regions of gonad genes. Recent reports of 46,XX testicular DSD patients with duplications
and 46,XY gonadal dysgenesis patients carrying deletions ~ 500-600kb upstream of SOX9 suggest the presence of a gonad
enhancer of SOX9 . Using a comprehensive tiling luciferase approach we identified two novel putative enhancers within this
region. The enhancer showing the strongest activity in vitro was further analysed and used to generate transgenic reporter
mice. We show that this enhancer mediates SOX9 auto-regulation in vitro and leads to strong reporter gene expression in
embryonic gonads at the time of sex determination and gonad differentiation. Our results strongly suggest that deletions or
duplications (CNVs) of this enhancer lead to DSD. While this enhancer appears to be responsible for the maintenance of SOX9
expression, we have identified an additional enhancer close to human SOX9 , which may be responsible for SRY-dependent
up-regulation of SOX9 and subsequent testis development.
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Tue(3)-O30-6
First genome-wide CNV association meta-analysis on anthropometric traits in 71,288 adults
Aurelien Mace 1,2 ，Ruth JF Loos 3,4 ，Jacques S Beckmann 2 ，Sebastien Jacquemont 5 ，Andres Metspalu 6 ，
Lude Franke 7 ，Timothy M Frayling 8 ，Alexandre Reymond 9 ，Zoltan Kutalik 2,10 ，GIANT Consortium
1:Department of Medical Genetics, University of Lausanne, Switzerland、2:Swiss Institute of Bioinformatics, University of Lausanne,
Lausanne, Switzerland、3:The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York,
USA、4:The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, USA、5:Service
de Genetique Medicale, Centre Universitaire Hospitalier Vaudois, Lausanne, Switzerland、6:Estonian Genome Center, University of Tartu,
Tartu, Estonia、7:University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands、
8:Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK、9:Center of Integrative Genomics, University of Lausanne,
Lausanne, Switzerland、10:Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, Switzerland
Many common SNPs influence disease susceptibility, but explain only part of the heritability. On the other hand, we have
shown that the rare 16p11.2 copy number variant (CNV) has substantial effect on body-mass index (BMI). It is likely that
additional CNVs could further contribute.
As SNP-array based CNV calling has high false positive rate, we first developed a novel quality score (QS) to estimate the
probability of a CNV call being true. The QS optimally combines available CNV- and sample-related quality metrics. Simu-
lation results showed that our QS-based association could yield up to 5-fold increase in power compared to classical filtering
approaches, in particular for CNVs up to 10% frequency and low quality.
Using the inferred probabilistic CNV calls we performed a genome-wide CNV association meta-analysis on anthropometric

traits using 34 cohorts of the GIANT consortium, representing 71,288 unrelated adults genotyped on various Illumina plat-
forms. Results from this large meta-analysis showed 4.4-fold enrichment of low P-values (P<0.05) for known obesity CNVs and
gave new insights on the impact of the 16p11.2 region: beyond replicating the known effects of the 220kb deletion (P=2E-6)
and 600kb rearrangements (P=3E-5), we found that the 220kb deletion (frq=0.03%) increases BMI mainly through increas-
ing weight (by 1.26 SD, P=5E-8) and the 600kb deletion (frq=0.02%) does so by principally decreasing height (by 0.85 SD,
P=1E-6) along with a small increase in weight (P=1E-3). A further highlight - at the limit of genome-wide significance level
for CNV associations (P<2E-7) - includes a link between the rare (frq=0.01%) duplication of a region encompassing ENOX1
and higher weight (P=5E-7). We are currently extending the meta-analysis to ~ 190K individuals including samples from the
UK BioBank. This large CNV-association study is best positioned to shed light on the impact of CNVs on anthropometric
traits in the adult general population.
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Tue., April 05, 2016 15:40-17:10 Room K (2F)
Chair：Michael A. Hauser（Departments of Medicine and Ophthalmology, Duke Molecular Physiology Institute, Duke
University, USA）
Chair：Shinya Matsuura（Department of Genetics and Cell Biology, Research Institute for Radiation Biology and Medicine,
Hiroshima University, Japan）
Tue(3)-O31-1
Unraveling the role of genomic imprinting at 16q24.1 in pathogenetics of alveolar capillary dysplasia with
misalignment of pulmonary veins and maternal uniparental disomy 16
Pawel Stankiewicz 1 ，Avinash V Dharmadhikari 1 ，Jenny J Sun J Sun 2 ，Brandi Carofino 1 ，Kadir Caner Akdemir 3 ，
Claire Langston 4 ，Edwina Popek 4 ，Monica J Justice 5 ，Mary E Dickinson 6 ，Russell Ray 2 ，Partha Sen 7,8 ，
Przemyslaw Szafranski 1
1:Department of Molecular and Human Genetics, Baylor College of Medicine, USA、2:Department of Neuroscience, Baylor College of
Medicine, Houston, Texas, USA、3:Genomic Medicine Department, MD Anderson Cancer Center, Houston, Texas, USA、4:Department of
Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA、5:Genetics & Genome Biology Program, SickKids, Toronto,
Canada、6:Department of Molecular Physiology & Biophysics、7:Department of Pediatrics, Baylor College of Medicine, Houston, Texas,
USA、8:Department of Pediatrics, Northwestern University, Chicago, Illinois, USA
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare lethal developmental lung disorder

caused by heterozygous SNVs or deletion CNVs of FOXF1 . We have accumulated the largest collection of ACDMPV samples
in the world (N=141 families). In ~ 25% of children with ACDMPV, we identified overlapping deletion CNVs, involving
fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082 that enabled to define a tissue-specific enhancer
region mapping ~ 270 kb upstream to FOXF1 . We now describe novel deletion CNVs at the FOXF1 locus in 14 unrelated
ACDMPV patients. In aggregate, all 31 deletion CNVs, for which parental origin was determined, arose de novo with 30 of
them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in
human lungs. Surprisingly, we also identified four ACDMPV families with pathogenic SNVs in FOXF1 that arose on paternal
chromosome 16. Interestingly, additional clinical features observed in ACDMPV (heart defects, pulmonary hypoplasia, gut
malrotation, hydronephrosis, and single umbilical artery) have also been reported in patients with maternal UPD(16). In
contrast, relatively normal phenotype was reported in a few patients with paternal UPD(16). Most recently, duplication
CNVs involving FOXF1 were associated with pyloric stenosis, mesenterium commune, and aplasia of the appendix. Modeling
Foxf1 overexpression in mice by knocking-in a Cre-inducible Foxf1 allele at the ROSA26 locus and activating it using the
vascular Tie2-cre resulted in embryonic and perinatal lethality. MicroCT, and plethysmography analyses revealed hypoplastic
lungs, abnormal breathing, gastrointestinal and vascular abnormalities in these mice. We propose that genomic imprinting
at 16q24.1 plays an important role in long-range regulation of FOXF1 expression and variable ACDMPV manifestation and
may be also responsible for the key phenotypic features of maternal UPD(16).
Tue(3)-O31-2
Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity
of a lncRNA within the LOXL1 locus
Michael A Hauser 1,2,3,4 ，Inas F Aboobakar 2 ，Chiea-Chuen Khor 5 ，Allison E Ashley-Koch 1 ，Yutao Liu 6 ，
Trevor R Carmichael 7 ，Susan E.I. Williams 7 ，Mineo Ozaki 8 ，Aung Tin 3,4 ，W. Daniel Stamer 2 ，
R. Rand Allingham 2,3,4
1:Medicine, Duke University, USA、2:Ophthalmology, Duke University、3:Singapore Eye Research Institute、4:Singapore National Eye
Center、5:Genome Institute of Singapore、6:Cellular Biology & Anatomy, Georgia Regents University、7:Ophthalmology, Neurosciences,
University of the Witwatersrand、8:Ozaki Eye Hospital
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Exfoliation syndrome (XFS) is a common, age-related, systemic fibrillinopathy. It greatly increases risk of exfoliation glaucoma
(XFG), a major worldwide cause of irreversible blindness. Coding variants in the lysyl oxidase-like 1 (LOXL1) gene are strongly
associated with XFS in all studied populations, but a functional role for these variants has not been established. To identify
additional candidate functional variants, we sequenced the entire LOXL1 genomic locus (40 kb) in 50 indigenous, black South
African XFS cases and 50 matched controls. The variants with the strongest evidence of association were located in a well-
defined 7-kb region bounded by the 3’-end of exon 1 and the adjacent region of intron 1 of LOXL1. We replicated this
finding in US Caucasian (91 cases/1031 controls), German (771 cases/1365 controls) and Japanese (1484 cases/1188 controls)
populations. The region of peak association lies upstream of LOXL1-AS1, a long non-coding RNA (lncRNA) encoded on the
opposite strand of LOXL1.We show that this region contains a promoter and, importantly, that the strongly associated XFS
risk alleles in the South African population are functional variants that significantly modulate the activity of this promoter.
LOXL1-AS1 expression is also significantly altered in response to oxidative stress in human lens epithelial cells and in response
to cyclic mechanical stress in human Schlemm canal endothelial cells. Taken together, these findings support a functional
role for the LOXL1-AS1 lncRNA in cellular stress response and suggest that dysregulation of its expression by genetic risk
variants plays a key role in XFS pathogenesis
Tue(3)-O31-3
Genetic correlations between circulating miRNAs and lipid profiles reveal novel biomarkers of CVD risk

Joanne E Curran 1 ，Scott M McAhren 2 ，Satish Kumar 1 ，Juan Peralta 1 ，Hemant Kulkarni 1 ，Gerard Wong 3 ，
Jacquelyn M Weir 3 ，Christopher K Barlow 3 ，Mark Kowala 2 ，Peter J Meikle 3 ，John Blangero 1 ，Laura F Michael 2
1:South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, USA、2:Lilly Research
Laboratories, Eli Lilly and Company, Indianapolis IN、3:Baker IDI Heart and Diabetes Institute, Melbourne AU
Cardiovascular disease (CVD) is the leading cause of death in the US, and prevention of CVD focuses on improving the
lipid profile of patients at risk. The human plasma lipidome consists of many thousands of lipid species. We have previously
measured 315 such lipid species in the San Antonio Family Heart Study (SAFHS) cohort. These lipid species represent
valuable endophenotypes for identifying genes involved in lipid metabolism related to CVD. Recent evidence has implicated
microRNAs (miRNAs) in CVD pathogenesis. miRNAs are short evolutionarily conserved, noncoding RNA species that control
gene regulation at the post-transcriptional level. An expanded understanding of the function of miRNAs in gene regulatory
networks associated with CVD will enable identification of novel genetic mechanisms of disease and of novel biomarkers
associated with disease. Here we perform an analysis of circulating miRNAs associated with the human lipidome. We profiled
plasma miRNAs in 384 SAFHS members to identify miRNAs that potentially influence the human lipidome as biomarkers
or mediators of CVD. Our analysis identified 402 known and 83 novel human miRNAs. The most striking association was
observed between 4 different miRNAs and LPC 20:1: miR-330-3p (p=1.21x10-7 ), miR-125b-5p (p=4.61x10-7 ), miR-146a-5p
(p=2.18x10-6 ) and miR-130b-5p (p=3.41x10-6 ). Additionally, miR-330-3p showed a significant association with LPC 16:1
(p=1.48x10-6 ). All of these miRNAs were strongly correlated negatively with the lipid species indicating that increased
lipid levels are associated with decreased miRNAs. LPC species have been shown previously to have favorable health effects
including with decreased risk for CVD, decreased cIMT and HbA1c levels. Given the significant associations between these
miRNAs and LPC species, our preliminary analyses indicate that these miRNAs may serve as biomarkers of increased genetic
liability to CVD.
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Tue(3)-O31-4
miRNA expression quantitative trait loci and parent-of-origin effects in human cell lines
Alexander W Drong 1 ，Quin Wills 2 ，Rory Bowden 1,2 ，George Nicholson 2 ，Sarah Keildson 1 ，Mahim Jain 5 ，
Fredrik H Pettersson 1 ，George Davey Smith 3 ，Sue Ring 4 ，Mark I McCarthy 1,6 ，Chris Holmes 2 ，Nicholas J Timpson 3 ，
Cecilia Lindgren 1
1:Wellcome Trust Centre for Human Genetics, University of Oxford, UK、2:Department of Statistics, University of Oxford, Oxford, UK、
3:MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, UK、
4:School of Social and Community Medicine, University of Bristol, UK&、5:Department of Molecular and Human Genetics, Baylor College
of Medicine, Houston, TX, USA、6:Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK
Background:
MicroRNAs (miRNAs) are widely studied post-transcriptional regulators of gene
behavior. However, their individual roles and the germline genetics of their functional variability remain poorly understood.
Here we set out to characterize the genetic landscape regulating miRNA expresssion.
Methods:
We present the expression of more than 800 miRNAs in African and European lymphoblast cell lines derived from the
HapMap collection. Total RNA was extracted from 30 European (CEU) and 30 African (YRI) mother:father:child trios

from cell lines. All culture samples were randomised, and hybridized in duplicate across four Illumina v2 DASL miRNA
expression microarrays. Standard Illumina background subtraction, log2 transformation and quantile normalization applied
to the resulting data set. We then carried out a cis-eQTL (± 500 kB) analysis using those samples overlapping the 1000
Genomes Phase 3 CEU/YRI genotypes by fitting a linear model adjusted for ethnicity. Parent-of-Origin analyses were carried
out by fitting the transmitted paternal/maternal alleles as specified in the HapMap3 Release 2 phased genotypes. All p-values
were adjusted at the 5% FDR level.
Results:
The miRNA expression profiles in the lymphoblasts demonstrated strongly correlated clusters and plausible correlations with
mRNAs. However, few genetic associations with miRNA expression were suggested. We find 800 miRNAs/SNP pairs with
a significant cis-eQTL in the combined analysis of European and African samples, adjusted for ethnicity. In addition, in an
analysis for parent-of-origin effects, we find that 122 and 194 miRNAs/SNP pairs to be driven by the maternal and paternal
genotype alone.
Conclusions:
These results add to fill knowledge gaps left by genome-wide association studies (GWAS) and show that a number of miRNA
transcripts are under genetic control. In addition, parent-of-origin effects show potential for imprinted miRNA loci.
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Tue(3)-O31-5
Gene co-expression network analysis identifies gene modules associated with clinical phenotype in
Williams syndrome
Ryo Kimura 1 ，Kiyotaka Tomiwa 2 ，Tomonari Awaya 3 ，Takeo Kato 3 ，Masatoshi Nakata 1 ，Yasuko Funabiki 4 ，
Toshio Heike 3 ，Masatoshi Hagiwara 1
1:Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Japan、2:Todaiji Medical & Educational Center、
3:Pediatrics, Kyoto University Graduate School of Medicine、4:Human Coexistence, Kyoto University Graduate School of Human and
Environmental Studies
Williams Syndrome (WS) is caused by a 7q11.23 heterozygous deletion containing 26-28 genes. WS is characterized by various
symptoms including hyper sociability. However, it remains unclear a biologically relevant signature about global dysregulations
caused by deletion at 7q11.23. In contrast, Autism Spectrum Disorder (ASD) is a characterized by impairments in social
communication and presence of restricted/repetitive patterns of behavior. Therefore, WS and ASD have been described as
“opposite” disorders in terms of their social behavior. A better understanding of the differences between these two disorders
could provide insights into gene-behavior relationships. In this study, we performed integrated network analysis to identify
genes and pathways related to specific phenotypes.
This study included a total of 154 subjects, including 94 discovery samples (32 WS, 32 ASD and 30 controls) and 60
independent replication samples (26 WS, 17 ASD and 17 controls). To evaluate behavioral problems, we used the Child
Behavior Checklist (CBCL) or the Adult Behavior Checklist (ABCL) and the Social Responsiveness Scale-2 (SRS-2). In

addition to standard differential expression analysis using peripheral blood, we applied weighted gene co-expression network
analysis (WGCNA) to identify genes and pathways related to specific phenotypes in WS.
We identified 206 differentially expressed genes in WS compared to ASD and controls. Using WGCNA, we identified 7
modules associated with WS and 1 module associated with ASD. Moreover, by integrating co-expression with transcription
factor binding site (TFBS) and histone modification analysis using ENCODE data, we found the WS-associated transcriptional
changes were predicted to be co-regulated by transcriptional regulators.
Our findings using network-based approach support the importance of transcriptome and epigenetic changes in the variable
phenotype associated with WS.
Tue(3)-O31-6
Diagnosis of bacterial and viral infection using a minimal host blood RNA expression signature
Myrsini Kaforou 1,2 ，Jethro A Herberg 1 ，Victoria J Wright 1 ，Clive J Hoggart 1 ，Andrew J Pollard 3 ，Saul N Faust 4,5
，
Sanjay Patel 5 ，Lachlan JM Coin 2,6 ，Federico Martinon-Torres 7 ，Jane C Burns 8,9 ，Michael Levin 1
1:Paediatrics, Medicine, Imperial College London, UK、2:Genomics of Common Disease, School of Public Health, Imperial College London,
UK、3:Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, UK、4:NIHR Wellcome Trust Clinical
Research Facility, University of Southampton UK、5:University Hospital Southampton NHS Foundation Trust, Southampton, UK、6:Institute
for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia、7:Translational Paediatrics and Infectious Diseases
section, Department of Paediatrics, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain、8:Department of
Paediatrics, University of California San Diego, La Jolla, California, USA、9:Rady Childrens Hospital San Diego, San Diego, California,
USA
Background: Distinction between bacterial and viral infections is currently unreliable, resulting in unnecessary hospitalisation,
invasive investigation and treatment of innumerable febrile patients worldwide. The reliability of recently introduced molecular
diagnostics is limited as infections may be found in inaccessible sites or the causative pathogen may be present in undetectable
numbers. In this study we sought to identify host blood transcriptional biomarkers to discriminate bacterial from viral disease.
Methods: A case-control paediatric cohort was established comprising of children with definite bacterial and viral infection
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(discovery&validation). Illumina gene expression arrays were used to measure whole blood RNA. After pre-processing, a novel
variable selection method was used to identify a signature comprising the smallest set of best discriminator genes.
Results: The minimal diagnostic gene signature distinguishing bacterial from viral infection was identified in the discovery
cohort and tested in the validation group and a group of patients with indeterminate aetiology. A disease risk score1 for every
patient based on a handful of genes showed 100% sensitivity and 96% specificity of in the validation group. In the group of
patients with undetermined aetiology the signature retrospectively classified half of the patients that had been treated with
antibiotics, as having viral infection. The feasibility of the implementation of the gene signature as a diagnostic test using
pH-sensing complementary metal-oxide semiconductor (CMOS) technology2 has been evaluated.
Conclusions: The gene signature distinguishes between bacterial and viral infection with high sensitivity and specificity. It
holds great potential for development as a point-of-care diagnostic test exploiting recent significant advances in the field of
bio-technology and bio-engineering.
References:
Kaforou, M., et al. (2013) PLoS Med, 10, e1001538.
Toumazou C. Et al (2013) Nature Methods, 10.1038
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[O32] Pharmacogenetics 1
Tue., April 05, 2016 13:50-15:20 Room H (1F)
Chair：Filippo Martinelli Boneschi（Department of Neuro-rehabilitation & INSPE, Scientific Institute San Raffaele, Italy）
Chair ：Hsin-Chou Yang（Institute of Statistical Science, Academia Sinica, Taiwan）
Tue(3)-O32-1
Regulation of Mucocutaneous Inflammation by Cold Medicine-Related Stevens-Johnson Syndrome sus-
ceptibility gene, IKZF1
Mayumi Ueta 1,2 ，Hiromi Sawai 2 ，Junji Hamuro 4 ，Yuki Hitomi 2 ，Chie Sotozono 3 ，Katsushi Tokunaga 2 ，
Shigeru Kinoshita 1
1:Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Japan、
2:Department of Human Genetics, Graduate School of Medicine, The University of Tokyo、3:Department of Ophthalmology, Kyoto
Prefectural University of Medicine、4:Kyoto Prefectural University of Medicine
Stevens-Johnson syndrome (SJS) is an acute inflammatory vesiculobullous reaction of the skin and mucosa, such as the ocular
surface, oral cavity, and genitals. In patients with extensive skin detachment and a poor prognosis, the condition is called
toxic epidermal necrolysis (TEN). Severe ocular complications (SOC) appear in not all, but about 40% of SJS/TEN patients
who diagnosed by dermatologists and cold medicines including multi-ingredient cold medications and NSAIDs were the main
causative drugs for especially SJS/TEN with SOC in all SJS and TEN.

In genome-wide association study (GWAS) using the Affymetrix AXIOM Genome-Wide ASI 1 Array, we found the association
between IKAROS Family Zinc Finger 1 (IKZF1 ) and CM-SJS/TEN with SOC in Japanese population and also found there
was the association between IKZF1 SNPs and CM-SJS/TEN with SOC not only in Japanese, but also in Korean and Indian
population. Furthermore, we found that the ratio of Ik2/Ik1, which are splicing variants of IKZF1 mRNA isoforms, was
significantly associated with the IKZF1 SNPs. Ik1is the full-length IKZF1 isoform, while Ik2 (IKZF1 isoform lacking exon
4-encoded amino acids) isoform lack the DNA-binding ability and seem to be a dominant-negative form against the Ik1 iso-
form, and the failure of immune-tolerance by excess signaling in the antigen receptors is prevented by this dominant-negative
isoform. We found that the relative quantity of Ik2, a dominant-negative form, was significantly lower in individuals with the
susceptible genotypes at IKZF1 SNPs.
To investigate the function of IKZF1, we produced the Ikzf1 transgenic mice in which the Ik1 isoform was artificially-
introduced in the cells expressing keratin 5 and we found that the Ikzf1 transgenic mice expressed mucocutaneous inflamma-
tion, suggesting that Ikzf1 could regulate mucocutaneous inflammation. It is possible that excessive inflammation induced
by IKZF1 contributes to pathogenicity of CM-SJS/TEN with SOC.
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Tue(3)-O32-2
Pharmacogenetic and Epigenetic evaluation of CYP19 in PCOS patients underwent ovulation induction
cycles
Parvaneh Afsharian 1 ，Shahrzad Ghazisaeidi 1,2
，Zahra Ghezelayagh 1,2
，Ali Asghar Akhlaghi 3 ，Marzieh Shiva 4 ，
Maryam Shahosseini 1
1:Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran,
Iran、2:Faculty of Basic Sciences and Advanced Technologies in Biology at University of Science and Culture, Tehran, Iran、3:Department
of Epidemiology and Reproductive Health, Reproductive Epidemiology Research Center, Royan Institute, ACECR, Tehran, Iran、
4:Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive
Biomedicine, ACECR, Tehran, Iran
Polycystic ovarian Syndrome (PCOS) is the most common cause of anovulatory infertility. Letrozole (aromatase inhibitor),
is the second line of treatment after clomiphene citrate (CC). The product of CYP19 catalyzes estrogen biosynthesis from
androgens. Our scope was to find a relation between common polymorphisms of CYP19 and drug response. Also to
investigation the role of epigenetic markers in gene regulation in granulosa cells of PCOS patients.
In our study, 220 IUI candidates (103 PCOS patients, 117 normal ovulatory women) and 98 fertile women participated, after
DNA extraction, exon 7, introns 2 and 4 of CYP19 were amplified via PCR. Selected SNPs were detected via sequencing or
RFLP. Number of antral follicles was considered as drug response which was monitored by ultrasonography. Among failed
IUI patients, 27 women were undergone IVF/ICSI (11 PCOS patient, 16 normal ovulatory women) and their granulosa cells
were isolated. CYP19 expression was evaluated by qPCR. Epigenetic markers were quantified via ChIP coupled with qPCR.

We observed in SNP rs2414096, PCOS patients bearing AA responded better to Letrozole than CC (p=0.03). Our study
revealed no correlation between other polymorphisms and drug response. Rs11575899 (TCT insertion in Intron 4) was detected
more frequent in PCOS groups (p=0.04). CYP19 expression level was lower in PCOS patients(p=0.01). The level of DNA
methylation and H3K9me in regulatory region of this gene was higher and the level of H3K9ac was lower in PCOS samples
(p= 0.1 & 0.04 and 0.03 respectively) which confirmed the low level of gene expression. For the first time our study showed
the probable role of aromatase gene in PCOS treatment in personalized medicine point. It seems rs2414096 can be a proper
candidate for more research in this field. Further research is needed to understand more details in role of CYP19 in PCOS.
Tue(3)-O32-3
Clinical response to Nabiximols (Sativex) on spasticity and pain is paralleled by a down-regulation of
immune-related pathways in Multiple Sclerosis patients
Filippo Martinelli Boneschi 1,2 ，Melissa Sorosina 2 ，Laura Ferre’ 1 ，Ferdinando Clarelli 2 ，Vittorio Martinelli 1 ，
Federica Esposito 1,2 ，Giancarlo Comi 1,2
1:Scientific Institute San Raffaele, Italy、2:Laboratory of Human Genetics of Neurological Disorders, Scientific Institute San Raffaele
The aim of the study is to identify gene networks and pathways induced by Nabiximols treatment by analyzing the transcrip-
tional profiling of whole blood in MS patients and to identify a baseline signature of response to treatment.
BACKGROUND: Nabiximols (Sativex) treatment is effective in reducing muscle spasticity and pain in MS patients.
DESIGN/METHODS: We collected whole blood at baseline and 4-week (4-wk) follow-up of 93 Nabiximols-treated MS pa-
tients, and of 34 at 14-week (14-wk) follow-up. We used a whole-genome microarray-based transcriptome profiling using
Illumina technology. Functional enrichment analysis was run using WebGestalt, DAVID and EnrichNet, and relevant path-
ways were defined as those significant in 2/3 tools. Network analysis was performed using STRING interactome resource.
RESULTS: We selected 19 patients high responders (R) (> 20% improvement in the spasticity numerical rating scale (NRS)
at 4-week, and > 30% at 14-week; mean change) and compared to 14 non-responders (NR) (< 20% improvement in the
NRS at 4-week). After quality-control steps, we identified a signature which discriminates between R and NR at baseline

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that includes 22 genes, of which 18 are influenced by Interferon-beta administration in ex-vivo experiments. Moreover, genes
down-regulated by drug treatment at 4-week follow-up are enriched in immune-related pathways including chemokine signal-
ing, antigen processing and presentation and toll-like receptor signalling pathway. The induction is evident only in R patients,
while in NRs there are no major effects.
CONCLUSIONS: Even if used for spasticity and pain, there is a strong modulation of the drug on the immune system found
only in R patients, suggesting that the action of the drug at central system parallels the one in peripheral system. An
additional interesting finding of the study is the potential link between interferon-beta and endocannabinoids, which needs
to be further explored.
Tue(3)-O32-4
A comprehensive analysis of genetic diversity in important pharmacogenes in the 1000 Genomes Project
Phase 3 populations
1,2,3 2,4 1,2,3 2,4
Galen E.B. Wright ，Bruce C. Carleton ，Michael R. Hayden ，Colin JD Ross
1:Medical Genetics, University of British Columbia, Canada、2:Child and Family Research Institute、3:Centre for Molecular Medicine and
Therapeutics、4:Pediatrics, University of British Columbia
Background
Inter-individual differences in response to medications are known to have a strong genetic component. By leveraging publically

available genomic data, the spectrum of genetic variation in genes that influence either response to medications or adverse
drug reactions can be investigated extensively.
Methods
Genes were selected based on relevance to pharmacogenomics according to the PharmGKB database and the literature.
Genetic variants in these regions of interest were extracted from the 1000 Genomes Project data from 26 global popula-
tions (n=2504). Variants were then annotated using the Ensembl VEP and analysed in further detail utilising the program,
VCFtools and the software environment, R.
Results
A total of 11902 genetic variants were found in the 58 genes that met inclusion criteria, with over 80% of the dataset comprising
of rare variants. Seven genes were excluded due to accessibility to sequencing technologies and there was an overrepresentation
of cytochrome P450 genes found in segmental duplications (P=0.006). Pharmacogenomic variation tended to be most similar
within continental populations and 16 gene regions contained a highly differentiated marker. Samples carried a median of
five clinical variants with a high level of evidence and 36% of samples carried at least one loss of function (LOF) variant.
LOF variants were found in 64% of the pharmacogenes, and CYP3A5 , which influences tacrolimus dose, displayed the highest
number of unique LOF variants.
Discussion
These data demonstrate that current sequencing technologies can successfully identify large amounts of clinical pharma-
cogenomic variation. Since the relative frequency of deleterious variants is inversely correlated with allele frequency, future
approaches need to consider this class of variation to fully understand the full spectrum of genetic diversity contributing to
pharmacogenomic traits.
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Tue(3)-O32-5
Comprehensive exploration of the high-risk rare variants for the cold medicine-related Stevens-Johnson
syndrome/ toxic epidermal necrolysis (CM-SJS/TEN) with Severe Ocular complications by whole-exome
sequencing
Seik-Soon Khor 1,4 ，Yuki Hitomi 1,4 ，Mayumi Ueta 2,3,4
，Hiromi Sawai 1 ，Khun Zawlatt 1 ，Chie Sotozono 3 ，
Shigeru Kinoshita 2 ，Katsushi Tokunaga 1
1:Graduate School of Medicine, Department of Human Genetics, The University of Tokyo, Japan、2:Department of Frontier Medical Science
and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan、3:Department of Ophthalmology, Kyoto
Prefectural University of Medicine, Kyoto, Japan、4:These author contributed equally to the work
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute inflammatory vesiculobullous reactions of
the skin and mucous membranes. Although the occurrence of SJS/TEN is rare at about 1-6 cases per million, mortality rates
are higher than other drug rush (SJS: 3%, TEN: 27%).
HLA-A and IKZF1 have been recently reported as susceptible genes for Cold Medicine-Related SJS/TEN (CM-SJS/TEN)
in Asian populations by genome-wide association study (GWAS). However, other genetic factors of CM-SJS/TEN including
rare variants and structural variants remains to be discovered.
In order to identify the functional variants for CM-SJS/TEN with severe ocular complications, whole-exome sequencing was
performed in 128 Japanese patients using ion Proton (Thermo-Fisher Scientific). After data cleaning, the following average

scores per individual were acquired: 7.29±0.11 billion bases; 42.8±5.8 million reads; 170±7.16 of read length; 95.0±0.8 % of
on target reads; 90.0±2.9 % of uniformity; x117±17.1 of coverage. In total, approximately 200,000 variants were identified
(including 60,000 nonsynonymous and splice site variants), with 50,722±736 variants per individual, were called by Torrent
suite software with high stringency parameters using NCBI hg19 as the reference.
In order to evaluate the accuracy of variant calling, we compared the genotypes of approximately 5,000 variants which were
overlapped on the Axiom chip (Affymetrix) from our previous GWAS using same CM-SJS/TEN sample set (Ueta M et al.,
2015). The concordance rate of genotypes between GWAS and exome sequencing was more than 99%.
The identification of high-risk rare variants which have extreme effect on the pathogenesis of CM-SJS/TEN are carried out
by comparing variants identified with approximately 1,000 Japanese individuals whole-genome sequencing database (Tohoku-
Medical Megabank). In this presentation, we will report the preliminary result of the identification of high-risk rare variants.
Tue(3)-O32-6
Ancestry-informative pharmacogenomic loci
Hsin-Chou Yang 1 ，Chia-Wei Chen 1 ，Yu-Ting Lin 1 ，Shih-Kai Chu 1
1:Institute of Statistical Science, Academia Sinica, Taiwan
Ancestry informative markers (AIMs) are a type of genetic marker informative for tracing the ancestral ethnicity of
individuals1,2 . Our studies observed AIMs enriched in expression quantitative trait loci2 (eQTL) and associated with adverse
drug reaction and drug response3 . An example of ancestry-informative pharmacogenetic locus (PGx) is rs1045642 on MDR1 ;
it is an ancestry-informative eQTL associated with adverse drug reactions to amitriptyline and nortriptyline and drug
responses to morphine. Identification of ancestry-informative PGx is beneficial to precision medicine in different populations.
This study analyzed more than 36 million of single nucleotide variation in the 1000 Genomes Project - Phase I, which
provided the whole-genome sequencing data of 1,092 individuals from 14 global populations. Approximately ten millions
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of AIMs were identified for global populations; 9116, 3570, 5038, and 11521 AIMs were identified for African-ancestry,
American-ancestry, East Asian-ancestry, and European-ancestry populations, respectively. On the basis of online information
of pharmacodynamics and drug absorption, distribution, metabolism, and excretion, we established ancestry-informative PGx
resources (http://hcyang.stat.sinica.edu.tw/databases/1kgp_pharm.html). The results and databases from our investigations
regarding the interrelationship between ancestral ethnicity and PGx provide rich resources for practical applications in
population genomics and medical genomics.
1
Rosenberg, N.A., et al. (2003). Am J Hum Genet 73,1402-1422.
2
Yang, H.-C., et al. (2012). BMC Genomics 13, 346.
3
Yang, H.-C., et al. (2014). BMC Genomics 15, 319.
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[O33] Pharmacogenetics 2
Tue., April 05, 2016 15:40-17:10 Room H (1F)
Chair：Mia Wadelius（Medical Sciences, Clinical Pharmacology, Uppsala University, Sweden）

Chair ：Pei-Chieng Cha（Division of Molecular Brain Science, Kobe University Graduate School of Medicine, Japan）
Tue(3)-O33-1
The influence of pharmacogenetics on the time to Acute Coronary Syndromes (ACS) recurrence in a UK
cohort study
Peng Yin 1 ，Andrea Jorgensen 1 ，Andrew Morris 1 ，Richard Turner 2 ，Richard Fitzgerald 2 ，Rod Stables 3 ，
Anita Hanson 2 ，Munir Pirmohamed 2
1:Department of Biostatistics, University of Liverpool, UK、2:Department of Molecular & Clinical Pharmacology, University of Liverpool、
3:Liverpool Heart and Chest Hospital
To identify genetic loci associated with response to cardiovascular drugs, we have undertaken a GWAS in Non-ST-segment
elevation acute coronary syndromes (ACS) patients recruited to a UK study. The cohort included 1,470 patients admitted to
hospital and followed up prospectively for up to 48 months after hospital discharge (D/C).
Our primary outcome was defined as time to the occurrence of any of the following events after D/C: myocardial infarction

(MI), stroke or cardiovascular death.
Patients were genotyped using the lllumina Omni Express array. After quality control, the genotype scaffold was imputed up
to the 1000 Genomes Phase I reference panel (all ancestries, March 2012 release).
We began by considering clinical risk factors associated with outcome in a Cox proportional hazard regression framework. We
then tested for the association of SNPs with outcome under an additive dosage model after adjusting for the clinical factors
identified above and principal components to account for population structure.
We identified a coding variant (rs2939905) in CTNNA3 gene with strong evidence of association with the primary outcome:
minor allele frequency (MAF) 0.15, hazard ratio (95% CI) 2.41 (1.64-3.57), p=6.2 x10-7 . This gene encodes for a protein which
plays a role in cell-cell adhesion in muscle cells. Mutations in this gene have previously been associated with arrhythmogenic
right ventricular dysplasia, familial 13.
Another coding variant (rs6857016) in PALLD gene also demonstrated strong evidence of association: MAF 0.47, hazard
ratio (95% CI) 1.63 (1.32-2.01), p=3.2x10-6 . This gene encodes a cytoskeletal protein that is required for organizing the
actin cytoskeleton and involved in the control of cell shape, adhesion, and contraction. Genetic variations in this gene have
previously been associated with a risk to myocardial infarction.
Our study highlights that coding variants mapping to CTNNA3 and PALLD are associated with time to a recurrent cardio-
vascular event.
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Tue(3)-O33-2
Antithyroid drug-induced agranulocytosis is associated with different human leukocyte antigen alleles in
Asia and Europe
Mia Wadelius 1 ，Niclas Eriksson 2 ，Luisa Ibanez 3 ，Emmanuelle Bondon-Guitton 4 ，Reinhold Kreutz 5 ，
Alfonso Carvajal 6 ，Maribel Lucena 7 ，Esther Sancho Ponce 8 ，Javier Martin 9 ，Tomas Axelsson 10 ，Qun-Ying Yue 11
，
Patrik K Magnusson 12 ，Par Hallberg 1 ，EuDAC
1:Medical Sciences, Clinical Pharmacology, Uppsala University, Sweden、2:Uppsala Clinical Research Center and Department of Medical
Sciences, Uppsala University, Uppsala, Sweden、3:Fundacio Institut Catala de Farmacologia, Hospital Universitari Vall d’Hebron, Universitat
Autonoma de Barcelona, Barcelona, Spain、4:Service de Pharmacologie Médicale et Clinique, Centre Hospitalier Universitaire, Faculte
de Medecine de l’Universite de Toulouse, Toulouse, France、5:Charite - University Medicine, Institute of Clinical Pharmacology and
Toxicology, Berlin, Germany、6:Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, Valladolid, Spain、
7:Farmacologia Clinica, IBIMA, H Universitario Virgen de la Victoria, Universidad de Malaga, Malaga, Spain、8:Capio Hospital General
de Cataluna HGC, Sant Cugat del Valles, Spain、9:Instituto de Parasitologia y Biomedicina Lopez Neyra Avda, Armilla, Granada, Spain、
10:Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden、11:Medical
Products Agency, Uppsala, Sweden、12:Swedish Twin Registry, Department of Medical Epidemiology and Biostatistics, Karolinska
Institutet, Stockholm, Sweden
Background: Drug-induced agranulocytosis is a potentially life-threatening adverse reaction. Recently an association between
agranulocytosis induced by antithyroid agents and the human leukocyte antigen alleles HLA-B*38:02 and HLA-DRB1*08:03
was discovered in Chinese individuals. The European Drug-induced Agranulocytosis Consortium (EuDAC) aimed to find
genetic variants predisposing to drug-induced agranulocytosis in a European population.
Material and methods: Adults with drug-induced agranulocytosis, defined as an absolute neutrophil count <0.5*109 /L (<500
per µL) were compared with population controls. Cases and controls were genotyped using the Illumina arrays HumanOmni

2.5M, HumanOmni1-Quad 1M, and HumanOmniExpress 700K. Genotyped datasets were phased and imputed, and HLA
alleles were predicted. After quality checks, 9,380,034 variants and 65 HLA alleles were tested for association. The genome-
wide significance p-value threshold was 5.33*10-9 .
Results: In all, 234 cases from Sweden, Spain, France and Germany were compared with 5,170 population controls. Genome-
wide significant associations for all drugs were observed with the EHMT2 gene and the HLA region on chromosome 6. The
strongest signal came from 39 patients whose agranulocytosis was induced by antithyroid agents. The top SNP was the
intronic EHMT2 SNP rs652888, odds ratio (OR) 4.73 [95% CI 3.00, 7.44], p = 1.92*10-11 . The top predicted HLA alleles were
HLA-B*27:05 and HLA-B*08:01. In a multiple model including these HLA alleles, the OR for HLA-B*27:05 was 7.30 [95%
CI 3.81, 13.96], p = 1.91*10-9 . The OR increased to 16.91 [95% CI 3.44, 83.17], p = 5.04*10-4 when utilizing only Swedish
cases and controls matched for hyperthyroidism.
Conclusion: We found a genome-wide association between agranulocytosis induced by antithyroid agents and HLA-B*27:05
in Europeans. We believe that risk variants for agranulocytosis are population specific, and that multiple alleles will need to
be analysed in admixed populations.
Tue(3)-O33-3
Neuronal enrichment analysis of treatment response in obsessive-compulsive disorder
Yin Yao 1 ，Haide Qin 1 ，Jack Samuels 2 ，Gerald Nestadt 2
1:Statistical Genomics, National Institute of Mental Health, USA、2:Johns Hopkins Medical School, Department of Psychiatry
Approximately 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin re-
uptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated
using genome-wide association study (GWAS). With the aim to detect specific genetic variations potentially influencing SRI
response, we carried out a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified
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as ’response’ (n=514) or ’non-response’ (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score
Test (the MQLS test) to conduct a single marker association study correcting for relatedness, . We used an adjusted logistic
model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912
(P=1.76 × 10-8 ), which is in close proximity of the DISP1 gene on 1q41-q42, a microdeletion region implicated in neuro-
logical development. The other six SNPs providing suggestive evidence of association (P<10-5 ) were rs9303380, rs12437601,
rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and
rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10-6 and 8.41 × 10-6 , respectively. The other 35 variations
with signals of potential significance (P<10-4 ) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and
GPC6. More importantly, our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmis-
sion system and the serotonergic system. Although the results presented may provide new insights into genetic mechanisms
underlying treatment response in OCD, studies with larger sample sizes are needed. The STAR*D data will be used as a
potential validation dataset for detecting genetic variants underlying the SRI’s treatment effect.
Tue(3)-O33-4
Genome-wide association study (GWAS) identifies genetic determinants of response to Zonisamide treat-
ment in Parkinson’s disease patients with "wearing-off"
Pei-Chieng Cha 1 ，Wataru Satake 1 ，Yuko Ando 1 ，Ken Yamamoto 2 ，Miho Murata 3 ，Tatsushi Toda 1

1:Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Japan、2:Department of Medical Chemistry,
Kurume University School of Medicine, Fukuoka, Japan、3:Department of Neurology, National Center Hospital, National Center of Neurology
and Psychiatry, Tokyo, Japan
Parkinson’s disease (PD) is a chronic progressive movement disorder. Although symptoms of PD could be controlled effectively
by levodopa, long-term administration of levodopa often leads to motor fluctuations, such as “wearing-off” and dyskinesia.
Recently, a sulfonamide antiepileptic drug, Zonisamide (ZNS), has been indicated to improve“wearing-off”without increasing
dyskinesia when used as adjunct therapy for PD. To understand the genetic basis of the benefit of ZNS on PD, we conducted
a GWAS on 100 PD patients who received ZNS of 50mg/day. Replication study was performed on another 100 PD patients
who received ZNS of 25mg/day. All subjects were recruited from a multicenter, randomized, double-blind, placebo-controlled
study that aims to determine the efficacy of ZNS in treating “off” time. With response to ZNS therapy defined as “a
decrease of at least 1.5 hours in daily “off” time after completing 12 weeks of ZNS therapy” based on patients’ diaries,
we evaluated the associations of 626,982 SNPs with response to ZNS. Among the 19 SNPs showing suggestive associations
with ZNS response (PTrend <1x10-4 ) that were examined in the replication study, one reached genome-wide significant level
(PCombined =4.23x10-8 ). Although we also evaluated associations of SNPs with decrease in total UPDRS Part III score upon
ZNS therapy, with response to treatment defined as a decrease in total score of at least 5 points, none of the 42 SNPs with
suggestive associations in GWAS achieve genome-wide significant association after replication study. Our findings imply
that ZNS may act through different mechanisms in treating “wearing-off” and improving motor symptoms of PD patients.
Subsequent validation of our findings in independent cohorts and functional analysis on the implicated genomic loci may shed
light on the mechanisms that underlie the beneficial effect of ZNS in PD patients.
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Tue(3)-O33-5
Two component mixture modelling approach integrating genetic and clinical variables in analysis of time
to remission in epilepsy.
Ben R Francis 1 ，Andrea Jorgensen 1 ，Andrew Morris 1 ，Andres Ingasson 3 ，Anthony Marson 1 ，Michael Johnson 2 ，
Graeme Sills 1 ，EpiPGX consortium
1:Department of Biostatistics, University of Liverpool, UK、2:Imperial College London、3:deCODE
Time to twelve months seizure freedom (remission) after randomisation to an antiepileptic drug (AED) is an important
outcome in the treatment of epilepsy with an established genetic component to variable response.
A collaborative dataset of 1,706 patients of European ancestry has been assembled via the EpiPGX Consortium to investigate
genetic risk factors for remission and other epilepsy-related outcomes. Genotype data were subject to quality control and
individuals with <90% match with European reference data were removed from downstream association analyses. The cleaned
data was then imputed up to the 1000 Genome reference panel (March 2012 release, all ancestries) using IMPUTE2.
Two sub-populations exist for time to remission; those who enter remission and those not susceptible to remission. A
traditional survival analysis approach was therefore inappropriate, as the assumption of a homogenous population is violated,
and may lack power to detect SNP associations. To consider these two sub-populations, mixture modelling with cure fraction
was implemented in a two component model.

The two component model is computationally expensive and cannot be applied on the scale of the whole genome. Therefore,
to test association, deviance residuals for susceptibility to remission and survival were derived, after adjustment for relevant
clinical covariates. We performed multivariate association analysis of SNPs with “reverse regression” modelling in the
PLEIOTROPY software. No SNP associations attained the threshold of genome-wide significance (p<5x10-8 ). However,
lead SNPs in several loci attained nominal significance (p<1x10-5 ), including: IQCK (rs724614, p=9.36x10-7 ) and PDE3A
(rs7484691, p=7.62x10-7 ).
Further investigation of these loci will be undertaken by performing computationally expensive two component survival
modelling, including SNP genotypes in the model alongside clinical covariates.
Tue(3)-O33-6
Genome-wide association study of L-asparaginase-induced pancreatitis in pediatric patients
Britt I Drogemoller 1 ，Hisaki Fujii 2 ，Shinya Ito 2 ，Bruce Carleton 1 ，Colin Ross 1 ，
Canadian Pharmacogenomics Network for Drug Safety
1:Pediatrics, University of British Columbia, Canada、2:Clinical Pharmacology and Toxicology, The Hospital for Sick Children
Background: L-asparaginase is highly effective in the treatment of pediatric acute lymphoblastic leukemia. Unfortunately, this
treatment is accompanied with debilitating adverse drug reactions, such as pancreatitis. As treatment dose and formulation
have not been able to explain the inter-individual differences that are observed, it seems likely that genetic factors may play
an important role in the development of pancreatitis. Therefore, this study aims to identify the genetic variants associated
with L-asparaginase-induced pancreatitis.
Methods: A total of 123 patients who have been treated with L-asparaginase were recruited from 13 oncology units across

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Canada. Extensive demographic and clinical data have been collected for all patients and genotyping of 740,000 genetic
variants spread throughout the entire genome has been performed using the Illumina HumanOmniExpress array. Statistical
analyses were performed using the Golden Helix SNP and Variation Suite v8 and the programming environment, R.
Results: Investigation of the clinical variables revealed that factors such as gender, treatment dose and formulation were
not significantly associated with the development of L-asparaginase-induced panceatitis (P < 0.05). Initial genome-wide
association analyses did, however, identify eight regions in the genome that are nominally associated with L-asparaginase-
induced pancreatitis (P < 1x10-5 ).
Conclusion: This study has identified a subset of genetic variants that may be involved with the development of L-asparaginase-
induced pancreatitis. If these results can be replicated, these data can be used to improve our understanding of L-asparaginase-
induced pancreatitis, and in so doing, guide strategies to prevent the occurrence of this adverse drug reaction.
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Thu., April 07, 2016 8:00-9:30 Annex 1 (1F)
Chair：Anne Goverde（Department of Clinical Genetics / Department of Gastroenterology & Hepatology, Erasmus MC,
University Medical Center Rotterdam, Netherlands）
Chair ：Hideki Makishima（Department of Pathology and Tumor Biology, Kyoto University）
Thu(5)-O34-1
Germline mutations in familial prostate cancer
Takahide Hayano 1 ，Hiroshi Matsui 2 ，Hirofumi Nakaoka 1 ，Nobuaki Ohtake 2 ，Kazuhiro Suzuki 2 ，Ituro Inoue 1
1:Division of Human Genetics, National Institute of Genetics, Japan、2:Department of Urology, Gunma University Graduate School of
Medicine
Objectives:
Prostate cancer (PC) is the second frequently diagnosed cancer and fifth leading cause of cancer death among men in
worldwide. Family history is a well known risk factor for PC. A meta-analysis showed that first-degree relatives of an affected
patient are 2.48 times more likely to develop PC. Several susceptibility genes were identified in familial PC such as BRCA2
and HOXB13 . Comprehensive search for germline mutations in Japanese familial PC has not been reported. In this study,

we have searched responsible genes with germline mutations in 140 Japanese PC patients in 66 families.
Methods:
We have conducted exome sequencing and Sanger sequencing of blood DNA from patients with familial PC. Twenty-two
PC patients from seven families (three to four patients in each family) were analyzed by exome sequencing to find shared
rare nonsynonymous germline mutations in each family (discovery phase). After that, additional 118 PC patients from 59
families (59 affected pairs) were analyzed (validation phase). Fifty-nine PC patients from each family were analyzed by exome
sequencing. Then shared gene mutations were confirmed by Sanger sequencing using the other patient in each family.
Results:
In the discovery phase, we found a BRCA2 mutation in one family and two novel HOXB13 mutations in two families. We
also found two novel TRRAP mutations in two families. These genes with mutations were mutually exclusive in the seven
PC families. In the validation phase, we found additional shared mutations in BRCA2 , HOXB13 , and TRRAP in mutually
exclusive manner. In total, these three genes with mutations accounted for 13.6% (9/66) of the PC families.
Conclusion:
We identified TRRAP as a novel susceptibility gene in addition to known PC susceptibility genes (BRCA2 and HOXB13 ).
Further scrutinization of genetic and functional studies of TRRAP may provide new insight for the development of PC.
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Thu(5)-O34-2
Imbalance of miR-194 -CUL4B negative feedback loop favoring CUL4B upregulation enhances the ma-
lignancy of non-small-cell lung carcinoma
Yongxin Zou 1 ，Jun Mi 1 ，Xiaohua Lin 1 ，Juanjuan Lu 1 ，Xiaochen Liu 1 ，Hui Zhao 1 ，Zhaoyang Wang 1 ，Huili Hu 1 ，
Peishan Li 1 ，Hao Dou 1 ，Baichun Jiang 1 ，Changshun Shao 1 ，Yaoqin Gong 1
1:Institute of Medical Genetics, School of Medicine, Shandong University, China
CUL4B, a scaffold protein that assembles CRL4B ubiquitin ligase complexes, is overexpressed in many types of cancers and
represses tumor suppressors through epigenetic mechanisms. However, the precise roles of CUL4B in non-small-cell lung
carcinoma (NSCLC) and mechanisms of its regulation remain to be elucidated. Here, we show that CUL4B was upregulated
in NSCLC tissues compared with corresponding non-tumorous tissues. Knockdown of CUL4B suppressed cell proliferation,
induced cell cycle arrest in vitro and reduced tumourigenicity in vivo. We further demonstrated that overexpression of miR-
194 significantly repressed the activity of luciferase reporter carrying the 3’ UTR of CUL4B containing the binding site of
miR-194 and reduced the endogenous protein level of CUL4B, whereas mutation of the miR-194 binding site in 3’ UTR
disrupted the repressive effect of miR-194. Overexpression of miR-194 as well as CUL4B knockdown inhibited cell migration,
while ectopic expression of CUL4B could attenuate the inhibitory effects of miR-194 on migration. These results suggest that
CUL4B was a direct target of miR-194. Moreover, we also showed that p53 could suppress CUL4B expression through miR-
194 at posttranscriptional levels. Interestingly, CUL4B could epigenetically repress expression of miR-194 by trimethylation
of lysine 27 on histone 3 on the miR-194 promoter. Silencing of CUL4B, in turn, downregulated the expression of RBX1,

a target of miR-194 and a subunit of CRL4, thus creating a double negative feedback loop between miR-194 and CRL4 in
NSCLC cells. Together, our data demonstrate an important role of CUL4B in the pathogenesis of human lung cancer and
reveal CUL4B as a potential target in cancer therapy.
Thu(5)-O34-3
Withdrawn

Thu(5)-O34-4
Cost-effectiveness of routine screening for Lynch syndrome in endometrial cancer patients up to 70 years
of age
Anne Goverde 1,2 ，Manon C.W. Spaander 2 ，Helena C. van Doorn 3 ，Hendrikus J. Dubbink 4 ，
Ans M.W. van den Ouweland 1 ，Carli M. Tops 5 ，Sjarlot G. Kooi 6 ，Judith de Waard 7 ，Robert F. Hoedemaeker 8 ，
Marco J. Bruno 2 ，Robert M.W. Hofstra 1 ，Esther W. de Bekker-Grob 9 ，Winand N.M. Dinjens 4 ，
Ewout W. Steyerberg 9 ，Anja Wagner 1 ，The LIMO study group
1:Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Netherlands、2:Department of Gastroenterology
and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands、3:Department of Gynaecology, Erasmus MC,
University Medical Center Rotterdam, the Netherlands、4:Department of Pathology, Erasmus MC, University Medical Center Rotterdam,
the Netherlands、5:Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands、6:Department of
Gynaecology, Albert Schweitzer Hospital, Dordrecht, the Netherlands、7:Department of Gynaecology, Sint Franciscus Gasthuis, Rotterdam,
the Netherlands、8:Pathology laboratory Pathan, Rotterdam, the Netherlands、9:Department of Public Health, Erasmus MC, University
Medical Center Rotterdam, the Netherlands
Aim To assess the cost-effectiveness of routine screening for Lynch Syndrome (LS) in endometrial cancer (EC) patients ≤70
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years of age.
Methods Consecutive EC patients ≤70 years of age were routinely screened for LS by analysis of microsatellite instability,
immunohistochemistry and MLH1 hypermethylation, followed by germline mutation analysis if indicated. Health benefit in
life years gained (LYG) was based on the number of LS carriers detected among EC patients and their relatives. We calculated
the incremental cost-effectiveness ratio (ICER) for LS screening among EC patients ≤70 years compared with EC patients
≤50 years and compared with the revised Bethesda guidelines.
Results Screening of 179 EC patients identified 7 LS carriers; only 1 was ≤50 years and 6 were 51-70 years of age. Germline
mutation analysis of relatives additionally identified 27 LS carriers (18 and 9 per age category respectively). LS screening
resulted in 13,7 LYG, or 8,1 and 5,6 LYG per age category. The ICER for LS screening in EC patients ≤70 years compared
with ≤50 years was €27,665/LYG. The revised Bethesda guidelines identified 3/7 (43%) LS carriers among EC patients and
22/27 (81%) LS carriers among relatives. The ICER for routine LS screening in EC patients ≤70 years of age compared with
the revised Bethesda guidelines was €34,696/LYG. Both ICERs remained <€45,000/LYG in sensitivity analyses.
Conclusion Routine screening for LS by analysis of microsatellite instability, immunohistochemistry and MLH1 hypermethy-
lation in EC patients ≤70 years is a cost-effective strategy, allowing colorectal cancer prevention in EC patients and their
relatives.
Thu(5)-O34-5
Universal testing of mismatch repair protein deficiency in colorectal cancer and its usefulness for identi-

fication of Lynch syndrome patient
Takeshi Nakajima 1,2 ，Shigeki Sekine 3 ，Yoshimi Nakajima 1 ，Mineko Ushiama 4 ，Taku Sakamoto 1 ，Takahisa Matsuda 1 ，
Yutaka Saito 1 ，Yukihide Kanemitsu 5 ，Hiromi Sakamoto 4 ，Teruhiko Yoshida 2,4 ，Kokichi Sugano 2,6
1:Endoscopy Division, National Cancer Center Hospital, Japan、2:Department of Genetic Counseling, National Cancer Center Hospital、
3:Pathology Division, National Cancer Center Hospital、4:Division of Genetics, National Cancer Center Research Institute、5:Colorectal
Surgery, National Cancer Center Hospital、6:Oncogene Research Unit/Cancer Prevention Unit, Tochigi Cancer Center Research Institute,
Tochigi, Japan
Background: National Comprehensive Cancer Network guideline recommend the routine colorectal cancer (CRC) tumor
testing for detecting of Lynch syndrome (LS) patient using immunohistochemistry (IHC) for mismatch repair (MMR) proteins
and/or microsatellite instability (MSI) test (Universal test). This study aimed to examine the feasibility of the universal test
in Japanese CRC patients.
Methods: We recruited invasive CRC patients who are younger than 70-years-old or meets the revised Bethesda Guideline
in the patients who underwent surgery or endoscopic resection from September 2013 through August 2015 in our institution.
After obtaining written informed consent and IHC for four MMR proteins (MLH1, MSH2, PMS2, and MSH6) were performed
using formalin-fixed paraffin-embedded sections of primary CRC tissues. The patients with tumors showing loss of expression
in any of MSH2, PMS2, and MSH6, or the patients with both loss of MLH1 expression and negative BRAF mutation were
referred to genetic counseling clinic, where germline mutation testing was performed with written informed consent.
Results: Among recruited 317 CRC patients (187 men, 130 women, average age was 66[28-83]), 280 patients (88%) were
enrolled for this study. Loss of expression was not observed in 247 patients and 17 patients were candidate for genetic testing
due to IHC results (MLH1 with BRAF mutation negative: 9, MSH2: 5, MSH6: 0, PMS2: 3). So far, 11 patients underwent
genetic testing for MMR gene and 5 patients were diagnosed as LS (MSH2 : 2, PMS2 : 2). No pathogenic mutation was
observed in 2 patients and the results of 4 patients were pending. In addition, 3 of 5 patients did not meet the revised
Bethesda Guideline.
Conclusion: Universal method using IHC test is useful for detecting LS patient even in the patients who does not meet the
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revised Bethesda Guideline in Japanese CRC patients.
Thu(5)-O34-6
Comprehensive methylation analysis of imprinting-associated differentially methylated regions in colorec-
tal cancer
Hidenori Hidaka 1,2 ，Ken Higashimoto 1 ，Saori Aoki 1 ，Hidetaka Watanabe 1 ，Hitomi Yatsuki 1 ，Kenichi Nishioka 1 ，
Keiichiro Joh 1 ，Toshiyuki Maeda 3 ，Yasuo Koga 4 ，Ryuichi Iwakiri 2 ，Hirokazu Noshiro 4 ，Kazuma Fujimoto 2 ，
Hidenobu Soejima 1
1:Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan、
2:Department of Internal Medicine and Gastrointestinal Endoscopy, Saga Medical School, Saga, Japan、3:Department of Pediatrics, Faculty
of Medicine, Saga University, Saga, Japan、4:Department of Surgery, Saga University Faculty of Medicine, Saga, Japan
The expression of imprinted genes is regulated by the methylation status of differentially methylated regions (DMRs). The
disruption of imprinting causes various congenital malformation syndromes, such as imprinting disorders, and is deeply
involved in the development and progression of cancer. In colorectal cancer (CRC), aberrant methylation of the IGF2 /H19
imprinting domain has been reported. However, there have been no comprehensive analyses of methylation of DMRs in
CRC. We quantitatively analyzed the methylation status of 38 DMRs in 106 CRC tissues and corresponding normal tissues
using bisulfite-pyrosequencing. Cases with metastasis, preoperative chemotherapy, and inflammatory bowel diseases were not
subjected to this study. The methylation analysis revealed that on average, 9.2 ± 6.1 DMRs per case were hypermethylated
and 2.9 ± 2.3 DMRs were hypomethylated, indicating a frequent occurrence of hypermethylation. We found 6 particular

DMRs to be aberrantly methylated in 50% or more of the CRC samples. Of these, five sites (PEG1 , TRAPPC9 , NDN ,
NESP55 , GNASXL) showed hypermethylation, i.e. a high frequency of hypermethylated DMRs and the IGF2 -DMR0 site
showed hypomethylation. In addition, in 11% of cases showed a positive CpG island methylator phenotype (CIMP) and in 7%
of cases the long interspersed nucleotide element 1 (LINE1) was hypomethylated. High frequency hypermethylation of DMRs
and the hypomethylation of IGF2-DMR0 did not correlate with CIMP status, LINE1 hypomethylation, and clinicopathological
factors. Additionally, 9 DMRs were aberrantly methylated in less than 10% of cases. H19 DMR was included in these DMRs,
indicating that hypermethylation of H19 DMR was less frequent than expected. Our results suggest that certain DMRs
are susceptible to aberrant methylation but another subset is resistant. The mechanism causing aberrant methylation of
imprinting-associated DMRs might be different from CIMP or LINE1.
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Thu., April 07, 2016 9:45-11:15 Annex 1 (1F)
Chair：Stuart MacGregor（Statistical Genetics Laboratory, QIMR Berghofer Medical Research Institute, Australia）
Chair ：Mitsuru Emi（Thoracic Oncology, University of Hawaii Cancer Center, USA）
Thu(5)-O35-1
Whole-exome Analysis of Hereditary Microsatellite-stable Colorectal cancer in Israel
Revital Kariv 1 ，Guy Rosner 1 ，Hana Strul 1 ，Nathan Gluck 1 ，Sivan Caspi 1 ，Leon Raslin 2
1:Tel aviv sourasky Medical center, Israel、2:Vanderblit Ingram cancer Center, Vanderblit university
To identify new candidate variants and genes associated with risk of hereditary microsatellite-stale colorectal cancer (CRC)
in Israel, we sequenced 10 exomes of unrelated high-risk patients with personal and familial history of microsatellite-stable
CRC. Seven families met Amsterdam I criteria, 2 families met Bethesda criteria, and 1 family met Amsterdam II criteria.
All patients were Jewish including seven Ashkenazi, two Mediterranean (Lebanon and Syria), and one North African origin.
Mean age at diagnosis was 44.3 years (range 28 to 53 years). Whole-exome sequencing followed by stepwise bioinformatics
filtering to select candidate variants and genes based on variant frequency, predicted functional role, and pathway. Assuming
a dominant mode of inheritance of a rare disease, we limited our analysis to rare variants in known CRC genes (minor allele

frequency-MAF ≤0.01) and very rare variants in known cancer genes (MAF ≤0.001). We selected functional variants including
missense, stop-gain, stop-loss, frameshift, and ncRNA variants. Several bioinformatics tools (SIFT, PROVEAN, PolyPhen-2,
MutationAssessor, MutationTaster, GERP++, VEST) predicted variant impact and only variants predicted as deleterious by
all methods were included. We found 37 variants in 37 unique cancer genes, 33 SNVs (31 nonsynonymous and one stopgain)
and three frameshift indels. Almost all variants were novel (81%, n= 30) in genes involved in regulation of apoptosis and
cell cycle, DNA repair, cell adhesion, and signal transduction. In CRC genes only five nonsynonymous variants met our
stringent filtering criteria including variants in MSH2 , POLE, and POLD1 . In addition, we identified two candidate variants
in DNA polymerases other than POLE and POLD1. Several candidate variants are being used for segregation analysis in
families. The candidate genes discovered in our study can increase genetic diagnosis rate and affect policy for surveillance
and prevention of hereditary CRC.
Thu(5)-O35-2
Hepatitis B Virus HBx Activates Notch Signaling via Delta-like 4/Notch1 in Hepatocellular Carcinoma
Pornrat Kongkavitoon 1 ，Pisit Tangkijvanich 1 ，Nattiya Hirankarn 1 ，Tanapat Palaga 1
1:Chulalongkorn university, Thailand
Hepatitis virus B (HBV) infection is one of the major causes of hepatocellular carcinomas (HCC). HBx protein encoded in
HBV genome is one of the key viral factors leading to malignant transformation of infected cells. HBx functions by interfering
with cellular functions, causing aberration in cellular behaviour and transformation. Notch signalling is a well-conserved
pathway involved in cellular differentiation, cell survival and cell death operating in various types of cells. Aberration in the
Notch signalling pathways is linked to various tumors, including HCC. The role of HBx on the Notch signalling in HCC,
however, is still controversial. In this study, we reported that HBV genome-containing HCC cell line HepG2 (HepG2.2.15)
expressed higher Notch1 and Delta-like 4 (Dll4), compared to the control HepG2 without HBV genome. This upregulation
coincided with increased appearance of the cleavage of Notch1, indicating constitutively activated Notch signaling. Silencing
of HBx specifically reduced the level of Dll4 and cleaved Notch1. The increase in Dll4 level was confirmed in clinical specimens
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of HCC lesion, in comparison with non-tumor lesions. Using specific signalling pathway inhibitors, we found that MEK1/2,
PI3K/AKT and NF-B pathways are critical for HBx-mediated Dll4 upregulation. Silencing of HBx clearly decreased the level
of phosphorylation of Akt and Erk1/2. Upon silencing of Dll4 in HepG2.2.15, decreased cleaved Notch1, increased apoptosis
and cell cycle arrest were observed, suggesting a critical role of HBx-Dll4-Notch1 axis in regulating cell survival in HCC.
Furthermore, clonogenic assay and wound healing assay confirmed the important role of Dll4 in regulating cell survival and
invasion of HBV-genome containing HCC cell line. Taken together, we reported a link between HBx and the Notch signalling
in HCC that affects cell survival of HCC, which can be a potential target for therapy.
Thu(5)-O35-3
miR-19b up-regulates hTERT expression by inhibition of PITX1 in melanoma cells
Takahio Ohira 1 ，Naohiro Sunamura 1 ，Daigo Inaoka 1 ，Yuji Nakayama 2 ，Mitsuhiko Osaki 3 ，Futoshi Okada 3,4
，
Mitsuo Oshimura 4 ，Hiroyuki Kugoh 1,4
1:Division of Molecular Genetics and Biofunction, Tottori University Graduate School of Medical Science, Japan、2:Division of Functional
Genomics, Research Center for Bioscience and Technology, Tottori University, Tottori, Japan、3:Division of Pathological Biochemistry,
Tottori University Faculty of Medicine, Tottori, Japan、4:Chromosome Engineering Research Center, Tottori University, Tottori, Japan
Activation of telomerase, which has been frequently associated with cellular immortality and proliferation, constituted a key
step in cancer development. In our previous study, using chromosome engineering technology which can introduce a normal
human chromosome into cancer cells, we identified paired-lilke homeodomain1 (PITX1 ) gene as a novel of telomerase reverse

transcriptase (hTERT ) suppressor gene. In addition, we confirmed down-regulation of PITX1 expression might contribute
to the progression of cutaneous malignant melanoma (CMM) via promoting cell proliferative activity. These data suggests
that PITX1 is a tumor suppressor gene in melanoma cells. However, the molecular basis of the process is still unclear.
Here, we report that miR-19b up-regulation inhibits PITX1 expression which induces hTERT transcription and promotes
of cell growth. We assayed expression levels of miR-19b in melanoma cell lines by using qRT-PCR. miR-19b expression
levels were higher in most melanoma cells compared with normal cells. And, overexpression of miR-19b shows significant
down-regulation of PITX1 in 293T and induced to increased hTERT mRNA transcription level and cell growth. To determine
whether PITX1 are regulated by miR-19b in cancer cell, we used a 3-UTR reporter assay. The reporter plasmid and the
miR-19b expression vector were cotransfected into 293T cells and the activity of luciferase reporter was monitored. Although
the luciferase activity of PITX1 3-UTR reporter plasmid was downregulated, but not in response to controls and mutation
reporter vector which including binding site of miR-19b. Futhermore, Knockdown of miR-19b shows that enhanced PITX1
protein levels and inhibited hTERT expression levels in melanoma cell line A2058 cells. These data indicate that miR-19b
regulates telomerase activity by directly targeting PITX1 , therefore this path way have potential controlling melanoma cell
proliferation and development.
Thu(5)-O35-4
The role of germline genetic variation in Breslow’s depth, a predictor of survival after melanoma
Matthew H Law 1 ，Casey Rowe 2 ，Anne E Cust 3 ，John L Hopper 4 ，Graham J Mann 5 ，Gemma Cadby 6 ，
Sarah V Ward 6 ，Eric Moses 6 ，David C Whiteman 7 ，Nicholas K Hayward 8 ，Kiarash Khosrotehrani 2 ，
Stuart Macgregor 1
1:Statistical Genetics, QIMR Berghofer Medical Institute, Australia、2:The University of Queensland, UQ centre for Clinical Research,
Brisbane, Australia、3:Cancer Epidemiology and Prevention Research, Sydney School of Public Health and Melanoma Institute Australia.、
4:Centre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology, Melbourne School of Population Health, University of
Melbourne, Melbourne, Australia、5:Westmead Institute of Cancer Research, University of Sydney at Westmead Millennium Institute and
Melanoma Institute Australia, Sydney, Australia、6:Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry and
Health Sciences, The University of Western Australia, Australia、7:Cancer Control Group, QIMR Berghofer Medical Research Institute,
Brisbane, Australia、8:Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
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Risk of melanoma, the deadliest form of skin cancer, is influenced by environmental (ultraviolet radiation, UVR) and genetic
factors (e.g. pigmentation or naevi). Genome-wide association studies (GWAS) have identified genetic variants associated
with melanoma risk but studies addressing outcome (survival) have made only limited progress.
Melanoma Breslow’s depth, the degree of lesion invasion into the skin, is a predictor of survival after melanoma. While time
to medical intervention is a major factor in lesion thickness at time of diagnosis/surgery we addressed here the possibility
that germline variants may influence Breslow depth. Parallel to ongoing analysis of risk and survival in melanoma we have
undertaken a study to try to identify evidence of a genetic basis to variation in lesion thickness using 4,723 melanoma cases
from 5 melanoma GWAS datasets.
Normally, twin or family studies can be used to estimate the proportion of trait variation attributable to genetic factors
(heritability). However, this is not possible for lesion thickness as diagnosis of a family member leads to increased tumour
surveillance by relatives. This can induce a negative correlation between relatedness and lesion size, which would attenuate
familial correlations.
To overcome this limitation we have applied the GREML method, as implemented in the Genome-wide Complex Trait Analysis
(GCTA) software, to ‘unrelated’ melanoma cases to estimate the proportion of variation in lesion thickness attributable to

genotyped SNPs (array heritability, h2 array ). We found that germline factors may influence variation in lesion thickness
(h2 array = 0.08, SE = 0.06, P = 0.09 for the test of h2 array > 0 vs. h2 array = 0). In addition, we report on an initial GWAS
meta-analysis of lesion thickness on the same melanoma cases.
Thu(5)-O35-5
Founder BAP1 Mutation in Four American Families Predisposes to Malignant Peritoneal Mesothelioma,
Uveal Melanoma, and other cancers
Mitsuru Emi 1 ，Sandra Pastorino 1 ，Masaki Nasu 1 ，Erin Froles 1 ，Haining Yang 1 ，Michele Carbone 1
1:Thoracic Oncology, University of Hawaii Cancer Center, USA
The BAP1 cancer syndrome is characterized by a high incidence of malignant mesothelioma (MM), uveal melanoma (UM),
cutaneous melanoma (CM), clear cell renal cell carcinoma (ccRCC), and it is expected that the clinical phenotype will continue
to broaden in scope. Molecular screening for BAP1 gene mutations among 29 patients selected for clinically apparent familial
MM led to the identification of a heterozygous C base deletion mutation (c.1832delC, p.Leu573fs*3) shared by four of those
patients. The frame shift deletion is predicted to truncate the BAP1 protein, and immunohistochemistry analysis of tumor
specimens revealed predominant cytoplasmic staining. Based on 657,893 SNPs using the Illumina OmniExpress combined
with genotype data of the 1000 Genomes Project (1000G), our haplotype phasing around the BAP1 gene of all samples showed
that the pairwise extent of shared segments between any of the four MARF patients ranged in length from 9.1 to 34.2 Mbp.
Through a combined molecular genomic and genealogical approach, we ascertained, to our knowledge, the largest known
genealogically connected BAP1 cancer syndrome kindred (K4), whose members can trace descent from a common ancestor in
the 17th century. This pedigree provided a unique opportunity to examine effects on tumor expression on various body sites
and would facilitate study of gene-gene and gene-environment interaction involving the BAP1 gene.
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Thu(5)-O35-6
Large scale meta-analysis identifies several new risk loci for development of esophageal adenocarcinoma
and Barrett’s esophagus
Stuart MacGregor 1 ，Puya Gharahkhani 1 ，Rebecca Fitzgerald 2 ，Tom Vaughan 3 ，Ian Tomlinson 4 ，Ines Gockel 5 ，
Claire Palles 4 ，Michael Knapp 6 ，Markus M Noethen 7,8 ，Jessica Becker 7,8 ，Paul Pharoah 9 ，David Whiteman 10 ，
Janusz Jankowski 11,12 ，Johannes Schumacher 7,8 ，
Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) and The Wellcome Trust Case Control Consortium
2 (WTCCC2)
1:Statistical Genetics, QIMR Berghofer Medical Research Institute, Australia、2:Medical Research Council (MRC) Cancer Cell Unit,
Hutchison-MRC Research Centre and University of Cambridge, Cambridge, United Kingdom、3:Division of Public Health Sciences, Fred
Hutchinson Cancer Research Center, Seattle, WA, USA、4:Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford,
UK、5:Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany、6:Institute
for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany、7:Institute of Human Genetics, University of
Bonn, Bonn, Germany、8:Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany、9:Centre for Cancer Genetic
Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom、10:Cancer Control, QIMR Berghofer
Medical Research Institute, Brisbane, Australia、11:University Hospitals Coventry & Warwickshire NHS Trust, Warwickshire, United
Kingdom、12:Warwick Medical School, University of Warwick, Warwickshire, United Kingdom
Esophageal adenocarcinoma (EA) is a rapidly fatal cancer, with rising incidence in the developed world. Barrett’s esophagus
(BE), a metaplastic change of esophageal epithelium, is associated with greatly increased risk of EA. We recently showed
both BE and EA show moderate heritability, with strong overlap between the polygenes underlying each condition. Recent
genome-wide association studies (GWAS) have identified eight loci associated with BE and/or EA. To investigate additional
loci underpinning the risk of BE and EA, we meta-analysed 6,177 cases of BE, 4,120 cases of EA, and 17,067 unscreened
controls. Given the strong genetic overlap between BE and EA, we also combined BE and EA (10,297 cases total) to maximize

power.
Our analysis of BE+EA identified eight new loci increasing risk of BE and EA in single variant tests, with gene-based tests
implicating further loci. These include an association in CFTR (rs17451754 [G], P=5.21×10-10 , OR=1.19) as well as in two
other regions known to affect obesity related traits (TPPP/CEP72 and MFHAS1 ). TPPP/CEP72 has also been implicated
in ulcerative colitis. Additionally, at the gene HTR3C , we identify for the first time an association signal where the effect
is only on EA (rs9823696 [A], P=2.01×10-8 , OR=1.17) and not mediated via BE (rs9823696 [A], P= 0.494, OR= 1.02 for
BE). We performed tests for enrichment of a wide range of functional genomic annotations, revealing that a small number
(including DNase-I hypersensitive sites in stomach cells) are over represented amongst the top hits. We used an empirical
bayes approach based on the significant functional annotations to further reweight our GWAS results, increasing the number
of implicated loci. Further investigation of these new risk loci and downstream biological pathways will help in improving our
understanding of the etiology of BE and EA, and paves the way for subsequent development of treatments.
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[O36] Ethical, Legal, Social and Policy Issues in Genetics

Thu., April 07, 2016 8:00-9:30 Annex 2 (1F)
Chair：Adrian Thorogood（Centre of Genomics and Policy, McGill University, Canada）

Chair ：Kaori Muto（Department of Public Policy, The Institute of Medical Sciences, The University of Tokyo, Japan）
Thu(5)-O36-1
Care to share? An international comparison of research directives to promote data sharing among
decisionally-incompetent adults living with dementia
Adrian Thorogood 1 ，Vasiliki Rahimzadeh 1 ，Bartha M Knoppers 1 ，Anna Maki-Petaja-Leinonen 2 ，Martin Bobrow 3 ，
Ageing and Dementia Task Team, Global Alliance for Genomics and Health
1:Centre of Genomics and Policy, McGill University, Canada、2:Faculty of Law, University of Helsinki、3:Emeritus Professor of Medical
Genetics, Cambridge University
The incidence and prevalence of dementia-related diseases are increasing in parallel to the ageing global population. This
is true across high, middle and low-income countries. Advances in genomics promise the expansion of effective therapeutics
through innovative drug discovery, risk reduction and delay of dementia progression. International data sharing is the
cornerstone of genomic reserach and therefore critical to realizing these promises. Data sharing in the context of international
dementia research is contingent upon reconciling jurisdictional data protection laws with the particular ethical safeguards

that research involving decisionally-incompetent adults requires. This scoping review of the literature provides insight into
the ethical, legal, and social considerations of data sharing in the dementia research population, specifically. It compares the
legal legitimacy of research directives for decisionally-incompetent adults across North America and Europe, and proposes
policy recommendations in light of the comparative findings. Variations in the limits to surrogate decision-making for research
participation and distinctions in the type of research under which data sharing is permitted emerged as prominent themes.
Sobering epidemiological projections demonstrate the extent to which most international healthcare systems are underprepared
for meeting the needs of an ageing population. Anticipatory governance of data sharing in dementia research that involves
populations with decisional vulnerability is an area of limited policy attention this review aims to ameliorate.
Thu(5)-O36-2
Holding Researchers to Account for Responsible Genomic Data Sharing
Adrian Thorogood 1 ，Calvin WL Ho 2 ，Bartha M Knoppers 1
1:Centre of Genomics and Policy, McGill University, Canada、2:Yong Loo Lin School of Medicine, National University of Singapore
Concern for data misuse, data hoarding, and unauthorized access in an era of exploding data generation and use has prompted
calls for strengthening accountability in genomic research. Accountability is responsibility towards another, supported by
transparency (e.g., monitoring or account-giving) and the application of consequences. In the context of data sharing,
genomic researchers are accountable to both participants and to society. The legitimacy of these claims is growing, reinforced
by views of researchers as stewards of participant data and public funds. In contrast, the mechanisms for holding researchers
to account remain weak. Ethics bodies lack the mandate, resources, or expertise to promote responsible data sharing. Data
sharing requirements imposed by funding agencies, journals, and institutions are vague and ineffective. Researchers (or access
committees) managing access to data struggle to monitor or enforce access conditions, and are prone to unjustified data
withholding. Conversely, researchers seeking access must contend with long delays, unjustified refusals, and a thicket of
discrepant access conditions. In the absence of strong legal or regulatory accountability, host institutions are grudgingly
left to oversee researchers. To stem the erosion of trust between stakeholders, the Global Alliance for Genomics and Health
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(GA4GH) has developed an Accountability Policy that provides guidance for strengthening accountability mechanisms for
genomic data sharing. This policy builds on the GA4GH’s Framework for Responsible Sharing of Genomics and Health-
related Data, which aims to activate the human right of citizens to benefit from the progress of science. More specifically, the
Accountability Policy addresses the need for clear responsibilities; enhanced transparency; processes for handling complaints
and investigating incidents; management of conflicts of interest; as well as both facilitative and punitive responses in cases of
non-compliance.
Thu(5)-O36-3
European Legal Perspectives on Cloud Computing in Cross-Border Translational Genome Research
1
Fruzsina Molnar Gabor
1:Heidelberg Academy of Sciences and Humanities, Germany
The decrease in sequencing costs and the massively increased amount of sequenced genomes in research has led to the
application of sequencing technologies on a translational level. The big collections of highly diverse patient data differing in
their sensitivity need new technological solutions in order to be processed and shared on an international level.
Cloud computing has vast advantages for cross-border translational genome research. However, the decreased user control
and increased provider control of data in clouds raise uncertainty whether this technology is appropriate to handle sensitive

data. Based on compliance related concerns with regard to the data protection law of the European Union, member states
make reservations regarding the transfer of personal data into third countries by cloud computing. The legal basis for personal
data transfer into the US, the Safe Harbor Agreement, was recently declared invalid by the European Court of Justice.
The upcoming European Data Protection Regulation (EDPR) in its current wording does not address specific regulatory issues
of cloud computing for research. However, detailed analysis shows that the challenges for complying with EU data protection
law by using clouds in genome research are attached to the definition of personal data, to the conditions of data transfer to
third countries, to security and transparency issues such as the access to data and the monitoring of users’ behavior, and
lastly, to data location. The involvement of commercial cloud service providers hampers these challenges.
Results show how these challenges can be dealt with according to the EDPR and how personal data can actually be transferred
into third countries. Results also identify the improvements needed in the legal approach. However, in order to take advantage
of cloud technology in this important field worldwide, the readiness to respond to each other’s concerns of both cloud service
providers and regulators is necessary.
Thu(5)-O36-4
Return of individual genomic research results in patient biobanks: Ethical challenges for Biobank Japan
Kaori Muto 1 ，Hyunsoo Hong 1
1:The Institute of Medical Science, The University of Tokyo, Japan
With the major aim of identifying genetic variants associated with susceptibility to complex diseases or related to drug
toxicity, Biobank Japan (BBJ) has become one of the largest patient-oriented biobanks in the world. During 2003-08, the 1st
cohort collected DNA, serum, and clinical information from 200,000 patients who had either one or multiples of 47 common
diseases. The 2nd cohort has been targeting 38 common diseases and collecting DNA and clinical information since 2013. In
the past decade, the return of research results (RORs) and incidental/secondary findings (IF/SFs) became hot ethical issues
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in genomic studies worldwide and became a challenge for BBJ. In this presentation, the authors review RORs and IF/SFs
in the case of BBJ. In 2012, because of budget pressure, Japanese ministries criticized about current “no return” policies
with patient biobanks. When governmental ethical guidelines were revised in Japan in 2013, IF/SFs became an major ethical
issue, requiring scientists to formulate IF/SF policies prior to informed consent. Since then, RORs and IF/SFs have been
divided and not been discussed together. BBJ obtained consent from the 1st cohort participants that their individual results
would not be returned but obtained nothing with regard to IF/SFs. The same ROR policy was applied to the 2nd cohort,
but participants are informed about the possibility of the return of IF/SFs. If any IF/SFs are observed, their scientific and
clinical validity must be reviewed. Then, BBJ must re-identify the anonymous data source to contact physicians of candidate
patients. BBJ also must consider the appropriateness of timing, clinical implications raised by the results, their effects on
ongoing therapies, and whether re-contact is practically available and ethically valid. Unless scientists obtain consent to
follow up patients’ personal whereabouts and to re-identify anonymous data sources, promising to return any findings is not
practicable.
Thu(5)-O36-5
Ethical premises in the prenatal diagnosis of birth defects in Cuba
Beatriz Marcheco-Teruel 1 ，Iris A Rojas-Betancourt 1
1:National Center of Medical Genetics, Cuba

A systematic and in-depth study was conducted aimed to explore the practical application of ethical and legal principles
established for medical genetic services in Cuba for the last 30 years as well as the level of satisfaction among users of these
services. Several surveys were designed and completed to collect information about the knowledge and attitudes toward new
genetic technologies, genetic testing and the understanding of genetic counseling process in users and providers of medical
genetic services. Summaries of working papers from workshops where experts of the national network of medical genetic
services have discussed about these topics in the last 6 years were also considered. The surveys and research protocols
design was made taking into account the universally accepted ethical principles, and those recommended by WHO and other
international bodies, as well as the Cuban laws and resolutions on these topics. As one conclusion of such work, this study
presents the ethical premises for prenatal diagnosis of birth defects that were consensed for clinical practice and researches
as part of prenatal genetic testing in Cuba. It includes general standards on prenatal diagnosis and selective abortion, the
consensus for the approach regarding non directiveness of genetic counseling services in the country and the procedures related
to the disclosure of genetic information. This proposal is supplemented with other standards inherent to the scientific research
such as: informed consent, ethical aspects of scientific publications and professional ethics elements. These ethical premises
guarantee the respect to the rights and dignity of those persons who look for genetic counseling and prenatal diagnosis services,
and will be part of a manual for the provision of services in the medical genetics network of Cuba.
Thu(5)-O36-6
Socialising the Genome
Anna Middleton 1 ，Julian Borra 2 ，Vivienne Parry 3 ，Katrina Nevin-Ridley 3 ，Amy Sanders 4 ，Julian Rayner 1
1:Wellcome Genome Campus, UK、2:Thin Air Factory, London, UK、3:Genomics England, London, UK、4:Wellcome Trust, London, UK
How to start a conversation about genomics with people who may know nothing about it? This is particularly relevant for
patients involved in the 100,000 Genomes Project, a landmark new UK sequencing project taking place within the NHS.
We aimed to ’socialise’ genomics for participants and their families using an innovative method that combines evidence from
social science with creative story telling as used by the advertising industry. We have done this through the use of animations
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designed to get patients talking with their families or health professionals. Through insights gained from five focus groups
with membership drawn from the British public, we were able to develop core themes on which to base our animations.
Using the creative skills of a senior advertising director from an established advertising company the themes were turned
into a number of narratives. These deliver information about genomics using metaphors and cultural context, as opposed to
scientific text or drawings. Feedback on each of the animations has been gathered from a representative British public group
of 500 people as well as from 1,000 participants and publics. Six novel, evidence based animations have been created that
turn genomics from a previously antisocial concept for many, to a social one for both participants in the 100,000 Genomes
Project and a wider public. The animations will be used as part of a public engagement campaign for Genomics England. We
will show our open access animations in our presentation. They are freely available for anyone to use, irrespective of where
they live in the world.
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[O37] Therapy for Genetic Disorders

Thu., April 07, 2016 9:45-11:15 Annex 2 (1F)
Chair：Jan P. Kraus（Dept. of Pediatrics, University of Colorado School of Medicine, USA）

Chair ：Yu-ichi Goto（Medical Genome Center, National Center of Neurology and Psychiatry, Japan）
Thu(5)-O37-1
Disruption of Microtubule Dynamics in Rett Syndrome (RTT): a Possible New Therapeutic Target
1,2,3 1,2
John Christodoulou ，Wendy Gold ，Tamara Lacina 4 ，Sarah Williamson 1 ，Laurence Cantrill 5
1:Western Sydney Genetics Program, Children’s Hospital at Westmead, Australia、2:Discipline of Paediatrics and Child Health, Sydney
Medical School, University of Sydney、3:Discipline of Genetic Medicine, Sydney Medical School, University of Sydney、4:Faculty of Biotech-
nology, Hochschule Mannheim - University of Applied Sciences, Germany、5:Microscope Facility, Kids Research Institute, Children’s Hospital
at Westmead, Sydney, Australia
Background: RTT is a severe neurodevelopmental disorder, caused by mutations in Methyl-CpG-binding protein 2 (MECP2 ).
MeCP2 disruption affects the expression of specific genes, contributing to disease pathophysiology. The microtubule network
is critical to neuronal function through its role in trafficking cargoes including Brain Derived Neurotrophic Factor containing
vesicles and mitochondria. The acetylation status of a-tubulin is critical to the stability of the microtubule network. Recent
studies have revealed reduced tubulin acetylation, increased microtubule-specific histone deacetylase 6 (HDAC6) expression
and microtubule instability in Mecp2 -deficient cells, suggesting a potential link between these irregularities and the neurobi-

ology in RTT.
Hypothesis: Pharmacological inhibition of HDAC6 restores microtubule dynamics and mitochondrial trafficking in MECP2 -
mutation positive cortical neurons.
Methods: Mitochondrial velocity and microtubule stability were analysed in cultured primary cortical neurons isolated from
hemizygous Mecp2T158A mouse pups, a RTT model that faithfully recapitulates the human disorder, and in cultured skin
fibroblasts from two males with pathogenic MECP2 mutations.
Results: We found that both the patient fibroblasts and RTT mouse cortical neurons had reduced acetylated tubulin and
increased HDAC6 protein levels. We also demonstrated that mitochondrial velocity was reduced in the Mecp2T158A cortical
neurons and that the microtubule network was unstable in the RTT patient fibroblasts. An HDAC6 inhibitor restored tubulin
acetylation levels in the patient fibroblasts and improved microtubule stability. We have commenced a trial of an HDAC6
inhibitor in Mecp2 T158A mice, with preliminary data showing improved motor performance.
Conclusion: Pharmacological HDAC6 inhibition provides a novel therapeutic option for RTT, restoring neuronal trafficking
deficits, potentially stabilizing the neurological phenotype associated with the disorder.
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Thu(5)-O37-2
Vosoritide (BMN 111) in Children with Achondroplasia: Initial results from a Phase 2, open-label,
sequential cohort, dose-escalation study
Sagar A. Vaidya 1 ，Melita Irving 2 ，Carlos Bacino 3 ，Xiaofan Cao 1 ，Joel Charrow 4 ，Valerie Cormier-Daire 5 ，
Wolfgang Dummer 1 ，Paul Harmatz 6 ，Leonid Katz 1 ，Kevin Larimore 1 ，John Phillips 7 ，Julie Hoover-Fong 8 ，
Ravi Savarirayan 9
1:BioMarin Pharmaceutical Inc., USA、2:Guy’s and St. Thomas’ NHS Foundation Trust, Evelina Children’s Hospital, London, UK、3:Baylor
College of Medicine, Houston, TX, USA、4:Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA、5:Institut Imagine,
Universite Paris Descartes, Hopital Necker - Enfants Malades, Paris, France、6:UCSF Benioff Children’s Hospital Oakland, Oakland, CA,
USA、7:Vanderbilt University Medical Center, Nashville, TN, USA、8:Johns Hopkins University School of Medicine, Baltimore, MD, USA、
9:Murdoch Children’s Research Institute, Royal Children’s Hospital Victoria, University of Melbourne, Parkville, Victoria, Australia
Objectives Achondroplasia (ACH) is characterized by impaired endochondral bone growth. Vosoritide (BMN 111) is a potent
stimulator of endochondral bone growth. This phase 2, multi-center, open-label, sequential cohort, dose-escalation study was
designed to evaluate the safety, tolerability and efficacy of daily subcutaneous injections of vosoritide in children with ACH
aged 5-14 years.
Design Subjects completed at least 6 months of pre-treatment growth measurements in a natural history study prior to
enrollment. 26 children with ACH (12 male, 14 female, mean age 7.8 ± 1.8 years) were assigned to one of three cohorts: 2.5
µg/kg/day (n = 8), 7.5 µg/kg/day (n = 8), and 15.0 µg/kg/day (n=10) at a fixed dose for 6 months. Safety was assessed
by measures including incidence of adverse events (AEs), vital signs, and clinical laboratory tests. Efficacy was measured by

changes in annualized growth velocity and anthropometry.
Results Vosoritide was well-tolerated across all dose cohorts. The majority of AEs were mild and included injection site
reactions, asymptomatic hypotension, and headache. No serious AEs were reported, and no AEs led to permanent treatment
discontinuation. Mean (SD) baseline annualized growth velocities (pre-treatment) based on 6 months of natural history data
were 3.76 ± 1.11 cm/year, 2.89 ± 1.39 cm/year, and 4.04 ± 2.28 cm/year in the 2.5, 7.5 and 15.0 µg/kg/day dose cohorts,
respectively. Six month post-treatment mean annualized growth velocities were 3.38 ± 0.89 cm/year, 4.17 ± 1.28 cm/year,
and 6.06 ± 1.07 cm/year in the 2.5, 7.5, and 15.0 µg/kg/day dose cohorts, respectively. A mean increase of 2.01 ± 2.00
cm/year (95% CI 0.58, 3.44; p = 0.0111) was observed in the 15.0 µg/kg/day dose cohort, representing a 50% improvement
in mean annualized growth velocity. Clinically significant changes in body proportions were not observed after 6 months.
Conclusions These data support further development of vosoritide for the treatment of children with ACH.
Thu(5)-O37-3
Salbutamol inhibits ubiquitin-mediated survival motor neuron protein degradation in spinal muscular
atrophy cells
Nur Imma Fatimah Harahap 1 ，Dian Kesumapramudya Nurputra 1 ，Mawaddah Ar Rochmah 1 ，Ai Shima 1 ，
Naoya Morisada 1,2 ，Toru Takarada 3 ，Atsuko Takeuchi 3 ，Yumi Tohyama 4 ，Shinichiro Yanagisawa 5 ，Hisahide Nishio 1,2
1:Community Medicine and Social Healthcare Science, Kobe University, Graduate School of Medicine, Japan、2:Department of Pediatrics,
Kobe University Graduate School of Medicine、3:Analytical Center, Kobe Pharmaceutical University、4:Division of Biochemistry, Faculty of
Pharmaceutical Sciences, Himeji Dokkyo University、5:Division of Medical Economics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo
University
Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is currently incurable. SMA
is caused by decreased levels of the survival motor neuron protein (SMN), as a result of loss or mutation of SMN1 . Although
the SMN1 homologue SMN2 also produces some SMN protein, it does not fully compensate for the loss or dysfunction of
SMN1 . Salbutamol, a β 2-adrenergic receptor agonist and well-known bronchodilator used in asthma patients, has recently
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been shown to ameliorate symptoms in SMA patients. However, the precise mechanism of salbutamol action is unclear. We
treated SMA fibroblast cells lacking SMN1 and HeLa cells with salbutamol and analyzed SMN2 mRNA and SMN protein
levels in SMA fibroblasts, and changes in SMN protein ubiquitination in HeLa cells. Salbutamol increased SMN protein levels
in a dose-dependent manner in SMA fibroblast cells lacking SMN1 , though no significant changes in SMN2 mRNA levels
were observed. Notably, the salbutamol-induced increase in SMN was blocked by a protein kinase A (PKA) inhibitor and
deubiquitinase inhibitor, respectively. Co-immunoprecipitation assay using HeLa cells showed that ubiquitinated SMN levels
decreased in the presence of salbutamol, suggesting that salbutamol inhibited ubiquitination. The results of this study suggest
that salbutamol may increase SMN protein levels in SMA by inhibiting ubiquitin-mediated SMN degradation via activating
β 2-adrenergic receptor-PKA pathways.
Thu(5)-O37-4
Enzyme replacement therapy for homocystinuria
Jan P. Kraus 1 ，Erez M. Bublil 1 ，Tomas Majtan 1 ，Insun Park 1 ，Richard Carrillo 1 ，June Ereno-Orbea 2 ，
Louis A. Martinez-Cruz 2 ，Helena Hulkova 3 ，Viktor Kozich 3 ，Warren Kruger 4
1:Pediatrics, University of Colorado School of Medicine, USA、2:Structural Biology Unit, Center for Cooperative Research in Biosciences,
Bizkaia, Derio, Spain、3:Institute of Inherited Metabolic Disorders, Charles University, First Faculty of Medicine and General University
Hospital, Czech Republic、4:Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, U.S.A.
Cystathionine beta synthase (CBS) deficient homocystinuria is caused by a deficiency of CBS, primarily due to missense

mutations. Biochemically, the disorder is characterized by highly elevated homocysteine, methionine, S-adenosylhomocysteine,
nearly absent cystathionine and low cysteine. Clinically, the patients suffer from vascular disease, strokes, skeletal deformities,
dislocated eye lenses and mental retardation. CBS, a regulatory enzyme of the transsulfuration pathway, binds three cofactors,
heme, whose function remains an enigma, pyridoxal 5’-phosphate, feature of the catalytic site where homocysteine and serine
are condensed to cystathionine, and S-adenosylmethionine, which upon binding greatly stimulates CBS activity. The major
objective of our study was to determine whether administration of recombinant human CBS to circulation as an enzyme
replacement therapy (ERT) would normalize the pathogenic phenotype of several mouse models of homocystinuria. We found
that subcutaneous application of PEGylated, C-truncated CBS nearly prevents histopathological changes in the liver and
dramatically improves survival of a full knockout mouse model, which is otherwise lethal. Our results strongly suggest that
CBS ERT will be a viable alternative to the existing therapies for homocystinuria.
Thu(5)-O37-5
Development of a novel pig model of Duchenne muscular dystrophy and evaluation of antisense-mediated
exon skipping
Kana Hosoki 1 ，Yusuke Echigoya 1 ，William Duddy 2 ，Terence A. Partridge 3,4
，Eric P. Hoffman 3,4
，Joe N. Kornegay 5 ，
Christopher Rogers 6 ，Toshifumi Yokota 1,7
1:Department of Medical Genetics, University of Alberta Faculty of Medicine and Dentistry, Canada、2:Center of Research in Myology,
Sorbonne University, UPMC Univ., Paris, France、3:Research Center for Genetic Medicine, Children’s National Medical Center, Washington
DC, USA、4:Department of Integrative Systems Biology, George Washington University School of Medicine, Washington DC, USA、5:De-
partment of Veterinary Integrative Biosciences, Texas A&M University, TX, USA、6:Exemplar Genetics, IA, USA、7:The Friends of Garrett
Cumming Research & Muscular Dystrophy Canada HM Toupin Neurological Science Endowed Research Chair, AB, Canada
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by mutations in the dystrophin (DMD) gene
and a lack of dystrophin protein. DMD is one of the most common lethal genetic disorders worldwide, and patients exhibit
progressive muscle degeneration and wasting leading to death as a result of heart or respiratory failure. While mouse models
such as mdx have been employed in deciphering the mechanisms of DMD, their usefulness in the translational research is
limited due to their mild disease phenotypes. To address the discrepancy between mouse models and human DMD patients, we
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developed a gene-targeted porcine (pig) model of DMD with exon 52 deletion in the mutation hotspot, which can potentially
serve as a new large animal model. The pig model exhibited severe muscle symptoms similar to human DMD patients. As
therapeutic outcomes derived from large animal models can be more reliably extrapolated to human patients, we employed
the newly established porcine model to test the efficacy and toxicity of exon skipping therapy. Exon skipping employs 15-30
base pair short DNA-like molecules called antisense oligonucleotides (AO) that can modulate the mRNA splicing around the
mutated part of the gene and restore truncated yet functional dystrophin protein as seen in milder Becker muscular dystrophy
patients. Currently several phase II/III clinical trials for exon skipping drugs for DMD are being conducted. We designed new
AOs targeting exon 51 (applicable to 13% of patients), exon 53 (applicable to 10% of patients), and exons 45-55 (applicable
to 45% of patients) in the DMD gene using AO design software we recently developed [Echigoya et al, PLOS One 2015]. We
are currently testing the AO-mediated exon-skipping therapy in the pig model. Our new animal model of DMD could help
pave the way for novel drug discovery and translation into human clinical trials.
Thu(5)-O37-6
RNA/ENA chimera antisense oligonucleotide (AO85) was safely administered and shown to induce
dystrophin exon 45 skipping in Duchenne muscular dystrophy patient: the first clinical study
Yasuhiro Takeshima 1 ，Tomoko Lee 1 ，Hideki Shimomura 1 ，Yasuhiko Tanaka 1 ，Hiroyuki Awano 2 ，Atsushi Nishida 3 ，
Isao Ojima 3 ，Satoshi Minami 3 ，Akio Nakagawa 3 ，Kazumoto Iijima 2 ，Masafumi Matsuo 3
1:Department of Pediatrics, Hyogo College of Medicine, Japan、2:Department of Pediatrics, Kobe University Graduate School of Medicine、

3:Department of Physical Rehabilitation, Kobegakuin University
Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease and characterized by skeletal muscle
dystrophin deficiency due to mutations in the dystrophin gene. Expression of dystrophin is a fundamental treatment for
DMD. Antisense oligonucleotide (AO)-mediated exon skipping that convert out-of-frame mRNA into in-frame mRNA, thereby
enabling semifunctional dystrophin production, is recognized as the most promising treatment for DMD. Currently, two AOs
consisting of either 2′-O-methyl phosphorothioate RNA or phosphorodiamidate morpholino are in clinical trials. Recently, a
new modified nucleotide of 2′-O, 4′-C -ethylene-bridged nucleic acid (ENA) has been invented and shown to have high binding
affinity for the complementary RNA strand and nuclease resistance. In this study we provides the first evidence that AO85,
which is an 18-mer antisense RNA/ENA chimera against dystrophin exon 45 sequence, was safely administered and induced
the skipping of exon 45 in a DMD case. The protocol of this study was approved by our ethics committees. A 7-year-old
DMD case with exon 44 deletion was enrolled. During one administration session AO85 at a dose of 0.5 mg/kg was infused
intravenously at one-week interval for 4 weeks. And the session was repeated six times during three years. The patient’s
vital signs, blood and urine test, ECG, and echocardiogram revealed no apparent adverse reaction. Skipping of exon 45 from
dystrophin transcript was examined by RT-PCR using mRNA isolated from biopsied muscle tissue. Before treatment a single
amplified product with exon 44 deletion was obtained, whereas an additional product corresponding to exon 45 skipping
was obtained one week after 4-week administration, in which the translational reading frame was restored. These findings
demonstrate for the first time that AO85 is administered safely to children with DMD, and effectively induced exon skipping
in DMD skeletal muscles.
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Thu., April 07, 2016 8:00-9:30 Room A (2F)
Chair：Desheng Liang（State Key Laboratory of Medical Genetics, Central South University, China）
Chair：Mayumi Sugiura-Ogasawara（Obstetrics and Gynecology, Research Center for Recurrent Pregnancy Loss, Nagoya
City University, Graduate School of Medical Sciences, Japan）
Thu(5)-O38-1
Risk assessment of medically assisted reproduction and advanced maternal ages in the development of
Prader-Willi syndrome due to UPD(15)mat
1,2
Keiko Matsubara ，Nobuyuki Murakami 2 ，Maki Fukami 1 ，Masayo Kagami 1 ，Toshiro Nagai 2 ，Tsutomu Ogata 1,3
1:Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Japan、2:Department of Pediatrics,
Dokkyo Medical University Koshigaya Hospital、3:Department of Pediatrics, Hamamatsu University School of Medicine
Recent studies have suggested that disomic oocyte-mediated UPD(15)mat is increased in patients with Prader-Willi syndrome
(PWS) born after medically assisted reproduction (MAR). However, it remains unknown whether the increase is primarily due
to MAR procedure itself or advanced maternal childbearing ages as a predisposing factor for the disomic oocyte production.
To examine this matter, we studied 122 naturally conceived PWS patients (PWS-NC group) and 13 MAR-conceived patients
(PWS-MAR group). The relative frequency of disomic oocyte-mediated UPD(15)mat was significantly higher in PWS-MAR

group than in PWS-NC group (7/13 vs. 20/122, P=0.0045), and the maternal childbearing ages were significantly higher
in PWS-MAR group than in PWS-NC group (median [range], 38 [26-45] vs. 30 [19-42], P=0.0015). However, the logistic
regression analysis revealed no significant association between the occurrence of disomic oocyte-mediated UPD(15)mat and
MAR, after adjusting for childbearing age (P=0.25). Consistent with this, while the frequency of ART-conceived livebirths
was higher in the PWS patients than in the Japanese general population (6.4% vs. 1.1%, P=0.00018), the distribution of
childbearing ages was significantly skewed to the increased ages in the PWS patients (P<2.2×10-16). These results argue
against a positive association of MAR procedure itself with the development of UPD(15)mat.
Thu(5)-O38-2
SNP Testing before IVF: searching for optimal number and contain
1
Andrei V Ivanov
1:Human Genetics, University Hospital of Saint-Petersburg State University, Russia
BACKGROUND:
At present, the patient preparation for IVF needs to undergo a series of planned studies, including the genotyping of single
nucleotide polymorphisms (SNP) alleles of some genes. In former USSR countries such investigation does not included in
overwhelming majority of health insurance programs and paid by patient. An important faced task is to determine the optimal
panel for SNP genotyping in terms of price/number of SNP.
MATERIALS AND METHODS:
During 2009-2015 in the University Hospital of St. Petersburg State University were analyzed blood samples from 550 women
with different reproductive system disorders preparing for IVF and 46 healthy women in control group. In total 28 SNP were
analyzed in the genes of thrombophilia factors, folic acid cycle, detoxification system and the renin-angiotensin system. The
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method used was Real-Time PCR.
RESULTS:
It was shown a significant increase in the frequency of pathological alleles of some polymorphisms in patients with habitual
failure of IVF, compared with the control group. As a result two options defined panels for optimal typing SNP before IVF
were composed. Standard panel includes 8 SNP, 5 in thromborhilic factors and 3 in folic acid cycle genes. They are 20210
G>A of F II gene, R506Q G>A of FV gene (mutation Leiden), -675 5G>4G of PAI-I gene, L33P T>C of ITGB3 gene, -455
G>A of FGB gene, 667 C>T of MTHFR gene, 2756 A>G of MTR gene and 66 A>G of MTRR gene. Extended panel of
15 SNP also includes 807 C> T of ITGA2 gene, T154M C>T of GP1BA gene, second polymorphism 1298 A>C in MTHFR
gene, polymorphisms of the renin-angiotensin gene AGT M235T T>C and -1166 A>C of AGTR1 gene, polymorphisms I105V
A>G and A114V C>T of detoxification system gene GSTP.
CONCLUSION:
The results of SNP genotyping can be adjusted for treatment tactics and IVF, and also medical support getting pregnant.
The success rate of IVF is increased as the result, especially in the group with the usual failure of IVF.

Thu(5)-O38-3
The examination of chromosome abnormality in couples with recurrent pregnancy loss
Hiroaki Aoki 1 ，Osamu Samura 1 ，Akiko Konishi 1 ，Michiko Suzuki 1 ，Momoko Inoue 1 ，Madoka Horiya 1 ，
Taizan Kamide 2 ，Eri IIkura 3 ，Tomohiro Tanemoto 1 ，Rie Tachimoto 1 ，Takayuki Haino 1 ，Nozomu Yanaihara 1 ，
Kohei Sugimoto 1 ，Aikou Okamoto 1
1:Obstetrics and Gynecology, The Jikei University School of Medicine, Japan、2:Obstetrics and Gynecology, The Jikei University Kashiwa
Hospital、3:Obstetrics and Gynecology, The Jikei University Daisan Hospital
Objective: Chromosome abnormality in either of couples is one of the risk factor of recurrent pregnancy loss. It is estimated
that there are two thousand patients of recurrent pregnancy loss per year in Japan because the last reported frequency of
chromosome abnormality in the patients are 4.6%.
Methods: We included the couples with recurrent pregnancy loss who were examined at our clinic between April in 2004 and
April in 2014. We investigated the type of chromosome abnormality, pregnancy and delivery history, and other backgrounds
of the couples with chromosome abnormality. This study was approved from the institutional review board
Results: In 1032 examined couples, pericentric inversion of chromosome 9. were found in 25 couples (2.4%), and chromosome
abnormality were found in 38 couples (3.7%), included 17 cases of balanced reciprocal translocation, 4 cases of Robertsonian
Translocation, and 17 cases of other chromosomal abnormality. Chromosomal abnormalities were found 25 cases in maternal
and 13 cases in paternal in the couples. 31 cases (81.6%) did not have live birth at chromosome analysis from blood culture.
Eight cases (47%) in balanced reciprocal translocation carriers and two cases (50%) in Robertsonian Translocation could give
live birth.
Conclusion: The incidence of chromosomal abnormality in couples with recurrent pregnancy loss was similar with that in
previous reports. The database about chromosomal abnormality in couples with recurrent pregnancy loss is necessary for
genetic counseling.
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Thu(5)-O38-4
Day 5 embryos show reduced aneuploidy rate compared to day 3 embryos in preimplantation genetic
diagnosis for reciprocal translocation carriers
Yoshiharu Nakaoka 1 ，Michiko Ammae 1 ，Tatsuya Nakano 1 ，Kayo Takahashi 1 ，Kanako Katsu 1 ，Hiroko Yamauchi 1 ，
Takao Himeno 1 ，Keijiro Ito 1 ，Ayumi Yamamoto 2 ，Ryota Kobayashi 2 ，Risa Mori 2 ，Aisaku Fukuda 2 ，Tomoko Inoue 3 ，
Yoshiharu Morimoto 3
1:IVF Namba Clinic, Japan、2:IVF Osaka Clinic、3:HORAC Grand Front Osaka Clinic
(Introduction)
For preimplantation genetic diagnosis (PGD) in Japan, chromosome analysis to identify chromosomal abnormalities is per-
mitted only for translocated chromosomes without aneuploidy screening of non-translocated chromosomes. On the other
hand, comparative genomic hybridization (CGH) provides accurate and comprehensive information about all chromosomes
of embryos. Therefore, we investigated the incidence of chromosomal abnormalities originating from translocated and non-
translocated chromosomes in day 3 and day 5 embryos undergoing PGD by using CGH.
(Material and Methods)
This study was approved by the Japan Society of Obstetrics and Gynecology. In total, 31 PGD cycles from 17 carrier couples
with reciprocal translocation were reviewed, including 20 cycles of day-3 embryo biopsies and 15 cycles of day-5 embryo biop-

sies. Average maternal age is 37.5 and 36.2 years old in day-3 and day-5 embryo biopsy, respectively. Chromosome analysis
was performed using CGH.
(Results)
The incidence of chromosome abnormalities in day 3 and day 5 embryos was 86.5% (77/89) and 80.9% (38/47); 59.5% (53/89)
and 63.9% (30/47), respectively, of abnormalities originated in translocated chromosomes. However, the incidence of abnor-
malities in non-translocated chromosomes in day 5 embryos (44.7% [21/47]) was significantly lower than that in day 3 embryos
(76.4% [68/89]). The aneuploidy rate, except for translocated chromosomes, was 27.0% (24/89) and 17.0% (8/47) in day 3
and day 5 embryos, respectively.
(Conclusion)
The incidence of abnormalities in non-translocated chromosomes shows a significant decrease from day 3 to day 5 embryos.
These findings suggest that day 5 embryos are suitable for the exclusion of aneuploidy during PGD for reciprocal translocation
carriers.
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Thu(5)-O38-5
Preimplantation genetic diagnosis and natural conception: a comparison of live birth rates in patients
with recurrent pregnancy loss associated with translocation
Shinichiro Ikuma 1,2 ，Takeshi Sato 3 ，Mayumi Sugiura-Ogasawara 3 ，Takashi Yamaguchi 2 ，Tamito Miki 2 ，
Motoi Nagayoshi 2 ，Atsushi Tanaka 2 ，Satoru Takeda 1
1:Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Japan、2:Saint Mother Obstetrics and Gynecology
Hospital、3:Department of Obstetrics and Gynecology, Nagoya City University, Graduate School of Medical Sciences
Background: PGD was initiated in 1998 as a means of preventing miscarriages in patients with RPL associated with translo-
cation. However, it is not established whether PGD can improve the live birth rate because there has been no cohort study
comparing patients undergoing or not undergoing PGD.
Objective: To compare the live birth rate of patients with RPL associated with a translocation undergoing PGD with that
of patients who chose natural conception.
Methods: A total of 126 patients were enrolled between August 2003 and November 2013. After genetic counseling, 52
patients desired natural conception and 74 patients chose PGD. Each patient wishing to undergo PGD was reviewed the
Ethics Committee of the Japan Society of Obstetrics and Gynecology and permission granted. PGD was performed by FISH
analysis. The obstetrical outcomes were compared between 37 patients undergoing PGD who were matched for age (<= 34
years) with the natural conception group, and 52 patients who selected natural conception. The subsequent outcomes were

ascertained from the medical records until July 2014.
Results: The live birth rates at the first trial of PGD and the first natural pregnancy after ascertainment of the carrier status
were 37.8% and 53.8%, respectively. Cumulative live birth rates were 67.6% and 65.4%, respectively, in the groups undergoing
and not undergoing PGD. The mean number of further miscarriages until a live birth took place in the PGD (0.24 ± 0.40)
group was significantly lower than that in the natural conception group (0.58 ± 0.78, p = 0.02). The time required to become
pregnancy was similar in both groups. The percentage of infertile patients was significantly higher in the PGD group.
Conclusion: While PGD significantly prevented further miscarriages, there was no difference in the live birth rate. These
data should be incorporated into the genetic counseling of patients with RPL and a translocation.
Thu(5)-O38-6
Genetic Counsellor’s Preferences for Public Coverage of Preimplantation Genetic Diagnosis: A Discrete
Choice Experiment
1,2 1,2
Elaine S Goh ，Wendy Ungar ，Deborah Marshall 3 ，Fiona A Miller 1
1:Institute of Health Policy, Management and Evaluation, University of Toronto, Canada、2:Child Health Evaluative Sciences, The Hospital
for Sick Children Research Institute, Toronto, Canada、3:Department of Community Health Sciences, University of Calgary, Calgary, Canada
Preimplantation genetic diagnosis (PGD) is an expensive technology that permits couples at high risk of a genetic disorder
to test an embryo prior to implantation. In the absence of Canadian policy regarding PGD use, the discretion of genetic
counsellors (GC) guides clinical practice. The study objective was to determine and quantify preferences for PGD coverage
arrangements - specifically, under what conditions and what extent public coverage should be provided.
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A discrete choice experiment (DCE) was undertaken with Canadian GC to quantify their stated PGD coverage preferences
considering the following attributes: PGD indication, risk of the condition, fertility status, family history and number of
cycles covered. Multinomial logit regression was used to estimate part-worth utilities and importance scores. Demographic,
practice and attitude characteristics were considered as factors driving preference. Part-worth utilities for each level were
added to inform total utility for certain clinical scenarios.
The study was completed by 126 GC (completed response rate of 41%). Risk of the condition had the highest importance
score and number of cycles covered had the lowest. GC with more than 10 years experience or who worked in the prenatal field
had positive preference for 1% risk of a condition. Infertile couples with a 50% risk of an adult-onset cancer predisposition
and unaffected children covered for 8 cycles had a higher total utility than fertile couples at a 1% risk of a childhood-onset
condition, with affected children, covered for 1 cycle.
This is the first study to quantify preferences of GC related to PGD coverage. Based on this study, policy recommendations
for PGD indication and risk should take into account clinical judgment. Secondly, eligibility for coverage could be based on
maximizing total utility of clinical situations using part-worth utilities derived from this study. This evidence may help to

promote discussion and shape national PGD policy.
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Thu., April 07, 2016 9:45-11:15 Room A (2F)
Chair：Do Yeong Hwang（Department of OB & Gyn, Hamchoon Women’s Clinic, Korea, South）
Chair：Haruhiko Sago（Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health
Thu(5)-O39-1
Risk level of intracytoplasmic sperm/spermatid injection for 116 non-mosaic Klinefelter syndrome (KS)
patients
Atsushi Tanaka 1 ，Motoi Nagayoshi 1 ，Shinichiro Ikuma 1 ，Tamito Miki 1 ，Takashi Yamaguchi 1 ，Izumi Tanaka 1 ，
Youichi Takemoto 1 ，Hiroshi Kusunoki 2 ，Seiji Watanabe 3 ，Satoru Takeda 4
1:Saint Mother Hospital, Japan、2:Faunal Diversity Sciences, Graduate School of Agriculture, Kobe University、3:Department of Anatomical
Science, Hirosaki University Graduate school of Medicine、4:Department of Obstetrics and Gynecology, Juntendo University School of
Medicine
Objective:It has been reported that the sex chromosome abnormality incidence rate for ICSI children increased when KS
patient sperm had been used. We investigated whether the sex chromosome abnormality incidence for ICSI children increased
when KS patient’s sperm/spermatid is used.

Design:We have performed a retrospective analysis of clinical outcome of ICSI in KS men using testicular sperm/spermatid
during 2007 ~ 2012.
In addition, we performed chromosomal analysis of 21 new born babies and FISH analysis of 500 round spermatids of KS
patients.
Material and methods:
In a clinical IVF setting, this study dealt with 215 men who had previously been diagnosed as having non-mosaic KS. ICSI
was performed using testicular sperm and spermatids were injected into electrically activated oocytes. We performed FISH
analysis for remaing spermatids to confirm they are haploid cells.
Results:
1. Out of 215 patients, slowly motile testicular sperms in 22 patients [A: 10.2% (22/215)], early stages of spermatid in 94
patients [B: 43.7% (94/215)] and no spermatogenic cells in 99 patients [C: 46.0% (99/215)] were found. Pregnancy rates per
treatment cycles miscarriage rates and delivery rates in group A, B, were [A: 22.9% (8/35), 12.5 % (1/8), 20.0% (7/35)],
[B: 16.0% (36/225), 22.2% (8/36), 12.4% (28/225)] respectively. 37 healthy babies were born (male:female= 15:22) with 21
normal karyotype. No major congenital abnormalities were observed.
2. FISH analysis for round spermatids showed 100% monosomic, no disomic cells (X=224/485, Y=261/485, XX,YY,XY=0/485).
3. Total number of new born babies from KS patients so far are about 150 (including our data) and about only 35 (including
our data) babies are proved to be chromosomaly normal.
Conclusions:
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Our data indicates the risk level of KS patients’ intracytoplasmic sperm or spermatid injection into oocytes is much lower
than previously expected.
Thu(5)-O39-2
New candidate genes for NTD and CHD screened from a PiggyBac transgenic mice library have higher
mutation rates in human NTD
Yufang Zheng 1,2,5 ，Zhongzhong Chen 1 ，Yingchun Jing 1 ，Zhiwen Shi 1 ，Shuxia Chen 1 ，Weiqi Liu 1 ，Jiaojiao Liu 4 ，
Chunyan Wang 4 ，Hong Xu 4 ，Tian Xu 2 ，Ting Zhang 3 ，Xiaohui Wu 2 ，Hongyan Wang 1,5
1:State Key Laboratory of Genetic Engineering and Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology, School
of Life Science, Fudan University, China、2:The Institute of Developmental Biology and Molecular Medicine, Fudan University、3:Capital
Institute of Pediatrics, Beijing, China、4:The children hospital of Fudan University, Shanghai, China、5:8. Obstetrics and Gynecology
Hospital, Fudan University
Neural tube defects (NTD) and congenital heart disease (CHD) are the top two birth defects in China and among the world.
Genetic factors play an important role in the progression of these diseases as more than 70% NTD can be attributed to
genetic factors. Identifying more causative genes and further understanding the genetic mechanism behind those birth defects
can help to establish a prenatal genetic screening list, which is a key step in reducing the incidence of NTD and CHD.
However, it is very hard to find relative pedigree due to the severity of those diseases. Therefore, animal models are very
important resource to sorting the candidate genes. By using the established PiggyBac transposon inserted transgenic mice,
we performed a large-scale screening on embryonic lethal lines for NTD or/and CHD phenotypes. Our screening covers 342

PB lines which are embryonic or perinatal lethal. According to MGI database, 295 lines had not been reported for knockout
mouse. Within those 295 lines, there are 28.8% (85/295) lines showing NTD and 6.4% (19/295) showing CHD phenotype.
Next we sequenced 100 random human NTD samples and compared with the 208 Chinese Han population in Genome1000
project. Those NTD associated candidate genes have significantly higher mutation rate (average 531.7 mutations/gene)
compare to other housekeeping genes, e.g. Hox genes (average 27.9 mutations/gene). Our work successfully identified large
number of new candidate genes for server birth defects e.g. NTD, which could provide new windows to understand the genetic
and molecular mechanisms behind NTD.
Thu(5)-O39-3
Mutations in CYP11B1 Gene of Vietnamese Patients with 11ß -hydroxylase Deficiency
1,2
Mai T.P. Nguyen
1:Human genetics, National Hospital of Pediatrics, Vietnam、2:Institute of Genome Research
Brief background: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease which is characterized by a
deficiency of one of the enzymes involved in the synthesis of cortisol from cholesterol by the adrenal cortex. CAH cases
arising from impaired 11 β-hydroxylase are the second common form. Mutations in the CYP11B1 gene are the cause of 11
β-hydroxylase deficiency.
Patients: This study was performed on five patients suspected congenital adrenal hyperplasia with clinical significations of
premature development such as enlarged penis, muscle development, virilization, high blood pressure and biochemical tests
for steroids confirmed the diagnosis of CAH.
Methods: . In this study, we used PCR and sequenced directly to identify mutation. Missense mutation of 11 β-hydroxylase
was expessed in COS-1 cells to study the effect of mutant on the conversion of 11-deoxycortisol to cortisol.
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Results: Results showed that two patients had compound heterozygous of mutations p.Arg43Gln and p.Ala386Val; 1 patient
had heterozygous of novel missense mutation p.Arg51Lys; 1 patient had a novel homozygous mutation of guanine (G) to
thymine (T) in intron 6 (IVS6+5G>T). A novel missense mutation p.Arg51Lys was detected in CYP11B1 which causes
a decrease of 29 ± 4.5% of 11 β-hydroxylase activity as compare to wild type. The patient with clinical manifestations,
biochemical disease of CAH classical forms such as external genital abnormalities, reduced cortisol and Na+, K+ and high
blood pressure. The analysis of mutation IVS6+5G>T by MaxEntScan boundary software indicated that this mutant could
affect the gene splicing during transcription.
Conclusion: The resulting of molecular genetics can be used to support genetic couselling and prenatal diagnosis.
Thu(5)-O39-4
Withdrawn


Thu(5)-O39-5
Parental decisions on prenatally diagnosed chromosome abnormalities before 22 weeks of gestation: A
Japanese multicenter retrospective study
Miyuki Nishiyama 1 ，Akihiko Sekizawa 2 ，Hiroaki Nakamura 3 ，Nobuhiro Suzumori 4 ，Setsuko Nakayama 5 ，
Takahiro Yamada 6 ，Masaki Ogawa 7 ，Yukiko Katagiri 8 ，Yoko Okamoto 9 ，Akira Namba 10 ，Haruka Hamanoue 11
，
Masanobu Ogawa 12 ，Kiyonori Miura 13 ，Shunichiro Izumi 14 ，Yoshimasa Kamei 10 ，Haruhiko Sago 1
1:Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Japan、2:Department
of Obstetrics and Gynecology, Showa University School of Medicine、3:Department of Obstetrics, Osaka City General Hospital、4:Department
of Obstetrics and Gynecology, Nagoya City University Graduate School of Medical Sciences、5:Department of Obstetrics and Gynecology,
Aiiku Clinic、6:Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine、7:Department of Obstetrics
and Gynecology, Tokyo Women’s Medical University、8:Department of Obstetrics and Gynecology, Toho University Omori Medical Center、
9:Department of Obstetrics, Osaka Medical Center and Research Institute for Maternal and Child Health、10:Department of Obstetrics
and Gynecology, Saitama Medical University、11:Department of Obstetrics and Gynecology, Yokohama City University Graduate School of
Medicine、12:Department of Obstetrics and Gynecology / Clinical Research Institute, National Kyusyu Medical Center、13:Department of
Obstetrics and Gynecology, Nagasaki University School of Medicine、14:Department of Obstetrics and Gynecology, Tokai University School
of Medicine
Objective: To investigate the parental decisions after a prenatal diagnosis of chromosome abnormalities before 22 weeks of
gestation in Japan. Method: We performed a retrospective analysis of 9,348 pregnant women who underwent fetal karyotyping
before 22 weeks of gestation at 14 hospitals from April 2008 to March 2015. The pregnancy outcomes and clinical data of
859 fetuses with chromosomal abnormalities were analyzed. We performed a multivariate logistic regression analysis with
the type of aneuploidy, parity, maternal age, natural conception, type of diagnostic procedure, and referral indications for
fetal karyotyping as factors related to the decision to terminate. Results: The overall termination rate was 68.8%: 89.6% for
autosomal trisomy and 39.0% for sex chromosome aneuploidy. The highest termination rate among the autosomal chromosome
aneuploidies was for trisomy 21 (94.0%), followed by trisomy 18 (84.1%) and trisomy 13 (80.0%). The highest termination
rate among the sex chromosome aneuploidies, was for 45,X (49.1%); the lowest was for 47,XXX (8.3%). A multivariate
logistic regression analysis revealed that among the autosomal and sex chromosome aneuploidies, trisomy 21 (OR=3.26;
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p<0.001) and 45,X (OR=2.75; p =0.040), respectively, were significantly associated with higher termination rates. The
reason for fetal karyotyping (i.e. abnormal ultrasound findings) was a significant negative factor in the decision to terminate
in cases of autosomal trisomy (OR=0.41; p =0.045). Conclusion: This retrospective study represents the largest study on
parental decisions after a diagnosis of fetal chromosome abnormalities before 22 weeks of gestation in Japan. The type of
aneuploidy and the indications for fetal karyotyping contributed to the parents’ decisions. These findings will provide valuable
information for assessing approaches among healthcare professionals who provide genetic counseling after a prenatal diagnosis
of chromosomal abnormalities.
Thu(5)-O39-6
Isolation of mesenchymal stem cells derived from human placental tissue and their expression of C19MC
microRNAs
Naoki Fuchi 1 ，Kiyonori Miura 1 ，Ai Higashijima 1 ，Tao-Sheng Li 2 ，Hideaki Masuzaki 1
1:Department of Obstetrics and Gynecology, Nagasaki University Graduate School of Medicine, Japan、2:Department of Stem Cell Biology,
Atomic Bomb Disease Institute, Nagasaki University
[Objective] Circulating placenta-specific C19MC miRNAs has been demonstrated to be the potential biomarkers of pregnant
disorders. We investigated the expression of C19MC miRNAs in mesenchymal stem cells (MSCs) from various placental
tissues.

[Method] This study protocol was approved by the IRB for Ethical, Legal and Social Issues. Normal placentas were ob-
tained at the first and third trimester following written informed consent. We expanded MSCs primarily from chorionic villi
(CV-MSCs) and chorionic plate (CP-MSCs) tissues and analyzed the mesodermal lineage differentiation of these MSCs. The
expressions of C19MC miRNAs were measured by real-time RT-PCR, and normalized with the endogenous U6.
[Result] Either CP-MSCs or CV-DCs positively expressed with MSC markers (CD44, CD73, CD90 and CD105), but negatively
with hematopoietic markers (CD34 and CD45), confirmed the characterization of MSCs. These cells could be differentiated
toward adipogenic, osteogenic and chondrogenic lineage. The relative expression levels of miR-517a and -518b, two represen-
tative members of C19MC miRNAs were 0.00184 and 0.00525 in first trimester CV-MSCs, 11.5 and 8.03 in third trimester
CV-MSCs, and 1.47 and 3.81 in third trimester CP-MSCs, respectively.
[Conclusion] Placenta-specific C19MC miRNAs was detected in MSCs from different placental tissues. Primarily expanded
MSCs may serve as useful tools for uncovering the molecular mechanism on pregnant disorders.
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Thu., April 07, 2016 8:00-9:30 Room E (1F)
Chair：Jozef Gecz（Paediatrics, The University of Adelaide, Australia）

Chair ：Ryota Hashimoto（Molecular Research Center for Children’s Mental Development, United Graduate School of
Chid Development, Osaka University, Japan）
Thu(5)-O40-1
Exome Sequencing of Pakistani Consanguineous Families Identifies 31 Novel Candidate Genes for Re-
cessive Intellectual Disability
Hans van Bokhoven 1 ，Saima Riazuddin 2 ，Mureed Hussain 1,3,4 ，Attia Razzaq 1,3,4 ，Zafar Iqbal 1 ，M Shahzad 2 ，
Daniel Lopo Polla 1 ，Y Song 5 ，A A Khan 4 ，Joris A Veltman 1,6 ，Z M Khan 7 ，Detelina Grozeva 8 ，Karen Carrs 9 ，
Tjitske Kleefstra 1 ，S A Riazuddin 10 ，Muhammad Ansar 1,3,4 ，F Lucy Raymond 8,9 ，S N Khan 4 ，Z M Ahmed 2 ，
Arjan PM de Brouwer 1 ，Sheikh Riazuddin 3,4
1:Human Genetics 855, Radboud University Medical Center, Netherlands、2:Department of Otorhinolaryngology-Head & Neck Surgery,
University of Maryland, Maryland, USA、3:Allama Iqbal Medical College, University of Health Sciences, Pakistan、4:National Center for
Excellence in Molecular Biology, University of the Punjab, Pakistan、5:Institute for Genome Sciences and Program in Personalized and
Genomic Medicine, University of Maryland School of Medicine, USA、6:Department of Clinical Genetics, GROW School for Oncology
and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands、7:Shaheed Zulfiqar Ali Bhutto Medical
University, Pakistan Institute of Medical Sciences, Pakistan、8:Department of Medical Genetics, Cambridge Institute for Medical Research,
University of Cambridge, Cambridge, United Kingdom、9:Department of Haematology, University of Cambridge, Cambridge, United
Kingdom、10:The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 2-3% of the general population.
Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that
cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here,
we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified
a single homozygous DNA variant, 29 affecting reported ID genes and 31 novel candidate ID genes. Causality of these
alleles was supported by co-segregation with the phenotype, frequency in control populations and the application of stringent
bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 20
genes that were either known or are novel candidates for ID. We mapped the novel candidate ID genes onto transcriptome
profiles of normal human brain tissues. In the temporal-parietal and sub-cortex during infancy to adulthood, novel ID genes
formed a network significantly enriched for transcriptional co-expression (p<0.0001). Proteins encoded by 11 novel ID genes
directly interact with previously reported ID proteins and participate in six known pathways essential for cognitive function
(p<0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are
critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and
provide new insights into the molecular mechanisms and transcriptome map of ID.
Thu(5)-O40-2
Protocadherin 19 (PCDH19) epilepsy, intellectual disability and autism limited to females
Jozef Gecz 1 ，Chuan Tan 1,2 ，Claire C Homan 1,3 ，Dale McAninch 3 ，Archa Fox 4 ，Daniel Pederick 3 ，Paul Q Thomas 3 ，
Lachlan Jolly 1,2 ，Raman Kumar 1,2 ，Duyen Pham 1,2
1:Paediatrics, The University of Adelaide, Australia、2:Robinson Research Institute, The University of Adelaide、3:School of Biological
Sciences, The University of Adelaide、4:University of Western Australia
PCDH19 is an X-chromosome δ 2 protocadherin gene, one of the most frequently mutated epilepsy genes, specifically in girls
with severe, early onset paediatric epilepsy. PCDH19 girls present with clusters of drug resistant seizures, intellectual disability,
autism and other behavioural comorbidities including ADHD or schizoaffective disorder. Contrary to the usual X-chromosome
inheritance, males with PCDH19 mutations are not affected unless they are somatic mosaics for the mutation. As such
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PCDH19 female epilepsy (PCDH19-FE) is a disorder driven by cellular mosaicism. We have demonstrated that alteration to
sex-biased gene expression plays a significant role. We identified p54nrb/NONO, a multifunctional nuclear paraspeckle protein
as a PCDH19 protein interacting partner. Based on our and published data we postulated and subsequently demonstrated that
PCDH19 protein regulates estrogen receptor alpha (ERa). Using MCF-7 (ERa+) and MDA-MB-231 (ERa-) breast cancer
cell lines, we show that PCDH19 protein is a positive regulator of ERa target genes. Importantly, this activity is further
enhanced by NONO and abolished by disease-causing PCDH19 mutations. These findings are consistent with our patient
transcriptome studies showing targets of nuclear hormone receptors and ERa in particular (e.g. APOD, OXTR, GRIA1
or AKR1C2 and 3 ) dysregulated. Additionally, we generated and characterized a Pcdh19 KO mice and an iPS-derived
model of PCDH19-FE supporting the role of PCDH19 in neuronal cell polarity and movement. Phase II clinical trial has
also been instigated with neurosteroid ganaxolone supplementation in PCDH19 patients who are allopregnanolone deficient.
Overall we define and characterize a novel mechanism(s) of PCDH19-FE including ERa-mediated gene dys-regulation as
one of the consequences. This novel PCDH19-NONO-ERa axis is of broader relevance not only to PCDH19-FE and its
neurodevelopmental and neuropsychiatric comorbidities, but also to various ERa-dependent cancers.
Thu(5)-O40-3
Maternal Copy Number Variants (CNV) transmission to their Autism Spectrum Disorder (ASD) sons
correlates with phenotypic traits
1,2,3,4 1,2,3,5 2,3,4
，Muhammad Asif ，Ines Conceicao ，Katarzyna Kwiatkowska 2 ，Celia Rasga 2,3
，

Astrid Moura Vicente
Francisco Couto 1
1:Faculdade de Ciencias da Universidade de Lisboa, Pakistan、2:Instituto Nacional de Saude Doutor Ricardo Jorge, Lisboa, Portugal、
3:Biosytems and Integrative Sciences Institute, Lisboa, Portugal、4:Instituto Gulbenkian de Ciencia, Oeiras, Portugal、5:Department of
Biosciences, COMSATS Institute of Information Technology, Sahiwal, Pakistan
Autism Spectrum Disorder (ASD) is characterized by impairments in social communication and repetitive behaviors, a clinical
presentation spectrum and a high male:female ratio. Behavioral traits in the ASD spectrum are prevalent in unaffected family
members, highlighting a trait heritability likely mediated by genetic factors that impact ASD risk. Here we tested the
hypothesis that CNV-transmitting parents of ASD children exhibit higher scores of quantitative ASD traits tests as compared
to CNV non-transmitting parents. Parental scores for the Social Responsiveness Scale (SRS) (N=456) and the Broader
Autism Phenotype Questionnaire (BAPQ) (N=341) and CNV inheritance patterns to affected children were obtained from
the Autism Genome Project database. We applied the Mann-Whitney U test to compare ASD traits in CNV transmitting
and non-transmitting parents.
There were no significant differences between the SRS and BAPQ scores from CNV-transmitting and non-transmitting parents.
However, when dissected by relative pairs, a significant difference between CNV transmitting and non-transmitting mothers
to their sons was identified for SRS (P=0.040), BAPQ global (P=0.008) and BAPQ domains scores aloofness (P = 0.015) and
pragmatic language deficits (P = 0.019). A trend for BAPQ global (P=0.048) in mother-all children pairs was also identified.
Our findings indicate that unaffected mothers who transmit CNVs of putative clinical significance to their affected sons tend to
have more ASD traits than the CNV-non-transmitting mothers. The results reinforce previous reports of significant maternal
transmission bias to sons, further correlating this increased risk with phenotypic presentation in mothers. The results further
support the prevalent hypothesis of a higher genetic risk tolerance in females due to putative protective factors, explaining
the maternal bias in CNV and ASD transmission to sons compared to daughters.
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Thu(5)-O40-4
Massively parallel sequencing in a case control cohort and extended families identifies noncoding risk
variants for autism spectrum disorder
Anthony J Griswold 1 ，Holly N Cukier 1 ，Derek Van Booven 1 ，Eden R Martin 1,2 ，Michael L Cuccaro 1,2
，
John R Gilbert 1,3 ，Jonathan L Haines 3 ，John P Hussman 4 ，Margaret A Pericak-Vance 1,2
1:John P. Hussman Insitute for Human Genomics, University of Miami, USA、2:Dr. John T. Macdonald Department of Human Genetics,
University of Miami、3:Department of Epidemiology and Biostatistics, Case Western Reserve University、4:Hussman Institute for Autism
Autism spectrum disorder (ASD) has a complex genetic etiology with hundreds of candidate genes implicated by association,
copy number, and exome sequencing studies. To investigate the largely unstudied contribution of noncoding variants to ASD,
we applied a two pronged strategy. First, we used custom capture to sequence evolutionarily conserved regions in 942 ASD
associated intergenic loci and intronic and flanking regions of 689 candidate genes in 2099 ASD individuals and 812 controls.
Second, we performed whole genome sequencing (WGS) on cousins in six multiplex, extended ASD pedigrees (n=15). We
applied comprehensive annotation including bioinformatics functional predictions for noncoding variants (GWAVA, CADD,
FATHMM-MKL). Structural variants (SVs) from WGS were called with the SWAN algorithm. Targeted sequencing in
the case-control cohort yielded 519,950 noncoding single nucleotide variants (SNVs) of which 7,223 were in the top 10%
of all computational prediction programs and therefore most likely functional. Among these are case specific rare variants
in highly conserved transcription factor binding sites upstream of ASD candidate genes (NRXN1 , CTNND1 ) and other
neurodevelopmental genes (FGFR2, SGK1, SETD7 ). By WGS, we identify more than four million SNVs and 100 SVs per
individual. Identical by descent and sharing filtering implicated likely functional variants in the putative promoters of ASD

candidate genes (e.g. CNTN4) and neuronal function genes (KCTD1) in individual families. In addition, rare deletions
disrupting the promoters of neurodevelopmental genes (WWWOX) and noncoding exons of lincRNAs (FIRRE) were found in
single families. While molecular experiments to determine the underlying effect of these variants are necessary, this approach
of applying computational methods to noncoding variation will enhance our ability to determine the functional consequences
of SNVs and broaden our understanding of the underlying genetic factors in ASD.
Thu(5)-O40-5
Identification of rare risk variants in voltage-gated channel genes (CACNA1C, CACNA1D, CACNA1S,
CACNA1I) in Japanese population of schizophrenia and autism spectrum disorder using Ion PGM plat-
form
Chenyao Wang 1 ，Hiroki Kimura 1 ，Jingrui Xing 1 ，Itaru Kushima 1 ，Branko Aleksic 1 ，Norio Ozaki 1
1:Nagoya University, Japan
Several large-scale whole exome sequencing studies in schizophrenia (SCZ) and autism spectrum disorder (ASD) identified
rare variants with modest or strong effect size as genetic risk factors. Dysregulation of cellular calcium homeostasis might
be involved in SCZ and ASD pathogenesis, and genes coding for L-type voltage-gated calcium channel (VDCC) subunits
Cav1.1 (CACNA1S), Cav1.2 (CACNA1C), Cav1.3 (CACNA1D) and T-type VDCC subunit Cav3.3 (CACNA1I) were recently
identified as risk loci for psychiatric disorders. We investigated rare mutations with possibly damaging effects in those genes
in Japanese sample of SCZ and ASD.
We prioritized four candidate genes (CACNA1C, CACNA1D, CACNA1S, CACNA1I) for psychiatric disorders in subset of
VDCC genes based on genome-wide association studies, exome sequencing and functional genomic studies. Then, mutation
screening of exon regions of those 4 genes using Ion Torrent Personal Genome Machine (PGM) was performed in a Japanese
sample of 370 SCZ patients and 192 ASD patients. Variant filtering were applied to identify those that were not registered in
dbSNP database or have MAF<1% in East-Asian samples from ESP and 1000 Genomes, and are damaging non-synonymous,
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splicing site single nucleotide variants (SNVs) or small insertion and deletion predicted by in-silico analyses. All of those
filtered mutations were confirmed by Sanger method. If parental samples were available, segregation analysis were employed
for measuring the inheritance pattern. Under our filter, we discovered 1 nonsense SNV (p.C1471* in CACNA1D), 1 in-frame
deletion (p.E1675del in CACNA1D), 2 de novo SNVs (p.A36V in CACNA1C, p.V947I in CACNA1S), 8 missense SNVs that
are categorized as damaging by 5 different in-silico tools.
Our analysis investigated several rare and possibly damaging variants on the risk for SCZ and ASD in VDCC genes, especially
within L-type VDCC genes.
Thu(5)-O40-6
Systematic integration of brain eQTL and GWAS identifies ZNF323 as a novel schizophrenia risk gene
and suggests recent positive selection based on compensatory advantage on pulmonary function
Xiong-jian Luo 1 ，Manuel Mattheisen 2 ，Ming Li 3 ，Liang Huang 4 ，Marcella Rietschel 5 ，Anders D Borglum 2 ，
Thomas D Als 2 ，Edwin J van den Oord 6 ，Karolina A Aberg 6 ，Ole Mors 7 ，Preben Bo Mortensen 8 ，Zhenwu Luo 9 ，
Franziska Degenhardt 10 ，Sven Cichon 11 ，Thomas G Schulze 12 ，Markus M Nothen 10 ，Bing Su 13 ，Zhongming Zhao 14 ，
Lin Gan 15 ，Yong-gang Yao 16
1:Genetic and Psychiatry, Kunming Institute of Zoology, Chinese Academy of Sciences, China、2:Department of Biomedicine and Centre for
Integrative Sequencing (iSEQ), Aarhus University, Denmark、3:Lieber Institute for Brain Development, Johns Hopkins Medical Campus,
Baltimore, MD, USA、4:First Affiliated Hospital of Gannan Medical University, Ganzhou, China、5:Department of Genetic Epidemiology in
Psychiatry, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany、6:Center for

Biomarker Research and Personalized Medicine, Virginia Commonwealth University、7:Centre for Psychiatric Research, Aarhus University
Hospital, Risskov, Denmark、8:National Centre for Register-based Research, Aarhus University, Aarhus, Denmark、9:Department of
Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA、10:Department of Genomics, Life & Brain
Center, and Institute of Human Genetics, University of Bonn, Bonn, Germany、11:Division of Medical Genetics, Department of Biomedicine,
University Basel, Basel, Switzerland、12:Department of Psychiatry and Psychotherapy, University Medical Center Georg-August-University,
Goettingen, Germany、13:State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of
Sciences, Kunming, Yunnan, China、14:Departments of Biomedical Informatics and Psychiatry, Vanderbilt University School of Medicine,
Nashville, TN, USA、15:Flaum Eye Institute and Department of Ophthalmology, University of Rochester, Rochester, NY, USA、16:CAS
Center for Excellence in Brain Science, Chinese Academy of Sciences, Shanghai, China
Genome-wide association studies (GWAS) of schizophrenia have identified multiple risk variants for schizophrenia. However,
it remains unclear how these risk variants contribute to schizophrenia risk as most of the identified risk variants reside in
non-coding regions and without obvious functional consequence. Accumulating evidence suggests that a large proportion
of schizophrenia risk variants perturb gene expression rather than protein function. Here we identify ZNF323 as a novel
schizophrenia risk gene through integrating the whole brain eQTL data and SNP findings from GWAS. We found that
ZNF323 was significantly down-regulated in hippocampus of schizophrenia patients and multiple schizophrenia risk variants
were associated with the expression level of ZNF323 . We successfully replicated the association between eSNP (rs1150711)
of ZNF323 and schizophrenia in three independent samples (n=10,243). More importantly, the effect direction of rs1150711
in the replication sample is the same as in the screening sample (n=32,143). Meta-analysis (n=42,386) further confirmed
the association between rs1150711 and schizophrenia (P=2.82×10-10 ). Interestingly, our evolutionary analyses suggested
that the risk allele of rs1150711 (T allele) and ZNF323 might have undergone recent positive selection in human popula-
tion. Remarkably, we found that rs1150711 is also significantly associated with pulmonary function (P=6.62×10-5 ) and the
schizophrenia-associated risk allele (T allele) at rs1150711 has a protective effect on pulmonary function. Our study illustrates
a possible mechanism for maintaining the schizophrenia risk variants in the human gene pool, therefore provides a starting
point to dissect the evolution enigma of schizophrenia.
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Thu., April 07, 2016 9:45-11:15 Room E (1F)
Chair：Murim Choi（Department of Biomedical Sciences, Seoul National University College of Medicine, Korea, South）
Chair：Kazuya Iwamoto（Department of Molecular Brain Science, Faculty of Life Sciences, Kumamoto University, Japan）
Thu(5)-O41-1
Investigating the transcriptome wide impact of expanded polyalanine tract mutations in ARX contribut-
ing to intellectual disability and seizures
Tessa R Mattiske 1 ，Kristie PY Lee 1,2
，Jozef Gecz 1,2
，Cheryl A Shoubridge 1,2
1:School of Medicine, The University of Adelaide, Australia、2:Robinson Research Institute, The University of Adelaide
Aristaless related homeobox (ARX) gene encodes a paired-type homeodomain transcription factor with critical roles in embry-
onic development. Mutations in ARX give rise to intellectual disability (ID), epilepsy and brain malformation syndromes. Our
recent investigations in mice modelling the two most frequent polyalanine expansions (PAE ) in ARX seen in human patients
demonstrated that aggregation of mutant Arx protein does not occur in the embryonic brain, instead a marked reduction in
mutant Arx protein expression in the developing forebrain was identified. While both mice models display similar reductions
in mutant Arx protein, each displays a distinct phenotype that recapitulates the phenotypes seen in patients; Arx(GCG)7 (PA1)
mice have seizures in addition to learning and memory problems, with seizures not reported in the Arx432-455dup24 (PA2) mice.

To investigate the genetic mechanism(s) underpinning these differences we chose a transcriptome wide approach of RNA-seq
to analyse gene expression in the developing (12.5dpc) mouse forebrain. Here we report 238 genes significantly deregulated
(Log2FC >+/-1.1, P-value <0.05) when both mutations are compared to wild-type (WT) animals. When each mutation is
considered separately, a greater number of genes were deregulated in the severe PA1 mice (825) than is noted in the PA2
animals (78) compared to WT. A recent study has demonstrated estradiol administration during early postnatal development
prevented spasms in infancy and seizures in adult Arx PA1 mutants. Our RNA-seq analysis at E12.5dpc of embryonic devel-
opment identified a ‘core’ pathway including two key effectors; HDAC4 and Twist1. This pathway contains down stream
targets enriched with estrogen repose elements. Hence, we predict key pathways disrupted in the mutant mice contribute
to the phenotypes and that transcriptional changes involved in the estrogen response pathway may be potential targets for
treatment of infantile epileptic seizures.
Thu(5)-O41-2
Maternal Effects and Maternal Factors in OCD and Tourette Disorder
Dorothy E Grice 1 ，Heidi A Browne 1 ，Amirhossein Modabbernia 1 ，Sven T Sandin 1 ，Eric T Parner 2 ，
Christina Hultman 3 ，Diana E Schendel 2 ，Joseph D Buxbaum 1 ，Avi Reichenberg 1
1:Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA、2:Aarhus University, Denmark、3:Karolinska
Institute, Sweden
Background: Maternal effects, i.e., effects from environmental and/or genetic influences that act from the maternal level to
impact the phenotype of the offspring, are a critical source of variance for many traits but are understudied in psychiatric
disorders.
Methods: To assess for maternal effects in obsessive-compulsive disorder (OCD) and Tourette disorder (TD), we examined
OCD and TD recurrence risk patterns using a large Danish epidemiological cohort of 1.4 million cases and compared the
risk conveyed to offspring from affected mothers and from affected fathers. To assess for specific maternal factors that may
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underlie maternal effects, we analyzed the role of prenatal maternal smoking in risk for OCD and TD in 73,073 singleton
pregnancies from the Danish National Birth Cohort and calculated incidence rates per 1000 person-year for OCD and TD.
Smoking behaviors were divided into none, light (<10 cigarettes per day) and heavy (10+ cigarettes per day).
Outcomes: For both OCD and TD, recurrence risk to offspring was significantly higher when conveyed from affected mothers
compared to affected fathers, indicating an important role for maternal effects. A specific maternal factor, maternal smoking,
was associated with increased risk for TD and OCD. Heavy smoking was associated with a 66% increased risk of TD (aHR
1·66; 95%CI, 1·17-2·35) and the association followed a dose-response relationship, with aHR 1·01 (95%CI, 0·77-1·33)
for light smoking and aHR 1·18 (95%CI, 0·94-1·48) for any smoking.
Interpretations: Our studies indicate that maternal effects may play an important role in risk for OCD and TD. Prenatal
maternal smoking, a specific maternal factor, was associated with increased risk of TD even after correction for maternal
psychiatric history, socioeconomic status, and partner smoking. This finding points to a pathway linking prenatal tobacco
exposure and altered brain development.
Thu(5)-O41-3
Genome-Wide Analysis of Attention-Deficit/Hyperactivity Disorder in Korean Children

Hyo-Won Kim 1 ，Kukju Kweon 1 ，Eun-Soon Shin 2 ，Yeonho Joo 1
1:Department of Psychiatry, University of Ulsan College of Medicine, Asan Medical Center, Korea, South、2:DNA Link, Inc. Bioinformatics
Background: Attention-deficit/hyperactivity disorder (ADHD) is known as a highly heritable disorder. However, molecular
mechanism of ADHD is largely unknown. This study aimed to identify genetic susceptibility loci of ADHD utilizing GWAS
and sib-TDT in Korean children with ADHD.
Methods: A total of 135 subjects (71 cases and 64 controls) for genome-wide association study (GWAS), and 54 subjects
(27 probands and 27 unaffected siblings) for sibling-transmission disequilibrium test (sib-TDT) were included. The subjects
were genotyped using the Affymetrix Axiom ™ KORV1.0-96 Array. For the replication, Fluidigm 48.48 Dynamic Arrays and
SNaPshot ™ assay were used. Among the SNPs included in the GWAS and sib-TDT, we searched the SNP clusters where
there are more than three SNPs within 100k bp whose p-value are lesser than 1.00E-03. For replication, SNPs which are near
identified SNP clusters but not included in the GWAS and sib-TDT were selected.
Results: No variant reached genome-wide significance (p<5.00E-08) in both GWAS and sib-TDT, but two nominally significant
(p<1.00E- 05) variants were identified in GWAS. Five hundred and nineteen SNPs for GWAS and 14 SNPs for sib-TDT showed
p-value are lesser than 1.00E-03. Moreover, 20 SNP clusters were identified. In replication analysis, 8 SNPs in clusters which
contain FAM76A and STX12, 20 SNPs in clusters with FNDC7 and STXBP3, and 17 SNPs in cluster with NEGR1 were
significantly associated with ADHD in GWAS. Five SNPs in cluster with TERF1 and SBSPON showed significantly association
with ADHD in sib-TDT.
Conclusion: The results of our study suggest that FAM76A, STX12, NEGR1, FNDC7, STXBP3, TERF1 and SBSPON genes
might be related to ADHD.
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Thu(5)-O41-4
An Ultraconserved Brain-specific Transcriptional Enhancer within the ADGRL3 (LPHN3) Gene Under-
pins ADHD Susceptibility
Ariel F Martinez 1 ，Yu Abe 1 ，Sung-Kook Hong 1 ，Kevin Molyneux 1 ，David Yarnell 1 ，Heiko Lohr 2 ，Wolfgang Driever 2 ，
Mauricio Arcos-Burgos 3 ，Maximilian Muenke 1
1:Medical Genetics Branch, National Institutes of Health, USA、2:Institute of Biology I, Faculty of Biology, University of Freiburg、3:John
Curtin School of Medical Research, The Australian National University
Genetic factors predispose to attention deficit/hyperactivity disorder (ADHD), the most frequently diagnosed neurodevelop-
mental condition in school-age children worldwide. Previous studies have reported genetic variants predisposing to ADHD
and disruptive behaviors in a region of the ADGRL3 (LPHN3) gene. This finding has been replicated in 10 ADHD cohorts
from distinct regions and ethnicities, making ADGRL3 the most consistently replicated gene associated with this condition.
Using in silico, in vitro and in vivo approaches, we identified an ultraconserved element within ADGRL3 that functions as a
transcriptional enhancer. An ADHD risk haplotype harbored in this element reduces enhancer activity by approximately 40%
in rat neuroblastoma and human astrocytoma cells (p<0.0001). This enhancer also drives GFP expression in the zebrafish
brain in a tissue-specific manner sharing many aspects of the expression pattern of endogenous ADGRL3 . Our results uncover
the first evidence of non-coding common variants with potential functional implications for the pathology of ADHD.

Thu(5)-O41-5
Autistic MeCP2 mutations lost regulation on miR197/ADAM10/NOTCH and affected neural progenitor
cells differentiation
Hongyan Wang 1,3 ，Yufang Zheng 1,2 ，Yumeng Wang 1,2 ，Yahui Liu 1 ，Zhangmin Yang 5 ，Yanqing He 5 ，
Xiaohong Gong 1 ，Bing Su 6 ，Keping Hu 7 ，Zilong Qiu 8 ，Dong Liu 9 ，Yasong Du 4
1:State Key Laboratory of Genetic Engineering and Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology, School
of Life Science, Fudan University, China、2:Institute of Developmental Biology & Molecular Medicine, Fudan University、3:The Obstetrics
& Gynecology Hospital of Fudan University、4:Shanghai Mental Health Center, Shanghai Jiaotong University、5:Shanxi Normal University
School of Life Sciences、6:Kunming Institute of Zoology, Chinese Academy of Sciences、7:The Institute of Medicinal Plant Development,
Chinese Academy of Medical Sciences, Beijing、8:The Institute of Neuroscience, Chinese Academy of Sciences, Shanghai、9:Nantong
University, Jiangsu, China
Mutations of MeCP2 (Methyl-CpG-binding protein 2), a X chromosome gene, has been identified in both Rett syndrome and
autism spectrum disorder (ASD) patients. We sequenced MeCP2 gene in a Chinese Han cohort with 288 ASD patients and
383 matched controls, and five rare missense mutations (T197M, G232A, H371R, E394K, G428S) were identified in six ASD
patients. However, the function and contribution of MeCP2 mutations in ASD have not been well understood. Our study
revealed that wild type (WT) MeCP2 promoted neuronal differentiation in both in vivo electroporated mouse cortex and in
vitro cultured primary mouse neural progenitor cells (NPCs), but autistic MeCP2 mutants (T197M, G232A, E394K, G428S
but not H371R) lost such function. WT MeCP2 promoted neuronal differentiation by inhibiting the Notch signaling via
the S2 enzyme of Notch receptor, ADAM10. Such regulation was due to up-regulation of miR197 by WT MeCP2. MiR197
regulated ADAM10 via its 3’-UTR. The autistic MeCP2 mutants lost the up-regulation effect on miR197, which in turn
caused lose-of-function on promoting NSCs differentiation into neurons. Such lose-of-function could be rescued by adding
miR197 in both embryonic mouse cortex and cultured primary NSCs. What’s more, a tissue specific allele imbalance of
MeCP2 was found in front cortex but not other tissues of both mouse and Rhesus monkey (Macaca mulatta), which may
contribute to less ASD in female carriers.
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Thu(5)-O41-6
A recurrent mutation in γ-aminobutyric acid type B (GABAB) receptor R2 causes a Rett-like phenotype
Murim Choi 1 ，Yongjin Yoo 1 ，Jane Jung 2 ，Yuna Lee 3 ，Youngha Lee 1 ，Hyosuk Cho 1 ，Jin S Lee 4 ，Je S Lee 5 ，
Chansik Hong 6 ，Sang-Yoon Park 7 ，Jinhong Wie 6 ，Ki J Kim 4 ，Yong S Hwang 4 ，Seok-Geun Lee 7 ，Hee-Jung Choi 8 ，
Insuk So 6 ，Byung C Lim 4 ，Jae Y Sung 3 ，Hosung Jung 2 ，Yong B Shin 5 ，Jong-Hee Chae 4
1:Department of Biomedical Sciences, Seoul National University, Korea, South、2:Department of Anatomy, Brain Research Institute, and
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine、3:Graduate School of Medicine, Korea University、
4:Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children’s Hospital、5:Department
of Rehabilitation Medicine, Pusan National University College of Medicine、6:Department of Physiology, Seoul National University College
of Medicine、7:Department of Science in Korean Medicine, Cancer Preventive Material Developmental Research Center, College of Korean
Medicine, Kyung Hee University、8:Department of Biological Sciences, Seoul National University College of Natural Sciences
Rett syndrome (RTT) is a devastating neurodevelopmental disorder. About 90% of RTT patients carry a mutation on
MECP2 , a DNA-methylation regulator, and CDKL5 and FOXG1 mutations explain a small group of MECP2 mutation-
negative RTT patients. However, some RTT patients do not carry mutations in any of these genes, suggesting that other
genes might contribute to the disease pathogenesis. Here we report two unrelated patients with an identical de novo mutation
in GABA(B) receptor R2 (GABBR2 ) displaying clinical features similar to those of MECP2 mutation carriers. GABBR2
forms a heterodimeric G-protein coupled receptor (GPCR) complex with GABBR1 to constitute the metabotropic GABAB
receptor. The mutant receptor displays reduced response to its ligand in vitro, and mutant construct-expressing animals
exhibited RTT-like behaviors. This finding underscores GABA signaling as an RTT-causing pathway and is a potential
therapeutic target for RTT patients.
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ICHG2016 697

Thu., April 07, 2016 8:00-9:30 Room B-1 (2F)
Chair：Reha M. Toydemir（Pathology, University of Utah, USA）

Chair ：Hiroshi Kawame（Division of Genomic Medicine Support and Genetic Counseling, Tohoku University, Japan）
Thu(5)-O42-1
MICRODELETION OF 12q14.2q14.3 IN THREE MEMBERS OF A FAMILY DETECTED BY SNP-
ARRAY ANALYSIS
Rita Fischetto 1,5 ，Orazio Palumbo 2 ，Federica Ortolani 1 ，Pietro Palumbo 2 ，Maria Pia Leone 2,3
，
Maria Cristina Di Gilio 4 ，Leopoldo Zelante 2 ，Massimo Carella 2 ，Francesco Papadia 1
1:U.O.C. Malattie Metaboliche-Genetica-Medica, A.O.U. Policlinico Consorziale Bari, Italy、2:Laboratorio di Genetica Medica, IRCSS Casa
Sollievo della Sofferenza, S.Giovanni Rotondo, Italy.、3:Dipartimento di Scienze del suolo, della pianta e degli alimenti, Università degli
Studi di Bari "Aldo Moro", Italy、4:U.O.S Genetica Medica, Ospedale Bambin Gesù, Roma, Italy、5:Istituto Biologia e Genetica; Medicina
e Chirugia; Università degli Studi di Bari
The 12q14 microdeletion syndrome has been firstly described in 2007 (Menten et al), studying the molecular basis of os-
teopoikilosis, an autosomal dominant bone dysplasia with benign, symmetric, asymptomatic osteosclerosis areas. To date 18
cases of 12q14 microdeletion have been reported, displaying phenotypic and genetic variability. We report on three familial
cases, a mother and two brothers, with severe proportionate short stature:osteopoikilosis was present in mother and elder

brother ( 16ys) not in younger brother ( 6ys), who showed mild developmental delay. SNP array analysis, performed by
using the Affymetrix CytoScan HD Arrays, revealed in all patients a 1.9 Mb heterozygous copy number loss within chromo-
some region 12q14.2q14.3 encompassing 2,024 oligonucleotide probes and a 14 RefSeq gene region (C12orf56, XPOT, TBK1,
RASSF3, GNS, TBC1D30, FLJ41278, WIF1, LEMD3, MSRB3, RPSAP52, HMGA2, LLPH, TMBIM4 ) and 3 non-coding
RNAs (MIR548C, MIR548Z, MIR6074 ).In addition, the younger brother carried a paternal microduplication in 11q13.4, 400
kb in size, including the SHANK2 gene, which could be hypothesized to be responsible for mild cognitive delay.Comparing
the clinical and molecular data of our patients with those previously reported, we performed a detailed genotype-phenotype
correlation, corroborating the hypothesis that HMGA2 haploinsufficiency is causative for proportionate very short stature,
as in reported patients, and confirming that deletion in LEMD3 could determine a Buschke-Ollendorff phenotype completely
disclosed in adult patients. Moreover we suggest as good functional candidates for the clinical features observed in these
patients the genes XPOT , TBK1 and WIF1 , but confirmation needs more patients and functional studies.We conclude that
12q14 microdeletion syndrome is a genomic disorder recognizable in young patients with low birth weight, height curve below
the third centile and familial proportionate osteodysplastic short stature
Thu(5)-O42-2
Expressive Language Delay and Characteristic Facial Features - A Novel 7p22.3p22.2 Microdeletion
Syndrome?
Andrea C Yu 1 ，Regina M Zambrano 2 ，Ingrid Cristian 3 ，Sue Price 4 ，Christine Armour 1,5
1:Department of Genetics, Children’s Hospital of Eastern Ontario, Canada、2:Division of Clinical Genetics, Department of Pediatrics,
Louisiana State University Health Science Center、3:Division of Genetics and Metabolism, Department of Pediatrics, Nemours Children’s
Hospital Orlando、4:Department of Clinical Genetics, Northampton General Hospital、5:Children’s Hospital of Eastern Ontario Research
Institute
The clinical use of genomic microarrays in the evaluation of patients with developmental delay has led to the discovery of
many novel microdeletion and microduplication syndromes. However, there are still a number of areas in the genome where
the genotype-phenotype correlation is not well described. There are only two reports in the literature describing individuals
with pure monosomy 7p22.3p22.2. Most other reported cases either involve a much larger region of the 7p arm or have an
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additional copy number variation which is larger in size and believed to be the greater contributor to the individual’s clinical
presentation. There have been no studies to date which describe the overall phenotype which may be attributed to a deletion
within the region of 7p22.3p22.2. We report five patients with overlapping microdeletions at 7p22.3p22.2 who presented with
expressive language delay and a characteristic facial appearance which included a broad nasal bridge, a prominent glabella
and arched eyebrows. Cardiac malformations were also seen in three of our five patients. Although the deletions varied in size,
there was a 0.47 Mb common region of overlap which contained the genes: EIP3B, CHST12, LFNG, BRAT1, TTYH3, AMZ1,
and GNA12. We propose that these patients represent a novel and distinctive microdeletion syndrome. We recommend that
all patients with 7p22.3p22.2 microdeletions should receive early speech language therapy. Also, as part of these patients’
initial evaluation, a thorough cardiac exam should be performed and an echocardiogram should be considered.
Thu(5)-O42-3
Delineation of the 9q31 microdeletion syndrome
1,3
Reha M Toydemir ，Emanuele Panza 2 ，Sarah L Dugan 3 ，Lorenzo D Botto 3
1:Pathology, University of Utah, USA、2:Human Genetics, University of Utah、3:Pediatrics, University of Utah
Interstitial deletions of chromosome 9q31 are very rare. The deletions in most patients in the literature have been detected by
conventional cytogenetics, with reported breakpoints ranging between 9q21 to 9q34. Therefore an accurate description of a
“9q31 microdeletion syndrome” could not be established. However, recently a small region of overlap (SRO) of approximately

3.4 Mb, and containing 8 genes, has been proposed based on microarray studies.
We report clinical description of two unrelated patients with overlapping 9q deletions based on SNP microarray analysis.
The first patient had a 9MB deletion, while the second patient’s deletion was 21.6 Mb. The common clinical features of
our patients and those in literature include developmental delay, short stature and diabetes. The second patient showed
additional features not reported in other 9q31 deletions, such as hearing loss, ventriculomegaly, cleft lip palate and small
kidneys, which could be due to the influence of the genes in the region beyond the SRO. Of interest, these genes include
WHRN (OMIM 607928; associated with autosomal recessive Usher syndrome type 2), TNC (OMIM 187380; associated with
autosomal dominant deafness 56), and CRB2 (OMIM 609720; associated with autosomal recessive ventriculomegaly with
cystic kidney disease).
In conclusion, we further delineate the 9q31 microdeletion syndrome and also discuss the clinical significance of the genes in
the larger deletions. Additional cases will help fine mapping the critical region and will allow identification of the causative
genes.
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Thu(5)-O42-4
Noonan syndrome and related disorders associated with coloboma: five case reports and review of
literature
Yline Capri 1 ，Hend Dridi 1 ，Fabien Guimiot 2,3 ，Delphine Heron 4 ，Marianne Till 5 ，Nicole Philip 6 ，Helene Dollfus 7,8
，
Liza Vera 9 ，Helene Cave 1 ，Alain Verloes 1,3
1:Clinical Genetics, CHU Robert Debre, France、2:Foetopathology, CHU Robert Debre、3:Paris VII University, INSERM UMR1141、4:Medical
genetics, La Pitie-Salpetriere、5:Cytogenetics, CHU Lyon、6:Medical genetics, CHU Marseille、7:Strabourg University, INSERM EA3949、
8:Medical Genetics, CARGO, CHU Strasbourg、9:Ophtalmology, CHU Robert Debre
Noonan syndrome is a multiple congenital malformation disease whose incidence is evaluated from 1/1000 to 1/2500 living
births, quite frequent among the rare diseases. Characteristic features are short stature, facial dysmorphism, heart defects
and cryptorchidism. Orthopedic, renal malformations, development delay and intellectual disability are also observed. Eyes
complications are less described but very common since 95% of patients with Noonan syndrome displayed at list one or more
ophthalmologic findings. Most of those findings are external features belonging to the characteristic facial dysmorphism of
Noonan syndrome (hypertelorism, ptosis, down slanting palpebral fissures and epicanthic folds). Strabismus and refractive
errors (myopia, hypermetropia and astigmatism) are also frequent. Fundus changes are reported less frequently. Few cases of
iris and/or optic disc coloboma in patients with Noonan syndrome or related disorders have been described since 1987. Only
one study focused on eye abnormalities in Noonan syndrome had found coloboma in 4%. None of the previously Noonan
syndrome cases with coloboma was confirmed by molecular analysis.

We describe 5 new cases of Noonan syndrome (or related disorders) with iris and/or optic disc coloboma and review the 10
previously reporter cases. Elevated incidence of Noonan syndrome could let thought that association with coloboma would
be fortuitous but the 2 familial cases (one family previously reported and one new family) may suggest that coloboma is a
rare complication of Rasopathy.
Thu(5)-O42-5
Sex chromosomal Abnormalities in Egyptian DSD patients
Inas M Mazen 1 ，Mona M Mekkawi 2 ，Alaa K Kamel 2 ，Aya A Elaidy 1
1:Clinical Genetics and Endocrinology, National Research Centre, Egypt、2:Medical Cytogenetics, National Research Centre
Abstract
Background
Sex chromosome DSD constitute an important category in the definition of DSD. The study included 379 patients comprising
a wide spectrum of presenting features, associated with different arrays of chromosomal abnormalities. Patients were subjected
to detailed clinical examination, pubertal staging, cytogenetic and FISH analysis. Laparoscopy with gonadal biopsy and FISH
on gonadal tissue cells were done when indicated.
Results
The most commonly presenting feature was ambiguous genitalia (116 patients) followed by male infertility (97 patients).
Short stature associated with TS phenotype was detected among 67patients. Patients presenting with primary/secondary
amenorrhea constituted 43 of the patients, while multiple congenital anomalies or dysmorphism associated with genital
anomalies was found in 28 patients.
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Abnormal sex chromosomal constitution was found in 188 patients (49.6%). They included both numerical and structural
sex chromosomal abnormalities. The most common numerical abnormality was 47,XXY followed by 45,X which had occurred
in a pure form or in mosaicism with one or more cell lines. Structural sex chromosomal abnormalities showed a wide range
of variability. The most common structural abnormality was iso(Xq), which was detected among 31 patients presenting
with short stature or primary amenorrhea. Isodicentric Y abnormality was detected in 9 patients. Other Sex chromosomal
abnormalities included X;Y translocation, Y;19 and Y;14 translocation, ring X, add (Xq), dup (Xp) and del (Xp). XX
testicular DSD with SRY translocated to the Xp was found in 4 patients, one of them presented with Down syndrome.
Conclusion
This study confirms the dosage effect of sex chromosomes on somatic development and the phenotypic diversity of their
presentation among different age groups.
Thu(5)-O42-6
Male-to-female (XY) sex reversal and systemic lupus erythematosis: Association of functional Xp disomy
including DAX-1 and TLR7
Rie Kawakita 1,2 ，Azumi Sakakibara 1 ，Yukiko Hashimoto 1 ，Yuki Hosokawa 1 ，Rika Fujimaru 1 ，

Nobuyoshi Tamagawa 2 ，Hiroaki Nakamura 2 ，Tohru Yorifuji 1,2
1:Department of Pediatric Endocrinology and Metabolism, Osaka City General Hospital, Japan、2:Department of Genetic Medicine, Osaka
City General Hospital
DAX-1 (NR0B1 ) on Xp21.3 plays an essential role in the differentiation of adrenals and gonads. Duplication of DAX-1 is
known to be one of the causes of male-to-female sex reversal, and a few reports described very rare comorbid condition such
as XY sex reversal and systemic lupus erythematosis (SLE). In a 15 year-old girl with multiple congenital anomalies including
male-to-female sex reversal and severe mental retardation, we identified unbalanced derivative Y chromosome with an X-Y
translocation. Her karyotype was 46, X, der(Y)t(X;Y)(p11.4;q11.2) and SRY on Yp11.3 was intact. Her external genitalia
were normal female phenotype (Tanner stage 1) and MRI did not detect her internal genital structures (uterus, cervix and
ovaries). She was diagnosed with SLE nephritis at 13-years of age and treated with steroids and immunosuppressive drugs. An
array-based comparative genomic hybridization revealed an approximately 40 Mb duplication of Xp11.4-pter including DAX-1
and TLR7 (Toll-like receptor 7). X inactivation doesn’t occur in the duplicated Xp region on derivative Y chromosome, so we
speculated that the duplication of DAX-1 resulted in XY sex-reversal. TLR7 on Xp22.3 encodes a transmembrane receptor
that is essential to recognize invading viruses in the innate immunity response. Activation of TLRs stimulates type I interferon
production that can lead to autoimmune diseases including SLE. In the study of BXSB lupus model mice, manifestation of
severe lupus nephritis is caused by duplication of tlr7 because BXSB mice have derivative Y chromosome translocated X
chromosome region including tlr7 (known as Y-linked autoimmune acceleration locus). To date, 3 patients with functional
Xp disomy including DAX-1 and TLR7 associated with sex reversal and SLE have been reported, therefore, duplication of
TLR7 appears to be a genetic predisposing factor for SLE in humans.
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Thu., April 07, 2016 9:45-11:15 Room B-1 (2F)
Chair：Hsiang-Yu Lin（Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan）

Chair ：Tomoki Kosho（Department of Medical Genetics, Shinshu University School of Medicine, Japan）
Thu(5)-O43-1
Clinical and Molecular Characterisation of Frontonasal Dysplasia
Patrick JJ Yap 1 ，Stefanie Eggers 2,3 ，David J Amor 1,3 ，George McGillivray 1 ，Kate Pope 1,2
，Martin Delatycki 2,4
，
Matthew Hunter 5,6 ，Naomi Baker 2,3 ，Peter Farlie 2,3 ，Tiong Y Tan 1,2,3
1:Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Australia、2:Murdoch Children’s Research Institute, Royal
Children’s Hospital, Melbourne, Australia、3:Department of Paediatrics, University of Melbourne, Melbourne, Australia、4:Department
of Clinical Genetics, Austin Health, Heidelberg, Australia、5:Monash Genetics, Monash Medical Centre, Clayton, Australia、6:Dept of
Paediatrics, Monash University, Clayton, Australia
Frontonasal dysplasia (FND) refers to a heterogeneous group of conditions characterised by anomalous midline craniofacial
structures. Several recurrent syndrome patterns with or without known molecular aetiology have been described. Some
sub-types are caused by biallelic mutations in ALX1, ALX3 and ALX4, each associated with a distinctive phenotype. Other
well-described FND subtypes with identified molecular cause include Craniofrontonasal dysplasia (EFNB1 ) and Acromelic
frontonasal dysplasia (ZSWIM6 ) which are inherited in an X-linked and dominant manner, respectively. Given the clinical

and genetic heterogeneity of FND, we hypothesise that novel phenotypic subgroups are yet to be characterised. We identified
patients with a diagnosis of FND from the Victorian Clinical Genetics Services and Royal Children’s Hospital (RCH)
Craniofacial Clinic databases. We also recruited patients prospectively from the RCH outpatient clinic and inpatient referrals.
We invited these patients for deep phenotyping and 3-dimensional photography. We initially performed microarrays on all
patients to exclude chromosomal imbalances. We have developed a custom SureSelect next generation sequencing panel
to screen for pathogenic mutations in ALX1, ALX3, ALX4, MSX2, EFNB1 and ZSWIM6 . Those without mutations in
these genes were analysed with whole exome sequencing to identify novel variants causative of the FND phenotype. We also
present 3-D photography data to objectively document the FND-related facial features, followed by analysis and comparison
of the features of each phenotypic subgroup. Our cohort of 12 probands comprises Craniofrontonasal dysplasia (5), FND
(5) and Oculoauricolofrontonasal syndrome (1), as well as a 3-generational family with a novel Xq13.1 duplication involving
the EFNB1 gene. Our findings confirm that FND is a clinically and genetically heterogeneous group that requires detailed
phenotyping in order to establish the causative molecular lesion.
Thu(5)-O43-2
Co-occurrence of Sturge-Weber syndrome phenotype and Klippel-Trenaunay-Weber syndrome phenotype
in a patient: Molecular evidence of the shared pathological basis of the two conditions
Yuri Sakaguchi 1 ，Toshiki Takenouchi 1,2
，Takao Takahashi 1 ，Kenjiro Kosaki 2
1:Department of Pediatrics, Keio University School of Medicine, Japan、2:Center for Medical Genetics, Keio University School of Medicine
Introduction:Vascular overgrowth is associated with two classic congenital nevus syndromes: Sturge-Weber syndrome (SWS),
and Klippel-Trenaunay-Weber syndrome (KTW). The former is characterized by a port-wine stain over the ophthalmic
division of the trigeminal nerve accompanied by ipsilateral leptomeningeal angioma. The latter is characterized by truncal
and limb hemangioma accompanied by local overgrowth. The co-occurrence of SWS and KTW in a single patient has been
previously reported. However, whether this combinatory phenotype represents a chance association or a common molecular
mechanism between SWS and KTW remains uncertain.
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Clinical Report:A 15-year-old boy presented with the progressive enlargement of a lip hemangioma. In his early infancy,
he was diagnosed as having SWS based on facial hemangioma, bilateral congenital glaucoma, leptomeningeal angiomatosis,
epilepsy, and mild mental retardation. In addition, he was diagnosed as having KTW based on extensive hemangiomas on
his body and extremities. At the age of 16 years, he developed difficulty speaking and swallowing. He underwent surgical
resection of the lip hemangioma. A specimen from the affected tissue was obtained at the time of surgery. DNA was extracted
from the affected tissue and the patient’s peripheral blood. Subtractive medical exome sequencing identified a characteristic
mutation in GNAQ, p.Arg183Gln, which has been recurrently observed in SWS patients.
Discussion:We identified a somatic mutation in GNAQ, p. Arg183Gln, resulting in SWS in a patient with a KTW and SWS
combinatory phenotype. The present observation provides further molecular credence to the notion that SWS and KTW
share a common etiological basis. Together with a recent report on a cohort of KTW patients with a somatic mutation in
PIK3CA, we further suggest the genetic heterogeneity of KTW. Intriguingly, the two eponyms are associated with a single
distinguished and observant dermatologist, Dr. Fredrick Parkes Weber.
Thu(5)-O43-3
CDC42 as a new human disease causative gene
Tomoko Uehara 1 ，Nobuhiko Okamoto 2 ，Toshiki Takenouchi 1,3
，Shinobu Ida 4 ，Kenjiro Kosaki 1

1:Center for Medical Genetics, Keio University School of Medicine, Japan、2:Department of Medical Genetics, Osaka Medical Center
and Research Institute for Maternal and Child Health、3:Department of Pediatrics, Keio University School of Medicine、4:Department of
Gastroenterology and Endocrinology, Osaka Medical Center and Research Institute for Maternal and Child Health
Introduction. CDC42, which encodes a Ras-related GTP-binding protein, is a critical regulator for the cell cycle and actin
cytoskeleton formation. Although, in mice, the conditional homozygous knockout of Cdc42 results in macrothrombocytopenia
and structural abnormality in the central nervous sytem, there has been no report of CDC42 -mutated disease phenotypes in
human. Clinical Report. Patient 1: The proposita was born at term and exhibited developmental delay during her infancy.
She walked independently at age 3 years. She exhibited poor visual acuity and congenital nystagmus with ophthalmologic
investigations revealing retinal dysplasia with left congenital falciform retinal detachment. During her childhood, she had
persistent and progressive lymphedema in her legs, pericardial effusion, hydrothorax, ascites, and hypoalbuminemia. She had
macrothrombocytopenia. Whole exome sequencing in trio revealed de novo mutation in CDC42 (p.Tyr64Cys).
Patient 2: The proposita was born at term. Her psychomotor development was delayed. She walked independently at
4 years. At 18 years, she had severe intellectual disability with no meaning words. Her physical examination showed
midfacial hypoplasia and mild ptosis, camptodactyly of fingers, lymphedema in her right lower extremity and persistent
macrothrombocytopenia. The patient had the same de novo mutation in CDC42 (p.Tyr64Cys). Discussion. Two unrelated
female patients with developmental delay and macrothrombocytopenia, who had the same mutation in CDC42 . The present
observation of the two unrelated patients with the similar phenotypes and mutation in the same CDC42 establishes a novel
clinically recognizable syndromic form of thrombocytopenia. From a molecular standpoint, tyrosine at position 64 in Cdc42
is known as a critical residue for downstream signal transduction. The shared features between the two patients included
developmental delay, macrothrombocytopenia, camptodactyly, lymphedema, and distinctive facial features.
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Thu(5)-O43-4
Two novel mutations in the FUCA1 gene causing fucosidosis
Wipa Panmontha 1 ，Ponghatai Damrongphol 1 ，Tayard Desudchit 1 ，Vorasuk Shotelersuk 1 ，Kanya Suphapeetiporn 1
1:Chulalongkorn University, Thailand
Fucosidosis is a rare autosomal recessive lysosomal storage disorder. It is characterized by progressive mental and motor
deterioration, growth retardation, angiokeratomas, visceromegaly and seizures. The disease is caused by deficiency of α
-L-fucosidase (EC3.2.1.51) activity encoded by the FUCA1 gene. Mutations in the FUCA1 gene have been found to cause
the disease. Here, we report a Thai boy with fucosidosis in a non-consanguineous family. Whole exome sequencing and
array-based comparative genomic hybridization analysis revealed that he was compound heterozygous for a novel single-base
pair deletion in exon 4, c.670delC (p. P224LfsX2) inherited from his father, and a large deletion inherited from his mother.
Both mutations have never previously been reported; thus the current report expands the FUCA1 mutational spectrum.
Thu(5)-O43-5
Ocular Features in Patients with Mucopolysaccharidosis
Hsiang-Yu Lin 1,2,3,4 ，Chih-Kuang Chuang 2 ，Wei-Chun Chan 5 ，Dau-Ming Niu 6 ，Pao Chin Chiu 7 ，Wen-Hui Tsai 8 ，
Wuh-Liang Hwu 9 ，Shuan-Pei Lin 1,2,3,4,10

1:Department of Pediatrics, Mackay Memorial Hospital, Taiwan、2:Department of Medical Research, Mackay Memorial Hospital, Taipei,
Taiwan、3:Department of Medicine, Mackay Medical College, New Taipei City, Taiwan、4:Mackay Junior College of Medicine, Nursing and
Management, Taipei, Taiwan、5:Department of Ophthalmology, Mackay Memorial Hospital, Taipei, Taiwan、6:Department of Pediatrics,
Taipei Veterans General Hospital, Taipei, Taiwan、7:Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan、
8:Department of Pediatrics, Chi Mei Medical Center, Tainan, Taiwan、9:Department of Pediatrics, National Taiwan University Hospital,
Taipei, Taiwan、10:Department of Infant and Child Care, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan
Background
The mucopolysaccharidoses (MPS) are a group of rare lysosomal storage disorders characterized by the accumulation of gly-
cosaminoglycans in various tissues and organs. Ocular problems are very common in patients with MPS with the involvement
of the cornea, sclera, trabecular meshwork, retina, and optic nerve. We determined the prevalence and severity of ocular
complications in these patients.
Methods
We retrospectively reviewed the clinical ophthalmic features and electrodiagnostic results of 50 patients with the diagnosis of
MPS (34 males and 16 females; age range, 1.1 to 34.9 years; 9 with MPS I, 17 with MPS II, 17 with MPS IVA, and 7 with
MPS VI).
Results
Among 44 patients with the available data of visual acuity, 15 patients (34%) had a visual acuity of less than 0.5 equivalent
in their better eye, including 71% of MPS VI, 38% of MPS IVA, 29% of MPS I, and 14% of MPS II. Severe corneal opacities
were existed in 57% of MPS VI and 11% of MPS I patients, compared with none of MPS II and MPS IVA patients. Among
41 patients with the available data of refraction, 6 patients (15%) had myopia (< -0.50 D), 29 patients (71%) had hyperopia
(> 0.50 D), as well as 29 patients (71%) had high astigmatism (> 1.50 D). Ocular hypertension was found in 52% (16/31)
of patients, including 71% of MPS VI, 60% of MPS II, 38% of MPS IVA, and 33% of MPS I. There were 22% (10/45),
33% (14/43), and 79% (15/19) of MPS patients with lens opacities, retinopathy, and visual pathway dysfunction by visual
evoked potential abnormality, respectively. Intraocular pressure was positively correlated with the severity of corneal opacity
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(p<0.01).
Conclusions
Ocular complications with significant reduction in visual acuity are common in MPS patients. Diagnostic problems may arise
in these patients with severe corneal opacification, especially for MPS VI and MPS I. These findings and the follow-up data
can be used to develop quality of care strategies for them.
Thu(5)-O43-6
Two-dimensional Speckle Tracking Echocardiography in 53 Patients with Mucopolysaccharidosis
Hsiang-Yu Lin 1,2,3,4,5 ，Chih-Kuang Chuang 2 ，Ming-Ren Chen 1,3,4
，Dau-Ming Niu 5,6
，Chung-Lieh Hung 3,4,7
，
Shuan-Pei Lin 1,2,3,4,8
1:Department of Pediatrics, Mackay Memorial Hospital, Taiwan、2:Department of Medical Research, Mackay Memorial Hospital, Taipei,
Taiwan、3:Department of Medicine, Mackay Medical College, New Taipei City, Taiwan、4:Mackay Junior College of Medicine, Nursing and
Management, Taipei, Taiwan、5:Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan、6:Department of Pediatrics,
Taipei Veterans General Hospital, Taipei, Taiwan、7:Division of Cardiology, Department of Internal Medicine, Mackay Memorial Hospital,
Taipei, Taiwan、8:Department of Infant and Child Care, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan
Background

The mucopolysaccharidoses (MPS) are a group of rare inherited metabolic diseases that can cause damages in various organs
including the heart. Cardiac abnormalities have been observed in patients with MPS of any types, with the most documented
abnormalities being cardiac valve thickening, valvular regurgitation and stenosis, and cardiac hypertrophy. We determined
the cardiologic features of patients with MPS by two-dimensional speckle tracking echocardiography.
Methods
We studied 53 Taiwanese patients with MPS (31 males and 22 females; age range, 1.1 to 34.9 years; 7 with MPS I, 16 with
MPS II, 9 with MPS III, 14 with MPS IVA, and 7 with MPS VI) using comprehensive echocardiography and 2-dimensional
speckle tracking.
Results
The mean z scores of global longitudinal peak systolic strain (GLS), left ventricular mass index (LVMI), interventricular septum
diameter in diastole (IVSd), and left ventricular posterior wall diameter in diastole (LVPWd) of these 53 MPS patients were
1.71, 0.35, 1.66, and 1.03, respectively. The most severe GLS was observed in a subgroup of MPS VI, followed by MPS II and
MPS I. Z scores > 2 were identified in 45%, 13%, 40%, and 29% for GLS, LVMI, IVSd, and LVPWd, respectively. Diastolic
dysfunction was identified in 12 patients (23%). All 53 MPS patients had valvular heart disease. Tricuspid regurgitation
(100%) was the most common presentation, followed by mitral regurgitation (92%), aortic regurgitation (57%), and pulmonary
regurgitation (53%). The z scores of GLS and LVMI, and the severity scores of mitral regurgitation, aortic regurgitation,
mitral stenosis, and aortic stenosis were all positively correlated with the increasing age (p<0.05).
Conclusions
Cardiac abnormalities of MPS patients aggravated with the increasing age. The most severe cardiac diseases were observed
in subgroups of patients with MPS VI, MPS II, and MPS I. These findings and the follow-up data can be used to develop
quality of care strategies for these patients.
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Thu., April 07, 2016 8:00-9:30 Room B-2 (2F)
Chair：Andrew P. Morris（Department of Bioinfomatics, University of Liverpool, UK）

Chair ：Akira Hata（Department of Public Health, Chiba University Graduate School of Medicine, Japan）
Thu(5)-O44-1
Trans-ethnic meta-analysis and genomic annotation reveals novel loci and effector genes for kidney
function in diverse populations
Andrew P Morris 1,2 ，Anubha Mahajan 2 ，Kyle Gaulton 2 ，Jeffrey Haessler 3 ，Yukinori Okada 4 ，Adrienne Stilp 5 ，
John Whitfield 6 ，Cathy Laurie 5 ，Nora Franceschini 7
1:Department of Biostatistics, University of Liverpool, UK、2:Wellcome Trust Centre for Human Genetics, University of Oxford、3:Public
Health Sciences Division, Fred Hutchinson Cancer Research Center、4:Graduate School of Medical and Dental Sciences, Tokyo Medical and
Dental University、5:Department of Biostatistics, University of Washington、6:QIMR Berghofer Medical Research Institute、7:Department
of Epidemiology, University of North Carolina
Genome-wide association studies (GWAS) have identified several loci for reduced estimated glomerular filtration rate (eGFR),
a measure of kidney function used to define chronic kidney disease (CKD). However, these loci typically map to large genomic
intervals, limiting progress in identifying causal transcripts and understanding of the pathogenesis of CKD. We performed
trans-ethnic meta-analysis to: (i) identify novel loci that are shared across ancestry groups; (ii) localise variants “driving”

GWAS signals by leveraging differences in linkage disequilibrium structure between diverse populations; and (iii) gain insight
into mechanisms through which GWAS signals impact kidney function by integrating genetic fine-mapping and genomic
annotation.
We considered 9 GWAS (71,638 individuals of European, African American, Hispanic, and East Asian ancestry), each imputed
up to the 1000 Genomes Project reference panel (March 2012 release). We identified 20 loci at genome-wide significance
(p<5.0x10-8 ), including two not previously reported, mapping to LRP2 (p=5.6x10-10 ) and NFATC1 (p=1.3x10-8 ). We
constructed “credible sets” driving GWAS signals at each locus, and resolved fine-mapping to a single variant at PDILT-
UMOD, and two variants each at NFATC1 and SLC34A1 . Across loci, we demonstrated significant enrichment for overlap
with Dnase I hypersensitivity sites (DHS) in multiple human kidney cell types, suggesting a likely effect of eGFR GWAS
signals on kidney function through regulatory mechanisms. DHS credible variants were expression quantitative trait loci for
RGS14 (at the SLC34A1 locus) and NFATC1 , thereby highlighting likely effector genes for GWAS signals in these regions.
Our findings provide evidence that trans-ethnic GWAS and genomic annotation is useful for discovery of eGFR loci and
prioritisation of potential causal variants that can be taken forward for experimental validation, enhancing our understanding
of the pathophysiology of CKD.
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Thu(5)-O44-2
MicroRNA Transcriptome Changes in Multiple Brain Regions of Subjects with Alcohol Use Disorders
Huiping Zhang 1 ，Hongyu Zhao 2 ，Joel Gelernter 1
1:Psychiatry, Yale University School of Medicine, USA、2:Biostatistics, Yale University School of Medicine
Alcohol use disorders (AUDs) are characterized by compulsive and uncontrolled alcohol use, leading to social and occupational
impairments. While genetic variation can result in an increased risk of AUDs, chronic alcohol consumption can independently
lead to alcohol tolerance and dependence. However, it is unknown how chronic alcohol consumption alters gene expression
and leads to neuroadaptations underlying AUDs. There is evidence that small noncoding microRNAs (miRNAs), which
regulate target gene (or mRNA) expression at the posttranscriptional level, are abundant in the brain and play important
roles in a variety of biological processes such as neuronal differentiation and synapse formation and plasticity. Thus, brain
miRNAs that regulate the expression of alcohol-responsive mRNAs may act upstream of alcohol-induced neuroadaptations.
In the present study, we profiled miRNA transcriptomes in six brain regions of eight pairs of male AUD and control subjects
[matched by age, brain weight, brain pH, postmortem interval (PMI), and smoking history] using Affymetrix’s miRNA
4.0 microarrays, and identified 12 differentially expressed (more than 2-fold changes) miRNAs in the prefrontal cortex, the
hippocampus, the amygdala, the putamen, and/or the cerebellum. One specific miRNA (miR-412-5p) was downregulated (a
7-11 fold decrease) in multiple brain regions of AUD subjects. This miRNA was predicted (by at least three miRNA target
prediction programs) to target several addiction-related genes such as GABRB1 , GRIN2A, and POMC . Taken together, the
present study identified differentially expressed miRNAs that are either specific or common for certain brain regions of AUD

subjects, thus providing insights into the underlying molecular mechanisms of AUDs. However, further studies are needed to
verify whether AUD-associated brain miRNA expression changes are the consequences of chronic alcohol consumption or the
causes of AUDs.
Thu(5)-O44-3
Targeted-bisulfite sequence analysis of the methylation of CpG islands in the PNPLA3 , SAMM50 , and
PARVB of patients with nonalcoholic fatty liver disease: relationship to their mRNA expression and
rs738409 genotype
Kikuko Hotta 1 ，Yuji Ogawa 2 ，Yasushi Honda 2 ，Kento Imajo 2 ，Satoru Saito 2 ，Masato Yoneda 2 ，Atsushi Nakajima 2
1:Department of Medical Innovation, Osaka University Hospital, Japan、2:Department of Gastroenterology and Hepatology, Yokohama City
University Graduate School of Medicine
Aims: Aims of this study was to investigate whether the progression of nonalcoholic fatty liver disease (NAFLD) is affected
by epigenetic factors as well as by genetic variation. Methods: The protocol was approved by the ethics committees of Kyoto
University and Yokohama City University. Written informed consent was obtained from each study participant. We enrolled
randomly 65 Japanese patients with NAFLD and 30 patients with chronic hepatitis C who had undergone liver biopsy.
Patients were divided according to the fibrosis stage into groups with mild or advanced groups. We performed targeted-
bisulfite sequencing to determine the levels of DNA methylation of 4 CpG islands (CpG99, CpG71, CpG26, and CpG101) in
the regulatory regions of PNPLA3 , SAMM50 , PARVB variant 1, and PARVB variant 2, respectively. The hepatic mRNA
levels of PNPLA3 , SAMM50 , and PARVB were measured using qPCR. Results: CpG26 in the regulatory region of PARVB
variant 1, was markedly hypomethylated in the livers of patients with advanced NAFLD. Conversely, CpG99 in the regulatory
region of PNPLA3 was substantially hypermethylated in these patients. These differences in DNA methylation were also
observed in the liver of patients with chronic hepatitis C. PNPLA3 mRNA levels in the liver of the same section of a biopsy
specimen used for genomic DNA preparation were lower in patients with advanced NAFLD compared with those with mild
NAFLD and correlated inversely with CpG99 methylation in liver DNA. Differences in DNA methylation levels of CpG99
and PNPLA3 mRNA levels were observed in the NAFLD patients with MM genotype of rs738409 but not in those with IM
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+ II genotypes. Conclusions: Hypermethylation of CpG99 and hypomethylation of CpG26 may be related to the ultimate
outcomes of patients with liver fibrosis. Genetics and epigenetic analyses suggest that PNPLA3 and PARVB are involved in
the progression of NAFLD.
Thu(5)-O44-4
Genome-wide multi-phenotype and eQTL analyses detect novel signals for omega fatty acids and provide
insights into their biology
Annique J. Claringbould 1,2 ，Fiona Haagenbeek 2,3 ，Reedik Magi 4 ，Pasi Soininen 5 ，Marjo-Riitta Jarvelin 6,7,8,9
，
BIOS Consortium 1 ，Marika Kaakinen 2 ，Inga Prokopenko 2
1:Department of Genetics, University Medical Centre Groningen, Netherlands、2:Department of Genomics of Common Disease, Imperial
College London, United Kingdom、3:Department of Biological Psychology, VU University Amsterdam, The Netherlands、4:Estonian Genome
Center, University of Tartu, Estonia、5:Computational Medicine, University of Oulu, Finland、6:Center for Life Course Epidemiology and
Systems Medicine, University of Oulu, Finland、7:Department of Epidemiology and Biostatistics, Imperial College London, UK、8:Biocenter
Oulu, University of Oulu, Finland、9:Unit of Primary Care, Oulu University Hospital, Finland
Single-trait genome-wide association studies (GWAS) have highlighted many genetic loci affecting cardiometabolic phenotypes,
including blood lipids. Fatty acid (FA) levels are refined measures of lipid traits, and joint analysis of multiple FA increases
power to detect the genetic signals underlying their metabolism. We aimed to elucidate susceptibility to cardiovascular disease
through multi-phenotype analysis (MPA) of omega FA levels. We undertook multi-phenotype GWAS with epidemiological
and nuclear magnetic resonance-derived metabolite data from the Northern Finland Birth Cohorts 1966 and 1986 (N =4949

and N =3055, respectively). Individuals were genotyped on Illumina HumanCNV370DUO and HumanOmniExpressExome,
and imputed to the 1000 Genomes reference panel. MPA was performed with the PLEIOTROPY software, which models
all linear combinations of phenotypes as predictors of the observed genotype. The meta-analysis of the two cohort results
detected 10 signals associated with omega-3, -6, -7, -9 and other polyunsaturated FA (p<5x10-8 ). We identified novel FA
loci at MACROD1 and CLDN5 . FA signals in PCSK9, GCKR, FADS1, ZNF259 , LIPC , PDXDC1 , PBX4 and APOE have
previously been associated with triglycerides and total cholesterol, but not specifically with omega FA. Expression quantitative
locus (eQTL) analysis based on the Dutch BIOS consortium RNA-seq data (blood, N =2116) indicated 8 out of 10 MPA-
identified signals with significant effects on gene expression levels, thus providing further insight into underlying biology. For
instance, the eQTL effect on the APOE locus affirms the role of omega FA in Alzheimer’s disease, and the MACROD1 eQTL
effect on PRDX5 expression suggests a role in protection against oxidative stress, a pathway that is known to be influenced
by omega-3 FA. We identified genetic loci and differentially expressed genes involved in FA metabolism empowered by a
combination of precise measures of blood metabolite levels, MPA and eQTL analysis.
Thu(5)-O44-5
Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects for
LPA
1,2,3
Johannes Kettunen ，MAGNETIC consortium
1:Computational medicine, University of Oulu, Finland、2:National Institute for Health and Welfare, Helsinki, Finland、3:NMR Metabolomics
Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
Metabolic phenotypes are highly heritable and have great potential in providing insight into genetic variation influencing
both metabolism and complex diseases. We present the largest evaluation of genetic variance in human metabolism so
far. We combined 123 metabolic phenotypes from blood samples of 24,925 individuals from fourteen European cohorts and
associated 62 loci with blood metabolite concentrations. 8 of the loci were new. For 15 loci the lead SNP was low frequency,
for 8 a coding variant and 22 involved transcription factor binding sites. We showed that two loci, known for Mendelian
amino acid metabolism disease with severe neurological manifestations, also harbor low-frequency variants affecting the same
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ICHG2016 708
circulating amino acid in healthy population samples. Moreover, we show new evidence that the biosynthesis of lipoprotein(a)
(Lp(a)), a known coronary heart disease (CHD) biomarker, is associated with very-low-density lipoprotein metabolism and
other lipoprotein particles. Causality of metabolite associations was shown with a genetic risk score (GRSLp(a) ) for Lp(a),
which composed of 18 SNPs independently associated with circulating Lp(a) levels at genome-wide significance in a discovery
cohort. GRSLp(a) SNPs were confirmed in a replication cohort, where GRSLp(a) explained 45% of Lp(a) variance. Linking
GRSLp(a) to electronic health records of over 17 000 population-based persons showed that the risk score was associated with
CHD outcomes but not with any other disease-category. (ICD10:I20-I25 category, P=6.4×10-10 , Nevents =1251, OR=1.28
per one unit increment in GRSLp(a) )). We present a new hypothesis for the biosynthesis of Lp(a) and our results together
with previous findings reinforce the observation that LPA-targeting treatment has great potential for CHD risk reduction in
humans.
Thu(5)-O44-6
Exome chip meta-analysis identifies novel low-frequency variants contributing to central body fat distri-
bution
Tugce Karaderi 1 ，Anne E Justice 2 ，Kristin L Young 2,3 ，Heather M Highland 2 ，Mariaelisa Graff 2 ，
Valerie Turcot 4 ，Paul Auer 5 ，Nancy L Heard-Costa 6,7 ，Claudia Schurmann 8 ，Yingchang Lu 8 ，
L Addriene Cupples 6,9 ，Caroline S Fox 6 ，Thomas W Winkler 10 ，Niels Grarup 11 ，Robert A Scott 12 ，
Mark McCarthy 13 ，Karen Mohlke 14 ，Ruth JF Loos 8 ，Ingrid Borecki 15 ，Kari E North 2 ，Cecilia M Lindgren 1 ，
on the behalf of BBMRI, GOT2D, CHARGE and GIANT Consortia

1:Wellcome Trust Centre for Human Genetics, University of Oxford, UK、2:Department of Epidemiology, University of North Carolina at
Chapel Hill, USA、3:Carolina Population Center, University of North Carolina at Chapel Hill, USA、4:Montreal Heart Institute, University
of Montreal, Canada、5:Department of Biostatistics, University of Wisconsin-Milwaukee, USA、6:The Framingham Heart Study, National
Heart, Lung, and Blood Institute, USA、7:Department of Neurology, Boston University School of Medicine, USA、8:The Genetics of Obesity
and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount
Sinai, USA、9:Department of Biostatistics, School of Public Health, Boston University, USA、10:Department of Genetic Epidemiology,
Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany、11:The Novo Nordisk Foundation
Center for Basic Metabolic Research, University of Copenhagen, Denmark、12:MRC Epidemiology Unit, University of Cambridge, UK、
13:Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, UK、14:Department of Genetics, University of North
Carolina at Chapel Hill, USA、15:Department of Genetics Division of Statistical Genomics, Washington University School of Medicine, USA
Fat distribution is an important predictor of cardiometabolic disease risk. Evidence suggests genetic factors contribute to
fat distribution, measured as waist-to-hip ratio adjusted for BMI (WHR). Forty-nine loci have been associated with WHR in
previous genome-wide association studies (GWAS) targeting common variants [minor allele frequency (MAF)≥5%] mainly in
European populations. Our aim was to identify low-frequency coding variants (LFV, MAF<5%) associated with WHR using
exome chip data from 344,369 individuals of European, African, Asian and Hispanic descent. Fixed effects meta-analyses
stratified by sex and ancestry were performed, and also combined for single nucleotide variant (SNV) and gene-based results.
Gene-based analyses used a strict definition of non-synonymous and missense SNVs annotated as damaging by 5 algorithms.
Analyses included up to 246,329 SNVs (218,195 with MAF<5%) and 9,268 genes. Conditional analyses were carried out
to detect novel associations independent of the previously known GWAS signals. Associations with four out of five LFVs
(RAPGEF3 , MAF=0.01, β=-0.09, P=1.3E-13; KIAA0408, MAF=0.009, β=0.11, P=2.1E-13; HIST1H1T, MAF=0.001, β
=0.23, P=4.3E-8; FGFR2, MAF=0.001, β=0.26, P=1.4E-7) reaching chip-wide significance (P<2.5E-7) in the all-ancestry
sex-combined analysis were novel. RAPGEF3 was also significantly associated with WHR (β=-0.08, P=6.9E-14) and BMI
(β=0.05, P=4.7E-12) in the gene-based analysis. RAPGEF3 and FGFR2 are expressed in adipose tissue and the brain,
respectively. RAPGEF3 plays a role in the GLP1 pathway controlling insulin secretion. FGFR2 controls a range of biological
processes by regulating cell proliferation and differentiation, and is implicated in birth weight. Our results highlight the
importance of targeting LFVs in large studies to detect potentially functional variants. Dissecting these associations may
identify possible population-specific variants providing insights into the physiology of central adiposity.
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Thu., April 07, 2016 9:45-11:15 Room B-2 (2F)
Chair：Derek M. Dykxhoorn（John P. Hussman Institute for Human Genomics, Universty of Miami Miller School of
Medicine, USA）
Chair ：Michiaki Kubo（Center for Integrative Medical Sciences, RIKEN, Japan）
Thu(5)-O45-1
Pathogen lineage based analysis of host genetic risk factor in young onset tuberculosis
Yosuke Omae 1 ，Surakameth Mahasirimongkol 2 ，Licht Toyo-oka 1 ，Hideki Yanai 3 ，Supalert Nedsuwan 4 ，
Sukanya Wattanapokayakit 2 ，Nat Smittipat 5 ，Prasit Paliittapongarnpim 5 ，Pathom Sawanpanyalert 6 ，
Nuanjun Wichukchinda 2 ，Ekawat Pasomsub 5 ，Taisei Mushiroda 7 ，Michiaki Kubo 8 ，Katsushi Tokunaga 1
1:Faculty of Medicine, The University of Tokyo, Japan、2:Medical Genetics Center, Medical Life Sciences institute, Department of Medical
Sciences, Ministry of Public Health, Thailand、3:Fukujuji Hospital, Japan Anti-tuberculosis Association, Kiyose, Japan、4:Chaing Rai
Prachanukroh Hospital, Ministry of Public Health, Thailand、5:Department of Microbiology, Faculty of Science, Mahidol University,
Thailand、6:Food and Drug Administration, Ministry of Public Health, Thailand、7:Research Group for Pharmacogenomics, RIKEN Center
for Integrative Medical Sciences, Yokohama, Japan、8:RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
Tuberculosis (TB) is one of the three major infectious diseases. Although one-third of world population is infected by
Mycobacterium tuberculosis (M. tb), only 5-10% of infected people develop TB and contribution of host genetic factors to TB
onset has been suggested. We have reported young age onset TB specific genetic risk factor through genome-wide association

study focusing on the heterogeneity of TB onset (Mahasirimongkol S. et al., JHG 2012). In this study, we further focused
on the heterogeneity of M. tb genome and assessed its possible interaction with the host genetic factors. We first determined
the lineage of M. tb by the PCR-based method and classified them into Beijing, EAI or non-Beijing non-EAI lineage. Among
the 405 patients recruited in the previous report, we could identify the pathogen lineage in 240 cases including 70 young
cases. Stratification by lineage revealed that the risk of one SNP on chromosome 20 was specific for non-Beijing (EAI and
non-Beijing non-EAI) lineage infected group (p=4.13×10-5 , n=36) and not associated with Beijing lineage infected group
(p=0.149, n=34), when we compared to the healthy control group. We further evaluated this effect in independent sample set
recruited from Thailand and assessed whether this lineage specific association can be replicated. The p-values in replication
set were 1.70×10-5 in non-Beijing lineage group (n=53) and 0.185 in Beijing lineage group (n=70). When we combined
these two sample sets, their p-values were 3.39×10-9 for non-Beijing group (OR=2.69, 95%CI 1.92-3.77) and 0.055 for Beijing
group (OR=1.42, 95%CI 0.99-2.03), respectively. These results suggest that host genetic risk is affected by pathogen genetic
background in TB and indicate the importance to analyze the interaction between host and pathogen genome. We are now
increasing the sample size and analyzing the difference of pathogen genome sequence which can be associated with host genetic
risk for TB.
Thu(5)-O45-2
Transcriptome analysis reveals autism-specific convergent molecular pathways during neurogenesis
Derek M. Dykxhoorn 1,2 ，Brooke A. DeRosa 1 ，Kinsley Belle 1 ，Catherine Garcia-Serje 1 ，Holly N. Cukier 1 ，
Joycelyn M. Lee 1 ，Michael L. Cuccaro 1,2 ，Jeffery M. Vance 1,2 ，Margaret A. Pericak-Vance 1,2
1:John P. Hussman Institute for Human Genomics, Universty of Miami Miller School of Medicine, USA、2:Dr. John T. Macdonald
Foundation Department of Human Geneics, University of Miami Miller School of Medicine
Recent studies have shown that genes harboring autism spectrum disorder (ASD) risk variants are enriched for genes expressed
during early neocortical development, including those involved in regulation of transcription, chromatin remodeling, cell
adhesion, signaling complexes, and synapse function. These findings raise the possibility that common molecular etiologies
underlie ASD pathogenesis.
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ICHG2016 710
To that end, patient-specific induced pluripotent stem cell (iPSC) lines were derived from 6 unrelated, idiopathic ASD
individuals, as well as, lines from 5 unrelated, control individuals. Each ASD individual had rare variants identified through
whole exome sequencing of extended multiplex families. iPSCs were differentiated into cortical neurons and transcriptome
analysis (RNA-seq) was performed on the neurons at three time points during their in vitro development (days 35, 85 and
135). Pathway and gene ontology (GO) analysis were performed on the differentially expressed (DE) genes identified in the
transcriptome data.
Our results implicate disturbances in transcriptional regulation, WNT signaling, chromatin remodeling, cell adhesion and
migration, and synapse development across all of the time points. To highlight some of these findings, specific pathways
enriched in early neurons (day 35) include those involving WNT/MET signaling (p = 3.71x10-7 ) and calcium signaling
(2.41x10-7 ). DE genes in midpoint neurons (day 85) map to pathways involving cell migration (p = 1.34-6 ) and GABAergic
neuron signaling transmission (p = 2.86-9 ). In more mature neurons (day 135), DE genes are enriched in pathways involving
chromatin remodeling (p = 1.49-24 ), calcium signaling (p = 8.92-20 ), and WNT-mediated axon guidance (p = 4.71-5 ). These
results provide functional evidence that common molecular mechanisms underlie ASD pathogenesis and suggest a temporal
order to the disturbance of cellular functions.
Thu(5)-O45-3
Analysis of the planar cell polarity regulator gene PTK7 in neural tube defects

1,2
Richard H Finnell ，Gary M Shaw 3 ，Elizabeth Ross 4
1:Nutritional Sciences and Chemistry, The University of Texas at Austin, USA、2:Fudan University、3:Stanford University School of Medicine、
4:Weill Cornell Medical College
Neural tube defects (NTDs), including anencephaly, spina bifida and craniorachischisis, are severe birth defects that affect
0.5-1 in 1000 births. Recently, mutations in planar cell polarity (PCP) pathway genes were implicated in the pathogenesis
of NTDs in both the mouse model and in human cohorts. Mouse models indicate that the homogenous disruption ofPtk7
gene, a PCP regulator, results in craniorachischisis, while embryos that are double heterozygous for Ptk7 and Vangl2 Lp
mutations result in spina bifida. In this study, we sequenced exons of the human PTK7 gene in 192 spina bifida patients and
190 controls from a California population. Included were live-born cases with spina bifida. Controls were randomly selected
among all liveborn infants corresponding to the same geographic area and birth time periods as cases. DNA for genotyping
was obtained from newborn bloodspots. We identified three rare (MAF < 0.01) missense heterozygous PTK7 mutations
(p.Thr186Met, p.Arg630Ser and p.Tyr725Phe) in spina bifida cases. Two of the variants (p.Arg630Ser and p.Tyr725Phe)
which were predicted to be damaging by PolyPhen, were absent in well-matchedall controls, as well as in ExAC control
database. No novel damaging missensePTK7 mutation was identified in control subjects. Our study suggests that missense
mutations in PTK7 appear to contribute to the genetic risk of spina bifida in the studied population.
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ICHG2016 711
Thu(5)-O45-4
Rare variants in the COL5A1 gene are associated with risk for keratoconus, a blinding eye disease
Kathryn P Burdon 1 ，Sionne EM Lucas 1 ，Richard A Mills 2 ，Nicholas B Blackburn 1,3
，Paul Leo 4 ，
Jac C Charlesworth 1 ，Matthew A Brown 4 ，Jamie E Craig 2
1:Menzies Institute for Medical Research, University of Tasmania, Australia、2:Department of Ophthalmology, Flinders University、3:South
Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley、4:Diamantina Institute, University of Queensland and
Translational Research Institute, Princess Alexandra Hospital
Keratoconus is a common and complex eye disease characterised by the progressive thinning and conical protrusion of the
cornea at the front of the eye. It has a prevalence of around 1 in 2000 people and results in lifelong severe visual impairment.
It has a strong genetic component and genome-wide association studies (GWAS) for both keratoconus and central corneal
thickness (CCT) have highlighted a number of loci that may be involved.
We selected twelve candidate genes from top GWAS loci and sequenced them in 349 Australian keratoconus patients using
Haloplex (Agilent) enrichment and a MiSeq (Illumina) sequencer. Reads were aligned to human reference hg19 and variants
called using SureCall (Agilent). Variants of interest were included based on minor allele frequencies of <1% in the non-Finnish
European ExAC population and were predicted to be damaging by SIFT or PolyPhen2 or were splice or stop variants. The
number of variants observed in each gene was compared to that in a control cohort of 993 Australians with exome sequence
data available from the TruSeq exome enrichment kit sequenced on an Illumina HiSeq with variants called through the GATK
pipeline and subjected to the same filtering criteria.

Two genes (RXRA and ZNF469 ) were removed from the analysis due to lack of coverage in the control data. No enrichment
for rare coding variants was seen in the KCND3 , RAB3GAP1, HGF, IMMPL2, MPDZ, NFIB, FOXO1 , FNDC3B or BANP
genes. A significant enrichment (p<0.005) was observed in COL5A1 (Chi-sq p=0.0007, OR=2.6[1.5-4.4]). This gene had a
carrier rate of 3.1% (n=30) for rare variants in controls, compared to 7.7% (n=26) in cases. Thirty-four unique variants were
detected with only three being present in both cases and controls. COL5A1 is an important structural component of the
cornea and mutations in this gene may directly affect corneal integrity. This study shows for the first time that rare variants
in COL5A1 may be involved in keratoconus risk.
Thu(5)-O45-5
Examining the Genetic Architecture of Age-related Macular Degeneration (AMD) in the Amish
Jonathan L Haines 1 ，Rebecca J Sardell 2 ，Joshua Hoffman 1 ，Jessica N Cooke Bailey 1 ，Srinivas R Sadda 3 ，
William K Scott 2 ，Dwight Stambolian 4 ，Margaret A Pericak-Vance 2
1:Epidemiology & Biostatistics, Case Western Reserve University, USA、2:Hussman Institute for Human Genomics, Miller School of
Medicine, University of Miami、3:Department of Ophthalmology, Doheny Eye Institute、4:Departments of Ophthalmology and Genetics,
University of Pennsylvania
AMD is the leading cause of visual impairment in the aging population. Treatment is restricted to the most severe form,
primarily slows or stops further visual loss, and is variably effective. Substantial progress has identified common and rare
genetic variants that explain up to 60% of the heritability of the risk of developing AMD but uncovering the remaining
heritability, relating genetic variation to clinical endophenotypes, and identifying genetic predictors of disease progression are
critical unanswered questions. We have undertaken studies of the Amish communities in the United States, who are culturally
and genetically isolated, have large stable families, and relatively homogeneous environmental exposures. We examined the
genetic architecture of AMD in the Amish and found that the genetic risk score in Amish cases was significantly lower than
in non-Amish cases (P <1 x 10-5), but higher than Amish controls (P=4 x 10-3). We performed whole exome sequencing
in a small Amish multiplex nuclear family and identified a novel mutation in the CFH gene (P503A), which is significantly
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associated with AMD (P<5 x 10-5) and appears to be unique to the Amish. We examined clinical endophenotypes using Ocular
Coherence Tomography (OCT) imaging to quantify fine-scale retinal features. Of 560 Amish ~ 64% were unaffected (AREDS
grade 0/1), 10% had early AMD (grade 2), 11% had intermediate AMD (grade 3) and 6% advanced AMD (grades 4/5).
Grade (rs =0.85) and choroidal thickness (r=0.84) were highly correlated between left and right eyes. Choroidal thickness
was moderately correlated with AREDS grade in both eyes (rs =-0.30). Choroidal thickness was highly repeatable within
individuals (0.78) and moderately heritable (h2 =0.32). These data confirm that the Amish are an excellent study population
that can identify new risk variants for AMD. The Amish provide critical information on the heritability of endophenotypes
and have already defined the heritability of choroidal thickness.
Thu(5)-O45-6
Familial insight: Identifying glaucoma susceptibility variants by exome sequencing in extended pedigrees
Jac Charlesworth 1 ，Kathryn Burdon 1 ，Juan Peralta 2 ，Nicholas Blackburn 1,2
，Joanne Curran 2 ，Mary Wirtz 3 ，
David Mackey 4 ，John Blangero 2
1:University of Tasmania, Menzies Institute for Medical Research, Australia、2:South Texas Diabetes and Obesity Institute, University of
Texas Rio Grande Valley, USA、3:Casey Eye Institute, Oregon Health and Science University, USA、4:Lions Eye Institute, University of
Western Australia
Primary open angle glaucoma (POAG) is a chronic optic neuropathy and one of the leading causes of visual impairment and
blindness worldwide. It is a complex disease with a significant but mostly unexplained genetic component (80% heritability).

Clinical diagnosis is derived from several quantitative traits, including intraocular pressure, optic nerve degeneration measured
by cup-to-disc ratio and central corneal thickness, each with a strong and independent genetic component.
Pedigree-based deep sequencing projects, particularly those focused on previously localised genetic signals, should lead to
rapid causal gene/variant identification. Data are rapidly accumulating that rare or private variants have a large cumula-
tive effect on normal phenotypic variation and are extremely important to disease. By exploiting Mendelian transmission,
pedigree-based studies represent an implicit enrichment strategy, allowing the efficient capture of statistically relevant num-
bers of rare variants for disease association.
We sequenced the expanded exome (62Mb) of 253 individuals from five extended POAG pedigrees, selected based on their
contribution to independent and significant linkage signals (LOD>3) for each POAG-relevant trait. Using families not only
enriches for rare variation, but also allows imputation of missing data and error checking by transmission. We further increase
our power by reducing the initial search space to rare or novel variants within the 20Mb linkage intervals for each trait.
Preliminary results from only the first pedigree (prior to final imputation and error checking) identified an uncommon
(MAF<5%) and predicted deleterious risk haplotype (using CADD, SIFT and PolyPhen2) in PLXND1 (involved in angio-
genesis and axonal guidance) under the primary cup-to-disc ratio linkage peak.
By sequencing pedigrees displaying strong prior evidence for variant segregation (linkage signals) this study will identify rare
variation influencing POAG-relevant quantitative traits.
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Thu., April 07, 2016 8:00-9:30 Room C-1 (1F)
Chair：Christian T. Thiel（Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nuremberg, Germany）

Chair ：Tadashi Kaname（Genome Medicine, National Center for Child Health and Development, Japan）
Thu(5)-O46-1
Identifying a splice site mutation in RAB3GAP1 in Martsolf Syndrome by whole exom sequencing and
revealing the function of the novel mutation
Mustafa Ozen 1,2,3 ，Asuman Koparir 2 ，Omer F. Karatas 3,4 ，Emre Kirat 2 ，Seda S. Yılmaz 2 ，Bugra Ozer 5 ，
Betul Yuceturk 2,5 ，Mahmut S. Sagiroglu 5 ，Adnan Yuksel 1
1:Department of Medical Genetics, Biruni University, Istanbul, Turkey、2:Department of Medical Genetics, Istanbul University Cerrahpasa
Medical School, Istanbul, Turkey、3:Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA、4:Molecular
Biology and Genetics Department, Erzurum Technical University, Erzurum, Turkey、5:Advanced Genomics and Bioinformatics Research
Center, The Scientific and Technological Research Council of Turkey (TUBITAK-BILGEM), Kocaeli, Turkey
Martsolf (MS, MIM# 212720) and Micro Warburg syndromes (MWS, MIM# 600118) are autosomal recessive inherited
allelic disorders share similar clinical features including microcephaly, developmental delay, brain malformations, ocular
abnormalities, and spastic diplegia. MS is a genetically heterogeneous extremely rare syndrome with about 20 patients
reported in the literature. In current study, we present a Turkish female with MS. She had facial dysmorphism, severe motor-

mental retardation, congenital cataract, microcephaly, corpus callosum hypoplasia and hypogonadotropic hypogonadism.
Since the associated genes are various and quite long, we utilized whole-exome sequencing (WES) as a diagnostic tool for
identifying the molecular basis of Martsolf syndrome and we confirmed suspected variants by Sanger sequencing. As a
result, we found a novel homozygous splice site mutation in intron 22 of RAB3GAP1 and confirmed it by Sanger sequencing.
Parents were demonstrated to be heterozygous for this mutation. To further investigate the pathogenicity of the mutation,
we analyzed the relative expression level of RAB3GAP1 in both peripheral blood cells of the patient and a control individual
and demonstrated the reduced expression of RAB3GAP1 in the patient sample. Here, we report a MS associated novel splice
site mutation for the first time in the literature and suggest that this mutation is responsible for milder phenotype.
Thu(5)-O46-2
Adult mice expressing a Braf Q241R mutation on an ICR/CD-1 background exhibit a cardio-facio-
cutaneous syndrome phenotype
Shin-ichi Inoue 1 ，Mitsuji Moriya 1,2 ，Sachiko Miyagawa-Tomita 3 ，Yasumi Nakashima 4 ，Daiju Oba 1 ，Tetsuya Niihori 1 ，
Misato Hashi 5 ，Hiroshi Ohnishi 5 ，Shigeo Kure 2 ，Yoichi Matsubara 1,6 ，Yoko Aoki 1
1:Department of Medical Genetics, Tohoku University School of Medcine, Japan、2:Department of Pediatrics, Tohoku University School
of Medicine、3:Department of Veterinary Technology, Yamazaki gakuen University、4:Department of Pediatrics, Seirei Hamamatsu General
Hospital、5:Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences、6:National Research Institute for
Child Health and Development
Activation of the RAS pathway has been implicated in oncogenesis and developmental disorders called RASopathies. Germline
mutations in BRAF have been identified in 50-75% of patients with cardio-facio-cutaneous (CFC) syndrome, which is char-
acterized by congenital heart defects, distinctive facial features, short stature and ectodermal abnormalities. We recently
demonstrated that mice expressing a Braf Q241R mutation, which corresponds to the most frequent BRAF mutation (Q257R)
in CFC syndrome, on a C57BL/6J background are embryonic/neonatal lethal, with multiple congenital defects, preventing
us from analyzing the phenotypic consequences after birth. Here, to further explore the pathogenesis of CFC syndrome, we
backcrossed these mice onto a BALB/c or ICR/CD-1 genetic background. On a mixed (BALB/c and C57BL/6J) background,
all heterozygous BrafQ241R/+ mice died between birth and 24 weeks and exhibited growth retardation, sparse and ruffled fur,
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liver necrosis, cardiomegaly and atrial septal defects. In contrast, 31% of the heterozygous BrafQ241R/+ ICR mice survived
over 74 weeks. The surviving BrafQ241R/+ ICR mice had CFC syndrome-related phenotypes including growth retardation,
sparse and ruffled fur, a hunched appearance, craniofacial dysmorphism, long and/or dystrophic nails, cardiomegaly and
splenomegaly. Furthermore, the phenotype of extra digits, ovarian cysts and enlarged testes, which have not been reported in
patients with CFC syndrome, were observed in the BrafQ241R/+ ICR mice. The BrafQ241R/+ ICR mice also showed learning
deficits in the contextual fear-conditioning test. Echocardiography indicated the presence of pulmonary stenosis and atrial
septal defects in the BrafQ241R/+ ICR mice, which were confirmed by histological analysis. These data suggest that the
heterozygous BrafQ241R/+ ICR mice show similar phenotypes as CFC syndrome after birth and will be useful for elucidating
the pathogenesis and potential therapeutic strategies for RASopathies.
Thu(5)-O46-3
Massively parallel sequencing of a targeted panel for the diagnosis of Disorders of Sex Development
Andrew H Sinclair 1 ，Stefanie Eggers 1
1:Molecular Development, Murdoch Children’s Research Institute, Australia
Disorders of Sex Development (DSDs) are congenital conditions in which development of gonadal or anatomical sex is atypical.
The cause is often a breakdown of the complex network of gene regulation responsible for proper development of testes
or ovaries. Currently, most DSD patients cannot be given an accurate diagnosis, which severely comprises their clinical

management. We aim to identify the underlying changes in genes associated with DSD in an effort to provide an accurate
diagnosis as well as gaining insights into gonad development.
As part of this study we have assembled a large cohort of DSD patient samples (1,053 DSD patient DNA samples, comprising
60% 46,XY DSD, 5% 46,XX DSD, 15% unexplained androgen insensitivity; 3% premature ovarian failure; 17% DSD with
other syndromes).
We have developed a targeted DSD panel combined with massively parallel sequencing for the in depth analysis of up to 1,034
genes. This DSD gene panel includes all known high frequency genes (eg SRY , SOX9 , NR5A1 ), low frequency genes (eg
CBX2 ) and entire gene pathways (eg Androgen, WNT , MAPK , TGF β). The panel also includes potential novel DSD genes,
small regulatory regions and miRNAs. The DSD targeted panel is relatively inexpensive, has excellent coverage (relative to
exomes) and is quick to analyse allowing rapid turn-around in a clinical diagnostic setting.
In a pilot study of 300 patients we were able to provide a diagnosis for 40% of DSD patients. This is a substantial increase
in diagnostic rates compared to all other methodologies. In addition, the panel allows us to detect the sex chromosome
complement as well as large and small deletions and duplications (CNVs) affecting known DSD genes. The targeted DSD
panel is undergoing clinical accreditation for implementation by the Victorian Clinical Genetics Service as a certified clinical
diagnostic test. We believe that rapid, accurate diagnosis of DSD patients will assist in their clinical management and improve
patient outcomes
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Thu(5)-O46-4
Systematic evaluation of patients with idiopathic short stature using whole exome sequencing
Christian T Thiel 1 ，Nadine N Hauer 1 ，Sarah Schuhmann 1 ，Eva Schoeller 1 ，Marie T Wittmann 1 ，Steffen Uebe 1 ，
Arif B Ekici 1 ，Heinrich Sticht 2 ，Helmuth-Guenther Doerr 3 ，Andé Reis 1
1:Institute of Human Genetics, Friedrich-Alexander-University of Erlangen-Nuremberg, Germany、2:Institute of Biochemistry Friedrich-
Alexander-University of Erlangen-Nuremberg、3:Department of Pediatrics and Adolescent Medicine Friedrich-Alexander-University of
Erlangen-Nuremberg
Shortness of stature is a common medical concern in childhood and has an incidence of 3% in the general population. After
excluding defects of the growth hormone pathway and recognizable syndromes the underlying cause remains unknown in
approximately 70-80% of patients.
In some of these patients the underlying diagnosis is omitted by the lack of clinical features characteristic for known syndromic
forms of short stature. To address this in patients with idiopathic short stature we thoroughly built a study group of more
than 500 families with idiopathic short stature. We systematically selected 100 individuals where growth hormone defects,
common genetic causes of short stature or copy number variations were excluded and performed whole exome sequencing.
Variants were selected unbiased based on all modes of inheritance in agreement with the segregation in the families and their
potential effect on protein function.
We confirmed mutations in known short stature genes in 11 patients. These syndromes have been reported to be associated

with further clinical issues providing mandatory medical guidance for these patients.
In addition, we recognized novel candidate genes involved in epigenetic modification, cell cycle regulation, ubiquitination and
protein synthesis in up to 54 % of the patients. Even though, recessive, dominant and x-linked inherited variants were observed
in these candidate genes, we confirmed autosomal dominant de novo as the predominant inheritance model in idiopathic short
stature. Thus, our data underlines the rare variant - frequent disease hypothesis for the extreme end of the growth spectrum.
In conclusion, whole exome sequencing identified the underlying genetic defect in up to 65% of the patients with idiopathic
short stature. As the clinical spectrum of most genetic defects is yet to be explored, an unbiased genetic analysis of patients
with idiopathic short stature can establish a diagnosis in these cases.
Thu(5)-O46-5
Novel candidate gene for congenital alveolar proteinosis with hypogammaglobulinemia identified by whole
exome sequencing analysis
Kazutoshi Cho 1 ，Takuma Akimoto 1 ，Itaru Hayasaka 1 ，Hisanori Minakami 1 ，Tadashi Ariga 2 ，Masafumi Yamada 2 ，
Masahiro Ueki 2 ，Naomichi Matsumoto 3 ，Noriko Miyake 3 ，Atsushi Fujita 3 ，Hirokazu Kanegane 4 ，Satoshi Miyamoto 4 ，
Satoru Ikemoto 5 ，Kazunaga Agamatsu 6 ，Norimoto Kobayashi 6
1:Maternity and Perinatal Care Center, Hokkaido University Hospital, Japan、2:Department of Pediatrics, Hokkaido University Graduate
School of Medicine, Sapporo, Japan、3:Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama,
Japan、4:Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan、5:Division of General
Pediatrics, Saitama Children’s Medical Center, Saitama, Japan、6:Department of Pediatrics, Shinshu University, School of Medicine, Nagano,
Japan
Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of surfactant like substance in alveolar spaces and
hypoxemic respiratory failure. Congenital forms of PAP (CPAP) are caused by mutations in genes (SFPTB, SFPTC and
ABCA3 ) responsible for surfactant production, processing, or transport in alveolar type II cells. CPAP also develops by
disorders in genes (CSF2RA, CSF2RB and GATA2 ) responsible for surfactant catabolism in alveolar macrophages. In this
study, we performed whole exome sequence analysis in a family affected by CPAP with hypogammaglobulinemia without
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mutations in the responsible genes described above. A heterozygous amino acid change in a gene was identified in three
affected siblings but not in other family members without CPAP. A 4%- mosaicism of this mutation was detected in DNA
from their mother’s peripheral blood mononuclear cells. Thus, this CPAP seemed inherited as an autosomal dominant trait.
This result prompted us to further screen for additional mutations of this gene in patients affected by CPAP with unknown
etiology. We identified two additional de novo heterozygous mutations of this gene in two sporadic patients from different
families manifesting similar clinical features. Some of the findings shared by the five patients from 3 families support the
defects are in surfactant catabolism in alveolar macrophages: 1) infantile onset without respiratory symptoms at birth, 2)
few, small and not foamy alveolar macrophages, 3) resolution of pulmonary lesions with stem cell transplantation.
Thu(5)-O46-6
Whole exome sequencing identifies homozygous mutation in ERCC1 in three sibling with a complex
phenotypic disorder
Zeynep Ocak 1 ，Tulay Ozlu 2 ，Tarik Ocak 1 ，Yavuz Bayram 3 ，Davut Pehlivan 3,4
，Ender Karaca 3 ，Richard A. Gibbs 5 ，
James R. Lupski 3,5,6,7
1:Medical Genetics, Kanuni Sultan Suleyman Research and Training, Turkey、2:Department of Obstetrics and Gynecology, Abant izzet
Baysal University Medical Faculty, Bolu, Turkey.、3:Department of Molecular and Human Genetics, Baylor College of Medicine, Houston,
TX, USA、4:Section of Neurology, Department of Pediatrics, Baylor College of Medicine, One Baylor、5:Human Genome Sequencing Center,
Baylor College of Medicine, Houston, TX, USA、6:Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA、7:Texas
Childrens Hospital, Houston, TX, USA

Hypergonadotropic hypogonadism (HH), Xeroderma pigmentosum (XP), short stature, and intellectual disability (ID) can
rarely occur together as a complex phenotypical spectrum. Several genetic defects have been shown to cause HH, XP, and
ID. Here, we report three siblings who were born to a first degree cousin marriage presenting with HH, XP, short stature,
microcephaly, and ID. Two sisters, at 20 and 18 years of age, had primary amenorrhea, lack of secondary sex characteristics,
and pre-pubertal sized uteri with invisible ovaries at pelvic ultrasound imaging. Their brother had normal secondary sexual
development at 29 years of age. All had normal karyotype and cranial MRI results. Whole exome sequencing (WES) in
two affected female siblings showed homozygous mutations in ERCC1 (c.466C>T; p.R156W). The identified variant was
predicted to be deleterious by multiple computational algorithms (i.e., Polyphen-2, MutationTaster, SIFT, and LRT) and
observed only in our internal database (~ 4800 exomes) in two other individuals but in heterozygous state and not observed
in other publicly available databases. Segregation analysis within the family revealed that the affected siblings (2 female and
1 male) were homozygous and both parents and an unaffected brother were heterozygous carriers for the identified variant.
Factors that potentiate the roles of these homozygous variants in the emergence of this complex phenotype are their segregation
in the family, localization on highly conserved regions of the genome and extremely low frequency in the databases. Utilizing
this family, we discuss the molecular mechanism of a complex phenotype in which there is an overlap with the findings of
cerebro-oculo-facio-skeletal syndrome and xeroderma pigmentosum/Cockayne syndrome complementation group. Elucidation
of novel genetic defects causing a complex phenotypic disorder will provide major insights into the knowledge of the regulation
of human biological function.
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Thu., April 07, 2016 9:45-11:15 Room C-1 (1F)
Chair：Vanessa Sancho-Shimizu（Department of Virology and Paediatrics, Imperial College London, UK）

Chair ：Yoko Aoki（Department of Medical Genetics, Tohoku University School of Medicine, Japan）
Thu(5)-O47-1
Study on molecular mechanism of episodic pain with Nav 1.9 channel mutations
Jing Yu Liu 1 ，Luyao Yang 1 ，Xiangyang Zhang 1 ，Jingmin Wen 1 ，Wei Yang 2 ，Cheng Wang 1 ，Lunan Gao 1 ，
Junyu Luo 3 ，Jing Yao 4 ，Xue Zhang 2
1:Key Laboratory of Molecular Biophysics of the Ministry of Education, School of Life Science and Technology, Huazhong University
of Science and Technology, China、2:McKusick-Zhang Center for Genetic Medicine and State Key Laboratory of Medical Molecular
Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College、3:School of Chemical
Engineering and Pharmacy, Wuhan Institute of Technology、4:College of Life Sciences, Wuhan University
Pain serves as a defense system to protect the body against further injury and promotes healing of damaged tissues. Up to
10% of the worldwide population is affected with pain, and chronic pain significantly diminishes their quality of life in many
affected individuals. The mechanisms of chronic pain are unknown. Many ion channel genes have so far been associated with
human genetic pain disorders. Here we report two large Chinese families (including 28 patients) with autosomal dominant
episodic pain. We performed a genome-wide linkage scan with microsatellite markers after excluding mutations in three known

genes (SCN9A, SCN10A and TRPA1 ) and mapped the genetic locus on chromosome 3p22.3-p21.32. By using whole exome
sequencing followed by conventional Sanger sequencing, we identified two missense mutations in SCN11A encoding voltage-
gated sodium channel Nav 1.9, c.673C>T (p.Arg225Cys) and c.2423C>G (p.Ala808Gly) (one in each family). Each mutation
showed a perfect co-segregation with the pain phenotype in the corresponding family, and neither of them was detected in
1021 normal individuals. We expressed the two SCN11A mutants in mouse dorsal root ganglion (DRG) neurons and showed
that both mutations enhanced the channel’s electrical activities and induced hyperexcitablity of DRG neurons. Heterozygous
knock-in mice carrying the orthologous mutation (p.A796G, corresponds to the human p.A808G) showed sensitivity to pain
and DRG neurons from these knock-in mice showed similar enhanced channel’s electrical activities as expressing human
mutation p.A808G in mouse DRG. Taken together, our results suggest that gain-of-function mutations in SCN11A can be
causative of an autosomal dominant episodic pain disorder. This study provides rationale base for developing analgesic drug.
Thu(5)-O47-2
Assembling the complex immune region haplotypes using Long Read Single Molecule Real-Time Se-
quencing
Swati S Ranade 1 ，Richard Hall 1 ，Kevin Eng 1 ，Chul-woo Pyo 2 ，Dave Roe 3 ，Primo Baybayan 1 ，Lawrence Hon 1 ，
Daniel E Geraghty 2 ，Cynthia Vierra-Green 3 ，Steve Kujawa 1 ，Martin Maiers 3
1:Pacific Biosciences, USA、2:Fred Hutchinson Cancer Research Center, Seattle, USA、3:Center for International Blood and Marrow
Transplant Research, Minneapolis, USA
Identification of causal genetic factors contributing to disease is the ultimate goal of any genetic study. While most common
disease/common variant hypothesis have been tested in many genome-wide association studies, few advancements have been
made in identifying causal variants. A number of recent findings now point away from common variants and focus on
aggregates of rare variants as causal factors of complex disease. However, one of the major challenges of dissecting the
mechanisms underlying these aggregates is the inability to obtain completely phased sequences of extended genomic regions.
This task gets even more daunting when one is trying to fine map within the complex immune regions. To address this
challenge, we have explored two targeted sequencing approaches alongside single-molecule, long-read sequencing for obtaining
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complete and haplotype-resolved sequencing across extended immunogenomic regions. These include direct sequencing of
both fosmid libraries (30-40 kb) enriched using recombineering capture probes, and long, randomly sheared targets (~ 10 kb)
enriched using the NimbleGen SeqCap EZ hybridization-based enrichment. The performance of these methods for enrichment
of segments spanning the Common Extended Haplotype (CEH) within the MHC and the complete haplotype of KIR were
evaluated for feasibility and scalability in association studies. While the NimbleGen data analysis relied on previously known
references, the phase-preserved, full-length fosmid sequences spanned at least two heterozygous variants and could be de
novo assembled. Both the methods generated data that could be assembled into consensus sequences with accuracy above
99.99%.The de novo assemblies produced complete haplotypes of MHC and KIR gene clusters, in their correct order, and
identified the correct genotypes of genes comprised within them. These methods are thus easily adaptable for previously
uncharacterized haplotypes for causal variant fine mapping studies.
Thu(5)-O47-3
Mutations in MECOM, encoding oncoprotein EVI1, cause radioulnar synostosis with amegakaryocytic
thrombocytopenia
Tetsuya Niihori 1 ，Meri Ouchi-Uchiyama 2,3 ，Yoji Sasahara 2 ，Takashi Kaneko 4 ，Yoshiko Hashii 5 ，Masahiro Irie 2,3 ，
Atsushi Sato 3 ，Yuka Saito-Nanjo 2,3 ，Ryo Funayama 6 ，Takeshi Nagashima 6 ，Shin-ichi Inoue 1 ，Keiko Nakayama 6 ，
Keiichi Ozono 5 ，Shigeo Kure 2 ，Yoichi Matsubara 1,7 ，Masue Imaizumi 3 ，Yoko Aoki 1
1:Department of Medical Genetics, Tohoku University School of Medicine, Japan、2:Department of Pediatrics, Tohoku University School
of Medicine、3:Department of Hematology and Oncology, Miyagi Children’s Hospital、4:Department of Hematology-Oncology, Tokyo

Metropolitan Children’s Medical Center、5:Department of Pediatrics, Osaka University Graduate School of Medicine、6:Division of Cell
Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine、
7:National Research Institute for Child Health and Development
Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is an inherited bone marrow failure syndrome,
characterized by thrombocytopenia and congenital fusion of the radius and ulna. A heterozygous HOXA11 mutation has
been identified in two unrelated families as a cause of RUSAT. However, HOXA11 mutations are absent in a number of
individuals with RUSAT, which suggests that other genetic loci contribute to RUSAT. In the current study, we performed
whole exome sequencing in an individual with RUSAT and her healthy parents and identified a de novo missense mutation
in MECOM , encoding EVI1, in the individual with RUSAT. Subsequent analysis of MECOM in two other individuals
with RUSAT revealed two additional missense mutations. These three mutations were clustered within the 8th zinc finger
motif of the C-terminal zinc finger domain of EVI1. Chromatin immunoprecipitation and quantitative polymerase chain
reaction assays of the regions harboring the ETS-like motif that is known as an EVI1 binding site showed a reduction in
immunoprecipitated DNA for two EVI1 mutants compared with wild-type EVI1. Furthermore, reporter assays showed that
mutations in EVI1 altered both AP-1- and TGF β-mediated transcriptional responses. These functional assays suggest that
transcriptional dysregulation by mutant EVI1 could be associated with the development of RUSAT. We report missense
mutations in MECOM resulting in a Mendelian disorder that provide compelling evidence for the critical role of EVI1 in
normal hematopoiesis and in the development of forelimbs and fingers in humans.
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Thu(5)-O47-4
Beta-globin haplotypes in Hemoglobin E and normal individuals from seven minority groups of Yunnan
province, China
Zhaoqing Yang 1 ，Hongxian Liu 1 ，Kai Huang 1 ，Shuyan Liu 1 ，Hao Sun 1 ，Keqin Lin 1 ，Xiaoqin Huang 1 ，Jiayou Chu 1
1:Institute of Medical Biology, Chinese Academy of Medical Sciences, China
Little is known about the distribution and origin of hemoglobin E (HbE) in minority groups in the malaria-endemic Yunnan
province in China, who have similar ethnic origins and geographic relationships with the HbE-prevalent populations of
Southeast Asian countries. The prevalence of HbE was examined in 1488 individuals from seven native minority groups of
Yunnan, and β-globin gene cluster haplotypes were determined on 1420 chromosomes. The prevalence of HbE ranged from
1.5-39.1 %. Higher HbE prevalence was correlated with the minority groups of Tibeto-Burman origin and groups from the
Dehong district. There gene frequencies of HbE were significantly different among Chinese Thai groups living in different
geographic districts. The analysis of β-globin gene cluster haplotypes showed that the β E -globin genes in Yunnan were
mostly associated with three haplotypes on chromosomes with gene framework 2. The number of haplotypes observed in
the Yunnan groups ranged from 8 to 16, the phylogenetic analysis and distribution pattern of the haplotypes reflected the
relationships among Yunnan minorities and other Asia populations, and the geographic classifications of the populations.
This study, for the first time, reported population-based data on the heterogeneity of the HbE gene frequency and beta-globin
haplotype distribution in the native minorities from the Yunnan province. Our findings suggest that natural selection of
malaria, ethnic origin and epistatic interactions may be the responsible factors of varying importance for the remarkable

E
variation in HbE frequency among these minority groups, and there appears to be a common origin of the β -globin
gene in populations from Yunnan and Southeast Asia. The diversity of the beta-globin haplotypes could reveal the genetic
relationship of Chinese ethnic populations to some extent.
Thu(5)-O47-5
Heterozygous mutations in NFKB1 cause immunodeficiency and autoinflammatory episodes
Meri Kaustio 1 ，Emma Haapaniemi 2,3 ，Helka Nurkkala 4 ，Giljun Park 5 ，Elisabet Einarsdottir 3,6 ，Fitsum Tamene 4 ，
Luca Trotta 1 ，Ekaterina Morgunova 3 ，Kaarel Krjutskov 3 ，Jaana Syrjanen 7 ，Anssi Lagerstedt 8 ，Merja Helminen 9 ，
Timi Martelius 10 ，Timo Hautala 11 ，Satu Mustjoki 5,12 ，Janna Saarela 1 ，Juha Kere 2,3,6 ，Markku Varjosalo 4 ，
Mikko Seppanen 10,13
1:Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland、2:Folkhalsan Institute of Genetics, Helsinki, Finland、
3:Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden、4:Institute of Biotechnology, University of Helsinki,
Helsinki, Finland、5:Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki,
Helsinki, Finland、6:Center for Innovative Medicine, Karolinska Institutet, Stockholm, Sweden、7:Department of Internal Medicine,
Tampere University Hospital, Tampere, Finland、8:Fimlab Laboratories, Tampere University Hospital, Tampere, Finland、9:Tampere
Center for Child Health Research, Tampere University Hospital, Tampere, Finland、10:Adult Immunodeficiency Unit, Infectious Diseases,
Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland、11:Department of Internal Medicine, Oulu
University Hospital, Oulu, Finland、12:Helsinki University Central Hospital Comprehensive Cancer Center, Helsinki, Finland、13:Rare
Diseases Center, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
The NF-kB signaling pathway is a key regulator of immune responses. Accordingly, mutations in several genes of the
pathway have been found to cause immunodeficiency. Using next generation sequencing methods and linkage analysis, we
investigated three unrelated Finnish kindreds with immunodeficiency and autoinflammation. In all 13 affected individuals,
we identified heterozygous variants in NFKB1 , encoding for the NF-kB family members p50/p105. Patients harboring a
p.I553M variant presented with antibody deficiency, infection susceptibility, and multi-organ autoimmunity. In addition to
hypogammaglobulinemia, patients with a p.H67R change suffered from autoinflammatory episodes including aphthae, gut
disease, febrile attacks and small vessel vasculitis characteristic of Behcet’s disease. Similarly, in patients with a p.R157X
stop-gain variant, the main symptom was a hyperinflammatory response to routine surgery.
Functional analyses indicated that both missense variants led to a reduction in p50/p105 function, whereas the p.R157X
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variant likely leads to rapid elimination of the truncated transcript. The p.H67R variant reduced nuclear entry of p50,
which in luciferase-reporter assays led to a decrease in transcriptional activity. The p.I553M mutation, in turn, reduced
phosphorylation of the NF-kB inhibitor p105 decreasing its stability during TNF induction. Both missense mutations also
led to altered protein-protein interactions in affinity purification mass spectrometry.
Although common variants in NFKB1 have previously been associated with Behcet’s disease, monogenic forms of the disease
have not been reported. Our findings suggest that a subset of Behcet’s and other autoinflammatory diseases may be caused
by rare, monogenic variants and highlight the importance of careful homeostasis between components of the NF-kB pathway.
Thu(5)-O47-6
Whole exome sequencing of an extended family with invasive meningococcal disease
Vanessa Sancho Shimizu 1 ，Alberto Lopez-Lera 2,3 ，Evangelos Bellos 4 ，Bayarchimeg Mashabt 1 ，Heidi Makrinioti 5,6
，
Ross P Walton 5,6 ，Margarita Lopez-Trascasa 2,3 ，Michael Levin 1
1:Dept of Paediatrics and Virology, Imperial College London, UK、2:Immunology Unit, Hospital Universitario La Paz and Hospital La Paz
Research Institute (IdiPAZ), Madrid, Spain、3:Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud
Carlos III (ISCIII), Madrid, Spain、4:The Department of Genomics of Common Disease, School of Public Health, Imperial College London,
UK、5:Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, UK. Medical Research Council (MRC)
and Asthma UK Centre in Allergic Mechanisms of Asthma, London UK、6:Centre for Respiratory Infection, Imperial College London, UK
Invasive meningococcal disease (IMD) is a rare disease affecting children and young adults due to infection with Neisseria

meningitidis. Most people have been exposed to N. meningitidis, but the majority do not develop IMD, suggesting that
those that succumb to invasive disease may possess an underlying genetic susceptibility. The notion of a genetic contribution
to disease manifestation is also supported by the finding that patients with congenital complement deficiencies or properdin
deficiency are susceptible to recurrent IMD. We carried out whole exome sequencing of an extended family with three first
cousins who suffered from IMD with the aim of identifying Mendelian single gene mutations. We searched for rare or novel,
predicted deleterious mutations that were shared among the three cousins which narrowed down the candidate list to a handful
of genes. A heterozygous missense mutation in IL1LR1 was identified as the candidate pathogenic mutation. IL1RL1 encodes
the protein ST2 which is a subunit of the IL33 receptor and can additionally be found in soluble form (sST2) which has a role
as a decoy receptor to IL33. We have carried out functional assays on serum and blood samples from patients that reveal an
increased expression of sST2 in the patients’cells which may interfere with proinflammatory cytokine secretion and neutrophil
chemotaxis in the context of Neisseria infection. Furthermore, we searched in our database of over 150 whole exome sequenced
childhood IMD patients and identified another unrelated patient that carried a heterozygous missense mutation in the residue
next to the familial mutation. The identification of genes involved in IMD will provide a dissection of meningococcal immunity
in natural conditions and a more comprehensive understanding of IMD pathogenesis which may be used to improve vaccine
and treatment strategies.
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Thu., April 07, 2016 8:00-9:30 Room C-2 (1F)
Chair：Roberto Giugliani（Department of Genetics, Federal University of Rio Grande Do Sul, Brazil）

Chair ：Yoshikatsu Eto（Advanced Clinical Research Center & Institute of the Treatment of Genetic Disorders, Southern
Tohoku Brain Research Institute, Japan）
Thu(5)-O48-1
Phenotypic variability in the form of pulmonary manifestations and molecular analysis in two patients
with Niemann Pick-disease type C from India
Krati R Shah 1 ，Jayesh Sheth 1 ，Frenny Sheth 1 ，Mehul Mistry 1 ，Harsh Patel 1 ，Mamta Muranjan 2 ，Jijo Joseph 3
1:Institute of Human Genetics, India、2:Seth G.S. Medical College, Mumbai、3:MGM Medical College, Navi Mumbai
Niemann Pick-C(NPC) is an inherited metabolic disorder which occurs due to defect in cellular cholesterol trafficking. NPC
is a clinically heterogeneous disease with variable age of onset ranging from prenatal to perinatal period onto adolescence
with multiple organ systems being involved. Here, we present two cases with primary involvement of lung.
First, a three-year-old male child born to third degree consanguineous parents with no perinatal and natal concerns presented
with dyspnoea and hepatomegaly noticed at one year of age. Computed Tomography (CT) scan of thoracic region showed

consolidation with mediastinal lymphadenopathy. Broncho-alveolar lavage revealed moderate amount of foamy macrophages
and bone marrow examination showed presence of foam cells. Molecular analysis identified a homozygous T-to-C transition
in intron 1 of the NPC2 gene.
Second, 18 months old female child born to nonconsanguineous parents presented with respiratory distress, motor delay,
failure to thrive and hepatosplenomegaly. Lung biopsy was suggestive of alveolar proteinosis and liver biopsy done revealed
foamy macrophages. Molecular analysis identified novel mutation c.141C>A change in exon 2 of NPC2 gene.
Our study demonstrate that NPC may present in early years of life with pulmonary involvement as the major concern and
subsequently leading towards other organ system involvement. An early suspicion of NPC will help us to clinch its diagnosis
and management.
Thu(5)-O48-2
The Canadian Inherited Metabolic Diseases Research Network: Initial findings from a pan-Canadian
longitudinal study of affected children
Beth K Potter 1 ，Pranesh Chakraborty 2 ，Monica Lamoureux 2 ，Kylie Tingley 1 ，Doug Coyle 1 ，Jonathan B Kronick 3 ，
Kumanan Wilson 1 ，Valerie Austin 3 ，Catherine Brunel 4 ，Daniela Buhas 5 ，Maggie Chapman 6 ，Alicia KJ Chan 7 ，
Sarah Dyack 6 ，Annette Feigenbaum 3 ，Michael Geraghty 2 ，Alette Giezen 8 ，Jane Gillis 6 ，Shailly Jain 7 ，
Erica Langley 2 ，Julian Little 1 ，Jennifer MacKenzie 9 ，
+ B Maranda, A Mhanni, G Mitchell, JJ Mitchell, L Nagy, A Pender, M Potter, C Prasad, K Siriwardena, R Sparkes,
S Stockler, Y Trakadis, L Turner, C VanKarnebeek, H Vallance, J Walia, BJ Wilson
1:University of Ottawa, Canada、2:Children’s Hospital of Eastern Ontario、3:University of Toronto/ Hospital for Sick Children、4:CHU
Ste-Justine、5:Montreal Children’s Hospital、6:Dalhousie University、7:University of Alberta、8:BC Children’s Hospital、9:Queen’s University
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Objectives: The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) is a practice-based research network
designed to develop evidence needed to improve outcomes for children with inborn errors of metabolism (IEM).
Design and Methods: As part of CIMDRN’s clinical research stream, we are enrolling Canadian children born between 2006
and 2015 and diagnosed with one of 30 targeted IEM. The clinical database, hosted on Research Electronic Data Capture
(REDCap), collects retrospective and prospective information from participants’ medical charts. The data include clinical
descriptors and indicators of prognosis, interventions received and potential modifiers of intervention effectiveness, clinical
outcomes, and intermediate indicators of disease management.
Results: Patient recruitment is on-going at 11 of the 14 participating treatment centres within the provinces of British
Columbia, Alberta, Manitoba, Ontario, Quebec, and Nova Scotia. To date (November 2015), 335 children have been enrolled,
with data entered for 311 participants (10 deceased). CIMDRN participants’ diagnoses include 25 of CIMDRN’s 30
target diseases - phenylalanine hydroxylase deficiency (n=96), other amino acid disorders (n=14), medium-chain acyl-CoA
dehydrogenase deficiency (n=55), other fatty acid oxidation disorders (n=39), urea cycle disorders (n=17), organic acid
disorders (n=41), and other IEM (n=49). CIMDRN’s cohort is 51% male and balanced across the eligible age range: <=1
year (n=62), 2-3 years (n=76), 4-5 years (n=60), 6-7 years (n=64), 8-9 years (n=38). Of those with case ascertainment data,
77% were identified through population-based newborn screening.
Conclusions: We have established a rich and sustainable dataset and have begun analyses to generate the practice-based
evidence needed to overcome critical challenges of clinical longitudinal research toward improved care and outcomes for IEM.

Thu(5)-O48-3
Relative Frequency of Lysosomal Storage Diseases in Brazil: 1982-2015 Report from a Reference Center
Roberto Giugliani 1,2,3 ，Kristiane Michelin-Tirelli 2 ，Jurema F de Mari 2 ，Fernanda Bender 1,2 ，
Fernanda Medeiros 2 ，Ana P Scholz 2 ，Fernanda Bittencourt 2 ，Regis R Guidobono 2 ，Maira G Burin 2 ，
MPS Brazil Network, LSD Brazil Network, NPC Brazil Network, IEM Brazil Network
1:Department of Genetics, UFRGS - Federal University of Rio Grande do Sul, Brazil、2:Medical Genetics Service, Hospital de Clinicas de
Porto Alegre, Brazil、3:INAGEMP, National Institute of Population Medical Genetics, Brazil
The Medical Genetics Service of Hospital de Clinicas de Porto Alegre, located in the Southern part of Brazil, has the most
comprehensive laboratory for the diagnosis of lysosomal storage diseases (LSDs). From 1982 to 2015, this laboratory was able
to identify 3,286 cases of LSDs (average of almost 100 cases/year), diagnosed on samples of 60,000 high risk patients from all
Brazilian regions referred for investigation. Screening methods included quantitation and electrophoresis of urinary GAGs,
thin layer chromatography of urinary oligosaccharides and syalyloligosaccharides, assay of chitotriosidase activity in plasma,
and other selected procedures performed according tothe clinical suspicion. Diagnoses were confirmed by specific fluorimetric,
colorimetric or radioisotopic enzyme assays, and/or by the identification of the pathogenic mutations, usually in blood
samples. The most common LSDs diagnosed (over 100 cases each) were Gaucher disease (726 cases), Mucopolysaccharidosis
(MPS) II (419 cases), MPSVI (285 cases), MPS I (276 cases), Acid Sphingomyelinase Deficiency/ASMD (213 cases), GM1
Gangliosidosis (176 cases), MPS IVA (175 cases), Metachromatic Leucodystrophy (150 cases), Fabry disease (118 cases),
MPS III B (102 cases), and Krabbe disease (101 cases). These results indicate that LSDs, although individually rare, may
be frequent when investigation is concentrated in reference laboratories. Large numbers of cases enable centers to obtain
experience in managing these conditions, and also to perform natural history studies, and to participate in clinical trials. It is
important to mention that the majority of patients identified could benefit from the therapeutic alternatives already available
or in clinical development.
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Thu(5)-O48-4
Plasma Oxysterol and Lysosphingomyelin-509 as Potential Biomarkers for Japanese Patients with
Niemann-Pick C disease measured by Tandem MS and their Changes with Miglustat Treatment
Yoshikatsu Eto 1 ，Takeo Iwamoto 2 ，Ayumi Takamura 3 ，Miwa Fujisaki 1 ，Masayo Kashiwazaki 1 ，Kaoru Eto 4 ，
Norio Sakai 5
1:Advanced Clinical Research Center, Institute of Neurological Diseases, Japan、2:Core Laboratory, Tokyo Jikei University School of
Medicine、3:Department of Biological Regulation, School of Health Science, Tottori Univsersity、4:Department of Pediatrics, Tokyo Womens
Medical School、5:Department of Child Health, School of Health Science, Osaka University
Niemann-Pick C (NPC) is a neurodegenerative brain disorder caused by gene mutation in either NPC1 (95%) or NPC2
Protein(5%). Clinically, this disorder is highly heterogeneous ranged from neonatal period to adult age. The diagnosis of
NPC is based on Filipin Staining in cultured skin fibroblasts and also gene mutation analysis. However, this procedure is
invasive and takes time. As non-invasive procedure, we carried out to determine plasma oxysterol, 7-ketocholesterol from
110 patients with neonatal cholestasis or neurological symptoms such as myoclonic epileptic seizure, vertical eye movement
disorder, mental retardation, dysphagia and cataplexy using HPLC- Tandem-MS ( Bruker, Maxis 3G). Almost 22 patients
showed elevated more than 40ug/ml in plasma 7-ketocholesterol, suggesting that these patients are NPC. Furthermore,
we measured plasma lysosphingomyelin-509 among patients with NPC. Three of them are elevated lysoSM-509, more than
0.9ug/DBS. The measurement of plasma 7-ketocholesterol and lysoSM-509 is useful biomarkers for the differential diagnosis of
NPC patients from other neurodegenerative disorders. The amounts of oxysterol in plasma are decreasing tendency following
to oral administration of Miglustat in three Japanese patients with late onset type and juvenile type of NPC. These results

suggest that the measurement of these biomarkers in plasma from patients with NPC can be utilized for monitoring the
treatment efficacy by Miglustat and may also apply for the evaluation of disease mechanisms of NPC.
Thu(5)-O48-5
Pharmacological chaperones for the cure of metabolic diseasesPharmacological chaperones for the cure
of metabolic diseases
Maria Vittoria Cubellis 1 ，Valentina Citro 1 ，Vincenzo Riso 1 ，Rosita Del Prete 1 ，Enza Di Meo 1 ，Antonia Paone 1 ，
Chiara Cimmaruta 1 ，Giuseppina Andreotti 2
1:Biology, University Federico II, Italy、2:Istituto di Chimica Biomolecolare; CNR, Italy
Pharmacological chaperones (PC) as small molecule therapeutics represent a novel paradigm for the treatment of disorders
arising from mutations that destabilize proteins and thus reduce their level in the cell. A large share of pathological missense
mutations can be treated with PC, but their widespread usage is hindered by the fact that for any given disease only some
genotypes are responsive.
Fabry disease represents an archetype with 250 mutations analyzed in vitro and 24 in clinical trial. We derived rules to predict
which mutations cause severe loss of activity and which are likely to be responsive to PC. We produced a user-friendly web
application, FABRY_CEP, to help clinicians Choose Eligible Patients [1].
Sometimes the effect of mutations is quite intricate as in the case of a frequent genotype, F119L/R141H, associated with
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phosphomannomutase2 (PMM2) deficiency, the most common disorder of glycosylation. The active form of PMM2 is a
dimer and F119L affects activity indirectly, by destabilizing the quaternary structure. R141H occurs in the active site and
consequently abolishes the activity. The association between the two mutants however, has beneficial effects on the specific
PMM2 activity. Heterodimers are formed where F119L and R412H contributes a functional active site and an effective
dimerization interface respectively. For the patients carrying F119L/R141H genotype the primary cause of the disease is not
an intrinsic deficiency of catalytic competence, as it might have been foreseen analyzing separately the two mutants, but the
instability of the proteins. This finding opens the possibility of extending the approach with PC to such patients. We have
identified a potential lead compound in glucose1,6 bisphosphate. This molecule is able to stabilize thermodinamically the
mutants, favour dimerization and potentiate specific activity of PMM2.
1 Cammisa, M. et al. (2013). Orphanet J Rare Dis 8: 111.
Thu(5)-O48-6
Transthyretin-type Cerebral Amyloid Angiopathy in Post-transplant Patients with Hereditary ATTR Amy-
loidosis: Correlates between Clinical Findings and Amyloid-PET Imaging
1,2,3 1,2
，Masahide Yazaki ，Kazuhiro Oguchi 3 ，Tsuneaki Yoshinaga 1 ，Shu-Ichi Ikeda 1

Yoshiki Sekijima
1:Department of Medicine (Neurology & Rheumatology), Shinshu University, Japan、2:Institute for Biomedical Sciences, Shinshu University、
3:Jisenkai Brain Imaging Research Center
Objective: Liver transplantation markedly improves survival in hereditary ATTR amyloidosis. However, the prolonged dis-
ease duration induces de novo central nervous system (CNS) amyloidosis, ATTR-type cerebral amyloid angiopathy (CAA),
as choroid plexus continues to produce variant transthyretin. We investigated the prevalence and clinical features of post-
transplant CNS symptoms in hereditary ATTR amyloidosis patients and their Pittsburgh compound B (PIB)-positron emission
tomography (PET) imaging correlates.
Methods: We monitored prevalence and type of CNS symptoms in 53 consecutive post-transplant patients with hereditary
11
ATTR amyloidosis. C-PIB-PET was performed in 14 patients with various disease durations. We also analyzed pathological
and biochemical characteristics of ATTR amyloid deposition in the brain of a post-transplant patient.
Results: Transient focal neurological episodes (TFNEs) attributed to ATTR-type CAA were found in 11.3% of post-
transplanted hereditary ATTR amyloidosis patients. TFNE occurred on average 16.8 years after onset of the disease. Patients
11 11
with longer duration of illness (> 10 years) showed increased C-PIB retention in the brain. The C-PIB accumulation
pattern in hereditary ATTR amyloidosis was unique and completely different from those in Alzheimer’s disease or Ab-type
CAA. In the autopsy case, ATTR amyloid deposition was mainly localized to leptomeningeal vessels and leptomeninges of
the brain. Amyloid fibrils in the brain were almost completely composed of variant TTR.
Interpretation: TFNE due to ATTR-type CAA occurred frequently in post-transplant patients with long disease durations.
11
C-PIB-PET is a useful diagnostic tool for ATTR-type CAA. ATTR amyloid deposition in the CNS, as measured by PIB-
PET, was detected approximately 10 years before onset of TFNE.
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ICHG2016 725

Thu., April 07, 2016 9:45-11:15 Room C-2 (1F)
Chair：Amal M. Alhashem（Pediatrics- Division of Medical Genetics, Prince Sultan Military Medical City, Saudi Arabia）
Chair ：Seiji Yamaguchi（Pediatrics, Shimane University School of Medicine, Japan）
Thu(5)-O49-1
Molecular genetic study of PKU patients from Russia with a view to their subsequent treatment with
BH4
Polina Gundorova 1 ，Anna A Stepanova 1 ，Alexander V Polyakov 1
1:Federal State Budgetary Institution Research Centre for Medical Genetics, Russia
Phenylketonuria - autosomal recessive disorder associated with the metabolism of phenylalanine (PA). Mutations in the
PAH gene lead to reduce in activity of phenylalanine hydroxylase (PAH) and causes phenylketonuria (PKU). Mutations in
genes which provide synthesis and metabolism of the PAH cofactor tetrahydrobiopterin (BH4) are the causes of hyperpheny-
lalaninemia (HPA). Currently, there is a prevalent practice of treatment of PKU and HPA patients with formulations of
tetrahydrobiopterin (BH4). It was suggested that these drugs are applicable not only in the treatment of HPA patients, but
also in PKU patients with mutations in PAH gene.

A total of 435 unrelated PKU and HPA patients from 13 regions of the Russian Federation were investigated.
DNA of the probands was analyzed for the presence of 19 common mutations in PAH gene by MLPA-method: R408W,
P281L, R261Q, R158Q, R252W, IVS4+5G>T, IVS10-1G>A, IVS12+1G>A, ex5del, L48S, A403V, Y414C, E280K, E390G,
R243Q, R243X, R261H, IVS2+5G>A, IVS2+5G>C. In some probands Sanger sequencing of PAH , PTS, QDPR genes was
conducted.
As a result of the analysis overall allelic frequencies of“hard” and “mild” mutations in different regions of the Russian
Federation were calculated, on average they accounted 64.8% and 13.3% respectively. The allelic frequency of the R408W
mutation in each region was determined, the sample average is 49.9%. BH4 responsive patients (3%) were identified, including
probands with two “mild” mutations in the PAH gene (8 pers.), as well as patients with a confirmed diagnosis of HPA and
mutations in PTS (4 pers.) and QDPR genes (1 pers.). We defined a group of patients who do not respond to BH4 treatment
(193 pers.). Among them there are 122 probands with genotype R408W/R408W, also we identified other non-responsive
genotypes.
For the groups of patients with unknown treatment effect (229 pers.) we developed tactics for further clinical and molecular
diagnostics.
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Thu(5)-O49-2
Molecular Characterisation of Hyperphenylalaninemia in Korea
Yong Hee Hong 1 ，Byong Hwa Rho 2 ，Dong Hwan Lee 3
1:Department of Pediatrics, Soonchunhyang University Bucheon Hospital, Korea, South、2:Department of Dermatology, Wootaeha’s Skin
Clinic、3:Department of Pediatrics, Soonchunhyang University Hospital
The occurrence of PKU varies among ethic and geographic regions, reaching approximately 1 in 15,000 newborns. Two
hundred eleven patients were diagnosed with hyperphenylalaninemia in Soonchunhyang University Hospital from 1994 to
2015 in Korea. Among them, 195 patients were confirmed to classic PKU (n=160), BH4 responsive PKU (n=28), benign
hyperphenylalaninemia (n=10), PTPS deficiency (n=11) and DHPR deficiency (n=1). Several mutations reoccurred with
high frequency including R243Q (18%), Y204S (12%), IVS4-1G>A (7.8%), Y356X A (7.8%), R241C (7.8%), A259T (6.1%),
T278L (6.5%) from 256 independent alleles. Although some common characteristics of allele frequency and distribution
were identified among oriental populations, several distinctive characteristics were revealed in Korean patients. Although the
R413P allele is the most prevalent form (30.5%) in Japanese, we detected it in only six alleles (2.3%). The A259T allele, which
has not yet been found in oriental populations, was frequently found in this study. We also observed that tetrahydrobiopterin
(BH4) responsiveness was associated with specific genotypes (R53H, R241C, R408Q and T278I), suggesting there are some
correlations between phenotype and genotype. 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency was associated with
genotypes (c.272A>G, c.347A>G, c.259C>T, c.616A>G, c.155A>G).

Thu(5)-O49-3
Treatment of biotin-responsive basal ganglia disease: Open comparative study between the combination
of biotin plus thiamine versus thiamine alone
Amal M Alhashem 1 ，Brahim Tabarki 1
1:Pediatrics, Prince Sultan Military Medical City, Saudi Arabia
Objective
To compare the combination of biotin plus thiamine to thiamine alone in treating patients with biotin-responsive basal ganglia
disease in an open-label prospective, comparative study.
Methods
Twenty patients with genetically proven biotin-responsive basal ganglia disease were enrolled, and received for at least 30
months a combination of biotin plus thiamine or thiamine alone. The outcome measures included duration of the crisis,
number of recurrence/admissions, the last neurological examination, the severity of dystonia using the Burke-Fahn-Marsden
Dystonia Rating Scale (BFMDRS), and the brain MRI findings during the crisis and after 30 months of follow-up.
Results
Ten children with a mean age of 6 years1/2 were recruited in the biotin plus thiamine group (group 1) and ten children (6
females and 4 males) with a mean age of 6 years and 2 months were recruited in the thiamine group (group 2). After 2 years
of follow-up treatment, 6 of 20 children achieved complete remission, 10 had minimal sequelae in the form of mild dystonia
and dysarthria (improvement of the BFMDRS, mean: 80%), and 4 had severe neurologic sequelae. All these 4 patients had
delayed diagnosis and management. Regarding outcome measures, both groups have a similar outcome regarding the number
of recurrences, the neurologic sequelae (mean BFMDS score between the groups, p = 0.84), and the brain MRI findings. The
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only difference was the duration of the acute crisis: group 1 had faster recovery (2 days), versus 3 days in group 2 (p = 0.005).
Conclusion
Our study suggests that over 30 months of treatment, the combination of biotin plus thiamine is not superior to thiamine
alone in the treatment of biotin-responsive basal ganglia disease.
Thu(5)-O49-4
Diversity of disease distribution and genetic background of inherited metabolic diuseases of organic and
fatty acids in Asian countries
Seiji Yamaguchi 1 ，Yuki Hasegawa 1 ，Naoaki Shibata 1 ，Hironori Kobayashi 1 ，Kenji Yamada 1 ，Ryosuke Bo 1 ，
Takeshi Taketani 1 ，Seiji Fukuda 1 ，Toshiyuki Fukao 2 ，Yanling Yang 3 ，Sunita Bijarnia 4 ，Iswar Verma 4 ，
Dung Vu Chi 5 ，Nahn Nguyen Thu 5
1:Pediatrics, Shimane University School of Medicine, Japan、2:Pediatrics, Gifu University Graduate School of Medicine、3:Pediatrics, Pekin
University 1st Hospital, China、4:Medical Genetics, Sir Ganga Ram Hospital、5:Pediatrics, National Hospital of Pediatrics Hanoi, Vietnam
We have performed the high risk screening for diagnosis of organic academia (OA) and fatty acid oxidation defect (FAOD),
using GC/MS and/or MS/MS as well as molecular investigation in collaboration with several Asian countries including China,
Vietnam, India and so on. We found diversity of disease distribution and genetic background among Asian countries.

Dried urine or blood filter papers from symptomatic patients for analysis of GC/MS (urinary organic acid) or MS/MS (blood
acylcarnitines), respectively, were used for transportation from Asian countries to Shimane University during the period
between 2000 and 2014. Liquid urine or serum samples were used for Japanese hospitals. Molecular studies were performed
using cultured cells or genomic DNA samples.
Diversity of disease distribution: In all countries, methylmalonic acidemia (MMA) was a most common disease. In Japan,
urea cycle disorder, and propionic academia (PPA) are followed. In Vietnam, 3-ketothiolase deficiency (BKTD) was most
common. Maple syrup urine disease, and oxoprolinemia are relatively common in Vietnam and India. In China, frequency of
MMA was significantly high, in particular combined MMA and homocystinuria (HCY).
Genetic diversity: 1) MMA: In China, 42% of MMA are combined type of MMA and HCY due to CblC defect, 609G>A in
MMACHC gene. 2) BKTD: in Vietnamese, c.662C>G in T2 gene is common, covering 72%. 3) PPA: In Japanese, Y435C
mutation in PCCB gene is common in the mild form of PPA, at prevalence of 1 in 86 alleles. 4) MCAD deficiency: common
mutation 985A>C among Caucasian is famous. Japanese specific common mutation, c.449delCTGA, covering about 45%,
was found. It is still unknown how about in the other Asian countries.
Newborn mass screening (NBS) is increasingly popular in Asian countries. The diversity of disease distribution and genetic
mutations will be made more clear with the spread of collaboration studies and expanded NBS using MS/MS.
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Thu(5)-O49-5
Molecular characterization of beta-ketothiolase deficiency in 9 Indians: Discovery of 3 novel mutations
in ACAT1 gene
1,2
Elsayed Abdelkreem ，Hideo Sasai 1 ，Hiroki Otsuka 1 ，Radha Rama Devi Akella 3 ，Usha Dave 4 ，Toshiyuki Fukao 1
1:Department of Pediatrics, Gifu University, Japan、2:Department of Pediatrics, Sohag University, Egypt、3:Department of Pediatric Neu-
rology and Metabolic Medicine, Rainbow Hospital for Women and Children, Hyderabad, India、4:MILS International, India
Beta-ketothiolase (T2) deficiency is an autosomal recessive metabolic disease caused by mutations in ACAT1 gene. This
disease affects isoleucine catabolism and ketone body utilization and characterized clinically by intermittent ketoacidotic
episodes.
We herein report 9 Indians with beta-ketothiolase deficiency. They were suspected based on their clinical presentations
(ketoacidotic episodes) and increased urinary isoleucine catabolic metabolites. Genomic DNA analysis revealed 6 different
mutations in ACAT1 gene; M193R, E85del, c.1124A>G, I323T, 1015-1016insAAAG, and IVS7+1g>a, in which the last 3
are novel ones. IVS7+1g>a mutation affects a critical point of the splice donor site of intron 7, thus aberrant splicing is the
usual consequence. Transient expression of mutant cDNAs was done at 37°C, followed by T2 enzyme assay, revealed that
1015-1016insAAAG mutation has no activity while I323T retains some.
The molecular analysis of ACAT1 gene in suspected T2 deficient cases not just confirms the diagnosis, leading to a better
prognosis in such cases, but also provides an efficient screening tool for detection of asymptomatic patients in other family

members before the development of any acute or chronic clinical manifestations.
Thu(5)-O49-6
Human thioredoxin-2 deficiency impairs mitochondrial redox homeostasis and causes early-onset neu-
rodegeneration
Eliska Holzerova 1,2 ，Katharina Danhauser 3 ，Tobias B. Haack 1,2 ，Laura S. Kremer 1,2 ，Irina Ingold 4 ，
Sho Kobayashi 4,5 ，Caterina Terrile 2 ，Ertan Mayatepek 3 ，Jose P. Friedmann Angeli 4 ，Marcus Conrad 4 ，
Tim M. Strom 1,2 ，Thomas Meitinger 1,2 ，Holger Prokisch 1,2 ，Felix Distelmaier 3
1:Institute of Human Genetics, Technische Universitaet Muenchen, Germany、2:Institute of Human Genetics, Helmholtz Zentrum Muenchen,
Germany、3:Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Heinrich-Heine-
University Duesseldorf, Germany、4:Institute of Developmental Genetics, Helmholtz Zentrum Muenchen, Germany、5:Division of Animal
Production, Specialty of Bioproduction Science, The United Graduate School of Agricultural Sciences, Iwate University, Morioka, Japan
Reactive oxygen species (ROS) are common by-products of cellular metabolism, whereby mitochondria are a major site for
H2O2 generation. In this context, tight regulation of mitochondrial H2O2 levels is critical for their ability to participate
in physiological cell signaling and to avoid nonspecific oxidative damage. Therefore, an efficient enzymatic machinery has
developed within the mitochondrial matrix. Key proteins involved in these processes are members of the thioredoxin and the
glutathione systems. The mitochondrial thioredoxin system is composed of thioredoxin-2 (TXN2), thioredoxin reductase 2,
peroxiredoxin-3 and -5. TXN2 is ubiquitously expressed with highest expression levels in brain. It is encoded by a nuclear gene,
TXN2, containing a mitochondrial targeting sequence. Moreover, TXN2 is involved in controlling the intrinsic-mitochondrial
apoptotic pathway. Animal studies suggest that TXN2 is essential for prenatal development since total absence of TXN2 in
a mouse knock-out model causes exencephaly and embryonic lethality.
In this study, we describe by using exome sequencing a 16-year-old adolescent suffering from early-onset neurodegeneration
and severe cerebellar atrophy, associated with a homozygous stop mutation in TXN2. TXN2 protein was not detectable in
patient fibroblasts, confirming the predicted loss of function. Cellular studies revealed increased ROS levels, impaired oxidative
stress defence and secondary mitochondrial dysfunction with reduced cellular respiration and diminished ATP production.
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Re-expression of TXN2 restored all these parameters confirming the causal role of the mutation. Supplementations with
antioxidants effectively suppressed cellular ROS production, and led to moderate clinical improvement during short-term
follow-up of the patient.
Our report highlights the importance of TXN2 for neurodevelopment. Moreover, our results underline the importance of
antioxidant treatment in affected patients.
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Thu., April 07, 2016 8:00-9:30 Sakura (1F)
Chair：Noah Zaitlen（Medicine, University of California San Francisco, USA）

Chair：Qihua Tan（Department of Public Health and Department of Clinical Research, University of Southern Denmark,
Denmark）
Thu(5)-O50-1
Gene Network: Accurate prediction of gene functions and prioritization of disease variants
Juha Karjalainen 1 ，Sipko van Dam 1 ，Niek de Klein 1 ，Patrick Deelen 1 ，Vinod Kumar 1 ，Lude Franke 1 ，
Cisca Wijmenga 1
1:Genetics, University Medical Center Groningen, Netherlands
Functions of most protein-coding genes have been described and regulatory functions have been attributed to a subset of
annotated lncRNAs. Yet, many pathway annotations are still incomplete and cell-type specific functions for most lncRNAs
are unknown. Many patients remain unsolved due to the challenge of pinpointing causal variants amongst hundreds of
candidates. We have developed a method to accurately predict functions of genes and prioritize variants for patients by using
a diverse set of 22,000 publicly available human RNA-seq samples.

Our method robustly matches protein-coding genes to biological processes and identifies potential regulator lncRNAs. We
recently found that SNPs associated with immune diseases control expression of lncRNAs that are involved in inflammatory
processes (submitted). We predicted the lncRNA AC104820.2 to function in T-cell proliferation and found it to be strongly
expressed in CD8+ T-cells. Moreover, we predict the lncRNA AP002954.4 to regulate cytokine responses and defense against
fungal infection. In agreement with this, the SNP controlling AP002954.4 was found to modulate cytokine levels in fungus-
stimulated human PBMCs.
Furthermore, we have developed a novel method to prioritize variants and genes for patients with severe disorders. The
method utilizes co-regulation information extracted from the large RNA-seq dataset and phenotype information associated
with either a disease or an individual patient. We prioritize the correct gene for several OMIM diseases based on their
phenotypes and we have pinpointed likely causal variants for two severely ill newborns.
We have created a user-friendly web tool for exploration of tissue-specific expression and predicted pathways, as well as
prioritization of candidate disease genes based on phenotypes and variants. The tool interactively visualises co-regulation
networks, allowing for readily identification of potential regulators for any biological process of interest.
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Thu(5)-O50-2
Joint whole-genome analysis of associations between host and hepatitis C virus diversity in a patient
cohort
Vincent Pedergnana 1 ，Azim M Ansari 2,3
，Paul Klenerman 2 ，Eleanor Barnes 2 ，Chris Spencer 1 ，
STOP-HCV Consortium
1:Wellcome Trust Center for Human Genetics, UK、2:Nuffield Department of Medicine, University of Oxford、3:Oxford Martin School,
University of Oxford
Joint analysis of both human and viral genomes in the context of infection can inform on underlying molecular interactions
and can be used to help patients and doctors make better decisions about treatment. The hepatitis C virus has a highly
diverse RNA genome and thus is difficult to sequence. As part of the STOP-HCV consortium (www.stop-hcv.ox.ac.uk) we
used a new, efficient, high-throughput method for sequence-specific enrichment and characterization of whole virus genomes
capable of unbiased detection of virus variants to sequence the virus of 560 chronically infected patients. In parallel, we
also genotyped over 800,000 SNPs in the patients’ genome, using the Affymetrix UK Biobank array, and used statistical
imputation to obtain data at over 10 million SNPs as well as classical HLA alleles. Perhaps for the first time, paired human
genotyping data and novel whole-genome viral sequencing data allows a systematic study of the relationship between hepatitis
C virus diversity and host genomics.

We develop and apply a new statistical method to look for evidence that host genetics is associated with viral sequence
motifs (so-called footprints) in patients infected with hepatitis C. Using an analysis adjusted for viral and human population
structure, we inferred footprints of host immune pressures on the pathogen, including a strong signal of association at a
previous described HLA-A footprint in the NS3 viral protein (P < 10-13 ). Interestingly, whole-genome-to-genome analysis
also confirmed that other viral sites are associated with human genetic variations outside of the HLA locus. In particular,
one of these viral sites is also associated with viral load. Together these new approaches allow a joint assessment of clinically
relevant genetic markers in both patient and pathogen, information that is going to be potentially readily available for
clinicians in the new era of stratified medicine.
Thu(5)-O50-3
Powerful and efficient association testing in cohorts with large phenotypic collections
Noah Zaitlen 1 ，Hugues Aschard 2 ，Joel Mefford 1 ，John Witte 1 ，Peter Kraft 2
1:Medicine, UCSF, USA、2:Genetic Epidemiology, HSPH.
Variability in complex human traits is associated with many factors, including exposures, biomarkers and genetic variants.
Identifying the genetic variants that are causally associated with human phenotypes among the tens of millions of variants
that are typically tested remains a challenge. Current strategies to improve power to identify modest genetic effects mostly
consist of applying univariate statistical approaches such as linear or logistic regression (LR) and increasing study sample
sizes. While successful, these approaches do not leverage the environmental and genetic factors shared between the tens
or hundreds of clinical phenotypes typically collected in contemporary cohorts. Here we develop two methods that improve
identification of small effects in studies where a large number of correlated variables have been measured on the same samples.
First we derive a data-driven approach that leverages our previous work (Zaitlen et al PG 2012, Aschard et al AJHG 2015)
to inteligently select covariates that will increase power for each SNP-phenotype pair considered. Simulations provide direct
support that out method can achieve dramatic increases in statistical power equivalent to a two or even three or four fold
increase in sample size. Next we derive an extension to Linear Mixed Model methods (LMMs) allowing them to run efficiently
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even when hundreds of phenotypes are considered, while current LMMs methods lose efficiency after ten phenotypes. To
demonstrate the power of our approach in real data, we performed a genome-wide screen for cis expression QTLs in the
GEUVADIS cohort. We examined the expression of 12,167 genes in 375 individuals of European descent. At a stringent FDR
of 0.1% standard LR identified 1,660 genes with at least one cis-eQTL while our approach identified 2,154 genes, and increase
of 30%. As more cohorts move toward large-scale phenotypes collections, MC will improve the ability of the community to
identify associated genetic variants.
Thu(5)-O50-4
Metabolic and transciptomic associations of change in body fat percentage.Metabolic and transciptomic
associations of change in body fat percentage
Annika Wennerstrom 1,2 ，Maria Hagnes 3 ，Jari Jokelainen 3,4
，Pekka Jousilahti 1 ，Johannes Kettunen 3 ，
Markus Perola 1,2 ，Sirkka Keinanen-Kiukaanniemi 3,4
1:THL, Finland、2:University of Helsinki, The Institute for Molecular Medicine Finland (FIMM), Biomedicum Helsinki, Finland, Nordic
EMBL Partnership for Molecular Medicine、3:Center for Life Course Health Research, Oulu Finland、4:MRC and Unit of Primary Health
Care, Oulu Univeristy Hospital, Oulu Finland
The overall objective of this study was to characterize the effects of systematized exercise and lifestyle intervention on
metabolism and gene expression activity. We aimed to investigate the associations between changes in the metabolome and
the body mass composition among young men going through their military service period.

We determined the NMR metabolome (~ 200 metabolites), anthropometric and body composition measurements and aerobic
performance before the start of military service and at the end of the service (n=718). The DILGOM cohort (NMR data in
two different time points, year 2007 and 2014;n= 1273, gene expression data; n=518) representing the Finnish population,
was utilized as a control material for the metabolic associations with change in bodyfat% and to study the associations of
bodyfat% on whole blood gene expression.
Here, we analyzed the relation between changes in bodyfat% and metabolic biomarkers as a longitudinal study examining
changes over two time periods taking into consideration physiological measures. We found the change in bodyfat% adjusted
by Cooper’s test result, smoking, length of service and BMI was associated with 73 lipid measures and amino-acids in the
army cohort. The most significant association being with free cholesterol in large HDL (p=2x10-14 ) in the army cohort
and replicated in DILGOM (men only p=9x10-18 , both women and men: p=2.13x10-20 ). 55 of the metabolic associations
were replicated. Increased bodyfat% was also associated with the increase in systemic inflammation (GlycA: army recruits;
p=0.00019, DILGOM; p=9.65x10-14 ). The gene expression analysis showed that the bodyfat% associated cross sectionally
(p< 4x10-9 ) with two genes OLR1 , previously associated with atherosclerosis and risk of myocardial infarction, and LTF (e.g.
anti-inflammatory activity). To conclude, the increase in the bodyfat% alters the metabolic profile towards cardiovascular
risk and increases systemic inflammation.
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Thu(5)-O50-5
Gene by environment interaction in human longevity as observed in Danish birth cohorts from 1895 to
1915
Qihua Tan 1 ，Rune Lindahl-Jacobsen 1 ，Marianne Nygaard 1 ，Lene Christiansen 1 ，Kaare Christensen 1
1:EBB, Dept of Public Health, University of Southern Denmark, Denmark
The frequencies of variants of major candidate genes (APOE and FOXO3A) have been shown to vary in long-lived individuals
of different Danish birth cohorts (Nygaard et al. 2014), e.g. with significantly decreased frequencies in the recent birth cohorts
for the e4e4 genotype and also for the minor allele of rs776239 of FOXO3A gene. The study collected genotype and survival
information on 5 birth cohorts, 1895 (132 subjects), 1905 (1424 subjects), 1910 (176 subjects), 1911 (130 subjects) and 1915
(1105 subjects) with a total of 2712 subjects aged over about 95 years at in-take. Since genotype frequency in a population
cannot be expected to change over a very short period of 10 (1905 to 1915) to 20 (1895 to 1915) years, we assume that
the reported change in genotype frequencies in the long-lived subjects could reflect cohort-specific genetic risk on longevity
resulted from gene-environment interaction. Based on the same observations and recently updated mortality information in
the 5 birth cohorts, we conduct a survival analysis on all 2712 subjects by introducing cohort-specific population survival from
population statistics and specifying and estimating linear and nonlinear patterns for the risk of gene by cohort interaction.
Our novel analysis provides statistically significant evidence to the varying genetic risk on human longevity due to interaction
with changing environmental condition by major candidate genes.

Thu(5)-O50-6
A linear algebraic method for evaluating the relation between power and the pattern of linkage disequi-
librium in multiple testing
Tapati Basak 1 ，Ryo Yamada 1
1:Statistical Genetics, Unit of Statistical Genetics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Abstract: Multiple testing is fundamental issue in genetic epidemiology. It is useful only when studies have adequate statistical
power. Since, the density of potentially affecting markers as well as Linkage Disequilibrium (LD) pattern in each gene varies
significantly. So, multiple marker tests for a set of categorical phenotype by considering LD structure can improve the power
of testing. Most proposed LD tests are constructed for single marker. So, the power of a single marker association test suffers
because LD information contained in neighboring markers is ignored. On the other hand, haplotypes which is a collection of
ordered markers is more powerful than individual and unorganized markers. We propose a Spherization based linear algebraic
method which handles multiple marker tests in the context of geometric statistics. Our method defines multiple tests in a
higher dimensional space. Finally, we investigate the relation between power and the pattern of LD.
Keywords: Multiple testing; Spherization; Power; Linkage Disequilibrium
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Thu., April 07, 2016 9:45-11:15 Sakura (1F)
Chair：Jonathan Marchini（Department of Statistics, University of Oxford, UK）

Chair ：Atsuko Imai（Department of Cardiovascular Medicine / Genome Informatics, Osaka University Graduate School
Thu(5)-O51-1
A genome wide association study of pathological inflammatory responses in leprosy
Vinicius M Fava 1,2 ，Aurelie Cobat 3,4 ，Jeremy Manry 1,2 ，Marianna Orlova 1,2 ，Nguyen Van Thuc 5 ，Milton O Moraes 6 ，
Mariane M.A Stefani 7 ，Ana Carla P Latini 8 ，Andrea Belone 8 ，Nguyen Ngoc Ba 5 ，Vu Hong Thai 5 ，Laurent Abel 4,5,9 ，
Alexandre Alcais 4,5,9 ，Erwin Schurr 1,2
1:Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Canada、2:The
McGill International TB Centre, Departments of Human Genetics and Medicine, McGill University、3:Laboratory of Human Genetics of
Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163、4:University Paris Descartes, Imagine
Institute, Paris, France、5:Hospital for Dermato-Venerology、6:Laboratório de Hanseníase, Instituto Oswaldo Cruz, FIOCRUZ、7:Tropical
Pathology and Public Health Institute, Federal University of Goiás, Goiânia、8:Lauro de Souza Lima Institute、9:St Giles Laboratory of
Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University
Background: Leprosy is a chronic dermato-neurological infectious disease caused by Mycobacterium leprae. Among commu-
nicable diseases, leprosy is a leading cause of permanent disabilities mainly due to pathological inflammatory responses coined
Type-1 Reactions (T1R). Clinical and environmental factors have been associated with T1R susceptibility; however, studies

of the host genetic contribution to T1R outcome are scarce. Here we evaluated the association of host genetic factors with
T1R using a genome wide association approach (GWAS).
Methods: A GWAS scan followed by imputation resulted in approximate 6 million genetic variant to be tested for association
with T1R. Evidence of association was evaluated in two Vietnamese family-based samples: A set of T1R-affected and a second
set of T1R-free families. Only SNPs significant for T1R-affected families with significant evidence of heterogeneity relative to
T1R-free families were considered T1R-specific. T1R-specific loci with P < 1.0 e-6 in the GWAS were selected for a stepwise
replication in independent population samples from Vietnam and Brazil.
Results: A total of 1490 subjects were used for the GWAS while 1880 samples were used for the replication phase. In the
T1R GWAS, a suggestive signal was observed in chromosome10p21 (P min = 8.2 e-7 ). SNPs representing seven SNP bins in
2
linkage disequilibrium (r < 0.8) were selected for further analyses. Two T1R risk SNP bins in chromosome region 10p21
were replicated in two independent case-control samples from Vietnam and Brazil (P < 0.01 for both). A pooled analysis
resulted in a strong association with T1R (P min = 1.4 e-8 ; OR = 1.54, 95% CI = 1.33 - 1.79). The region associated with
T1R is located between two recombination hot spots where a single lncRNA gene was located.
Conclusion: Our findings denote the first hypothesis free approach in the study of excessive inflammatory responses in leprosy.
We identified a regulatory gene as a potential mediator in T1R pathogenesis.
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Thu(5)-O51-2
Empirical estimation of genome-wide significance thresholds based on the 1000 Genomes Project dataset
Masahiro Kanai 1 ，Toshihiro Tanaka 1,2
，Yukinori Okada 1,3
1:Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental
University, Japan、2:Bioresource Research Center, Tokyo Medical and Dental University、3:Laboratory for Statistical Analysis, RIKEN
Genome-wide association studies (GWAS) have successfully identified thousands of loci associated with human diseases and
traits. To assess the statistical significance of associations between tested variants and traits, GWAS should employ an
appropriate threshold that accounts for the massive burden of multiple testing in the study. In the current literature, most
studies commonly set a genome-wide significance threshold at the level of P = 5.0 × 10−8 , which is equivalent to the
Bonferroni-corrected threshold (α = 0.05) for 1 million independent variants. However, the variants tested in a study are
inevitably dependent on many population-specific factors, such as linkage disequilibrium pattern and minor allele frequency,
suggesting that the appropriate threshold for genome-wide significance might vary for different populations. We report here
empirical estimation of genome-wide significance thresholds for different ancestral populations based on GWAS simulations,
using the 1000 Genomes Phase 3 dataset with five ancestral populations: Africans (AFR; n = 661), Europeans (EUR;
n = 503), Admixed Americans (AMR; n = 347), East Asians (EAS; n = 504), and South Asians (SAS; n = 489). The
resulting estimated empirical genome-wide significance thresholds were P sig = 3.24 × 10−8 (AFR), 9.26 × 10−8 (EUR), 1.83
× 10−7 (AMR), 1.61 × 10−7 (EAS), and 9.46 × 10−8 (SAS). We additionally conducted trans-ethnic meta-analyses across all
ancestral populations (ALL) and all ancestral populations except for AFR (δ AFR), which yielded the following: P sig = 3.25

× 10−8 (ALL) and 4.07 × 10−8 (δ AFR). Our results indicate that the currently and widely used genome-wide significance
threshold (P = 5.0 × 10−8 ) is overly stringent for all ancestral populations except for Africans; however we should employ a
more stringent threshold when conducting a meta-analysis, regardless of the presence of African samples.
Thu(5)-O51-3
Family-Control analysis based on Hamming distance for prioritizing candidate pathogenic variants
Atsuko Imai 1,2 ，Akihiro Nakaya 1 ，Somayyeh Fahiminiya 3 ，Martine Tetreault 3 ，Jacek Majewski 3 ，Yasushi Sakata 2 ，
Seiji Takashima 2,4 ，Mark Lathrop 3 ，Jurg Ott 5,6
1:Department of Genome Informatics, Osaka University Graduate School of Medicine, Japan、2:Department of Cardiovascular Medicine,
Osaka University Graduate School of Medicine、3:McGill University and Genome Quebec Innovation Centre、4:Department of Medical
Biochemistry, Osaka University Graduate School of Medicine、5:Institute of Psychology, Chinese Academy of Sciences、6:Laboratory of
Statistical Genetics, Rockefeller University
[Purpose]A major challenge in current exome sequencing in autosomal recessive (AR) families is the lack of an effective method
to prioritize potentially pathogenic single-nucleotide variants (SNVs). AR families are generally too small for linkage analysis,
and length of homozygous regions is unreliable for identification of causative variants. Various common filtering steps usually
result in a list of candidate variants that cannot be narrowed down further or ranked.
[Methods]To prioritize shortlisted SNVs we consider each homozygous candidate variant, and homozygous SNVs within a
distance d of it, varying d from 100kb to 1000kb. We compare resulting arrays of genotypes between an affected family
member and each of a number of control individuals and argue that, in a family, differences between family member and
controls should be larger for a pathogenic variant and SNVs flanking it than for a random variant. We assess differences
between arrays in two individuals by the Hamming distance (the number of genotypes differing between two individuals) and
develop a suitable test statistic, maximized over d, which is expected to be large for a causative variant and flanking SNVs.
[Results]We prioritize candidate variants based on this statistic and applied our approach to six patients with known pathogenic
homozygous variants and found these to be in the top 2 to 10 percentiles of ranks. We plan to extend this approach to
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autosomal dominant and other modes of inheritance.
[Conclusion]In conclusion, we developed a novel statistical method; Family-Control analysis using Hamming Distance, to
prioritize SNVs in small AR families and, thus, to localize pathogenic variants underlying AR traits.
Thu(5)-O51-4
Significant impact of miRNA-target gene networks on genetics of human complex traits
Masahiro Kanai 1 ，Yukinori Okada 1,2 ，Tomoki Muramatsu 3 ，Naomasa Suita 1,4 ，Eiryo Kawakami 5 ，
Valentina Iotchkova 6,7 ，Nicole Soranzo 6,7 ，Johji Inazawa 3,8 ，Toshihiro Tanaka 1,8,9
1:Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University, Japan、2:Laboratory for Statistical
Analysis, RIKEN Center for Integrative Medical Sciences、3:Department of Molecular Cytogenetics, Tokyo Medical and Dental University、
4:Advanced Medicinal Research Laboratories, Ono Pharmaceutical CO., LTD.、5:Laboratory for Disease Systems Modeling, RIKEN
Center for Integrative Medical Sciences、6:Human Genetics, Wellcome Trust Sanger Institute、7:Department of Haematology, University
of Cambridge、8:Bioresource Research Center, Tokyo Medical and Dental University、9:Laboratory for Cardiovascular Diseases, RIKEN
MicroRNA (miRNA), a short endogenous noncoding RNA, plays major roles in a variety of biological processes. However,
the impact of miRNA on the genetics of human complex traits, particularly in the context of miRNA-target gene networks,
has not been fully assessed. Here, we developed a novel analytical method, MIGWAS, to comprehensively evaluate the

enrichment of genome-wide association study (GWAS) signals in miRNA-target gene networks. We obtained GWAS results
of the 18 human complex traits from a total of > 1.75 million subjects and evaluated the relative enrichment of the association
signals between miRNAs and target genes as predicted by multiple public miRNA databases (miRDB, miRmap, PITA, and
TargetScan). Of the 18 evaluated traits, rheumatoid arthritis (RA), estimated glomerular filtration rate (eGFR), and adult
height exhibited significant enrichment of the association signals in miRNA-target gene networks (P < 0.05/18 = 0.0028, most
significant enrichment in RA with P = 1.7 × 10-4 ). These results were consistent with current literature-based knowledge of
the traits on miRNA obtained through the NCBI PubMed database search (adjusted P = 0.024). Our method provided a
list of miRNA and target gene pairs with excess genetic association signals, part of which included drug target genes. Our
study clearly indicated the significant impact of miRNA-target gene networks on the genetics of human complex traits, and
provided resources which should contribute to drug discovery and nucleic acid medicine.
Thu(5)-O51-5
Tensor decomposition uncovers trans eQTL networks in the multi-tissue EuroBATS study
Jonathan Marchini 1 ，Victoria Hore 1 ，Ana Vinuela 2,3
，Alfonso Buil 4 ，Mark McCarthy 2,5
，Kerrin Small 3
1:Department of Statistics, University of Oxford, UK、2:Wellcome Trust Center of Human Genetics, University of Oxford、3:Department of
Twin Research and Genetic Epidemiology, King’s College London, UK、4:Department of Genetic Medicine and Development, University of
Geneva, Switzerland、5:Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK
Uncovering trans eQTL networks in gene expression studies of multiple tissues is challenging. To tackle this problem, we
have developed a general framework for decomposing 3D tensors of multi-tissue gene expression datasets into sparse latent
factors, where latent factors consist of networks of co-varying genes and determine active tissue subsets. We fit our model
using variational Bayes, which allows fast inference and handles missing data. We then use the individual scores vector of each
factor as a phenotype in a GWAS to identify genetic variants that drive the gene network associated with that component.
This approach is analogous to the use of PCA to find biologically meaningful structure in genetic variation datasets, but is
more general, and can be used to integrate datasets from different -omics technologies.
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We have applied our method to data from the EuroBATS project which consists of RNA sequencing on 845 related individuals
in adipose, skin and LCLs. Our method uncovers many sparse components that exhibit strong statistical and biological
significance (a) a KLF14 mediated network of gene expression in adipose tissue, (b) we link transactivators CIITA and RFX5
with genes in the MHC class II (p<1e-10 ), (c) we link the transactivator NLRC5 /CITA with genes in the MHC class I, (d)
we find a component with gene loadings at LSM11 and several histone gene clusters together with a cis eQTL in the region
of the LSM11 which is known to be involved in histone RNA processing, (e) we uncover a link between genetic variation in
the SENP7 gene on chr3 (p<1e-10 ) and a cluster of zinc finger genes on chromosome 19, (f) we identify UPS18 as a regulator
of a network of genes enriched for annotation of ’response to type I interferon’ (p<1e-41). We also find dense components
that correlate strongly (p<1e-20 ) with confounding variables such as insert size, GC content and date of the sequencing.
Thu(5)-O51-6
Estimating the shared genetic basis of complex phenotypes between populations from summary statistics
gives evidence for widespread non-additive and rare variant effects
Brielin C Brown 1 ，Alkes Price 3,4
，Noah Zaitlen 2
1:Department of Computer Science, University of California Berkeley, USA、2:Department of Medicine, Lung Biology Center, UC San
Francisco、3:Deparment of Epidemiology, Harvard School of Public Health、4:Deparment of Biostatistics, Harvard School of Public Health
Many phenotypes vary in their global distributions, but the mechanisms driving these changes are largely unknown. Still,

multiethnic disease studies are common and therefore expanding the concept of genetic correlation to multiple populations is
important. Transethnic allele frequency (AF) differences invalidate the standard definition: the correlation of AF-normalized
effect sizes. This motivates two extensions: the correlation of per-allele effects (ρgp ) and the correlation of population-AF
normalized effects (ρgn ). These quantities capture two important questions about transethnic phenotypes: how do the same
mutations differ in their phenotypic effects, and how are these differences affected by changes in AF? There are many reasons
that ρgp,n may be less than one: unobserved rare variants linked to observed SNPs, gene interactions with marginal effects
modified by differences in AF, gene-environment interactions, and differences in sub-phenotype. We show that the Z-scores
are multivariate normal as a function of the heritabilities (h1 2 , h2 2 ), ρgp,n and reference LD and use approximate maximum
likelihood to fit the model in linear time. We show via simulation that our method produces unbiased estimates and is robust
to model violations. We apply our method to European and Southeast Asian RA and T2D data, as well as European and
Yoruban gene expression data from gEUVADIS. We find ρgp in RA and T2D to be 0.49 (0.06) and 0.62 (0.08), respectively,
while ρgn is 0.47 (0.06) and 0.60 (0.08). Our gEUVADIS analysis reveals that the mean ρgp across all genes is only 0.34 (0.01),
but increases substantially when h2 is nontrivial in both populations: mean ρge =0.75 (0.01) when h1 2 and h2 2 are above
0.2. Our results show that global differences in SNP effect size of complex traits can be large and are strongly impacted by
non-additive and rare effects. In contrast, effects sizes of gene expression appear to be more conserved where it is strongly
genetically regulated.
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[O52] Evolutionary and Population Genetics 1

Thu., April 07, 2016 8:00-9:30 Room I (2F)
Chair：Arbel Harpak（Department of Biology, Stanford University, USA）

Chair ：Yoko Satta（Department of Evolutionary Studies of Biosystems, SOKENDAI (The Graduate University for
Advanced Studies), Japan）
Thu(5)-O52-1
Large effects of mutation rate variation and epistasis on the distribution of allele frequencies in humans
Arbel Harpak 1 ，Anand Bhaskar 2 ，Jonathan Pritchard 1,2,3
1:Biology, Stanford University, USA、2:Genetics, Stanford University、3:Howard Hughes Medical Institute, Stanford University
Large-sample human exome sequencing efforts give us an unprecedented opportunity to examine in detail how mutation and
natural selection have acted to shape human variation in recent millennia. Here, we ask how inter-species substitution patterns
can inform our expectations for intra-species evolution. We approach this question by overlaying human polymorphism data
from over 60,000 people together with primate divergence data. We find that human mutations that occurred independently
on the lineage of another primate segregate at significantly higher frequencies in humans than do mutations that are otherwise
conserved in primates, shifting the respective site frequency spectrum (SFS) toward common variants. Furthermore, the more
closely related to humans the species in which the substitution occurs is, the more pronounced is the shift towards common

variants. Surprisingly, this trend is largely driven by mutation rate variation, which had negligible effect on the SFS in
previous, smaller sample sizes. Notably, we find that even small differences in mutation rates carry considerable effects on
the human SFS in large samples, presenting a caveat to the widely used infinite-sites model for recent human evolution. Our
analysis also suggests this trend is partly driven by epistatic effects - mutations that were fixed in a genomic context that is
more similar to the human context are more likely to be benign for humans. We therefore hypothesize epistasis may have an
important role in determining the deleteriousness of human variants.
Thu(5)-O52-2
Whole-genome reference panel of Tohoku Medical Megabank Organization (ToMMo) and allele fre-
quency of pathological variants
Yumi Yamaguchi-Kabata 1 ，Yosuke Kawai 1 ，Kaname Kojima 1 ，Naoki Nariai 1,2 ，Yukuto Sato 1 ，Takahiro Mimori 1 ，
Fumiki Katsuoka 1 ，Jun Yasuda 1 ，Masayuki Yamamoto 1 ，Masao Nagasaki 1
1:Tohoku University, Japan、2:University of California
Although reports of common genomic variants and their frequencies are accumulating for various populations, many of
low-frequency variants remain undetected or have unknown frequencies. A catalogue of genomic variants from whole-
genome sequencing and estimates of variant frequencies for each population are needed to provide a foundation for ge-
nomic medicine. Tohoku University Tohoku Medical Megabank Organization (ToMMo) have sequenced whole genomes of
1,070 cohort participants, and constructed the whole-genome reference panel (1KJPN). We started partial public release of
whole-genome Japanese reference panel, and opened a website “integrative Japanese Genome Variation Database (iJGVD;
http://ijgvd.megabank.tohoku.ac.jp/)”. The current release of iJGVD provides SNV frequency data obtained from the 1070
individuals. We are annotating variants of 1KJPN with biological and medical information, and identified 4,368 pathologi-
cal SNVs by corresponding to the known pathological variants recorded in the Human Gene Mutation Database (HGMD).
These pathological variants included 1,002 variants categorized as disease-causing (DM) variants. Individual variant load for
disease-causing variants was calculated for each derived allele frequency. The estimates are very similar with those in East

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Asian populations (Japanese in Tokyo, Han in Beijing, and Han Chinese South) in the 1000 Genomes Project (1KGP). The
allele frequencies of the pathological variants in 1KJPN were compared with those in each of 14 populations of 1KGP. As a
result, 2,638 HGMD variants showed significantly different allele frequency (P value<10−5 ; Fisher’s exact test) in comparison
to at least one population of the 1KGP. In fact, incidence rates for inherited diseases vary among populations, and frequency
difference in the pathological variants between populations may partially explain the difference in the disease incidence.
Thu(5)-O52-3
Touching the limits of being alive: the distribution of genome-wide CNV loads in healthy human cohort
is right truncated due to ongoing purifying selection
Konstantin Popadin 1 ，Katrin Mannik 1 ，Aurelien Mace 2 ，Margit Noukas 3,4 ，Evelin Mihhailov 3,4 ，Olga Vakhrusheva 5 ，
Marco Garieri 6 ，Georgii Bazykin 5 ，Andres Metspalu 3,4 ，Zoltan Kutalik 2 ，Alexandre Reymond 1
1:Center for Integrative Genomics, University of Lausanne, Switzerland、2:Department of Medical Genetics, Faculty of Biology and Medicine,
University of Lausanne, Switzerland、3:Estonian Genome Center, University of Tartu, Estonia、4:Institute of Molecular and Cell Biology,
University of Tartu, Estonia、5:Institute for Information Transmission Problems (Kharkevich Institute), Russia、6:University of Geneva
Medical School, University of Geneva, Switzerland
The majority of methods predicting deleterious impact of genetic variants on fitness analyze the effect of each mutation
independently. Here we elaborate upon a new approach based on the distribution of the number of deleterious variants per
individual genome, in our case the Copy Number Variant (CNV) load. If CNVs affect fitness independently of each other the

CNV load per genome will be distributed according to Poisson. However if CNVs interact under negative epistasis, resulting
in a greater-than-additive fitness drops, we expect selection to eliminate carriers of too high CNV load leading to right
truncated distribution. We assessed this hypothesis using a set of potentially deleterious CNVs (carrier frequency < 0.01;
length > 0.35 Mb; disrupting at least one gene) called from genotyping arrays of apparently healthy unrelated individuals
from the Estonian biobank. Firstly, analyzing 3953 individuals we found only 11 carriers of two or more CNVs as compared
to 16 carriers expected under Poisson distribution (3596 individuals carry zero CNVs and 346 carry one CNV). Secondly,
bearing in mind the ’female protective model’ proposing that females are more tolerant towards the deleterious variants load,
we performed gender-specific analyses. We observed that the number of carriers of two or more CNVs is significantly lower
in males versus females (average difference is 3, p<1E-12, 50% jackknife resampling of matched datasets) suggesting that the
CNV interaction is under a greater negative epistatic mode in males than in females, potentially explaining the decreased
tolerance of males to deleterious variants load. Thirdly, analyzing CNV loads, estimated for CNVs of different ploidy, length,
location and frequency we uncover predominant modes of interaction within and between different classes of CNVs. Altogether
we conclude that this genome-wide approach highlights properties of ongoing purifying selection against deleterious variants
in human population.
Thu(5)-O52-4
Health and population effects of rare gene knockouts in adult humans with related parents
Vagheesh M Narasimhan 1 ，Konrad J Karczewski 2 ，John Wright 3 ，Karen A Hunt 4 ，Daniel G MacArthur 2 ，
Yali Xue 1 ，Shane McCarthy 1 ，Richard Trembath 4 ，Chris Tyler-Smith 1 ，Eamonn R Maher 5 ，Richard Durbin 1 ，
David A van Heel 4
1:Wellcome Trust Sanger Institute, UK、2:Massachusetts General Hospital, Boston, USA、3:Bradford Institute for Health Research、4:Queen
Mary University of London、5:University of Cambridge
Complete gene knockouts are highly informative about gene function. We exome sequenced 3,222 British Pakistani-heritage
adults with high parental relatedness, discovering 1,111 rare-variant homozygous likely loss of function (rhLOF) genotypes
predicted to disrupt (knockout) 781 genes, a discovery rate far higher than in outbred or isolate populations. Based on
depletion of rhLOF genotypes, we estimate that 13.6% of knockouts are incompatible with adult life, and find 1.6 heterozygous
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recessive lethal LOF variants per adult. Linking to comprehensive electronic health records, we observed no effect of rhLOF
genotypes on prescription or doctor-consultation rate, and no disease-related phenotypes in 33 of 42 individuals with rhLOF
genotypes in genes previously associated with recessive Mendelian diseases. Using phased whole genome sequencing of a
healthy PRDM9 knockout mother, her child and controls, we show atypical meiotic recombination sites away from PRDM9
hotspots, demonstrating PRDM9 redundancy in humans.
Thu(5)-O52-5
Spread of reduced activity of STX promoter in modern humans
Naoko T. Fujito 1 ，Yoko Satta 1 ，Masaya Hane 2 ，Atsushi Matsui 3 ，Ken Kitajima 2 ，Chihiro Sato 2 ，
Toshiyuki Hayakawa 4
1:School of Advanced Sciences, SOKENDAI (The Graduate University for Advanced Studies), Japan、2:Bioscience and Biotechnology
Center, Nagoya University、3:Primate Research Institute, Kyoto University、4:The Graduate School of Systems Life Sciences, Kyushu
University
STX is an enzyme responsible for the transfer of polysialic acids (PSA) to a neural cell adhesion molecule (NCAM). The
abnormality in the amount of PSA on NCAM is observed in patients of schizophrenia and bipolar disorder. Variants of
the STX gene are also associated with various mental disorders, such as schizophrenia, bipolar disorder, mood disorder and
autism. Thus STX is supposed to play an important role in higher brain function of humans. Three SNP sites (core SNPs)
in the STX promoter region are known to cause alterations in the promoter activity and might be associated with mental

disorders. Based on the combination of core SNPs, we classified the haplotypes of STX promoter region as promoter types,
and found four promoter types, i.e., "CGC", "TGT", "TCT" and "CGT", in humans by determining haplotype sequences from
genomic DNA of 63 individuals from a wide range of ethnic groups. The phylogenetic study revealed that all the promoter
types emerged about 0.6 MYA and each type emerged 0.1 ~ 0.2 MYA, which is coincidentally prior to the African exodus.
Further analysis using haplotype sequences from the SNP data of the 1000 genome project (2504 individuals) reveals that
each of "CGC", non-African "TGT", and one subtype of the "TCT" ("TCT1") shows the quite high homozygosity in the ~ 18
kb region surrounding the core SNPs, suggesting a possible signature of natural selection. Interestingly, the boundaries of this
high homozygosity region are very sharp and shared among the three promoter types. Frequency of three promoter types are
summed up to ~ 80% of each non-African population and to ~ 30% of each African populations. Moreover, the result of the
promoter assay indicated that the "CGC" and "TCT1" have significantly lower promoter activity than an ancestral "African
TGT". Although it is necessary to examine the promoter activity of the "non-African TGT", it raises a possibility that some
global selection for lower promoter activity of the STX gene is ongoing.
Thu(5)-O52-6
Evolution of the ‘fused’ gene family across primates
Hirofumi Nakaoka 1 ，Vanessa Romero 1 ，Ituro Inoue 1 ，Kazuyoshi Hosomichi 1
1:National Institute of Genetics - Japan, Ecuador
The Epidermal Differentiation Complex (EDC) on chromosome 1 is a dense cluster of genes expressed during the late differ-
entiation of the epidermis and is responsible for maintaining hydration and structure of the skin. The cluster organization
of this complex might suggest adaptation during evolution and is strongly associated with a variety of skin disorders. EDC
includes the CE precursor family, S100A family and the ‘fused’ gene family. The ‘fused’ genes members are: cornulin,
filaggrin, filaggrin-2, hornerin, repetin and trichohyalin. These genes have a similar organization showing an initial S100
domain followed by a tandem repeat region and a C-terminal domain. In this study, we focus on the repeat region of each
gene and the evolution pathway among primates with short divergence time to fully understand any recent repeat variation.
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We demonstrated that each member of the ‘fused’ genes undergo different selective pressure, which suggests a complex model
for the adaptive evolution of the EDC. Our results showed that the filaggrin repeat regions within these specific genes have
the highest nucleotide diversity between them. The phylogenetic analyses across primates suggest that recent independent
duplication events created the repeat sequences of filaggrin in macaque and orangutan, and trichohyalin in marmoset, which
are the only ones with phenotype variation related to copy number variation. The comparisons of the repeat sequences
detected the signatures of positive selections on filaggrin, filaggrin2, hornerin and repetin within a species and specific codons
and branches across species. We suggest that repeat variation across species may be a consequence of non-random events
accompanied by species-specific adaptive traits.
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[O53] Evolutionary and Population Genetics 2

Thu., April 07, 2016 9:45-11:15 Room I (2F)
Chair：Anders Eriksson（Biological and Environmental Sciences & Engineering Division, King Abdullah University of
Science and Technology, Saudi Arabia）
Chair：Jong Bhak（Biomedical Engineering, UNIST (Ulsan National Institute of Science and Technology), Korea, South）
Thu(5)-O53-1
HUGO-Pan Asian Population Genomics Initiative (PAPGI) project for mapping genomic diversity of Asia
Jong Bhak 1 ，HUGO-Pan Asian Population Genomics Initiative (HUGO-PAPGI)
1:The Genomics Institute, Ulsan National Institute of Science and Technology (UNIST), Korea, South
PAPGI (Pan-Asian Population Genomics Initiative) is a HUGO Asian genome project to map the diversity of Asian popu-
lations. We have collected over 120 whole genomes from Eurasia and other continents to compare them with a simple but
robust genetic distance measurement method. Various bioinformatics comparisons showed highly accurate genetic distance,
population history in the past 100,000 years, probable migration routes, and the predicted influence of environmental factors
on their expansion and migration. PAPGI is the second phase of the consortium which started as the Pan Asian SNP Initiative
(PASNPI) with the original objectives of: (1) characterizing genetic relatedness and origins of Asian populations; (2) creating

a freely accessible Asian SNP database; and (3) developing a framework for the exchange & sharing of resources. PAPGI is a
collaborative population study based on whole genome data involving labs across Eurasia. The first data freeze was released
recently and in this presentation, we will share the results of our comparative analyses.
Thu(5)-O53-2
Spatially explicit models and whole genome analysis for reconstructing the colonisation of Asia
Anders Eriksson 1,2 ，Kyusang Lee 3 ，Jong Bhak 3 ，Andrea Manica 2 ，Timothy Ravasi 1 ，
Pan-Asian Population Genomics Inititative (PAPGI)
1:Integrative Systems Biology Laboratory, King Abdullah University of Science and Technology, Saudi Arabia、2:Department of Zoology,
University of Cambridge、3:Biomedical Engineering, Ulsan National Institute of Science & Technology
The availability of next-generation sequencing data offers the possibility of asking sophisticated questions about how Asia was
populated by anatomically modern humans and subsequent population bottlenecks, migrations and admixtures. However,
the wealth of information available from complete genomes needs to be matched with clear, hypothesis driven approaches
that allow us to distinguish among the sometimes subtly different scenarios that have been proposed by anthropologists.
In this talk, I will present a new spatially explicit framework, informed by past climate and an ethnically diverse panel of
human high-quality whole genomes, for describing the colonisation of Asia. Simpler versions of this framework has been used
successfully to look at the out of Africa expansion of anatomically modern humans and their possibly hybridisation with
Neanderthal, and thus offer great promise in helping us unravel the details of the colonisation of the Asian continent. To
accommodate the complex history of Asia, we applied the MSMC tool to pairs of genomes in our panel to reconstruct the
signatures of common ancestry within and between populations through time, reflecting population bottlenecks and gene flow
between populations, and used a novel statistical analysis to identify the timing and extent of gene flow during population
splits and subsequent contacts. In addition to the main out-of-Africa bottleneck, we see events consistent with the expansion
of agriculture in Europe and East Asia, at approximately 10k and 4k years ago respectively. This information allowed us to
specify waves of migration in the spatially explicit model, and we validated our approach by comparing the pairwise empirical
cross-coalescent patterns from MSMC to the same patterns estimated directly from simulated gene genealogies in the spatial
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model.
Thu(5)-O53-3
Large-scale whole genome sequencing of the Estonian population reveals novel loss-of-function variants
and new insights into the population history
Reedik Magi 1 ，Mart Kals 1 ，Mario Mitt 1 ，Kalle Parn 1 ，Mait Metspalu 2 ，Lili Milani 1 ，Tonu Esko 1 ，Andres Metspalu 1
1:Estonian Genome Center, University of Tartu, Estonia、2:Estonian Biocentre
Altogether 2244 whole genomes of geographically diverse individuals from Estonia were sequenced to a median depth of 30x
using Illumina HiSeq with TruSeq PCR-free library preparation method. We found 19M SNVs and 6.6M indel variants with
allele count larger than two and of which 8.4M were novel. Within this study we have analysed both loss-of-function variants
revealed as well as the population structure of Estonia.
We found a total of 14,531 autosomal loss-of-function (LOF) SNVs and indels in 6,991 genes. Out of these genes, 3.3%
contained homozygous or compound heterozygotes LOF variants with minor allele frequency less than 2%. By combining the
data of complete gene knockouts of individuals with their disease history and variety of available endophenotypes (proteomics,
NMR, biochemistry) will help us to study the function of these genes and will lead to better understanding the phenotypic
consequences of the variation within these genes.

To study the fine-scale genetic structure and origin of the Estonian population, we have compared our sequenced samples
with pan Eurasian panel of high coverage genomes from hundreds of populations. We used haplotype based methods to reveal
the genetic clusters among Estonians and compared each cluster against populations’ panel to search for population mixture
events. We plan to compare the frequencies of common diseases across these genetic clusters with their haplotype frequenciess
to identify novel associated disease loci.
Thu(5)-O53-4
Fine-Scale Population Structure in Europe
Stephen Leslie 1,2 ，Garrett Hellenthal 3 ，Simon Myers 4 ，Peter Donnelly 4,5
，
International Multiple Sclerosis Genetics Consortium
1:Statistical Genetics, Murdoch Childrens Research Institute, Australia、2:School of Mathematics and Statistics, University of Melbourne、
3:University College London Genetics Institute, UK、4:Department of Statistics, University of Oxford, UK、5:Wellcome Trust Centre for
Human Genetics, Oxford, UK
There is considerable interest in detecting and interpreting fine-scale population structure in Europe: as a signature of
major events in the history of European populations, and because of the effect undetected structure may have on genome-
wide association studies (GWAS). Population structure has been a minor concern for most recent GWAS, but will likely be
important for future studies seeking associations to rare variants. Thus far, genetic studies across Europe have been limited
to small numbers of markers, or to methods that do not specifically account for linkage disequilibrium. Consequently, these
studies were unable to group samples into clusters of similar ancestry on a fine (within-country) scale with high confidence.
We describe an analysis of fine-scale population structure using genome-wide SNP data on 6,209 individuals, sampled mostly
from Western Europe. Using the novel algorithm fineSTRUCTURE, adapted for specific aspects of our analysis, the samples
were clustered purely based on genetic similarity, without reference to the sampling locations.
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When plotted on a map of Europe, striking associations can be observed between the inferred clusters and geography.
Interestingly, modern country boundaries are mostly significant: we see clear evidence of clusters that exclusively contain
samples from a single country. At a high level we see: the Finns are the most differentiated from the rest of Europe (as might
be expected); a clear divide between Sweden/Norway and the rest of Europe (including Denmark); and an obvious distinction
between southern and northern Europe. We also observe considerable structure within these countries on a hitherto unseen
fine-scale.
Using new techniques we examine the genetic relationships between the inferred clusters. We interpret our results with respect
to geographic and linguistic divisions, and the historical and archaeological record. This is the largest detailed analysis of
very fine-scale genetic structure within Europe.
Thu(5)-O53-5
SNPs associated for height explain about half of the height difference between two historical subpopu-
lations in Finland
1,2,3
Markus Perola
1:Health, National Institute for Health and Welfare, Finland、2:University of Helsinki, Institute for Molecular Medicine, Finland (FIMM)
and Diabetes and Obesity Research Program、3:University of Tartu, Estonian Genome Center, Tartu, Estonia

Finland is historically a genetic isolate but it also has significant substructure due to several bottleneck events and local
subisolates. Historically Finland is divided in early settlement (Western+Southern Finland) and late settlement regions
(Eastern+Northern Finland). There are notable epidemiological differences between the late and early settlements of Finland,
for example a significant difference in cardiovascular disease (CVD) incidence and risk factors, the CVD risk being higher in
the East. Interestingly, the Eastern Finns are also historically considered to be shorter than Western, however this difference
in height has been more of an anecdotal type than a scientifically investigated topic. Here I have analyzed 14445 Finns,
who have been voluntary participants in the population-based prospective study Finrisk for the differences in height and
height-associated genomic SNPs. A total of 7532 participants were from the early and 6913 from the late settlement area. All
were genome-wide genotyped and imputed to 1000 Genomes phase 3. A multilocus quantitative genetic score was constructed
for height (GSH) using 689 height SNPs and their effect sizes reported by the GIANT consortium. The GSH associated with
the geographical origin (late/early) of the individuals (p=2x10-66 ), however the predictive value of GSH for the area of origin
was poor (R2 =0.02, adjusted for age and sex). The participants that originated from the late settlement of Finland were
on average 1,4cm (~ 0.2SD) shorter than the ones from the early settlement (adjusted for age and sex, p=8x10-42 ). When
adjusted for GSH, this difference fell to 0.6cm (p=9x10-12 ). The results were similar for both females (n=7573) and males
(n=6872) when analyzed separately. The results suggest that the difference in height between the early and late settlements
of Finland is mostly due to genetic variation between the two populations.
Thu(5)-O53-6
Characterization of 20,000 Clinically Relevant Variants in 50,000 Non-European Individuals
Eimear E Kenny 1 ，Christopher R Gignoux 2 ，Stephanie Rossi 3 ，Christopher S Carlson 3 ，Carlos D Bustamante 2 ，
Noura S Abul-husn 1 ，The Population Architecture using Genomics and Epidemiology Study
1:Icahn School of Medicine at Mo, USA、2:Stanford University、3:Fred Hutchinson Center for Cancer Research
Vast quantities of rare variants in human populations make questions of causality, penetrance and expressivity for any partic-
ular variant difficult to ascertain. This problem is compounded by the recent observations from population genetics that rare
variants are typically restricted to one or a few closely related populations, with implications that causal variants discovered
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in one population are unlikely to translate to another.
To address this, we generated a panel of 2,720 clinically relevant genes, curated from ClinVar, HGMD, and OMIM in consul-
tation with domain experts, and pharmacogenes from PharmGKB. Within these genes, we selected 15,000 variants previously
classified as pathogenic, and 5,000 loss-of-function variants we classified as likely pathogenic. These variants were included
on the Illumina Infinium Multi-Ethnic Genotype Array (MEGA) which was used to genotype 50,000 individuals, including
African American, Afro-Caribbean, North, Central and South American, Japanese, and Native Hawaiian Islanders, as part
of the Population Architecture using Genomics and Epidemiology (PAGE) Study. These data are linked to broad epidemio-
logical trait and disease information, and a subset of 12,500 are linked to longitudinal electronic medical records (EMR).
We will present data on the frequencies of known and likely pathogenic variants, and will report phenotypic evidence to
support causality and penetrance for a subset of CRVs segregating in PAGE. For example, we have already uncovered a
skeletal dysplasia variant in COL27A1 that is observed only in Puerto Ricans, and is in homozygosity in six individuals with
extreme short stature (mean 4’ 2” females and 4’ 10” males). EMR data supports features of skeletal dysplasia despite a
lack of diagnosis in those individuals. Follow up work will focus on characterizing other rare disease variants and uncovering
monogenic forms of complex disease in this cohort.
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Thu., April 07, 2016 8:00-9:30 Room J (2F)
Chair：Roberto Mendoza-Londono（Medical Genetics, The Hospital for Sick Children and University of Toronto, Canada）
Chair ：Tomohiro Nakayama（Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon Uni-
versity School of Medicine, Japan）
Thu(5)-O54-1
Genetic causes of Intellectual disability
Amal M Mohamed 1 ，Alaa K Kamel 1 ，Nivin A Helmy 1 ，Sayeda A Hammad 1 ，Hesham F Kayed 1 ，Marwa M Shehab 1 ，
Asaad S Gerzawy 1 ，Maha M Ead 1 ，Ola M Ead 1 ，Mona K Mekkawy 1 ，Maha S Zaki 2 ，Mona S Aglan 2 ，
Samira M Ismaeel 2 ，Hala E Bassiouny 2 ，Mona A Abdel Razek 2 ，Samia A Temtamy 2
1:Human Cytogenetics, National Research Center, Egypt、2:Clinical Genetics, National Research Center
The prevalence of intellectual disability (ID) is ranging from 1-3% of the general population; more than 50% of ID patients
are undiagnosed. This study included 2696 patients with ID through a project funded by the National Research Centre
Egypt. The patients referred over five years 2010-2014 to the Human Cytogenetics Department from the outpatient’s clinics
of Clinical Genetics Department, National Research Centre. The aim of this study is to reveal the genetic causes of ID and
raising the percentage of diagnosed patients through the use of technological improvement. All the patients were subjected

to thorough clinical examination, pedigree analysis, cytogenetics, Fluorescence in situ hybridization (FISH) using different
FISH probes, multiple ligation probe amplification (MLPA) and soon array CGH analysis will be performed on collected trio
DNA samples.
Out of 2696 patients, 620 had Down syndrome (23%), chromosomal abnormalities found in 170 patients (6.3%), FISH
using different probes including total subtelomere probes were performed on 106 patients with chromosomal abnormalities to
identify the marker chromosome and to delineate the nature of structural chromosome abnormalities. Microdeletion syndromes
were diagnosed clinically in 156 patients (5.8%). Microdeletion was detected by FISH in 46 patients (1.7%). MLPA using
subtelomere kit performed on 50 ID patients, one patient had deletion subtelomere 1q and duplication 4p and confirmed by
FISH. The genetic causes of ID in this study could be diagnosed in 31% of patients. This year the project aimed to apply
MLPA using its different kits for ID, and also by the application of array CGH for copy number variance and methylation
array CGH and by using next generation sequencing (NGS) targeted sequencing we hope to raise % of identified genetic
causes of ID.
Thu(5)-O54-2
Triaging of epileptic encephalopathy patients for massive parallel sequencing testing
1,3,4 2,3 2,3 2,3
Bruce H. Bennetts ，Kavitha Kothur ，Deepak Gill ，Richard Webster ，Katherine Holman 1 ，Gladys Ho 1
1:Sydney Genome Diagnostics, The Children’s Hospital at Westmead, Australia、2:Department of Neurology, The Children’s Hospital at
Westmead、3:Discipline of Paediatric and Child Health, The University of Sydney、4:Discipline of Genetic Medicine, The University of
Sydney
Epileptic encephalopathies (EE) are a large heterogeneous devastating group of refractory epilepsy disorders generally asso-
ciated with early onset of seizures and some cognitive, motor and behavioural dysfunction as a result of the epileptic activity.
Given phenotypic and genotypic heterogeneity, massively parallel sequencing (MPS) provides the advantage of testing multiple
genes. A diagnostic panel of 82 genes associated with EE with clear evidence for pathogenicity was designed in conjunction
with the paediatric neurologists. MPS was performed using the Illumina TruSight One panel which includes 4813 genes
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associated with Mendelian disorders. The EE genes were analysed using bioinformatics filtering.
An internal review process aimed at preventing inappropriate ordering of MPS testing, authority to order testing for internal
hospital patients was given to a neurology review team to decide who should have the EE panel performed. External patients
were tested if a request and consent form were complete. We have compared the yield of pathogenic or likely pathogenic EE
panel results from internal neurology referrals, internal clinical genetic referrals and external referrals.
The yield of pathogenic or likely pathogenic variants was low (7-10%) in referrals from non-neurologists (internal clinical
geneticists (2/20) and external clinicians (3/42)) compared to neurology referrals (35.5% 17/48). The patients from non-
neurology referrals were more likely to have milder epilepsy and global developmental delay whereas undiagnosed refractory
epilepsy cases were chosen for testing in neurology referrals.
This report highlights the importance of appropriate case selection in improving the diagnostic yield of MPS testing. The
triaging of well characterised patients allows for correct testing to be chosen, gene panel versus a full exome or whole genome
sequencing. This improves the cost effectiveness of testing and reduces the likelihood of incidental findings.
Thu(5)-O54-3
Diagnostic whole exome sequencing of danish families with rare genetic diseases

Lotte Risom 1 ，Jakob Ek 1 ，Elsebet Ostergaard 1 ，Morten Duno 1
1:Dept. of Clinical Genetic, Copenhagen University Hospital, Rigshospitalet, Denmark
Whole exome sequencing (WES) has proven to be a successful screening tool for the identification of candidate genes causing
rare genetic diseases and is used with increased frequency as a clinical diagnostic tool especially in atypical cases. A precise
molecular diagnosis is important for optimal treatment, follow-up and prognosis. Another important reason for performing
WES is a request in some families for prenatal testing in subsequent pregnancies.
We here present the result of a study on primarily Danish pediatric patients referred for WES on the bases of a variety of
indications. Most of the patients had undergone numerous analyses including array CGH, gene panels, metabolic analysis
etc. before WES was initiated. All the patients have prior to WES been discussed with the clinical geneticist who has seen
the patient in order to provide detailed and complete clinical information to the lab.
In approx. one third of patients we identified the causative variants. The majority of the pathogenic variants were previously
unreported, and one fifth were de novo in the proband. Prenatal diagnosis was performed in a substantial fraction of the
families where a molecular diagnosis was obtained.
Conclusion: This study illustrates the usefulness of WES to identify rare mutations in Danish families with different diagnoses.
The combined collaborative effort of clinicians and laboratory scientists was essential for reaching a definitive diagnosis, and
illustrates that WES is a multi-disciplinary task.
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Thu(5)-O54-4
Diagnosis of Skeletal Dysplasias by Exome Sequencing: The Canadian Experience
Roberto Mendoza-Londono 1 ，Lucie Dupuis 1,2 ，Peter Kannu 1,2 ，Andrew Howard 2,3 ，Jennifer Stimec 2,4 ，
Jennifer Harrington 2,5 ，Christian Marshall 6 ，Tara Paton 6 ，Michael Brudno 6,7 ，Taila Hartley 8 ，Amanda Smith 8 ，
Stephen Scherer 6 ，Kym Boycott 8 ，Care4Rare Canada Consortium
1:Medical Genetics, The Hospital for Sick Children and University of Toronto, Canada、2:The Bone Health Centre, The Hospital for Sick
Children、3:Department of Orthopaedic Surgery、4:Department of Diagnostic Imaging、5:Division of Endocrinology、6:The Centre for
Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario、7:Computational
Biology、8:Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada
Skeletal dysplasias (SD) are a heterogeneous group of disorders that affect 1 in 2000 live born. The diagnosisis has been based
on clinical assessments and X-ray evaluations. Next generation sequencing techniques and exome sequencing (WES) have
revolutionized the diagnosis of rare disorders with genetic and phenotypic heterogeneity. In order to assess the effectiveness
of WES in the diagnosis of rare SD we recruited 16 (7 males and 9 females) patients with undiagnosed SD from the SD clinic
at the Hospital for Sick Children in Toronto, Canada. All but one of the families had a single individual affected. Detailed
phenotypic and family history information was recorded in the Phenotips ™ program and ontology terms were used in the
analysis of the sequencing information. WES was performed on the index patients first and a list of possible responsible genes
was selected by computational filtering methods. Variants of significance were tested in the relevant family members to confirm
segregation patterns and aid in the evaluation of pathogenicity. We achieved a final diagnosis in 10 of 16 cases (62%). Seven
had atypical presentations for mutations in a known gene (44%) (NPR2 , DYM, COL2A1, ARID1B, ACVR1). We identified
2 novel gene-associated phenotypes (12%) (SPARC and PSPRY1 ). One case had more than one diagnosis. Six cases remain

unresolved. Overall diagnostic rate of WES was 62%, which is higher than average for other studies but not unexpected.
Factors that may increase yield in this population include the severity of the cases, the fact that we took advantage of case
matching by phenotype and genotype and that the pathways involved in skeletal development are better characterized. We
conclude that WES is an effective tool to diagnose patients with disorders with significant genetic heterogeneity. Improving
access to next generation sequencing technologies, either through large gene panels or WES, will have significant impact on
the care of these patients.
Thu(5)-O54-5
Clinical validation of a Targeted Massively Parallel Sequencing Panel for Craniosynostosis
Tony Roscioli 1,2,3 ，Eric Lee 4 ，Ying Zhu 5 ，Nicole Snow 3 ，George Elakis 4 ，Mark J Cowley 1,2 ，Velimir Gayevskiy 1 ，
Kevin Ying 1 ，Corrina Walsh 4 ，Anne Turner 3 ，Marcel E Dinger 1,2 ，Wanda Lattanzi 6 ，Simeon Boyd 7 ，
Michael F Buckley 4
1:Kinghorn Centre for Clinical Genomics, Kinghorn Centre for Clinical Genomics, Australia、2:St Vincents Clinical School, University of
New South Wales, Darlinghurst, Australia、3:Department of Medical Genetics, Sydney Childrens Hospital, Randwick, NSW, Australia、
4:SEALS Haematology and Genetics Laboratories, New South Wales Health Pathology, Randwick, Sydney, NSW, Australia、5:Royal
North Shore GOLD Service, Sydney, NSW, Australia、6:Universita Cattolica del Sacro Cuore, Rome, Italy、7:UC Davis MIND Institute,
Sacramento, USA
Craniosynostosis is a group of disorders characterised by the premature fusion of one or more cranial sutures. Most syndromic
craniosynostoses are due to recurrent sequence variants in the fibroblast growth factor receptor (FGFR) or TWIST1 genes.
We report on molecular testing of an Australian and New Zealand cohort of 205 individuals with craniosynostosis, in whom
no causative variants have been identified within the FGFR1-3 hotspot regions and the TWIST1 gene. This cohort was used
to clinically validate a custom 21-gene Ion Torrent AmpliSeq panel on the Ion Proton system. A proprietary bioinformatics
pipeline was used to prioritise variants according to predicted functional impact and population allele frequency. Pathogenic
or likely pathogenic variants were identified in 29 individuals (14%), and confirmed by bi-directional Sanger sequencing.
The majority of variants were identified in TCF12 and EFNB1 (62%), most commonly in those with uni- or bi-coronal
craniosynostosis, or Saethre-Chotzen-like phenotypes. Pathogenic variants were also identified in ALX4 , EFNA4 , FGF10 ,
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and POR. In view of the increased diagnostic yield in FGFR- and TWIST1-negative coronal craniosynostosis, we propose
that testing in these individuals should be extended to include at least TCF12 and EFNB1 .
Thu(5)-O54-6
NGS-based diagnostic DNA analysis in syndromal and nonsyndromal obesity.NGS-based diagnostic DNA
analysis in syndromal and nonsyndromal obesity
Bert van der Zwaag 1 ，Elisabeth F.C. van Rossum 2 ，Erica L.T. van den Akker 2 ，Patrick H.A. van Zon 1 ，
Vincent L. Wester 2 ，Ignace M.C. Janssen 3 ，Hans Kristian Ploos van Amstel 1 ，Mieke M. van Haelst 1
1:Department of Genetics, UMC Utrecht, Utrecht, The Netherlands、2:Department of Internal Medicine, Obesity Center CGG, Erasmus
MC, University Medical Center Rotterdam, Rotterdam, The Netherlands、3:Vitalys Obesitas Centrum, Vitalys Klinieken, Velp, The
Netherlands
In the past few decades, there has been an exploding prevalence of obesity with its subsequent morbidity and mortality
forming a major threat to public health. Although generally considered to be generated by environmental factors, it is
remarkable that despite sharing the same ‘obesogenic’ environment not all Westernized people are obese. A number of genes
have indeed been identified that, when mutated, can cause obesity in humans. Nevertheless, mutations in these genes (e.g.
MC4R, POMC, LEP, LEPR, PCSK1), combined with chromosomal aberrations (e.g. deletion 16p11.2, 15q11-q13) explain no
more than ~ 6% of the heritability shown by twin studies. Next generation sequencing techniques now provide a time- and
cost-efficient method to identify mutations in large panels of known disease genes and to additionally screen a large number

of candidate genes involved in or associated with a trait. We developed a custom NGS enrichment kit (the ‘Obesitome’)
aimed at enrichment of 255 either known obesity genes or putative obesity candidate genes. Analysis of 53 obesity related
genes is offered as a diagnostic analysis through our genome-diagnostics laboratory. The remaining 202 candidate genes can
be analyzed in a research setting, to identify novel obesity-related genes. We present the results of diagnostic analysis in
(syndromal) morbidly obese patients (N>900). A clear molecular diagnosis can be made in up to ~ 6% of the patients and
possible pathogenic mutations needing further follow-up were detected in an additional ~ 8% of patients. These results prove
the validity of genetic testing in obesity and open new avenues to providing genotype-based personalized treatment in this
population.
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Thu., April 07, 2016 9:45-11:15 Room J (2F)
Chair：Paul F. Lasko（McGill University, Canada）

Chair ：Jun Mitsui（Department of Neurology, The University of Tokyo, Japan）
Thu(5)-O55-1
Beyond the ACMG 56: Parental choices and initial results from a comprehensive whole genome
sequencing-based search for predictive genomic variants in children
M Stephen Meyn 1,2,3,4,5 ，Nasim Monfared 5 ，Christian Marshall 6,7 ，Daniele Merico 1,6 ，Dmitri J Stavropoulos 7,15
，
Robin Z Hayeems 5,8 ，Michael Szego 6,9,10 ，Rebekah Jobling 2 ，Marta Girdea 1,11 ，Gary D Bader 3,12 ，
Michael Brudno 1,11 ，Ronald D Cohn 1,2,3,4,5 ，Stephen W Scherer 1,3,5,6,13 ，Randi Zlotnik Shaul 4,8,14 ，
Cheryl Shuman 3,4 ，Peter N Ray 1,3,5,6,7 ，Sarah C Bowdin 2,4,5
1:Program in Genetics and Genome Biology, The Hospital for Sick Children, Canada、2:Division of Clinical and Metabolic Genetics, The
Hospital for Sick Children、3:Department of Molecular Genetics, University of Toronto、4:Department of Paediatrics, University of Toronto、
5:Centre for Genetic Medicine, The Hospital for Sick Children、6:The Centre for Applied Genomics, The Hospital for Sick Children、
7:Department of Paediatric Laboratory Medicine, The Hospital for Sick Children、8:Program in Child Health Evaluative Services, The
Hospital for Sick Children、9:Joint Centre for Bioethics, University of Toronto、10:Centre for Clinical Ethics, St. Joseph’s Health Centre、
11:Department of Computer Science, University of Toronto、12:The Donnelly Centre, University of Toronto、13:The McLaughlin Centre,
University of Toronto、14:Department of Bioethics, The Hospital for Sick Children、15:Department of Laboratory Medicine and Pathology,
University of Toronto
Objective: The overall goal of the SickKids Genome Clinic is to pilot paediatric genomic medicine. To this end we have

assessed parental interest in predictive secondary medically-actionable variants (MAVs) and used whole genome sequencing
(WGS) to determine the frequency and nature of these MAVs in children.
Design: The Genome Clinic conducts diagnostic WGS for 150+ children/year who are undergoing genetic evaluations. With
parents’ permission, we search childrens’ genomes for predictive MAVs in 2800+ disease genes listed in the NIH Clinical
Genomic Database.
Results: Of 373 families approached to date, 56% agreed to participate. 58% of participants chose to learn their child’s
secondary adult-onset MAVs. Among these parents, 79% decided to learn their own status for these variants. Bioinformatics
analysis of the first 100 patient genomes yielded 2957 candidate variants in 1132 genes (~ 30 variants/genome.) ~ 70% of
candidates were listed in HGMD. However, subsequent manual assessment rejected >90% of variants for dominant diseases
listed in HGMD as disease causing due to inadequate evidence of pathogenicity. After manual assessment, 33/100 children
had at least one reportable predictive MAV. 9 MAVs occurred in a 2013 ACMG-guideline reportable gene. Expanding our
search 50 fold to include 2800+ disease genes yielded 29 additional reportable predictive MAVs. Return of predictive MAVs
and assessment of their penetrance is underway.
Conclusions: Parental opinions vary widely regarding return of predictive MAVs and comprehensive genomic analysis can
yield predictive MAVs in 1/3 of children, with the number of reportable predictive MAVs constrained by disease prevalence
and imperfect variant interpretation.
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Thu(5)-O55-2
EuroGentest Guidelines for Diagnostic Next Generation Sequencing
Gert Matthijs 1 ，Erika Souche 1 ，Marielle Alders 2 ，Anniek Corveleyn 1 ，Sebastian Eck 3 ，Ilse Feenstra 4 ，
Valerie Race 1 ，Erik Sistermans 5 ，Marc Sturm 6 ，Marjan Weiss 5 ，Helger Yntema 4 ，Egbert Bakker 7 ，Peter Bauer 6 ，
Participants to the EuroGentest workshop on Diagnostic NGS Guidelines
1:Center for Human Genetics, University of Leuven, Belgium、2:Department of Clinical Genetics, Academic Medical Centre (AMC),
University of Amsterdam、3:Center for Human Genetics and Laboratory Medicine Dr. Klein, Dr. Rost and Colleagues, Martinsried、
4:Department of Human Genetics, Radboud University Medical Center, Nijmegen、5:Department of Clinical Genetics, VU University
Medical Center, Amsterdam、6:University Hospital of Tuebingen, Institute of Medical Genetics and Applied Genomics、7:Department of
Clinical Genetics, Leiden University Medical Center
We present, on behalf of EuroGentest and the European Society of Human Genetics, guidelines for evaluation and validation of
next-generation sequencing (NGS) for diagnosis of genetic disorders. While the exploitation of NGS for research purposes has
been rapidly implemented, the diagnostic use brings specific challenges like the validation of the methods, clinical interpretation
of results, and storage and exchange of data.
NGS guidelines have already been issued by genetic professional societies world-wide. A EuroGentest expert group has been
working on compiling, integrating and completing these guidelines. Among other statements, the guidelines deliver major
definitions like ‘diagnostic utility’ and ‘reportable range’. We believe that defining the diagnostic utility is the laboratory’
s first duty when preparing to offer diagnostic NGS. We propose a ‘scoring system’ for NGS assays that depends on quality
and comprehensiveness. With this system, referring physicians, patients, and stakeholders in the health care system will

be enabled to compare different tests. This scoring system is new, as it does not feature in any other guideline. As far as
‘reportable range’ is concerned, we propose the use of 3 specific percentages depending on the reference (technical target,
coverage of transcript in a gene panel, coverage with reference to the genome) which will again allow to compare individual
results within runs, between tests and between laboratories. The guidelines also feature a generic template for reporting
NGS results. While dealing with informed consent, unclassified variants and unsolicited findings, again from the laboratory
standpoint, is already addressed in aforementioned guidelines, the distinction of diagnostic and research is a very relevant
topic when it comes to the “duty to re-contact”.
The guidelines shall contribute to the harmonization and standardization of diagnostic NGS testing.
Thu(5)-O55-3
Data sharing improves the diagnostic yield of clinical exome sequencing and identifies new disease genes
Koen L.I. van Gassen 1 ，Martin Elferink 1 ，Marc C. van Tuil 1 ，Patrick van Zon 1 ，Jacques C. Giltay 1 ，
Mieke M. van Haelst 1 ，Eva H. Brilstra 1 ，Nine V. Knoers 1 ，Gijs van Haaften 1 ，Hans Kristian Ploos van Amstel 1
1:Department Genetics, University Medical Center Utrecht, Netherlands
Diagnostic trio whole exome sequencing (WES) has proven to be an important tool for diagnosing heterogeneous genetic
diseases. Especially for patients with syndromic or non-syndromic intellectual disability, WES is increasingly being used as
part of the genetic diagnostic workup. Here we show that by applying routine diagnostic WES for intellectual disability in a
group of 150 patients and their parents, 54 patients (36%) received a molecular genetic diagnosis in a known disease associated
gene. In an additional 64 patients (42.7%), one or more variants of uncertain clinical significance were identified in candidate
genes, either de novo occurring or recessively inherited. By sharing these candidate genes and associated phenotypes through
the GeneMatcher online database and by querying other data sharing repositories, we were able to provide a molecular genetic
diagnosis (e.g. in the genes PPP2R1A; PPP2R5D; SPATA5 ; DDX3X ; HIVEP2 ; CHAMP1 ) for an additional 15 patients
(10%). Thus in total, 46% of all patients received a molecular genetic diagnosis by applying trio based diagnostic WES, which
is higher than reported in most studies. Although data sharing does require a substantial investment in time and attention, we
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propose to consider candidate gene and phenotype sharing as good clinical practice when applying WES in standard clinical
care.
Thu(5)-O55-4
The Undiagnosed Diseases Network International (UDNI): Clinical and Laboratory Research to Meet
Patient Needs
Paul F. Lasko 4 ，John J Mulvihill 1 ，G Baynam 2 ，W Gahl 1 ，S C Groft 1 ，K Kosak 3 ，B Melegh 5 ，D Taruscio 6 ，
Undiagnosed Diseases Network International
1:Division of Genomic Medicine, National Human Genome Research Institute, USA、2:Princess Margaret and King Edward Memorial
Hospitals、3:Center for Medical Genetics, Keio University、4:McGill University、5:Department of Medical Genetics, Pecs, Hungary、6:Istituto
Superiore di Sanita, Rome
From ancient times, precise diagnosis has been the heart of the art of medicine, part of every doctor’s skills and habits,
but many patients remain without a diagnosis, despite thorough evaluations. In 2008, the US NIH started an Undiagnosed
Diseases Program (UDP), with the twin goals of providing answers to patients with mysterious conditions that have long eluded
diagnosis and advancing medical knowledge about diseases. In seven years, 863 patients were evaluated and a specific diagnosis
was made in aout 25%. The UDP has been expanded, as the Undiagnosed Diseases Network, with six additional clinical sites
around the nation, a coordinating center, two DNA sequencing cores, a model organisms screening center, a metabolomics
core, and a central biorepository. After meetings in Rome and Budapest, clinician scientists from seven nations have launched

the UDNI (Australia, Canada, Hungary, Italy, Japan, Sweden, and the United States). The objectives are to improve the
level of diagnoses and care for such patients by common protocols, facilitate research in disease etiology, and recreating a
collaborative research community. A comprehensive -omics approach would include exomic and genomic sequencing as well
as metabolomics, such as glycomics, proteomics, and lipidomics. To date, certain principles are being implemented: Engaging
centers of excellence, fostering a collaborative research environment, establishing a cooperative governance structure, designing
a common research protocol, providing a uniform patient experience, collecting data by recognized standards, protecting
patient data, observing ethical, legal, and social guidelines, devising broad data sharing, stimulating dissemination of results,
and ensuring a well functioning network. A Board of Directors will integrate working committees, including Patient Advocacy,
Clinical Management, Sequencing, Databases, and Repositories.
Thu(5)-O55-5
Need to concern about contamination by circulating fetal DNA
Jianli Dong 1 ，Hai Wu 1 ，Gengming Huang 1 ，Zurina Romay-Penabad 1
1:Pathology, University of Texas Medical Branch, USA
Detection of circulating cell-free fetal DNA in maternal plasma has been used in noninvasive prenatal diagnostics. Studies
have showed that the fetal fractions average approximately 13.5% of total DNA in maternal plasma at 11-13 weeks’ gestation
and increase with gestational age. During the second and third trimesters as high as 40% fetal DNA in maternal circulation
has been reported. The existence of such a significant amount of fetal DNA in maternal circulation raises the concern of“fetal
DNA contamination” when intended tests are for the pregnant women. We routinely screen for cystic fibrosis transmembrane
conductance regulator (CFTR) mutations using Abbott Cystic Fibrosis Genotyping Assay and examine factor 5 (F5 ) and
factor 2 (F2 ) mutations using GenMark Thrombophilia Risk Test. We performed a study to determine the sensitivity of our
assays to detect minor alleles. Samples with CFTR delF508, 621+1G>T, and intron 8 variant 5T, F5 1691G>A, and F2
20210G>A mutations were used to obtain various mutant allele frequencies. We found that both CFTR mutant alleles were
readily detected at 25% allele frequency, and the existence of 37.5% and 12.5% of mutant alleles effectively changed the testing
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result from wild-type to indeterminant for F5 and F2 mutations, respectively. Since the absolute quantity of fetal DNA and
its ratio to total DNA are greater in the plasma than in the cellular compartment, we have use cells instead of plasma or
blood spot to extract genomic DNA when mutation assays are requested for pregnant women. We also review allele peak
heights of our CFTR results and repeat indeterminant F5 and F2 tests keeping in mind that one possible cause of test failure
is interference from fetal alleles. We believe that it is necessary to understand the sensitivity of mutation assays, to choose
the most appropriate testing material, and carefully review test results to avoid the impact of “fetal DNA contamination”.
Thu(5)-O55-6
Preconception screening results for Mendelian diseases in East Asian populations
Michal Golan-Mashiach 1 ，Erez Tzur 1 ，Itamar Shamshins 1 ，Lital Isaacs 1
1:Dr Gene Honk Kong limited, Hong Kong
BACKGROUND Mendelian diseases collectively account for ~ 20% of infant mortality and ~ 10% of pediatric hospitaliza-
tions. We present carrier rates of Mendelian diseases in East Asian population.
METHODS Two preconception panels were designed to detect pathogenic recessive mutations in Han Chinese. Mutations
relevant for this population were collected from NCBI PUBMED, Wangfang Data, Vip Information and more.

Basic preconception panel detects 160 pathogenic mutations, harbored by 12 genes, was analyzed on 197 Han Chinese individ-
uals (saliva samples) screened by Sequenom MassARRAY iPLEX ™ .Extended preconception panel detects 1020 pathogenic
recessive mutations, spanning over 159 genes.
We analyzed carrier rates for both panels, using the East-Asian data set of the Exome Aggregation Consortium which presents
exome sequences of 4,327 unrelated East-Asian individuals.
RESULTS ExAC mutation frequency data was available for 92 out of 160 basic panel mutations. 8.4% of individuals were
heterozygotes- a carrier rate of 1 in 11.9. Similar results for these mutations were obtained in a cohort of 197 Han Chinese
(7.6%). Results for the complete panel of 160 mutations showed that 1 in 6 of carrying at least one pathogenic mutation
(16.75%).
Extended panel analysis by ExAC data set was limited to 422 mutations out of our 1020 mutations. Total carrier rate was 1
in 4.83 (20.68%).
Highest carrier rates were found for Non-Syndromic Hearing Loss and Deafness-1 in 24, Methylmalonic academia-1 in 28,
Phenylalanine hydroxylase deficiency-1 in 40, Niemann-Pick Disease Type-1 in 42 and Gaucher disease-1 in 50.
DISCUSSION This study presents carrier rates for over 100 of Mendelian diseases in East Asian populations. Complete
analysis of the extended panel (159 genes, 1020 mutations) is expected to produce even higher carrier rates. Our results
suggest that 1 in 357 couples (0.28%) carry pathogenic mutations for the same disease and may benefit greatly from being
informed and consulted.
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[O56] Cardiovascular Genetics 1

Thu., April 07, 2016 8:00-9:30 Room K (2F)
Chair：Elena V. Zaklyazminskaya（Medical Genetics Laboratory, Petrovsky Russian Research Centre of Surgery, Russia）
Chair：Hiroko Morisaki（Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research
Institute, Japan）
Thu(5)-O56-1
TTN truncating mutations double the diagnostic yield for DCM and NCCM patients; three years of
experience with a targeted panel for cardiomyopathies
Marjon A van Slegtenhorst 1 ，Marianne van Tienhoven 1 ，Judith M.A. Verhagen 1 ，Jaap I. van Waning 1 ，
Ingrid M.B.H. van de Laar 1 ，Kadir Caliskan 2 ，Michelle Michels 2 ，Marja W. Wessels 1 ，Danielle F. Majoor-Krakauer 1 ，
Hennie T. Bruggenwirth 1 ，Rogier A. Oldenburg 1
1:Department of Clinical Genetics, Ee2475, Erasmus Medical Center, Netherlands、2:Department of Cardiology, Thoraxcenter, Erasmus
Medical Center
Cardiomyopathies show a wide range of genetic and clinical heterogeneity, with >50 causative genes known to date. Sanger
sequencing of eight cardiomyopathy genes detected pathogenic mutations in about 35% of the hypertrophic cardiomyopathy
(HCM) cases, and in 15% of the dilated cardiomyopathy (DCM) and noncompaction cardiomyopathy (NCCM). In the past
three years, we applied a targeted NGS panel (48 genes) approach including the Titin gene (TTN ), encoding the largest

known human protein that plays a central role in sarcomere organization. TTN truncating mutations have been found to be
a major cause of DCM, but this type of mutation has not frequently been reported in NCCM or HCM.
NGS sequencing was performed of 350 HCM patients, 160 DCM patients and 100 NCCM patients. The majority of mutations
in HCM patients were detected in the genes that were previously tested with Sanger sequencing. Therefore, NGS achieved
only a slight increase in diagnostic yield in HCM. In contrast sixteen DCM patients (~ 14%) and 13 NCCM patients (~ 13%)
showed a truncating mutation in exons encoding the A-band of TTN (exons 259-359), while no mutations were detected in
350 HCM patients in this region. This A-band of Titin was recently reported to contain the majority of truncating mutations
in DCM patients (Roberts et al. Sci Transl Med. 2015,14;7; 270).
In conclusion, targeted NGS is an effective approach for cardiomyopathy diagnostics, resulting in doubled diagnostic yield for
DCM and NCCM patients. Some additional mutations in HCM patients in newly added genes were identified, resulting in
a slight increase in diagnostic yield. However, substantial gain was achieved by identifying truncating mutations in TTN in
DCM and NCCM.
Thu(5)-O56-2
Characterizing functional regulatory variants in iPSC-derived human cardiomyocytes
Paola Benaglio 1 ，Christopher DeBoever 1 ，Angelo Arias 1 ，Frauke Drees 1 ，Hiroko Matsui 1 ，He Li 1 ，
Agnieszka D’Antonio-Chronowska 1 ，Kelly Frazer 1
1:Pediatrics, UC San Diego, USA
Our goal is to demonstrate the utility of using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to
understand how non-coding DNA variants influence cardiomyocyte molecular phenotypes. Genetic variants that associate
with common diseases are enriched in non-coding regulatory regions of disease-relevant cell types. Therefore the study of
disease-relevant tissues is a fundamental requisite to interpret these associations, but has so far been hampered by the lack
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of proper in-vitro models. The technology of human iPSC, which can be differentiated into the affected cell types, offers a
powerful, yet unexplored tool to functionally characterize human regulatory variants. We have generated a well-characterized
collection of human iPSCs from 222 different individuals. All 222 individuals have whole-genome sequence data available.
We are differentiating each iPSC line into cardiomyocytes and generating RNA-Seq, ATAC-Seq, profiling three histone marks
and DNA methylation. We are using these data to identify common and rare genetic variants associated with molecular
phenotypes, some of which are relevant for cardiac biology. Here, I will focus on the characterization of iPSC-CMs from 7
related individuals by RNA-Seq, ChIP-Seq (H3K27ac, NKX2.5, SRF), Gro-Seq and ATAC-Seq. Epigenetic profiles from our
iPSC-CMs are more similar to those obtained from fetal heart than any other tissue in the Roadmap Project and are enriched
for SNPs associated with cardiac phenotypes and diseases by GWAS. Comparing the intensities of ChIP-Seq peaks, we have
determined that ~ 5% differ between individuals. SNPs are enriched in these variant peaks and show high correlation between
genotype and peak intensity, suggesting that DNA variants underlie epigenetic differences between iPSC-CMs derived from
different people. These findings highlight the extraordinary potential of iPSC-CMs as a model to dissect the impact of human
genetic variants on cardiac function and disease.
Thu(5)-O56-3
Genomic prediction of coronary heart disease
Michael Inouye 1 ，Gad Abraham 1 ，Samuli Ripatti 2 ，Veikko Salomaa 3 ，Nilesh Samani 4

1:Centre for Systems Genomics, University of Melbourne, Australia、2:Institute of Molecular Medicine, University of Helsinki、3:National
Institute of Health and Welfare, Finland、4:Cardiovascular Research Unit, University of Leicester, UK
Genetics plays an important role in coronary heart disease (CHD) but the clinical utility of a genomic risk score (GRS) relative
to clinical risk scores, such as the Framingham Risk Score (FRS), is unclear. We generated a GRS of 49,310 SNPs based on a
CARDIoGRAMplusC4D Consortium meta-analysis of CHD, then independently tested this using five prospective population
cohorts (three FINRISK cohorts, combined n=12,676, 757 incident CHD events; two Framingham Heart Study cohorts (FHS),
combined n=3,406, 587 incident CHD events). The GRS was strongly associated with time to CHD event (FINRISK HR=1.74,
95% CI 1.61-1.86 per S.D. of GRS; Framingham HR=1.28, 95% CI 1.18-1.38), and was largely unchanged by adjustment for
clinical risk scores or individual risk factors, including family history. Integration of the GRS with clinical risk scores (FRS
and ACC/AHA13 score) improved prediction of CHD events within 10 years (meta-analysis C-index: +1.5-1.6%, P<0.001),
particularly for individuals ≥60 years old (meta-analysis C-index: +4.6-5.1%, P<0.001). Men in the top 20% of the GRS had
3-fold higher risk of CHD by age 75 in FINRISK and 2-fold in FHS, and attaining 10% cumulative CHD risk 18y earlier in
FINRISK and 12y earlier in FHS than those in the bottom 20%. Furthermore, high genomic risk was partially compensated
for by low systolic blood pressure, low cholesterol level, and non-smoking. Overall, our study shows a GRS based on a large
number of SNPs substantially improves CHD risk prediction and encodes decades of variation in CHD risk not captured by
traditional clinical risk scores.
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Thu(5)-O56-4
Fatty Acid Oxidation Genes in Childhood Arrhythmia: A Pathway Forgotten
Zahurul A Bhuiyan 1 ，Elhadi H Aburawi 2 ，Lihadh Al-Gazali 2 ，Harsha D Devalla 3 ，Abdelaziz Beqqali 4 ，
Arie O Verkerk 4 ，Zenia Tiang 5 ，Safar Al-Shahrani 6 ，Samuel Dudley 7 ，Arthur A.M. Wilde 4,8 ，Roger S.Y. Foo 5 ，
Jumana Al-Aama 8 ，Robert Passier 3
1:Laboratoire de diagnostic moleculaire, University Hospital Lausanne (CHUV), Switzerland、2:Department of Pediatrics, College of
Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates、3:Department of Anatomy & Embryology, Leiden University
Medical Center, Leiden, the Netherlands、4:Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center,
Amsterdam, University of Amsterdam, the Netherlands、5:Department of Cardiology, National University of Singapore, Kent Ridge,
Singapore、6:Department of Cardiology, King Khaled University School of Medicine, Abha, Saudi Arabia、7:Lifespan Cardiovascular
Institute, Warren Alpert Medical School of Brown University, RI, USA、8:Princess Al-Jawhara Al-Brahim Centre of Excellence in Research
of Hereditary Disorders, Jeddah, Saudi Arabia
Primary Cardiac Arrhythmias in children are usually caused by mutation (s) in genes responsible for cardiac action potential
generation and propagation. Arrhythmia causal mutations have frequently been described in cardiac channels & its ancillary
protein encoding genes. Bonnet et al. (1999) first described a series of young patients with fatty acid oxidation defects, who
presented with arrhythmia.
We have examined 4 consanguineous families with cardiac arrhythmias and sudden cardiac deaths (SCD) of children. In
the 1st and 2nd family, 7 children presented with exertion-induced arrhythmias in early childhood. ECG showed borderly
prolonged QTc to catecholaminergic polymorphic ventricular tachycardia (CPVT). In the 3rd family, children suffered SCD
during their sleep with no relation to exertion but with repolarization abnormality on ECG. In the 4th family, SCDs were

reported between 4 d & 6 yr with no detectable abnormality on ECG. Whole exome sequencing was performed to explore the
genetic defect. Patient-specific stem cell induced-cardiomyocytes (hiPSC-CM) were generated to evaluate their pathology.
No mutation was found in any major genes linked to arrhythmias. Segregation analysis suggested recessive inheritance. Exome
sequencing identified homozygous mutations in 3 different genes in 4 families, definitively/putatively involved in cardiac fatty
acid oxidation.
In the first two families, splice site mutation (c.331+1G>A) was found in SRD5A2L2, a heart expressed gene. hiPSC-CM
demonstrated elevated diastolic Ca2+ concentration, action potential prolongation and adrenergic induced triggered activity.
Antiarrhythmic medication flecainide significantly reduced the triggered activity.
In the remaining two families: 3rd gene is a predominantly cardiac expressed fatty acid oxidation gene, and the 4th one is
linked to electron transfer mechanism. Functional analyses are underway and evaluation is also in progress for potential
development of gene targeted therapy.
Thu(5)-O56-5
High prevalence of psycho-neurological complications are associated with mutation in SCN5A gene
1,2
Elena V. Zaklyazminskaya ，Irena V. Pronicheva 3 ，Amiran Sh. Revishvili 3
1:Medical Genetics Laboratory, Petrovsky Russian Research Centre of Surgery, Russia、2:Pirogov Russian National Research Medical Uni-
versity、3:Bakulev Research Centre of Cardiovascular Surgery
Introduction. The SCN5A gene encodes the alpha subunit of the cardiac Nav1.5 sodium channel, which is responsible for
the inward sodium current (INa). Genetic alterations in the SCN5A gene result in various cardiac arrhythmias, dilated car-
diomyopathies, and mixed arrhythmogenic syndromes, characterized by syncopes and high risk of cardiac sudden death. The
correct diagnosis can be discovered with delay, and many patients have a long history of follow-up in neurological departments
under neurologic diagnosis. It was recently demonstrated that the Nav1.5 transcripts were detected in skeletal muscles, brain,
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and some non-excitable cells.
Methods and patients. We did perform DNA diagnostics for primary arrhythmias since 1998 year, and 232 unrelated families
underwent molecular genetic testing, including sequencing of SCN5A gene by Sanger or within PGM Ion Torrent target genes
resequencing. Detailed clinical and instrumental examinations including ECG, EchoCG, cardiac MRI, and neurological ex-
amination were performed for SCN5A mutation carriers (probands) regardless of underlying diagnosis of primary arrhythmia.
Results. Twenty-one mutations in 22 probands in SCN5A gene were found, one proband have carried two mutations in two
SCN5A alleles inherited from both parents. Two probands had epileptic activity confirmed by EEC, and three probands were
diagnosed with endogenous depression required long-term medical therapy. Totally 5 probands (23%) had major psycho-
neurological abnormalities.
Conclusion. It seems that the prevalence of different psycho-neurological abnormalities in SCN5A-mutations carriers is higher
than previously thought. Emotional disturbances and epilepsy represent not only the most common misdiagnosis of cardiac
channelopathies but might be an integral part of more complex clinical phenotype.
Thu(5)-O56-6
Up-regulation of FLT1 by a novel functional SNP increases risk of coronary artery disease through an

inflammatory activation
Kouichi Ozaki 1 ，Takashi Morizono 2 ，Tatsuhiko Tsunoda 2 ，Michiaki Kubo 3 ，Toshihiro Tanaka 1,4,5
1:Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Japan、2:Laboratory for Medical Science Mathematics, RIKEN
Center for Integrative Medical Science, Yokohama, Japan、3:RIKEN Center for Integrative Medical Science, Yokohama, Japan、4:Bioresourse
Research Center Tokyo Medical and Dental University, Tokyo, Japan、5:Department of Human Genetics and Disease Diversity, Tokyo Medical
and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan
Coronary artery disease (CAD) is common disease and leading cause of death in many countries. The onset of CAD depends
on interactions multiple genetic and environmental factors. Recent large-scale association analysis for CAD identified fifteen
new loci with genome wide statistical significance. Replication for the genetic association in other ethnic population is one
of important issue to investigate a clinical benefit in the future. We conducted the reproducibility for the association of the
fifteen single nucleotide polymorphism (SNP) loci and CAD with approximately 7,900 cases and 6,500 controls in a Japanese
population. We found a convincing association with statistical significance for a SNP in FLT1 , encoding fms-related tyrosine
kinase 1, for CAD susceptibility (P < 10-7 ). Fine mapping using tag SNPs in the FLT1 locus revealed that another SNP
conferred the risk of CAD (P < 10-11 ). The SNP, located within intron 1 in FLT1 , enhanced the transcriptional level of
FLT1. RNAi experiment against FLT1 showed that the suppression of FLT1 resulted in decreased expression of inflammatory
adhesion molecules. Expression of FLT1 was also observed in endothelial cells of human coronary artery. Our results indicate
that the increased expression of FLT1 by a functional SNP implicates activation in an inflammatory cascade that is associated
with the risk of coronary artery disease.
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[O57] Cardiovascular Genetics 2

Thu., April 07, 2016 9:45-11:15 Room K (2F)
Chair：Geneviève Galarneau（The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at
Mount Sinai, USA）
Chair：Takayuki Morisaki（Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Japan）
Thu(5)-O57-1
Two common single nucleotide polymorphisms in the Renalase gene increase the susceptibility to essential
hypertension
Amrita Anand Iyer 1 ，Parshuram J Sonawane 1 ，Kalyani Ananthamohan 1 ，Lakshmi Subramanian 1 ，Saurabh Sharma 2 ，
Madhu Khullar 2 ，Ajit S Mullasari 3 ，Nitish R Mahapatra 1
1:Department of Biotechnology, Indian Institute of Technology, Madras, India、2:Department of Experimental Medicine and Biotechnology,
Postgraduate Institute of Medical Education and Research, Chandigarh、3:Institute of Cardiovascular Diseases, Madras Medical Mission,
Chennai
Renalase is a recently discovered secretory enzyme that is expressed in kidneys, neuronal tissues, skeletal muscle, heart
and liver. A genetic link between renalase and hypertension has been reported in Chinese and Caucasian populations.
We undertook case-control studies in two ethnically-distinct Indian populations to assess possible associations between two
renalase single nucleotide polymorphisms [SNP] (viz. rs2576178, A>G and rs10887800, A>G in the promoter and intron

6 regions, respectively) and essential hypertension. We genotyped 659 North Indian and 1206 South Indian subjects by
polymerase chain reaction-restriction fragment length polymorphism method. An increase in the variant allele frequency of
both SNPs was observed in hypertensive cases as compared to normotensive controls in both populations. Logistic regression
yielded nominal association of both SNPs with hypertension in South Indian population (rs2576178: GG vs AA OR=1.54,
95% C.I.=0.97-2.43, p=0.049; rs10887800: GG vs AA OR=1.43, 95% C.I.=1.00-2.03, p=0.047) and in the North Indian
population (rs2576178: AG vs AA OR=1.44, 95% C.I.=1.04-1.98, p=0.028; rs10887800: GG vs AA OR=1.59, 95% C.I=1.00-
2.52, p=0.048). A meta analysis of these two SNPs utilizing data from seven different studies showed a global significance
in their associations with hypertension when the fixed effect model was considered (rs2576178: A vs G OR=1.17, 95%
C.I.=1.08-1.27, p=0.0001; rs10887800: A vs G OR=1.13, 95% C.I.=1.04-1.23, p=0.003). Transfection of promoter-luciferase
reporter/intronic region-luciferase reporter plasmids harboring the variant G alleles showed reduced luciferase activities in
kidney HEK-293 and neuroblast IMR32 cells. Computational predictions suggested differential binding of several transcription
factors (viz. CREB, c-Rel and IRF-1) at the promoter SNP site. Thus, the renalase SNPs rs2576178 and rs10887800 appear
to be functional and increase the risk of hypertension in various ethnic populations.
Thu(5)-O57-2
APOL1 risk allele is associated with early diagnosis of hypertension and a 2-3 mmHg increase in systolic
blood pressure in young African American adults
Genevieve Galarneau 1 ，Girish N Nadkarni 1 ，Stephen B Ellis 1 ，Rajiv Nadukuru 1 ，Stuart A Scott 1 ，
Rongling Li 2 ，Laura J Rasmussen-Torvik 3 ，Abel N Kho 3 ，M Geoffrey Hayes 3 ，Jennifer A Pacheco 3 ，
Teri A Manolio 2 ，Rex L Chisholm 3 ，Dan M Roden 4 ，Joshua C Denny 4 ，Eimear E Kenny 1 ，Erwin P Bottinger 1 ，
The eMERGE Network
1:Icahn School of Medicine at Mount Sinai, USA、2:National Human Genome Research Institute, National Institutes of Health、3:Feinberg
School of Medicine, Northwestern University、4:Vanderbilt University Medical Center
APOL1 is associated with end-stage renal disease in hypertensive African Americans (AA). We explored whether the APOL1
risk allele is associated with blood pressure (BP) traits in AA in three biobanks in the Electronic Medical Records and
Genomics (eMERGE) network.
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The discovery cohort consisted of 5,204 AA from Mount Sinai BioMe biobank. Replication cohorts consisted of additional
AA from BioMe (n=1,623), Vanderbilt BioVU (n=1,809) and Northwestern NUgene (n=567). Median follow-up was of 5, 3,
6 and 8 years, respectively. SNPs determining the APOL1 G1 and G2 alleles were genotyped in BioMe and imputed with
Illumina 1M data in BioVU and NUgene. We performed association tests with APOL1 high-risk status (two copies of G1/G2)
and used METAL for meta-analyses of replication cohorts.
There were 14%-16% APOL1 high-risk individuals across cohorts. In 457 APOL1 high-risk individuals with hypertension
(HTN), median documented onset of HTN was 2-5 years younger (Pdis =0.04 and Prep =3x10-4 in a Cox proportional hazards
analysis with age, sex and BMI as covariates).
To test if there were age-specific associations between the APOL1 risk status and systolic (SBP) or diastolic (DBP) blood
pressure, we divided the cohorts in 20-year age groups (20-39, 40-59 and 60-79) and performed linear regressions with
sex and BMI as covariates. In the 20-39 yo AAs without antihypertensive medications, the risk status accounted for 2-3
mmHg SBP elevation (Ndis =946; Pdis =0.04; Prep =1.9x10-3 and Ndis =822; Pdis =0.07; Prep =0.04 with sex, BMI and eGFR
as covariates). The association between APOL1 high-risk status and SBP was already observed in 20-29 yo (Ndis =424;
Pdis =0.02; Prep =7.2x10-3 ) at which age we did not observe an association with eGFR (Ndis =403; Pdis =0.96; Prep =0.75;
Pcom =0.77).
Conclusion: Compared to other known BP loci, APOL1 is a large effect size locus for SBP in young AAs that may account

in part for well-documented higher BP and health disparities associated with HTN in younger AAs.
Thu(5)-O57-3
DNA methylation in arteries and peripheral blood of patients with atherosclerosis
Anton V. Markov 1,2 ，Maria S. Nazarenko 1,2
，Aleksei A. Sleptcov 1,2
，Aleksei V. Frolov 3 ，Olga L. Barbarash 3 ，
Valery P. Puzyrev 1,2
1:Laboratory of Population Genetics, Research Institute of Medical Genetics, Russia、2:Tomsk State University、3:Research Institute for
Complex Problems of Cardiovascular Diseases
Development of atherosclerotic plaque is accompanied by changes in expression of series of genes involved in molecular and
cell pathological events, and corresponding epigenetic alterations. High-throughput technologies allow genome-wide scanning
for loci differentially methylated in vivo in various tissues. The aim of our study was to estimate DNA methylation patterns
in artery tissues and peripheral blood leukocytes of Russian patients with atherosclerosis. We investigated genomic DNA
samples extracted from advanced atherosclerotic lesions of carotid (n=60) and coronary (n=22) arteries, normal internal
thoracic arteries (ICAs, n=22), saphenous veins (SVs, n=22) and peripheral blood leukocytes (PBLs, n=85) obtained from
those patients. Genome-wide methylation screening was performed on Illumina microarray-based platform «Infinium Hu-
manMethylation27 BeadChip» (including 27578 CpG-sites of 14425 genes), and the results for certain loci were verified by
bisulfite pyrosequencing. We demonstrated artery tissues and PBLs are highly differentiated based on their DNA methylation
patterns. Variable methylation in atherosclerotic plaques compared to ICAs was found for genes involved in immune response,
inflammation, apoptosis, responses to various stimuli (e.g. lipids), cell differentiation, and morphogenesis. The most used
in arterial grafting ICAs and SVs differed from each other by variably methylated loci associated with embryogenesis and
developmental processes. Besides, we verified HOXD4 promoter region (coding miR-10b) and MEST exon 1a are hypomethy-
lated, but AATK exon 11 is hypermethylated in atherosclerotic plaques and PBLs in comparison with ICAs and SVs. Thus
investigation of DNA methylation variability in vessels and PBLs enriches current knowledge about molecular pathobiology
of atherosclerosis. The study was supported by the Russian Science Foundation (14-15-00305).
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Thu(5)-O57-4
A locus near GRAMD1B is associated with serum level of atheroprotective anti-phosphorylcholine: ge-
netic effects shared with chronic lymphocytic leukemia
Xu Chen 1 ，Stefan Gustafsson 2 ，Robert Karlsson 1 ，Jie Song 1 ，Iffat Rahman 3 ，Jun Su 3 ，Lars Lind 4 ，
Gunnar Engstrom 5 ，Kenneth Caidahl 6 ，Johan Frostegard 3 ，Patrik K.E Magnusson 1
1:Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden、2:Department of Medical Sciences, Molecular
Epidemiology and Science for Life Laboratory, Uppsala University、3:Institute of Environmental Medicine, Karolinska Institutet, Stockholm,
Sweden、4:Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University、5:Department of Clinical Sciences, Lund
University, Malmo, Sweden、6:Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Background : Phosphorylcholine is a major exposed epitope in oxidized low-density lipoproteins. Blood level of IgM antibodies
against phosphorylcholine (anti-PC) has previously been reported to be negatively associated with the risk of atherosclerotic
cardiovascular disease (ASCVD). Anti-PC level is significantly heritable but no specific genetic variants involved have been
identified so far.
Methods and Results: Independent genome-wide association studies for anti-PC level were performed in three Swedish cohorts
(TwinGene, PIVUS and MDC) and subsequently included in a discovery meta-analysis (total N=3001). The results revealed
two genome-wide significant loci: 1p31.3 (P=1.7x10-8 ) and 11q24.1 (P=4.4x10-8 ). Validation of these two loci was attempted
in a fourth Swedish cohort (PRACSIS, N=643). The locus on chromosome 1 did not replicate, while the chromosome 11 locus
did (P=4x10-4 ). The chromosome 11 locus is close to the gene GRAMD1B, which previously has been reported to influence
the risk for chronic lymphocytic leukemia (CLL) in large GWAS meta-analyses. Inspired by this apparent sharing of genetic

influences between a blood marker for ASCVD and CLL, we undertook twin-based structural equation modeling of ASCVD
and CLL in the Swedish Twin Registry(80000 complete twin pairs). The two diseases showed a phenotypic correlation of 0.52
(95% CI 0.46-0.59) a bivariate heritability (the proportion of the phenotypic correlation attributed to genetics) of 61% (95%
CI 59-73%) and a genetic correlation of 0.74 (95% CI 0.70-0.98).
Conclusions: Genetic variants close to GRAMD1B at 11q24.1 that increase the risk for CLL are co-localized with variants
influencing blood level of atheroprotective anti-PC, indicating a potential common immunological mechanisms underlying
anti-PC, ASCVD and CLL.
Thu(5)-O57-5
Familial Thoracic Aortic Aneurysms and Dissections (FTAAD) with ACTA2 Mutation in Japanese
Takayuki Morisaki 1 ，Akiko Yoshida 1 ，Tomohiko Watanabe 1 ，Kazufumi Ida 1 ，Hiroaki Sasaki 2 ，Tatsuya Oda 2 ，
Hiroshi Tanaka 2 ，Kenji Minatoya 2 ，Hiroko Morisaki 1
1:Bioscience and Genetics, and Medical Genetics, National Cerebral and Cardiovascular Center, Japan、2:Cardiovascular Surgery, National
Cerebral and Cardiovascular Center
More than ten genes were identified to be pathogenic for young and familiar aortic diseases since FBN1 gene mutations were
identified in Marfan syndrom,. We have investigated genetic mutations for more than 1,500 Japanese patients and their family
member with young or hereditary aortopathy. Among them, we identified 21 mutations for ACTA2 gene in 34 patients in
addition to 438 FBN1 mutations in patients with Marfan syndorome, and diagnosed these patients with familial thoracic
aortic aneurysms and dissections (FTAAD) with ACTA2 mutation. These patients did not show any syndromic feature of
connective tissue disorders characteristic for Marfan syndrome, therefore they were not diagnosed as genetic aortopathy until
the genetic study was performed. On the other hands, some of these patients with R179 or R258 mutation did show cerebral
arterial characteristics including stretched and narrowed peripheral arteries with or without cerebral arterial aneurysms. Also,
patients with FTAAD with ACTA2 mutation tended to have the characteristics of ascending thoracic aortic aneurysm or
descending aortic aneurysm/dissection rather than dilatation of Valsalva sinus. Since clinical characteristics sometimes do
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not help to get proper diagnosis of genetic disease in these patients, it may be important to perform a genetic study for better
management of patients and relatives. Better recognition of FTAAD with gene mutation is needed to prevent aortic events
in these patients.
Thu(5)-O57-6
Context-specific eQTLs implicate potential obesity-related transcriptional control by diet in men
Arthur Ko 1,2 ，Marcus Alvarez 1 ，Elina Nikkola 1 ，Rita M Cantor 1 ，Mete Civelek 3 ，Aldons J Lusis 1,4 ，
Johanna Kuusisto 5 ，Michael Boehnke 6 ，Karen L Mohlke 7 ，Markku Laakso 5 ，Paivii Pajukanta 1,2,8
1:Department of Human Genetics, University of California, Los Angeles, USA、2:Molecular Biology Institute at UCLA、3:Center for
Public Health Genomics, University of Virginia、4:Department of Medicine, David Geffen School of Medicine at UCLA、5:Department of
Medicine, University of Eastern Finland and Kuopio University Hospital、6:Department of Biostatistics and Center for Statistical Genetics,
School of Public Health, University of Michigan、7:Department of Genetics, University of North Carolina, Chapel Hill、8:Bioinformatics
Interdepartmental Program, UCLA
Obesity is a serious risk factor for cardiometabolic disease but GWAS variants explain only 2.7% of the variance of body
mass index (BMI). Taken together with the continuous increase in obesity prevalence, environmental and gene-environment
interactions (GxEs) likely play a major role in the epidemic susceptibility to obesity world-wide. Accordingly, we hypothesized
that the cellular obese environment alters the effects of regulatory DNA variants, leading to allele-dependent responses to
obesity. These regulatory variants may display context-specific interactive effects on gene expression that can be mapped as
context-specific expression quantitative trait loci (cseQTL). We investigated two obesity traits, BMI and fat mass percent

(fat%), for transcriptome-wide trait-SNP interaction effects on gene expression. We used ~ 8.9M variants and adipose RNA-
sequence data on 14,763 expressed genes in 789 men from the Finnish METSIM cohort to test the significance of trait-SNP
interaction term on expression (FDR<5%). Overall, we identified 58 BMI cseQTL genes (cse-genes) regulated by 307 cis
(±1Mb) variants (cseSNPs), and 58 fat% cseQTL-genes regulated by 251 cis cseSNPs, with six genes overlapping between
the two traits. Notably, 54.1% of the cseSNPs do not display a nominal cis eQTL effect (P<0.05), suggesting that they only
act in an obesity-dependent manner. Six fat% cse-genes, ACLY , LCOR, PDCD4 , PRMT5 , PTGER3 , and SEMA3G, have
previously been identified for diet-induced obesity in mouse and human studies, suggesting them as diet-dependent cseQTLs.
The expression of the 58 fat% cse-genes explains a large proportion (17.7%) of fat% variance (P<0.001 by permutations, and
significantly more than random gene sets (P=0.004)). In summary, we demonstrate cseQTLs as a form of GxEs in obesity.
Specifically, more than half of cseQTLs show no regulatory effect without mediation by obesity and many diet-induced obesity
genes show context-specific transcriptional regulation.
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Thu., April 07, 2016 8:00-9:30 Room H (1F)
Chair：Jian-Min Chen（INSERM U1078 and EFS-Bretagne, Brest, France）

Chair ：Issei Imoto（Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate
School, Japan）
Thu(5)-O58-1
Alternative Splicing in Response to Ionizing Radiation
Niema Razavian 1 ，Vivian G Cheung 1
1:University of Michigan, Department of Pediatrics, Howard Hughes Medical Institute, USA
This project expands our understanding of cellular response to ionizing radiation by identifying alternatively spliced genes in
human B-cells. Over 50% of cancer patients receive radiation therapy. Previously, our group and others have identified that
changes in gene expression are a critical component of radiation response. Advances in RNA sequencing technologies now
facilitate the detection of gene expression changes as well as alternative splicing events. Here, we exposed cultured B-cells from
10 individuals to 10 Gy of ionizing radiation, and performed RNA sequencing before, and 2 and 6 hours following radiation
treatment. From about 60 million reads per sample, we determined the expression levels of genes and their isoforms, as well
as quantified five types of splicing events: cassette exons, retained introns, mutually exclusive exons, and alternative 5’ and

3’ splice sites. We found that the total expression levels of 3,081 genes changed significantly (ANOVA, p<0.01) following
radiation treatment. Among these radiation responsive genes are ATM , MDM2 , and GADD45B. Moreover, the expression
levels of gene isoforms also changed: for example, of the three RAD45B isoforms, one was induced, one was repressed, and
a third remained unchanged following radiation treatment. Among the over 16,000 splicing events detected, we found 379
cassette exons, 138 retained introns, 15 mutually exclusive exons, and 91 alternative 5’ or 3’ splice sites in irradiated cells.
These radiation-induced splicing events occurred primarily in genes involved in apoptosis, DNA damage response, and cell
cycle regulation. Finally, to understand how this stress response is controlled, we identified 12 groups of genes with similar
patterns of radiation-induced splicing. In this presentatio, I will describe radiation-induced alternative splicing by discussing
the genes that are alternatively spliced and sequence motifs that are enriched among these genes.
Thu(5)-O58-2
RNA sequencing reveals stress responses of iPSC-derived endothelial cells isolated from peripheral blood
mononuclear cells of supercentenarians
1,2 1,2
Cristine R. Casingal ，Hirofumi Nakaoka ，Yasumichi Arai 3 ，Nobuyoshi Hirose 3 ，Ituro Inoue 1,2
1:Division of Human Genetics, National Institute of Genetics, Japan、2:Department of Genetics, The Graduate School for Advanced Studies,
Kanagawa, Japan、3:Center for Supercentenarian Study, Keio University School of Medicine, Tokyo, Japan
Exceptional longevity (EL) is thought to be the outcome of multiple processes that involves genetic and environmental factors.
One of the features involved in EL is a higher stress resistance. Recent studies on the naked mole rat, a subterranean long-
lived mammal, showed remarkable endurance/tolerance to various genotoxic stresses. Thus we hypothesized that resistance
or flexibility against stresses may be a determinant of EL. Our objective is to investigate transcriptional responses of induced
pluripotent stem cell-derived endothelial cells (iPSC-ECs) from supercentenarians (SC) and controls (CTRL) after stress
treatment.
We analyzed 33 RNA sequence data of iPSC-ECs isolated from peripheral blood mononuclear cells of nine SC and four CTRL
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before and after hypoxia and hydrogen peroxide (H2 O2 ) treatments. To assess gene expression changes, pairwise comparisons
were tested.
Our results showed that the number of differentially expressed genes (DEGs) increased by 46% after hypoxia treatment from
470- (CTRL_NULL vs. SC_NULL) to 874 DEGs (CTRL_HY vs. SC_HY). By evaluating the overlap of these comparisons,
we identified 666 DEGs that were exclusive to hypoxia treatment; however, these DEGs were not enriched to any gene ontology
(GO) process. For the H2 O2 treatment, the number DEGs decreased by 40% from 470- (CTRL_NULL vs. SC_NULL) to
280 DEGs (CTRL_ H2 O2 vs. SC_ H2 O2 ). The 217 DEGs exclusive to H2 O2 treatment were enriched to GO process involved
in cell-cell signaling.
Gene expression analysis identified specific genes that responded to stress treatment. We investigated the involvement of
these DEGs in stress response. The result of this study may provide a better understanding of their contributions to EL.
Thu(5)-O58-3
Differential extracellular abundance of COG5 in synovial fluid following meniscal injury supports its role
as a major susceptibility gene for knee osteoarthritis
Liyong Wang 1,2 ，Danica D. Vance 3,4 ，Arpit Mehta 1 ，Evadnie Rampersaud 1 ，Bryson P. Lesniak 4 ，Jeffery M. Vance 1,2
，
Margaret A. Pericak-Vance 1,2 ，Lee D. Kaplan 3

1:John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, USA、2:Dr. John T. Macdonald Foundation
Department of Human Genetics, University of Miami Miller School of Medicine、3:UHealth Sports Performance and Wellness Institute,
University of Miami Miller School of Medicine、4:Department of Orthopedic Surgery, New York Presbyterian Hospital, Columbia University
Medical Center
Genome-wide association studies (GWAS) identified a region on chromosome (Chr) 7q22 as the top hit for knee Osteoarthritis
(OA), where six genes (PRKAR2B, HPB1 , COG5 , GPR22 , DUS4L and BCAP2 ) reside. Dissecting roles of these genes in
OA by association studies is limited by the high linkage disequilibrium in the region. To this end, we have adopted a knee
injury model to study molecular changes during OA development. Traumatic knee injury is a robust risk factor to OA: ~ 50%
of knees with a previous injury develop OA 5 ~ 15 years post-injury. We hypothesize that molecular changes are initiated
at the time of injury and evolve during the symptom-free period, leading to manifestations of OA years later. To monitor
molecular changes within the joint in vivo, extracellular RNAs in the synovial fluid were analyzed in eight male patients (24
~ 48 years of age) at different time points (1 ~ 7 months) after a meniscal injury. Extracellular RNAs were sequenced on
Illumina HiSeq2000. The normalized RNA level is expressed as count per million (CPM). In total, 764 species of extracellular
RNAs (including coding, non-coding RNA and microRNA) were present in the synovial fluid (CPM>1 in ≥ two samples).
At false discovery rate (FDR) of 0.05, 65 RNAs were increased and 78 RNAs were decreased in samples with longer injury
duration (late) compared to samples with shorter injury duration (early), demonstrating dynamic changes following injuries.
Among the six genes on Chr 7q22, only COG5 is detected in our study. The abundance of COG5 is decreased by >10 times
in late samples compared to early samples (FDR=4.7x10-3 ). Others have shown that the risk allele reported in GWAS is
associated with lower COG5 expression in cartilage. We propose that lower COG5 expression directed either by the risk
allele or an injury increases OA risk. Our study supports COG5 as a susceptibility gene for knee OA and suggests the utility
of using RNA biomarkers in synovial fluid in OA study.
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Thu(5)-O58-4
Heterogeneity in the individual transcriptomic response to severe sepsis
Katie L Burnham 1 ，Emma E Davenport 1 ，Jayachandran Radhakrishnan 1 ，Peter Humburg 1 ，Paula Hutton 2 ，
Christopher S Garrard 2 ，Charles J Hinds 3 ，Julian C Knight 1
1:Wellcome Trust Centre for Human Genetics, UK、2:Adult Intensive Care Unit, John Radcliffe Hospital, Oxford, UK、3:William Harvey
Research Institute, Barts and the London School of Medicine, UK
Sepsis remains a major global health issue with mortality rates >30%. Although conventionally considered a single unified
disease, substantial clinical heterogeneity is seen. Investigation of this variation could yield insights into pathogenesis and
provide opportunities for precision medicine. We therefore aim to use transcriptomic profiling to identify clinically relevant
differences between patients upon admission to the intensive care unit (ICU).
We present data for 505 patients with severe sepsis due to community acquired pneumonia (CAP) or faecal peritonitis (FP)
recruited to the Genomic Advances in Sepsis study. Detailed phenotypic information was recorded and serial samples taken
over the first five days following admission to ICU. Gene expression in leukocytes was quantified for 47,231 probes using
Illumina HumanHT-12v4 Expression BeadChip arrays. We hypothesised that inter-individual patient heterogeneity would
exist both within and between sepsis aetiology groups CAP and FP.
We identified two subgroups with distinct immune response profiles in the CAP discovery cohort (n=265), one of which had
higher mortality (14-day mortality following ICU admission p=0.005) and features of immunosuppression. We designed a

classification model, in which gene expression was more informative than clinical covariates, and replicated our findings in a
CAP validation cohort (n=106). We observed comparable groups within FP patients (n=118), with an immunosuppressed
phenotype similarly associating with mortality (p=0.03). Differential gene expression between CAP and FP patients in the
derivation and validation cohorts indicated an anti-viral response unique to the CAP patients, who also demonstrated a
stronger pro-inflammatory response.
Our findings highlight the value of functional genomic approaches for identifying heterogeneity within patient cohorts and
have important implications for clinical management and patient stratification.
Thu(5)-O58-5
Inter-individual Variations in Nature and Diversity of Human Facial Skin Microbiome are Significantly
Predicted by Sebum and Hydration Levels in Specific Facial Regions
Souvik Mukherjee 1 ，Rupak Mitra 2 ，Arindam Maitra 3 ，Satyaranjan Gupta 2 ，Srikala Kumaran 2 ，Amit Chakrabortty 2 ，
Partha P Majumder 3
1:BioMedical Genomics Centre, National Institute of Biomedical Genomics, India、2:Unilever R&D, Bangalore, Karnataka, India、3:National
Institute of Biomedical Genomics, Kalyani, West Bengal, India
The skin microbiome varies widely between individuals.The causes of these variations are inadequately understood. We
tested the hypothesis that inter-individual variation in facial skin microbiome can be significantly explained by variation
in sebum and hydration levels in specific facial regions of humans. We measured sebum and hydration from forehead and
cheek regions of healthy female volunteers (n=30). Metagenomic DNA from skin swabs were sequenced for V3-V5 regions
of 16S rRNA gene. Altogether, 26 phyla were identified; predominantly Actinobacteria (66.3%), Firmicutes (17.7%), Pro-
teobacteria (13.1%) and Bacteroidetes (1.4%). About 1000 genera were identified; predominantly Propionibacterium (58.6%),
Staphylococcus (8.6%), Streptococcus (4.0%), Corynebacterium (3.6%) and Paracoccus (3.3%). To assess temporal changes,
a subset (n=24) of individuals were sampled two months later. Stepwise multiple regression analysis showed that cheek
sebum level was the most significant predictor of microbiome composition and diversity followed by forehead hydration
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level; forehead sebum and cheek hydration levels were not. With increase in cheek sebum, the prevalence of Actinobacteria
(p=0.001)/Propionibacterium (p=0.002) increased, whereas microbiome diversity decreased (Shannon Index, p=0.032); this
was opposite for other phyla/genera. These trends were reversed for forehead hydration levels. Our findings provide first
direct evidence that levels of sebum and hydration in specific regions of facial skin are significantly associated with distri-
bution of specific bacterial taxa inhabiting the stratum corneum.The community structure (Bray-Curtis Index) varied across
individuals, whereas the community membership (Jaccard Index) was relatively conserved. Considerable differences were
observed in reference skin microbiome between Asian (this study) and Western populations, reinstating the need for more
such studies in non-Western populations with diverse population histories.
Thu(5)-O58-6
Meta-analysis of 1343 small complex mutations causing human inherited disease reveals a new mutational
signature characteristic of the action of translesion synthesis DNA polymerases in the human genome
1,2,3 1,2,3 4
Jian-Min Chen ，Claude Ferec ，David N Cooper
1:Institut National de la Sante et de la Recherche Medicale (INSERM), U1078, Brest, France、2:Etablissement Francais du Sang (EFS)
Bretagne, Brest, France、3:Faculte de Medecine et des Sciences de la Sante, Universite de Bretagne Occidentale (UBO), Brest, France、
4:Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom
Spontaneous germline mutations are the driving force behind both human genome evolution and inherited disease. Therefore,
understanding their rate, mutational signatures and generative mechanisms has always been a central theme in human

genetics. Among the different approaches employed to study these issues, the meta-analysis of mutations causing human
inherited disease has three key advantages. First, as a unique source of naturally occurring mutations, pathogenic mutations
harbor important informational clues as to the nature of the underlying mutational mechanisms that impact upon the human
genome. Second, owing to negative selection, most of the rare disease-causing mutations should have occurred comparatively
recently. Third, the authenticity of mutations (particularly those complex ones) can be ensured by manual evaluation of
the original reports. The Human Gene Mutation Database (HGMD; www.hgmd.org) represents a comprehensive collation of
mutations underlying human inherited disease. Based upon mutational signatures of multiple-nucleotide substitution (MNS)
mutations (two or more nucleotide changes occurring without any net gain or loss of bases with respect to the reference allele
in closely spaced sites), we have recently postulated two properties of translesion synthesis (TLS) DNA polymerases in DNA
repair: namely, the generation of neo-microhomologies for potentiating strand-misalignment, and additional micro-lesions
within the templated inserts when recruited to stalled replication forks. Herein we meta-analyzed all 1343 small complex
mutations (concurrently generated deletion and insertion at a same site resulting in a net gain or loss of bases; either loss or
gain of bases is <20 bp) registered in the Professional version of HGMD (as of June 2013). This analysis not only provided
supporting evidence for our previous postulate but also revealed a new mutational signature characteristic of the action of
TLS DNA polymerases in the human genome.
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ICHG2016 766
[O59] Health Services Research

Thu., April 07, 2016 9:45-11:15 Room H (1F)
Chair：Beatriz Marcheco-Teruel（National Center of Medical Genetics, Havana, Cuba）

Chair ：Hiroshi Tanaka（Tohoku Medical Megabank Organization, Tohoku University, Japan）
Thu(5)-O59-1
Impact of Genome Sequencing on the Medical Care of Healthy Adults: A Randomized Controlled Trial
Jason L. Vassy 1,2 ，Kurt D Christensen 2 ，Dmitry Dukhovny 3 ，Carrie Blout 2 ，Jill Oliver Robinson 4 ，Joel B. Krier 2 ，
Michael F Murray 5 ，Amy L McGuire 4 ，Robert C Green 2,6 ，for the MedSeq Project
1:VA Boston Healthcare System, Harvard Medical School, USA、2:Brigham and Womens Hospital, Harvard Medical School、3:Oregon Health
& Science University、4:Baylor College of Medicine、5:Geisinger Health System、6:Partners HealthCare Personalized Medicine
Background: Genome sequencing (GS) in healthy adults might enable early disease prevention and detection, but it might
also lead to costly and harmful medical interventions. We measured medical care and costs after GS to quantify theses risks
and benefits.
Methods: In the MedSeq Project, 9 primary care physicians (PCP) were enrolled to participate with their patients (n=100)
in a trial of GS in primary care. Eligible patients were 40-65 years old and deemed generally healthy by their PCPs. Patients

were randomized to receive a family history report only (FH) or a FH report plus an interpreted GS report (FH+GS). The
GS reports included variants in ~ 4600 genes associated with monogenic disease, recessive carrier states, and polygenic risk
estimates for 8 cardiometabolic traits. The PCP and patient met to discuss the reports, and the PCP completed a survey
identifying any clinical actions taken as a result. Six months after disclosure, chart reviewers abstracted data on utilization and
concordance with U.S. Preventive Services Task Force (USPSTF) Grade A and D guidelines. Medical costs were determined
from billing data and Medicare price weights. We compared outcomes in the 2 arms with non-parametric tests.
Results: After 98 results discussions to date, PCPs reported ordering significantly more cardiac tests for FH+GS vs. FH
patients (7 vs. 0, p=0.01), but not more lab tests (7 vs. 3), imaging studies (2 vs. 0), or referrals (6 vs. 6, all p>0.2). Among
the first 64 patients, the arms did not differ at 6 months in concordance with USPSTF guidelines, including colorectal cancer
screening and aspirin use, or in total imaging tests (22 vs. 30, p=0.75) or specialty visits (73 vs. 61, p=0.51). Mean 6-month
costs were ＄ 800 (FH) and ＄ 1136 (FH+GS, p=0.49).
Conclusion: Introducing GS to the care of healthy adults impacts PCPs’ immediate clinical decision-making but might not
change concordance with prevention guidelines or increase downstream healthcare utilization and costs.
Thu(5)-O59-2
Assessing the Clinical Utility of Family Health History for Guiding Preventive Care in the General Popu-
lation
Lori A Orlando 1 ，Rachel A Myers 1 ，Adam H Buchanan 2 ，R. Ryanne Wu 1 ，Elizabeth R Hauser 1 ，
Geoffrey S Ginsburg 1
1:Medicine, Duke University, USA、2:Geinsinger Health System
BACKGROUND: Family health history (FHH) is one of the most predictive risk assessment measures available. Numerous
guidelines and organizations support collecting and utilizing FHH to guide the selection of appropriate preventative and risk
management strategies, yet systematic assessment is rarely done in clinical care. This abstract presents the clinical utility of
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systematic FHH-based risk assessment when integrated into clinical care. METHODS: All patients with upcoming appoint-
ments in two primary care clinics were invited to complete MeTree, a program that collects three generation FHH to identify
risk level and appropriate guideline-based risk management for those at increased risk for breast, colon, or ovarian cancers,
hereditary cancer syndromes, or thrombosis. Recommendations are presented to providers and patients. To assess clinical
utility we conducted chart reviews one year after MeTree completion to assess whether patients received the recommended
risk management prior to completing MeTree vs. after. Primary outcome: agreement between risk management and risk
level before MeTree (pre-MeTree) compared to after (post-MeTree). RESULTS: Participants N=488; 42% (N=203) received
increased risk management recommendations. Agreement: pre-MeTree 0.04% (N=1); post-MeTree 73% (N=149). Optimiz-
ing risk management: Pre-MeTree 1/18 (5.6%) undergoing increased risk management were at increased risk. Post-MeTree
149/160 (93.1%) were at increased risk. This led to a reduction in high-risk strategies for patients not at high-risk from 17/18
(94.4%) to 11/160 (6.9%). CONCLUSIONS: In this pilot MeTree integration in primary care improved uptake of risk-stratified
guidelines and reduced “over-” and “under-use” of high-risk services. Further study in broad-based populations will help
to better understand the potential impact of systematic FHH-based risk assessment on quality, effectiveness, and equity in
the U.S. healthcare system.
Thu(5)-O59-3
A national program for preventing sickle cell anemia: the 30 years Cuban experience
1

Beatriz Marcheco-Teruel
Sickle-cell anemia is a genetic disease inherited with a recessive autosomal pattern. For a couple of carriers, there is a 25%
risk of having an affected offspring in each pregnancy. As average 3.5% of the Cubans carry a risk allele for this anemia, a
value which is almost double in the most Eastern part of the country. Every pregnant woman has the option of taking a test
to identify their risky condition. The preventive component of the program is based on the identification of the pregnant and
their husband as a couple at risk, the availability of genetic counseling at primary care level, the prenatal molecular test, the
option of terminate the pregnancy if it is requested when an affected fetus is confirmed and the early medical care for affected
children. From 1982 to December 2014, more than 4 million pregnants have been screened and out of them 153493 were
detected to be carriers or already affected by the disease. 87.2% of their husbands consented for the test about whether or
not they were carriers, and 7091 couples were identified as at risk of having an affected child. In 1982, at the beginning of the
program, there were around 100 births of affected children per year in the country. Thirty years later, with a 99% coverage
of pregnancies studied along the country, it has decreased to 10 affected newborns per year, most of them from couples that
even when they knew the condition of their future child, decided to continue pregnancy. In such cases, the national health
system has been prepared for their early care, backed up by multidisciplinary teams headed by hematologists in each Cuban
province, who are responsible for the healthcare and patients follow-up. The results of the Cuban strategy for sickle cell
anemia prevention show that it is possible, for a developing country, the design and implementation of a nationwide strategy
for the control and prevention of a genetic disorder in order to reduce its impact on mortality and morbidity of the population.
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Thu(5)-O59-4
Epidemiology and health system impact of true-positive and false-positive newborn screening results for
phenylketonuria in Ontario, 2006-2012
Beth K Potter 1 ，Sara D Khangura 1 ，Pranesh Chakraborty 1,2,3 ，Christine Davies 2 ，Doug Coyle 1 ，
Kumanan Wilson 4,5 ，Marni Brownell 6 ，Linda Dodds 7 ，Annette Feigenbaum 8,9 ，Deshayne B Fell 10 ，
Astrid Guttmann 5,8 ，Steven Hawken 5 ，Robin Hayeems 8 ，Jonathan B Kronick 8,9 ，Anne-Marie Laberge 11 ，
Aizeddin Mhanni 12 ，Meranda Nakhla 13 ，Cheryl Rockman-Greenberg 12 ，Rebecca Sparkes 14 ，Keiko Ueda 15 ，
Hilary Vallance 16 ，
with Brenda J Wilson, University of Ottawa; and on behalf of the Canadian Inherited Metabolic Diseases Research
Network
1:University of Ottawa, Canada、2:Newborn Screening Ontario、3:Children’s Hospital of Eastern Ontario、4:Ottawa Health Research
Institute、5:Institute for Clinical Evaluative Sciences、6:Manitoba Centre for Health Policy、7:Dalhousie University、8:The Hospital for
Sick Children、9:University of Toronto、10:Better Outcomes Registry and Network Ontario、11:Hopital Sainte-Justine、12:University of
Manitoba、13:Montreal Children’s Hospital、14:Alberta Children’s Hospital、15:BC Children’s Hospital、16:University of British Columbia
Objectives: Although population-based newborn screening (NBS) for phenylketonuria (PKU) has been in place in Canada
for decades, the health system impact of true-positive (TP) and false-positive (FP) results is poorly understood. We used
health administrative data from the province of Ontario to compare health services use in children who received TP, FP, and
screen-negative results.
Methods: Infants who underwent NBS for PKU in Ontario from 2006-2012 were identified as TP, FP or screen-negative.
We followed each child until his/her birthday in 2013, using person-years to calculate rates of emergency department (ED)

visits, inpatient hospitalizations and physician visits. Rate ratios (RRs) were generated and adjusted for sex, gestational age,
birthweight, socioeconomic status, and urban/rural residence.
Results: Of 877,299 eligible infants, 57 (0.006%) screened TP and 166 (0.02%) FP. ED visit rates were similar across the
three groups. However, relative to children with screen-negative results, those with TP or FP results for PKU experienced
higher rates of hospitalization; adjusted RRs were 6.15 (3.88-9.90) for TP and 5.09 (3.80-6.86) for FP results. Adjusted RRs
for physician visits were 1.49 (1.28-1.74) for TP and 2.97 (2.71-3.26) for FP results. Associations were strongest in the first
year of life.
Conclusion: Infants in Ontario with TP or FP NBS results for PKU from 2006-2012 had more frequent hospitalizations
and physician visits compared with screen-negative controls. In children with TP results, this may reflect monitoring to
establish metabolic control or inpatient admission to evaluate BH4-responsiveness. In children with FP results, findings may
be confounded by prematurity and/or underlying illness that requires total parenteral nutrition (TPN). In Ontario, newborns
with NBS results suggestive of TPN are referred for evaluation. Our findings underscore the importance of a health system
that can effectively support children with positive NBS results.
Thu(5)-O59-5
Three Dimentional Motion Capture System for Quantitative Evaluation of Motor Functions applied to
Healthy Adult and Spinal Muscular Atrophy Patient with Thyrotropine Releasing Hormone Therapy
Naoki Matsumaru 1,2 ，Zenichiro Kato 2,3 ，Katsura Tsukamoto 1 ，Ryo Hattori 4 ，Norihito Shimizu 4 ，Yasutaka Shii 4 ，
Hidenori Ohnishi 3 ，Norio Kawamoto 3 ，Toshiyuki Fukao 3 ，Tadayuki Kato 4 ，Takaaki Aoki 5 ，Kei Miyamoto 5 ，
Haruhiko Akiyama 5 ，Michinori Funato 6
1:Global Regulatory Science, Gifu Pharmaceutical University, Japan、2:Division of Structural Medicine, The United Graduate School
of Drug Discovery and Medical Information Sciences, Gifu University、3:Department of Pediatrics, Graduate School of Medicine, Gifu
University、4:Department of Rehabilitation, Gifu University Hospital、5:Department of Orthopedic Surgery, Graduate School of Medicine,
Gifu University、6:Department of Clinical Research, National Hospital Organization, Nagara Medical Center
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ICHG2016 769
Functional motor scales, such as Hammersmith motor function scale, are successfully employed to monitor clinically meaningful
changes. Since the scales are ordinal data, subtle improvements are inexpressable due to large gaps between scale points. We
have, thus, established a method, utilizing 3D-motion capture system, to evaluate motor functions as a linear measurement.
Our method estimates motor functionalities of the upper limb with two indexes: "Spatial Deviation (SpDe)" and "Direction
Variance (DiVa)". Intuitively, SpDe is the spatial volume occupied during the up-down movement of the arm, indicating the
repeat accuracy of the movements. The index of DiVa represents, in a sense, the smoothness of the arm motion.
We experimented on an adult and a SMA type II patient to demonstrate the usefulness of our method. The subjects were
instructed to perform the flexion movement multiple times continuously, composing one test. The movements of the right
elbow are tracked with 3D-motion capture system. For the non-handicapped adult, deteriorated motor functions are simulated
by holding 8kg weight, and two tests are performed with and without the load. For the SMA patient, two tests are performed
before and after Thyrotropine Releasing Hormone therapy to estimate the therapeutic efficacy. Comparing two tests for each
subject, the difference was apparent from visual assessment. Comparing with respect to the two indexes of SpDe and DiVa,
the difference was statistically significant with 5% significant level. We believe that these indexes reflect the motilities of the
upper limbs. Furthermore, the therapeutic efficacy can be evaluated with these indexes.
Advantages of this analysis method include the sharability of the data. The movement trajectories are just a data sequence
of xyz coordinates. With the help of developing standard evaluation protocols and constructing data warehouse, data can be
shared with all the other SMA researchers to bring ideas together for curing SMA.

Thu(5)-O59-6
Informing policy and practice: a 360 degree evaluation of the impact of prospective WES in comparison
to standard care
Clara L. Gaff 1 ，Ivan Macciocca 1,2 ，Melissa R. Martyn 1,3 ，William J. Wilson 4 ，Deborah Schofield 5 ，
Susan M. White 2,6 ，Zornitza Stark 2 ，Paul James 6,7 ，Andrew Roberts 7,8 ，Monique Ryan 9 ，Tim Day 7 ，Maie Walsh 2 ，
Patrick Kwan 7 ，Peiro Perucca 7 ，Alex Boussioutas 6,7,10 ，Graham Taylor 2 ，Alicia Oshlack 3 ，Natalie Thorne 1 ，
Tim Bakker 1 ，Evaluation team, Genetic Counselling team and the Melbourne Genomics Health Alliance
1:Melbourne Genomics Health Alliance, Australia、2:Victorian Clinican Genetics Services, Vic, Australia、3:Murdoch Childrens Research
Institute, Vic, Australia、4:Commonwealth Scientific and Industrial Research Organisation (CSIRO), Australia、5:University of Sydney,
NSW, Australia、6:University of Melbourne, Vic, Australia、7:Melbourne Health, Vic, Australia、8:Walter and Eliza Hall Institute, Vic,
Australia、9:Royal Children’s Hospital, Vic, Australia、10:Peter MacCallum Cancer Centre, Vic, Australia
Implementation of genomic medicine requires evidence to guide policy on the appropriate use of testing, secure funding for
testing, and ensure adoption of the most cost effective service delivery model.
The Melbourne Genomics Health Alliance is uniquely placed to evaluate the potential impact of genomic sequencing on
mainstream clinical practice. The Alliance includes five independent tertiary hospitals and five accredited testing laboratories
utilising common standards and tools for genomic sequencing, including a single shared clinical bioinformatics pipeline.
Analysis is restricted to genes related to the patient’s condition. Raw data is stored to permit reanalysis.
The impact of singleton whole exome sequencing (WES) on care was evaluated by prospectively offering testing to adults and
children (n=315) with germline or somatic conditions (inherited neuropathies, epilepsy, childhood-onset Mendelian conditions,
acute myeloid leukaemia and hereditary colorectal cancer), in parallel with standard investigations.
A“360 degree” impact evaluation of WES in comparison to standard care was conducted, drawing diverse data sources
including test results, clinical notes, hospital cost data, participant surveys (n>160) and semi-structured interviews with
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clinicians (n>28) and other stakeholders (n=14).
Preliminary analysis (n=228) shows pathogenic or likely pathogenic variants were detected in 30% of patients (range 10-60%).
Reanalysis of stored data to detect variants in newly identified genes or a wider list of genes has resulted in additional diagnoses.
Condition-specific detection rates, cost and impact on management in comparison to standard care will be presented, as well
as clinician and participant views on clinical and personal utility, and impact of the study on adoption of WES in wider
clinical practice.
This evaluation will inform the beginning of policy development to guide the use - and non-use - of genomics in clinical
practice.
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Abstracts
Poster Session
ICHG2016 772
Poster Session
Cancer Genetics 1
Mon., April 04, 2016 19:40-20:40 Event Hall (1F)
Mon(2)-P-1
TP53 gene status in patients with Diffuse large B-cells lymphoma
Elena Voropaeva 1 ，Tatiana Pospelova 2 ，Mikhail Voevoda 1 ，Vladimir Maximov 1
1:Institute of Therapy and Preventive Medicine, Russia、2:Novosibirsk State Medical University
Different mechanisms such as deletions and mutations of TP53 have been shown to be involved in lymphomogenesis. Methy-
lation of promoter region of TP53 is associated with low expression levels of this gene. The goal of this work was to study
the mutations, loss of heterozygosity (LOH) and hypermethylation of the promoter region TP53 gene frequencies in Russian
patients with Diffuse large B-cells lymphoma (DLBCL).
Material and Methods: Genomic DNA was isolated from formalin-fixed, paraffin embedded tissue blocks of 74 patients with
DLBCL. Direct sequence analysis of TP53 gene was performed. LOH in the TP53 gene was determined by D17S796 in
tumoral and normal tissue of patients. Methylation status of TP53 promotor was studied using methylation-specific PCR.
Poster Session
Results: 28 mutations in the coding sequence of the TP53 gene were identified: 18 (64,29%) - missense, 6 (21.43%) - silent,
2 (7.28%) - nonsense, 1 (3.50%) - frameshift and splice. Four patients had a multiple mutations. p.Cys275Ser, p.Val272Glu,
p.Thr155Ile and p.Arg212Term have met several times in the cohort. The potentially protein function damaging of TP53
mutations were found in 17 (22.9%) patients, including the p.Arg212Term and p.Ala189fs. LOH in the TP53 gene was de-
tected in 4 cases from 17 patients (11.8%) with potentially function damaging of p53 mutations. All of the damaging missense
mutations with the exception of p.Pro316His are located in DNA binding region (DBR). IVS4-30T>C, IVS6-36G>C and
IVS9+12T>C should be noted among the intronic mutations as a potentially significant. The frequency of TP53 promoter
region hypermethylation in our study was 5.4%.
Conclusions: Codons 275, 155, 272 and 212 were the hot spots of mutation in our study. High frequency of TP53 mutations
in region of the gene encoding the DBR is a reflection of their functional selection. The frequencies of TP53 promoter region
hypermethylation and LOH in the TP53 gene in our study were very low.
Mon(2)-P-2
Withdrawn

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Mon(2)-P-3
Germline mutation and IHC result of MLH1 and MSH2 in young-onset nonpolyposis colorectal cancer
in Thai families: Two novel germline mutations of MLH1 in two siblings and a novel mutation of MSH2
Atchara Tunteeratum 1 ，Artit Jinawath 2 ，Chanon Kunasol 1 ，Natini Jinawath 3 ，Jakrise Eu-ahsunthornwattana 1 ，
Manisa Busabaratana 1 ，Kanoknan Srichan 1 ，Thanyachai Sura 1
1:Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand、2:Pathology, Faculty of Medicine Ramathibodi
Hospital, Mahidol University、3:Research center, Faculty of Medicine Ramathibodi Hospital, Mahidol University
Background:
Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome I (OMIM#120435) is an autosomal dominant trait
and caused by a germline mutation in mismatch repair (MMR) genes. HNPCC is caused by mutations in the MLH1 and
MSH2 genes which account for 90% of HNPCC cases.
Objective:
1. To study the incidence and correlate the genotype-phenotype relationship of germline mutation in MLH1 and MSH2
2. To correlate IHC result and germline mutation in MLH1 and MSH2
3. To encourage genetic testing for MLH1 and MSH2 in at-risk pre-symptomatic patient.
Poster Session
Methods:
We recruited all young-onset (age < 50 years) non-polyposis colorectal cancer in Ramathibodi hospital since 2005 until
present. Direct whole gene sequencing in MLH1 and MSH2 was applied in all cases after confirmed of malignancy by tissue
pathological report. Their tissues were also tested by immunohistochemistry for MLH1 and MSH2 protein expression. Their
at-risk relatives would also be encouraged to have genetic test and an appropriate cancer surveillance program to prevent
developing of CRC.
Results:
In our two expanded-families which their family history fit to Amsterdam II criteria, we found CC deletion at c.1404 and G
deletion at c.2210+1 in MLH1 of two siblings in Family#1 and G deletion at c.2210+1 in MSH2 in Family#2. These are
novel mutations causing frameshift mutation in both MMR genes without clinical difference.
Conclusion:
HNPCC is a genetically heterogeneous disease. Our preliminary result revealed 2 new disease-causing mutations in MLH1 and
MSH2 genes which parallel with their absent of MLH1 protein expression of two siblings in a family. Germline analysis may
help us screened in pre-symptomatic cases and offer an appropriate cancer screening program. This will help the susceptible
patients to receive early diagnosis and treatment before develop advanced CRC.
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Mon(2)-P-4
Low grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma: studies on impact of gene fusions
on gene expression profile and tumor development
Elsa Arbajian 1 ，Linda Magnusson 1 ，Jenny Nilsson 1 ，Karolin Hansén Nord 1 ，Fredrik Mertens 1
1:Clinical Genetics, Lund University, Sweden
Bone and soft tissue tumors (BSST) are a group of heterogeneous lesions of mesenchymal or neuroectodermal. They are
often characterized by specific genetic rearrangements in the form of deregulated genes or chimeric fusion genes resulting from
structural chromosomal aberrations - translocations, inversions and deletions. Sclerosing epithelioid fibrosarcoma (SEF) and
low grade fibromyxoid sarcoma (LGFMS) are two fibroblastic/myofibroblastic soft tissue tumor types thought to be closely
related. This relationship was initially suggested by the finding of a subset of cases showing morphologic overlap of both
SEF and LGFMS characteristic features. However, several recent studies have shown a genetic dichotomy where the majority
of each of SEF and LGFMS cases displayed different characteristic fusion genes, EWSR1 -CREB3L1 and FUS-CREB3L2
respectively. As these tumors displayed few other known genetic aberrations, it is reasonable to assume that morphologic
and biologic differences are related to type of gene fusion. Thus we intend to study differences in gene expression profiles in
inducible Tet On 3G cell lines expressing these fusions, as well as in tumor tissue.
Mon(2)-P-5
Pediatric individualized dosing of Cyclophosphamide using Pharmacogenetics of CYP2B6 as a response-
Poster Session
biomarker in Rhabdomyosarcoma Egyptian Patients
1,2 3,4
Rania M Labib ，Enas Elnadi ，Dina Yassin 5 ，Mohamed E.A Abdelrahim 2
1:Research, Children’s Cancer Hospital, Egypt、2:Clinical Pharmacy, Faculty of Pharmacy, Beni Suef University, Beni Suef, Egypt、3:Pediatric
Oncology, Children’s Cancer Hospital-Egypt、4:Pediatric Oncology, Beni Suef University faculty of medicine, Beni Suef, Egypt、5:Molecular
Biology, Children’s Cancer Hospital-Egypt, Cairo, Egypt
Rhabdomyosarcoma (RMS) is a small blue round cell malignant tumor accounting for 7% of childhood malignancies and
for over 50% of all soft tissue sarcoma. Cyclophosphamide (CPA) is a prodrug used in the treatment of RMS. CYP2B6 is
one of the highly polymorphic liver CYP450 drug metabolizing enzymes involved in CPA bioatcitvation. Here, we aimed to
determine 3 single nucleotide polymorphisms (SNPs) in CYP2B6 (G516T, A785T and C1459T) and frequencies of CYP2B6*4
CYP2B6*5, CYP2B6*6, CYP2B6*7 and CYP2B6*9 alleles in Egyptian RMS. Moreover, investigate whether variation in
CYP2B6 influences outcome and recurrence among those patients. Analysis of the genotype and allele frequencies of the 3
SNPs in 73 RMS patients revealed that the minor allele frequencies of G516T, A785G and C1459T were 0.26, 0.37 and 0.03,
respectively. The frequency of the heterozygous-type G516T allele was 37% and the frequency of the homozygous variant allele
was 8.2%. The frequency of A785G heterozygous allele was 50.7% and the homozygous variant allele frequency was 12.3%.
For the C1459T, the heterozygous allele was small 4.1% and smaller for the homozygous variant allele frequency which was
1.4%. We also examined the association between genotypes and response phenotypes, overall survival, and failure free survival
(FFS). In our study, our results did not provide evidence for the involvement of CYP2B6 studied SNPs in the prognosis of
CPA treated RMS patients. Patients who are carriers of at least one mutant CYP2B6 allele in A785G, G516T (but not
C1459T) and are treated with CPA based treatment had higher FFS although not statistically significant. Furthermore,
haplotypic analysis also confirmed the non association results. To our knowledge, this is the only study providing a prelimiary
overview to role of CYP2B6 SNPs in pediatric RMS Egyptian population.
Keywords: Rhabdomyosarcoma; cyclophosphamide; CYP2B6 polymorphisms; pharmacogenomics; precision medicine
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Mon(2)-P-7
The ESR1 Gene rs1801132 variation and Breast Cancer risk in Iran
Sakineh Abbasi 1 ，Samira Kalbasi 2
1:Tehran University of Medical Sciences, Tehran, Iran、2:University of Tehran, Tehran, Iran
Iranian breast cancer patients are relatively younger than their Western counterparts. Evidence suggests that alterations in
estrogen signaling pathways, including ESR1( estrogen receptor-α ), occur during breast cancer development in Caucasians.
Epidemiologic studies have revealed that age-incidence patterns of breast cancer in Asians differ from those in Caucasians.
Genomic data for ESR1 in either population is therefore of value in the clinical setting for Iranian breast cancer.
A case-control study was conducted to establish a database of ESR1 polymorphisms in Iranian women population in order to
compare Western and Asian with Iranian (Asian-Caucasians) distributions and to evaluate ESR1 polymorphism as an indicator
of clinical outcome. DNA was extracted from Iranian women with breast cancer referred to Imam Khomeini Hospital Complex
clinical breast cancer group (150 patients) and in healthy individuals (147 healthy control individuals). PCR single-strand
conformation polymorphism technology was performed.
A site of silent single nucleotide polymorphism (SNP) rs1801132 was found, The frequency of allele 1 in codon 325 (CCC →
CCG) was significantly higher in breast cancer patients (39.6%) than in control individuals (28.9%; P = 0.007). The allele
CCG had also significant association with the occurrence of lymph node metastasis.
Data suggest that ESR1 polymorphisms in exon 4 codon 325 is correlated with various aspects of breast cancer in Iran. ESR1
Poster Session
genotype, as determined during presurgical evaluation, might represent a surrogate marker for predicting breast cancer lymph
node metastasis.
Mon(2)-P-8
To Investigate the Mechanism and Function of Nucleobindin-2 in Human Hepatoma Cells
1,3
Jui-Hsiang Hung ，Ren-Hao Li 1 ，Kuan-Han Lee 2,3
1:Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan, Taiwan、2:Institute of Pharmacy, Chia Nan University
of Pharmacy and Science, Tainan, Taiwan、3:Drug Discovery and Development Center, Chia Nan University of Pharmacy and Science, Tainan,
Taiwan
Hepatocellular carcinoma (HCC) is a common malignancy affecting approximately one million people worldwide annually.
Many studies have indicated that induction of endoplasmic reticulum stress was observed in hepatoma. Expression of mutant
proteins or viral infection may interfere with proper protein folding activity in the endoplasmic reticulum (ER). Recently
studies have indicated that overexpression of nucleobindin-2 (NUCB-2) is observed in clinical tumor samples such as gastric
cancer, prostate cancer and breast cancer. However, the effect of NUCB-2 overexpression on tumor cells is still unclear. In
this study, we want to identification of the novel role and mechanisms of NUCB-2 overexoression in tumor cells. Our results
indicated that two ER stress inducers, tunicamycin or brefeldin A, increased NUCB-2 expression in three cell lines (Huh-
7/MCF-7/HepG2) and animal model. NUCB-2 mRNA expression level was induced by ER stress as determined with RT-PCR
and real-time PCR, and induction of NUCB-2 protein level was significantly increased by ER stress. Furthermore, nuclear
translocation of NUCB-2 were observed during ER stress. The role of NUCB-2 in mediating tunicamycin-induced apoptosis
was also investigated, and downregulation of NUCB-2 expression by NUCB-2 shRNA significantly promoted tunicamycin-
induced apoptosis in Huh-7 cells. In addition, induction of ER stress by HBV large surface mutant protein pre-S2D was
observed in Huh-7 cells. The result has shown that increased ER stress by pre-S2D protein was significantly enhanced NUCB-
2 expression. We also observe that overexpression of NUCB-2 was corrected with ER stress in human hepatocellular carcinoma
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ICHG2016 776
tumor samples. Consequently, this mechanistic research may provide a molecular basis to develop a potent pharmaceutical
agent in clinical use.
Mon(2)-P-9
Drug Metabolizing Enzymes Polymorphisms May Determine Response and Toxicity of Chemotherapy
based Treatment in Breast Cancer Patients: a North Indian Study
Sonam Tulsyan 1 ，Gaurav Agarwal 2 ，Punita Lal 3 ，Balraj Mittal 1
1:Genetics, SGPGIMS, India、2:Endocrine & Breast Surgery, SGPGIMS、3:Radiotherapy, SGPGIMS
Objectives: Higher order gene- gene interaction analysis along with adjustment for confounding factors was performed
to determine the influence of variations in genes encoding phase 0 (SLC22A16 ); phase I (CYP450, NQO1 ); phase II
(GSTs, MTHFR, UGT2B15 ) and phase III (ABCB1 ) drug metabolizing enzymes (DMEs) with response and toxicity of
chemotherapeutic drugs in breast cancer treatment.
Methods: 234 North Indian breast cancer patients were genotyped for 19 polymorphisms- SLC22A16 146A>G, SLC22A16
1226T>C, CYP3A4*1B, CYP3A5*3, CYP2B6*5, CYP2B6*9, CYP2C8*3, CYP2C9*2, CYP2C9*3, CYP2C19*2, NQO1
609C>T, GSTM1, GSTTI, GSTP1 313A>G, MTHFR 677C>T, UGT2B15 253A>C, ABCB1 1236C>T, ABCB1
Poster Session
2677G>T/A and ABCB13435C>T by PCR or PCR-RFLP or Taqman allelic discrimination assay.
According to RECIST, tumor response to neo-adjuvant chemotherapy (NACT) was recorded in 111 patients while grade
2-4 toxicity was recorded in 234 patients according to NCI-CTCAE. Binary logistic regression and GMDR analysis was
performed. All statistical analysis was adjusted for potential confounding factors like age, clinical stage, grade, lymph node
status, hormone receptor and her 2 neu expression. Bonferroni test for multiple comparisons was applied and p value was
considered to be significant at <0.025.
Results: On applying logistic regression, CT genotype of ABCB1 1236C>T polymorphism reached statistical significance
with response to NACT [p=0.013]. However, none of the polymorphisms reached statistical significance with grade 2-4
toxicity.
On GMDR analysis, interaction of CYP3A5*3, NQO1 609C>T, ABCB1 1236C>T polymorphisms yielded the highest testing
accuracy for response to NACT (CVT=0.62). However, CYP2C19*2, ABCB1 3435C>T combination of polymorphisms
yielded the best interaction model (CVT=0.57) for grade 2-4 toxicity.
Conclusion: Higher order gene- gene interaction along may provide a better prediction of chemotherapy based treatment
outcomes in North Indian breast cancer patients.
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Mon(2)-P-10
Integrated miRNA and mRNA expression profiling to identify biomarkers for response to treatment in
rectal cancer
Marta Cuadros 1 ，Carlos Cano 4 ，Raquel Conde 5 ，Antonio Herrera 2,3
，Ana Comino 5 ，Victoria Sanchez 1,3
，
Pedro Medina 2,3 ，Pablo Palma 5
1:Department of Biochemistry and Molecular Biology III e Immunology, Medicine College, University of Granada, Spain、2:Department of
Biochemistry and Molecular Biology II, University of Granada、3:GENYO, Centre for Genomics and Oncological Research: Pfizer/University
of de Granada/Junta de Andalucía, Granada、4:Department of Computer Science and Artificial Intelligence, University of Granada、
5:Division of Colon & Rectal Surgery, Department of Surgical Research, Virgen de las Nieves Hospital, Granada
Locally advanced rectal cancer (LARC) is regularly treated with neoadjuvant chemoradiation and surgery. However, only 50%
of patients showed any kind of response, thereby a need for strategies to assess treatment response is needed to personalize
therapy.
We studied possible biomarkers in patients with LARC to identify miRNAs and their targets that could be useful as biomarkers
for response to chemoradiation.
A comprehensive analysis of mRNA and miRNA expression was performed in tumor samples from pre-treatment patients by
CodeLink bioarrays and TaqMan  OpenArray MicroRNA Panels. Some of the most interesting results were validated by
Poster Session
quantitative real-time PCR (qPCR), and transfection assays. Expression profiling of mRNA and miRNAs clearly differentiated
responder and non responder tumor patients. A detailed analysis identified genes encoding proteins associated with several
canonical pathways, such as MYC mediated apoptosis signalling.
Our data suggest that miRNAs and their targeted pathways play an important role in response to treatment of LARC, and
provided novel candidates for molecular biomarkers or treatment targets.
Mon(2)-P-12
Modification of association between polymorphism in genes UGT1A6 and PAFAH1B2 with colorectal
cancer risk by aspirin use
Harsh Sheth 1 ，Emma Northwood 2 ，Faye Elliott 2 ，Jennifer Barrett 2 ，Cornelia M. Ulrich 3 ，Michael S. Jackson 1 ，
Mauro Santibanez-Koref 1 ，Michelle Cotterchio 4 ，Robert Haile 5 ，Graham Casey 6 ，Mark Jenkins 7 ，John Hopper 7 ，
Noralane Lindor 8 ，Polly A. Newcomb 9 ，John Burn 1 ，David Timothy Bishop 2
1:Institute of Genetic Medicine, Newcastle University, UK、2:Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK、
3:Huntsman Cancer Institute, University of Utah, Salt Lake City, USA、4:Cancer Care Ontario, Toronto, Canada、5:Stanford Cancer
Institute, Stanford, California, USA、6:University of Southern California, Los Angeles, California, USA、7:The University of Melbourne,
Carlton, Australia、8:Mayo Clinic, Rochester, Minnesota, USA、9:Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
SNPs have been attributed to modulate inverse association between aspirin use and colorectal cancer (CRC) risk. Our aim
was to identify SNPs in genes involved in aspirin pathways that can explain variation in its efficacy of preventing CRCs.
We tested gene x environment (GxE) interaction for 43 SNPs in 16 genes and aspirin use in relation to CRC risk using 2
population based case-control studies: UK-Leeds Colorectal Cancer Study Group and NIH-Colon Cancer Family Registry. A
combined total of 3325 cases and 2262 controls of European decent were analysed. Summary ORs and 95% CI were obtained
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using random effects meta-analysis of study specific log odds and standard error estimates generated from logistic regression
models. Likelihood ratio test was used to determine the statistical significance of the interaction. P-value was adjusted for sex,
age and study site. Meta-analysis of the interaction term for 2 SNPs in UGT1A6 and PAFAH1B2 genes showed interaction
with aspirin use and CRC risk (P interaction ≤0.05). Stratification by aspirin use showed association for increased risk of CRC
with SNP variant allele in aspirin users [PAFAH1B2 (rs4936367 OR=1.32, 95% CI=0.79-2.22; rs7112513 OR=1.28, 95%
CI=0.82-2.01); UGT1A6 (rs2070959 OR=1.38, 95% CI=1.06-1.79; rs1105879 OR=1.36, 95% CI=1.05-1.75)] but not in non-
users [PAFAH1B2 (rs4936367 OR=0.91, 95% CI=0.76-1.10; rs7112513 OR=0.90, 95% CI=0.72-1.14); UGT1A6 (rs2070959
OR=0.97, 95% CI=0.81-1.15; rs1105879 OR=0.99, 95% CI=0.85-1.15)]. Stratification by tumor site showed association for
increased risk of colon cancer only with the variant alleles of rs2070959 and rs1105879 in UGT1A6 gene in aspirin users
but not in non-users (P interaction ≤0.02). Candidate gene investigation of GxE interaction showed modulation of association
between 2 SNPs in UGT1A6 and PAFAH1B2 genes and CRC or colon cancer risk by aspirin use. Both genes are involved in
aspirin metabolism and validation of these findings in other studies is warranted.
Mon(2)-P-13
A germline RAD51C duplication in breast and ovarian cancer
Liisa M. Pelttari 1 ，Anders Kvist 2 ，Ake Borg 2 ，Carl Blomqvist 3 ，Ralf Butzow 1,4
，Kristiina Aittomaki 5 ，
Heli Nevanlinna 1
1:Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland、2:Department of
Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden、3:Department of Oncology, University of Helsinki
and Helsinki University Hospital, Helsinki, Finland、4:Department of Pathology, University of Helsinki and Helsinki University Hospital,
Helsinki, Finland、5:Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Poster Session
RAD51C functions in homologous recombination repair of DNA double-strand breaks and germline mutations in the gene
have been found to increase the risk of ovarian cancer. A large 64 kb duplication encompassing most of the RAD51C gene was
identified in the germline DNA of a familial breast cancer patient. The duplication starts 31 kb upstream of RAD51C and ends
in intron 7. We screened the relatives with available DNA samples for the mutation with PCR assay. Two of the three sisters
affected with breast cancer were duplication carriers whereas no duplications were observed in healthy females. Other cancer
cases in the family included ovarian cancer and various other cancer types such as Hodgkin lymphoma, rectum and prostate
cancer among distant relatives. We further genotyped the duplication in unselected cohorts of breast (n = 1855) and ovarian
(n = 553) cancer cases, in additional familial breast and ovarian cancer patients (n = 775), and in healthy female population
controls (n = 1273). Seven additional duplication carriers were identified among cases and none among controls. The highest
frequency, 0.5%, was observed among ovarian cancer cases (p = 0.032 as compared to controls) suggesting the duplication
may increase the risk of ovarian cancer. Further functional studies are warranted to evaluate whether the duplication affects
the expression of RAD51C.
Mon(2)-P-14
Cytogenetic and molecular assessment of oral cancer risk in smokeless tobacco users and their association
with socio economic strategies
1,2
Ramachandran Chandirasekar ，K Murugan 1 ，B Lakshman Kumar 3 ，R Jayakumar 4 ，V Uthayakumar 1,2
1:Department of Zoology, Bharathiar University, India、2:PG and Research Department of Zoology Sri Vasavi College Erode, India、3:De-
partment of Biotechnology, Kongunadu arts and science college, Coimbatore - 641 046、4:Department of Molecular medicine, Faculty of
medicine, University of Malaysia, Kuala Lumpur, Malaysia
Smokeless tobacco (SLT) use is a growing health problem, particularly in Asia and Africa. It is estimated that over 90% of
the global smokeless tobacco use burden is in South Asia. Around 100 million people use smokeless tobacco in India and
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Pakistan alone. Use of betel quid with tobacco have an almost five-time higher risk of developing oral cancer as compared
to non chewers and are closely linked to socio economic cultural conditions. In the study area, we observed several children’
s and adolescents have imbibed the habit of SLT usage through their familial lineage. So the primary aim of the study was
to evaluate the frequencies of cytogenetic biomarkers like CA, MN, genotoxic (comet assay), gene polymorphic (Tp53 and
XRCC1) and gene expressions in smokeless tobacco users and controls. About 143 smokeless tobacco users were categorized
into groups on the basis of duration of their habit were enrolled for this study and an equal number of age, sex matched
non-tobacco users as controls. Complete life style activity details were observed and blood and buccal samples were collected
and used for analysis. Result of the study revealed that smokeless tobacco users displayed varied levels of genomic damages
when compared to non-users and a positive correlation was observed between various endpoints such as CA, MN, Comet
and SNP changes) and duration of habit. Novel SNP changes (Tp53 and XRCC1gene) and base deletions were observed in
individuals with higher duration of the habit of SLT usages. Molecular changes in pre-malignant lesions have the potential to
give important clues for the early detection of oral cancer. Understanding the biology of oral carcinogenesis is important in
the diagnosis of high-risk patients, monitoring preventive interventions and assessing cancer risk. Thus the research elucidates
the clinical paradigm of the effects of SLT usage and it also to create a general awareness among the people on the carcinogenic
effects of SLT usages.
Mon(2)-P-15
The association of patatin-like phospholipase domain-containing protein 3 polymorphism with the de-
velopment and prognosis of hepatocellular carcinoma in Thai population
Poster Session
Pisit Tangkijvanich 1 ，Apichaya Khlaiphuengsin 1 ，Natthaya Chuaypen 1 ，Rattanaporn Kiatbumrung 1 ，
Sunchai Payungporn 1 ，Nutcha Pinjaroen 2
1:Research Unit of Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Thailand、
2:Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Background: Recent studies have also shown an association between single nucleotide polymorphism (SNP) in the patatin-
like phospholipase domain containing 3 (PNPLA3 ) (rs738409, C>G) and hepatocellular carcinoma (HCC) development in
patients with alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH). However, it is not clear whether this
SNP affects HCC development and prognosis in Thai patients with chronic viral hepatitis.
Methods: The SNP was determined by real-time PCR based on TaqMan assays in 200 healthy controls and 388 patients of
HCC (211 with chronic HBV infection, 98 with chronic HCV infection, 29 with ASH and 52 with NASH).
Results: The frequencies of C allele in patients with HCC and controls were 63.7% and 67.5%, respectively, whereas the
frequencies of G allele were 36.3% and 32.5%, respectively. The frequency of G allele was comparable between patients
with viral-related HCC and controls. G allele significantly higher in patients with ASH/NASH-related HCC compared with
controls (OR=1.53, 95% CI=1.05-2.23, P=0.0280). Similar results were also found under additive (OR=2.54, 95% CI=1.18-
5.45, P=0.027) and recessive models (OR=2.34, 95% CI=1.16-4.71, P=0.018). Among patients with HCC, the G allele showed
a trend toward an association with ASH/NASH-related HCC compared with viral-related HCC (OR=1.38, 95% CI=0.97-1.97,
P=0.076). This association was statistically significant under additive (OR=2.16, 95% CI=1.07-4.38, P=0.032) and recessive
(OR=2.15, 95% CI=1.13-4.08, P=0.020) models. HBV-related HCC exhibited large tumors and more advanced stages than
the other HCC groups. There were no difference between the SNP groups regarding clinical characteristics, tumor stage and
overall survival.
Conclusions: These data suggest the influence of PNPLA3 polymorphism on HCC occurrence in patients with ASH/NASH
but not among patients with chronic viral hepatitis. However, the polymorphism was not found to be associated with the
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prognosis of HCC.
Mon(2)-P-16
Circulating MicroRNAs as Potential Biomarkers in Hepatocellular Carcinoma
Yu Jin 1 ，Guat Lay Lee 1,2,3
1:National Cancer Centre Singapore, Singapore、2:National University of Singapore、3:Duke-NUS Graduate Medical School Singapore
Liver cancer is the sixth most common cancer type, and the third leading cause of cancer deaths. Hepatocellular carci-
noma (HCC) accounts for 85 to 90% primary liver cancer cases. Both genetic and epigenetic factors could contribute to
hepatocarcinogenesis, including microRNAs (miRNAs), a group of small non-coding RNAs that are de-regulated in HCC
tumor tissues as well as in plasma and serum. In this study, we profile the circulating miRNA signature in HCC patients
and explore potential non-invasive biomarkers. We first measure 751 miRNA expression in plasma samples from 10 normal
healthy individuals and 19 HCC patients. In total, 68 miRNAs are differentially expressed in HCC patients, and 21 miRNAs
are associated with clinical characteristics. We validate the candidate miRNAs in the second cohort including 40 normal
healthy, 30 chronic hepatitis B (CHB) carriers and 36 HCC patients. In the validation groups, 32 miRNAs are consistently
de-regulated in the HCC samples compared to the normal healthy group. Moreover, seven miRNAs are up-regulated in CHB
patients, and four miRNAs show increased expression in both CHB and HCC patients. By receiver-operating characteristics
Poster Session
analysis, we find six up-regulated and two down-regulated miRNAs as potential diagnostic markers for HCC, as they are
consistently de-regulated in both discovery and validation cohorts, and exhibit more than 80% sensitivity and specificity. The
best miRNA marker achieves 94% sensitivity and 97% specificity for differentiating HCC patients from normal individuals.
Moreover, combination of two circulating miRNAs shows 100% accuracy in the validation cohort. Lastly, two circulating
miRNAs are associated with clinical characteristics in both cohorts, and might be used as prognostic markers. To conclude,
we identify a group of circulating miRNAs that could be developed as biomarkers for HCC. Most of these miRNAs have not
been extensively investigated in HCC and are worthwhile for further characterization.
Mon(2)-P-17
FANCM c.5101C>T mutation and breast cancer survival
Johanna I. Kiiski 1 ，Anna Tervasmaki 2,3 ，Rainer Fagerholm 1 ，Sofia Khan 1 ，Liisa M Pelttari 1 ，Tuomo Mantere 2,3
，
Katri Pylkas 2,3 ，Arto Mannermaa 4,5 ，Robert Winqvist 2,3 ，Anne Kallioniemi 6 ，Kristiina Aittomaki 7 ，
Carl Blomqvist 8 ，Heli Nevanlinna 1
1:Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Finland、2:Laboratory of Cancer
Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Finland、3:Laboratory
of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre, NordLab, Oulu, Finland、4:School of Medicine, Institute
of Clinical Medicine, Pathology and Forensic Medicine, and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio,
Finland、5:Imaging Center, Clinical Pathology, Kuopio University Hospital, Kuopio, Finland、6:BioMediTech, University of Tampere
and Fimlab Laboratories, Tampere, Finland、7:Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital,
Helsinki, Finland、8:Department of Oncology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Hereditary predisposition to breast cancer is caused by variation in multiple genes involved in DNA repair. Recently, we
identified a new breast cancer allele in the Finnish population in Fanconi Anemia pathway gene FANCM . The c.5101C>T
(p.Q1701X) nonsense mutation increased the risk of breast cancer over twofold among the familial cases, and 3.5 fold increased
frequency was seen among the triple-negative patients. Here, we studied tumor characteristics and patient survival associated
with the FANCM c.5101C>T mutation among 3933 breast cancer patients in four breast cancer patient series in Finland.
The mutation was associated with poor 10-year breast cancer-specific survival in the pooled data set stratified for study
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(P = 0.018, HR = 1.65, 95% CI = 1.09-2.52), with more pronounced survival effect among familial cases from the Helsinki
series (P = 0.0018, HR = 2.93, 95% CI = 1.5-5.76). Breast tumors from the FANCM c.5101C>T mutation carriers were
more often triple negative (P = 0.06 compared with wild type tumors), which is in line with the earlier risk analysis of
the mutation. However, the mutation associated with reduced survival also in the ER-positive group of patients. Reduced
survival and increased risk for local recurrence was seen for mutation carriers especially among patients who had not received
radiotherapy whereas no such effect was observed among radiotherapy treated patients. There was a significant interaction
between FANCM c.5101C>T mutation and radiotherapy (P = 0.03, HR = 0.374), indicating FANCM mutation carrier
patients may specifically benefit from radiation treatment.
Mon(2)-P-18
Fine mapping of nasopharyngeal carcinoma susceptible region discovered by genome-wide association
study
Wen-Hui Su 1 ，Chi-Ching Chiu 1 ，Kai-Ping Chang 2
1:Dept. of Biomedical Sciences, Chang Gung University, Taiwan、2:Department of Otolaryngology, Head and Neck Surgery, Chang Gung
Memorial Hospital at Lin-Kou
Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy closely associated with genetic factors and Epstein-Barr virus
(EBV) infection. Several genome-wide association studies (GWAS) have recently published; all confirmed the involvement of
genes in the MHC region in NPC. Through whole genome imputation process, we combined two independent NPC GWAS
datasets and try to fine mapping our previous discovery. In total, 115 new susceptible SNPs located in chromosome 5, 6, 7,
Poster Session
12, 15, 16 and 18 with p-values lower than 1E-04 were discovered using 458 NPC cases and 472 controls in combined dataset.
However, 105 new susceptible SNPs were located in previously discovered NPC susceptible chromosome 6p MHC region. To
further fine mapping the susceptible loci to HLA gene coding region, secondary imputation were preformed in MHC region
to predict the susceptible amino acid located within HLA genes. The amino acid position 62 of the HLA-A gene was strongly
associated with NPC risk (P = 4.30E-14). Multiple significant associated variants located in the antigen recognition groove
suggested the potential role of host-virus interaction between NPC and EBV providing a biological basis for the SNP-based
associations reported.
Mon(2)-P-19
Polymorphism in chromosome 5 is associated with survival specifically among breast cancer patients
treated with endocrine therapy
Sofia Khan 1 ，Rainer Fagerholm 1 ，Perunthadambil Kadalayil 2 ，William Tapper 2 ，Kristiina Aittomaki 3 ，Jianjun Liu 4 ，
Diana Eccles 2 ，Carl Blomqvist 5 ，Heli Nevanlinna 1
1:Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland、2:Faculty of Medicine,
University of Southampton, Southampton General Hospital, Hants, United Kingdom、3:Department of Clinical Genetics, Helsinki University
Hospital and Genome Scale Biology Research Program, University of Helsinki, Helsinki, Finland、4:Human Genetics, Genome Institute of
Singapore, Singapore、5:Department of Oncology, Helsinki University Hospital, Helsinki, Finland
Majority of breast cancer patients have estrogen receptor (ER) positive cancer. Endocrine therapies are the most commonly
used therapy to treat this type of breast cancer. While most of these patients respond well to endocrine therapies, significant
proportion does not benefit from these therapies. The aim of our study was to identify inherited genetic variations that might
predict survival among patients receiving adjuvant endocrine therapies.
We performed a meta-analysis of three genome-wide studies originating from Finland, UK and Germany with altogether 2853
patients receiving endocrine therapy evaluating 275,827 single-nucleotide polymorphisms (SNPs).
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We identified a common SNP in chromosome 5 associating statistically significantly with reduced survival among endocrine-
treated patients and with no effect to the survival among ER-negative patients or ER-positive cases not receiving endocrine
therapy. In a multivariate analysis adjusted for conventional prognostic factors, we found a statistically significant interaction
between the SNP and endocrine treatment among patients with ER-positive tumor, indicating a predictive, treatment-specific
effect of the SNP on breast cancer survival. Analyses of public microarray data and subsequent in silico analyses suggest a
link between the locus and the expression patterns of multiple genes involved in endocrine treatment resistance.
If confirmed in other large datasets, these findings may help in the development of improved personalized treatment by
identifying patients who would not benefit from endocrine treatment.
Mon(2)-P-20
Gene expression and relapse of superficial cell carcinoma. A microarray analysis
Jaroslav Mares 1 ，Marcela Klabanova 2 ，Jaroslava Duskova 3 ，Ales Horinek 3 ，Marek Babjuk 1
1:Inst. Biol. Med. Genet., 2nd Faculty of Medicine, Charles University, Czech Republic、2:Diana Lucina、3:1st Faculty of Medicine, Charles
University
Treatment of bladder superficial tumours is dependent on the risk of recurrence and it is therefore clinically important
to identify bladder cancer with high risk of intravesical recurrence after transurethal bladder tumour resection. For the
improvement of recurrence prognosis we applied gene expression microarray analysis to two groups of bladder tumours
Poster Session
(superficial bladder tumours with no or late relapse during the period of two years versus early relapse ones). Data from
microarray containing 29,019 targets (Applied Biosystems) were subjected to a panel of statistical analyses to identify bladder
cancer recurrence-associated gene expression changes. After validation 33 genes manifested significant differences between
both groups. The significant expression was observed in the group of patiens without recurrence by 30 genes of which the
highest differences were detected by NINJ1, GNE, ANXA1, TNFSF15, WDR34, ARHGEF4, PRICKLE1, PSAT1, RNASE1,
TM4SF1, TSPAN1, PLOD2 and WDR72. These genes code for proteins involved in signal transduction, vascular remodeling
and vascular endothelial growth inhibition mainly. Specially, PRICKLE1 and TNFSF15 were described to be linked with
WNT/beta-catenin signaling and angiogenesis regulation and MTOR pathway. Loci of genes with signifciant changes of gene
expression were located on characteristic chromosomes for bladder cancer: 9q, 17q, 2q and 16p. On the basis of this findings
we documented a number expression changes among which some seem to form clinically useful relapse markers of superficial
bladder tumours. Research was supported by MSM21620808 and Diana Lucina.
Mon(2)-P-21
Effect of Paclitaxel on miRNA expression in prostate cancer
Murat Samli 1 ，Hale Samli 2 ，Buse Vatansever 2 ，Nazlihan Aztopal 2 ，Deniz Dincel 2 ，Ahmet Sahin 1 ，Faruk Balci 2
1:Department of Urology, Acibadem University, Turkey、2:Genetic, Uludag University
Microtubule-targeting agents are one of the important classes of drugs to treat cancer. The drug resistance in cancer cells
develops and consequently limits the clinical effectiveness of these agents. The functional role of miRNAs in the resistance to
the MTA has recently begun to be studied and understood. To understand the role of miRNAs in the resistance to paclitaxel
prostate cancer cell lines PC-3, DU-145, VCaP, and normal prostatic epithelial cell line PNT1A and paclitaxel resistant
cultures of these cell line subcultures were used. In all cell lines, in order to determine the cytotoxicity to paclitaxel, IC50
values of logarithmic dilutions of 1/1000-1/100,000 were treated for 24, 48 and 72 hours of cell line culture and viability
testing was performed with MTT/SRB. Paclitaxel resistance determined by drug concentration of resistant group cells of has
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been shown to be much higher than the control group of cells. Then, the expression of 86 miRNAs from the sensitive and
resistant cell lines were analyzed by RT-PCR which may show difference in expression, and so effecting the development and
progression of PCa. Consequently, differential expressions of miRNAs have been identified and those show significant changes
in miRNA expression were detected in both groups; expression differences were reported as follows; upregulated miRNA was
miR-141-3p and downregulated miRNAs were miR-146b-5p,miR-200c-3p,miR-96-5p in PNTA1AR when compared to PNT1A;
upregulated miRNAs were miR-34b-3p,miR-375 and downregulated miRNAs were miR-200b-3p,miR-20b-5p,miR-616-3p in
DU-145R when compared to DU-145; upregulated miRNA was miR-374b-5p and downregulated miRNA was miR-26b-5p in
PC-3R when compared to PC-3; upregulated miRNAs were miR-100-5p,miR-148a-3p,miR-200b-3p in VCapR when compared
to VCaP. Results obtained in this study may be used to overcome the miRNA-associated drug resistance in tumor cells. Note:
This study’s supported by TUBITAK, project no 2013S012
Mon(2)-P-22
Analysis of cytogenetic alterations and polymorphism in MTHFR gene of Colorectal Cancer patients in
Indian population
Vellingiri Balachandar 1 ，Krishnan Padmavathi 1 ，SN Dharwadkar 3 ，Keshavarao Sasikala 2
1:Human Genetics and Molecular Biology, Bharathiar University, India、2:Human Molecular Genetics Laboratory, Department of Zoology,
Bharathiar University、3:KLE University, Bangalore, India
Objective: Colorectal cancer (CRC) is the most common types of cancer worldwide. Methylene tetra hydro folate reductase
(MTHFR) gene is considered to have significant effect on CRC susceptibility. The incidence of CRC showed considerable
Poster Session
variation among ethnic groups in multiracial countries. The present study tries to investigate the clinic-pathological, chro-
mosomal and gene variants in South Indian population mainly targeting on MTHFR gene in CRC patients.
Methods: Patients with CRC (n= 61) and healthy controls (n= 61) were evaluated by analyzing the tumor marker Carci-
noembryonic Antigen (CEA), hormones, chromosomal alterations and MTHFR genotypes by standard protocols.
Results: Among the CRC patients analyzed, frequent alterations were observed in chromosomes 22p, 18q, 17p, 10q, 5q and 1p.
Higher CEA and hormones correlate with adverse prognosis P < 0.05). The MTHFR C677T genotypes shows insignificant
results and none of the variant alleles were associated with the risk of CRC in our population.
Conclusion: Karyotypic investigation has provided precious information on chromosomal aberrations in CRC, which is sup-
portive in monitoring treatment regimens. Since, there was no significant association of MTHFR polymorphisms but there
may be a little association with CRC, suggesting that assessment of genes may offer an approach for identifying individuals
at high CRC risk in South Indian population.
Key words: Colorectal cancer, MTHFR gene, Chromosomal alterations
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Mon(2)-P-23
Identification of Genetics alterations in Colorectal Cancer Patients in Coimbatore Population, South
India
Dhivya Venkatesan 1 ，Kuchi Bhotla Haripriya 1 ，Subramium Mohana Devi 1 ，Keshavarao Sasikala 1 ，
Balachandar Vellingiri 1
1:Department of Human Genetics and Molecular Biology, Bharathiar University, India
Colorectal Cancer (CRC) is the third leading cause of cancer in males and fourth in females in worldwide and the fourth most
common cause of death. The aim of our research is to identify the chromosomal alterations, biomarker level (Carcinoembryonic
antigen) and mutation seen in MTHFR (methylene tetra hydrofolate reductase) gene respectively. A total of 30 subjects
which includes 15 CRC and equal number of healthy individuals were selected as controls in South Indian population. The
experimental subjects and controls were divided into two groups based on age as Group I ≤ 55 and Group II > 55years.
The study conducted by observing chromosomal alterations using Trypsin G-banding, finding out the biomarker level and
mutational studies in MTHFR by performing PCR-RFLP techniques. Compared to healthy controls, chromosomal anomalies
were observed in all 15 CRC patients with deletions in 17p, 5p 21, 18q, 22p, 18q, 15p, and 1p. The higher percentage of
deletions found were 46, XY, del 18p-. The levels of tumor marker Carcinoembryonic antigen (CEA) were highest in CRC
patients and also MTHFR with Ala/Val variation. The polymorphism of MTHFR might play an important role in the
susceptibility of South Indian population to CRC.
Mon(2)-P-24
Poster Session
Detection of BRCA1 gene polymorphism in Breast Cancer Patients in South Indian population
1,2
Balasubramanian Venkatesh ，P Mani 4 ，Vellingiri Balachandar 1 ，Keshavarao Sasikala 3
1:Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India、2:Department of Microbial
biotechnology, Bharathiar University, Coimbatore, India、3:Human Molecular Genetics Laboratory, Department of Zoology, School of Life
Sciences, Bharathiar University, Coimbatore, Tamilnadu, India、4:SIMPRA (sharmila institute of medicinal products research academy)
#203/2, medical college road, thanjavur, tamilnadu, India.
Background: Breast cancer is the most common cancer in women and accounts for between 18-25% of all female malignancies
world-wide. In India, breast cancer is the second most common malignant condition among women. BRCA1 is mapped to
chromosome 17q21.
Objective: The present study aims to analyze the BRCA1 gene mutation in breast cancer patients, as a molecular marker for
diagnosing the disease.
Method: The subjects with breast cancer were selected from patients attending the Oncology department of different Hospitals
in South India.
A total of 15 women were screened with breast cancer. Equal numbers of mentally normal, physically healthy females were
used as controls. We sought to identify those changes that may be associated with development and progression of Breast
cancer for Genotypic analysis of BRCA1 Gene by SSCP.
Results: The BRCA1 mutations were detected in 4 familial breast cancer patients, out of the 15 breast cancer patients
analyzed. The BRCA1 mutation 185 delAG, which results in the generation of a stop codon at position 39 in exon 2 was
detected.
Conclusion: Identification of the predisposition of the breast cancer BRCA1 gene, speculate that the BRCA1 protein may be
useful in the treatment of breast carcinoma as a decision making biomarker for aggressive treatment. Therefore this work is
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an eye-opener for the patients, and it will help to produce a healthy society.
Key Words: Breast Cancer, BRCA1, Genotypic analysis
Mon(2)-P-25
Association of MYCN status with certain prognosis factors of neuroblastomas
Quang Dinh Vu 1 ，Ngoc Diem Ngo 1 ，Huy Xuan Nguyen 1 ，Lan Tuyet Phung 2 ，Son Ngoc Tran 3 ，Cong Dinh Le 4 ，
Thach Ngoc Hoang 5 ，Mai Thi Chi Tran 6 ，Van Thi Hong Nguyen 7
1:Human Genetics Department, National Hospital of Pediatrics, Vietnam、2:Oncology Department, National Hospital of Pediatrics、
3:Surgery Department, National Hospital of Pediatrics、4:Radiology Department, National Hospital of Pediatrics、5:Pathology Department,
National Hospital of Pediatrics、6:Biochemistry Department, National Hospital of Pediatrics、7:Genetics Department, Biology Faculty,
Hanoi University of Sciences HUS
Neuroblastoma (NBL) is the most common extracranial cancer of early childhood. It accounts approximately 15% of all
childhood cancer-related mortality. Age, stage, biochemical parameters, Shimada histopathological classification and genomic
profile are the common prognostic factors. NBL genetic features have been used for risk stratification for more than 20 years,
in which the amplification of the MYCN gene (MYCNA), observed in 20-25% of NBL, is widely used as the most powerful
prognostic factor.
Poster Session
Objective: This work aim to study, in a series of 71 NBL patients, the association of MYCNA with certain prognostic factors.
Methods: MYCNA was identified by FISH. The MYCN status was calculated following the other clinical and biological
factors.
Results: MYCNA is found on 19/71 (26,8%) of NBL cases(ca).
For the age, the 0-12month (m) group has 7/36 MYCNA. The next ones are the 12-18m (3/8ca),18-60m (8/21ca), and >60m
(1/6ca).
With INRGSS stage, the number of MYCNA in L1 is 1/7ca, L2 is 8/36ca, M is 5/11ca, and Ms is 1/2ca. 1 relapsed case with
non-MYCNA and 14 unknown cases (5 MYCNA).
The primary tumors in abdomen also have a higher proportion of MYCNA (16/55ca) than in chest (1/10ca) and neck (0/2ca);
4 unknown cases (2 MYCNA).
The favorable and unfavorable histology groups showed small different frequencies of MYCNA, (9/37ca) and (7/27ca). 7
unclassified cases (3 MYCNA).
All patients, who have VMA/HVA>1, are not MYCNA (0/17). The remaining group has 14/38 MYCNA; 16 unknown
patients (5 MYCNA).
In 16 patients of high level of LDH (>3 times than normal), there are 11 MYCNA. This proportion of intermediate LDH
level (>1 - 3 times) is 4/16 patients. The normal group have 1/27 MYCNA. 12 unknown patients (3 MYCNA).
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Conclusion: The MYCNA is strongly associated with worse prognosis factors, including age >18m, stage M, unfavourable
histology, VMA/HVA<1 and high LDH level. But the MYCN status determined by FISH is one of the most important tools
for treatment stratification.
Mon(2)-P-26
CYTOGENETIC INVESTIGATION, BIOCHEMICAL ALTERATIONS AND METHYLENETETRAHY-
DROFOLATE REDUCTASE (MTHFR) GENE POLYMORPHISM IN BREAST CANCER PATIENTS IN
TAMIL NADU POPULATION
Shantkriti S 1 ，Sangeetha Raman 2 ，Senthil Kumar Sadasivam 1 ，Sasikala Keshavarao 2 ，Balachandar Vellingiri 3
1:Department of Biotechnology, National College, Tamilnadu, India、2:Human Genetics Laboratory, Department of Zoology, Bharathiar
University, Coimbatore, Tamil Nadu, India、3:Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar
University, Coimbatore, Tamil Nadu, India
Background:Breast cancer is the commonest cancer worldwide,second to cervical cancer in women mortality.Environmental
and genetic factors play important role in cancer development and prognosis.It is the most commonly diagnosed malignancy
in women worldwide (22%), in India (18.5%) it ranks second to cervical cancer.The present study involve Cytogenetic inves-
tigation,biochemical alterations and Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism analysis in breast
cancer patients in Tamil Nadu population.
Methods:Peripheral blood samples were obtained from 40 Breast cancer patients and 40 Healthy controls and investigated by
Conventional Cytogenetic analysis using Giemsa Trypsin Giemsa (GTG) banding,Chromosomal alterations confirmed by Flu-
Poster Session
orescent In situ Hybridization.Biochemical parameters analyzed using Spectrophotometer and MTHFR gene polymorphism
by Restriction Fragment Length Polymorphism analysis.
Results:In present investigation, Breast cancer cases showed a higher frequency cytogenetic abnormality largely involved in
loss of 16q and 17p and gain of 1q in patients.Major chromosomal aberrations like deletion, translocation, inversion and
mosaic were also identified.Elevated frequency of Biochemical alteration was statistically significant (p < 0.001 ) in patients
compared to controls. MTHFR gene polymorphisms showed a significant association in breast cancer patients compared to
controls.
Conclusions:Cytogenetics and molecular analysis play a major role in early detection and screening of breast cancer pa-
tients.Extent of rise in parameters can be one of the criteria to establish its diagnostic value.Future challenges will be
identifying causal variants and determining how these low-penetrance alleles interact with each other and with environmental
factors to usefully implement them in clinical medicine for informed treatment decisions.
Keywords:Breast Cancer, Chromosomal Instability, Biochemical alterations, Restriction Fragment Length Polymorphism
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Mon(2)-P-27
ANO7 is associated with aggressive prostate cancer
Elina Kaikkonen 1 ，Hannu-Pekka Schukov 1 ，Gudrun Wahlstrom 1 ，Csilla Sipeky 1 ，Juha-Pekka Pursiheimo 1 ，
Vidal Fey 1 ，Peter Bostrom 2 ，Markku Kallajoki 3 ，Pekka Taimen 3,4 ，Pirkko-Liisa Kellokumpu-Lehtinen 5 ，
Johanna Schleutker 1
1:Medical Biochemistry and Genetics, University of Turku, Turku, Finland、2:Department of Urology, Turku University Hospital and
University of Turku, Turku, Finland、3:Department of Pathology, Turku University Hospital, Turku, Finland、4:Department of Pathology,
University of Turku, Turku, Finland、5:School of Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland
Prostate cancer (PCa) is one of most commonly diagnosed cancers worldwide, representing the second most common cause
of male cancer-related death in the United States, the third in the European Union, and the sixth worldwide with over 250
000 annual deaths. Of all cancers, PCa has been reported as one of the most heritable diseases. Genetic factors were recently
estimated to account for 58% of the risk. Accordingly, genome wide association studies have confirmed already over 100
susceptibility loci in the human genome. Despite these findings, only a few high risk genes have been identified and molecular
mechanisms underlying the causal actions and biological effects of the identified risk variants remain weakly understood.
This is especially true for aggressive and lethal PrCa, for which also the risk variants are most poorly known. ANO7 is a
prostate specific and androgen regulated gene with unknown function belonging to the anoctamin family of Ca2+ -regulated
Cl- -channels. ANO7 protein expression is high in normal prostate epithelial cells but downregulated during cancer progression.
Importantly, it resides on a genomic area shown to be associated with PCa risk. In this study ANO7 was sequenced both from
tumors and blood on Illumina MiSeq from libraries prepared using the Illumina TruSeq Custom Amplicon Sample Prep Kit.
Variant calling and data filtering were made using an in-house pipeline. From the discovery set (70 samples), we selected three
variants for further analysis. These variants are rare (MAF<0.01) and they all have damaging effects according to mutation
Poster Session
prediction programs. We genotyped more patients (both unselected and familial, altogether 1500 samples) and 1500 healthy
controls. Our preliminary data suggests that these variants are more frequent in PCa patients than controls. Homozygosity
in any of these variants is extremely rare but when present, it seems to correlate with aggressive disease.
Mon(2)-P-28
Three microRNAs are associated with poor prognosis in squamous cell carcinoma of the lung
Sana Yokoi 1,2 ，Endi Xia 1,3 ，Sotaro Kanematsu 2 ，Yusuke Suenaga 1 ，Hitomi Kondo 2 ，Noriko Otsuka 2 ，
Yasumitsu Moriya 4 ，Toshihiko Iizasa 4 ，Ichiro Yoshino 3
1:Cancer Genome Center, Chiba Cancer Center Research Institute, Japan、2:Division of Gene Diagnostics, Chiba Cancer Center、
3:Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University、4:Division of Thoracic Diseases, Chiba Cancer
Center Hospital
Squamous cell carcinoma of the lung (Sq) is the second major pathological type of lung cancer. Unlike adenocarcinoma, Sq
has only few molecular target drug. MicroRNA (miR) is a major part of post-transcriptional regulators functioning as tumor
suppressor genes or oncogenes. MiR will regulate target molecules related to carcinogenesis and malignancy in Sq. In this
study, using The Cancer Genome Atlas dataset including copy number variation, RNA sequence, miR sequence from 484
lung cancer cases, the correlation between genomic copy number and expression of miR was analyzed. Thirty four miRs were
identified as the candidates especially for Sq distinguished from adenocarcinoma. Furthermore, four miRs were up-regulated
in amplified regions and associated with poor prognosis independently in Sq. Moreover, those who had the tumor with high
expression in three of four miR showed worst prognosis. To explore miR-mRNA network, we also predicted the target genes
for each miR. From 734 common target genes, three showed positive correlation with the expression between the gene and
three miRs. In conclusion, three miRs were up-regulated in Sq and associated with poor prognosis and three common target
genes were identified. They would provide the new insights into therapeutic strategy for Sq.
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Mon(2)-P-29
Clinical Significance of MLH1 Methylation and CpG Island Methylator Phenotype as Prognostic Markers
in Patients with Gastric Cancer
1,2
Yoshiko Mori ，Kunitoshi Shigeyasu 1 ，Takeshi Nagasaka 1 ，Shinichi Toyooka 2,3
，Toshiyoshi Fujiwara 1
1:Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan、2:Clinical
Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences、3:General Thoracic Surgery,
Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Background: To improve the outcome of patients suffering from gastric cancer, a better understanding of underlying genetic
and epigenetic events in this malignancy is required. Although CpG island methylator phenotype (CIMP) and microsatellite
instability (MSI) have been shown to play pivotal roles in gastric cancer pathogenesis, the clinical significance of these events
on survival outcomes in patients with gastric cancer remains unknown.
Methods: This study included a patient cohort with pathologically confirmed gastric cancer who had surgical resections.
A cohort of 68 gastric cancers was analyzed. CIMP and MSI statuses were determined by analyzing promoter CpG island
methylation status of 28 genes/loci, and genomic instability at 10 microsatellite markers, respectively. A Cox’s proportional
hazards model was performed for multivariate analysis including age, stage, tumor differentiation, KRAS mutation status,
and combined CIMP/MLH1methylation status in relation to overall survival (OS).
Results: By multivariate analysis, longer OS was significantly correlated with lower pathologic stage (P=0.0088), better tumor
differentiation (P=0.0267) and CIMP-high and MLH1 3’ methylated status (P=0.0312). Stratification of CIMP status with
regards to MLH1 methylation status further enabled prediction of gastric cancer prognosis.
Poster Session
Conclusions: CIMP and/or MLH1 methylation status may have a potential to be prognostic biomarkers for patients with
gastric cancer.
Mon(2)-P-31
Discovery of a gene alteration that causes clear cell carcinoma of the ovary
Yusuke Shibuya 1 ，Hideki Tokunaga 1 ，Jun Yasuda 2 ，Sakae Saito 2 ，Bin Li 1 ，Nobuo Yaegashi 1
1:Department of Obstetrics and Gynecology, Tohoku University Hospital, Japan、2:Department of Integrative Genomics, Tohoku Medical
Megabank Organization
Background:
Ovarian clear cell carcinoma (OCCC) is the most refractory subtype of ovarian epithelial cancer. Conventional treatment of
epithelial ovarian cancer has hardly any effect for OCCC. OCCC usually grows from endometriosis and develops frequently
to Japanese compared to western people (25%, 5% of epithelial ovarian carcinoma). Somatic mutation of ARID1A (60%)
and PIK3CA (40%) have been already known, but these mutations seems to be insufficient to support the characteristics of
OCCC. Then the aim of this study is to discover the novel genomic alterations causing OCCC. Secondly, we want to find new
target of treatment of this disease.
Methods:
With institutional approval, seventy OCCC tumors were identified with FFPE tumor specimens from surgeries performed
between 2007 and 2015. All specimens with clinical data underwent genotyping by exome sequence and SNP arrays. Exome
library was prepared with Sure Select Human All Exon V6. Copy number analysis was performed by Japonica array (SNP
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array made by Tohoku medical megabank organization with 1000 Japanese normal person’s genome data).
Results:
Copy number analysis discloses partial trisomy of long arm of chromosome 8. Some oncogenic gene was amplified more than
half of the samples. An exome sequence discloses frameshift change of ARID1A (3 of 3 sample) and nonsynonymous mutation
of PIK3CA (2 of 3 samples). Novel nonsynonymous mutation of DNA damage repair gene was discovered (3 of 3 samples).
Discussion:
We found several somatic genetic alterations, either novel or reported, in OCCC. We will compare between clinical stages
and investigate gene ontology analyses of those genes. After discovering a promising gene, we are going to prove it by the
experiment using the cultured OCCC cells.
Mon(2)-P-32
Identification of transcriptomic signatures in multiple myeloma using single cell RNA-sequencing
1,2 2,4
Da-eun Ryu ，Hae-Ock Lee ，Kihyun Kim 3 ，Woong-Yang Park 2,4
1:Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan Univer-
sity, Korea, South、2:Samsung Genome Institute、3:Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center、
4:Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine
Poster Session
Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. Due to the expansion of plasma cells, massive
production of immunoglobulins occurs in MM patients, in particular of IgG or IgA types. Previous studies identified gene
expression profiles as well as DNA level heterogeneity within tumor associated with poor patient outcome. However, the
relationship between the clonal heterogeneity and the poor prognostic gene expression is not known. Also, heterogeneity
at gene expression levels has not been explored in MM. Here, we performed single-cells tumor RNA sequencing from 10
MM patients and identified the MM-specific transcriptome signatures in comparison to normal blood B-cells from 10 healthy
donors. The external RNA spike-in controls show a detection limit of 20 RNA molecules and a dynamic range close to 10 to
the fifth, indicating high quality of single cell RNA sequencing data. To find significantly expressed genes in MM, we analyzed
the gene expression patterns using previously reported MM gene signature and other cancer-related genes-sets, in reference
to the clinical features. Our data demonstrate variable level of transcriptome heterogeneity in cancer-related signatures for
different patients, and suggest the presence of a sub-population with high oncogenic potentials.
Mon(2)-P-33
FRY Pancreas-Specific Methylation and Clinical Application
Nakarin Kitkumthorn 1 ，Ratakorn Srisuttee 2 ，Somboon Keelawat 3 ，Phonthep Angsuwatcharakon 2 ，
Apiwat Mutirangura 2
1:Oral Biology, Faculty of Dentistry, Mahidol University, Thailand、2:Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok,
Thailand、3:Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Recently, we reported using methylation array analysis that, among 22 organs, FRY was selectively methylated in pancreatic
tissue (Gene. 553: 31-41, 2014). In this study, methylation status of FRY was validated in 24 pancreatic tissues and 80 other
tissues from 13 organs by Bisulfite DNA sequencing, COmbined Bisulfite Restriction Analysis (COBRA) and real-time PCR
techniques. The results in normal pancreatic tissue, 21 of 24 samples were methylated, whereas the other normal tissues were
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totally unmethylated. Furthermore, FRY was also methylated in pancreatic ductal adenocarcinoma (PDAC). Consequently,
using this aspect for clinical application, we further evaluated to use as PDAC diagnosis in adenocarcinoma of unknown
primary origin. Investigation of the efficiency in differentiating from other eight common adenocarcinomas (stomach, lung,
endometrium, ovary, prostate gland, bile duct, colon and breast) was performed. The results displayed this marker effectively
indicated 25 PDAC among 151 other common adenocarcinomas with 100% of sensitivity and 99.77% specificity. Besides,
for PDAC screening purpose, we tested 23 bile samples from benign biliary obstruction patient and 24 bile samples from
pancreatic cancer patient. The results showed significant higher level of FRY methylated DNA in pancreatic cancer patient
group with the P-value = 0.00956. In summary, the methylation of FRY is prominently specific to both normal pancreatic
tissue and PDAC. Moreover, this epigenetic marker has greater potential for screening PDAC from bile of biliary obstruction
patient and capable to distinguish PDAC from adenocarcinoma in cases with unknown origin.
Mon(2)-P-34
Chromosome 3p rearrangement and BAP1 mutations in renal cell carcinomas and malignant mesothe-
liomas
Tomoko Hashimoto-Tamaoki 1,4 ，Yoshie Yoshikawa 1 ，Yoshikazu Togo 2 ，Masataka Zozumi 3 ，Chika Sato 4 ，
Seiichi Hirota 3 ，Shingo Yamamoto 2
1:Department of Genetics, Hyogo College of Medicine, Japan、2:Department of Urology, Hyogo College of Medicine, Hyogo, Japan、
3:Division of Surgical Pathology, Department of Pathology, Hyogo, Japan、4:Department of Clinical Genetics, Hyogo College of Medicine,
Hyogo, Japan
Poster Session
We previously reported that >60% of malignant mesotheliomas (MMs) derived from Japanese patients had biallelic somatic
mutations in the BAP1 gene, located in 3p21. We also found germline rare variants in chromatin remodeling genes and
transcription factor genes, which might be responsible for development of MMs (Int J Cancer, 2015). Recent reports showed
that BAP1 and PBRM1 genes, located next to BAP1 , were also mutated in sporadic renal cell carcinomas (RCCs). We,
therefore analyzed 3p regions in sporadic RCCs of Japanese patients, in comparison to 3p rearrangements in RCCs with that
in MMs.
Genomic DNAs were obtained from 45 sporadic RCC tissues, including 42 clear cell type (ccRCC) and 3 chromophobe type
(chRCC). Forty ccRCCs had VHL inactivation by biallelic mutations or methylation, and 39 of the 40 had LOH between 3p14.1
and 3p25.3. Thirty-five of the 39 showed monoallelic 3p loss at least between 3p14.3 and 3p22.2, indicating hemizygosity of
BAP1 and PBRM1 . Loss-of-function mutations of BAP1 were detected in a remaining allele in 4 ccRCCs of the 35, and
PBRM1 mutations in 21 without BAP1 mutations. Biallelic mutation was detected in one ccRCC. Immunostaining of BAP1
protein was negative in all 5 ccRCCs with BAP1 mutations. Interestingly, 10 ccRCCs with hemizygous normal BAP1 were
also negative. In three chRCCs, on the other hand, no mutations were detected in the BAP1 and PBRM1 genes, and BAP1
staining was positive, indicating that molecular basis of chRCCs is quite different from that of ccRCCs.
We found that BAP1 mutations, but not other mutations, correlate to shorter recurrent-free survival (p<0.046), suggesting
that genomic loss of the BAP1 gene may be one of prognostic factors for RCCs. Finally, comparison of genomic rearrangements
between MMs and RCCs showed multiple microdeletions in the BAP1 region were more frequent in MMs, indicating that
MMs had higher genomic instability than RCCs..
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Mon(2)-P-35
Functional Characterization of Coexistent KRAS/PIK3CA and NRAS/PIK3CA Mutations in Colorectal
Cancer
Joshua Reginald P. Malapit 1 ，Andrea Francesca M. Salvador 1 ，Reynaldo L. Garcia 1
1:Disease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular Biology and Biotechnology, University of the
Philippines - Diliman, Philippines
Cancer is a complex disease arising from mutations in key oncogenes and tumor suppressors. Recent sequencing efforts on
several cancer types report coexistent mutations in genes functioning in different pathways within the same cancer. Among
the major signaling networks implicated are the MAP-Kinase pathway involved in cellular proliferation, differentiation, and
growth, and the PI3K/Akt/mTOR pathway involved in cell survival. In colorectal cancer, coexistent mutations in the
RAS and PIK3CA genes of the MAPK and PI3K/AKT/mTOR pathways respectively are observed 40-60% of the time.
Individuals harboring these mutations together have been found unresponsive to targeted therapies that impinge on the MAPK
or PI3K/AKT/mTOR pathway exclusively. Understanding how these combinatorial mutations coordinately alter various
cellular and physiological processes may reveal functional relationships between genes and pathways in tumor progression,
as well as provide better insight on the prognosis and treatment of the disease. In this study, rare KRAS/PIK3CA and
NRAS/PIK3CA coexistent mutations were characterized to assess their tumorigenic and metastatic potential. Uncommon
co-occurring mutations [RG1] reported in the Cancer Genome Atlas in exon 20 of PIK3CA (G1007R and Y1021C) and exon
3 and 4 of KRAS (Y71C) and NRAS (E132K) respectively were cloned into a multicistronic expression vector. NIH3T3 and
HCT116 colorectal cancer cells were co-transfected with each mutant PIK3CA construct and the corresponding coexistent
KRAS or NRAS mutant, and were phenotypically characterized and compared to cells transfected with a single mutant
Poster Session
construct and the WT version of its coexistent counterpart. The functional significance of these mutations in tandem were
observed in terms of changes in morphology, cytoskeletal organization, proliferative and migratory capacity, expression of
EMT markers and resistance to apoptosis.
Mon(2)-P-36
Thyrotropin-releasing hormone (TRH) methylation in squamous cell carcinoma
Kanwalat Chalertpet 1 ，Nakarin Kitkumthorn 2 ，Somboon Keelawat 3 ，Apiwat Mutirangura 4,5
1:Biomedical Sciences, Chulalongkorn University, Thailand、2:Department of Oral Biology, Faculty of Dentistry, Bangkok, Thailand、3:De-
partment of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand、4:Department of Anatomy, Faculty of Medicine,
Chulalongkorn University, Bangkok, Thailand、5:Center for Excellence in Molecular Genetics of Cancer and Human Diseases, Chulalongkorn
University, Bangkok, Thailand
The common role of promoter methylation in cancer is to inhibit tumor suppressor gene transcription. Consequently, tumor
phenotype is promoted. Thyrotropin-releasing hormone (TRH) is a hormone releasing from hypothalamus to stimulate the
release of thyrotropin from pituitary gland. The expression and role of TRH in squamous cells and squamous cell cancer
(SCC) have not been identified. This study will present a surprising evidences supporting that TRH may possess a role as a
tumor suppressor gene in SCC. We analyzed twelve methylation microarray experiments of Head and Neck SCC and cervical
SCC reported in the NCBI Gene Expression Omnibus. We found high incidence of TRH methylation SCC. To test the effect
of TRH on cell proliferation, we treated various concentrations of the hormone to cervical cancer cell lines; HeLa and C33a,
and head and neck cancer cell lines; WSU-HN6 and WSU-HN17. However, TRH could limit cancer cell proliferation in dose
dependent manner only in HeLa. Next, we evaluated TRH methylation statuses of seven SCC cell lines, nine micro-dissected
head and neck SCC (mHN-SCC) and nine micro-dissected oral mucosa (normal) by pyrosequencing. The results showed
methylation levels of all SCC cell lines, all mHN-SCC, and all normal oral mucosa were 80%, 50% and 5%, respectively. In
conclusion, SCC possesses high incidence of TRH promoter methylation. The very high incidences of this result represented
the potential of TRH methylation as a SCC screening marker. Finally, the possible mechanism, how TRH methylation plays
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a role in SCC development, should be further explored.
Mon(2)-P-37
Characterization of UROC3 as a novel prognostic biomarker and therapeutic target for oral cancer
1,2 1,2
Thang Manh Phung ，Atsushi Takano ，Yoshihiro Yoshitake 3 ，Masanori Shinohara 3 ，Yoshinori Murakami 4 ，
Yataro Daigo 1,2
1:Center for Antibody and Vaccine Therapy, Research Hospital, The Institute of Medical Science, The University of Tokyo, Japan、
2:Department of Medical Oncology and Cancer Center, Shiga University of Medical Science、3:Department of Oral and Maxillofacial
Surgery of Kumamoto University、4:Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo
Oral cancer (OC) is one of the frequent cause of cancer-related death worldwide. Current therapies for OC include surgery,
radiotherapy, and chemotherapy. However, local and regional recurrences account for up to 90% of treatment failures after
surgery and radiotherapy. Therefore, next generation treatments for OC are eagerly awaited. To identify new prognostic
biomarkers and therapeutic targets for OC, we focused on up-regulated in oral cancer 3 (UROC3 ) as a candidate. Immunohis-
tochemical analysis using tissue microarray covering 99 OC tissues confirmed that UROC3 protein was expressed in 67 cases
of 99 OC tissues (68%), but not in normal oral epithelia. High levels of UROC3 protein expression was significantly associated
with poorer prognosis for OC patients (P = 0.0244 by log-rank test). Furthermore, knockdown of UROC3 expression by
siRNAs against UROC3 suppressed its protein expression and significantly inhibited the growth of OC cells through induction
of apoptosis. UROC3 could be a novel prognostic biomarker and a therapeutic target for OC patients.
Poster Session
Mon(2)-P-38
Not HOXB13 p.G84E, but p.R217C appears to be associated with increased breast cancer risk in the
Dutch population
Margriet Collee 1 ，Jingjing Liu 2 ，Wendy J.C. Prager-van der Smissen 2 ，Marjanka K. Schmidt 3 ，
Sten Cornelissen 3 ，Roy Lamping 1 ，Anja Nieuwlaat 1 ，John A. Foekens 2 ，Maartje J. Hooning 2 ，Senno Verhoef 4 ，
Ans W.M. van den Ouweland 1 ，Frans B.L. Hogervorst 4 ，John W.M. Martens 2,5 ，Antoinette Hollestelle 2
1:Department of Clinical Genetics, Erasmus MC Cancer Institute, Rotterdam, The Netherlands、2:Department of Medical Oncology,
Erasmus MC Cancer Institute, Rotterdam, The Netherlands、3:Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam.
The Netherlands、4:Division of Diagnostic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands、5:Cancer Genomics, The
Netherlands
HOXB13 plays an important role in breast tumorigenesis as high expression of HOXB13 predicts poor outcome and adverse
response to endocrine therapy. At the genetic level, the HOXB13 p.G84E mutation confers a four to five-fold increased
prostate cancer risk and thus HOXB13 p.G84E might also be associated with increased breast cancer risk. Previous studies
investigating this association, however, reported conflicting results. Therefore, we now have comprehensively interrogated the
entire HOXB13 coding sequence for mutations in 1250 non-BRCA1&2 familial breast cancer cases and 800 controls. In total,
seven missense mutations were identified of which five were seen only once. The p.G84E mutation, however, was identified
in 4 (0.33%) of 1215 cases and 6 (0.79%) of 759 controls. Another recurrent mutation, p.R217C, was found in 6 (0.50%) of
1206 cases and 1 (0.13%) of 765 controls. Because both mutations were predicted to be damaging, we further evaluated their
association with breast cancer risk by expanding our case-control study to include a total of 4520 non-BRCA1&2 familial
breast cancer cases and 3127 controls. Custom genotyping revealed that p.G84E was present in 22 (0.50%) of 4415 cases
and 22 (0.71%) of 3089 controls (OR=0.70, 95% CI=0.39-1.26, P=0.23). The HOXB13 p.R217C mutation, however, was
identified in 16 (0.36%) of 4444 cases and 3 (0.10%) of 3077 controls (OR=3.70, 95% CI=1.08-12.72, P=0.033, P adj =0.066).
Our results show that HOXB13 p.R217C rather than p.G84E appears to be associated with breast cancer risk. HOXB13
p.R217C is thus a putative novel moderate-risk breast cancer susceptibility allele.
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Mon(2)-P-39
Leukemia Inhibitory Factor (LIF) plays a role in Chordoma Progression
Ozlem Silan Coskun 1 ，Sukru Gulluoglu 1,2
，Ozlem Turksoy 1 ，Aysegul Kuskucu 2 ，Omer Faruk Bayrak 2
1:Biotechnology, Yeditepe University, Turkey、2:Medical Genetics
INTRODUCTION: Chordoma is chemoresistant and radioresistant tumor, therefore radical surgery is the only treatment
option. LIF is a multifunctional protein that takes part in different roles in different tissues through a number of pathways
such as JAK/STAT3, PI3K/AKT, MAPK and/or ERK1/2, which are related to cancer. Limited studies about LIF and
cancer suggest that LIF has a complex role in the disease depending on the cancer type. In this study we investigate the
effect of LIF on chordoma for the first time.
METHODS: Two chordoma cell lines U-CH1 and MUG-Chor1 were cultivated using Human Recombinant LIF between 1
and 8 weeks. 1, 3, 5 and 8 weeks intervals were used for real-time PCR and functional tests. 3 weeks samples were used for
whole transcriptome microarray analysis (GeneAtlas HuGene2.1 ST Array Strip, Affymetrix). Tumorosphere formation assay
was conducted on agarose coated plates. Transwell cell culture inserts were used to evaluate the migration capacity of the
experimental groups. Colony formation capacity was measured with soft agar assay. A drug resistance study using Paclitaxel
and Bortezomib was done.
RESULTS: Our results show that LIF has a significant effect on stemness properties and aggressive traits of chordoma cells.
The migration, colony formation, tumorosphere formation, chemoresistance capabilities of chordoma cells were increased by
Poster Session
LIF administration. Microarray analysis demonstrated that LIF has a significant effect on gene networks involving tumor
inflammation, migration, invasion and metastasis.
CONCLUSION: These are the first findings to our knowledge about the effect of LIF on chordoma. LIF promotes migration,
invasion, survival, anchorage independent growth, tumorosphere formation capabilities of chordoma cells. These traits might
be contributing factors of chordoma cancer stem cells, metastasis, chemoresistance and chordoma progression to an advanced
and fatal stage.
Mon(2)-P-40
Microsatellite instability, hMLH1 methylation and BRAF V600E mutation in sporadic colorectal cancer
Loraine Kay D Cabral 1 ，Ma. Luisa D Enriquez 1,2
，The Colorectal Cancer Study Group-St. Luke’s Medical Center
1:Research and Biotechnology, St. Luke’s Medical Center, Philippines、2:Department of Biology, CENSER, De La Salle University, Manila
Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by microsatellite instability (MSI) and germline mu-
tation in the MMR genes. There are reports of sporadic cases of colorectal cancer (CRC) showing MSI, but rather than a
germline mutation in the MMR gene, it is associated with the methylation of the hMLH1 gene. Presence of the BRAF V600E
mutation in hMLH1 methylated tumors could differentiate between sporadic CRC from hereditary CRC. This paper presents
our work on sporadic CRCs in terms of MSI status, hMLH1 methylation and V600E mutation of the BRAF gene. Genomic
DNA from 54 CRC paired normal and tumor biopsies from the same patients were tested for MSI by High Resolution Melt
(HRM) analysis using the Bethesda Panel of Markers. hMLH1 methylation screening was done using bisulfite conversion and
methylation specific PCR (MS-PCR). BRAF V600E mutation screening was carried out using Amplification Refractory Mu-
tation System (ARMS)-PCR. Results revealed that MSI and hMLH1 methylation were significant only in proximally located
tumors (p values = 0.043 and 0.029 respectively). These data suggest that the regional difference between proximal and distal
colon is not only attributed to their morphology, function, and environment but also to their genetic nature. There was higher
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incidence of methylation of hMLH1 in the normal biopsies compared with the tumor tissues (35.2% vs. 9.3% respectively).
In addition, all of the hMLH1 methylated normal tissues carry the BRAF V600E mutation. This finding may suggest that
methylation could have inactivated certain genes like TSG and other genes containing microsatellite repeats in their coding
regions leading to the development of neoplasm. Another hypothesis would be that MMR inefficiency thru methylation of
hMLH1 promotes a hypermutable phenotype, and mutation in BRAF is one of these. Results of this study support the role
of both genetic and epigenetic factors in colorectal cancer.
Mon(2)-P-41
A Cancer-SNP-Panel-based case-control study of genetic susceptibility to cancer in Thai individuals
Jakris Eu-ahsunthornwattana 1 ，Juthamat Kunnatham 2 ，Nathanon Borisut 2 ，Natini Jinawath 3 ，Thanyachai Sura 1
1:Div of Medical Genetics, Dept of Internal Medicine, Ramathibodi Hospital, Mahidol University, Thailand、2:Faculty of Public Health,
Mahidol University、3:Program in Translational Medicine, Ramathibodi Hospital, Mahidol University
Genetic susceptibility has been implicated in various types of cancers, particularly those that are hereditary or familial. Since
cancers are multi-stage process involving accumulation of mutations, there may be a different type of genetic susceptibility that
could enhance this process even in non-familial cases. To find the more general susceptibility loci which could be involved in
carcinogenesis in Thai population, we selected 591 individuals from cohorts 1 and 2 of the Rama-EGAT study for genotyping.
Started in 1985, this study is a longitudinal study of employees of the Electricity Generating Authority of Thailand (EGAT),
originally aimed to study cardiovascular diseases, but has since been extended to including other illnesses including cancers.
Among the 591 individuals selected, 84 have been diagnosed with cancer which does not fit with hereditary or familial cancer
Poster Session
syndrome, whilst the remaining 507 individuals have never been diagnosed with cancer as of 2010. Genotyping was done using
Illumina GoldenGate Cancer SNP Panel, which contains a selection of 1421 SNPs associated with cancers. In this study,
1314 SNPs passed the quality control procedure and were analysed using a score test, adjusted for sex, age, body mass index
(BMI), smoking status and alcohol consumption, as implemented in the qtscore function in the GenABEL package. We found
35 SNPs from 31 genes/loci that are associated with cancers at the false discovery rate (FDR) of 0.05. The top loci are: CD86
(Benjamini-Hochberg FDR adjusted p = 0.0007), TP73L (0.0024-0.0173), SOD2 (0.0024), RERG (0.0024), CTLA4 (0.0033),
LTA (0.0033), ABCB1 (0.0152), CYP7B1 (0.0152) and IL4R (0.0152). These tend to have role in immunological response
or cellular senescence and apoptosis and may explain why they have effect on wider range of cancers. This may add to the
insight on carcinogenesis in this population, and may allow identification of individuals who are at higher risk of developing
cancer.
Mon(2)-P-42
Functional Sequelae of the Novel NRAS Mutation E132K
Ryan Timothy D. Yu 1 ，Robert Lorenz C. Chua 1,2
，Reynaldo L. Garcia 1 ，Joshua P. Malapit 1 ，
Jose Lorenzo M. Ferrer 1
1:National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Philippines、2:University of Gottingen
The Ras superfamily of monomeric GTPases is known to be a molecular switch for the signaling pathways for cell proliferation,
differentiation, motility, and apoptosis. Among the three isoforms of Ras, KRAS was shown to be most commonly mutated
in colorectal cancer. Mutations in codons 12 and 13 of KRAS have been observed in 30-40% of colorectal tumors. Mutations
in KRAS can also be used as a biomarker to screen anti-EGFR responders from non-responders, but these mutations have
been observed to account for only 40% of the non-responder population, indicating that there are other mutations in the
RAS-RAF-MEK and RAS-PIK3CA-Akt pathways, which ought to be characterized as biomarkers. Further mutations in
the Ras isoform NRAS have also been identified in colorectal cancer patients. In this study, we expressed constructs of the
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E132K mutation, an uncharacterized novel mutation in NRAS reported in the COSMIC database, as well as those of wild
type NRAS, and 2 canonical mutants of NRAS, Q61K and G12D. We phenotypically characterized the novel mutation in
NIH3T3 cells, and compared them with the wild type and canonical mutants in terms of changes in morphology, changes in
cytoskeletal organization, proliferative capacity, migratory capacity, frequency of focus formation, and resistance to apoptosis.
Mon(2)-P-43
POLYMORPHISMS IN FOLATE METABOLIZING GENES AMONG CANCER PATIENTS FROM
WEST UKRAINE
Iryna Dmytruk 1 ，Halyna Makukh 1 ，Lilya Chorna 1 ，Nataliya Kitsera 1
1:SI Institute of hereditary pathology NAMS of Ukraine, Ukraine
A crucial role for the control of DNA methylation as well as DNA synthesis and repair mechanisms is played by the provision
of adequate pools of methyl groups through the functional activity of methylenetetrahydrofolate reductase (MTHFR) and
methionine synthase (MTR) in one-carbon metabolism. It has been suggested that changes in the expression levels or activity
of folate key enzymes associated with the folate-methionine metabolic polymorphisms may lead to differences in susceptibility
to cancer development. The purpose of the study was to explore the carrier frequency of MTHFR 677 C> T and MTR 2756
A> G polymorphisms among patients with breast cancer and leukemia.
Genotyping of MTHFR 677 C> T and MTR 2756 A> G was performed in 60 patients with leukemia, 90 patients with breast
cancer and in 100 healthy persons without cancer pathology in anamnesis. The molecular - genetic analysis was performed
Poster Session
by PCR (Polymerase Chain Reaction) and RFLP (Restriction Fragment Length Polymorphism). Statistical analysis was
conducted by Chi-square tests and odds ratio (OR) was calculated.
The 2756 AA genotype frequency of MTR gene was significant higher in patients with breast cancer (0.67) vs control (0.50).
The increased risk of breast cancer development was associated with MTR 2756 AA genotype (OR = 2.00 CI - 95%: 1.11 -
3.60) and 2756 A alelle of MTR gene (OR = 1.75 CI - 95%: 1.08 - 2.84). The distribution of genotypes and alleles of
polymorphic loci 677 C> T of MTHFR gene did not shown statistically significant difference between group of patient with
breast cancer and patient with leukemia compared to control group.
The results suggest that the 2756 A> G polymorphic variant of MTR gene play a role in the susceptibility to breast cancer
development within West Ukrainian population.
Mon(2)-P-44
Investigations on the effects of miRSNPs on the tumor suppressive capacity of PTEN
Mia Helena B Reisland 1 ，Kenneth Anthony R Roquid 1 ，Reynaldo L Garcia 1
1:Disease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular Biology and Biotechnology, Philippines
Phosphatase and Tensin Homolog (PTEN) functions as tumor suppressor that negatively regulates the PI3-kinase cell sur-
vival pathway, the cellular proliferation pathway, and other mechanisms that contribute to the hallmarks of cancer. When
dysregulated, PTEN tends to lead to higher cancer susceptibility including, liver, prostate, and colorectal cancer. In this
study, we report the successful cloning of the 3’UTR of PTEN into the vector pmirGLO and miR-4465 into pmirZsGreen
to further study miRNA regulation of PTEN expression. Two SNPs were generated and introduced into the 3’UTR, one
SNP found directly within the binding region of miR-4465 (mut-1264), and the other close to the binding region (mut-1261).

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Further, the wild-type and SNP-bearing 3’UTRs of PTEN were fused to the coding region by gene-SOE’ing to enable
characterization of its tumor suppressive capacity in the cell line HCT 116. Various assays were performed with the variants
with respect to the wild-type such as cellular proliferation, apoptosis, scratch wound and other assays.
Mon(2)-P-45
Functional Characterization of the Rare BRAF Mutations R462G and T440A
Kevin Kent Vincent C Canlas 1 ，Reynaldo L Garcia 1
1:National Institute of Molecular Biology and Biotechnology, Disease Molecular Biology and Epigenetics Laboratory, Philippines
The RAS/RAF/MEK/ERK pathway is one of the extracellular-to-nuclear signal transduction pathways that are aberrantly
regulated during tumorigenesis, and activating mutations (particularly in KRAS and BRAF) have already been used for
cancer assessment and drug effectivity screening. Mutations in BRAF have been identified in various cancer types, at around
40-70% of malignant melanomas and roughly 10% of colorectal cancers. The canonical V600E (Val to Glu) mutation is the
predominant and most characterized mutation, situated in the activation segment of BRAF whose region is mutated in ~
90% of all BRAF mutations. Recent studies have found another hotspot, at codon 11, which harbors mutations that are
largely uncharacterized. These rare mutations could be the key to understanding resilient tumors, wherein their genome
instability increase tumor survival which may lead to drug resistance and possible relapse. The study aims to characterize
rare mutations of BRAF in terms of morphology and invasiveness. Two mutations in codon 11, R462G (Arg to Gly) and
T440A (Thr to Ala), were mined from the Catalogue of Somatic Mutations in Cancer (COSMIC) database under colorectal
Poster Session
cancer samples. Bioinformatic analysis and protein modeling revealed shifts in the kinase domain that could potentially affect
BRAF activity. Expression constructs for transient overexpression were generated for the wild-type, V600E canonical mutant,
and the two rare mutants R462G and T440A, which were then transfected to HCT 116 and NIH 3T3 cell lines. Morphological
analysis using fluorescence microscopy was done to assess phenotypic changes leading to tumorigenesis in the mutant BRAF
transfected cells. This was followed by semi-quantitative PCR using the epithelial-mesenchymal transition (EMT) markers
Twist and vimentin to elucidate the downstream pathways that are affected. The findings suggest that R462G and T440A
mutations may be good predictive markers for cancer prognosis.
Mon(2)-P-46
Phenotypic Characterization of the Putative KRAS mutant E31D
Jonathan P Chan 1 ，Arlou Kristina J Angeles 1 ，Reynaldo L Garcia 1 ，Robert Lorenz C Chua 1 ，
Joshua Reginald P Malapit 1
1:National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Philippines
Mutations in the KRAS gene are implicated in colorectal cancer incidence as canonical mutations in codons 12 and 13 in exon
2 of KRAS are found in about 30-40% of colorectal tumors. Such mutations cause the expression of a dysfunctional KRAS
protein. This results in a constitutively active pathway initiated by cell surface receptors like EGFR, which leads to cancer
associated properties like increased cell proliferation and survival. Thus, analyzing the mutational status of KRAS proves
useful in detecting nonresponders to anti-EGFR therapy. However, the two canonical mutations currently do not predict
all patients who will not respond well to such a treatment and thereby justifies the search to find additional biomarkers.
This study investigates a rare KRAS mutation in codon 31 (E31D) found after a genetic screen of CRC specimens at the
University of the Philippines Manila-Philippine General Hospital. Preliminary characterization of this mutation by transient
overexpression in NIH3T3 cells found that it caused increased focus formation and gross changes in cellular morphology. Actin
staining showed thinly defined stress fibers as well as extensive formation of filopodia and pseudopodia. Results from a scratch

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wound assay further indicate increased motility, which all suggest an appreciable effect of E31D KRAS on cellular migration
similar to the canonical mutations. E31D KRAS mutants were likewise characterized by qRT-PCR to measure changes in
gene expression. It was found that vimentin expression was upregulated upon transfection, contributing to the transforming
capacity of the mutation. Changes in Bcl-2 expression were also studied to investigate the effect of E31D KRAS on apoptosis.
Furthermore, work is underway to create an NIH3T3 cell line bearing the E31D mutation using the CRISPR/Cas9 system to
enable characterization of the mutation at physiological levels of expression.
Mon(2)-P-47
Phenotypic Characterization of the Putative Oncogenic PIK3CA Mutants Q661K and C901R
Arman A Ghodsinia 1 ，Reynaldo L Garcia 1 ，Robert Lorenz Chua 1 ，Joshua Malapit 1
1:National Institute of Molecular Biology and Biotechnology, University of the Philippines-Diliman, Philippines
PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase, Catalytic Subunit Alpha) is a protein coding gene that activates
the PI3K-Akt pathway. This pathway promotes cellular survival, growth, proliferation, and motility. Activating mutations in
PIK3CA prevent cells from properly responding to apoptotic signals, and are common in breast (27%) and colorectal (19%)
cancers. Although around 60-65% of PIK3CA mutations in colorectal cancer (CRC) are found in exon 9, most mutations
associated with resistance to EGFR targeted therapy are found in exon 20 (20-25% of all PIK3CA mutations). These
mutations lead to constitutively active oncoproteins that bypass the normal-EGFR initiated signaling cascade, leading to
dysregulated PIK3CA effectors associated with resistance to anti-EGFR targeted therapy, cell survival, and cancer. In this
Poster Session
study, two novel mutations, found in codon 661 (Q661K) and codon 901 (C901R) were identified from the Catalogue of Somatic
Mutations in Cancer (COSMIC) database. Expression constructs were generated to overexpress these rare PIK3CA mutants
in NIH3T3 and HCT116 cell lines as well as the wild type and two canonical (E545K and H1047R) mutant controls. The
rare mutants were phenotypically characterized and compared to the canonical mutants and wild type controls, in terms of
changes in morphology, cytoskeletal organization, proliferative and migratory capacity, frequency of focus formation, vimentin
expression, and resistance to apoptosis.
Mon(2)-P-48
Evaluation of genome-wide association study-identified SNPs at 4q12, 17q12, and 6p21.32 with cervical
cancer susceptibility in a Japanese population
Kiyonori Miura 1 ，Hiroyuki Mishima 2 ，Shuhei Abe 1 ，Yuko Murakami 1 ，Naoki Fuchi 1 ，Ai Higashijima 1 ，
Yuri Hasegawa 1 ，Shoko Miura 1 ，Masako Masuzaki 1 ，Masanori Kaneuchi 1 ，Koichiro Yoshiura 2 ，Hideaki Masuzaki 1
1:Obstetrics and Gynecology, Nagasaki University, Japan、2:Human Genetics, Nagasaki University School of Medicine
This study investigated whether genome wide association study-identified cervical cancer susceptibility loci (4q12, 17q12, and
6p21.32) were replicated in the Japanese population. Associations between invasive cervical cancer and three cervical cancer
susceptibility loci (rs13117307 at 4q12, rs8067378 at 17q12, and rs4282438 and rs9277952 at 6p21.32) in the Han Chinese
population were investigated in a Japanese population. After receiving written informed consent, 214 unrelated Japanese
women with invasive cervical cancer, and 288 cancer-free Japanese women were recruited and DNA samples were obtained
(study protocol approved by Institutional Review Board for Ethical, Legal, and Social Issues of Nagasaki University). Of
the four single nucleotide polymorphisms, rs8067378 at 17q12 showed a significant association with invasive cervical cancer
(P=0.0071). Under a recessive model, the minor allele G of rs8067378 contributed to the risk of invasive cervical cancer
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(odds ratio=2.92, 95% confidence interval=1.40-6.36; P=0.0021). In conclusion, we show for the first time, to the best of our
knowledge, that an association between increased risk of invasive cervical cancer and rs8067378 at 17q12 in the Han Chinese
population is replicated in a Japanese population. In addition, Japanese women with the GG genotype of rs8067378 are a
candidate high-risk group for invasive cervical carcinoma.
Mon(2)-P-49
Genome-wide association study identified three copy number polymorphisms associated with sporadic
colorectal cancer risk in Singapore Chinese
LaiFun Thean 1 ，Peh Yean Cheah 1,2,3
，Yik Ying Teo 2 ，Woon Puay Koh 2,3
，Jian Min Yuan 4 ，Choong Leong Tang 1 ，
Min Hoe Chew 1
1:Singapore General Hospital, Singapore、2:National University of Singapore、3:Duke-NUS Graduate Medical School Singapore、4:University
of Pittsburgh
Background: Accumulating evidence indicated that variations in human genome such as single nucleotide polymorphisms
(SNPs) and copy number variations (CNVs) are significantly associated with complex disease risks. To date, more than 20
SNPs have been shown to be associated with colorectal cancer (CRC) risk. Common CNVs or copy number polymorphism
(CNP) that contribute to CRC susceptibility, however, remained unclear due to structural complexity. Aim: In this study,
we investigated the association of CNP for sporadic CRC risk in Singapore Chinese. Method: We performed genome-wide
association study (GWAS) on 1,000 Singapore Chinese CRC patients and 1,000 ethnicity-, age- and gender-matched healthy
controls using the Affymetrix SNP6 platform. CNV analysis was performed using Golden Helix SVS software. In order to
Poster Session
eliminate significant bias due to batch effect or other quality issues, we applied derived log ratio spread (DLRS) measurement,
wave correction, gender concordance and chromosomal abnormally screening to all 2,000 samples. Under principle component
analysis (PCA), we also corrected the first 16 principle components. Results: A total of 1830 ‘clean’ samples were reimported
and segmented under multivariate segmentation, followed by CN association testing. Seven regions ranging from 1-3Mb
passed the genome-wide significance criterion (-log 10 P ≥ 7.3). Three regions on chr3q13.12 and chr12p12.3 encompass genes
with relevant biological functions such as proliferation, tumorigenic potential and metastasis. These genes were previously
implicated in inhibiting migration and metastasis in ovarian cancer as well as to act as suppressor of metastasis in bladder
cancer cells. These candidate CNP regions are currently being validated in an indepent replication panel consisting another
1,000 cases and 1,000 healthy controls, using an optimized Taqman copy number assay with Multicopy Reference (MRef) as
normalizer.
Mon(2)-P-50
Withdrawn

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Mon(2)-P-51
Sensitive Mutation Detection by Sequencing Circulating Cell-Free DNA
1
Nan Fang
1:QIAGEN GmbH, Germany
Circulating DNA, the cell-free DNA (cfDNA) found in serum or plasma, has become a powerful tool in non-invasive prenatal
testing (NIPT), as well as in cancer liquid biopsy. In cancer testing, it has been shown that the quantity and integrity, as well
as the mutation content of the cfDNA in cancer patients differ from that in healthy controls. Therefore, cfDNA may serve as
a biomarker for cancer diagnosis, prognosis, and stratification. High-throughput sequence analysis of the cfDNA using next
generation sequencing (NGS) technologies provides a highly sensitive and specific method in detecting and characterizing
somatic mutations in cancer samples. However, the cfDNA concentration in serum or plasma is normally very low, which
makes sequencing library construction challenging. Here, we verified two protocols for highly sensitive targeted sequencing
of the cfDNA regarding sequencing library quality, uniformity, sensitivity, and specificity. One protocol is based on hybrid
capture method that combines an optimized cfDNA library construction protocol with high-efficiency adaptor ligation and
unbiased library amplification and target capture with 5’ biotin modified probes. The other protocol is based on target
enrichment by multiplex PCR and a novel amplicon sequencing library construction method that requires only one room-
temperature incubation step. We demonstrated that both protocols can be used to sensitively and specifically detect mutants
from cfDNA samples.
Poster Session
Mon(2)-P-52
Germline mutations in DNA mismatch repair genes in breast cancer patients
1,2,3
Ann S.G. Lee ，Melody Sze 1 ，Sandhya Shekar 1 ，Edward SY Wong 1 ，Claire Chan 1 ，Peter Ang 4,5
1:Division of Medical Sciences, National Cancer Centre, Singapore、2:Department of Physiology, Yong Loo Lin School of Medicine, National
University of Singapore, Singapore、3:Office of Clinical & Academic Faculty Affairs, Duke-NUS Graduate Medical School, Singapore、4:Di-
vision of Medical Oncology, National Cancer Centre, Singapore、5:OncoCare Cancer Centre, Mount Elizabeth Novena Specialist Centre,
Singapore
Lynch syndrome is an inherited cancer predisposition syndrome, caused by mutations in DNA mismatch repair (MMR) genes.
Whether or not breast cancer should be considered as part of the tumour spectrum has been a heavily debated issue, and
the contribution of MMR gene mutations in familial breast cancer remains to be elucidated. To estimate the frequency
of mutations in the MMR genes, we analysed the germline mutations in 266 patients with strong family history of breast
cancer or early-onset breast cancer, using targeted next-generation sequencing. Of these, 11 (4.1%) patients had mutations
in MSH6, MSH1, or PMS2 , which were pathogenic variants or variants computationally predicted to be damaging. Where
tumour samples were available, they were assessed for molecular evidence of MMR deficiency. One (25%) of four specimens
displayed the microsatellite instability (MSI) and loss of MMR protein expression characteristic of Lynch syndrome. MSI was
present in two (33.3%) of six cases, whereas three (50%) of six showed loss of protein expression. Despite the small sample
size, these findings point towards the involvement of MMR deficiency in familial breast cancer.
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Mon(2)-P-53
Up-regulation of non-coding RNAs in adult and pediatric liver cancers
Kosuke Hashimoto 1 ，Ana Maria Suzuki 1 ，Alexandre Dos Santos 2 ，Alessandro Bonetti 1 ，Xian-Yang Qin 3 ，
Alexandre Fort 1 ，Bogumil Kaczkowski 1 ，Alistair R.R. Forrest 1 ，Soichi Kojima 3 ，Marie Annick Buendia 2 ，
Jamila Faivre 2 ，Piero Carninci 1
1:RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa, Japan、2:INSERM, U1193,
Paul-Brousse Hospital, Hepatobiliary Centre, Villejuif, France、3:RIKEN Center for Life Science Technologies, Division of Bio-function
Dynamics Imaging, Wako, Saitama, Japan
An increasing number of non-coding RNAs (ncRNAs) are implicated in various human diseases including cancer, however
ncRNA transcriptome of liver cancer remains largely unexplored. We use CAGE to comprehensively map transcription start
sites (TSSs) and measure their expression in two types of liver cancers, human hepatocellular carcinoma and hepatoblastoma
with special emphasis on ncRNAs. We found thousands of significantly up-regulated ncRNAs in both types of liver cancers
compared to their matched non-tumors. In HCC, many LTR retroviral promoters are activated in a subfamily-specific manner.
Intriguingly, the expression of highly up-regulated LTRs tends to be limited in reproductive tissues, such as testis and placenta.
3’ RACE for 15 highly up-regulated LTRs revealed that the transcripts are multi-exon ncRNAs typically 0.5-2kb in length. On
the other hand, hepatoblastoma didn’t show strong activation of LTR promoters. Instead, we identified activated ncRNAs
that have TCF/LEF binding motifs, which are likely to be targets of the wnt/β-catenin pathway. Together, this study sheds
light on ncRNA transcriptome of liver cancers, which might play important roles in tumor progression.
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Poster Session
Complex Traits and Polygenic Disorders 1
Mon(2)-P-54
Rs738409 Polymorphism in PNPLA3 gene is associated with lower insulin resistance in Korean
MenRs738409 Polymorphism in PNPLA3 gene is associated with lower insulin resistance in Korean
Men
Jin Ho Park 1 ，BeLong Cho 1 ，Hyuktae Kwon 2
1:Family Medicine, Seoul National University Hospital, Korea, South、2:Family Medicine, Healthcare System Gangnam Center, Seoul National
University Hospital
Background & Aims: The rs738409 polymorphism is a well-known genetic risk factor for nonalcoholic fatty liver disease
(NAFLD). Considering NAFLD is closely associated with insulin resistance, the association between rs738409 variant and
insulin resistance is highly suspected.
Methods: We screened 1,648 Korean men who visited the Health Promotion Center and 1,189 were enrolled in final analysis.
Hepatic steatosis was evaluated by abdominal ultrasound and subjects with secondary causes of NAFLD were excluded from
NAFLD classification. Serum glucose and insulin levels were measured using overnight fasting blood sample. The homeostasis
Poster Session
model assessment estimated insulin resistance (HOMA-IR) index was calculated by multiplying glucose in mg/dl by insulin in
µU/ml/405. The cutoff value of 2.56 was used for insulin resistance diagnosis as previously reported in Korean men. HOMA-
IR index values were natural log-transformed after normality test. Rs738409 genotyping was performed using TaqMan assay
on a ViiA™ 7 Real-Time PCR System (Life Technologies, California, USA).
Results: The participants were predominantly middle-aged men (49.1 ±7.0 years; range, 30-60 years), and the frequencies
of insulin resistance were 17.5%. We performed multivariate regression analysis after adjustment for NAFLD status. The
rs738409 CG and GG genotype showed lower mean levels of HOMA-IR index compared to the CC genotype (P = 0.031
and < 0.001, respectively. Then, we checked the effect of the rs738409 G allele on HOMA-IR index levels in each NAFLD
and non-NAFLD subgroup stratified by NAFLD status using one-way ANOVA. In the non-NAFLD group, the CG and GG
genotypes compared to the CC genotype showed significantly lower mean levels of HOMA-IR index in an additive manner
(Sidak-corrected P = 0.018 and < .001, respectively).
Conclusion: The adiponutrin polymorphism rs738409 known as a NAFLD genetic risk factor was also associated with decreased
levels of insulin resistance assessed by HOMA-IR index.
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Mon(2)-P-55
Candidate genes for strabismus (esotropia and exotropia) susceptibility chromosomal loci
1
Toshihiko Matsuo
1:Ophthalmology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan
Purpose: Comitant strabismus is a multifactorial disorder with genetic and environmental background. Genetic influence
is evidenced by family history and monozygotic twin concordance. Environmental influence is supported by the association
with prematurity birth and perinatal hypoxia. An American group reported 7p22.1 as a chromosomal susceptibility locus for
esotropia in a Caucasian family. My group has identified new susceptibility loci, 4q28.3 and 7q31.2, for comitant strabismus,
including both esotropia and exotropia, in Japanese families. In this study, the two chromosomal loci were narrowed by single
nucleotide polymorphism (SNP) analysis.
Methods: SNP analyses in two chromosomal loci, 4q28.3 and 7q31.2, were done in genomic DNA of 114 patients and 90 normal
individuals of 55 families with comitant strabismus, including both esotropia and exotropia, which were used in the previous
study for loci identification. Tag SNPs in the two loci were first picked up from the JSNP database for Japanese. Finally, 24
rsSNPs were chosen in 4q28.3 locus, and 257 rsSNPs were chosen in 7q31.2 locus from the dbSNP database (NCBI). Each
SNP was identified on the platform of MassARRAY Analyzer 4 (96 well) iPlex SNP Genotyping (Sequenom).
Results: The genotype at rs4147590 SNP site in the 4q28.3 locus and the genotype at rs2239957 SNP site in the 7q31.2
locus were significantly different between the patients and normal individuals of the families (P<0.05, chi-square test without
Poster Session
Bonferroni correction). The SNP, rs4147590, was located in the intron of the gene, Microsomal glutathione S-transferase 2
(MGST2 ), while the SNP, rs2239957, was in the intron of the gene, wingless-type MMTV integration site family member 2
(WNT2 ).
Conclusions: MGST2 and WNT2 are candidate genes for the 4q28.3 and 7q31.2 chromosomal locus, respectively. Both genes
are known to be expressed in the brain and might be involved in the development of comitant strabismus. Whole exome
sequencing is now under way.
Mon(2)-P-56
Deep Resequencing of SULF2-PREX1 intergenic region in Nephrotic Syndrome
Khun Z Latt 1 ，Khor Seik-Soon 1 ，Kenjiro Honda 2 ，Yuki Hitomi 1 ，Eisei Noiri 2,3
，Katsushi Tokunaga 1
1:Department of Human Genetics, School of International Health, The University of Tokyo, Japan、2:Department of Nephrology and En-
docrinology, The University of Tokyo Hospital、3:Department of Haemodialysis and Apheresis, The University of Tokyo Hospital
Nephrotic syndrome is a clinical syndrome of renal damage and heavy proteinuria resulting from a number of etiologies. A
previously reported genome-wide association study (GWAS) in Japanese population had found association of rs11086243 in
the intergenic region between SULF2 and PREX1 with nephrotic syndrome. Fine-mapping of the region was performed by
genotyping of the tag SNPs in the intergenic region between SULF2 and PREX1 and a significant haplotype was identified
between two of the SNPs. In order to identify the primary SNPs in the region, deep resequencing of the haplotype region was
performed in 18 nephrotic syndrome cases using Ion Proton (Thermo-Fisher Scientific). Primer sets were designed using the
online version of Ion Ampliseq™ . The targeted resequencing was performed using the standard protocol by Thermo-Fisher
Scientific. Briefly, 22.3 Gbp of amplicons were generated after sequencing and an average of mean depth per sample of
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3693x was obtained with the 85.6% of average uniformity across all bases and an average 88.4% of reads mapped on the target
region. A total of 1320 novel variants were identified. After prediction of their potential functional impacts with RegulomeDB
database, we identified 6 novel variants in the region that are present in more than one case sample and having a RegulomeDB
functional impact score of 2c and predicted to be likely to affect the binding of transcription factors. These variants will be
confirmed using Sanger sequencing and corresponding functional studies will be performed depending on the location of the
novel variants.
Mon(2)-P-57
Contribution of variants in the FGD6 gene with endometriosis risk
1,2
Hien T. T Luong ，Jodie N Painter 2 ，Dale R Nyholt 2,3
，Grant W Montgomery 2
1:Pediatric department, Hanoi Medical University, Vietnam、2:Department of Genetics and Computational Biology, QIMR Berghofer Medical
Research Institue, Brisbane, Australia、3:Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane,
Australia
Endometriosis is a common, chronic gynaecological disease defined as pelvic pain and sub-fertility. The disease is inherited
as a complex trait, affects 6-10 % of women of reproductive age and up to 50% of women with infertility. Our group’s
genome-wide association (GWA) imputed and meta-analysis studies in women with and without endometriosis identified
evidence for association on chromosome 12q22. The association signals expand across location of the VEZT gene and an
adjacent gene, FGD6 . Fine-mapping the 12q22 region, no evidence was found for contribution of coding variants in FGD6
with endometriosis risk. However, evidence for association of top non-coding variants in 12q22 region from our previous GWA
Poster Session
data was confirmed in our set of 929 Australian endometriosis cases and 958 controls. The best association evidence was
identified for a variant, located in the promoter of FGD6 , rs6538617 (P = 0.021, 95%CI; OR = 1.20 (1.03 - 1.41), and other
three FGD6 non-coding variants in high LD together and with this variant. These variants together with the top non-coding
SNPs in the 12q22 region make the risk haplotype with higher frequency in cases than in controls and suggests a significant
association for this haplotype with endometriosis risk (p = 0.003). In ENCODE data, rs6538617 was located in areas of
multiple potential regulatory predictions in numerous cell types. Hence, further studies should be carried out in relevant
target tissues to determine regulatory effects of this variant on endometriosis risk.
Mon(2)-P-58
Genome-wide association study of clinically-ascertained gout identifies multiple risk loci and its associ-
ation with clinical subtypes
Airi Akashi 1 ，Hirotaka Matsuo 1 ，Ken Yamamoto 2 ，Hirofumi Nakaoka 3 ，Akiyoshi Nakayama 1 ，Masayuki Sakiyama 1 ，
Atsushi Takahashi 4,5 ，Takahiro Nakamura 6 ，Yuki Tanahashi 1 ，Nobuyuki Hamajima 7 ，Ituro Inoue 3 ，Michiaki Kubo 5 ，
Kimiyoshi Ichida 8 ，Hiroshi Ooyama 9 ，Toru Shimizu 10 ，Nariyoshi Shinomiya 1
1:Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Japan、2:Department of Medical Chem-
istry, Kurume University School of Medicine、3:Department of Integrated Genetics, National Institute of Genetics、4:Omics Research Center,
National Cerebral and Cardiovascular Center、5:Center for Integrative Medical Sciences, RIKEN、6:Laboratory for Mathematics, National
Defense Medical College、7:Department of Healthcare Administration, Nagoya University Graduate School of Medicine、8:Department of
Pathophysiology, Tokyo University of Pharmacy and Life Sciences、9:Ryougoku East Gate Clinic、10:Midorigaoka Hospital
Background/Purpose: Gout is a common disease caused by hyperuricemia. Recently, genome-wide association studies
(GWASs) of gout have been performed; however, most of them included self-reported gout cases. Therefore, the relationship
between genetic variation and clinical subtypes of gout is yet to be clarified. Here, we report a GWAS which was performed
with only clinically-defined gout cases.
Methods: A GWAS was performed with 945 clinically-defined gout cases and 1,213 controls in a Japanese male population.
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Furthermore, we conducted a replication study of 1,048 clinically-defined cases and 1,334 controls.
Results: Five susceptibility loci for gout were identified at the genome-wide significance level (p < 5.0 × 10-8 , which included
well-known urate transporter genes (ABCG2 and SLC2A9 ) and additional genes reported to have relationships with metabolic
pathways: rs1260326 (p = 1.9 × 10-12 ; OR = 1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p = 1.6 ×
10-23 ; OR = 1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus), and rs4073582 (p = 6.4 × 10-9 ;
OR = 1.66) of CNIH-2 (a gene for regulation of glutamate signaling). The latter two are identified as novel loci for gout.
Furthermore, the risk alleles of SNPs of ABCG2 and SLC2A9 significantly associated with clinical parameters underlying
specific subtypes. The risk allele of each SNP showed the linear relationships with the ratio of the case-control ORs for two
distinct types of gout (r = 0.96 [p = 4.8 × 10-4 ] for urate clearance and r = 0.96 [p = 5.0 × 10-4 ] for urinary urate excretion).
Conclusion: Our study provides a key to better understand the pathogenesis of gout and will be useful for developing
companion diagnostics of gout.
Mon(2)-P-59
Variant c.2262A>C in DOCK9 leads to exon skipping in keratoconus family
Marzena Gajecka 1,2 ，Justyna A. Karolak 1,2 ，Malgorzata Rydzanicz 3 ，Barbara Ginter-Matuszewska 1,2
，
Jose A. Pitarque 4 ，Andrea Molinari 4 ，Bassem A. Bejjani 5
1:Institute of Human Genetics, Polish Academy of Sciences, Poland、2:Department of Genetics and Pharmaceutical Microbiology, Poznan
University of Medical Sciences、3:Department of Medical Genetics, Medical University of Warsaw、4:Department of Ophthalmology, Hospital
Poster Session
Metropolitano、5:Sammamish, WA, USA
Keratoconus (KTCN) is a progressive eye disorder characterized by thinning and a conically shaped protrusion of the cornea,
resulting in impairment of visual function. Previously, we identified heterozygous nucleotide substitutions in DOCK9, IPO5,
and STK24 showing concurrent 100% segregation with the affected phenotype in the Ecuadorian family. As the pathogenic
consequences of these variants were not obvious, we performed in vitro splicing analyses to determine their functional signifi-
cance.
We generated expression constructs using patient DNA as a template corresponding to the wild-type and mutant alleles of
DOCK9 , IPO5 , and STK24. After transfecting HeLa cells with each construct, total RNA samples were extracted, reverse-
transcribed, and amplified using specific primers.
In vitro splicing analysis revealed that only c.2262A>C in exon 20 of DOCK9 led to aberrant splicing, resulting in the changed
ratio between two protein isoforms: a normal transcript and a transcript with exon skipping.
As a change in the balance between two protein isoforms is observed, the phenotypic effect is not obvious compared with the
complete removal of the normal transcript. However, based on the results of the bioinformatics analyses, we hypothesize that
the identified exon-skipping variant might disrupt the functional domains of DOCK9 protein and alter the biological role of
DOCK9 as a Cdc42 activator.
To summarize, we demonstrated that the c.2262A>C substitution in DOCK9 , previously identified in KTCN members of an
Ecuadorian family, leads to a splicing aberration. However, because the effect was observed in vitro, a definitive relationship
between DOCK9 and the KTCN phenotype could not be established. Our results indicate that further elucidation of the
causes of KTCN is needed.
This study was supported by Polish Ministry of Science and Higher Education and National Science Centre in Poland,
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2013/10/M/NZ2/00283, NN402591740 and Doctoral Scholarship Etiuda 1, 2013/08/T/NZ5/00754.
Mon(2)-P-60
Whole-exome sequencing reveals a novel gene as a cause of aggressive periodontitis in Japanese families
1,2
Takeaki Sudo ，Yukinori Okada 2 ，Hiroaki Kobayashi 1 ，Misa Gokyu 1 ，Yuichi Izumi 1 ，Toshihiro Tanaka 2,3
1:Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan、
2:Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental
University、3:Bioresource Research Center, Tokyo Medical and Dental University
[Background]
Aggressive periodontitis (AgP) is a severe type of periodontitis characterized by rapid alveolar bone destruction that results
in tooth loss early in the life. Although familial aggregation indicated involvement of genetic factors in the pathogenesis of
this disorder, exact causal gene has yet to be identified. To identify genetic risk factors of AgP, we performed whole-exome
sequencing analysis using family cases.
[Method]
Participants were recruited at Department of Periodontology, Tokyo Medical and Dental University. WES using Ion Proton
was performed for five AgP patients and one control in two genetically independent families. After variant calling, annotation
Poster Session
using snpEff/SnpSift and filtering was conducted. The filtering pipeline are as follows: 1) Filter Pass, 2) Shared variants
between two next generation sequencers, 3) Depth ≥10, 4) Not insertion/deletion, 5) Shared in affected patients and not shared
in unaffected family members, 6) Non synonymous coding, 7) MAF (minor allele frequency) ≤0.01 in the public databases
[HGVD (Human Genetic Variation Browser, NHLBI ESP (National Heart, Lung, and Blood Institute Exome Sequencing
Project), 1000 Genomes Project)]. Each filtered variants were confirmed by means of Sanger sequencing.
[Result & discussion]
We identified approximately 50,000 variants in each sample by WES. After filtering, one mutation was found to be shared
between the two families. We further conducted target resequencing of this candidate gene for 94 AgP participants and found
that two of them also had the same mutation, indicating that this gene is responsible for AgP.
Mon(2)-P-61
Association of HLA-DPB1 with ANCA-associated vasculitis in a Japanese population
Aya Kawasaki 1 ，Narumi Hasebe 1 ，Misaki Hidaka 1 ，Fumio Hirano 2 ，Ken-ei Sada 3 ，Shigeto Kobayashi 4 ，
Hidehiro Yamada 5 ，Hiroshi Furukawa 1,6 ，Kunihiro Yamagata 7 ，Takayuki Sumida 8 ，Nobuyuki Miyasaka 9 ，
Shigeto Tohma 6 ，Shoichi Ozaki 5 ，Seiichi Matsuo 10 ，Hiroshi Hashimoto 11 ，Hirofumi Makino 12 ，Yoshihiro Arimura 13
，
Masayoshi Harigai 14 ，Naoyuki Tsuchiya 1
1:Molecular and Genetic Epidemiology Laboratory, University of Tsukuba, Japan、2:Department of Pharmacovigilance, Tokyo Medical
and Dental University, Tokyo, Japan、3:Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences, Okayama, Japan、4:Department of Internal Medicine, Juntendo University Koshigaya Hospital,
Koshigaya, Japan、5:Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan、6:Clinical Research
Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan、7:Department of Nephrol-
ogy, University of Tsukuba, Tsukuba, Japan、8:Department of Rheumatology, University of Tsukuba, Tsukuba, Japan、9:Department
of Medicine and Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan、
10:Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan、11:Juntendo University School of Medicine,
Tokyo, Japan、12:Okayama University Hospital, Okayama, Japan、13:First Department of Internal Medicine, Kyorin University School of
Medicine, Tokyo, Japan、14:Institue of Rheumatology, Tokyo Women’s Medical Univsersity, Tokyo, Japan
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[Background] Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) include microscopic polyangiitis
(MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA). MPA and EGPA are associated with myeloper-
oxidase (MPO)-ANCA, while GPA is associated with proteinase 3 (PR3)-ANCA. Epidemiologic difference in AAV between
European and East Asian populations is well-known. We have reported association of DRB1*09:01-DQB1*03:03 haplotype
with MPA and MPO-ANCA positive AAV in Japanese. Recent genome-wide association studies in European populations
also reported contribution of HLA class II region to susceptibility to AAV. In this study, we examined whether HLA-DPB1
alleles are associated with AAV in a Japanese population.
[Methods] HLA-DPB1 genotypes were determined at the“four-digit” level by PCR-SSOP. Association was tested in 468
Japanese AAV patients (284 MPA, 92 GPA, 56 EGPA, and 35 unclassifiable) and 593 healthy controls. Among the patients,
377 were positive for MPO-ANCA and 61 for PR3-ANCA.
[Results] DPB1*04:01 was decreased in MPA (P=0.0060, Pcorr =0.054, OR=0.48) and MPO-ANCA positive AAV (P=0.00021,
Pcorr=0.0019, OR=0.40). With respect to PR3-ANCA, a tendency toward increase of DPB1*04:01 was observed in PR3-
ANCA positive AAV, although the difference did not reach significance possibly due to the small sample size (P=0.085,
OR=1.77). No significant association was detected in overall GPA. When GPA patients were classified according to ANCA
specificity, DPB1*04:01 was positively associated with PR3-ANCA positive GPA (P=0.025, OR=2.39), but not with MPO-
ANCA positive GPA (P=0.12, OR=0.21).
[Conclusion] HLA-DPB1 allele was differentially associated with MPO-ANCA and PR3-ANCA positive AAV in the Japanese
Poster Session
population.
Mon(2)-P-62
Variants discovery by amplicon-based exome sequencing for adult population of Yamagata Cohort Study
in Japan
Hidenori Sato 1 ，Shingo Koyama 1 ，Mitsuru Emi 2,3
，Shinya Sato 3 ，Takeo Kato 3 ，Isao Kuboto 3 ，Hidetoshi Yamashita 3
1:Genome Informatics Unit, Yamagata University, Faculty of Medicine, Japan、2:University of Hawaii, Cancer Center、3:Yamagata University,
Faculty of Medicine
Whole Exome sequencing (WES) using capture-based or amplicon-based technologies is rapidly spreading world wide, which
apply basic genome study and clinical fields. There are many database of capture-based technology in world wide, but the
variants database of amplicon-based technology is scarce. The aim of this study is construct the reference variants database
using amplicon-based exome sequencing, wit an aim to support clinical sequencing and utlization for patient care.
We performed whole-exome sequencing on 194 healthy adult population of Yamagata Cohort, which locate in North-East
Japan. Blood samples were collected from these subjects after obtaining informed consent. Genomic DNA of all samples were
sequenced by amplicon-baed exome with the Ion Torrent system, 200-bp platform with Ampliseq Exome kit. Reads were
aligned to the UCSC reference genome build hg19 using both BWA and BOWTIE2. The variants were called with general
linear model-based GATK and haplotype-based Platypus software.
In our analysis, approximately 199,000 variants are discovered in this group of healthy adults in Yamagata cohort. Comparison
between data form Illumina 660W SNP-chip and those from Ion Torrent WES, disclosed concordance rate of 98.3% in matched
genotyping data.
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70,367 variants exactly matched to those in common snp138 database, but other 128,584 variants are not in the databases. In
addition, 13,351 variants are not present in the Human genetic variant database of Kyoto University nor are 16,271 variants
in the ExAC database.
We contemplate that our result can constitute a reference database for amplicon-based exome variants in healthy adult
Japanese population.
Mon(2)-P-63
The B Lymphoid Tyrosine Kinase (BLK ) gene polymorphisms and susceptibility to Kawasaki diseases
1,2
Chia-Jung Chang ，Tai-Ming Ko 1 ，Yuan-Tsong Chen 1 ，Jer-Yuarn Wu 1
1:Institute of Biomedical Sciences, Academia Sinica, Taiwan、2:Graduate Institute of Microbiology, College of Medicine, National Taiwan
University
The BLK loci have been reported to associate with Kawasaki disease (KD) in two genome-wide association studies (GWAS)
conducted in a Taiwanese population of Han Chinese ancestry (Taiwanese) and in Japanese cohorts. In order to confirm the
importance of BLK in KD susceptibility, we conducted replication studies in populations of Korean- and European-descent
and performed a meta-analysis of the current and previously published studies. The rs2736340-located linkage disequilibrium
(LD) within the BLK region comprising the promoter and first intron was strongly associated with KD, and the combined
results of Asian studies including Taiwanese, Japanese, and Korean populations (2,539 KD patients and 7,021 controls)
provided very compelling evidence of association (rs2736340, OR = 1.498, 1.354-1.657; P = 4.74 ×10-31 ). We determined the
Poster Session
expression of BLK in the B cells of KD patients with the risk allele of rs2736340. In EBV-transformed B cell lines derived
from KD patients, and in purified B cells from KD patients obtained during the acute stage, those with the risk allele of
rs2736340 expressed significantly lower levels of BLK. These results suggest that peripheral B cells play a pathogenic role
in KD. Decreased BLK expression in peripheral blood B cells may alter B cell function and predispose individuals to KD.
To elucidate the mechanisms involved in human BLK gene regulation and expression, multiple cis-elements were predicted
using TFSEARCH database, and the BLK regulatory region was identified using the luciferase assay in the human BLK gene
promoter. A decrease in BLK was associated with the T allele of SNP5 which was in strong LD with the KD-associated
SNP rs2736340 and located with the CREB site by interfering with binding of the CREB transcription factor to the BLK
promoter. Our findings reveal an important role for BLK expression in B cell during acute KD and CREB transcription
factor binding to SNP5 is an important factor for regulating BLK expression.
Mon(2)-P-64
IkBL regulates susceptibility to HIV-1 infection
Akinori Kimura 1 ，Taeko K. Naruse 1 ，Daisuke Sakurai 1 ，Jianbo An 1 ，Hitoshi Ohtani 1 ，Hiroshi Terunuma 2 ，
Emi E. Nakayama 3 ，Tatsuo Shioda 3 ，Gaurav Sharma 4 ，Narinder K. Mehra 4 ，Gurvinder Kaur 4
1:Medical Research Institute, Tokyo Medical and Dental University, Japan、2:Biotherapy Institute of Japan、3:Research Institute for
Microbial Diseases, Osaka University、4:All India Institute of Medical Sciences
<Objective> IkBL gene (NFKBIL1 ) mapped within the HLA region is polymorphic in the promoter and showed difference in
gene expression; 01 allele was associated the lowest expression. IkBL competes with CLK1 for binding to ASF/SF2, resulting
in the inhibition of alternative splicing of immune-related genes and influenza virus M gene. In this study, we investigated a
possible association of IkBL with HIV-1 infection and/or development of AIDS in Indian and Japanese populations.
<Materials and Methods> Indian population; HIV-infected patients (n=88) and healthy controls (n=122). Japanese popu-
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lation; HIV-infected patients (n=10), HIV-infected but not developed AIDS more than 10 years without anti-HIV therapy
(long-term non-progressor, LTNP, n=60), and healthy controls (n=88). They were genotyped for IkBL allele by direct se-
quencing. COS cells were transfected with an IkBL construct to obtain a stable cell line highly expressing the IkBL protein
(COS-IkBL). COS and COS-IkBL cells were transiently transfected with a HIV-1 construct and production of p24 in culture
medium was measured by ELISA.
<Results and Discussion> The frequency of 01 allele was significantly high in the Indian HIV-infected patients (0.619 vs.
0.484, OR=1.74, corrected p=0.03). Similarly, an increased frequency of 01 allele was observed in the Japanese HIV-infected
patients (0.500 vs. 0.346, OR=1.74, p=ns), while there was no difference in the frequency of 01 allele between the Japanese
LTNPs and controls (0.375 vs. 0.364, OR=1.01, p=ns), suggesting that low expression of IkBL was associated with the sus-
ceptibility to HIV-1 infection but not to AIDS progression. Production of p24 was significantly suppressed by over-expression
of IkBL in COS cells (COS vs COS-IkBL; 85.7±11.5 vs. 41.5±7.1, p=0.006), implying that IkBL suppressed the replication
of HIV-1 in COS cells.
<Conclusions> IkBL may confer a resistance to HIV-1 infection by regulating replication of HIV-1.
Mon(2)-P-65
APOBEC3H polymorphisms are associated with susceptibility to HIV-1 infection and development of
AIDS in Asian populations
Poster Session
Taeko K. Naruse 1 ，Daisuke Sakurai 1 ，Hitoshi Ohtani 1 ，Hiroshi Terunuma 2 ，Yasumasa Iwatani 3 ，Wataru Sugiura 3 ，
Gaurav Sharma 4 ，Narinder K. Mehra 4 ，Gurvinder Kaur 4 ，Akinori Kimura 1
1:Medical Research Institute, Tokyo Medical and Dental University, Japan、2:Biotherapy Institute of Japan、3:Clinical Research Center,
National Hospital Organization Nagoya Medical Center、4:All India Institute of Medical Sciences
<Objective> Apolipoprotein B mRNA-editing catalytic polypeptide-3 (APOBEC3 ) gene family encodes cellular DNA cyto-
sine deaminases that are involved in anti-retroviral activity. Human APOBEC3H (A3H) is a member of APOBEC family.
The A3H protein is polymorphic including N15del (rs139292) and R105G (rs139297) composing of different haplotypes. It
was reported that A3H proteins encoded by different haplotypes showed difference in stability and activity in vitro; hapA
(15N-105G) protein is unstable, hapB (15N-105R) protein is stable, and hapC (15del-105R) protein has no enzyme activity.
In this study, we analyzed the association of APOBEC3H with HIV/AIDS in Japanese and Indian populations.
<Materials and Methods> Japanese population: HIV-infected patients (n=191), HIV-infected but not developed AIDS more
than 10 years without anti-HIV therapy (long-term non-progressor; LTNP, n=93), and healthy controls (n=421). Indian
population: HIV-infected patients (n=241) and healthy controls (n=286). They were genotyped for rs139292 and rs139297.
Haplotype association was assessed by using Haploview with permutation test.
<Results and Discussion> The frequency of hapC (no activity type) was significantly increase in the HIV patients in both
Japanese (0.322 vs 0.262, OR=1.33, p<0.0001) and Indian (0.475 vs 0.400, OR=1.3, p=0.04), indicating the association of
hapC with susceptibility to HIV infection. On the other hand, hapB (stable type) did not show association with HIV-1
infection in both Japanese and Indian, but its frequency was increased in the LTNPs (0.097 vs 0.040, OR=2.55, p<0.0001),
suggesting that the hapB conferred the protection against development of AIDS. The frequency of hapA (unstable type)
was slightly decreased in the HIV patients in both Japanese (0.634 vs 0.697, OR=0.75, p=ns) and Indian (0.479 vs 0.544,
OR=0.77, p=ns), but the association was not statistically significant.
<Conclusions> AOBEC3H played a role in the pathogenesis of HIV/AIDS in vivo.
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Mon(2)-P-66
Delay discounting, genetic sensitivity, and leukocyte telomere length
Richard P. Ebstein 1 ，Onn-Siong Yim 2 ，Xing Zhang 3 ，Poh San Lai 2
1:Psychology, National University of Singapore, Singapore、2:Human Genetics Lab at Department of Paediatrics, National University of
Singapore、3:Future Resilient System, Singapore-ETH Center
There is an increasing interest in correlates of aging in a greying world, especially early in life, and leukocyte telomere
length (LTL) is an emerging marker of aging at the cellular level. However, little is known regarding its link with the
degree of impatience and willingness to take risk that represent fundamental determinants of decision making. We first
measured the degree of impatience, risk proneness (willingness to take risks) and relative LTL in a sample of 1158 Han
Chinese undergraduates using incentivized economic tasks. A highly significant correlation was observed between LTL and
impatience (delay discounting) in female subjects that was robust controlling for age, risk proneness, as well as health-related
variables. We then asked if endogenous factors such as genes could impact the effect of impatient behavior on LTL. The G
allele of oxytocin receptor gene rs53576, which has figured prominently in investigations of social cognition and psychological
resources, significantly mitigates the negative impact of impatience on cellular aging. We also examined a set of inflammatory
markers as well as both polymorphic estrogen receptors. The current results contribute to understanding the relationship
between economic preferences particularly impatience and risk attitude and cellular aging for the first time, and showed that
oxytocin and estrogen receptor polymorphism moderated accelerated cellular aging in women who tended to make impatient
choices.
Poster Session
Mon(2)-P-67
Identification of novel susceptibility region for Tuberculosis on Chromosome 5q31.1
Jing Hao Wong 1 ，Ayaka Nakauchi 1 ，Surakameth Mahasirimongkol 2 ，Hideki Yanai 1,3 ，Akihiko Mabuchi 1 ，
Xiaoxi Liu 1,4 ，Taisei Mushiroda 5 ，Taku Miyagawa 1 ，Naoto Keicho 6 ，Katsushi Tokunaga 1
1:Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan、2:Medical Genetics Center,
Medical Life Sciences Institute, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand、3:Fukujuji Hospital,
Japan Anti-Tuberculosis Association (JATA), Kiyose, Japan、4:RIKEN Brain Science Institute, Wako, Saitama, Japan、5:Laboratory for
Pharmacogenetics, RIKEN Center for Genomic Medicine, Tsurumi-ku, Yokohama, Kanagawa, Japan、6:Department of Pathophysiology
and Host Defense, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association (JATA), Tokyo, Japan
Tuberculosis (TB) is a complex disease, of which progression is dependent upon both genetic and environmental factors and the
genetic architecture of TB susceptibility remains largely unknown. Previously, a genome-wide linkage study (GWLS) in Thais
showed that chromosome 5q23.3-31.3 region had suggestive linkage to TB susceptibility. A further SNP-based association
analysis of TB multiplex Thai families on the candidate region on chromosome 5q31 also identified significant associations in
three 3-SNP haplotypes. The present study aims to identify novel susceptibility gene(s) and loci for TB susceptibility within
an approximately 1 Mbp target region in the chromosome 5q31.1 region.
Next-generation sequencing (NGS) of the target region was performed in 13 young patients from Thai multi-case families
using the Ion Torrent Personal Genome Machine (PGM). Data from the Ion Torrent PGM was analyzed using two different
software, the Ion Variant Caller plugin and the CLC Genomics Workbench v5.5. In total, 904 variants were detected in the
sequenced region. The variants were filtered to select those located in genes of interest (remaining variants n=291), and
variants that were previously studied and their proxies were also filtered out (remaining variants n=219). Variants with
minor allele frequencies of at least 0.05 in the Southern Han Chinese (CHS) population from the 1000 Genomes international
database were then selected as candidates (n=23). To further narrow down the candidates, the variants were further filtered
using Ensembl’s Variant Effect Predictor (VEP) tool. Eventually, 10 variants from six genes in the chromosome 5q31.1
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region were prioritized for further analysis.
This study demonstrates that NGS can be combined with filtering and selection criteria, can be effective in identifying
potentially new susceptibility loci for TB.
Mon(2)-P-68
Association study of OPRD1 gene variants with susceptibility to opioid addiction in a northern Iranian
population; a candidate gene approach for methadone maintenance treatment
Alireza Sharafshah 1 ，Parvaneh Keshavarz 1 ，Hedyeh Fazel 1
1:Cellular and Molecullar research center, Faculty of medicine, Guilan University of Medical Science, Iran
Although methadone is an effective prescribed treatment, its efficacy range is significantly variable among patients which
can be explained by genetic elements. OPRD1 is one of the most important genes related to drug dependence, tolerance,
reward pathway, hypoxia/ischemia, and mesolimbic dopamine system. We aimed for the first time in an Iranian population
to characterize the impact of rs2236857, rs2236855, and rs760589 variants on occurrence of opioid addiction among patients
underwent Methadone Maintenance Treatment. Samples were examined among 202 healthy individuals and 202 opioid addict
subjects. All participants were men who aged between 20- 60 years old. Genomic DNA were extracted from whole blood
samples by Salting Out procedure. All three variants were genotyped by ARMS-PCR in the study subjects. All analysis
was performed by SNPalyze ver.8.1 software. There were a significant difference in allele frequency of rs2236857, rs2236855
Poster Session
and rs760589 polymorphisms between case and control subjects (P= 0.001, P= 0.001, and P= 0.02 respectively). According
to Genotype frequency, rs2236857, rs2236855 and rs760589 were showed a significant contributions to occurrence of opioid
addiction among study groups under a co-dominant hereditary model [P = 0.002, OR = 1.52; 95CI (1.16-1.99), P= 0.001, OR=
1.58; 95CI (1.20-2.09) and P= 0.03, OR =1.30; 95CI (1.02-1.67) respectively]. By haplotype analysis, four haplotypes were
revealed a significant difference in frequency between cases and controls. The most common haplotype with overall frequency
36% involved T-C-G (major-major-major alleles) represented a highest significant difference among the study group (P=
3.3E-8). In conclusion, rs2236857, rs2236855, and rs760589, variants of OPRD1, might have a remarkable association with
susceptibility to opioid addiction. These variants can be considered as appropriate candidates for pharmacotherapy of MMT
and required to be investigated in another populations.
Mon(2)-P-69
A polymorphism in CCR1 /CCR3 is associated with narcolepsy
Hiromi Toyoda 1 ，Taku Miyagawa 1 ，Asako Koike 2 ，Seik Soon Khor 1 ，Makoto Honda 3 ，Katsushi Tokunaga 1
1:Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Japan、2:Research & Development Group, Hitachi,
Ltd.、3:Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science
Type 1 narcolepsy is characterized by excessive daytime sleepiness, nocturnal sleep fragmentation, and cataplexy. Etiology
of narcolepsy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1 *15:01-
DQB1 *06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify
additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples.
An initial sample set comprising 409 cases and 1‚562 controls was used for the GWAS of 525‚196 single nucleotide polymor-
phisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then
genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region
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of chemokine (C-C motif) receptor 1 (CCR1 ) and upstream of CCR3 (rs3181077, P = 1.6 × 10-5 , odds ratio [OR] = 1.86).
This rs3181077 association was replicated with the independent sample set (P = 0.032, OR = 1.36). We measured mRNA
levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were sig-
nificantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. We
also performed electroencephalographic recording in Ccr3 knockout mice and found that sleep/wake status of Ccr3 knockout
mice were significantly different compared to wild-type mice. During the light period, the overall amount of wakefulness was
increased, and time spent in both rapid eye movement (REM) sleep and non-REM sleep was shorter in Ccr3 knockout mice,
indicating sleep fragmentation.
Our findings provide evidence for the involvement of impaired CCR1/CCR3 functions in the etiology of narcolepsy.
Mon(2)-P-70
Association of the I264T variant in the sulfide quinone reductase-like (SQRDL) gene with osteoporosis
in Korean postmenopausal women
Jeonghyun Kim 1,2 ，Hyun-Seok Jin 3 ，Eunkuk Park 1,2
，Bo-Young Kim 4 ，Ryun-Jin Lee 1,2
，Gyu-Bin Lim 1,2
，
Seon-Yong Jeong 1,2
1:Department of Medical Genetics, Ajou University School of Medicine, Suwon, Korea, South、2:Department of Biomedical Sciences, Ajou
University Graduate School of Medicine, Suwon, Republic of Korea、3:Department of Biomedical Laboratory Science, College of Life and
Health Sciences, Hoseo University, Asan, Republic of Korea、4:Division of Intractable Disease, Center for Biomedical Sciences, National
Institute of Health, Korea Centers for Disease Control & Prevention, Cheongju, Republic of Korea
Poster Session
A large number of susceptibility genes/loci for osteoporosis and/or osteoporosis-related traits have been identified. So far,
a few nonsynonymous SNPs (nsSNPs) that cause alterations in the amino acid sequence of proteins have been reported
to be associated with osteoporosis-related phenotypes. In this study, we aimed to find novel nsSNP(s) associated with
postmenopausal osteoporosis by a systematic association study and to elucidate functional role of the identified nsSNP(s) in
the pathogenesis of osteoporosis. We performed a genome-wide association analysis of 1,180 nsSNPs in 405 individuals with
osteoporosis and 722 normal controls of the Korean Association Resource cohort. A logistic regression analysis revealed 72
nsSNPs that showed a significant association with osteoporosis (p<0.05). The top 10 nsSNPs showing the lowest p-values
(p=5.2×10-4 -8.5×10-3 ) were further studied to investigate their effects at the protein level. Based on the results of an in silico
prediction of the protein’s functional effect based on amino acid alterations and a sequence conservation evaluation of the
amino acid residues at the positions of the nsSNPs among orthologues, we selected one nsSNP in the SQRDL gene (rs1044032,
SQRDL I264T) as a meaningful genetic variant associated with postmenopausal osteoporosis. Overexpression of the SQRDL
I264T variant in the preosteoblast MC3T3-E1 cells significantly increased alkaline phosphatase activity, mineralization, and
the mRNA expression of osteoblastogenesis markers, Runx2 , Sp7 , and Bglap genes, whereas the SQRDL wild type had no
effect or a negative effect on osteoblast differentiation. The results of the statistical and experimental analyses indicate
that the SQRDL I264T nsSNP may be a crucial susceptibility variant for osteoporosis in Korean postmenopausal women
that is involved in osteoblast differentiation. This work was supported by the NRF grant funded by the Korea government
(2013R1A1A2010123 and 2015 008728).
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Mon(2)-P-71
Association of genes polymorphisms from various functional classes with type 1 diabetes complications
and their combination
Nataliya Tarasenko 1 ，Irina Goncharova 1,2
，Anton Markov 1
1:Federal State Budgetary Scientific Institution The Research Institute for Medical Genetics, Russia、2:Research Institute for Complex Issues
of Cardiovascular Diseases
Diabetic angiopathy is the main cause of early disability and mortality in patients with diabetes mellitus. Our case-control
study included 285 patients with type 1 diabetes: 148 with diabetic retinopathy (DR), 123 with diabetic nephropathy (DN),
114 with diabetic neuroangiopathy (DNA) and 69 patients with combination of three complications; and 300 controls. All
patients were of Russians and live in the Siberian region (Tomsk).We studied 58 SNPs of 48 genes which are involved in the
fibrogenesis, responsible for endothelial function and associated with type 1 and 2 diabetes and diseases of the cardiovascular
continuum. In this work we performed genotyping by mass spectrometry on the "Sequenom MassARRAY" (USA). We found
associations of DR with following markers: ADAMDEC1 rs3765124; DDX5 rs1991401; IFNL2 rs12980602; ITGA4 rs1143674;
ITGB5 rs1007856; LIG1 rs20579; MMP3 rs679620. DN was associated with polymorphic variants: ADAMDEC1 rs3765124;
CD247 rs6668182; COL1A1 rs2075555; ITGA4 rs1143674; ITGB5 rs1007856; MMP3 rs679620; PARP4 rs4986819. DNA
had association with following markers: ADAMDEC1 rs3765124; CD247 rs6668182; DDX5 rs1991401; IFNL2 rs12980602;
ITGA4 rs1143674; LIG1 rs20579; MMP3 rs679620; MTAP rs7023329; PARP4 rs4986819; TAS2R38 rs1726866. Association
with all the complications together was found for the genes: ADAMDEC1 rs3765124; DDX5 rs1991401; DNMT3A rs7590760;
ITGA4 rs1143674; MMP3 rs679620. We found the specific marker: COL1A1 rs2075555 for DN; MTAP rs7023329 and
TAS2R38 rs1726866 for DNA and DNMT3A rs7590760 for the combination of three complications. Thus, genes involved in
Poster Session
metabolism (DDX5, DNMT3A, LIG1, MMP3, MTAP, PARP4 ), signal transduction and cell communication (ADAMDEC1,
ITGA4, ITGB5, TAS2R38 ) are involved to the development of specific complications of type 1 diabetes.
Mon(2)-P-72
Whole exome sequencing of twins for Biliary Atresia
1,2
Ohsuke Migita ，Akira Matsui 3 ，Kenichiro Hata 2
1:St. Marianna University School of Medicine, Japan、2:National Research Institute for Child Health and Development、3:College of Nursing
St. Luke’s International Hospital
Biliary atresia (BA) is characterized by complete inability to excrete bile from the liver to the duodenum due to sclerosing
inflammation of the extra- and intrahepatic bile ducts. It is one of the most lifethreatening hepatobiliary disorders in child-
hood. It may start in fetal, in perinatal or early in postnatal life. What causes this inflammation remains unclear in spite
of extensive investigation. It is assumed that multiple genetic and environmental factors might affect individuals with BA.
Several susceptibility loci have been identified for BA, but major genetic factors have been unclear.
Family members, especially twins, share genetic and environmental backgrounds. Twin studies remain a favorable means to
find genetic factors. We collected the DNA from seven families with BA which had at least one affected child in their family.
We performed whole exome sequencing of BA patients and twin siblings.
Using exome sequencing to find rare variants which could not or could rarely be found in control data or rarely find those in
control data, we made a the list of non-synonymous variants in the family. Our exome sequencing identified candidate genes
with biliary atresia. It is still unknown the affective nucleotide variants including our variants list.
In this study, we evaluate extensively genetic polymorphisms of the variants in BA patient and investigated the functional
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properties of the nonsynonymous SNPs. It would be concluded that intolerant changes may lie in mechanisms of BA suscep-
tibility.
Mon(2)-P-73
Whole Genome Sequencing Approach to Discover Susceptibility Genomic Variants in a Multiplex Nuclear
Family of Schizophrenia
Shun-Chun Yu 1 ，Hsuan-Yu Chen 2 ，Sung-Liang Yu 3 ，Chih-Min Liu 4,5
，Hai-Gwo Hwu 1,4,5
，Wei J. Chen 1,4,5,6
1:Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taiwan、2:Institute of Statistical Science, Academia Sinica,
Taipei, Taiwan 115, R.O.C.、3:Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College
of Medicine, Taipei, Taiwan、4:Department of Psychiatry, College of Medicine and National Taiwan University Hospital, National Taiwan
University、5:Graduate Institute of Brain and Mind, College of Medicine, National Taiwan University Hospital, National Taiwan University、
6:Genetic Epidemiology Core, Center of Genomic Medicine, National Taiwan University
With the advent of next-generation sequencing (NGS), it becomes feasible to search the whole genome for rare genetic variants
specific to schizophrenia patients. We hence postulated that high density nuclear families of schizophrenia may help identify
certain inherited rare variants that can be used for replication in other multiplex families of schizophrenia. We selected
one high density schizophrenia family from Taiwan Schizophrenia Linkage Study (TSLS). NGS was performed to sequence
the whole genomes of a 5-member nuclear family, in which the mother and 2 children affected with schizophrenia, and the
father and another child unaffected. Both dominant and recessive inheritance models were used to explore schizophrenia
related genomic variations. The results showed that total 1,147 variants (6 exonic single nucleotide variants; SNVs) selected
under recessive inheritance model. Whereas there were 39,330 variants (230 exonic SNVs) selected under the dominant
Poster Session
inheritance model. In addition, 14 non-synonymous exonic SNVs that exhibited inheritance in the family but not seen in
1000 genomes project were identified for those in accordance with dominant inheritance model. Among 14 candidate SNVs, 3
non-synonymous exonic SNVs passed the validation by Sanger sequencing. Our findings demonstrated the utility of NGS in
identifying inherited rare genetic variants that are potentially associated with multiplex schizophrenia. In particular, the 3
non-synonymous exonic SNVs warrant replication in other multiplex families from TSLS. One of the non-synonymous exonic
SNVs was identified in 9 cases (some of them were affected sib-pairs) from TSLS. This may lead to discovery if rare but
inheritable susceptibility variants for schizophrenia and their underlying pathophysiology.
Mon(2)-P-74
Association of a variant in interleukine 13 (IL13) with food allergy in the Japanese population
Tomomitsu Hirota 1 ，Mayumi Tamari 1 ，Sakura Sato 2 ，Noriyuki Yanagida 2 ，Motohiro Ebisawa 2 ，Takanori Imai 3 ，
Teruaki Matsui 4 ，Komei Ito 4 ，Satoru Doi 5
1:RIKEN Yokohama Institute, Japan、2:Sagamihara National Hospital、3:Showa University School of Medicine、4:Aichi Children’s Health
and Medical Center、5:Osaka Prefectural Medical Center
Background: The prevalence of food allergy (FA) has dramatically increased over the past several decades, particularly in the
developed countries. FA is an adverse health effect arising from immunoglobulin E-mediated immune responses that occur
reproducibly on exposure to a given food. Recent GWASs have shown that IL13 gene locus on chromosome 5q31 is associated
with allergic diseases like bronchial asthma (BA) and atopic dermatitis (AD); however influences of genetic variations in the
IL13 gene on susceptibility to FA remain unclear.
Objective: To investigate whether variants of IL13 gene are associated with FA and FA related phenotypes in the Japanese
population.
Methods: We re-sequenced the IL13 gene region by PCR-directed sequencing. Tag SNPs were selected using the Tagger
algorithm and genotyped by multiplex PCR Invader assay. We performed association studies of FA using two independent

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Japanese populations (1st population, 598 cases and 982 controls; 2nd population 280 cases and 892 controls). Overall, 341
FA patients (39 %) have BA and 574 FA patients (65 %) have AD.
Results: We found a total of 14 variants including a non-synonymous substitution (rs20541; Arg144Gln). Among four tag
SNPs, we observed a significant association at rs20541 (meta-analysis, combined P = 1.8×10-7; OR, 1.4; 95% CI, 1.2-1.6).
In further analyses of patient subgroups, we observed a strong association between rs20541 and FA with AD (P = 1.4×10-9;
OR, 1.5; 95% CI, 1.3-1.8).
Conclusion: rs20541 of IL13 gene is significantly associated with FA in the Japanese population. Although further genetic
and functional analyses are needed, these findings improve our understanding of common genetic factors for BA, AD, and FA.
Mon(2)-P-75
CYP27A1 rs19969157 is the rare variant associated with atopic dermatitis with high serum IgE levels
Hisato Suzuki 1 ，Emiko Noguchi 2 ，Yuka Makino 2 ，Hisako Enomoto 3 ，Mayumi Tamari 4 ，Tomomitsu Hirota 4
1:Department of Child Health, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan、2:Department of Med-
ical Genetics, Faculty of Medicine, University of Tsukuba、3:Department of Dermatology, Sogo-Moriya-Daiichi Hospital、4:Laboratory for
Respiratory and Allergic Diseases, Core for Genomic Medicine, Center for Integrative Medical Sciences, RIKEN
Atopic dermatitis (AD) is a common chronic inflammatory skin disease which often accompanied by high serum IgE levels.
There was familial aggregation in AD, and AD is considered to be a complex disorder that both genetic and environmental
Poster Session
factors are involved in. Previously, the loss of function mutations in the filaggrin (FLG) gene has been identified to be
associated with AD in both European and Asian population. Like filaggrin, we assumed that other rare variants with large
effect size may play a role for disease pathogenesis of AD. To identify rare variants associated with AD, we carried out exome
analysis using DNA obtained from AD patients.
We enrolled 40 patients diagnosed with AD by board certified dermatologists and whose total serum IgE levels were greater
than 1000 IU/ml for exome analysis. Nine variants were identified which were <1% of allele frequency of in 1000genomes
project phase I JPT/CHB population but >5% of allele frequency in the atopic dermatitis exome samples.
In these 9 candidate variants, we carried out replication study using 468 AD patients with total serum IgE ≥1000 IU/ml and
935 Japanese controls. CYP27A1 rs199691576 (A/G) was confirmed to be associated with AD with high serum IgE levels
(p=0.012). CYP27A1 is involved in metabolism of Vitamin D3, which plays important roles to modulate immune function
and previous studies reported that polymorphisms of genes belongs to Vitamin D pathway have been associated with allergy-
related phenotypes. Recently, Wang et al reported that G allele of rs4674343 (G/A) in CYP27A1 , had protective effect on the
development of atopic eczema in Chinese population. Our data suggest that minor allele frequency of rs199691576 belonging
to Vitamin D pathway may be involved in AD.
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Mon(2)-P-76
miRNA modulation of extracellular matrix gene-gene interactions and susceptibility to ACL rupture
Kyle Willard 1 ，Sasha Mannion 1 ，Colleen J Saunders 2 ，Mary-Jessica Laguette 1 ，Malcolm Collins 1 ，
Alison V September 1
1:Division of Exercise Science and Sports Medicine, Department of Human Biology, University of Cape Town, Cape town, South Africa、
2:South African National Bioinformatics Institute/MRC Unit for Bioinformatics Capacity Development, University of the Western Cape,
Bellville, South Africa
The role of miRNA in modulating genes that determine the functional capacity of tendons and ligaments is not fully un-
derstood. Compromised functional capacity of tendons and ligaments have been associated with musculoskeletal soft tissue
(MSK) injuries such as Achilles tendinopathy and anterior cruciate ligament (ACL) ruptures. Variants within genes that
encode proteins regulating fibrillogenesis such as BGN (rs1126499, rs1042103), COL5A1 (rs12722) and DCN (rs516115) have
previously been associated with susceptibility to MSK injuries. A miRNA mediated transcript instability was proposed as a
possible biological mechanism for this COL5A1 3’UTR injury association. The functional significance of the other 2 loci are
unknown. The aim of this study was to identify potential genetic signatures across the BGN , COL5A1 and DCN loci in an
attempt to characterize the disease susceptibility for MSK injuries.
Pseudohaplotypes were constructed from the genotype data of BGN (rs1126499, rs1042103), COL5A1 (rs12722) and DCN
(rs516115) loci, for 227 participantswith surgically diagnosed ACL ruptures and 234 asymptomatic controls. Statistical anal-
yses between the CON and ACL groups as well as sex-specific interactions were investigated. Significance was accepted at
p<0.05. miRNA recognition motifs within these three regions were then determined using DIANA tools. This study identified
several novel pseudohaplotypes associated with altered susceptibility to ACL rupture. In addition, several miRNA recognition
Poster Session
motifs were identified in range of these susceptibility loci.
In conclusion, the study has implicated defined genetic intervals between BGN (rs1126499, rs1042103), COL5A1 (rs12722)
and DCN (rs516115) with susceptibility to ACL ruptures. In addition, it has identified eight plausible miRNA recognition
sequences. The biological significance of these genomic signatures now need to be explored including their effects on the
functional capacity of tendons and ligaments.
Mon(2)-P-77
Genetic and functional assessment of rare alleles of NAFLD susceptibility loci in Japanese
Supichaya Boonvisut 1 ，Sadahiko Iwamoto 1 ，Nakayama Kazuhiro 1 ，Watanabe Kazuhisa 1
1:Division of Human Genetics, Center for Molecular Medicine, Jichi Medical Uni versity, Japan
Genome wide association studies of non-alcoholic fatty liver disease (NAFLD) have identified multiple loci, in which minor
alleles of non-synonymous SNPs in PNPLA3 and TM6SF2 are expected to be defective in transportation of lipids into
endoplasmic reticulum (ER) of hepatocytes and excretion of VLDL. Rare loss-of -functional variants of MTTP have also been
associated with manifestation of liver steatosis with severe reduction of plasma lipid levels. This study aims to identify the
rare variants in PNPLA3 , MTTP and TM6SF2 genes, and to evaluate their genetic associations with NAFLD and functional
influences on ER lipid transportation. [Materials and method] Japanese males without alcoholic abuse history chosen in
totally 3013 people genome were 950 participants and were used as discovery panel. Whole coding regions of three genes,
PNPLA3 , MTTP, and TM6SF2, dividing into thirty-four amplicons were tagged by MID. Groups of each forty-eight samples
were resequenced by 454 GS junior. Mapping and mutation detection were performed by CLC workbench software. Suspected
mutations were confirmed by direct sequencing. Rare non-synonymous or splicing polymorphisms observed in multiple
individuals were genotyped by Taqman probe in total 3013 Japanese samples. Non-synonymous rare base substitutions were
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induced in PNPLA3 cDNA and transfected into Huh7 cells. Lipid accumulation and VLDL excretion in cDNA transfected
Huh7 cells were evaluated. The effects of splicing variants were assessed by inserting the exons in a mini gene. [Result
and discussion] The 454 sequencing followed by confirmation with direct-sequencing identified 29 rare variants, in which 10
variants were synonymous and 16 were non-synonymous base substitutions, 2 variants were splicing variants and 1 variant
was a frame-shift base deletion. A non-synonymous variant in MTTP reduced NAFLD risk. A non-synonymous variant and
a splicing variant in PNPLA3 increased NAFLD risk. Functional assessment will be shown.
Mon(2)-P-78
Decoding Musculoskeletal Soft Tissue Injuries
Alison V September 1 ，Andrea Gibbon 1 ，Kyle Willard 1 ，Rene Van Wyk 1 ，Colleen J Saunders 2 ，Junaid Gamieldien 2 ，
Malcolm Collins 1
1:Human Biology, University of Cape Town, Division of Exercise Science and Sports Medicine, South Africa、2:South African National
Bioinformatics Institute/MRC Unit for Bioinformatics Capacity Development, University of the Western Cape, Bellville, South Africa
Achilles tendinopathy (AT) is a multifactorial condition characterized by pain and swelling of the Achilles tendon, accompanied
by decreased function. The etiology of AT is not fully understood, and several genetic loci have been associated with injury
risk. Variants contributing to susceptibility have primarily been identified using a hypothesis driven candidate gene approach.
The ability to identify all risk variants, including rare variants, using only this method is unlikely. Therefore, the aim of this
study was to further define the genetic signature of AT in established pathways by adopting next generation sequencing and
bioinformatics tools.
Poster Session
Ten cases and 10 controls representing divergent extremes of the injury spectrum were selected. Cases were <35 years of
age, had suffered bilateral AT and/or reported several AT injuries. Controls were >47 years of age, matched for intensity
and duration of physically activity who had not suffered from any tendon and/or ligament injuries. Paired end whole exome
sequencing (including untranslated regions) was performed on the Illumina Hiseq 2000/2500 platform at 30X coverage
Preliminary results identified 3016 variants mapping across the exome with allele frequency differences of >30% between
cases and controls. Several of these variants are located within pathways already characterized in the disease process. Signals
of interest include the matrix metalloprotease (MMP) gene cluster on chromosome 11q22, the region spanning the genes
encoding tenascin-C (TNC ) and the alpha 1 chain of type XXVII collagen (COL27A1 ) and the aggrecan gene (ACAN).
Furthermore, 25 loci mapping to specific miR-base genes were identified as plausible candidates by unsupervised hierarchical
clustering analyses.
Through this multidisciplinary approach, these signals are being explored using a case-control genetic association design in
larger cohorts and may provide valuable knowledge into the etiology of musculoskeletal soft tissue injuries.
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Mon(2)-P-79
Analyses of TGF-β stimulated gene expression levels of BGN in a susceptibility model for musculoskeletal
soft tissue injuries: A pilot ex vivo study
Mary-jessica N. Laguette 1 ，Leonardo Alves de Souza Rios 1 ，Kyle Willard 1 ，Malcolm Collins 1 ，Alison September 1
1:Human Biology, University of Cape Town, South Africa
Variants in several genes, including proteoglycan encoding genes such as biglycan (BGN ), have been implicated in modulating
the risk of musculoskeletal soft tissue injuries. Biglycan is involved in fibrillogenesis, tendon development and healing. TGF-
β is a mediator of the matrix remodelling pathway and, as observed in the context of injury and healing, is able to regulate
BGN expression. Variants within BGN associate with anterior cruciate ligament ruptures (rs1126499, C/T and rs1042103,
A/G) and with carpal tunnel syndrome (rs1126499).
The primary aim of this study was to examine the relative BGN mRNA expression, in skin fibroblasts of healthy individuals
with a known BGN genotype. Specifically, the effect of BGN rs1042103 (A/G) and rs1126499 (C/T) on its mRNA expression
was examined (a) at baseline (N=10) and (b) in response to TGF-β 1 treatment (N=4).
Participants were grouped according to their genotypes forming an increased (TT/AA and TT/AG at rs1126499/rs1042103
respectively, N=7) and a decreased risk group (CC/GG and CC/AA at rs1126499/rs1042103 respectively, N=3). Skin biopsies
were obtained from consenting healthy participants with a known genotype at the loci of interest. Primary skin fibroblast
cell lines were obtained. Cells were treated with 10ng/mL of purified TGF-β 1. Total mRNA was extracted, cDNA was
generated and Q-RT-PCR was performed. Relative expression of the target genes were compared between risk groups.
Poster Session
BGN mRNA expression was not statistically different between the increased (CC/GG and CC/AA) and decreased risk
(CC/GG and CC/AA) groups (p=0.84) at baseline. TGF-β 1 treatment resulted in elevated expression of BGN in both
groups with a higher expression observed in the decreased risk (CC/GG and CC/AA) group (2.40 ± 0.67; N=11) compared
to the increased risk (TT/AA and TT/AG) group (1.47 ± 0.74; N=6) (p=0.024). This pilot study highlights the possible
effect of variation at the DNA level on gene expression.
Mon(2)-P-80
The associate network approach identified of novel genes of tuberculosis susceptibility
Elena Bragina 1 ，Aleksey Rudko 1 ，Evgeny Tiys 2 ，Vladimir Ivanisenko 2 ，Maxim Freidin 1
1:Institut of Medical Genetics, Russia、2:Institute of Cytology and Genetics
Tuberculosis is a complex infection disease caused by Mycobacterium tuberculosis in susceptibility individuals. Genomic
researches revealed genes that contribute to the development of tuberculosis. However novel molecular targets are still needed
to acquire knowledge of pathogenetic mechanisms and to improve the outcomes of therapy of this disease.In the current
study, we carried out the reconstruction and analysis of associative network representing molecular genetic links between
proteins/genes involved in the development of tuberculosis. The associative network of tuberculosis was reconstructed using
the ANDSystem software (www.pbiosoft.com/en/andsystem/andsystem-free). For analysis genes associated with tuberculosis
from associative network we used genome databases Ensembl, NCBI, HuGE Navigator. In the associative network, well
studied proteins and genes with a decisive importance in the efficiency of the human immune response against a pathogen
predominated. In additional this approach identified 12 new genes (ADA, CP, CD80, CXCR4, HCST , MUC16 , CD69,
PACRG, AGER, SPP1, CD4, CD79A) encoding for the respective proteins in the associative network polymorphisms of
which has not been studied regarding the development of tuberculosis.
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This work is supported by the Russian Science Foundation under grant (15-15-00074).
Mon(2)-P-81
Search for genetic variations responsible for giant coronary aneurysms in Kawasaki disease patients by
whole exome sequencing
Yoshihiro Onouchi 1 ，Hidewaki Nakagawa 3 ，Daichi Shigemizu 4,5 ，Kouichi Ozaki 2 ，Yosikazu Nakamura 6 ，
Yuji Asami 7 ，Mitsuru Seki 7 ，Tohru Kobayashi 8 ，Yuta Kochi 9 ，Tatsushi Toda 10 ，Wataru Satake 10 ，Akira Hata 1 ，
Tatsuhiko Tsunoda 4,5 ，Toshihiro Tanaka 2,11 ，Japan Kawasaki Disease Genome Consortium
1:Department of Public Health, Chiba University Graduate School of Medicine, Japan、2:Laboratory for Cardiovascular Diseases, RIKEN
Center for Integrative Medical Sciences、3:Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences、
4:Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University、5:Laboratory for
Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences、6:Department of Public Health, Jichi Medical University、
7:Department of Pediatrics, Gunma University School of Medicine、8:Department of Development Strategy, Center for Clinical Research and
Development, National Center for Child Health and Development、9:Laboratory for Autoimmune Diseases, RIKEN Center for Integrative
Medical Sciences、10:Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine、11:Department of
Human Genetics and Disease Diversity, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences
Kawasaki disease (KD) is a systemic vasculitis syndrome of childhood with unknown etiology. In Japan, more than 10,000
children are newly affected with KD every year. Because of coronary artery lesions (CALs) represented by dilatations or
aneurysms in 15-25% of untreated patients, KD has become the leading cause of acquired cardiac diseases of childhood in
developed countries. Giant coronary aneurysms (GAns) with diameter larger than 8mm occurring in 0.2% of KD patients
are the most serious form of CALs which can be fatal due to rapture in the acute phase and also threatens patients’ life by
increasing risk for thrombotic occlusion for the life time. To investigate genetic determinants of GAns in KD, we conducted
Poster Session
whole-exome sequencing for 37 KD patients Exome capture was carried out by using Agilent SureSelect Human All Exon v5
and sequencing was conducted on Illumina HiSeq2000/2500 platform. We referred databases in dbSNP v144, 1000 genomes
phase3, ESP6500, ExAc, HGVD, Tohoku Medical Megabank and RIKEN in-house exome sequencing data in filtering out
the variants. By excluding intronic and synonymous variants and others with frequencies of 0.03% (incidence of KD in
the Japanese population) or higher in either of the databases from further analyses, we found 2,357 candidate genes with
mutations in at least one patients. Sequence validation by Sanger method prioritizing genes with mutations in 2 or more
patients is in progress. In addition, we are interested in a non-synonymous mutation of ITPKC gene seen in one patient and
was predicted to affect ITPKC protein function by both SIFT and Polyphen2. Considering that a common SNP in ITPKC
gene was associated with patients’risk for CAL formation (Onouchi et al. Nat Genet 2008, Onouchi et al. Pharmacogenomics
J 2013), genes being identified in this study would become good candidates for SNP association study for CALs.
Mon(2)-P-82
Fine-mapping of CDKN2B-AS1 in African Americans with primary open-angle glaucoma from a biorepos-
itory linked to de-identified electronic medical records
Nicole A Restrepo 1 ，Sarah M Laper 2 ，Dana C Crawford 1
1:Epidemiology & Biostatistics, Case Western Reserve University, USA、2:Eastern Virginia Medical School
Purpose: Primary open-angle glaucoma (POAG) is the second leading cause of permanent vision loss in the U.S. GWA-studies
have identified loci associated with POAG risk in European American (EA) and Japanese populations. African Americans
(AA) are ~ 15 times as likely to develop glaucoma vs EA, yet few studies have been performed in AA. As such, we have
fine-mapped and analyzed the CDKN2B-AS1 region to test whether this region also drives POAG risk in AA.
Methods: Combining ICD-9-CM diagnostic codes, CPT billing codes, and manual review of clinical records, we identified
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138 AA POAG cases and 1376 controls from the Vanderbilt de-identified EMR system. Cases/controls were genotyped on
Metabochip. We performed 286 single SNP tests of association for common variants (MAF>0.05) in the CDKN2B-AS1
region using logistic regression assuming an additive genetic model adjusted for age, sex, principal components, and median
diastolic blood pressure. Local ancestry was calculated with Local Ancestry in admixed Populations (LAMP) and % African
ancestry was tested for association with POAG status with logistic regression.
Results: We did not replicate associations previously described in EA and Japanese for SNPs in CDKN2B-AS1 at a corrected
threshold. In an unadjusted logistic regression model, % African ancestry was significantly associated with POAG status at
the CDKN2B-AS1 region [p = 2x10-16; OR = 4.8 (CI 5.84-3.75)].
Discussion: There are striking differences in minor allele frequencies for CDKN2B-AS1 SNPs ranging from 0.37-0.45 in
HapMap CEU compared to 7-9% among AA. We observed low linkage disequilibrium for this gene in African Americans.
Small genetic association studies of minority populations may be aided by gene-based approaches that get around the issues
of low power and genetic admixture. Despite a lack of association with individual SNPs, African ancestry at CDKN2B-AS1
appears to be strongly correlated with POAG risk.
Mon(2)-P-83
Whole exome sequencing in Thrombotic Storm patients identified rare variants in genes affecting effi-
ciency of the negative feedback system blocking thrombin formation
Poster Session
Karen Nuytemans 1 ，Lissette Gomez 1 ，Natalia Hoffman 1 ，Patrice Whitehead-Gay 1 ，Natalie Alves 1 ，
Craig S. Kitchens 2 ，Doruk Erkan 3 ，Leonardo R. Brandao 4 ，Andra H. James 5 ，Roshni Kulkarni 6 ，Thomas L. Ortel 5 ，
Margaret A. Pericak-Vance 1 ，Jeffery M. Vance 1
1:John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, USA、2:University of Florida, Gainesville、
3:Hospital for Special Surgery, Weill Medical College of Cornell University, New York, NY、4:Hospital for Sick Children, Toronto, ON,
Canada、5:Duke University Medical Center, Durham, NC、6:Michigan State University, East Lansing
Thrombotic storm (TS; www.thromboticstorm.com) is a rare and severe clinical phenotype that occurs in a small subset of
patients with venous thromboembolic disease. It is characterized by more than two acute arterial and/or venous thromboem-
boli, frequent events in unusual locations, progressive/recent unexplained recurrence and frequent refractory and/or atypical
response to therapy. We hypothesize that rare genetic variants explain a portion of the risk for TS.
We performed whole exome sequencing (WES) in 16 trios, additional siblings where available and 27 additional probands. Due
to the rarity and severity of the phenotype, variants are filtered on functionality (nonsense, missense and splice), conservation
and frequency (<5% in exome variant server and exome aggregation consortium). Two different models were tested in the
trios; de novo and recessive model. Data from the available unaffected siblings were used for variant filtering.
We identified 52 rare functional de novo variants and 85 rare functional compound heterozygous variant combinations. In-
terestingly, three of the de novo variants and one of the compound heterozygous combos are in genes potentially involved
in the formation of chondroitin sulfate (SLC26A2 , CHST15 , CHPF2 , STAB2 ). Additionally, many variants affecting genes
encoding proteins with thrombospondin domains, laminin domains, and proteins involved in extracellular matrix structure
and immune response are identified.
Thrombomodulin can be attached to the membrane by a chondroitin sulfate polymer increasing its ability to bring bound
thrombin in contact with membrane bound protein C. This interaction causes protein C activation, initiating a negative
feedback system decreasing thrombin formation. Our data suggests that variants involved in chondroitin sulfate formation
are conferring risk for TS. Additional analyses evaluating burden of variants in potential candidate genes in all probands are
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ongoing.
Mon(2)-P-84
Identification of Putative Autism Spectrum Disease [ASD] Predisposing Genes by Whole Genome Next
Generation Sequencing [WGNGS] & Complex Comparative Genome Analyses in an Extended Family
with ASD
Marios Kambouris 1,2 ，Abeer Fadda 3 ，Yasser Al-Sarraj 4 ，Dina Ahram 4 ，Sara Tomei 5 ，Ena Wang 5 ，
Hatem El-Shanti 4,6
1:Pathology-Genetics, Sidra Medical & Research Center, Qatar、2:Genetics, Yale University School of Medicine, New Haven, CT, USA、
3:Biomedical Informatics, Sidra Medical & Research Center, Doha, Qatar、4:Qatar Biomedical Research Institute Medical Genetics Center,
Hamad Bin Khalifa University, Doha, Qatar、5:Research Center, Sidra Medical & Research Center, Doha, Qatar、6:Pediatrics, University
of Iowa, Iowa City, IA, USA
A family with two males affected by ASD was studied to identify the genetic basis of ASD in the family. Two siblings, a
brother and his sister, each had a male child with ASD through marriage to their respective unrelated spouses. The first
family [F1] has one affected male child; the second [F2] has one affected male and one unaffected female children. The father
of F1 and the mother of F2 are brother and sister.
No aneuploidy or deletion/duplication defects were detected by Whole-Genome SNP CNV analyses. WGNGS for all members,
comparative genome analyses and data mining are as follows: [Only exonic variants considered, prioritized according to
increasing population frequency (0-1%), damaging effects according to mutation prediction models and will be presented in
Poster Session
table format].
1. The two ASD events are unrelated and due to individual de-novo variants. Trio analyses for identified 36 de novo variants
in F1 and 32 in F2. Variants in KCNH1 , ANKRD36C , FRG2C , LOC12989375 were in common
2. The two ASD events are due to heterozygous variants inherited from the related parents. In F1, 370 father-to-son
heterozygous variants, in F2, 398 mother-to-son heterozygous variants identified with 132 in common.
3. The related parents are protected from the damaging effects of ASD predisposing variants transmitted to their respective
children by protective variants that were not transmitted, hence ASD in their offspring. Analyses were for heterozygous
variants shared among the related parents but not transmitted to their affected children.
4. The non-related parents contributed rare predisposing variants, which in synergy with the inherited variants from the related
parents exceed a disease onset threshold in the affected offspring. For F1 mother-to-son heterozygous variant transmission;
For F2 father-to-son heterozygous variant transmission examined.
Complex comparative genome analyses are required to decipher the genetic basis of ASD in families with multiple affected
individuals.
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Mon(2)-P-85
Putative Relation Between Autism Spectrum Disease [ASD] and Hereditary Multiple Exostosis [HME]
Investigated by Whole Genome Next Generation Sequencing [WGNGS] & Comparative Genome Analyses
in a Family with ASD and HME with EXT-1 Mutations
Marios Kambouris 1,2 ，Abeer Fadda 3 ，Yasser Al-Sarraj 4 ，Dina Ahram 4 ，Sara Tomei 5 ，Ena Wang 5 ，
Hatem El-Shanti 4,6
1:Pathology-Genetics, Sidra Medical & Research Center, Qatar、2:Genetics, Yale University School of Medicine, New Haven, CT, USA、
3:Biomedical Informatics, Sidra Medical & Research Center, Doha, Qatar、4:Qatar Biomedical Research Institute Medical Genetics Center,
Hamad Bin Khalifa University, Doha, Qatar、5:Research Center, Sidra Medical & Research Center, Doha, Qatar、6:Pediatrics, University
of Iowa, Iowa City, IA, USA
A family with two male children affected with ASD and HME as well as an unaffected female child, was studied to identify
the Genetic basis of ASD in the family and the possible relation between ASD & HME.
Irie et al., [PNAS, 109 : 5052-5056, 2012] reported that Heparan Sulfate deficient mice due to inactivating EXT-1 mutations
exhibit Autism-like socio-communicative deficits and stereotypies suggesting a relation between MHE and ASD. The father
and both male children are clinicaly affected by HME and carry the known pathogenic EXT-1 c.C1018T/p.R340C dominant
mutation. Both male children are also affected by ASD; the father is not. The mother and the female child are not affected
either by HME or ASD and do not carry the EXT-1 mutation.
Whole-Genome SNP genotyping and CNV analyses did not detect aneuploidy or deletion/duplication defects as possible
ASD causes. WGNGS for all members, comparative genome analyses and data mining were as follows: [Only exonic variants
Poster Session
considered, prioritized according to increasing population frequency (0-1%), damaging effects according to mutation prediction
models and will be presented in table format].
1. The two ASD events are unrelated and are due to de-novo variants. Trio analyses identified 72 de-novo variants in the first
affected child and 56 in the second. Twelve were in common
2. The two ASD events are due to heterozygous variants inherited from both parents which in synergy exceed a disease
onset threshold in the affected offspring. Eighty father-to-son and 69 mother-to-son heterozygous variants shared between
the affected males were identified.
4. The HME unaffected parent [mother] contributed heterozygous variants in the Heparan Sulfate biosynthesis pathway that
in synergy with the EXT-1 mutation could be the genetic causes of ASD in the family.
WGNGS and comparative genome analyses were utilized to decipher the possible relationship between HME and ASD in this
unique family with members affected by both disorders.
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Mon(2)-P-86
Identifying candidate genes under linkage peaks for metabolic syndrome traits in a Japanese American
(JA) family
Karen L Edwards 1 ，Jia Y Wan 1 ，Trina M Norden-Krichmar 1 ，Stephanie A Santorico 2,3
，
American Diabetes Association GENNID Study Group
1:Epidemiology, University of California, Irvine, USA、2:Human Medical Genetics and Genomics Program, University of Colorado School
of Medicine, Aurora, Colorado, USA、3:Mathematical and Statistical Sciences, University of Colorado, Denver, USA
The Metabolic Syndrome (MetS) is a complex condition characterized by a cluster of risk factors, including obesity, lipid
abnormalities, hypertension and glucose intolerance. Previous work using Japanese American families and linkage analysis
identified a region on chromosome 7 with strong evidence for linkage in clusters of MetS traits (LOD=5.21, P=4.8 x 10-7
at 157 cM for a multivariate trait defined by body weight, plasma insulin and triglyceride (TG) levels). Sequencing was
performed in 14 individuals from a multiplex pedigree with the highest per-family LOD score for a 10,717,473 bp segment
of chromosome 7q35-36 spanning the 1-LOD support interval. After quality control with the exclusion of monomorphic sites
and of variants Mendelian inconsistent or not in Hardy-Weinberg equilibrium (P<10-4 ), there were 14,550 bialleleic variants
in 85 genes, which were annotated using UCSC genome browser data. In the first stage of analysis, family-based sequence
kernel association testing (famSKAT) filtered the top 5% of genes that were analyzed further in the second stage using a
variant-level measured genotype analysis (MGA), which accounts for family structure in a regression model with an additive
genetic variant effect. Permutation tests were used to assess statistical significance. Nine variants in the TPK1 gene were
significantly associated with plasma TG, and multiple variants in eight genes were associated with body weight. No variants
were identified that met the cutoff for statistical significance for insulin levels (i.e., no variants with MGA permutation p-value
Poster Session
< 0.005). Overall, it appears that within the linkage region, there are multiple genes influencing these traits, and there some
genes potentially with pleiotropic effects on both body weight and plasma TG levels in this Japanese American pedigree.
These results suggest that using families and targeting previously identified linkage regions may be a fruitful way to identify
genes for complex traits.
Mon(2)-P-88
Polymorphisms of genes involved in extracellular matrix homeostasis of ligaments and the risk of anterior
cruciate ligament injury
Mariana F Leal 1,2 ，Leonor C Loyola 1,2 ，Diego C Astur 2 ，Gustavo G Arliani 2 ，Carlos ES Franciozi 2 ，
Marilia C Smith 1 ，Pedro Debieux 2 ，Alberto C Pochini 2 ，Carlos V Andreoli 2 ，Benno Ejnisman 2 ，Moises Cohen 2
1:Morfologia e Genetica, Universidade Federal de Sao Paulo, Brazil、2:Ortopedia e Traumatologia, Universidade Federal de Sao Paulo
The anterior cruciate ligament (ACL) tears is one of the most frequently injured structures during high-impact sporting
activities. Recent studies suggested that ACL tears is a complex disease, in which genetic factor also contribute for the
disease susceptibility. Polymorphisms of COL1A1 , COL3A1 , COL5A1 , COL12A1 , GDF5 and MMP3 genes were associ-
ated with the risk of ACL tears in individuals from Poland and South Africa. Therefore, polymorphisms in genes involved
in the ligament structure and extracellular matrix homeostasis can contribute to extended ligament tears. However, fur-
ther studies are still necessary to understand if genetic factor contributes with this knee injury, especially in other pop-
ulations. In this study, we evaluated if the rs1800012 (COL1A1 ), rs42524 (COL1A2 ), rs3196378 (COL5A1 ), rs240736
(COL12A1 ), rs970547 (COL12A1 ), rs6728999 (FN1 ), rs2104772 (TNC ), rs185819 (TNXB), rs1009382 (TNXB), rs243865
(MMP2 ), rs243866 (MMP2 ), rs679620 (MMP3 ), rs522616 (MMP3 ), rs17577 (MMP9 ) and rs2252070 (MMP13 ) were asso-
ciated with the risk of ACL injury. We genotyped 203 Brazilian patients with ACL tears and paired 301 Brazilian controls
using TaqMan inventoried assays in a real-time PCR system. Univariate and multivariate logistic regression were performed to
investigate whether the studied polymorphisms may contribute to the risk of ACL injury. The frequencies of genotypes were
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in the Hardy-Weinberg equilibrium. The rare variants of rs185819 (adjusted p=0.012) and of rs17577 (adjusted p=0.026) were
associated with ACL tears by multivariate logistic regression. Moreover, the rs24385 TT (adjusted p=0.025) and rs243866
AA (adjusted p=0.025) genotype carriers presented an increased risk of ACL tears. Additionally, the rs240736 GG carriers
presented increased risk of ACL tears without menisci injury (adjuste p=0.028).Therefore, these genetic variants of TNXB,
MMP2 , MMP9 and COL12A1 may have a role in the ACL tears etiology.
Mon(2)-P-89
Effect of HLA polymorphisms on the survival in the patient with AIDS
Michio Yasunami 1 ，Nuanjun Wichukchinda 2 ，Reiko Miyahara 1 ，Naho Tsuchiya 1 ，Hitomi Nakamura 1 ，
Masahiko Mori 1 ，Archawin Rojanawiwat 2 ，Panita Pathipvanic 3 ，Pathom Sawanpanyalert 2 ，Koya Ariyoshi 1
1:Institute of Tropical Medicine, Nagasaki University, Japan、2:Department of Medical Sciences, Ministry of Public Health, Nonthaburi,
Thailand、3:Day Care Center, Lampang Hospital, Lampang, Thailand
Background: HLA class I polymorphisms are known to play crucial roles in the control of HIV and progression to AIDS but
not in the survival of the patients. The other HLA polymorphisms may associate with fatal outcome of the patients with HIV
infection.
Methods: Patients with chronic HIV infection were enrolled to a longitudinal observational study in Lampang Hospital, a
government referral hospital in Lampang, Thailand. A total of 556 HIV-1 CRF01_AE infected individuals were recruited
from July 2000 to October 2002, and census data of survival was obtained on October 15, 2004 before the national program
Poster Session
of antiviral treatment was introduced. CD4 count, viral RNA load and other information on clinical status were collected
upon enrollment. Genotypes of HLA-A, -B, -C, -DRB1 and TNF promoter were determined.
Results: Unlike HLA class I alleles, no effect of TNFA polymorphisms on chronic phase viral load was detected. TNFA
-308A allele exhibited dominant unfavorable effect on survival (TNFA -308GG vs -308AG+AA, Cox hazard ratio: 1.46,
p=0.034), and the effect was more strengthened in HIV-1 positive patients with low CD4 count at enrollment (Cox HR:
1.52, p=0.024). The effect of TNFA -308A was slightly enhanced by co-existence of HLA-DRB1*03:01 allele (Cox HR: 1.65,
p=0.010), suggesting the effect of HLA haplotype. Because of tight linkage between TNFA -308A and HLA-DRB1*03:01
alleles (forming ancestral haplotype AH58.1 in Asian population), it could not be distinguished whether the effect of TNFA
polymorphism is primary or secondary to other genetic factor(s) carried by AH58.1.
Interpretation: Multiple independent roles of HLA class I and other HLA polymorphisms in clinical features of HIV infection
were discovered.
Mon(2)-P-90
Association of SNPs of TLR pathway regulating innate immune responses with pediatric respiratory
infectious diseases in Vietnamese
Reiko Miyahara 1 ，Lay Myint Yoshida 1 ，Duc Ahn Dang 2 ，Kensuke Takahashi 1 ，Hitomi Nakamura 1 ，Dinh Thiem Vu 2 ，
Huu Tho Le 3 ，Hiroyuki Moriuchi 4 ，Sharon E Cox 5 ，Koya Ariyoshi 1 ，Michio Yasunami 1
1:Institute of Tropical Medicine, Nagasaki University, Japan、2:National Institute of Hygiene and Epidemiology, Hanoi, Vietnam、3:Khanh
Hoa Provincial Public Health Service, Nha Trang, Vietnam、4:Graduate School of Medical Sciences, Nagasaki University, Nagasaki, Japan、
5:Graduate School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan
Background: Toll-like receptors (TLRs) initiate innate immune responses by sensing molecular pattern of pathogenic microbes.
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Genetic variations in the genes in TLR-signaling pathway would explain individual difference in susceptibility to certain
infectious diseases.
Methods: A birth cohort of 1999 children was established in Nha Trang city, central coastal region of Vietnam and followed up
for 24 months to detect major health problems which required hospitalizations. Blood samples were collected at 24 months of
age. First 360 consecutive samples were used for overnight whole blood culture assay which was designed in order to evaluate
cellular responsiveness to lipopolysaccharide and synthetic lipopeptide Pam3CSK4, pathogen-mimics of Gram-negative and
Gram-positive bacteria, respectively, by the induced mRNA expression of 43 immunity-related genes standardized by the
expression levels of two house-keeping genes, RPLP0 and RPLP1. The effect of genotypes of 46 SNPs in 17 genes of the
TLR-signaling pathway on the gene expression was analyzed by ANOVA. The SNPs with significant effects on expression
levels of immune-related genes were further examined for the association with infectious diseases in 1494 children followed up
for 24 months using Cox-regression model.
Results: 232 events of hospital admission because of acute lower respiratory infections (LRTIs) among 180 children were
captured (71.6 per 1000 person x year). Polymorphisms in TLR2, TLR3, TLR10, and MyD88 exhibited significant influence
on induced mRNA expression of multiple immunity-related genes. Among those SNPs, carriers of A-allele of rs10004195 (in
TLR10 ), exhibiting lower cytokine responses, were at risk of acute LRTIs (A/T+A/A vs T/T , HR 1.48, 95%CI: 1.09-2.02,
p-value: 0.012).
Interpretation: A TLR10 variant with weaker blood cell responses was associated with the risk of acute LRTIs in Vietnamese
infants.
Poster Session
Mon(2)-P-91
Association of ADAMDEC1 polymorphism with common human diseases
1,2
Irina Goncharova ，Vera Ipatova 2 ，Nataliya Tarasenko 1 ，Oksana Makeeva 1,2
，Anton Markov 1
1:The Research Institute for Medical Genetics, Russia、2:Research Institute for Complex Issues of Cardiovascular Diseases
In this study we tested the hypothesis that polymorphisms in the genes involved in organ fibrogenesis influences the risk of
developing several common diseases, including coronary artery disease (CAD), myocardial infarction without traditional risk
factors (MI), chronic hepatitis C (HCV), and type 1 diabetes mellitus (T1D). A total of 900 patients and 285 individuals
of Tomsk population (Siberia, Russia) were recruited. Genotyping of 58 SNPs was performed, using mass spectrometry on
Sequenom MassARRAY (USA). The highest degree of pleiotropy was shown with ADAMDEC1 gene, because it’s polymorphic
variant rs3765124 was associated with all the studied pathologies. Genotype AA was associated with CAD due to their higher
frequency among patients (36.0%) compared with the control group (24.3%; OR=1.75 (1.18-2.58); p=0.004). Genotypes AA
and AG (OR=2.59 (1.01-7.06); p=0.047) and allele A (OR=1.60 (1.07-2.50); p=0.020) was associated with MI due to their
higher frequency among patients (90.2% and 63.1%) compared with the control group (77.9% and 51.1%, respectively). The
genotype AA (OR=1.90 (1.26-2.85); p=0.002) and allele A (OR=1.48 (1.14-1.92); p=0.003) was associated with T1D due
to their higher frequency among patients (36.6% and 58.1%) compared with the control group (24.3% and 51.1%). Diabetic
nephropathy was also found a higher frequency of genotype AA (OR=1.95 (1.19-3.21); p=0.007) and allele A (OR=1.44(1.04-
2.00); p=0.028) among patients (40.7% and 60.6%). Genotype AA (OR=1.8 (1.16-2.77); p=0.008) and allele A (OR=1.47
(1.11-1.95); p=0.006) were also associated with increased HCV. Thus, ADAMDEC1 gene which has broad pleiotropic effect
can be considered as a candidate gene for various common human diseases. The study was partially supported by the RFBR
(15-34-51220).

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Mon(2)-P-92
Whole genome rare variant association study identifies a non-genic region near TFAM associated with
severe emphysema
Josiah Radder 1 ，Yingze Zhang 1 ，Frank Sciurba 1 ，Steven Shapiro 1
1:University of Pittsburgh, USA
Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow limitation, due to a complex interaction
of environmental and genetic factors. Current genome-wide association studies (GWAS) of common variation only explain
a portion of the known heritability. We hypothesized that some of the unexplained heritability of COPD is attributable to
rare variation (minor allele frequency (MAF) < 0.01). We conducted an extreme-trait whole genome sequencing study of
emphysema and tested for association of rare variants.
We selected 70 subjects with severe emphysema and 70 subjects with no indication of emphysema of similar ages and smoking
histories from the SCCOR cohort at UPMC to undergo whole genome sequencing (WGS). Reads were aligned to GrCh37 and
variants were called according to GATK’s best practices. We filtered all SNPs with MAF > 0.01 in 1000 Genomes and 6500
exomes European American populations. Any SNP with no MAF recorded in one of these databases was excluded with an
empirical MAF > 0.01, leaving 5,423,566 rare SNPs (2,221,186 not in dbSNP138). We tested for association using SKAT-O
in 30kb regions across the genome with age, sex, pack years, and the first two principal components of ancestry analysis as
covariates. We identified all genes within 1Mb of our top regions and, using publically available mRNA expression data from
the lung genomics research consortium (LGRC), identified gene transcripts that are differentially expressed in COPD.
Poster Session
We identified a region on chr10q21 that is suggestively associated with emphysema. Although this region contains no genes, it
does contain potential regulatory sites. Expression of two gene transcripts within 1Mb of this region is significantly different
in COPD. TFAM , a mediator of mitochondrial transcription, was most significantly altered between the two groups and is
the top candidate association in this study. Further work is necessary to determine its potential role in emphysema.
Mon(2)-P-93
Trio-based exome sequencing case study in identifying the underlying genetic factors associated with
progressive flail arm syndrome, motor neuron disorder
Mahjoubeh Jalali Sefid Dashti 1 ，Helen Cross 2 ，Jeanine Heckmann 3 ，Junaid Gamieldien 1
1:South African National Bioinformatics Institute, South African National Bioinformatics Institute, South Africa、2:Department of Medicine,
Groote Schuur Hospital and University of Cape Town, Rondebosch, South Africa、3:Division of Human Genetics, Department of Medicine,
Groote Schuur Hospital and University of Cape Town, Rondebosch, South Africa
Flail Arm Syndrome (FAS) is an atypical presentation of amyotrophic lateral sclerosis (ALS) is an idiopathic, neurodegenera-
tive disorder affecting motor neurons. It is characterized by progressive weakness, fasciculation, and atrophy in the proximal
muscles of the upper limbs. Either recessive or de novo variants can result in sporadic occurrence of Flail arm syndrome.
While a number of genes have been associated to the disease in Caucasians, very little is known in the African population.
We performed trio-based whole exome sequencing of unaffected parents their FAS affected offspring in an admixed South
African family . Predicted deleterious variants were assessed for possible involvement in MND using path-based graph
theoretic querying in our internal biomedical semantic database, the BioOntological Relationship Graph (BORG), which
when ‘taught’ about a disease is able to uncover biologically-plausible genotype-to-phenotype links. Four de-novo predicted
function-impacting mutations in CCDC88C, CLCN7, POLG and WFS1 were identified as strong disease causing candidates.
In addition to confirming agreement of several prediction tools of their likely deleterious effect, all four novel mutations were
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ICHG2016 826
found to be in genes with roles in neuron apoptotic process, skeletal muscle atrophy, proximal muscle weakness, peripheral
neuropathy, which are key features of FAS.
We propose that one or more of the private mutations may be responsible for the development of FAS in may provide funda-
mental insight into the pathogenesis of motor neuron degeneration. Furthermore, as none of the genes have been previously
implicated in FAS or even ALS, the utility of our semantic discovery approach in the prioritization of candidate causative
variants in rare genetic disorders is also highlighted.
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ICHG2016 827
Poster Session
Bioinformatics and Genomic Technology
Mon(2)-P-94
New features of the UCSC Genome Browser - tools for research and the clinic
Robert M Kuhn 1 ，Luvina Guruvadoo 1 ，Angie S Hinrichs 1 ，Maximillian Haeussler 1 ，Matthew L Spier 1 ，
Jonathon Casper 1 ，Brian J. Raney 1 ，Ann S. Zweig 1 ，Donna Karolchik 1 ，W. James Kent 1
1:UC Santa Cruz Genomics Institute, University of California Santa Cruz, USA
The UCSC Genome Browser is a powerful web-based visualization tool used by researchers for 16 years to access the human
genome. Increasingly, clinical geneticists are using it to view chromosome imbalances in the context of many informative
annotations, such as aggregated copy-number variants, both benign and pathogenic. Many datasets have been gathered from
around the world and can be viewed together in the Genome Browser. These include ClinVar, EXAc, Exome Variant Server,
DECIPHER, DGV and others. Together with gene models and phenotypic association data, they offer one-stop annotation.
The ability to upload files to the Browser puts user data from either microarrays or whole-exome and -genome sequencing
into the image next to data from external contributors. Single-nucleotide variant data include dbSNP, OMIM Allelic Variant
Poster Session
SNPs, Personal Genome Project, 1000 Genomes Project, LOVD and UniProt.
Not as widely known are the ancillary tools available at the Browser, including the Variant Annotation Integrator (VAI) and
the Genome Browser-in-a-Box (GBiB). The VAI allows identification of the biochemical consequences of variants, allowing
the determination of missense, nonsense, frameshift and splice-site variations as well as intersection with histone modification
and DNAse hypersensitivity data. Fully configurable, VAI allows consideration of evolutionary conservation using UCSC’s
comparative genomics data and will identify known SNPs mapping at the same location, outputting SIFT and PolyPhen and
other variant scores.
The Genome Browser-in-a-Box puts a fully functional Genome Browser on your desktop, inside your digital firewall. GBiB
reverses the typical paradigm – the Browser resides next to your data, which does not have to leave the building, yet it has
access to all the data available on the web version. GBiB is a solution for those with restrictions on uploading data to the
UCSC site but who wish to access full Genome Browser functionality.
Mon(2)-P-95
f-tree: a novel and improved automated questionnaire-based pedigree chart creation software for use in
large-scale genome cohort studies
Tomoharu Tokutomi 1 ，Kayono Yamamoto 1,2
，Atsushi Shimizu 2 ，Akimune Fukushima 1,3
1:Department of Clinical Genetics, School of Medicine, Iwate Medical University, Japan、2:Division of Biomedical Information Analysis,
Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University、3:Division of Innovation and
Education, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University
The Tohoku Medical Megabank Project aims to restore community medical services negatively affected by the Great East
Japan Earthquake and create a next-generation personalized healthcare system by conducting large-scale genome-cohort
studies involving three-generations of local residents in the disaster-stricken areas. Genealogical information is critical for
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accurate genetic diagnoses. Typically, pedigree charts are manually created via face-to-face personal interviews held on an
individual basis, and they require specialized knowledge of clinical genetics, in addition to chart-creation skills. Thus, the
creation of pedigree charts is time and labor intensive. We developed a novel questionnaire-based software named “f-tree”
that enables a user to accurately and rapidly collect genealogical information and create pedigree charts. The software was
made available at http://iwate-megabank.org/en/genetic/ as a freeware program for the general public in July 2015. However,
f-tree complied with only 80% of the standard recommendations on pedigree information and symbols required. Here, we
further improved the software. The new f-tree fully complies with the international recommendations of standardized human
pedigree nomenclature including common pedigree symbols, pedigree lines, assisted reproductive technology symbols, and
pedigree symbols of genetic evaluation/testing information. It allows users to enter the following details by simply answering
the questionnaire: individuals affected with two or more conditions, number of siblings, consanguinity, adoption, surrogate
(gestational carrier), and ovum or sperm donor. Recording family trees per standard recommendations requires in-depth
knowledge, but f-tree automatically generates many genealogies simultaneously. Thus, the new improved f-tree is a useful
tool to correctly and easily understand pedigrees. In future, we would also like to add a calculator to determine disease risk
and inbreeding coefficient.
Mon(2)-P-96
A computational platform for human genome analysis and interpretation in Argentina
Patricio Yankilevich 1 ，Maximiliano de Sousa Serro 1 ，Daniel Koile 1
1:Instituto de Investigacion en Biomedicina de Buenos Aires. CONICET - Partner Institute of the Max Planck Society, Argentina
Poster Session
A personal genome interpretation platform is being developed to identify molecular and genetic variations within the Ar-
gentinean population. The analysis of genetic screening information will allow us to elucidate pathways and identify new
drug targets for local diseases. The platform may help to better understand the genetic basis of local diseases, to make more
accurate diagnosis, have a better understanding of prognosis and take better treatment decisions.
The platform workflow moves from reads (data) to identified variants (information) to selected risk variants associated with
disease (knowledge) to an online interactive final report which includes integrative and interactive visualizations, visual quanti-
tative assessments and ideograms to make the interpretation of results a more comprehensive experience to medical geneticists,
researchers and general users.
The pipeline use over 15 public open source algorithms, developed by research groups from leading institutions, which conform
today’s best practices in NGS data analysis. The pipeline is designed as seven independent modules, which sequentially
execute the different genome analysis tasks. The modules are listed below, showing some of the software packages, algorithms
and computational methods being used in brackets:
1. Secondary Analysis Module - QC, Alignment, Assembly
2. Tertiary Analysis Module - Variant Identification
3. Variant Annotation Module - Annotation of variants
4. Interpretation Module - Filtering and prioritization of variants
5. Final Report Module - Results, Statistics and Ideograms report

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6. Visualization Module - Genome and Variant visualization
7. RNA-Seq Analysis Module - Gene expression
Some of the biological knowledge bases being integrated into the pipeline are: dbSNP, dbVAR, COSMIC, HGMD, HAPMAP,
1000 Genomes, GWAS Catalog, PharmGKB, DrugBank, OMIM.
Mon(2)-P-98
PhaSTESt (v1.2), a user friendly tool for power calculations in pharmacogenomic studies with "time to
event" outcomes
Hamzah Syed 1 ，Andrea Jorgensen 1 ，Andrew P Morris 1
1:Biostatistics, University of Liverpool, UK
With the increased scale of genome-wide pharmacogenomic association studies and the complexity of clinical outcomes they
consider, there is a need for software to perform power calculations over a range of trial designs. There are already genetic
power calculators available for binary phenotypes and quantitative traits, but the key outcome of interest in pharmacogenomic
studies is often “time to event” data, which cannot adequately be modelled by existing software. To address this issue,
we have developed the user friendly software tool PhaSTESt (Pharmacogenomic Simulator for Time to Event Studies) to
perform power calculations and generate pharmacogenomic data with time to event outcomes over a range of study designs.
Poster Session
The software requires specification of genetic parameters, such as the magnitude of the SNP effect on the outcome and the
effect allele frequency. The varied collection of design scenarios includes adding a recruitment period, multiple treatments
with differential effects on outcome, SNP-treatment interactions and different censoring options. Time to event and censoring
data are then simulated on the basis of these specified model parameters by using a Weibull distribution, so as to allow for
the possibility of a deviation from a proportional hazards assumption. The data can then be analysed by means of a Cox
proportional hazards model or alternative regression models to account for non-proportional data, treatment and interaction
effects. To allow for flexibility of analysis using methods not supported by the power calculator, simulated datasets from each
setting can also be output. PhaSTESt was built using C# and developed as a Windows application, utilising pre designed
frameworks Math.NET and Accord.NET for the generation of pharmacogenomic data and statistical analyses, respectively. In
conclusion, this application offers a much needed tool for power calculations for time to event outcomes in pharmacogenomic
association study designs.
Mon(2)-P-99
NGS-SWIFT: A Cloud-Based Variant Analysis Framework Using Control-Accessed Sequencing Data from
dbGaP/SRA
Chunlin Xiao 1 ，Eugene Yaschenko 1 ，Stephen Sherry 1
1:NIH, USA
Genetic variation analysis plays an important role in elucidating the causes of various human diseases. The drastically reduced
costs of genome sequencing driven by next generation sequence technologies now make it possible to analyze genetic variations
with hundreds or thousands of samples simultaneously, but with the cost of ever increasing local storage requirements. The
tera- and peta-byte scale footprint for sequence data imposes significant technical challenges for data management and
analysis, including the tasks of collection, storage, transfer, sharing, and privacy protection. Currently, each analysis group
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must download all the relevant sequence data into a local file system before variation analysis is initiated. This heavy-weight
transaction not only slows down the pace of the analysis, but also creates financial burdens for researchers due to the cost
of hardware and time required to transfer the data over typical academic internet connections. To overcome such limitations
and explore the feasibility of analyzing control-accessed sequencing data in cloud environment while maintaining data privacy
and security, here we introduce a cloud-based analysis framework that facilitates variation analysis using direct access to the
NCBI Sequence Read Archive through NCBI SRA Toolkit, which allows the users to programmatically access data housed
within SRA with encryption and decryption capabilities and converts it from the SRA format to the desired format for data
analysis. A customized machine image (ngs-swift) with preconfigured tools, including NCBI SRA Toolkit and NGS Software
Development Kit, and resources essential for variant analysis has been created for instantiating an EC2 instance or instance
cluster on Amazon cloud. Performance of this framework has been evaluated using dbGaP study phs000710.v1.p1, and
compared with that from traditional analysis pipeline, and security handling in cloud environment has also been addressed.
Mon(2)-P-100
EIGEN: A spectral approach for the integration of functional genomics annotations for both coding and
noncoding sequence variants
Iuliana Ionita-Laza 1 ，Kenneth McCallum 1 ，Bin Xu 2 ，Joseph Buxbaum 3
1:Biostatistics, Columbia University, USA、2:Psychiatry, Columbia University、3:Psychiatry and Genome Sciences, Mount Sinai School of
Medicine
Over the past few years, substantial effort has been put into the functional annotation of variation in human genome sequence.
Poster Session
Such annotations can play a critical role in identifying putatively causal variants among the abundant natural variation that
occurs at a locus of interest. The main challenges in using these various annotations include their large numbers, and their
diversity. I will discuss an unsupervised approach (EIGEN) to derive an integrative score of these diverse annotations. I will
show that the resulting meta-score has good discriminatory ability using disease associated and putatively benign variants
from published studies (for both Mendelian and complex diseases), and is more strongly associated with the disease association
status of such variants compared with the recently proposed CADD score. Furthermore, I will show how the meta-score is
particularly useful in prioritizing likely causal variants in a region of interest when it is combined with sequencing data in the
framework of a hierarchical model. The EIGEN score has also the advantage that it can be easily adapted to specific tissues
or cell types of interest.
Mon(2)-P-101
An Evaluation of Methods for HLA Allele Imputation from SNP Genotypes
1,3 1,2 1,2
Allan J. Motyer ，Damjan Vukcevic ，Stephen Leslie
1:Statistical Genetics, Murdoch Childrens Research Institute, Australia、2:Department of Mathematics and Statistics, University of Mel-
bourne、3:Centre for Systems Genomics, The University of Melbourne, Australia
The human leukocyte antigen (HLA) genes play an essential role in immune function and are of major biological and clinical
interest. Typing of HLA alleles is critical for transplantation and is informative for many disease associations. The high
cost of accurate lab-based HLA typing has precluded its use in large-scale disease-association studies for HLA alleles. The
development of statistical methods to type alleles using linkage disequilibrium with combinations of nearby SNPs, called
HLA imputation, has allowed large cohorts of samples to be typed with high accuracy, so that massive numbers of affected
individuals and controls may be studied. This has resulted in many important findings, e.g. Wellcome Trust Case Control
Consortium 2 studies of multiple sclerosis, ankylosing spondylitis and psoriasis .
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Since the publication of the first HLA imputation method, HLA*IMP (2008), other approaches have been developed, including
HLA*IMP:02, HIBAG, SNP2HLA and MAGprediction. We have conducted a comprehensive study to evaluate these widely
used HLA imputation methods. To do this we assembled a multi-ethnic panel of over 10,000 samples with SNP data and
lab-based typing of alleles at 11 HLA genes. The performance of each method was evaluated via cross-validation and analyses
with independent reference and validation datasets. We assessed both the accuracy and calibration of each method, as well
as the effect of factors including SNP density and population stratification at the continental level. Our study aims to be a
guide to the optimal use of HLA imputation in practical settings. We make recommendations for the choice of method and
the selection and configuration of reference datasets. We show that judicious choices result in imputed HLA alleles with high
accuracy, equal to that of lab-based typing in many instances, enabling association studies for HLA alleles with increased
statistical power.
Mon(2)-P-102
Effect of various minor groove binding compounds on DNA-triplex containing (GAA)5 repeat: A com-
parative study to screen potential drug candidate for Friedrich’s ataxia therapeutics
Himanshu N Singh 1 ，Moganty R Rajeswari 1
1:Biochemistry, All India Institute of Medical Sciences, India
Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a hyper-expansion of GAA repeat
within intron 1 of the FXN gene, resulting reduced levels of frataxin protein mediated by RNA polymerase inhibition.
Poster Session
Therefore, destabilization of the DNA triplex would be of clinical interest. In present study, computational and spectroscopic
techniques were utilized to characterize interaction of minor groove binders and their influence on the DNA-triplex containing
G*GC and A*AT triplets. Three dimensional structure of DNA triplex was modelled in-silico and minimized by using
MMFF94 forcefiled and Steepest Descent algorithm at BALLView modelling framework. Six minor groove binders (MGBs):
SN6999, DAPI, Distamycin, Hoechst-33258, Netropsin and Spermidine were docked by Autodock(4.2) software and Hoechst (δ
G = -8.36 Kcal M-1 ; δ K = 1.13 × 106 ) was found to be the best drug candidate out of 6 MGBs, which was further validated by
various spectroscopic techniques. DNA-triplex was generated in-vitro by mixing TCCG(GAA)5 CGCT; AGCG(TTC)5 CGGA
and (AAG)5 synthetic oligonucleotides. UV-vis spectra of Hoechst (340 nm) demonstrated its binding with triplex which was
later confirmed with an induced peak at 354 nm in circular diachroism spectra of Hoechst. Red shift in fluorescence spectra of
Hoechst also confirmed its interaction with the triplex. CD-melting and UV-melting data revealed destabilization of triplex
by Hoechst 33258. Thermodynamic analysis of UV-melting curves also confer that DNA-duplex was favourable conformation
for the drug. The experimentally calculated value of Gibbs free energy δ G= -5.89 Kcal M-1 ) and binding constant (K = 1.92
× 105 ); hence as concurrent approximately to the docked Hoechst-DNA triplex complex. In conclusion, Hoechst-33258 could
be used to upregulate frataxin protein levels by means of DNA-triplex destabilization and therapeutic effectiveness of other
drugs.
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Mon(2)-P-103
Systematic analysis of mutation distribution in three dimensional protein structures identifies mutational
hotspot in Mendelian disease genes
Akihiro Fujimoto 1 ，Hidewaki Nakagawa 1
1:RIKEN, Japan
Protein tertiary structure determines molecular function, interaction, and stability of the protein, therefore distribution of
mutation in the tertiary structure can facilitate to identify new driver genes in cancer. To analyze mutation distribution
in protein tertiary structures, we developed a novel three dimensional permutation test. We analyzed somatic mutation
datasets of mutations in Mendelian disease genes obtained by the Clinvar database. Of the 465 genes that had ≥3 mutations
in the regions with tertiary structure data, 213 genes, including BRAF , TNFRSF1A, PTPN11, OCRL and PTEN , showed
significant skew. Our study suggests that systematic analysis of mutation distribution in the tertiary protein structure can
help identify mutational hotspot in Mendelian disease genes, and contribute to the functional interpretation of the role of the
mutations.
Mon(2)-P-104
In-silico Prediction of Causal Coronary Artery Disease Genes
1,2 1,2 1,2 3,4
Benedikt Reiz ，Ingrid Brænne ，Jeanette Erdmann ，Heribert Schunkert ，Leducq Consortium CAD Genomics
1:Institute for Integrative and Experimental Genomics, University of Luebeck, Germany、2:DZHK (German Research Centre for Cardio-
Poster Session
vascular Research), partner site Hamburg/Luebeck/Kiel, Luebeck、3:Deutsches Herzzentrum Muenchen, Technische Universitaet Muenchen,
Muenchen、4:DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich
Background: To date, we have identified 202 significant and suggestive coronary artery disease loci (CAD) through genome-
wide association studies (GWAS). Here, we report an extensive bioinformatics analysis to predict the causal genes underlying
the reported CAD loci.
Methods and results: We annotated each GWAS locus with respect to protein-altering SNPs, association with gene expression
and altered miRNA binding sites. In addition, we used the publicly available ENCODE dataset to identify SNPs within
regulatory regions of the genome, such as enhancer and promoter sites. Consistent with previous findings, we found that most
CAD-loci lie in non-coding regions. Around half of the loci affect gene expression robustly, 2/3 overlap promoter regions and
nearly all loci can be linked to other regulatory regions of the genome. In contrast, only a small percentage (5%) of SNPs
affects protein coding. Comparing our in-silico gene annotation with the genes traditionally assigned to the loci through
proximity mapping, we found that a substantial number of genes differs. Indeed, we identify around 100 genes not linked
with CAD before.
Conclusion: Our results significantly revise the list of potential causal CAD genes underlying the genome-wide association
signal and might help to shed new light on the genetic mechanisms of CAD.
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Mon(2)-P-105
UnderCover : A Next Generation Sequencing Coverage Analysis tool for Whole genome, exome and
custom targeted panel sequencing
1,2
Pavlos Antoniou ，Patricia Bignell 2 ，Joanne Mason 2 ，Anna Schuh 1,2
1:Nuffield Division of Clinical Laboratory Sciences, University of Oxford, UK、2:Oxford Molecular Diagnostic Centre, Molecular Haematology,
Level 4, John Radcliffe Hospital, Oxford, UK
Introduction: With the rapid advancement of Next Generation Sequencing (NGS) technologies and the development of robust
bioinformatics methods to analyse the data, whole genome re-sequencing (WGS) has now become feasible in medium sized
labs. Furthermore, exome and targeted panel sequencing (TPS) are already used in a diagnostic setting at many medical
centres. We describe UnderCover : a versatile tool that provides coverage information for WGS, exome and TPS runs to assess
whether the sequencing data has covered the genome and all the targets sufficiently for downstream analysis, in particular
for variant calling.
Materials and Methods: Undercover uses custom shell and Perl scripts and open source software including R, bedtools,
samtools and GATK to provide coverage statistics and colourful plots of the coverage quality of the run. The user input
includes the location of the BAM files to be analysed, a BED file containing regions of interest, (ROI) and an optional BED
file containing a list of expected variants of particular interest.
Results: UnderCover provides tables and plots describing among others: per chromosome coverage statistics, average gene
coverage and clinically actionable exon coverage. UnderCover reports the coverage in all sequencing targets of the ROI,
Poster Session
focusing on the exons and the expected variants in each exon, reporting all regions not sufficiently covered as an indication
of the suitability of the run for clinical diagnosis.
Conclusions: As NGS moves from research to clinic, this tool for assessing the quality and coverage of a run can be an integral
part of the lab’s bioinformatics pipeline. UnderCover is available as a standalone Linux application and may also be accessed
as a web framework application.
Mon(2)-P-106
Accurate detection of mutations from RNA-seq in lung adenocarcinoma for clinical translation of precision
medicine
Zhifu Sun 1 ，Naresh Prodduturi 1 ，Aditya Bhagwate 1 ，Ping Yang 1 ，Jean-Pierre Kocher 1
1:Health Sciences Research, Mayo Clinic, USA
Background. Tumor mutations are mostly detected from DNA; however, RNA-seq is increasingly popular as it not only
measures gene expression but also structural variants such as single nucleotide variants (SNVs), insertion/deletion (INDELs)
or fusion transcripts. The full utilization of the multi-level information will facilitate personalized medicine. However, the
challenge in RNA-seq is that long INDELs are often missed with high false SNVs.
Materials and Method. We first evaluated commonly used RNA-seq alignment and variant calling programs and identified
the issues of no calls for INDELs and false calls for SNVs. Based on our findings, we developed a highly sensitive and specific
RNA-seq variant and mutation detection workflow and applied it to two sets of lung adenocarcinoma. The mutations detected
were compared with exome-seq and correlated with clinical outcomes.
Results. The main cause of missed INDELs in RNA-seq was the sequence read alignment step, in which most aligners
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did not align reads with INDELs. For those who could align, they had varied sensitivity and were sequence read lengths
dependent. The sensitivity and specificity of INDEL callers were also highly variable. GSNAP and STAR came up as the
best aligners and GATK haplotype caller and Strelka were the best callers for SNVs/INDELs. Application of our workflow
to two adenocarcinoma datasets found important INDEL mutations not reported before and clinically targetable. The
mutations present in both DNA and RNA were more clinically relevant in outcome prediction and sub-classification of tumor
aggressiveness. Tumor mutation load from RNA was better predictor than DNA. With single RNA-seq, we could also measure
gene abnormal expression, pathway deregulation, and fusion gene transcripts for known and novel target identification.
Conclusions. With accurate pipeline, RNA-seq can be used to glean rich and important genomic information for personalized
tumor treatment selection and outcome prediction.
Mon(2)-P-107
Genomic Signal Processing algorithm for conserved and variable sequence search
Ernesto Borrayo 1 ，Adriana P Mendizabal 2 ，Alejandro Morales 3
1:Gene Research Center, University of Tsukuba, Japan、2:Farmacobiology Department, Universidad de Guadalajara、3:Computer Sciences
Department, Universidad de Guadalajara
Sequence comparison is one of the most used tools in bioinformatics.

Sequence searches, ether conserved or variable, hold at their core mentioned comparison as elementary tool. However, the
specific methodological procedure for each one is quite different. Although the search for genomic variants or conserved
Poster Session
domains methodologically go in different directions, it is not uncommon that during a research both methods are required,
subsequently involving more than one bioinformatic tool in order to adequately address the problem.
Here we present a Genomic Signal Processing (GSP) algorithm that is able to perform both conserved and variable sequence
searches in any given sequence set.
To search for variantions, we analyzed 1,000 synthetic sequences of the first three exons of the human COL3A gene that
included the reported SNPs of the ClinVar database with 10% random appearance chance.
For the conserved domains, 18S sequences from selected eukaryotic organisms were analyzed.
We found that by only modifying the threshold it is possible to use this GSP algorithm for both domain and variant search
in any sequence comparison. With a strict threshold, The algorithm is capable of pointing out the location of single changes
among sequences. In contrast, by lowering the similarity score, the algorithm is capable of selecting conserved regions among
overall dissimilar sequences.
In consequence, the present bioinformatic tool has the capability to cover both conserved and variable searches in sequence
comparison, which provides a comprehensive technique for research that requires any of these approaches.
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Mon(2)-P-108
Towards HLA imputation network: A network of HLA genotype imputation reference from multiple
populations
Seik-Soon Khor 1 ，Buhm Han 2 ，Hyunchul Choi 3 ，Minae Kawashima 1,4
，Hiromi Sawai 1 ，Kyuyoung Song 3 ，
Naoyuki Kamatani 5 ，Katsushi Tokunaga 1 ，HLA imputation network
1:Graduate School of Medicine, Department of Human Genetics, The University of Tokyo, Japan、2:Department of Convergence Medicine,
University of Ulsan College of Medicine & Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea、3:Department
of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea、4:Japan Science and Technology Agency
(JST), Tokyo, Japan、5:StaGen, Tokyo, Japan
The HLA genomics region encompasses a region of 7.6Mb on chromosome 6p21, this region encodes more than 200 genes
including classical HLA genes in class I region: HLA-A, -B, -C and class II region: HLA-DPA1 , -DPB1 , -DQA1 , -DQB1 ,
-DRA1 and -DRB1 . With the advancement of imputation algorithm, it is now possible to impute the HLA alleles up to
2-field from genome-wide SNP typing dataset. We have previously shown that a population specific reference is of utmost
importance to achieve highest imputation accuracies as different populations may harbor different arrays of rare HLA alleles.
Here, we report a network of population specific references generated by the HIBAG HLA imputation software. Our results
showed that population-matched HLA allele imputation consistently generate highly reproducible results compared to those of
non population-matched model or a multi-population reference model. For those in which the non population-matched model
is inevitable, we suggest the method of performing multiple HLA imputation testing based on similar genetic background
references; consequently, the imputed HLA alleles with the highest Call Threshold (CT) should provide the highest accuracies.
Multi-population reference should only be utilized as a last resort when similar genetic background references are not readily
available. We strongly encourage the participation of countries/research group with GWAS and HLA alleles data available
Poster Session
to our imputation network. Lastly, we are providing complimentary HLA genotype imputation service to academic institutes
with GWAS data.
Mon(2)-P-109
Bio-Virtuoso: A package of Docker containers for multiple source data retrieval, RDF conversion, and
triplestore deployment in a simplified manner
Hiroyuki Mishima 1 ，Koh-ichiro Yoshiura 1
1:Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Japan
Interpretation of human genomic data generated by massively parallel sequencing essentially requires integration of informa-
tion derived from public and private databases. Databases based on genomic physical positions, such as polymorphic site
information, can be simply integrated using table-oriented approaches. Application of complicated knowledge graphs, such
as disease-phenotype relationships and gene-function relationships, however, needs ontology-based data integration. Resource
description framework (RDF) is fundamental technology of the semantic web. Datasets using ontologies and ontologies them-
selves can be expressed using RDF. SPARQL is a RDF query language. SPARQL endpoints store RDF graphs and process
SPARQL queries. For practical use, SPARQL endpoints handling multiple graphs require to be single instances containing
whole graphs. Thus, before submitting queries to endpoints, developers have to deploy a triplestore, find appropriate source
of datasets to download, convert them into RDF, and load them into the triplestore.
To simplify these steps, we are developing a package called Bio-Virtuoso using the Docker virtualization technology. The
virtuoso-gloso container runs an instance of the Virtuoso triplestore. This container receives Turtle, RDF/XML, and OWL
format files via the HTTP POST method and internally put them into Virtuoso speedy using the isql command. Graph-
feeding containers download data from sources, convert them into RDF if necessary, and send them to virtuoso-gloso. Multiple
graph-feeding containers can be combined on demand. To date, we have supported data sources such as Human Phenotype
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Ontology (HPO), HPO-annotation, OMIM, ORPHANET, HGNC, OMIM Japanese translation by Gendoo, and Mammalian
Phenotype ontology (MP).
Bio-Virtuoso is expected to lower barriers to learn SPARQL using real dataset and develop SPARQL-based applications. The
project Github repository is at https://github.com/misshie/bio-virtuoso .
Mon(2)-P-110
Comprehensive Genetic Exploration of Skeletal Dysplasia Using Targeted Exome Sequencing
Jun-Seok Bae 1 ，Nayoung K.D. Kim 2 ，Woong-Yang Park 1 ，Tae-Joon Cho 3
1:Samsung Genome Institute, SungKyunKwan University, Korea, South、2:Samsung Genome Institute、3:Seoul National University
PURPOSE: The purpose of this study was to evaluate the clinical utility of targeted exome sequencing (TES) as a molecular
diagnostic tool for patients with skeletal dysplasia.
METHODS: A total of 185 patients diagnosed with skeletal dysplasia, or suspected to have it were recruited over a period
of 3 years. TES was performed for 255 genes associated with the pathogenesis of skeletal dysplasia, and candidate variants
were selected using a bioinformatics analysis. All candidate variants were confirmed by Sanger sequencing, correlation with
the phenotype, and a co-segregation study in the family.
RESULTS: TES detected“confirmed” or “highly likely” pathogenic sequence variants in 74% (71 of 96 cases) of the assured
clinical diagnosis category, as well as pathogenic sequence variants in 20.3% (13 of 64 cases) of the uncertain clinical diagnosis
Poster Session
category. TES successfully detected pathogenic variants in all 25 cases of previously known genotypes. The data also suggested
a copy number variation that led to a molecular diagnosis.
CONCLUSION: This study demonstrates the feasibility of TES for the molecular diagnosis of skeletal dysplasia. However,
further confirmation is needed for a final molecular diagnosis, including Sanger sequencing of candidate variants with suspected,
poorly captured exons.
Mon(2)-P-111
Performance comparison of four commercial human whole-exome capture platforms
Daichi Shigemizu 1,2 ，Yukihide Momozaw 3 ，Testuo Abe 2 ，Takashi Morizono 2 ，Keith A Boroevich 2 ，Sadaaki Takata 3 ，
Kyota Ashikawa 3 ，Michiaki Kubo 3 ，Tatsuhiko Tsunoda 1,2
1:Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Japan、2:Laboratory for
Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences、3:Laboratory for Genotyping Development, RIKEN Center
for Integrative Medical Sciences
Whole exome sequencing (WXS) is widely used to identify causative genetic mutations of diseases. However, not only have
several commercial human exome capture platforms been developed, but substantial updates have been released in the past
few years. We report a performance comparison for the latest release of four commercial platforms, Roche/NimbleGen’s
SeqCap EZ Human Exome Library v3.0, Illumina’s Nextera Rapid Capture Exome (v1.2), Agilent’s SureSelect XT Human
All Exon v5 and Agilent’s SureSelect QXT, using the same DNA samples. Agilent XT showed the highest target enrichment
efficiency and the best SNV and short indel detection sensitivity in coding regions with the least amount of sequencing. Agilent
QXT had slightly inferior target enrichment than Agilent XT. Illumina, with additional sequencing, detected SNVs and short
indels at the same quality as Agilent XT, and showed the best performance in coverage of medically interesting mutations.
NimbleGen detected more SNVs and indels in untranslated regions than the others. We also found that the platforms, which
enzymatically fragment the genomic DNA (gDNA), detected more homozygous SNVs than those using sonicated gDNA. We
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believe that our analysis will help investigators when selecting a suitable exome capture platform for their particular research.
Mon(2)-P-112
A Statistical Model for the Refinement and Ranking of Variant Calls
Tony Kuo 1 ，Jun Sese 1 ，Martin Frith 1 ，Paul Horton 1
1:BRD, National Institute of Advance Industrial Science and Technology, AIST, Tokyo, Japan
Many human diseases have a genetic component. Thus, genome sequencing has become an important method in the study
of genetic disorders. In particular, there is a great amount of interest in somatic mutations associated with cancer, as well
as mutations associated with rare inherited diseases. As such, variant discovery has become a routine analysis method in
research and in clinical settings. Currently, many tools and methods have been developed for the purpose of discovering
variants. However, the results from different tools do not often agree and are very sensitive to small changes in parameters,
implying the methods are not robust. It is known that uncertainties and ambiguities exist at all stages of the variant calling
process, likely due to the repetitive nature of the human genome. The calling of insertions and deletions in particular, tend
to have difficult to resolve ambiguities and remains unreliable. This is especially true for variant calling on a single sample or
individual.
Here, we present a statistical model to evaluate whether putative variants are significant. Given a set of variant calls, we
construct the putative mutant genome and calculate the likelihood of the sequencing data given the reference genome versus
Poster Session
the likelihood of the sequencing data given the mutant genome, something that current callers do not perform. Thus, our
statistical formuation defines a probabilistic model to explain the observed data, and treats both the uncertainty regarding
the orgin of the data and the hypothesized variant genome explicitly.
We have begun to try our method on simulated and real data (targeted, exome and whole genome sequencing). Based on our
manual inspection of numerous example of called variants, our ranking method appears promising as a way to reduce false
positives without losing many true positives.
Mon(2)-P-113
Identifying sequence differences among copy number variants from sequencing data
Takahiro Mimori 1 ，Naoki Nariai 2 ，Kaname Kojima 1 ，Yukuto Sato 1 ，Yosuke Kawai 1 ，Yumi Yamguchi-Kabata 1 ，
Masao Nagasaki 1
1:Tohoku University, Japan、2:University of California, San Diego
Genetic variation among individuals is essential resource for understanding phenotypic variation and causes for genetic disor-
ders. Although, a number of single nucleotide polymorphisms (SNPs) and short indels are identified at nucleotide resolution
via sequencing technologies, sequence differences of copy number variants (CNV) are less cataloged due to limited read length
of sequencing technologies.
We proposed a computational approach that is named CNValloc to identify sequences of alleles at CNV locus from population-
scale high-throughput sequencing (HTS) data. CNValloc simultaneously infers the copy unit alleles existing in population
and their copy numbers for each individual. We conducted simulation and real data studies to evaluate utility of CNValloc.
In the simulation studies, degree of concordance between inferred and true alleles were evaluated. We devised precision- and
recall-like metrics for the evaluation and confirmed that the metrics were ≥ 0.9 for data with mean coverage ≥ 10× per copy
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unit, which is a typical depth of coverage of HTS data. In real data study, we applied CNValloc to 1123 samples at highly
variable salivary amylase gene locus and a pseudogene locus, and confirmed consistency of the estimated alleles in a trio
samples with 11 offspring.
Mon(2)-P-114
Next Generation Sequencing Strategies to reconstruct Ancient African Mitochondrial Genomes
Tasneem Salie 1 ，Raj S Ramesar 1 ，Alan G Morris 1 ，John Parkington 1 ，Johannes Krause 2 ，Alissa Mittnik 2
1:Division of Human Genetics, University of Cape Town, South Africa、2:University of Tubingen, Germany
Introduction: A group of human skeletons, older than 2000 years, were excavated from an archaeological site in the Western
Cape, South Africa. These human skeletal remains were well enough preserved to determine the anthropological profiles
(sex, age and stature etc.). Additionally, we observed the paleo-pathological and traumatic changes on these skeletal remain.
Further studies of these individuals were required to confirm the biological relationships between these individuals. The
advancement of NGS technologies has made the goal of reconstructing ancient genomes very realistic. High-throughput
technologies have increased the potential of studying older organisms, here we present the methodologies used to analyze NGS
data and allow the reconstruction of genomes. In this study we use NGS data to characterize ancient mitochondrial genomes,
allowing us to elucidate the relationships existing between a group of individuals. This study focuses on the genetics of ancient
indigenous populations, to better understand the relationship between contemporary populations and previously existing
relatives. The aim of this study is to examine the possibility of familial relationships between these individuals. Methods:
Poster Session
High-throughput DNA sequencing technologies in combination with current improvements in ancient DNA recovery, library
construction and targeted DNA enrichment, we sought to reconstruct ancient mitochondrial genomes. Using the preliminary
data we have reconstructed the mitochondrial genomes using bioinformatics analysis. Results and Discussion: This study
is ongoing; phylogenetic analysis will enable us to determine the ancestral lineage of these individuals. This information is
integral to understanding the genetic diversity of past populations compared to the contemporary populations of Southern
Africa. This study will provide a better understanding of the genetic relationships at this archaeological site and add to the
genetic history of Southern Africa.
Mon(2)-P-115
Comparison of the clinical sequence using two platforms of hereditary disease panels and exome sequenc-
ing
Naoko Sato 1 ，Hiroyuki Ishiura 1 ，Jun Mitsui 1 ，Budrul Ahsan 1 ，Masaki Tanaka 1 ，Jun Goto 3 ，Shinichi Morishita 2 ，
Shoji Tsuji 1
1:Neurology, Graduate School of Medicine, The University of Tokyo, Japan、2:Department of Computational Biology, Graduate School
of Frontier Sciences, The University of Tokyo、3:Department of Neurology, International University of Health and Welfare Mita Hospital,
Tokyo, Japan
Introduction: Next generation sequencing (NGS) has been applied for clinical sequencing for molecular diagnosis of diseases
with Mendelian trait. Whole exome sequencing (WES) employs enrichment of exonic sequences followed by NGS, whereas
disease panels employs enrichment of exonic sequences of only causative genes followed by NGS. Objective: We evaluated the
efficacy of clinical sequencing employing two different types of panel of genetic diseases and WES. Methods: The subjects
were 5 neuromuscular disorders. For target enrichment, we used TruSight One sequencing panel (Illumina) for sequencing the
exon regions of 4,813 clinically relevant genes, and SureSelect Inherited Disease (Agilent) for sequencing those of 2,742 genes.
For WES, we used SureSelect V5+UTRs (Agilent). Massively parallel sequencing was achieved using a MiSeq (Illumina, 151
bp paired end) sequencer for the panel sequencing and a HiSeq (Illumina, 101 bp paired end) sequencer for WES. Target
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coverage was calculated using Qualimap v2.1. Duplicate reads were removed as per PICARD best practices. Single nucleotide
variant (SNV) calling was performed using SAMtools-1.2. Results: The median coverages of 3 platforms were 69.6 (53.6-78.1),
188.6 (166.2-213.3), and 88.8 (73.4-102) per run in Illumina panel, Agilent panel, and WES, respectively. 88.4 % (80.6-94.4) of
the target bases were covered by at least 20-fold in the Illumina panel, and 98.1 % (97.6-98.6) in the Agilent panel. In WES,
94.2 % (92.5-95.8) of the target bases were covered by at least 20-fold. Between two platforms of target resequencing, the less
the number of target genes is, the bigger the range covered by at least 20-fold is. In the common target region, 99.9 % of the
data matched in 3 platforms. Conclusion: Target resequencing employing a panel of genetic diseases enabled rapid molecular
diagnosis. The coverages of target bases slightly vary depending on the size of the target bases, which may be taken care of
in clinical sequencing.
Mon(2)-P-116
A combination of targeted enrichment methodologies for whole-exome sequencing reveals novel
pathogenic mutations
Fuyuki Miya 1,2 ，Mitsuhiro Kato 3 ，Tadashi Shiohama 4 ，Nobuhiko Okamoto 5 ，Shinji Saitoh 6 ，Mami Yamasaki 7 ，
Daichi Shigemizu 1,2 ，Tetsuo Abe 2 ，Takashi Morizono 2 ，Keith A Boroevich 2 ，Kenjiro Kosaki 8 ，
Yonehiro Kanemura 9,10 ，Tatsuhiko Tsunoda 1,2
1:Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Japan、2:Laboratory for
Medical Science Mathematics, Center for Integrative Medical Sciences, RIKEN、3:Department of Pediatrics, Showa University, School of
Medicine、4:Department of Pediatrics, Graduate School of Medicine, Chiba University、5:Department of Medical Genetics, Osaka Medical
Center and Research Institute for Maternal and Child Health、6:Department of Pediatrics and Neonatology, Nagoya City University
Graduate School of Medical Sciences、7:Department of Pediatric Neurosurgery, Takatsuki General Hospital、8:Center for Medical Genetics,
Keio University School of Medicine、9:Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National
Poster Session
Hospital Organization、10:Department of Neurosurgery, Osaka National Hospital, National Hospital Organization
Background:
Whole-exome sequencing (WES) is a useful method to identify disease-causing mutations, however, often no candidate mu-
tations are identified using commonly available targeted probe sets. In a recent analysis, we also could not find candidate
mutations for 20.9% (9/43) of our pedigrees with congenital neurological disorder using pre-designed capture probes (Sure-
Select V4 or V5). One possible cause for this lack of candidates is that standard WES cannot sequence all protein-coding
sequences (CDS) due to capture probe design and regions of low coverage, which account for approximately 10% of all CDS
regions.
Methods:
We combined a selective circularization-based target enrichment method (HaloPlex) with a hybrid capture method (SureSelect
V5; WES) to increase the coverage of CDS and to identify pathogenic mutations for pedigrees with no candidates through
standard WES analysis. We designed a probes set for complementary custom CDS sequencing (CCCS), and applied this
combination approach to the 7 (SureSelect V5) out of 9 pedigrees.
Results:
The combination method produced an observed regions with a read depth >10 for 97.4% of all CDS regions. We identified
novel pathogenic mutations in one pedigree with microcephaly (OMIM #608716) using the combination method. The muta-
tion was composed of two nonsense variants in ASPM gene, c.8098C>T [p.R2700*] and c.10168C>T [p.R3390*], identified
through WES and CCCS analysis, respectively. The variant call of latter locus was missed in standard WES as the region
had low read depth (<10) in all samples.
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Conclusion:
Our combination method of WES and CCCS contributed to an increase in the coverage of CDS (97.4%) and was successfully
able to identify novel pathogenic mutations. We believe that this combination method will contribute to the identifica-
tion of novel causative mutations, which are inaccessible by current pre-designed standard WES analysis, and to a greater
understanding of mechanisms and therapies for diseases.
Mon(2)-P-117
Happy families - the benefits and bioinformatics of using extended pedigrees for next-generation se-
quencing
1,2
Nicholas B. Blackburn ，Juan M. Peralta 1 ，Kathryn P. Burdon 2 ，Joanne E. Curran 1 ，John Blangero 1 ，
Jac C. Charlesworth 2
1:South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, USA、2:Menzies Institute for Medical Research,
University of Tasmania, Hobart, Australia
Our research uses exome (WES) and genome (WGS) sequencing in extended families to identify genes influencing complex
disease. Our pedigree based approach is an implicit enrichment strategy to identify disease-relevant rare variants while also
decreasing study costs by reducing the total sample size required.
Poster Session
At the individual sample level, both WGS and WES are known to have variability across regions and between samples, in
terms of sequencing depth (DP) and base pair quality (GQ). Instead of working with this variability, these parameters are
often used for the binning of variants into quality levels; discarding low confidence variants with DP<10 or GQ<20 prior to
analysis. This approach, while potentially increasing confidence, also increases the likelihood of missing true disease relevant
variation. Intuitively this may be mitigated by using the high confidence genotypes of related individuals to confirm low
confidence genotypes on a sample by sample basis; theoretically increasing the number of variants for analysis.
To confirm the utility of this approach, we used extended pedigrees from three WGS/WES studies of complex disease.
We utilized the tools available for Low Confidence variant restoration through imputation, including GIGI, ShapeIt2 and
MiniMac3 to determine whether imputation changes or improves the variant profile available for downstream analyses. Our
downstream pedigree-based variant prioritization includes heuristic filtering approaches (using ANNOVAR and an R based
pipeline) and family specific association testing (measured genotype association in SOLAR). Preliminary data from a single
family of seven siblings with 136,286 exomic sites shows that restricting analysis to sites of high confidence in all samples
discards 18% of variants, 64.3% of which are High Confidence in at least three of the siblings. This suggests the potential to
recover many of the low confidence variants and reduce the likelihood of discarding disease relevant variation.
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Mon(2)-P-118
Inferring the sequence and timing of admixture events in populations with complex admixture history
using genome-wide SNP-chip data
Irina Pugach 1 ，Rostislav Matveev 2 ，Brigitte Pakendorf 3 ，Mark Stoneking 1
1:Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Germany、2:Max Planck Institute for Mathematics in the
Sciences, Leipzig, Germany、3:Laboratoire Dynamique du Langage, UMR5596, CNRS and Université Lyon Lumière 2, Lyon, France
The increased availability of dense genotype and sequence data from diverse human populations has highlighted the importance
of admixture in the evolutionary history of humans. Various methods have been developed to identify and study signals of
admixture to infer population movements and their timing. Since most of these methods assume a single-pulse of admixture,
they are of limited utility for situations involving complex admixture scenarios. Disentangling the ancestries from many
different (possibly related) sources that mixed at different time points in the past remains a challenging problem. To unravel
this complexity we developed a new approach, the Admixture History Graph, which infers the sequence of admixture events
in a population with a complex admixture history. Furthermore, we adapted previously published wavelet transform analysis
for dating admixture to incorporate admixture events from multiple sources and occurring at different time points in the past.
Both approaches were tested on simulated data and applied to two comprehensive genome-wide SNP datasets from Siberia
and Oceania. While previous studies of the genetic history of the Siberian populations were hampered by the multi-layered
gene flow that appears to have taken place among these populations, our newly developed approaches combined with other
methods allowed us to disentangle this complexity and to describe considerable differences in the historical trajectories of the
Siberian peoples. In addition, some previous studies of regional variation in Oceania have suggested that the widely accepted
two-wave human settlement of Oceania, which involves the first out-of-Africa migration and the Austronesian expansion is
Poster Session
incomplete. Using the new methodology we are investigating the movements of people across the Solomon Islands archipelago
(which forms a gateway into the Remote Oceania), and their timing, as well as potential contact between populations following
the expansion into the Pacific.
Mon(2)-P-119
LAMPLINK: Additional functions for PLINK to detect SNP combination statistically significantly asso-
ciated with a trait
1,2 1,2 2
Aika Terada ，Koji Tsuda ，Jun Sese
1:The University of Tokyo, Japan、2:National Institute of Advanced Industrial Science and Technology
PLINK is a widely used software for genome-wide association study (GWAS). Its major functions list single SNPs statistically
significantly associated with a target trait, whereas identifying combinatorial effect of SNPs might contribute to answering
missing heritability. PLINK has a function to exhaustively assess epistatic effect of SNP pairs, but it cannot investigate com-
binatorial effect of three or more SNPs. Detecting such combinatorial effect is difficult not only for PLINK but also for other
GWAS analysis software because of low sensitivity of traditional multiple testing procedures and intractable amount of compu-
tational time. Recently, a fast multiple testing procedure, called Limitless Arity Multiple-testing procedure (LAMP) [Terada
et al, PNAS, 2013], was proposed for combinatorial effects discovery. When the recessive or dominant complementary model is
assumed as genetic model, the LAMP can enumerate any size of SNP combinations statistically significantly associated with a
trait, while the family-wise error rate theoretically controls under the equal level to the Bonferroni correction. We incorporate
the LAMP with PLINK and develop software named LAMPLINK. Our demonstration using 1000 Genomes project data
showed that LAMPLINK associated combinations of three or more SNPs with Japanese. The detected combination involved
SNPs that did not show significant association by single. LAMPLINK is available at http://a-terada.github.io/lamplink/ and
easily applied to an analysis pipeline with PLINK.
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Mon(2)-P-120
An integrated Chromosomal omics approach to decipher molecular mechanism of CGG repeat expansion
in Fragile X syndrome
Yuji Nakayama 1 ，Naohiro Sunamura 2 ，Kaori Adachi 1 ，Akiko Kashiwagi 4 ，Daigo Inaoka 2 ，Mitsuo Oshimura 3 ，
Hiroyuki Kugoh 2,3 ，Eiji Nanba 1
1:Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Japan、2:Department of Biomedical
Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Japan、
3:Chromosome Engineering Research Center, Tottori University, Yonago, Japan、4:Division of Laboratory Animal Science, Research Center
for Bioscience and Technology, Tottori University, Yonago, Japan
Fragile X syndrome (FXS, OMIM #300624) is the most common inherited form of mental retardation. FMR1 gene on human
X chromosome q27 region is responsible gene for FXS and contains a CGG triplet repeat in its 5’ UTR region. In FXS,
expansion of a CGG triplet repeat beyond 200 triplets called Full-Mutation (FM) exclusively occurs when Pre-Mutation (PM)
allele between 45 to 200 CGG triplets is maternally transmitted. Following repeat expansion, CpG hypermethylation across
the FMR1 promoter region occurs, giving rise to inactivation of FMR1 expression and result in FXS phenotypes. There
is a certain genomic circumstance that leads to CGG triplet repeats instability, however, key factors or as-yet-known CGG
repeats associating proteins which are responsible for CGG repeat instability have not been fully elucidated. To understand the
molecular changes in genetic and epigenetic status is crucial to cure for FXS and we set up an integrated chromosomal omics
approach, named Chromosome Immunoprecipitation (ChrIP). In ChrIP, protein complexes on or associated with specific
chromosomal/genomic region can be collected by lacO-lacI mediated immunoprecipitation and harvested genome-bound
proteins can be identified by subsequent mass spectrometric analysis. In our system, chromosomal engineering technology
enable us to maintain native genetic or epigenetic status of CGG repeat region, and as the first example, we could introduce
Poster Session
human X chromosome from normal, PM, and FM individuals into mouse cell in which genetic and epigenetic status as well
as FMR1 expression profiles are maintained as seen in human cells. Thus, CGG repeat region so called “chromosomal fragile
site” within suitable chromosome context can be stably handled in our system. Using this set of model cells, we are trying
to reproduce CGG repeat instability in vitro and to identify specific proteins related to effect a change in CGG triplet repeat
stability via ChrIP method.
Mon(2)-P-121
High Efficiency Automated DNA Extraction Methods for Degraded Old Skeletal Samples
Seung-Bum Hong 1 ，Yang-Seop Kim 1 ，Hee-Jung Ahn 1
1:Division of DNA Analysis, Scientific Investigation Laboratory, Criminal Investigation Command, Korea, South
In case of extreme degradation, bone may be the only suitable material available for successful STR genotyping. However,
relatively specialized techniques are required for the extraction of DNA from bone tissues, particularly when the bones have
been exposed to adverse environmental conditions and DNA is degraded and present in low concentrations. Therefore,
improving the quantity and/or quality of DNA samples would greatly increase the profiling success rate from highly degraded
bone samples. In this study, to optimize DNA extraction procedure for old and highly degraded skeletal remains, newly
developed automated DNA extraction system was compared to the traditional organic DNA extraction methods. We adopted
Chemagic MSM I system for automated DNA extraction, with optimized protocols for large volumes (range, 5-15 mL) of
bone samples. DNA was extracted from randomly chosen bone samples of the victims who were killed in the Korean War
and the efficiencies of extraction methods were compared by real-time polymerase chain reaction to measure DNA quantity
and the presence of inhibitors. Success rates of genotyping were analyzed by autosomal STR genotyping, Y-chromosomal
STR genotyping, and mtDNA sequencing analysis. Real-time assays for quantification revealed that human DNA yield from
skeletal samples did not show remarkable differences between two methods. However, Chemagic MSM I system showed lower
concentration of co-extracted PCR inhibitors than the traditional organic extraction methods. Furthermore, STR genotyping
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results showed that Chemagic MSM I system is more effective DNA extraction method for old skeletal remains than organic
extraction method. Therefore, here we suggest that the Chemagic MSM I is efficient automated DNA extraction system for
old and highly degraded bone samples and powerful and valuable tool for identification of old skeletal remains
Mon(2)-P-122
Sparse modeling of genetic variants using summary statistics from genome-wide association studies
Zheng Ning 1 ，Youngjo Lee 2 ，Yudi Pawitan 1 ，Xia Shen 1
1:Medical Epidemeology and Biostatistics, Karolinska Institutet, Sweden、2:Seoul National University
Genome-wide association studies (GWAS) have been widely used to identify the associations between genetic variants and
complex traits. Although GWAS can establish significant associations between genomic loci and complex traits, due to linkage
disequilibrium among the variants locally, multiple non-specific hits are generated in GWAS. To eliminate these non-specific
hits and fine-map each locus, sparse variable selection techniques such as LASSO (least absolute shrinkage and selection
operator) may be used. For GWAS, meta-analysis based on summary-level data has been developed, which increases power
and bypasses the restrictions on sharing individual-level data. Similarly, it is desirable to develop a meta-analysis for variable
selection methods, which is, however, statistically and practically very challenging. Here, we develop a novel approach to
perform various kinds of sparse variable selection of genetic variants using GWAS summary statistics. We show how the
method is helpful for fine-mapping in both simulation studies and real data analysis of summary statistics from multiple
meta-GWAS.
Poster Session
Mon(2)-P-123
Universal system for analysis most type of mutation
Oksana P Ryzhkova 1 ，Alexandr V Polyakov 1
1:Research Centre of Medical Genetics, Russia
At the present time, scientists use a lot of laboratory methods to identify possible causes of hereditary diseases. This is because
different mutations need different type of analysis. NGS and Sanger sequencing can detect missense/nonsense mutation and
small deletion/duplication. But these methods have some problems. NGS may have low/no coverage some regions and no
information about it. Sanger sequencing is not used for analyzing of the lengthy sequence. And both these methods cannot
detect gross deletion and duplication. MLPA can detect the latter but cannot sense another types of mutation. As a result
scientists need a lot of time and reagent to review DNA changes. We worked out a new system for analysis most type of
mutation. The basis of this method was AmpliSeq technology but we added fragmentary analysis between multiplex PCR
and sequencing. It was possible because we used own primers with complimentary to fluorescently labeled universal primer
fragment. The fragmentary analysis made possible to assess quality and quantity of each amplicon and to detect gross deletion
and duplication. This added stage saved us the trouble of low/no or different coverage between some regions. We check above
mentioned system by analysis of patients with Dushenne muscular dystrophy. All types of mutation were detected and have
been confirmed by MLPA and Sanger sequencing.
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Mon(2)-P-124
The intolerance to functional genetic variation of protein domains predicts the localization of pathogenic
mutations within genes
1,2 1,3
Ayal B Gussow ，Slave Petrovski ，Quanli Wang 1 ，Andrew S Allen 2 ，David B Goldstein 1
1:Columbia University, USA、2:Duke University、3:University of Melbourne
Ranking human genes based on their tolerance to functional genetic variation can greatly facilitate patient genome inter-
pretation. It is well established however that different parts of proteins can have different functions, suggesting that it will
ultimately be more informative to focus attention on functionally distinct portions of genes. Here we evaluate the intoler-
ance of genic sub regions using two biological sub region classifications. We show that the intolerance scores of these sub
regions significantly correlate with reported pathogenic mutations. This observation extends the utility of intolerance scores
to indicating where within genes pathogenic mutations are mostly likely to fall.
Mon(2)-P-125
The Qatar Genome Reference: A Population-Specific Tool for Precision Medicine in the Middle East
Juan L Rodriguez-Flores 1 ，Khalid A Fakhro 2,3 ，Michelle R Staudt 1 ，Monica D Ramstetter 1 ，Amal Robay 3 ，
Joel A Malek 3 ，Ramin Badii 4 ，Ajayeb Al-Nabet Al-Marri 4 ，Charbel A Khalil 3 ，Alaya Al-Shakaki 3 ，Omar Chidiac 3 ，
Dora Stadler 3 ，Mahmoud Zirie 4 ，Amin Jayyousi 4 ，Jacqueline Salit 1 ，Jason G Mezey 1,5 ，Ronald G Crystal 1
1:Department of Genetic Medicine, Weill Cornell Medical College, USA、2:Sidra Medical and Research Center, Doha, Qatar、3:Weill Cornell
Medical College, Doha, Qatar、4:Hamad Medical Corporation, Doha, Qatar、5:Cornell University, Ithaca, NY
Poster Session
Rare variants in human genomes discovered using sequencing technology are important for future genomic studies of precision
medicine, Mendelian diseases, and complex diseases such as diabetes. Thousands of genomes have been sequenced thus far,
but how does this data serve to improve interpretation the “n+1” genome, or next genome sequenced? In this study, we
demonstrate how alteration of the human reference genome, such that the variant allele is the major allele in a database
of previously sequenced genomes, is a pathway to improved genome interpretation. In order to facilitate precision medicine
in Qatar and beyond, a population-specific reference genome for the indigenous Arab population of Qatar (QTR1) was
constructed by incorporating allele frequency data from sequencing of 1,161 Qataris, representing 0.4% of the population.
The impact on SNP and indel detection of using the QTR1 reference genome was assessed by sequencing the genome of a
Qatari individual of Arab ancestry on four distinct platforms, and comparing genotypes obtained when aligning data to either
QTR1 or GRCh37, the standard reference genome. An improvement in read alignment and a reduction in genotype calling
errors were observed when employing QTR1 in either exome or genome sequencing. Furthermore, the impact on “n+1”
genome interpretation was assessed across Qatari sub-populations and for Middle Eastern populations inferred to be closely
related to Qataris in a combined population structure analysis of 5611 genomes. Not only were fewer variants observed when
using the QTR1 reference, but interpretation of potentially deleterious variants, such as missense and loss of function (LoF)
variants, was significantly improved.
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Mon(2)-P-126
CNVs assessment by whole exome sequencing in patients with multiple congenital malformations and
developmental delay
Leslie D Kulikowski 1,4 ，Evelin A Zanardo 1,4 ，Gil M Novo-Filho 1,4 ，Marilia M Montenegro 1,4 ，Alexandre T Dias 1,4 ，
Thais V Costa 1,4 ，Fabricia A Madia 1,4 ，Amon M Nascimento 1,4 ，Flavia B Piazzon 1,2,4 ，Fabiola P Monteiro 2 ，
Larissa S Costa 2,3 ，Marcia Dallamano 2 ，Joao P Kitajima 2 ，Chong A Kim 3 ，Fernando KoK 2
1:Pathology, University of São Paulo, Brazil、2:Mendelics Genomic Analysis, Sao Paulo, Brazil、3:Genetics Unity, Department of Pediatrics,
Children Institute, Universidade de São Paulo、4:Cytogenomics Laboratory - LIM 03, Universidade de Sao Paulo-HC-FMUSP, Sao Paulo,
Brazil
Efficient detection of the copy number variations is essential for the study of genetic diseases. Recently developed, the whole
exome sequencing, aims to complete assessment of exonic sequences in all genes, identifying mutations in rare and genetically
heterogeneous diseases. However, the identification of CNVs is not used routinely in this technique, and this evaluation
could increase its versatility as a detection method. We evaluated 16 patients with multiple congenital malformations and
developmental delay by whole exome sequencing technique - Nextera Exome Capture and HiSeq 2500 System for CNVs
assessment. We used array - HumanCytoSNP-850K BeadChip and iScan System (Illumina ) for comparison and confirmation
of the results and excluding the possibility of the other deletions and duplications. We performed the CNVs analysis using
Conifer (http://conifer.sourceforge.net/) and the ReadDepth (https://github.com/chrisamiller/readDepth). We identified
several different genomic alterations in all patients by the array and/or exome sequencing techniques, but the CNVs were
confirmed in 62,5% of the patients by both techniques. Among the alterations, the deletions correspond to ~ 36,8% and the
duplication to ~ 63,2%. The larger alteration found was to 10q23.12-q26.3 (12,433,500 bp) in the deletion and to 15q11.2-
q13.3 (9,764,036 bp) in the duplication, and the smaller alteration found was to 9p24.2 (104,767 bp) in the deletion and to
Poster Session
12p13.31 (124,833 bp) in the duplication. The extraction of CNVs information obtained from the whole exome sequencing is
an advantageous approach that should be investigated. Thus this study can upgrade the resolution and accuracy of search
pathogenic CNVs, and improve the cost-effectiveness and reduce the number of genomic tests required to reach a diagnosis
and thus lead to a deeper understanding of disease mechanisms allowing new therapeutic strategies and actions to prevent
these diseases.
Mon(2)-P-127
Analysis of the human subtelomeric regions to elucidate the real structure and pathogenesis of the related
diseases
Yoko Kuroki 1 ，Atsushi Toyoda 2 ，Hideki Noguchi 2 ，Kumiko Yanagi 1 ，Asao Fujiyama 2,3
，Tadashi Kaname 1
1:Department of Genome Medicine, National Research Institute for Child Health and Development, Japan、2:Center for Information Biology,
and Advanced Genomics Center, National Institute of Genetics、3:Principles of Informatics, National Institute of Informatics
Human subtelomeres have unique structure of the genome, which form the transitions between chromosome-specific sequence
and arrays of telomere repetitive sequence on the vicinity of chromosomal ends. Such regions show a complex genomic
structure. The regions consist of variable mosaics of multi-chromosomal blocks of the nucleotide sequences. The subtelomere-
specific repeats are identified as duplicated structures among the most of human subtelomeres. Abnormalities (e.g. deletions)
of the subtelomeric region are associated with human diseases such as intellectual impairment and malformation syndrome
(known as subteleomere deletion syndrome). The cause of subtelomeric abnormalities and precise relationship between their
variations and clinical phenotypes are not fully elucidated. It is known that the latest reference data of human genome
(GRCh38/hg38) are the most complete genome assembly in mammalian. However, there are still euchromatic gaps in several
subtelomeric regions, due to their complex genomic structures. In fact, gene contents, constitution of the DNA elements, and
variation of the copy number of the duplicated sequences in the subtelomeric regions have not been fully analyzed. Precise
analyses in the subtelomeric regions are important to understand the subtelomere deletion syndrome.
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To clarify the precise and exact structure of the human subtelomeres, we isolated Fosmid clones covering the human sub-
telomeric region and started to analyze their complete structures by NGS analysis.
We present an overview of our project and show the current status at the meeting.
Mon(2)-P-128
Poster Session
Application of High Throughput Chemical Genomics Screening Using Yeast Deletion Set for Taiwanofun-
gus Camphoratus
Edward Tsui 1 ，Samah Saharti 5 ，Huang Y Albert 2 ，Chen Daniel 4 ，Wang L Lilian 3 ，Chen C Jeremy 4
1:La Sierra University, USA、2:Biotech KC Inc、3:Rite Aid Corp、4:JC Acupuncture、5:Dept of Pathology, University of California, San
Deigo
Identification of medicinal useful compounds from herbal sources pose a special challenge. On reason is the diversity as
well as the complexity of compounds present in herbal extract. Furthermore, the separation of these compounds possess an
additional layer of difficulty in identifying medicinal useful compound. We construct a high throughput, automated, chemical
genomic assay system based on yeast deletion set in order help identify potential medicinal useful compounds. We apply
screening system to extracts derived from Taiwanofungus camphoratus, a medicinal mushroom also known as niu-chang-chih.
Studies indicated the anticancer property of Taiwanofungus camphoratus. However, much less is known of potential pathways
involvement as well the potential anticancer molecules in the Taiwanofungus camphoratus. To test the feasibility of screening,
we use a small molecule drug with well characterized biochemical effects and known gene target. Rapamycin is our choice of
molecule, an immunosuppressant drug used to prevent rejection in organ transplant. Rapaymycin exerts its action by binding
and inhibiting gene product, FK binding protein (FKBP) and affects the TOR pathway. To test if we can identify FKBP
using the system, we first add rapamycin to a gelatinous solid growth support on a culture plate. All 5,000 yeast deletion
clones are robotically "arrayed" onto the solid growth media. Several yeast clones are shown to grow differentially in presence
of rapamycin. The yeast clone with FKBP gene deletion was identified. We then apply the same system on Taiwanofungus
camphoratus. Because the purported medicinal property of Taiwanofungus camphoratus is in various complex polysaccharide
components. We focus on the extracts that is enriched for polysaccharides. Using the chemical genetic screening system, our
goal is to identify potential polysaccharide components with known cytotoxic profile.
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Mon(2)-P-129
PAFFT: A new homology search algorithm for third-generation sequencers
1,2 3,4
Kazuharu Misawa ，Ryo Ootsuki
1:Tohoku Medical Megabank Organization, Tohoku University, Japan、2:Graduate School of Medicine, Tohoku University、3:Faculty of
Chemical and Biological Sciences, Japan Women’s University、4:Department of Natural Sciences, Faculty of Arts and Sciences, Komazawa
University
In 2009, real-time sequencing from a single polymerase molecule was developed. DNA sequencers that can conduct real-time
sequencing from a single polymerase molecule are known as third-generation sequencers (1). Third-generation sequencers
enable sequencing of reads that are several kilobases long. However, the raw data generated from third-generation sequencers
are known to be error-prone (2). Because of sequencing errors, it is difficult to identify which genes are homologous to
the reads obtained using third-generation sequencers. We developed a new method for homology search algorithm, PAFFT
(3). This method is extention of the MAFFT algorithm which was used for multiple alignments (4). PAFFT detects global
homology rather than local homology so that homologous regions can be detected even when the error rate of sequencing is
high. PAFFT will boost application of third-generation sequencers.
Reference:
1. J. Eid et al. (2009). Real-time DNA sequencing from single polymerase molecules. Science 323: 133-8.
2. M. A. Quail et al. (2012). A tale of three next generation sequencing platforms: comparison of Ion Torrent, Pacific
Biosciences and Illumina MiSeq sequencers. BMC Genomics 13: 341 .
3. K. Misawa, R. Ootsuki (2015). PAFFT: A new homology search algorithm for third-generation sequencers. Genomics
Poster Session
106: 265-7.
4. K. Katoh, K. Misawa, K. Kuma, T. Miyata (2002). MAFFT: a novel method for rapid multiple sequence alignment based
on fast Fourier transform. Nucleic Acids Res 30: 3059-66.
Mon(2)-P-130
Iterative pruning method of unsupervised clustering for categorical data
1,2
Kridsadakorn Chaichoompu ，Sissades Tongsima 3 ，Philip J Shaw 4 ，Anavaj Sakuntabhai 5,6
，Kristel Van Steen 1,2
1:Montefiore Institute, University of Liege, Belgium、2:GIGA-R, University of Liege, Belgium、3:Genome Technology Research Unit, National
Center for Genetic Engineering and Biotechnology, Thailand、4:Medical Molecular Biology Research Unit, National Center for Genetic
Engineering and Biotechnology, Thailand、5:Functional Genetics of Infectious Diseases Unit, Institut Pasteur, France、6:Centre National de
la Recherche Scientifique, France
Single Nucleotide Polymorphisms (SNPs) are commonly used to identify population structures. Iterative pruning Principal
Component Analysis (ipPCA) utilizes SNP profiles to assign individuals to subpopulations without making assumptions
about ancestry. The strategy can be extrapolated to patient samples to identify molecular classes of patients. It is challenging
to investigate the utility of substructure detection using profiles based on pre-defined genomic regions-of-interest rather
than profiles based on SNPs. Using principles outlined in Fouladi, 2015, we can construct gene-based categorical variables
representing different summary gene profiles in a region. These gene-based new constructs no longer have an equal number
of unordered category levels.
Here, we present C-PCA, an extension of ipPCA to target perform iterative pruning for categorical variables using optimal
scaling. It allows performing non-linear principal component analyses to handle possibly non-linearly related variables with
different measurement levels. To show the power of C-PCA compared to ipPCA, we simulated 500 individuals and assigned
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them to two populations of equal size. We considered genetic population distances using Fixation Index from 0.001 to 0.006.
For each dataset, we simulated 10,000 independent random SNPs for 100 replicates using the Balding-Nichols model. These
were used numerically in ipPCA and as categorical in C-PCA analysis.
In conclusion, like ipPCA, we expect C-PCA to perform well in the presence of fine substructures. This paves the way to apply
C-PCA to DNA-seq data and input categorical variable derived from genomic regions-of-interest to which common and rare
variants are mapped. We foresee additional advantages of C-PCA in this context since region-based categorical variables are
likely to be non-linearly associated at the background of underlying gene-gene interaction networks. C-PCA is implemented
in R and is available at www.statgen.ulg.ac.be/software.html.
Mon(2)-P-131
HLA-HD, a high performance HLA typing algorithm using next generation sequencing results to create
a reliable catalog of HLA alleles
Shuji Kawaguchi 1 ，Koichiro Higasa 1 ，Ryo Yamada 1 ，Fumihiko Matsuda 1
1:Center for Genomic Medicine, Graduate School of Medicine Kyoto University, Japan
HLA molecules play central roles in antigen recognition and immune responses. Because of these functions, HLA genes are
Poster Session
often genetically related to immunopathologies and inflammatory disorders. An accurate HLA typing is essential for genetic
studies of such diseases as well as the selection of donors in organ transplantation and regenerative medicine.
Recently, NGS-based HLA typing has become more and more popular because of the following advantages; 1) high-throughput
data production using massive parallel sequencing technology and 2) each read represents the sequence of a single chromo-
some. Nevertheless, an accurate determination of HLA alleles is still difficult due to the complex genomic nature of this
multigene family locus. More than 90% of HLA alleles registered in the IMGT/HLA Database only cover the groove domain
(G-DOMAIN) which corresponds to the antigen presenting region of the HLA protein. Inaccurate HLA allele calling often
occurs because of the incompleteness of the reference when variations in other regions are also critical for the proper typing.
To circumvent such shortcomings, we have developed a new algorithm called HLA-HD (HLA typing from High-quality Dic-
tionary). This algorithm contains a unique feature of preparing a dictionary of HLA alleles for correct and unbiased mapping
of NGS reads. Then a successive calling algorithm picks up the most appropriate allele pair by taking into consideration the
sequence reads mapped to G-DOMAIN and other exons. HLA-HD can be used for typing of a variety of non-classical HLA
genes as well as classical HLA genes.
The evaluation of HLA-HD by using the WES data of 1000 Genome Project showed an equal or better performance for the
typing of classical HLA class I and class II genes as compared with other NGS-based HLA typing algorithms. Then, HLA-HD
revealed the limitations of conventional PCR-based HLA typing methods. In conclusion, HLA-HD is a useful algorithm to
create a reliable catalog of HLA alleles.
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Mon(2)-P-132
Functional Analysis of Human Methyl-CpG Binding Protein 2 by RNA Silencing and Expression Profiling
1,2,7
Injoo Kim ，Shin Hae Lee 3 ，Jinwoo Jeong 4 ，Jun Hyung Park 5 ，Mi Ae Yoo 6 ，Cheol Min Kim 1,2,7
1:Supercomputing center, Pusan National University, Korea, South、2:Research Center for Anti-Aging Technology Development, Pusan
National University、3:Department of Biological Sciences, Inha University、4:Department of Emergency Medicine, College of Medicine,
Dong-A University、5:Codes Division, Insillicogen, Inc.、6:Department of Molecular Biology, Pusan National University、7:Department of
Medical Informatics, School of Medicine, Pusan National University
Introduction: Methyl-CpG binding protein 2 (MeCP2) is a ubiquitous epigenetic factor that represses gene expression by
modifying chromatin. Mutations in the MECP2 gene cause Rett syndrome (RTT), a progressive neurodevelopmental disorder.
Recent studies have identified a novel role for MeCP2 in carcinogenesis. Specifically, functional ablation of MeCP2 suppresses
cell growth and proliferation of cancer cells. However, MeCP2’s function in adult tissues remains poorly understood.
Therefore, we investigated the role of human MeCP2 (hMeCP2) using RNA silencing and bioinformatics tools. Methods:
First, MeCP2 expression was silenced using annealed siRNA in HEK293 cells, and then a cDNA microarray was performed.
Next, functional analysis and transcriptional levels in target genes regulated by MeCP2 was investigated. Results: Among
the differentially expressed genes with a change in expression greater than two-fold, 189 genes were up-regulated and 91
genes were down-regulated. Genes related to apoptosis and cell proliferation (JUN, FOSL2, CYR61, SKIL, ATF3, BMABI,
BMPR2, RERE, and FALZ) were highly up-regulated. Genes with anti-apoptotic and anti-proliferative functions (HNRPA0,
HIS1, and FOXC1) were down-regulated. Using transcription factor binding site (TFBS) analysis within putative promoters
of novel candidate target genes of MeCP2, tumorigenesis-related transcription factors (TFs) were identified. Conclusions: The
present results provide insights into the new target genes regulated by MeCP2 under epigenetic control. This information
will be valuable for further studies aimed at clarifying the pathogenesis of RTT.
Poster Session
Mon(2)-P-133
MultiDCoX: Algorithm for Multivariate Differential Co-expression Analysis
Herty Liany 1 ，Krishna Murthy R. Karuturi 3 ，Jagath C. Rajapakse 2
1:Genome Institute of Singapore, Singapore、2:Nanyang Technological University、3:The Jackson Laboratory, USA
Abstract
Differential co-expression is the change in the degree of co-expression of a set of genes from one biological condition to an-
other. It has been successfully applied to identify changing interactomes of genes in a variety of biological studies involving
two-group and multi-group analyses in a univariate (single factor) analysis setting. However, no algorithm is available for
direct multivariate (multiple factors) analysis and identification of differential co-expression induced by different covariates
of interest. Multivariate differential co-expression is important in many biological studies as each sample is characterized by
many attributes or factors such as genetic markers, genotypes and treatments.
Results
We developed a novel formulation and computationally efficient algorithm called MultiDCoX to perform multivariate differen-
tial co-expression analysis. MultiDCoX is based on the gene set analysis adjusted for multiple covariates, which is in contrast
to most commonly employed differentially expressed gene pair analysis, followed by linear modelling and computationally
efficient greedy search. The simulations demonstrate that the algorithm can effectively identify differentially co-expressed
(DCX) gene sets and quantify the influence of covariates on the co-expression. The application on a breast cancer dataset has
revealed interesting biologically meaningful differentially co-expressed (DCX) gene sets and the factors that influenced their
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co-expression.
Conclusions
Similar to differential expression, differential co-expression also need to be analyzed in the context of multiple sample covari-
ates. MultiDCoX is a space and time efficient procedure to identify differentially co-expressed gene sets and successfully elicit
quantitative influence of covariates on co-expression of gene sets.
Mon(2)-P-134
Network biology to identify druggable targets for Parkinson’s disease
Jhumur Pani 1 ，Himanshu N Singh 2
1:Cytogenetics, MTA Infotech, India、2:School of Sciences, Noida International University
Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder. Mutations in numerous genes were reported
to be related with Parkinson’s disease, and studying the functional interaction in biological network has been valuable to
identify the druggable target. In present study, a list of 680 genes related to Parkinson’s disease was extracted from
gene-disease association database ’DisGeNET’. Further, undirected biological network model using mathematical graph
theory, was constructed to identify potential druggable targets. The results showed 328 nodes and 823 edges where nodes
denote genes and edges depict their functional interactions. Only 27 nodes (TFB1M, TFB2M, TFAM, FLT, FTH1, FTMT,
Poster Session
MAOA, MAOB, ASCL1, NEUROG2, GAD1, GAD2, RPH3AL, UNC13B, CD93, MBL2, FBN1, LTBP2, MSH, LINGO1,
NQO2, NBO1, CD200, CD200R1, ADH1A, ADH1C, AHD4) were found to be linked with one or two nodes. Nodes with low
connectivity were identified to be the most significant nodes to be considered as potential drug targets. Therefore, identified
27 nodes may be provided as potential therapeutic drug targets; however, further experimental validation is required.
Mon(2)-P-135
Differentially Expressed Genes-At-Risk in Affected Alzheimer’s Brain as Potential Biomarkers
Vishnu Swarup 1 ，Himanshu N. Singh* 2 ，Achal K. Srivastava 1
1:Neurology, All India Institute of Medical Sciences, New Delhi, India、2:Biochemistry, All India Institute of Medical Sciences, New Delhi,
India
Alzheimer’s disease (AD) is a late onset progressive, irreversible neurodegenerative disorder involving variations in expressions
of several genes in different brain regions simultaneously. Therefore, genome-wide expression analysis could be an effective
tool to identify such genes which may be useful for diagnosis and/or therapeutic targets.
The microarray data of six brain regions, entorhinal cortex, superior frontal gyrus, hippocampus, primary visual cortex,
middle temporal gyrus, and posterior cingulate cortex, was retrieved from GEO database. The“affy” package was utilized to
calculate mRNA expressions and t-test (p < 0.01) was applied to find significant differential expression in disease phenotype.
Network analysis was performed to identify potential drug targets for AD therapeutics.
Results showed 25 genes differentially expressed in the disease phenotype simultaneously among all studied brain regions.
Out of 25 genes, 14 genes were upregulated and 7 genes were downregulated in all the brain regions. Remaining 4 genes were
found to be upregulated in all brain regions except entorhinal cortex. Clustering analysis revealed that majority of genes
was belonging to either enzymes or their modulators (10), nucleic acid binding proteins (5), and cytoskeleton proteins (4).
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Network analysis showed six genes as potential therapeutic targets which were observed to be upregulated in all the brain
regions simultaneously and majorly affecting signaling pathways of the cell.
Therefore, identified genes can be used for the AD diagnosis/prognosis and few could be potential therapeutic targets.
However, further experimental validation is required.
Mon(2)-P-136
Publically available bioinformatics resources point to novel functions and epigenetic regulation of
BMP8A: a potential role in air quality-related peripheral arterial disease pathogenesis
Cavin K Ward-Caviness 1,2 ，Lucas M Neas 3 ，Colette Blach 2 ，Carol S Haynes 2 ，Karen LaRocque-Abramson 2 ，
Elizabeth Grass 2 ，Elaine Dowdy 2 ，Robert B Devlin 3 ，David Diaz-Sanchez 3 ，Wayne E Cascio 3 ，
Marie Lynn Miranda 4 ，Simon G Gregory 2 ，Svati H Shah 2,5 ，William E Kraus 2,5 ，Elizabeth R Hauser 2,6,7
1:Helmholtz Institute Munich, Germany、2:Duke Molecular Physiology Institute, Duke University Medical Center、3:National Health
and Environmental Effects Research Laboratory, US Environmental Protection Agency、4:National Center for Geospatial Medicine, Rice
University、5:Division of Cardiovascular Medicine, Duke University Medical Center、6:Department of Biostatistics and Bioinformatics,
Duke University Medical Center、7:Cooperative Studies Program Epidemiology Center-Durham, Veterans Affairs Medical Center
Peripheral arterial disease (PAD) is a common vascular disease characterized by atherosclerosis in the peripheral arteries,
and is associated with heart disease and death. We previously performed a genome-wide gene-by-traffic-related air quality
interaction study (GWIS) for PAD. This analysis identified 6 variants in the BMP8A 3’-untranslated region; each was
nominally associated with PAD (P < 0.05) via the interaction term, with rs755249 associated at a genome-wide significant
Poster Session
level (P = 2.29x10-8 ). We then used in silico methods to evaluate the regulatory potential of these variants. We identified
tissue-specific eQTLs via the Genotype Expression database (GTEx). To date, researchers have associated BMP8A with
spermatogenesis, and all 6 variants were eQTLs for BMP8A in testis tissue (P =2.3x10-6 - 2.0x10-7 ). However, the 6 variants
were significant BMP8A eQTLs in 7 additional tissues: tibial nerve, heart - left ventricle, heart - atrial appendage, esophagus
muscularis, brain-cortex, tibial artery, and subcutaneous adipose. The variants were consistently associated with BMP8A
expression in tibial nerve, with 5 of the 6 variants associated (P = 1.2x10-5 - 5.5x10-7 )— including rs755249 (P = 3.6x10-6 ).
Five of the 6 variants either introduced or removed a CpG site, implicating epigenetics as a mediating factor. Combining
sequence examination, GTEx, and bisulfite sequencing data from the Epigenome Roadmap consortium, we observed that the
rs755249 locus is methylated in esophagus muscularis tissue, the variant is a BMP8A eQTL (P = 1.5x10-5 ), and it removes the
CpG site. Additionally, the rs3738676 locus is methylated in adipose tissue, is a BMP8A eQTL in adipose tissue (P = 3.7x10-6 ),
and the minor allele removes this CpG site. Thus, the GWIS results and in silico analyses provide evidence that multiple
PAD-associated variants regulate BMP8A expression in several diverse tissues, likely in an epigenetically mediated manner.
Mon(2)-P-137
Kinship-assisted variant filtering for exome sequencing analysis of extended pedigrees
Evangelos Bellos 1 ，Lachlan Coin 1,2
，Vanessa Sancho-Shimizu 3,4
，Michael Levin 3
1:Genomics of Common Disease, Imperial College London, UK、2:Institute for Molecular Biosciences, University of Queensland、3:Section
of Paediatrics, Faculty of Medicine, Imperial College London、4:Section of Virology, Faculty of Medicine, Imperial College London
Whole-exome sequencing (WES) has proved to be a powerful tool for elucidating rare Mendelian disorders that tend to be
disproportionately affected by coding mutations. By combining the unbiased variant detection of sequencing technologies with
the efficiency of microarray platforms, WES has revolutionized the field of clinical genetics. Nevertheless, the comprehensive
nature of WES translates into a plethora of coding variants detected per sample, which complicates downstream biological
interpretation. Even in healthy control samples, WES can identify hundreds of variants that are predicted to be loss-of-
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function. Therefore, it is essential to filter WES-generated results in order to distinguish causative variants from neutral and
incidental findings that are unrelated to the phenotype of interest. WES of pedigrees with multiple probands has the potential
to substantially narrow down the scope by focusing solely on shared variation among related samples. Even in that case,
however, probands might share seemingly deleterious variants due to population structure and not due to recent common
ancestry. To that end, we propose a probabilistic framework for disentangling variants that are identical-by-state from those
that are identical-by-descent (IBD). This framework utilizes genealogical relatedness and an efficient algorithm for identifying
overlapping genomic segments among multiple samples. The results are used to restrict downstream analyses to variants that
belong to IBD segments. We have benchmarked our approach using a simulated WES pedigree, achieving a reduction of up
to 45% in the number of candidate variants. We have also demonstrated the advantages of our method on a real pedigree
with three first cousins who suffered from invasive meningococcal disease. All in all, our algorithm implements a key filtering
step that can aid the identification of truly causative mutations and reduce the need for functional validation experiments in
familial WES studies.
Mon(2)-P-138
NGS Library Prep Methods to Achieve Comprehensive Coverage for WGS and Targeted Sequencing at
Low DNA Input Quantities, Including FFPE Samples
Matthew Hymes 1 ，Laurie Kurihara 1
1:Swift Biosciences, USA
Poster Session
When performing whole genome sequencing (WGS) or targeted sequencing using hybridization based capture, unbiased, even
coverage of the genome is required in order to conduct comprehensive analysis from the lowest possible sequence read depth.
Highly efficient conversion of DNA fragments into library molecules is also necessary when DNA input quantity or quality is
limited. We have developed a library preparation method to achieve these results with high quality DNA as well formalin-
fixed, paraffin-embedded (FFPE) samples.
This method uniquely repairs damage on both the 3’and 5’termini to enhance ligation efficiency to sheared DNA fragments.
Combined with sequential ligation steps that optimize attachment to each terminus, this single tube ‘with bead’ method
supports PCR-free sequencing from inputs as low as 10 ng circulating, cell-free DNA (cfDNA) or 100 ng physically sheared
DNA. Input quantities down to 10 pg can be used with PCR amplification. Efficiency of library conversion is ~ 50% for
physically sheared DNA and up to 90% for circulating, cfDNA. Human WGS using this method demonstrates high complexity
with exceptional coverage of GC-rich promoter regions compared to other methods. With inputs as low as 1 ng human DNA
at 18X coverage, the genome was fully represented without loss of data or reduction in relative coverage of GC-rich promoter
regions.
For hyb capture enrichment, our method demonstrates a reduction of duplicate reads from inputs at 10 ng and 1 ng as
compared to other library preparation methods. Paired with an exome panel we observed 5% and 26% duplicates with 10
ng and 1 ng inputs respectively. Coverage uniformity was also preserved at these low inputs. Performance was maintained
with FFPE samples using the same input quantities from an AML cancer panel. This library preparation method creates a
practice for analyzing low-input samples, including poor quality FFPE materials.
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Poster Session
Clinical Genetics and Dysmorphology 1
Mon(2)-P-139
Comprehensive Genetic Screening of GJB2 , GJB6 and SLC26A4 among Non- Syndromic Hearing Loss
Patients in Eastern part of India
Bidisha Adhikary 1 ，Subhradev Biswas 2 ，Madhusudan Das 1 ，Silpita Paul 3
1:Zoology, University of Calcutta, India、2:IPGME &R, Kolkata、3:Department of Zoology University of Calcutta
Genetically caused deafness is highly heterogeneous disorder, affecting one in 500 new born. The diversity of genes and genetic
loci implicated in hearing loss defines the complexity of the genetic basis of hearing. In spite of this large heterogeneity,
mutations in the genes GJB2, GJB6 and SLC26A4 are major contributors. The mutation spectrum of these genes varies
among different ethnic groups. Few studies have focused on the southern and western regions of India related to this disease,
however, no such data is available from the eastern part of our country. Mutations in GJB2, GJB6 and SLC26A4 genes were
screened by bidirectional sequencing from 215 congenital non-syndromic hearing loss patients. The study revealed that 4.65%
and 6.97 % patients had mono-allelic and bi-allelic GJB2 mutations respectively. Six mutations were identified, p.W24X being
the most frequent one accounting for 71.05% of the mutated alleles. Mutations in GJB6 including the previously identified
Poster Session
deletion mutation (GJB6-D13S1830) were not identified in our study. Further, no patients harbored bi-allelic mutations in the
SLC26A4 gene or the common inner ear malformation Enlarged Vestibular Aqueduct (EVA).The mutation profile of GJB2
in our study is distinct from other parts of India, suggesting that the mutation spectrum of this gene varies with ethnicity
and geographical origin. The absence of GJB6 mutations and low frequency of SLC26A4 mutations suggest that additional
genetic factors may also contribute to this disease.
Mon(2)-P-140
Clinical and genetic study of cleft lip with or without cleft palate and its association with Interferon
regulatory factor 6 polymorphism in Egypt
1
Amira M. Nabil
1:Human Genetics, Medical Research Institute, Egypt
Orofacial clefts (OFC), comprising cleft lip with or without cleft palate and isolated cleft palate are the most common
congenital craniofacial malformations. Approximately 70% of cases of CL/P occur as isolated abnormalities. The majority
of non-syndromic CL/P cases are considered multifactorial in etiology. The remaining 30% occur as part of a syndrome
in which CL/P is only one manifestation. Several studies have demonstrated that non syndromic CL/P may be associated
with variation on Interferon regulatory factor 6 (IRF6) gene on 1q32.2 in several populations.The aim of the work was to
study different syndromes in which CL/P is one of the predominant features among a group of Egyptian patients. This will
allow proper diagnosis, management and genetic counseling and to assess the association of IRF6 polymorphism with non-
syndromic (isolated) CL/P.The study was conducted on 55 unrelated patients with cleft lip with or without cleft palate either
isolated, syndromic or association, and a number of healthy Egyptian controls. Only the patients with isolated NSCL/ P were
included in the molecular study using PCR/RFLP for detection of rs 2235371 (820G>A) IRF-6 polymorphism.Results and
conclusions : According to the underlying etiology of cleft lip/palate , the studied cases were categorized into three groups : 36
Isolated, 16 Syndromic and 3 association.For the point mutation polymorphism 820G>A, the obtained results revealed lack
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of association between IRF6 - rs2235371 (820G>A) polymorphism and isolated CL/P and thus this variant seems to be
not proper candidate for etiology of NSCLP at least in Egyptian patients. Sixteen cases were diagnosed as syndromic cleft
lip/palate cases, 5 cases were monogenic mendelian disorders, 5 case were sequence with 4 cases of chromosomal etiology, and
2 unrecognizable syndromes.
Mon(2)-P-141
Syndromic DSD; A study of 30 Egyptian cases using cytogenetic techniques
Mona A El Gammal 1 ，Inas M Mazen 1 ，Alaa K Kamel 1 ，Ahmed M Torky 1
1:Clinical Genetics, National Research Centre, Egypt
Abstract:
Background: Sexual development is a complex process that involves many genes, pathways and interactions. Disorders of
sex development (DSD) can result from a number of causes, some of which might cause an isolated disorder in the gonads
while others may result in developmental syndromes“Syndromic DSD”; causes include gene defects, defects in biochemical
Poster Session
pathways or unidentified causes. Results: over 3 years we collected 30 cases of “Syndromic DSD” and were studied by
conventional karyotyping and FISH, selected cases had molecular testing done when it was feasible. Twelve cases showed
chromosomal anomalies and 18 cases showed a normal karyotype; 4 of which were diagnosed clinically. Conclusion: Syndromic
DSD should be addressed with a more global approach than isolated DSD, Cytogenetic techniques should be the first line of
diagnosis and clinical judgment should direct molecular testing when needed. Correlation of the genotype to the phenotype
of these complex cases is not always possible particularly in cases with chromosomal aberrations as the phenotype may vary
based on the length of affected segment.
Mon(2)-P-142
Clinical and Cytogenetic Studies of Patients with Sex Chromosome Disorders of Sex Development (DSD)
1
Aya AB. Elaidy
Sex chromosome DSD is one of the three main categories of DSD. This study was conducted on patients collected from Clin-
ical Genetics and Endocrinology Clinics at National Research Centre over a period of one year to assess the frequency of sex
chromsome DSD and evaluate phenotype-genotype correspondence. Patients were subjected to thorough clinical examination
and cytogenetic investigations.
Cytogenetic analysis revealed that sex chromosome DSD represented 44% of total referring DSD patients, categorized into
two main groups; X chromosome abnormalities (56.3%) and Klinefelter syndrome (43.8%).
By phenotype genotype correspondence,Klinefelter syndrome presented post pubertal with primary infertility while prepu-
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bertal presented with features like dysmorphism, genital ambiguity and delayed milestones of development.
Short stature was a cardinal feature in patients with complete or partial X chromosome monosomy, either in pure or mosaic
forms. Patients with 45,X, in mosaicism with X chromosome, all reared as females, presented postpubertal with primary
amenorrhea.
Patients with 45,X, in mosaicism with Y chromosome, three patients, all had SRY +ve signal by FISH; one patient reared as
a female, presented with short stature and delayed puberty, was advised to do laparoscopy to exclude the risk of gonadoblas-
toma and the other two patients were reared as males presented with genital ambiguity and cryptorchidism; pathology reports
confirmed the diagnosis of mixed gonadal dysgenesis in one patient and ovotesticular DSD in the other.
One patient had trisomy X and presented with dysmorphic features which needs further study for X methylation.
In conclusion, this study reported a high frequency of sex chromosome DSD among total Egyptian DSD patients. Phenotype-
genotype correspondence revealed wide diversity in presenting features among different age groups which confirms the effect
of sex chromosomes on somatic development alongside their crucial role in sex development.
Mon(2)-P-143
A PLK4 mutation causing azoospermia in a man with Sertoli cell-only syndrome
Poster Session
Toshinobu Miyamoto 1 ，Yoshio Bando 2 ，Eitetsu Koh 3 ，Akira Tsujimura 4 ，Yasushi Miyagawa 4 ，Masashi Iijima 3 ，
Mikio Namiki 3 ，Masaaki Shiina 5 ，Kazuhiro Ogata 5 ，Naomichi Matsumoto 6 ，Kazuo Sengoku 1
1:Obstetrics and Gynecology, Asahikawa Medical University, Japan、2:Functional Anatomy and Neuroscience, Asahikawa Medical
University、3:Urology, Kanazawa University Graduate School of Medical Science、4:Urology, Osaka University Graduate School of Medicine、
5:Biochemistry, Yokohama City University Graduate School of Medicine、6:Human Genetics, Yokohama City University Graduate School
of Medicine
About 15% of couples wishing to have children are infertile; approximately half these cases involve a male factor. Polo-like
kinase 4 (PLK-4) is a member of the polo protein family and a key regulator of centriole duplication. Male mice with a
point mutation in the Plk4 gene show azoospermia associated with germ cell loss. Mutational analysis of 81 patients with
azoospermia and Sertoli cell-only syndrome (SCOS) identified one man with a heterozygous 13-bp deletion in the Ser/Thr
kinase domain of PLK4 . Division of centrioles occurred in wild-type PLK4 -transfected cells, but was hampered in PLK-4 -
mutant transfectants, which also showed abnormal nuclei. Thus, this PLK4 mutation might be a cause of human SCOS and
nonobstructive azoospermia.
Mon(2)-P-144
Two cases of monosomy of 3q with cerebral MRI findings
Yuri Dowa 1 ，Kiyoko Sameshima 2 ，Kenji Ichinomiya 3 ，Takashi Shiihara 1 ，Keiko Shimojima 4 ，Toshiyuki Yamamoto 4
1:Department of Neurology, Gunma Children’s Medical center, Japan、2:Devision of Medical Genetics, Gunma Children’s Medical Center、
3:Department of Neonatology, Gunma Children’s Medical Center、4:Tokyo Women’s Medical University Institute for Integrated Medical
Sciences
Owing to chromosomal microarray techniques, new submicroscopic unbalanced chromosomal rearrangement syndromes are
identified. 3q- syndrome was regarded as deletion from q27 or q28 to terminal region. But recently, 3q26.33-3q27.2 microdele-
tion constituted a new clinically recognizable syndrome.
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Case 1: A 2 year-old boy visited our hospital to diagnose the underlying disease. He was born at 33 weeks and 6 days of
gestation by caesarean section due to fetal distress. His birth weight was 1870g. He presented blepharophimosis, left ptosis,
micrognathia, and low set ears. In neonatal period, he showed pyloric stenosis and pulmonary stenosis. His MRI brain image
at 2 years and 10 months of age showed bilateral patchy T2 high intensity areas in deep white matter. Growth parameters and
development were delayed: head control was achieved at 15 months of age, walk at 5 years old, but no verbal communication
at 6 years of age. G-banded chromosomal test was reported as 46,XY,del(3)(q26.2q26.3). Human Genome CGH Microarray
Kit 60K (Agilent) detected 5.3 Mb microdeletion, not including SOX2 (3q26.33). His parents had normal karyotypes.
Case 2: A newborn baby was admitted a neonatal intensive care unit of our hospital because of low birth weight. She was
born at 36 weeks and 1 day of gestation and her birth weight was 1368g. She presented down slanted palpebral fissures,
micrognathia, and excess costal bones. She also presented apnea, laryngomalacia, gastroesophageal reflex growth retardation
and developmental delay. She often vomited, so she was fed by esophagogastroduodenal tube. Her MRI brain images showed
delay of myelination, volume loss of white matter, and thinning of corpus callosum. G-banded chromosomal test was reported
as 46,XX,del(3(q26.2q27)or del(3)(q26.3q29).
[Discussion]According to previous reports, cerebral MRI findings are rarely described. These are the first cases showing diffuse
white matter abnormal lesions in their brains.
Mon(2)-P-145
De novo 4q31.21 delection and 9q34.2 duplication in the same patient. A case report
Poster Session
1,2 1,2 1,2 2,3
Matías Pérez ，Margarita Martínez ，Adelardo Mora ，Amanda González
1:Unidad de Genética. Servicio de Análisis Clínicos., Hospital Virgen de las Nieves. Servicio Andaluz de Salud, Spain、2:Instituto Biosanitario
de Granada. Granada. Spain、3:FIBAO. Hospital Clínico San Cecilio. Granada. Spain
Structural aberrations of chromosomes are associates with various syndromes, although there are a lot of chomosomal gains
and losses that are not yet associated with a specific syndrome. Most of the cases are the novo, few cases are due to unbalanced
rearraments and others are inherents.
We present a thirteen months-old boy with microcephaly, trigonocephaly, plagiocephaly and speach and motor delay. He was
born at 36 gestation week in a gemelar pregnancy obtained by in vitro fertilization from healthy parents. Her gemelar brother
have not detectable pathology.
Karyotype in leucocites was normal (46;XY). Comparative Genomic Hybridization (CGH-Array) with the Nimblegen CGX
Cytogenetic Microarrays platform, suplied by PerkinElmer, was performed for the patient, parents and brother.
The CGH- Array was normal en both parents and brother, but the patient presented a delecction of 3,04 Mb in 4q31.21
and a duplication of 212,03 Kb in 9q34.2 (arr[hg19] 4q31.21(143,272,775-146,310,106)x1,9q34.2(137,103,263-137,315,288)x3
Abnormal Male). Both duplication and delecction are“de novo” and no previously described. The 4q31.21 delection have 14
genes included (11 OMIM) and with a high probability pathologic. The 9q34.2 duplication including the RXRA OMIM gene,
without triplosensitivity previously descrived, can be pathologic alone or in conjuntion whith another chromosomal aletration
or can be a polimorfism.
Chromosomic aberrations detected“de novo”and no previously described can be dificult to determine his pathologic potential,
and it is necesary to have in mind the patient pathology and genes involved in the delecction/duplication . In our case we
believed that both chromosomal alteration detected, alone or in conjuntion will be responsible of the patient pathology.
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Mon(2)-P-146
A case of 45,X male
Shinsuke Ninomiya 1 ，Noriko Tanaka 2
1:Department of Clinical Genetics, Kurashiki Central Hospital, Japan、2:Department of Pediatrics, Kurashiki Central Hospital
Introduction
45,X males have rarely been described. This peculiar karyotype mostly results from Y;autosome chromosome translocations
allowing for the presentation of Yp or at least of SRY. Clinical findings depends on the amount of Y euchromatin present
and on whether or not an euchromatic autosomal deletion has occurred. We report the third case of a Y;21 translocation in
a 45,X male patient who represents short stature and mild mental retardation.
Patient
The 12-year-old boy was referred to our hospital due to the short stature and mild mental retardation. His height was 131.5cm
(-3.0SD), weight 25.6 kg. There was no family history of congenital malformations, short stature, or mental retardation. His
external genitalia made no doubt of male.
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Cytogenetic analysis
Chromosome analysis was done on lymphocyte metaphases from this patient using routine GTG-banding. FISH study was
carried out by SRY probe, whole chromosome paint 21, SHOX, DYZ3, DAZ, and DYZ1. The sample of his parents was not
available.
The karyotype of this patient
45,X,-Y.ish der(21)t(Y;21)(p11.1;p11.1)(SHOX+,SRY+,DYZ3+,DAZ-,DYZ1-)
Discussion
1.SHOX and SRY existed on 21p in this patient. GCY (growth control gene(s) on the Y chromosome) probably contributes
to his short stature.
2.When the Y material is translocated on acrocentric chromosome there is usually no mental retardation. But this case has
mild mental retardation. Detail analysis including copy number changes has to be needed for clearing the cause.

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Mon(2)-P-147
Dosage changes of NIPBL cause various types of neurodevelopmental disability
Chihiro Hatano 1 ，Takayuki Yokoi 1 ，Yumi Enomoto 1 ，Yoshinori Tsurusaki 1 ，Toshiyuki Saito 2 ，Junichi Nagai 2 ，
Kenji Kurosawa 1
1:Division of Medical Genetics, Kanagawa Children’s Medical Center, Japan、2:Department of Clinical Laboratory, Kanagawa Children’s
Medical Center
Microduplication of 5p13 has been reported since 1980s. NIPBL is reported to be a key gene of this syndrome, and the
phenotype is completely different from the syndrome with the deletion. The major symptoms include developmental delay,
learning disability, autistic behaviors, and distinctive faces. Here we report a female patient caused by a duplication of 0.48Mb
in 5p13.2 including NIPBL gene.
She was born to nonconsanguineous parents at 37 weeks of gestation. Her birth weight was 2298g (-1.0SD), length 46cm (-
0.58SD), and the head circumference 27.5cm (-3.4SD). She had depressed nasal root, hypertelorism, and low-set ears. She had
scoliosis, but no other anomalies were detected by abdominal ultrasound sonography. She was able to roll at 9 months old, and
could not crawl at 11 months old. Her standard karyotyping revealed normal, 46,XX. We performed cytogenetic microarray
analysis, which revealed a 0.48Mb interstitial duplication at 5p13.2, extending from position36,809,705-37,292,146bp from 5p
terminal (hg19).
NIPBL has broad roles in sister chromatid cohesion, condensation, and DNA repair. Loss of function and haploinsufficiency of
NIPBL result in Cornelia de Lange syndrome, whereas duplication causes candidate features of chromosome 5p13 duplication
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syndrome (OMIM #613174). The fact indicates that NIPBL is a dosage-sensitive gene for developmental regulation. These
results suggest that dosage balance of cohesins and related factors is essential for neuronal development.
Mon(2)-P-148
Clinical and neuroimaging findings of an incomplete form of Moebius syndrome
Mitsuo Masuno 1 ，Kiyoshi Matsui 2 ，Koji Tanoue 2 ，Noriko Aida 3 ，Yuta Fujii 3 ，Makiko Ohyama 4 ，Jun Shibasaki 4 ，
Yasuko Yamanouchi 1 ，Kenji Kurosawa 5
1:Genetic Counseling Program, Graduate School of Health and Welfare, Kawasaki University of Medical Welfare, Japan、2:Division of General
Medicine, Kanagawa Children’s Medical Center、3:Division of Radiology, Kanagawa Children’s Medical Center、4:Division of Neonatology,
Kanagawa Children’s Medical Center、5:Division of Medical Genetics, Kanagawa Children’s Medical Center
BACKGROUND: Moebius syndrome is characterized by congenital, nonprogressive facial weakness with limited abduction
of one or both eyes and complicated by other cranial nerves involvements. We present here 3 patients with an incomplete
form of Moebius syndrome, showing congenital bilateral facial nerve paralysis and other cranial nerves involvements without
adductive nerve paralysis.
METHODS: Clinical data were reviewed for 3 patients. Perinatal history, neurological examination, comorbid anomalies,
medical home care and neuroimaging findings were summarized.
RESULTS: Two female and 1 male patients were 1 year old (death from aspiration), 7 years old, and 18 years old, respectively.
Pregnancy and delivery : one of monochorionic diamniotic twins (2 patients), polyhydramnios (1), cesarean section (2).
Neonatal characteristics : Apgar score 1/6, 8/9, 0/3, NICU admission (3), respiratory resuscitation (3), ventilator (1),
CPAP (2). Clinical characteristics : hypotonia (3), stridor (2), insufficient sucking and swallowing (3), jaw ankylosis (3),
micrognathia (2), hypoplastic tongue (2), tongue fasciculations (1), nasal dysarthria (2), poor coordination (2), walks with
limitations (1), epilepsy (1), autism (1), DQ or IQ<35 (3), conductive hearing loss (2), talipes planovalgus (2). Medical home
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care : suction apparatus (3), tube feeding and gastrostomy (3), oxygen therapy (1). Neuroimaging : pontine and medulla
hypoplasia (2), hypoplastic corpus callosum (2) on cranial MRI; hypoplasia of cranial nerve VII (2 unilateral, 1 bilateral),
normal cranial nerve VI (3) on constructive interference in steady state MRI sequence. Molecular cytogenetics : Chromosome
analysis using GTG banding (2) and array-CGH (1) showed normal results.
DISCUSSION: The present patients with an incomplete form of Moebius syndrome might be associated with tegmental
watershed infarcts after 12 weeks gestation, compared with those during 9-11 weeks gestation in most cases of Moebius
syndrome.
Mon(2)-P-149
Simpson-Golabi-Behmel syndrome: A prenatal diagnosis in a fetus with GPC3 and GPC4 gene microdu-
plications
Nadja Kokalj Vokac 1,2 ，Faris Mujezinovic 3 ，Danijela Krgovic 1 ，Ana Blatnik 1 ，Natasa Tul Mandic 4 ，
Tina Caks Golec 5 ，Tina Vesnovar Vipotnik 6 ，Boris Zagradisnik 1
1:Laboratory of Medical Genetics, University Medical Centre Maribor, Slovenia、2:Medical Faculty, University Maribor, Slovenia、3:De-
partment of perinatology, Clinic for gynecology and perinatology, University Clinical Centre Maribor, Slovenia、4:Division of Perinatology,
Department of Obstetrics and Gynecology, University Medical Center, Ljubljana, Slovenia、5:Institute of pathology, Faculty of Medicine,
University of Ljubljana, Slovenia、6:Department of Radiology, University Medical Center, Ljubljana, Slovenia
We describe the case of Simpson-Golabi-Behmel syndrome (SGBS) discovered prenataly. Fetal scan in 23rd week of pregnancy
identified male fetus with macrosomia, macrocephalia, dilatation of 3rd and 4th ventricle, hyperechogenic gut, agenesis of
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corpus callosum, cistical dilatated interhemispheric fissura, macrosomic kideny and liver, and kidney polyhydramnion.
Amniocentesis was performed. Molecular kariotyping using ISCA 4x180K arrays reveled two intersticial microduplications
on Xq26.2 in size of 574 kb and 115kb. A larger microduplications encompassed four OMIM genes, including whole GPC4
gene. A smaller microduplications was located within the GPC3 gene and embraced exons 6 and 7 of the longest transcript
of this gene. CNVs were inherited from the mother.
Persons with this SGBS are frequently affected by embrogenic tumors of kidneys. Also the mother had Wilms tumor in her
childhood. The pregnancy was terminated because of ruptured amniotic membrane and amniotic leakage. An autopsy of the
infant confirmed organomegaly seen on ultrasound. In addition, a ventricular septal defect, a complete agenesis of the corpus
callosum, cerebellar hypoplasia were observed. Distinct facial features were also present, including hypertelorism, short nose
with broad nasal bridge, macrostomia and macroglossia, nail hypoplasia, and an extra rib.
GPC3 and GPC4 are the two genes in which mutations are known to cause SGBS. There are only few reports on duplications
of GPC3 gene and one report of duplication of CPG4 gene causing SGBS in the literature. Mostly deletions and mutations
of GPC3 gene are described. In our presentation possible role of two genes involved in SGBS is discussed.
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Mon(2)-P-150
A lethal outcome of Costello syndrome due to a novel pathogenic variant in the HRAS gene - a case
report
Magdalena Pelc 1 ，Agata Skorka 1 ，Elzbieta Ciara 1 ，Dorota Jurkiewicz 1 ，Dorota Piekutowska-Abramczuk 1 ，
Joanna Trubicka 1 ，Paulina Halat 1 ，Krystyna Chrzanowska 1 ，Malgorzata Krajewska-Walasek 1
1:Department of Medical Genetics, The Children’s Memorial Health Institute, Poland
Costello syndrome (CS) is a rare RASopathy associated with germline mutations in the HRAS gene encoding a small GTPase
from the Ras family. In >80% of patients, mutations are clustered in codons 12 and 13 of HRAS and correlate with a typical,
relatively homogenous CS phenotype. So far, rarer variants occurring in other H-RAS residues have been associated with less
characteristic or attenuated CS features.
Here we report on an infant (Caucasian male) with a fatal course of CS in whom we identified a novel de novo pathogenic
variant c.179G>T (p.Gly60Val) in the switch II region of HRAS. At 4 weeks of age he had small VSD, PFO, and hyper-
trophic cardiomyopathy, but no arrhythmia. The neonatal course was complicated by grade IV bilateral intraventricular and
parenchymal hemorrhages. At age 3 months he presented with severe failure to thrive, loose and wrinkled palmoplantar skin,
and bilateral syndactyly of the second and third toes. The patient had coarse facial appearance, flat, broad nasal bridge,
epicanthal folds, low-set ears, and unilateral cryptorchidism. Due to severe feeding difficulties and persistent vomiting with
poor weight gain, at age 4 months he underwent fundoplication for gastroesophageal reflux and gastrostomy insertion. Nev-
ertheless, due to congestive heart failure and extreme malnutrition the child died at 8 months of age.
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Recent literature data suggest that mutations in codon 60 of HRAS cause an attenuated CS phenotype (i.e. p.Gly60Asp),
probably due to a distinct pathomechanism. However, our case and two other reported cases: a fatal course of RASopathy
associated with p.Gly60Val in another GTPase, K-RAS, and a typical RASopathy presentation observed for p.Gly60Glu in
N-RAS, indicate that a broader (also severe) phenotypic spectrum correlates with this region of Ras. Additional studies are
needed to elucidate the functional consequences of changes in residue 60 of Ras.
The research was supported by projects: NSC UMO-2011/03/N/NZ2/00516, CMHI S140/2014.
Mon(2)-P-151
Distinct skeletal phenotypes in a Korean boy with SOFT syndrome caused by compound heterozygous
mutations in POC1A
1,2
Jung Min Ko ，Soyoon Jung 1 ，Jeeun Seo 3 ，Choong Ho Shin 1 ，Murim Choi 2,3
，Tae-Joon Cho 4
1:Pediatrics, Seoul National University Hospital, Korea, South、2:Research Coordination Center for Rare Diseases, Seoul National University
Hospital、3:Biomedical Sciences, Seoul National University、4:Orthopedic Surgery, Seoul National University Hospital
SOFT syndrome is an extremely rare genetic dwarfism, which is characterized by short stature, onychodysplasia, facial
dysmorphism, and hypotrichosis. Since the causative gene, POC1A, was identified in 2012 by whole exome sequencing, only
about 10 patients with SOFT syndrome have been reported. Moreover, all the reported patients carried homozygous variants,
which were associated with consanguineous marriages in peoples of Arabic or Turkish ethnic backgrounds. POC1A is thought
to play a core role in centromere function of the primary cilia during cell division, and mutations of POC1A might result in
interference with the mitotic spindle formation during growth and development of skeletal and ectoderm-origin tissues and
lead to characteristic clinical manifestations. Therefore, SOFT syndrome could be considered as ciliopathy. Here, we report
a 9-year old boy with SOFT syndrome, who was born small for gestational age, skeletal dysplasia, profound short stature
resistant to growth hormone therapy, and sparse hair. Whole exome sequencing identified two novel compound heterozygous
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variants in POC1A from an outbred population, likely to impair the gene function in a recessive manner.
Mon(2)-P-152
Cerebellar vermis hypoplasia in CHARGE syndrome: clinical and molecular characterization of 18 unre-
lated Korean patients
Jung Min Ko 1 ，Young Bae Sohn 2 ，Choong Ho Shiin 1 ，Sei Won Yang 1 ，Jong Hee Chae 1 ，Jae-hyung Kim 3
1:Pediatrics, Seoul National University Hospital, Korea, South、2:Medical Genetics, Ajou University Hospital、3:Ophalomolgy, Chungbuk
National University Hospital
CHARGE syndrome (OMIM 214800) is a rare autosomal-dominan congenital malformation syndrome that results from
haploinsufficiency of the chromodomain helicase DNA-binding protein 7 (CHD7). We performed a phenotypic characterization
and genetic analysis of CHD7 in 18 Korean patients with CHARGE syndrome. Eighteen unrelated Korean patients (10 females
and 8 males; age range 0.0-19.6 years) with CHARGE syndrome were enrolled. Clinical data were collected by retrospective
review of medical records. A serial analysis via sequencing and multiple ligation-dependent probe amplification of CHD7 was
performed to determine the molecular genetic spectrum of the patients. The prevalence of cardinal symptoms was as follows:
coloboma (13/18, 72.2%), heart defects (13/18, 72.2%), choanal atresia/stenosis (4/18, 22.2%), retarded growth (10/18,
55.6%), genital anomalies (15/18, 83.3%) and ear abnormalities (18/18, 100%). Five patients had cerebellar vermis hypoplasia
(5/17, 29.4%) with no clinical symptoms or signs of cerebellar dysfunction. Furthermore, we identified genetic alterations in
all
18 patients, including 10 novel mutations. Considering its frequency among patients with CHD7 mutations, cerebellar vermis
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hypoplasia may be a clinical diagnostic clue of CHARGE syndrome, although it is not included in the diagnostic critieria.
And,
the identification of CHD7 mutations may help the confirmative diagnosis.
Mon(2)-P-153
Similarities of the Ectodermal dysplasia, hypohidrotic, with hypothyroidism and agenesis of the corpus
callosum (OMIM 225040) and cardio-facio-cutaneous syndrome (OMIM 115150)
Masaharu Moroto 1 ，Tomohiro Chiyonobu 2 ，Sachiko Tokuda 2 ，Kitaro Kosaka 2 ，Shigemi Morioka 3 ，
Toshiyuki Yamamoto 4 ，Yoko Aoki 5 ，Masafumi Morimoto 2
1:Department of Pediatrics, Fukuchiyama City Hospital, Japan、2:Department of Pediatrics, Graduate School of Medical Science, Kyoto
Prefectural University of Medicine、3:Department of Pediatrics, Fukui Aiiku Hospital、4:Tokyo Women’s Medical University Institute for
Integrated Medical Sciences、5:Department of Medical Genetics, Tohoku University School of Medicine
We report a case diagnosed with cardio-facio-cutaneous (CFC) syndrome. The diagnosis was delayed because of its similarity
to Ectodermal dysplasia, hypohidrotic, with hypothyroidism and agenesis of the corpus callosum. Several symptoms overlap
the two syndromes, including mental retardation, growth deficiency and ectodermal abnormalities.
The patient was the third child of a non-consanguineous marriage. Her two older siblings are normal. At a gestational age of
33 weeks, she was delivered at 2271g via cesarean section. After NICU admission, she suffered respiratory disturbance and
temporary cholestasis. Other problems were corpus callosum agenesis, ventricular enlargement and pulmonary stenosis.
She was given levothyroxine from age 8 months for hypothyroidism. At 2 years 6 months she started growth hormone
injections. She has hearing difficulty and psychomotor retardation.
On physical examination at 7 years old, her height was 98.5 cm (-4.1SD), and weight was 15.1 kg (-1.9SD). She had distinctive
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craniofacial features, including sparse scalp hair and eyebrows, prominent forehead, depressed nasal bridge, low-set ears, high
palate and cleft uvula. She also had prominent nipples and extremely dry skin. Her symptoms and clinical course matched the
Ectodermal dysplasia, hypohidrotic with hypothyroidism and agenesis of the corpus callosum. She has 46,XX chromosomes.
Array CGH revealed no abnormality. She was identified to be heterozygous for c.1406G>A (p.G469E) mutation in BRAF ,
eventually diagnosed with CFC syndrome.
CFC syndrome was first described in 1986. On the other hand, Ectodermal dysplasia, hypohidrotic with hypothyroidism and
agenesis of the corpus callosum was reported until 1996. The relation between the time of the appearance of CFC syndrome
and the disappearance of Ectodermal dysplasia, hypohidrotic with hypothyroidism and agenesis of the corpus callosum,
therefore, suggests that these two syndromes are the one and the same.
Mon(2)-P-154
A musical pathway to improve some cognitive functions in Williams syndrome
Lilian M J Albano 1 ，Rachel S Honjo 1 ，Michele M Nunes 1 ，Leslie D Kulikowski 1 ，Stephanie P Pegler 1 ，
Diogo C Q Soares 1 ，Jose R M Ceroni 1 ，Debora R Bertola 1
1:Pediatrics, Instituto da Crianca, Brazil
Williams syndrome (WS) is a developmental genetic disorder caused by a hemizygous microdeletion on chromosome 7q11.23.
Clinical features include characteristic facies, cardiovascular disease, and mental delay. Patients show hyperacusis and an
uneven cognitive profile. They have fluent and affective rich oral language, good facial recognition, and a high level of social
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responsiveness. On the other hand, they show impaired visual perception, and poor graphic and motor skills. We have studied
55 WS patients, confirmed by Multiplex Ligation-dependent Probe Amplification  (MLPA  ) using a kit with probes of WS
region (MRC Holland ™ ). The clinical characteristics of these patients were: typical facies (98%), neuropsychomotor delay
(98%), hypersocial behavior (94%), hyperacusis (94%) and congenital heart disease (82%). IQ evaluation was performed in 31
patients and ranged from 51 to 86 (mean 63). All patients showed visuospatial deficit and 22/31 had mild mental retardation.
We gather efforts to bring together 4 patients with special musical skills. All of them play more than one instrument and
also have rhythmic abilities. None is capable neither to follow nor to read a sheet music. One patient plays 13 different
instruments including violin, keyboard, flute, and piano. Two have absolute pitch and one of them has special vocal ability.
The patients’ parents have noticed their musical abilities in the first years of their lives. The first meeting of these 4 patients
resulted in a real and spontaneous concert without any rehearsal. Since WS presents characteristic musical abilities, it may be
a model system for further studies about cognitive and musical skills development, considering both environment and genes
involved in 7q.11.23 microdeletion. Therefore, further studies are required to clarify if the use of music tasks in a customized
educational program for learning may produce cognitive transfer in some neurocognitive abilities.
Mon(2)-P-155
Systemic and craniomaxillofacial characteristics of patients with Williams syndrome
Rina Hikita 1 ，Sahori Matsuno 1 ，Takuya Asami 1 ，Takuya Ogawa 1 ，Yoshiyuki Baba 1,2
，Michiko Tsuji 1 ，
Keiji Moriyama 1
1:Maxillofacial Orthognathics, Tokyo Medical and Dental University, Japan、2:Pedodontics and Orthodontics, National Center for Child
Health and Development
[Introduction and Aims] Williams syndrome (WS; MIM #194050) results from chromosomal deletion (7q11.23), and is
characterized by cardiovascular abnormalities, mental retardation, dysmorphic facial features, and high sociability. Few
reports have described the maxillofacial morphology of WS. Therefore, we investigated the craniomaxillofacial characteristics
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of WS. [Subjects and Methods] Eight Japanese children with WS (2 boys and 6 girls; mean age, 10.3 years) at the Tokyo
Medical and Dental University Dental Hospital (TMDU) and National Center for Children and Mothers were evaluated.
Interview, facial and intraoral photographs, cephalograms, panoramic tomograms, and cast models were obtained for all at
the first visit. [Results] All WS patients showed dysmorphic facial features (periorbital fullness, long philtrum, full cheeks,
and full lips), cardiovascular abnormalities, mental retardation, high sociability, and hyperacusis. The posterior cranial base
was shorter in the WS group than the Japanese norm, and the mean frontal bone thickness was significantly greater in the
WS group than that in the control group [30 healthy Japanese children in TMDU (7 boys and 23 girls; mean age, 10.3
years)]. Half of the WS group showed a retrognathic mandible and high angle and lingual inclination of lower incisors than
the Japanese norm. Pointed chin (deficiency of the chin button) was found in 75% of WS patients. Most WS patients
(87.5%) had a morphological tooth defect (microdontia, peg-shaped tooth, or enamel hypoplasia), and 75% of WS patients
were congenitally missing at least one tooth. The width of the mandibular and maxillary dental arches was narrower than
the Japanese norm. Angle Class II molar relationship was seen in 71.4% of WS patients, and excessive overjet (> +6.0 mm)
in 57.1%. [Conclusions] Our findings may benefit multidisciplinary treatment including pediatrics, genetic counseling, and
dentistry. Further studies are required to confirm these results.
Mon(2)-P-156
Two cases of AIS (androgen insufficiency syndrome) pursued different courses
Yoichiro Fujiwara 1 ，Mayuko Tsubouchi 1 ，Masako Eguchi 1 ，Motoi Inoue 1 ，Sayaka Funaki 1 ，Akino Morisaki 1 ，
Hitomi Oi 1 ，HIroyuki Yamamoto 1 ，Yoshiharu Yamada 1
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1:Department of Obstetrics and Gynecology, Kyoto City Hospital, Japan
In AIS, androgenic development is not established due to the genetic variation of androgen receptor, which results in female
phenotype, absence of uterus and cecal vagina, although its genotype, 46,XY. It is often diagnosed in adolescence by chro-
mosomal analysis because of primary amenorrhea, and genetic counseling(GC) is needed for the patient and her parents.
Furthermore, gonadectomy is suggested to prevent malignant change. Two complete AIS, which were treated after age of
twenties, and one of which had already developed seminoma and needed chemotherapy after gonadectomy, are presented.
Case 1, 23 yo, diagnosed as 46,XY in 14 yo but not informed that time, underwent testetomy after GC. After the operation,
she has decided to live as female gender.
Case 2, 31 yo, diagnosed as MRKH syn. in 11 yo, referred for huge abdominal mass and was suspected ovarian malignancy.
She underwent gonadectomy / lymphadenectomy and diagnosed as stage 2 seminoma. After GC, chromosomal analysis was
suggested and revealed 46,XY. After the operation, she is still refusing to inform her genotype to her family.
In counseling about AIS, it is important to explain about 1. Gender identity, 2. Infertility, 3. Gonadectomy, and 4. Vagino-
plasty.
In our cases, both were grown-up and understood well almost everything but gender identity. Sometimes in establishing
gender identity, they need help from others, especially close family member. In case 1, her parents had already known her
genetic gender, so they often can help her when she has trouble, even in future. But in case 2, she has to cope with any
problems by herself arising in future. Being treated with estrogen therapy, they come to the hospital every several months
and have the chance to be counseled any time. During that time we should offer the precise information about the disease
and support the establishment of their gender identity continuously.
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Mon(2)-P-157
A rare case of mosaic trisomy 7 in a 5 year old child
Danielle K Bourque 1 ，Julien Marcadier 2 ，Melanie Beaulieu Bergeron 1
1:Dept. of Medical Genetics, Children’s Hospital of Eastern Ontario, Canada、2:Clinical Genetics Unit, Alberta Children’s Hospital
We present a female child with mosaic trisomy 7. She was first seen at 5 years 9 months for assessment of developmental
delay, multiple congenital anomalies, and dysmorphic features. She is the product of a healthy second pregnancy of a 42 year
old mother. Her parents are African in origin, non-consanguineous, and the family history was unremarkable. She was born
at term and birth weight was at the 3rd centile. Clinical features included: global developmental delay, multiple congenital
anomalies (large secundum atrial septal defect, intracranial calcifications, and scoliosis), hypermobility, mild dysmorphic
features (prominent bilateral epicanthal folds and a flat nasal root), and extensive Blaschkolinear skin hypopigmentation.
Growth parameters were within normal limits. Prior to assessment in the CHEO Genetics clinic, cytogenomic analyses on
peripheral blood had shown a normal female karyotype and two copy number variants (CNV) of unknown significance by
microarray analysis: a 0.297 Mb triplication of 2q31.1 (involving PDK1 and RAPGEF4 ) and a 0.391 Mb deletion of 6q22.33
(involving PTPRK). Both CNVs were maternally inherited. As her clinical picture was suggestive of mosaicism, a skin biopsy
was obtained for chromosome analysis, which showed mosaic trisomy 7 in 5/30 examined metaphases. Due to the risk of
uniparental disomy after trisomy rescue, UPD testing was performed but was negative. Full trisomy 7 is generally lethal
in early embryonic development and postnatal mosaic trisomy 7 is an exceedingly rare condition. Previous studies have
identified Blaschkolinear skin pigment changes and developmental delay in patients surviving in to childhood; however, the
phenotypic spectrum is not well established. This case highlights the importance of performing analysis on different tissue
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samples, particularly skin, when there is a clinical suspicion of mosaicism as chromosome abnormalities may be restricted to
specific tissues and not be detectable in peripheral blood.
Mon(2)-P-158
CMA Analysis Identifies Homozygous Deletion of MCPH1 in 2 Brothers with Primary Microcephaly-1
Morteza Hemmat 1 ，Melissa J Rumple 2 ，Loretta W Mahon 1 ，melanie Morrow 2 ，Tamara Zach 2 ，Charles M Strom 1 ，
Arturo Anguiano 1 ，Mohamed M Elnaggar 1 ，Boris T Wang 1 ，Fatih Z Boyar 1
1:Cytogenetics, Quest Diagnostics Inc., USA、2:Banner Child Neurology
Homozygous mutations and deletions of the microcephalin gene (MCPH1; OMIM 607117) have been identified as a cause
of autosomal recessive primary microcephaly and mental retardation (Microcephaly 1, primary, autosomal recessive; MIM
#251200). We report the chromosome microarray (CMA) findings and family study of a patient with primary microcephaly.
The proband, a boy born at full term to consanguineous parents from Mexico, presented at 35 months of age with microcephaly
(44-cm head circumference), abnormal brain MRI findings, underdeveloped right lung, almond-shaped eyes, epicanthal folds,
bilateral esotropia, low hairline, relatively large ears, smooth philtrum, thin upper lip, and developmental delay.The proband
had 2 older brothers, ages 14 and 16, from the same consanguineous parents. The 14-year-old brother had a phenotype similar
to that of the proband, while both parents were apparently normal. The SNP-based CMA analysis in the proband detected a
homozygous 250-kb microdeletion at 8p23.2p23.1, extending from 6,061,169 to 6,310,738 bp. This genomic alteration indicates
a homozygous loss (zero copy) encompassing the first 8 exons of the MCPH1 . Follow-up studies detected the same homozygous
deletion in the affected brother, segregating with microcephaly and mental retardation. Regions of allelic homozygosity (ROH)
was also observed in the affected brothers. Since there is an increased risk for recessive disorders, presence of ROH may also
contribute the phenotype of the affected brothers.The parents were both hemizygous for this loss. To our knowledge, this is
the second report of homozygous deletion of the MCPH1 gene resulting in primary microcephaly and mental retardation in
a consanguineous family. This report provides a detailed clinical assessment of the affected brothers and their parents.

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Mon(2)-P-159
Two cases with mosaic trisomy 8 and 9 fortuitously detected by conventional G-banding chromosome
analysisImportance of conventional chromosome analysis to diagnose mosaicism with low frequency
1
Satoshi Ishikiriyama
1:Division of Cytogenetics and Clinical Genetics, Shizuoka Children’s Hospital, Japan
Almost all cases with trisomy 8 and 9 are mosaic. I diagnosed fortuitously two infants with exiguously mosaic trisomy 8 and
9 by conventional chromosome analysis.
The patient 1 was a 2-year- 9 month-old boy. He was referred to me because of mild developmental delay. Then, his DQ
was 82, height 91.2cm(-0.1SD), weight 12.8kg(-0.3SD), respectively. Nothing was particular in his family history. He suffered
from bilateral hydronephrosis due to ureteropelvic stenosis. At birth, his father was 49 years old and his mother 42 years old,
respectively. His birth weight was 2354g, height 45.7cm, head circumference 33.0cm, respectively. Nothing particular was
detected on examination. G banding chromosome analysis revealed his karyotype; 46,XY[28]/47,XY,+8[2].
The patient 2 was an 1-year-10 month-old girl. She was referred to me bcause of moderate developmental delay; DQ39. Then,
her height was 76.4cm(-2.2SD), her weight 8.36kg(-2.0SD), respectively. At birth, her father was 37 years old and his mother
35 years old, respectively. Her birth height was 45cm, birth weight 2128g, head circumference 33cm, respectively. G band
chromosome analysis in neonate revealed normal female karyotype; 46,XX. Nothing was particular in her family history. She
had frontal bossing, sunken eyes, telecanthi, up-slanting palpebral fissures, hypoplastic helix and micrognathia. Repeated G
banding chromosome analysis at three years old revealed her karyotype; 46,XX[28]/47,XX,+9[2].
Poster Session
It is difficult to diagnose mildly affected cases as mosaic trisomy 8 and 9, clinically. I am afraid of overlooking phenotypically
mild cases with exiguously mosaic trisomy 8 and 9. Thought array CGH analysis can detect minute deletions and duplications
on chromosomes, it cannot detect mosaicism with low frequency. So it is important to count chromosomes among more cells in
conventional chromosome analysis to avoid oversight on mosaicism. It is reasonable to dare repeat conventional chromosomal
analysis in specific situation.
Mon(2)-P-160
Structural brain abnormalities associated with deletion at chromosome 2p16.1
Hiroko Shimbo 1 ，Takayuki Yokoi 2 ，Seiji Mizuno 3 ，Hiroshi Suzumura 4 ，Noriko Aida 5 ，Jun-ichi Nagai 6 ，Kazumi Ida 2 ，
Yumi Enomoto 1 ，Chihiro Hatano 2 ，Kenji Kurosawa 2
1:Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama, Japan、2:Department of Medical Genetics, Kanagawa Chil-
dren’s Medical Center, Yokohama、3:Department of Pediatrics, Central Hospital, Aichi Human Service Center, Kasugai、4:Department
of Pediatrics, Dokkyo Medical University School of Medicine, Tochigi、5:Department of Radiology, Kanagawa Children’s Medical Center,
Yokohama、6:Laboratory Medicine, Kanagawa Children’s Medical Center, Yokohama
[Introduction] 2p16.1p15 deletion syndrome (OMIM#612513) is characterized by microcephaly, intellectual disability, delayed
language skills, autistic behavior, growth retardation, gross motor impairment, dysmorphic facies, and structural brain abnor-
malities. More than 20 patients have been reported in the literature with overlapping deletions including this region. Some
cases with 2p16.1p15 deletion have been suggested that haploinsufficiency of the zinc finger transcription factor BCL11A
(MIM*606557) might be one of the critical genes of the neural development. Here, we describe 4 patients with overlapping
deletion in 2p16.1p15 region and review of previously reported cases.
[Methods& Results] Array CGH was performed using the Agilent SurePrint G3 Human CGH Microarray Kit 8×60K (Agilent
Technologies). We have found two patients with a microdeletion of 2p16.1p15 and one with 2p16.1 including BCL11A, and
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one with 2p16.1p14 deletion, not including BCL11A. Clinically, microcephaly, intellectual disability, brain malformation, and
facial abnormalities were showed in all patients. MRI showed cerebellar hypoplasia or atrophy in 2 patients with 2p16.1p15
and slightly smaller size of cerebellum in one patient with 2p16.1 deletion, except a patient with 2p16.1p14 deletion without
BCL11A.
[Discussion] The evidence in our patients with a hemizygous BCL11A deletion has emphasized the importance in brain mat-
uration. Molecular genetic studies have reported that BCL11A interacts with calcium / calmodulin-dependent serine protein
kinase CASK (MIM*300749), a causal gene in mental retardation and microcephaly with pontine and cerebellar hypoplasia
(MICPCH) and the transcription factor TBR1 (MIM*604616), a essential gene for cerebrocortical development. BCL11A
haploinsufficiency might produce microcephaly, cortical dysplasia, and hypoplasia or atrophy of cerebellum.
Mon(2)-P-161
A study of Williams syndrome in children at Siriraj hospital, Bangkok, Thailand
Achara Sathienkijkanchai 1 ，Pattheera Sattabut 1 ，Nithiwat Vatanavicharn 1 ，Pornswan Wasant 1
1:Pediatrics, Faculty of Medicine Siriraj hospital, Mahidol University, Thailand
Background: Williams syndrome (WS) is caused by microdeletion of chromosome region 7q11.23. The clinical phenotypes of
WS include congenital heart disease (CHD), intellectual disability, dysmorphic facies, and hypercalcemia.
Poster Session
Objective: To study the clinical features of WS at Siriraj hospital and to compare with other studies.
Methods: We retrospectively reviewed medical records of WS at our hospital from 1st January 1987 to 1st April 2012. WS was
diagnosed by clinical findings and initial investigation, and then was confirmed by fluorescence in situ hybridization (FISH).
The study information includes clinical presentations, age of onset, family history, behavior, growth and development, were
recorded in case record forms.
Results: Thirteen patients with WS, there were 9 males (69%) and 4 females (31%). The most common clinical presentation
was CHD; 61.5%. The second common presentation was delayed development; 30.8%. The CHD is the earliest presentation
leading to diagnosis of WS. All of WS patients had delayed development. Ten patients with WS performed intellectual testing,
40% had mild mental retardation, 30% had moderate mental retardation and 30% had severe mental retardation. For other
clinical presentations, we found over friendly personality 33.3%, ADHD 16.7%, autistic disorder 8.3%, hypercalcemia 15.4%,
nephrocalcinosis 7.7%, and hypothyroid 7.7%.
Conclusion: The common clinical presentations of WS at Siriraj hospital were congenital heart disease and delayed develop-
ment. Early diagnosis can lead to prevent further complications and optimal genetic counseling for the family.
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Mon(2)-P-162
Chromosomal abnormalities in 1354 Japanese patients with azoospermia due to spermatogenic dysfunc-
tion
Yasuhiro Kido 1 ，Yuki Fujiwara 1 ，Takeshi Shin 2,3
，Hiroshi Okada 1,2,3
1:Genetic Counseling Center, Dokkyo Medical Universitiy Koshigaya Hospital, Japan、2:Department of Urology, Dokkyo Medical University
Koshigaya Hospital、3:Reproduction center, Dokkyo Medical University Koshigaya Hospital
Objectives: To evaluate the types and frequencies of chromosomal abnormalities in a large group of more than 1000 Japanese
patients with azoospermia due to spermatogenic dysfunction.
Methods: This is a single-center, retrospective, observational study. The subjects were 1354 Japanese patients with azoosper-
mia due to spermatogenic dysfunction that was confirmed by microdissection testicular sperm extraction. Types and frequency
of chromosome abnormalities were investigated in this population.
Results: Chromosomal abnormalities were detected in 24.1% of the study population. Sex chromosome anomalies (22.5%)
were more common than autosomal chromosome abnormalities (1.6%). Among the sex chromosome anomalies‚ Klinefelter
syndrome was the most common‚ occurring in 18.8% of the patients. Sex chromosome anomalies were detected in 2.0%‚ and
structural aberrations of the Y chromosome (1.8%) were more frequent than those of the X chromosome (0.2%).
Conclusions: Our results highlight the importance of blood karyotype analyses. Considering that about one-fourth of our
patients with azoospermia due to spermatogenic dysfunction had chromosomal abnormalities‚ we recommend that cytogenetic
Poster Session
analysis be made mandatory for such patients since the identification of chromosomal abnormalities would influence fertility
treatment protocols.
Mon(2)-P-163
Maxillofacial morphological characteristics of two Japanese patients with chromosome 18p deletion
syndrome
Michiko Tsuji 1 ，Kenji Ogura 1 ，Rina Hikita 1 ，Yukiho Kobayashi 1 ，Keiji Moriyama 1
1:Maxillofacial Ortthognathics, Tokyo Medical and Dental University, Japan
Introduction
Chromosome 18p deletion (18p-) syndrome (MIM #146390) was first described in 1963 by de Grouchy et al. The main clinical
manifestations are mental retardation; growth retardation; craniofacial dysmorphism including round face, micrognathia,
dysplastic ears, wide mouth, and dental anomalies; and abnormalities of the limbs, genitalia, brain, eyes, and heart. Since
2012, patients with 18p- syndrome have been covered by the national health insurance of Japan for orthodontic treatment.
However, few reports have described the maxillofacial features of 18p- syndrome.
Objective
To investigate the distinctive maxillofacial features of patients with 18p- syndrome.
Case
Case 1: A 9-year-old Japanese girl visited our orthodontic clinic with chief complaints of maxillary protrusion and crowding.
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The patient also had a short stature, mental retardation, hypotonia, and cervical synostosis. Ptosis blepharoplasty was
performed at 2 years of age and 18p- syndrome was diagnosed at 5 years of age. Case 2: An 11-year-old Japanese boy
visited our orthodontic clinic with a chief complaint of crowding. We noted that the patient had a short stature and mental
retardation. In this patient, 18p- syndrome was diagnosed at 1 year of age. Both cases showed the characteristic facial
features of 18p- syndrome, including a low nasal bridge, down-turned corners of the mouth, large protruding ears, and sparse
eyebrows. In the oral region, a high palate and crowding were observed. In addition, Case 1 showed excess overjet and Case 2
displayed a maxillary central supernumerary tooth. Cephalometric analyses showed that both cases demonstrated retardation
of the maxilla and mandible, a high mandibular plane angle, and smaller maxillary and mandibular lengths.
Conclusion
These results highlight the maxillofacial morphological features of patients with Japanese 18p- syndrome. However, additional
studies that include a larger number of patients are warranted to confirm these results.
Mon(2)-P-164
Cytogenetics in the Centre of Excellence for Human Genetics
Alaa K. Kamel 1 ，Amal M Mohamed 1 ，Nivin A Helmy 1 ，Sayda A Hammad 1 ，Hesham K Kayed 1 ，Marwa I Shehab 1 ，
Poster Session
Assad S Gerzawy 1 ，Maha M Eid 1 ，Ola M Eid 1 ，Mona K Mekkawy 1 ，Maha S Zaki 2 ，Mona S Aglan 2 ，
Ghada E Kammah 2 ，Ghada E Housieny 2 ，Mona O Ruby 2 ，Samia A Temtamy 2
1:Human Cyrogenetics, National Research Centre, Egypt、2:Clinical Genetics, National Research Centre
Establishment of centre of excellence for human genetics is largely needed for our scientific community and our society. The
aim of this study is to evaluate the diagnostic role of cytogenetics in the centre of excellence for human genetics. This work
was done through a project funded by the Science and Technology Development Fund (STDF) in the Academy of Science
and Technology, Egypt. In the 1st 18 months of the project we had 643 patients referred for cytognetic analysis from four
subspecialty human genetics clinics: multiple congenital anomalies (MCA), neurogenetic disorders, Limb malformations and
skeletal dysplasias and hereditary blood disorders . We had 175 patients with MCA, excluding Down syndrome, in this
group cytogenetic abnormalities were found in 27 patients (15.4%), There were 320 patients with neurogenetic disorders,
chromosomal abnormalities was found in 28 patients (8.7%). 70 patients had limb anomalies, chromosomal abnormalities
found in 11 patients (15.7%).There were 76 patients referred for diagnosis or exclusion of Fanconi anemia, 26 was found to be
positive Fanconi by diepoxy-butain test for breakage (33%).
FISH analysis was performed for 57 patients, 24 patients referred for microdeletion syndromes; 5 patients had deletion, seven
patients with marker chromosome; two of them were derived from chromosome 15. FISH was performed on 26 patients with
structural chromosome abnormalities to verify the nature of the abnormalities.
DNA samples were collected from the patients according to clinical evaluation. We started to perform multiple ligation probe
amplification (MLPA), especially in patients with intellectual disability/ MCA, microdeletion syndromes and Fanconi anemia.
We already established our array CGH laboratory.
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Mon(2)-P-165
FGFRL1 is a possible candidate for the severe renal phenotype in a case of Wolf-Hirschhorn syndrome
Yuko Tezuka 1 ，Minenori Eguchi-Ishimae 1 ，Erina Ozaki 2,3
，Kikuko Murao 4 ，Mariko Eguchi 1,2
，Eiichi Ishii 1
1:Department of Pediatrics, Ehime University Graduate School of Medicine, Japan、2:Division of Medical Genetics, Ehime University
Hospital、3:Total Medical Support Center, Ehime University Hospital、4:Division of Pediatrics, Ehime Prefectural Niihama Hospital
Background Wolf-Hirschhorn syndrome (WHS) is a congenital malformation syndrome resulting from haploinsufficiency of
its critical region on chromosome 4p16.3. WHSC1 gene is one of the responsible genes causing major phenotypes in WHS.
Renal symptoms frequently accompany WHS, but are rarely observed in cases with deletion less than 6Mb from the telomere.
FGFRL1 , located on 4p16.3, is known to be involved in early renal development making it one of the most likely candidate for
causing renal symptoms in WHS. Case A male patient was born in the 35 weeks of pregnancy with the birth weight of 1,717g.
Intrauterine growth restriction was indicated during pregnancy, and cleft palate, bilateral sensorineural deafness, poor weight
gain was noted. Right renal hypoplasia, left hydronephrosis, left vesicoureteral reflux were identified, and suffering from
chronic renal failure. Cytogenetic analysis revealed 46,XY,del(4)(p16.2).ish del(4)(D4S3359-) which led to the diagnosis of
WHS. Methods Peripheral blood sample was collected with written informed consent of his parents. Copy number of various
genes located on 4p16.2 to 4p16.3 were analyzed by quantitative PCR. Direct sequencing of all coding exons of FGFRL1 were
performed. Results Copy number analysis indicated that the deleted region in 4p16.2 spans approximately 5Mb in length
from its telomere, and the gene dosage of FGFRL1 as well as WHSC1 were reduced to half. No mutation was identified in
the entire coding sequences of FGFRL1 , however expression of the gene was undetectable in the peripheral blood cells of the
patient. Discussion Although it is not clear how the remaining allele lost its expression, complete loss of FGFRL1 expression
indicates possible pathological role on renal phenotype in the patient. Deletion of one allele of FGFRL1 and some additional
Poster Session
genetic changes in the other allele may have caused the manifestation of recessive trait in this patient.
Mon(2)-P-166
8q13 microdeletion detected in a Japanese case with mesomelia-synostoses syndrome
Issei Imoto 1 ，Takuya Naruto 1 ，Tomohiro Kohmoto 1,2
，Hideaki Horikawa 1,3
，Kiyoshi Masuda 1
1:Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan、2:Student Lab,
Tokushima University Faculty of Medicine、3:Support Center for Advanced Medical Sciences, Institute of Biomedical Sciences, Tokushima
University Graduate School
Mesomelia-synostoses syndrome (MSS, MIM #600383) is a rare autosomal-dominant a syndromal osteochondrodysplasia

characterized by mesomelic limb shortening, acral synostoses, and multiple congenital malformations due to a non-recurrent
microdeletion at 8q13 encompassing two contiguous genes: SULF1 and SLCO5A1 . To date five unrelated patients have been
reported worldwide. Here, we report the first Japanese case with MSS caused by a novel 591 kb deletion at 8q13 containing
those two genes.
An 11-year-old was the second child of non-consanguineous Japanese parents. She had multiple congenital anoanomalies,
such as blepharophimosis, blepharoptosis, micrognathia, low-set ear, hypoplastic calcaneus, bilateral ectopic ureters, and left
hydronephrosis. Throughout childhood, the limited extension of elbow joints, the bowing and shortening of the forearms, and
the ulnar deviation of the hands had not significantly progressed. Symmetrical deformity of the legs resulted in genua valga and
proximal dislocation of tibiae and fibulae had not significantly worsened, although malformed ankle joint and toes adversely
affected the patient’s gait. The patient remained to be undiagnosed until performing molecular cytogenetic diagnosis.
Targeted exome analysis using next-generation sequencing (NGS) detected deletion heterozygous deletion of SULF1 , and
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subsequently performed array-based copy number analysis detected a novel 591 kb deletion at 8q13 containing SULF1 and
SLCO5A1 . Clinical features of this patient were mostly matched with those of MSS, which was considered to be caused by
8q13 microdeletion, and a new clinical management strategy was initiated based on the diagnosis.
Our case suggest that molecular diagnosis of undiagnosed cases with rare genetic diseases using NGS and/or array helps to
end a diagnostic odyssey and provides tangible clinica benefit for individuals with idiopathic genetic disease.
Mon(2)-P-167
Complete 46,XY female of 14 cases and review of the literature
So Yeon Park 1 ，Shin Yeong Lee 1 ，Bom Yi Lee 1 ，Ju Yeon Park 1 ，Eun Young Choi 1 ，Yeon Woo Lee 1 ，Ah Rum Oh 1 ，
Jin Woo Kim 1 ，Hyun Mee Ryu 1,2
1:Laboratoy of Medical Genetics, Cheil General Hospital and Women’s Healthcare Center, Korea, South、2:Department of Obstetrics and
Gynecology, Cheil General Hospital and Women’s Healthcare Center
Objective: To assist in diagnosis and genetic counseling of complete 46,XY female by the main characteristics and causes.
Materials and Methods: Cytogenetic analysis was performed in 9,472 female patients at Cheil General Hospital between
September 1983 and December 2014. We investigated with 700 female patients including primary amenorrhea, infertility,
agenesis of uterus and ovaries, delayed puberty, dysgerminoma and sister chromosome abnormality. Clinical findings, basal
hormone profiles, and radiological readings were investigated. Additionally, DA-DAPI staining, CBG-banding, quantitative
Poster Session
fluorescence-polymerase chain reaction analysis, and fluorescence in situ hybridization were conducted to confirm the presence
of Y chromosome and SRY gene.
Results: We found 14 cases with complete 46,XY female. Among them, 12 cases were primary amenorrhea and two cases
were agenesis of uterus and ovary cyst dysgeminoma, respectively. Four cases were familial. Six cases had no uterus and high
levels of testosterone. Four cases were performed gonadectomy.
Conclusions: Although further genetic testing and research is needed for an accurate diagnosis, the present report would be
helpful for genetic counseling of XY female patient and their family, and understanding the genetic etiology as the causal
factor in amenorrhea
Mon(2)-P-168
A familial case of brain malformation with marker chromosome
Mika Nakajima 1 ，Tohru Ohta 2 ，Takeshi Kida 1 ，Susumu Mizukami 1
1:Pediatrics, Hakodate Chuo General Hospital, Japan、2:The Research Institute of Personalized Health Sciences, Health Sciences University
of Hokkaido
We report a familial case of brain malformation with a chromosome anomaly. One male proband had Chiari types II
malformation with spina bifida, myelomeningocele, hydrocephaly, diagnosed with magnetic resonance imaging (MRI). Another
male patient was a first full cousin of the first patient, who had Dandy-Walker variant (left ventricle enlargement, cyst of the
cerebellum). Other phenotype of the both patients was normal, but the mental retardation was observed in both cases. The
both mothers of the first patient and the second patient had no brain malformation confirmed with MRI and no any other
abnormal phenotype. Interestingly, karyotype analysis demonstrated that these both patients had 47XY, +mar and the both
mothers shared the identical marker chromosome, while healthy brothers of the second patient had no brain malformation
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with normal karyotype. To confirm the origin of the marker chromosome, microarray analysis was performed using two
patients’ and the both mother’s genomic DNA. However, in spite of the maker chromosome was visible size in standard
karyotype analysis, the origin was not able to be distinguished, probably meaning that the origin of the marker chromosome
must be satellite DNA or other repetitive DNA. Several familial Chiari malformation was previously reported as autosomal
dominant or recessive disease, and candidate locus or causative genes were described, but no association of the repetitive
DNA or ribosomal genes was reported. This putative association between brain malformation and marker chromosome with
incomplete penetrance in this family may be due to difference of the tolerance between male and female in impairment of
brain conformation, or imprinting-like effect of the genes located repetitive DNA on the marker chromosome.
Mon(2)-P-169
Inhibition of overactivated PIK3/AKT/mTOR signalling pathway as a therapeutic strategy for PIK3CA-
related overgrowth spectrum (PROS)
Yasuyo Suzuki 1 ，Yasushi Enokido 2 ，Kenichiro Yamada 1 ，Naoki Hanada 3 ，Tsuyoshi Morishita 4 ，Seiji Mizuno 5 ，
Nobuaki Wakamatsu 1
1:Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Japan、2:Department of Pathology, Institute
for Developmental Research, Aichi Human Service Center、3:Hanada Kodomo Clinic、4:Department of Plastic Surgery, Aichi Children’s
Health and Medical Center、5:Department of Pediatrics, Central Hospital, Aichi Human Service Center
Objective: The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signalling pathway is critical for cellular growth and
metabolism. Somatic activating mutations in PIK3CA, located in the helical domain (E542K and E545K) or kinase domain
(H1047R), are frequently identified in cancer and a spectrum of mosaic overgrowth disorders.
Poster Session
Methods: We report the case of a girl who presented with hyperplasia of the lower extremities, macrodactyly, and multiple
lipomatosis. These symptoms are indicative of a recently proposed clinical entity, PIK3CA-related overgrowth spectrum
(PROS). Moreover, the patient had sparse hair and thin skin, except in the pathologic regions. We performed direct sequencing
of all exons and exon-intron junctions of PIK3CA. We also calculated the mutant allele frequency using quantitative multiplex
PCR and analyzed PIK3/AKT/mTOR signalling with specific antibodies.
Results: Direct sequence analyses of genomic DNA, obtained from resected hyperplasic adipose tissue of the patient, identified
a mosaic mutation (c.3140A>G [p.H1047R]) in PIK3CA; this mutation was absent in the DNA of lymphocytes obtained from
the patient’s blood. The frequency of the PIK3CA mutant allele was determined by quantitative multiplex PCR; it was
13.7% in the adipose tissue from the patient’s chest and 3.4% in the skin of the perineum. Determination of H1047R allele
frequencies revealed an increased amount of mutant alleles in samples from regions with more adipose tissue, where the
PIK3/AKT/mTOR signalling was activated.
Conclusion: We confirmed that the PIK3/AKT/mTOR signalling pathway in the patient’s adipose tissue was activated; thus,
the pathway could be a therapeutic target for PROS treatment. To screen drug candidates for treating PROS, we established
new fibroblast cell lines derived from the patient as an experimental model. The effects of a proliferation inhibitor on the
overactivation of the PIK3/AKT/mTOR signalling pathway in fibroblasts of PROS will be discussed.
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Mon(2)-P-170
Molecular analysis of partial duplication of the chromosome 21 in two patients presenting Down syndrome
phenotype
Hidefumi Tonoki 1,3 ，Nobuhiro Takahashi 1 ，Koji Okuhara 1 ，Susumu Iizuka 1 ，Kadomi Monzaki 2 ，Reishi Fujiyama 2 ，
Daisuke Sato 3 ，Yoshio Makita 4 ，Tohru Ohta 5
1:Pediatrics, Tenshi Hosipital, Japan、2:Genetics Laboratory, Tenshi Hospital、3:Pediatrics, Hokkaido University Graduate School of
Medicine、4:Education center, Asahikawa Medical University、5:Research Institute of Personalized Health Sciences, Health Sciences University
of Hokkaido
Down syndrome (DS) is one of the most common congenital chromosomal abnormality syndrome, characterized by a particular
combination of features including mental retardation and very characteristic physical appearance. Usually, it is caused by
complete trisomy 21. In rare cases, however, it results from a partial trisomy 21. The fact that DS results from a partial
trisomy 21 indicates the presence of a critical chromosomal region. We report two Japanese patients with partial duplication of
chromosome 21. Patient 1 was a mentally retarded girl who was clinically diagnosed as Down syndrome soon after birth. Her
karyotype was 46,XX,idic(21)(q22.13)ins(13;21)(q12.1;q22.13q22.3)de novo. According to the Jackson score for the clinical
diagnosis of trisomy 21, she showed 10 /25 signs. Patient 2 was a seriously retarded girl who could not sit or speak by four
years of age. Her karyotype was 46,XX,-15,+der(21)t(15;21)(q12;q22.1).ish der(21) pat (D15Z1-, SNRPN1-, PML+). Her
appearance was a mixed with characteristics of Prader-Willi syndrome and Down syndrome. CGH analysis using Affymetrics
cytoHD revealed a 39.5Mb duplication of 21q in Patient 1, and a 36 Mb duplication of 21q in Patient 2. RCAN1 was estimated
to be duplicated in both patients, while DSCRs 3 and 4 was duplicated only in Patient 1. The minimum responsible region for
Down syndrome defined in a previous report maps between 37.94 and 38.64 and contains KCNJ6 , DSCR4 and KCNJ15 . This
region was duplicated in Patient 1 but not in Patient 2. Our report suggested RCAN1 might as well be a gene contributing
Poster Session
Down syndrome phenotype.
Mon(2)-P-171
Ring chromosome 9 with a 9p24.3-p24.1 deletion and 9p24.1-p21.1 duplication in a girl with develop-
mental delay and sex reversal
Yukako Muramatsu 1,2 ，Tamae Ohye 3 ，Tomohiko Nakata 1,2
，Takashi Hamajima 4 ，Mizuki Ito 3 ，Tomoya Takeuchi 2 ，
Masako Izawa 4 ，Hiroki Kurahashi 3
1:Pediatrics, Nagoya university graduate school of medicine, Japan、2:Pediatrics, Japanese Red Cross Nagoya Daiichi Hospital、3:Molecular
Genetics, Institute for Comprehensive Medical Science, Fujita Health University、4:Endocrinology and Metabolism, Aichi Children’s Health
and Medical Center
Telomeric 9p24.3 deletions are known to cause developmental delay and dysmorphic features. They also cause genital anomalies
in males, such as disorders of gonadal sex and genital differentiation anomalies. Sex reversal is closely related to the doublesex
and mab-3-related transcription factor (DMRT ) genes located on 9p. Duplications of 9p also demonstrate developmental delay
and dysmorphic features. This report documents the case of a girl aged 2 years with sex reversal harboring ring chromosome
9, and further analysis revealed an 8-Mb deletion at the end of the short arm and a contiguous 23-Mb duplication of the short
arm.
The subject was born to healthy parents after 39 of weeks gestation but displayed developmental delay, failure to thrive,
microcephaly, preaxial polydactyly, and myoclonic seizures. Chromosomal analysis revealed sex reversal in the subject.
Fluorescent in situ hybridization (FISH) analysis detected a positive signal for the sex determining region Y (SRY ) gene.
Magnetic resonance imaging scan of the abdomen could not detect the sexual glands and uterus. Luteinizing hormone-
releasing hormone and human chorionic gonadotropin loading tests revealed that the subject’s condition was equivalent to
that observed during complete gonadal dysgenesis. Microarray analysis demonstrated that there was an 8-Mb deletion at
the end of the short arm (9p24.3-p24.1) and a contiguous 23-Mb duplication of the short arm (9p24.1-p21.1). The deletion
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encompassed the DMRT genes. Deletion in the long arm was not observed.
It was considered that the 8-Mb terminal deletion at p24.1 was followed by the 23-Mb inverted duplication at 9p24.1-p21.1.
The broken end of the short arm was repaired by the telomere of the normal long arm to build a stable structure, and this
mechanism gave rise to ring chromosome formation.
Mon(2)-P-172
Possible disruption of cis and trans regulation due to 22q11.2 deletion
Anelisa G. Dantas 1 ，Diego R. Mazzotti 2 ，Vanessa K. Ota 1 ，Adriana Bortolai 1 ，Marcos L. Santoro 1 ，Chong Ae Kim 3 ，
Gianna G. Carvalheira 1 ，Sintia N. Belangero 1 ，Maria I. Melaragno 1
1:Genetics, Universidade Federal de Sao Paulo, Brazil、2:Psychobiology, Universidade Federal de Sao Paulo、3:Genetics, Instituto da Crianca,
Universidade de Sao Paulo
The 22q11.2 deletion syndrome results from a hemizygous deletion of chromosome 22 usually flanked by low copy repeat
regions (LCR), the 3 and 1.5 Mb deletions being the most frequent. The phenotype may be variable in patients with similar
deletions, and similar phenotypes may also be observed in patients with different size deletions, even without overlap. The
disruption of cis and trans interactions caused by the 22q11.2 deletion may be responsible for these phenotypic particularities
associated to the syndrome. We performed a microarray gene expression study on 14 patients with 22q11.2 deletion, 11 of
them with 3 Mb deletion and 3 with 1.5 Mb, all deletions detected by MLPA. The patients were matched to their controls
for age and gender. Validation was performed using Taqman probes. The study of gene expression by microarray identified
Poster Session
reduced expression of 48 transcripts corresponding to genes of the 22q11.2 deleted region, and also of genes flanking the
deleted region or genes located in other chromosomes. Five genes were chosen for validation by Taqman probes: DGCR8 and
CRKL, both localized in the deleted region; TUBA8 and GNAZ localized in the flanking region of the deletion and JAM3 , a
gene mapped in chromosome 11. The study using Taqman probes confirmed the reduced expression of the hemizygous genes,
the reduction in the expression of genes flanking the deletion and also the gene of chromosome 11 (p<0.05), replicating the
microarray data. This information may indicate that the deletion is causing a disruption of important interactions in cis,
shown by the altered expression of the flanking genes, and also interactions in trans, shown by the altered expression of the
gene localized in chromosome 11. This study contributes to the understanding of the molecular mechanisms involved in the
complex network of gene regulation, which is responsible for the characteristic phenotype of the 22q11.2 deletion syndrome.
(Financial support: FAPESP)
Mon(2)-P-173
Chromosomal microarray (CMA) in Brazilian patients with phenotypic alterations and normal G-banding
karyotypes
Maria I Melaragno 1 ，Mariana Moyses-Oliveira 1 ，Mileny S Colovati 1 ，Sylvia S Takeno 1 ，Helio R Oliveira-Junior 1 ，
Leonardo C dos-Santos 1 ，Anelisa G Dantas 1 ，Natalia N da-Silva 1 ，Leslie D Kulikowski 3 ，Flavia Piazzon 2 ，
Vera A Meloni 1 ，Chong A Kim 2 ，Ana B Perez 1
1:Genetics Department, Universidade Federal de Sao Paulo, Brazil、2:Instituto da Crianca, Universidade de Sao Paulo、3:Department of
Pathology, Universidade de Sao Paulo
Chromosomal rearrangements are a major cause of intellectual disability and congenital malformations. They can be identified
by standard karyotyping but the resolution level of this technique is limited to imbalances usually larger than 5-10 Mb.
Chromosomal microarray (CMA) has been proposed as the first clinical diagnostic test for individuals with developmental
disabilities or congenital anomalies, considering the method ´ s high resolution. However, due to the high cost of this
exam, it is not feasible for all patients. We analyzed 60 Brazilian patients who showed normal karyotypes at 550-band
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resolution but who presented phenotypic features highly suggestive of chromosomal abnormalities. CMA was performed
using different formats (Genome-Wide Human SNP 6.0 array, CytoScan 750K or CytoScan HD, by Affymetrix, or SurePrint
4x180K Microarray, by Agilent) and chromosomal abnormalities were reported based on GRCh37/hg19. Among the 60
patients studied, 26 (43%) showed normal array results, 4 (6.7%) had copy number variations of unknown significance, 16
(27%) showed terminal duplications/deletions, and 13 (22%) had interstitial imbalances. One patient with normal array
showed a ~ 50% absence of hererozigosity (AOH) suggesting incest and a probable recessive disease. The relatively high
detection rate of submicroscopic imbalances by array observed in our study can be explained by the strict criteria used to
select the patients. In cases of unbalanced translocations, fluorescence in situ hybridization (FISH) was necessary to identify
small balanced translocations in patients ´ parents, indicating the importance of associating cytogenetic and molecular
techniques in clinical genetics, given the implications for patient management and genetic counseling. In our study, CMA
allowed a full molecular characterization of the abnormal genomic regions, and led to the identification of relevant genes for
the patients ´ clinical features. Financial support: FAPESP.
Mon(2)-P-174
Novel mutations in PDE4D and molecular pathology of acrodysostosis without hormone resistance
Tadashi Kaname 1,8 ，Kumiko Yanagi 1,8 ，Chang-Seok Ki 2 ，Norio Niikawa 3 ，Gen Nishimura 4 ，Nobuo Mastuura 5 ，
Manami Iso 1,8 ，Yoko Kuroki 1,8 ，Seiji Mizuno 6 ，Sung Yoon Cho 7 ，Dong-Kyu Jin 7 ，Yoichi Matsubara 8
Poster Session
1:Department of Genome Medicine, National Center for Child Health and Development, Japan、2:Department of Laboratory Medicine and
Genetics, Sungkyunkwan University School of Medicine、3:Health Sciences University of Hokkaido、4:Department of Pediatric Imaging,
Tokyo Metropolitan Children’s Medical Center、5:Seitoku University、6:Department of Pediatrics, Central Hospital, Aichi Human Service
Center、7:Department of Pediatrics Samsung Medical Center, Sungkyunkwan University School of Medicine、8:National Research Institute
for Child Health and Development
Acrodysostosis without hormone resistance is a rare skeletal disorder characterized by brachydactyly, nasal hypoplasia, mental
retardation and occasionally developmental delay. Mutations in the gene encoding cAMP-hydrolyzing phosphodiesterase-4D
(PDE4D) have been reported to cause this rare condition but the pathomechanism has not been fully elucidated.
To understand the pathogenetic mechanism of PDE4D mutations, we analyzed the PDE4D gene in patients clinically diag-
nosed with acrodysostosis. Then, we found two novel missense mutations in the patients.
Our 3D modeling studies to predict changes in the binding efficacy of cAMP to the catalytic pocket in PDE4D mutants indi-
cated diminished enzyme activity in the two mutants. Ectopic expression of PDE4D mutants in HEK293 cells demonstrated
this reduction in activity, which was identified by increased cAMP levels. However, cells from an acrodysostosis patient
showed low cAMP accumulation, which resulted in a decrease in the phosphorylated cAMP Response Element-Binding Pro-
tein (pCREB)/CREB ratio. The reason for this discrepancy was due to a compensatory increase in expression levels of
PDE4A and PDE4B isoforms, which accounted for the paradoxical decrease in cAMP levels in the patient cells expressing
mutant isoforms with lowered PDE4D activity. Specific inhibitory PDE4D mutations may lead to the molecular pathology of
acrodysostosis without hormone resistance but that the pathological phenotype may be dependent on an over-compensatory
induction of other PDE4 isoforms that can be expected to be targeted to different signaling complexes and exert distinct
effects on compartmentalised cAMP signaling.
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Mon(2)-P-175
Subtelomeric rearrangements’ detection and characterization by combined use of MLPA kits in intellec-
tual disability patients
Cristina Rusu 1 ，Roxana Popescu 1 ，Mihaela Gramescu 1 ，Elena Braha 1 ，Lacramioara Butnariu 1 ，Monica Panzaru 1 ，
Adriana Sireteanu 2
1:Medical Genetics, University of Medecine and Pharmacy, Romania、2:Molecular Biology Lab, Regional Institute of Oncology, Iasi, Romania
Intellectual disability (ID) is a common disorder with heterogeneous causes, genetic factors being mainly involved in moder-
ate/severe forms. Out of the genetic causes, subtelomeric rearrangements (SR) and microdeletions/duplications are the most
important ones. The aim of this study was to evaluate the ability of a combination of MLPA kits to establish the diagnosis in
404 children with ID and multiple congenital anomalies. All patients were assessed for chromosome imbalance using standard
karyotype (377 normal, 27 uncertain result) and subtelomeric MLPA (P036 and P070 kits). Abnormal results detected by
both MLPA kits were further characterized using appropriate MLPA follow-up kits (P029-B1, P250-B2). Out of the 404
patients tested, 82 presented abnormal MLPA results: 22 cases with polymorphisms (abnormal results in a single screening
test) and 60 cases with subtelomeric deletions/ duplications (present in both screening tests and in the follow-up), leading to a
detection rate of 14.8%. SR were unique in 32 cases (19 deletions and 13 duplications), the most involved being chromosomes
9 and 18. SR were combined in 28 cases, the most frequently involved chromosomes being 2, 3, 5 and 18. Subtelomeric
MLPA helped us to clarify the diagnosis in 16 of the 27 cases with uncertain karyotype result. In conclusion, the use of
follow-up MLPA kits allowed us to confirm the abnormalities and to determine their size, as well as to characterize complex
chromosomal rearrangements in some cases. For services that do not have yet extensive access to microarray technology, the
combined use of MLPA kits represents an effective strategy that provides a precise diagnosis in an important proportion of
Poster Session
ID patients.
Mon(2)-P-176
Withdrawn

Mon(2)-P-177
Haploinsufficiency of HDAC4 and de novo nonsense mutation ofHDAC8 confirmed by whole exome
sequencing
Jeesuk Yu 1 ，Eunwoo Nam 1 ，Seung Heo 1 ，Seung Ho Lee 1 ，Yoonjin Kang 2 ，Taekyeong Yoo 2 ，Murim Choi 2 ，
Kyudong Han 3
1:Pediatrics, Dankook University Hospital, Korea, South、2:Biomedical Sciences, Seoul National University College of Medicine、
3:Nanobiomedical Science, Dankook University
Background : Pediatric epilepsy can be caused by various conditions including specific syndromes. It is noteworthy to know
the specific genetic cause for the understanding of the pathogenesis as well as management of epilepsy.
Case 1 : A 6-month-old female patient was brought to Dankook University Hospital due to developmental delay. She did
not reveal any notable abnormality at birth and had no specific family history. There were no significant findings on physical
exam. On her age of 1 year and 5 months, seizures developed 3 ~ 4 times every week and EEG showed frontal spike and wave
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discharges. Seizure was not recurred since 5 years of age on medication. Her hand radiograph showed brachydactly type E.
Brain MRI and chromosomal study did not show any specific abnormalities. By whole exome sequencing, de novo terminal
deletion of 2q37 including gene HDAC4 was identified.
Case 2 : A 9-year-and-11-month-old girl was brought to the Dankook University Hospital due to intractable seizure occurring
daily more than 1 episode which developed 2 years ago. She had dysmorphic faces such as deep bush eyebrows, anteverted
nares, micrognathia, and low posterior hairlines. She was short and severely impaired in intelligence. Her mother and elderly
sister also had cognitive impairment, although her mother can take care of herself and both of them had no seizures. EEG
showed intermittent spike discharges from the right fronto-temporal areas. Brain MRI revealed atrophy of fimbria in left
hippocampus. Whole exome sequencing performed in 4 family members revealed nonsense mutation of the gene HDAC8 in
patient, her sister, and her mother. Therefore, a familial X-linked Cornelia de Lange syndrome caused by HDAC8 nonsense
mutation was confirmed.
Conclusion : Here we report two rare cases with severe intellectual disability and epilepsy caused by de novo terminal deletion
of 2q37 including HDAC4 or de novo mutation of HDAC8 confirmed by whole exome sequencing.
Mon(2)-P-178
ELECTRONIC DATABASE OF OROFACIAL CLEFTS - APPROACH AND ADVANTAGES IN HEALTH
POLICIES
Poster Session
Elaine L Mendes 1 ，Vera L Gil-da-Silva-Lopes 1 ，Isabella Monlleo 2 ，Roberta M Volpe-Aquino 1
1:Genetics Departament, State University of Campinas, UNICAMP, Brazil、2:Faculty of Medicine, Federal University of Alagoas
CranFlow is a web based application to register the flow and management of clinical and genetic data of craniofacial
individuals in Brazil.(CranFlow). Aim: to present the CranFlow ´ s resources and its advantages for strategies of health
policy. Methods: Information of the patient is recorded after signing an informed consent. The registration form and the
Operating Manual, were based in a previous study of the BCFP, according to US National Birth Defects Prevention Study’
and ESF ’common core protocols’. Clinical definitions and classification used guidelines of the International Clearinghouse
for Birth Defects Surveillance and Research and Perinatal Database on International Typical Oral Clefts Working Group.
Dysmorphology signals were adapted to fit the Human Phenotype Ontology (HPO). Case coding is performed by Coordinator
Center (DGM/Unicamp) using the International Classification of diseases 10th Edition and the Online Mendelian Inheritance
in Man. Data are stored in a PostgreSQL database in a server located in the Information Technology Division (NTI), inside
the Faculty of Medical Sciences at the University of Campinas, following security standards for confidentiality.
CranFlow is composed by modules: (1) Patient registration and management, (2) Data correction, (3) Data validation, (4)
Coding, (5) Reports and data export support material, (6) Laboratory management and (7) Support materials, forms record
demographics and clinical and genetic information. The uniformity of terminology and clinical criteria, the level of detail and
the standardization of clinical issues improve consistency and uniformity of data and ensure the recovery of the information
for statistical analysis. Conclusion: The collected information allows personalized treatment, clinical genetic research, specific
public policies and genotype-phenotype correlation studies. Support: Fapesp and CNPq.

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Mon(2)-P-179
a web-based application for validation of A cost-effective INVESTIGATION OF 22q11.2 Deletion syn-
drome
Elaine L Mendes 1 ，Vera L Gil-da-Silva-Lopes 1 ，Ilária C Sgardioli 1 ，Fabiola P Monteiro 1 ，Roberta M Volpe-Aquino 1 ，
Tarsis P Vieira 1
1:Genetics Departament, State University of Campinas, UNICAMP, Brazil
This extensive clinical variability of 22q11.2 Deletion syndrome (22q11.2DS) represents a diagnostic challenge, often delaying
the appropriate treatment and genetic counseling. There is no consensus about the selection criteria adopted for 22q11.2DS
investigation, leading to difficulties to perform laboratorial investigation in a public health system. A clinical criteria for cost-
effective indication of confirmatory tests for this disorder was suggested by Monteiro et al. (2013). Based on this experience,
we developed an application which automatically analyzes the patient’s clinical signs and verifies if they meet the criteria
proposed (CranFlow). This analysis is performed on line in the first and subsequent evaluations of the patient. Information
is storage, allowing phenotype ´ s follow-up and comparison with diagnostic tests. Aim: to present the preliminary results of
the CranFlow ´ s validation phase for 22q11.2DS. Methods: Information collected: personal and familial history, physical
examination and subsidiary exams. From these, the application automatically verifies the number of clinical signs and indicates
if the patient fills the criteria for laboratorial investigation. As they are still in validation phase, all individual have been tested
free of charge by Fluorescence in situ Hybridization (FISH ). In cases where the technique of FISH is negative, a Genomic
Hybridization will be next step. Preliminary results from 300 patients are still in analysis. Conclusion:This approach will
allow diagnosis, genetic counseling and clinical follow-up standardized in different regions of the country and thus contributing
to array will be providing. This project will be useful for establishing parameters for a cost-effective investigation elucidate
Poster Session
the clinical complexity of the 22q11.2DS. Support: Fapesp and CNPq.
Mon(2)-P-180
MICROFORM OF HOLOPROSENCEPHALY AND TYPICAL ORAL CLEFT IN INDIVIDUAL WITH
PARTIAL 18Q TRISOMY AND 18P MONOSOMY RESULTING FROM MATERNAL PERICENTRIC
INVERSION
Elaine L Mendes 1 ，Vera L Gil-da-Silva-Lopes 1 ，Ana P dos Santos 1 ，Roberta M Volpe-Aquino 1 ，
Nilma L Viguetti-Campos 1 ，Tarsis P Vieira 1
1:Genetics Departament, State University of Campinas, UNICAMP, Brazil
Patients with 18p deletion present a wide clinical spectrum, including neurodevelopmental delay (ND) and cognitive im-
pairment, short stature, holoprosencephaly and facial dysmorphisms. Duplication 18q is found in individuals with dif-
ferent clinical signs, which overlaps the deletion 18p. We report a male patient evaluated by ND, cleft lip and palate
(CLP), dysmorphisms and a microform of holoprosencephaly characterized by single incisive and pellucid septum agene-
sis. He is the first child of a young and non consaguineous couple. Family history is unremarkable. Microarray analy-
sis (CytoScan 750K, Affymetrix) identified a deletion of 10.8 Mb in 18p and a duplication of 22.8 Mb in 18q - arr[hg19]
18p11.32p11.21(136,227- 0,951,507)x1,18q21.31q23(55,216,721-78,013,728)x3. Mother ´ s karyotype with GTG-banded was
46,XX,inv(18)(p11.2q21.3). GTG banding karyotype of the proband was: 46,XY,rec(18)dup (18q)inv(18)(p11.2q21.3)mat.
The clinical features presented by the patient were compatible with genomic imbalances found mainly in those described in
18p deletion, including the microform of holoprosencephaly, which has been associated previously with haploinsufficiency of
TGIF1 gene (18p11.31). This gene has also been associated with CLP. Two other genes in 18q, SALL3 and TSHZ1 (18q22.3-
q23) have also been associated with CLP. This report improves genotype-phenotype correlation. Support: Fapesp and CNPq
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Mon(2)-P-181
Partial 1q duplication and associated phenotype
Jose E. Baroneza 1,2,3 ，Marcos L. M. Morris 1 ，Patricia Teixeira 1 ，Cristina T. M. Medina 4 ，Mara S Cordoba 1 ，
Beatriz R. Versiani 5 ，Liege L. Roese 5 ，Erika L. Freitas 6 ，Ana C. S. Fonseca 6 ，Maria C. G. dos Santos 2 ，
Aline Pic-Taylor 1 ，Carla Rosenberg 6 ，Silviene F. Oliveira 1 ，Iris Ferrari 7 ，Juliana F. Mazzeu 7
1:Genetics and Morphology Departmant, Universidade de Brasilia, Brazil、2:Universidade Federal do Parana、3:Universidade Positivo、
4:Health Secretary, Federal District、5:Rede Sarah、6:Universidade de Sao Paulo、7:Medicine Faculty, Universidade de Brasilia
Duplications of the long arm of chromosome 1 are rare. Distal duplications are the most common and have been reported
as either pure trisomy or unbalanced translocations. The paucity of cases with pure distal 1q duplications has made it
difficult to delineate a partial distal trisomy 1q syndrome. We report two patients with overlapping 1q duplications detected
by G-banding. Array comparative genomic hybridization (CGH) and FISH were performed to characterize the duplicated
segments, exclude the involvement of other chromosomes and determine the orientation of the duplication. Patient 1 presents
a mild phenotype and carries a 22.5 Mb 1q41q43 duplication. Patient 2 presents a pure 1q42.13qter inverted duplication
of 21.5Mb, one of the smallest distal 1q duplications ever described and one of the few cases characterized by array CGH,
thus contributing to a better characterization of distal 1q duplication syndrome. Both patients present prominent metopic
suture therefore pointing to a candidate region for metopic craniosynostosis in the overlapping segment. Fifty-one OMIM
genes map to the region of intersection between the duplications on chromosome 1 (chr1: 225696992-239696544g19- hg18),
including WNT9A, WNT3A and RGS7. No other genes in the overlapping segment have been proposed as candidates for
craniosynostosis and, therefore, our data reinforces a possible role of RGS7 , WNT9A and WNT3A in the etiology of cranial
suture malformations.
Poster Session
Mon(2)-P-182
De novo NSD1 intragenic microduplication in a Patient with clinical presentation of Sotos syndrome
Eriko Nishi 1,2,3 ，Noriko Kubota 3 ，Michiko Arakawa 1,3
，Kosuke Izumi 1,4
，Kyoko Takano 1,2
，Eiko Hidaka 3 ，
Tomoki Kosho 1,2
1:Division of Medical Genetics, Nagano Children’s Hospital, Japan、2:Department of Medical Genetics, Shinshu University School of
Medicine、3:Life Science Research Center, Nagano Children’s Hospital、4:Research Center for Epigenetic Disease, Institute for Molecular
and Cellular Biosciences
Sotos syndrome (OMIM#117550) is a congenital malformation syndrome characterized by overgrowth, learning disability
ranging from mild to severe, craniofacial features including large skull, high-bossed forehead, long narrow face, and pointed
chin, and variable associated anomalies. The disorder is caused by heterozygous NSD1 (5q35) alterations: point mutations,
submicroscopic deletions involving NSD1 , and NSD1 intragenic deletions. Reverse clinical phenotype due to 5q35 microdu-
plication encompassing NSD1 gene, presenting short stature with delayed bone age, microcephaly, and developmental delay
in the absence of typical facial anomalies of Sotos syndrome has been reported in about 30 cases. [Novara et al., 2014]. We
have identified a de novo intragenic duplication of NSD1 in a boy with pre-postnatal overgrowth, macrocephaly, premature
eruption of teeth, neonatal hypoplasia, developmental delay, cryptorchidism, scoliosis, and craniofacial features including
large skull, high-bossed forehead, long narrow face, hypertelorism, downslanting palpebral fissures, high arched palate, and
pointed chin. He was the second child of a healthy 41-year-old mother and a healthy 42-year-old non-consanguineous father.
He was born by vaginal delivery at 40 weeks and 2 days of gestation. His birth weight was 3695g (+1.7SD), length was 55cm
(+2.9 SD), and OFC was 36cm (+1.9 SD). At the age of 2 years and 2 months, his weight was 14.45kg (+2.0SD), height
was 94.5cm (+2.5SD), and OFC was 54.5 cm (+3.5SD). His psychomotor development was delayed. G-banded karyotyp-
ing and FISH analysis showed normal male chromosomes. Direct sequencing of NSD1 showed no pathogenic variants. A
genome-wide SNParray analysis using the Affymetrix Cyto Scan HD revealed a de novo 24kb microduplication designated
as "arr [hg19]5q35.3(176628582-176630985)1* dn". His phenotypic features, compatible with the clinical diagnosis as Sotos
syndrome, suggest that the intragenic microduplication would disrupt NSD1 function.
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Mon(2)-P-183
Identification of Microduplitations on Chromosome 6q22 in A Sporadic Case with Congenital Generalized
Hypertrichosis
Yingzhi Huang 1 ，Jiajie Hao 2 ，Xiuli Zhao 1 ，Feng Zhang 3 ，Mingrong Wang 2 ，Xue Zhang 1
1:McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences - Peking Union Medical College, China、2:State Key
Laboratory of Molecular Oncology,Cancer Institute (Hoospital), Chinese Academy of Medical Sciences - Peking Union Medical College、
3:State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan
University, Shanghai, China
Congenital Generalized Hypertrichosis (CGH) is a phenotypic and genetic heterogeneous group characterized by excessive hair
growth all over the body independent of androgen, and can be classified into several types. Rearrangements on chromosome
4, 8, 17 and X, as well as point mutations in ABCA5 (onchromosome 17) have been reported to cause CGH.
In this study, a family with CGH was collected. The proband presented phenotypes similar to the Ambras form of CGH, while
his parents and siblings presented no similar phenotypes. Blood or oralepithelia cells were obtained from the proband, his
mother and all the four siblings after informed consent. Array comparative genomic hybridization (aCGH) analysis revealed
two microduplications (named as Dup1 and Dup2 respectively) on 6q22, which were validated to cosegregate with the disease
phenotype in the family by qPCR. A series of qPCR assays were conducted to narrow down the boundaries, followed by
gap-PCR attempts with different primer pairs until the breakpoints were amplified. Direct Sanger sequencing of the products
revealed that the two microduplications were linked to each other. The structure was assumed for the rearranged chromosome
through a further dual FISH assay. STR markers analysis within the microduplications suggested that both originated de
novo paternally.
Poster Session
Six genes are located or partially located within the two microduplications. GJA1 is the causative gene of oculo-dento-digital
dysplasia (ODDD), thus the variation in its copy number might be the cause of the ophthalmic and dental phenotypes in the
proband; RSPO3 and RNF146 are reported to be related to Wnt signaling pathway, which regulates hair follicle cycling, and
copy number variation of the two genes might lead to hypertrichosis, alone or in combination.
In all, it is the first time that chromosomal rearrangements on chromosome 6 are detected in patients with CGH. We also
inferred the structure of the rearranged chromosome, and speculated their origin.
Mon(2)-P-184
Mosaic ring chromosome 21 and monosomy 21 in a patient with anterior ectopic anus and perineal
lipoma
Takako Sasaki 1 ，Shuichi Yatsuga 1 ，Kikumi Ushijima 1 ，Miyuki Kitamura 1 ，Jyunko Nishioka 1 ，Yasutoshi Koga 1
1:Department of Pediatrics and Child Health, Kurume University School of Medicine, Japan
Introduction:Partial monosomy for a 21 chromosome were characterized by mental and physical retardation, microcephaly,
antimongoloid slant of eyelids, malformed and low set ears. The extent of the feature was depending on the region of the
deletion or duplication. No report exists mosaic ring chromosome 21 and monosomy 21 in a case with ectopic anus and
perineal lipoma. We report a case of 46,XX,r(21)(p13q22.3)/45,XX,-21 with an anterior ectopic anus and perineal lipoma.
case:The patient was bone with an anterior ectopic anus and perineal tumor at 40-week gustation. Birth weight was 3143g
(- 0.06 SD), and birth height was 49 cm (-0.36 SD). External malformation was not found except for external genitalia.
The patient did not have microcephaly, antimongoloid slant of eyelids, malformed and low set ears. External genitalia were
normal female with a clitoris at the top, labia minora and labium majus. Perineal tumor size was 1.5cm lipomatous swelling
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ICHG2016 880
between vagina and anterior ectopic anus. Perineal tumor suggested lipoma in magnetic resonance imaging (MRI). Renal
and cardiac abnormal findings were not detected by echo. We performed G-banding test. The karyotype was 45,XX,-21/
46,XX,r(21)(p13q22.3).
Discussion: Trisomy 21, Down syndrome, is one of the common chromosomal diseases. On the other hand, monosomy 21 is
rare. True monosomy 21 was reported as lethal phenotype. Perineal lipoma should be distinguished from undescended testis.
If the patient had other urogenital abnormalities, we may consider with disorder of sex development. Relationship between
perineal lipoma, anterior ectopic anus, and mosaic chromosome 21 is not explained yet.
Conclusion Possible contribution of perineum malformations with mosaic chromosome 21 cannot be excluded. We need further
analysis, such as CGH-array.
Mon(2)-P-185
Chromosome 8p abnormalities associated with severe global developmental delay: report of two cases
Ina O Focsa 1 ，Magdalena Budisteanu 1,2
，Andreea C Tutulan-Cunita 1 ，Sorina M Papuc 1 ，Carmen Burloiu 2 ，
Ioana Minciu 2 ，Aurora Arghir 1
1:V.Babes Nathional Institute of Pathology, Romania、2:Prof. Dr. Alex. Obregia Clinical Hospital of Psychiatry, Bucharest, Romania
Introduction: Chromosomal imbalances are frequent causes of global developmental delay (GDD), growth retardation and
Poster Session
dysmorphic features. Over 56 genetic conditions are related to changes in genes on chromosome 8. Chromosome 8p includes
484 genes and 110 pseudogenes, of which ~ 8% are involved in brain development and function.
Aim: We report on 2 pediatric patients with complex phenotype and genetic abnormalities associated with chromosome 8p.
Patients and methods: The first patient is a 14 year-old girl with severe GDD, autism, epilepsy, hyperkinesia, heteroaggressive
behavior, dysmorphic features, microcephaly. The second case is an 8 year-old girl with severe GDD, epilepsy, dysmorphic
features, congenital microcephaly and cataract, hypoacusia. aCGH investigation was performed in both cases (Agilent Tech-
nologies).
Results and discussion: aCGH revealed 8p anomalies in both cases, an interstitial proximal deletion in the first patient,
as a sole aberration, and an impure terminal duplication in the second patient. In the first case, the deletion (arr[hg19]
8p21.1p11.2 (25278984-41469578) x1) contains ~ 140 genes, many of which being related to neuropsychiatric disorders (e.g.
NGS1, CHRNA2, ADAM9, ELP3). In the second case, the 8p duplication (arr[hg19] 8p23.3p23.1(176452-8094773)x3) is as-
sociated with a 4p deletion (arr[hg19] 4p16.1p16.3(72447-9371067)x1) that includes the Wolf-Hirschhorn critical region. The
8p genomic imbalance in the second patient includes 116 genes, many of them involved in neurodevelopment (e.g. CLN8,
MCPH1).
Conclusion: Chromosome 8p represents a hot-spot for anomalies in neurodevelopmental disorders. While our first patient
brings new evidence on the role of 8p chromosome abnormalities in autism, a feature rarely associated with proximal inter-
stitial deletion 8p11.2p21.1, the second patient illustrates the contribution of concomitant genomic anomalies to composite
phenotypes.
Acknowledgment: National Project PN.92.033.02.03
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Mon(2)-P-186
Whole genomic analysis of Mayer- Rokitansky- Küster- Hauser syndrome
Kazumi Takahashi 1,2 ，Yuko Ohnuki 2,3,4 ，Shingo Suzuki 3 ，Mari Shinoda 1,2
，Yoshihiro Nishijima 1 ，Akane Kondo 1,2,5
，
Takahiro Suzuki 1 ，Takashi Shiina 3 ，Shunichiro Izumi 1,2
1:Department of Obstetrics and Gynecology, Tokai University School of Medicine, Japan、2:Department of Clinical Genetics, Tokai University
Hospital、3:Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine,Tokai University School of
Medicine、4:Department of Internal Medicine, Division of Neurology, Tokai University School of Medicine、5:Department of Obstetrics and
Gynecology, Shikoku Medical Center for Children and Adults
Background: The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenial absence of the uterus
and the upper two-thirds of the vagina, occurring in 1 out of 5000 females birth. Patients with MRKH syndrome have normal
development of secondary sex characteristics and a normal female karyotype (46, XX), typically present with amenorrhea
during adolescence. Although most cases are sporadic, familial clustering does occur and supports a genetic etiology. Several
chromosomal imbalances and candidate genes have been studied but no conclusive factor has yet been identified.
Methods: We searched for microdeletions or microduplications by high-resolution array- comparative genome hybridization
(CGH) in not only a patient MRKH syndrome but also her healthy parents and sister using an Agilent Human Genome CGH
microarray 1M kit (Agilent Technologies Inc.) with a resolution of 2.1 kb.
Results:
Array-CGH analysis disclosed de novo 6 deletions and 7 amplification compared with those of her parents and her sisiter.
Poster Session
Conclusion:
MRKH syndrome does not identified clear genetic causes. We found de novo 6 deletions and 7 amplification. Though one of
these is matched to the chromosomal region what already reported as deletion, this imbalance is expected to be a candidate
locus for MRKH syndrome. We here report with further analyses.
Mon(2)-P-187
A rare case of Happle-Tinschert syndrome
Mehmet Seven 1 ，Emre Kirat 1 ，Mehmet Bugrahan Duz 1 ，Elif Fenercioglu 1 ，Adnan Yuksel 2 ，Hakan Ulucan 1
1:Cerrahpasa Medical School of Istanbul University, Turkey、2:Biruni University
Happle-Tinschert syndrome is characterized by skin, bone, teeth and central nerve system abnormalities. It is a very rare
disease reported only 9 times so far. Main features are unilateral basaloid follicular hamartomas, ipsilateral skin atrofia, hypo-
or hyperpigmentation, asymmetric abnormalities of digits and toes, size difference between extremities, hypo- or adontia,
ventriculomegaly and decrease or increase in hairing. Intellectual disability is reported in a few cases. The cases are all
sporadic and no genes or mutations have been found so far. PTCH1 has been investigated in peripheric blood and skins of
some patients, but no mutations have been found. We here present a rare case with basaloid follicular hamartomas, ipsilateral
extremity shortness and ventriculomegaly.
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Mon(2)-P-188
Ehlers-Danlos syndrome and 22q11.21 microduplication in one patient
Soghra Jougheh Doust 1 ，Emily Fox 1
1:Pediatrics, Genetics Program, Peterborough Regional Health Centre, Canada
Chromosome 22q11.2 region is prone to rearrangements specifically deletions and duplications due to low copy number variants
(LCRs) in this region. The well-known DiGeorge syndrome or velocardiofacial syndrome (DGS/VCFS) is a syndrome caused
by common 1.5 Mb or 3 Mb deletions in this critical region. Recently reciprocal duplications involving 22q11.2 has been
suggested as a new entity with highly variable phenotype.
Our patient is a 23 year-old female initially diagnosed with Ehlers-Danlos syndrome(EDS)- hypermobility type. The patient
is found to have facial dysmorphism including up-slanting and short palpebral fissures, small and low-set ears, short nose,
smooth philtrum, high arched palate, and micrognathia. In addition, short stature, underdevelopment of breast tissue, nasal
speech and polydontia are the other features. The patient has a normal cardiac echocardiogram. She has high myopia. She
does not have learning or developmental issues.
The SNP array revealed a 2.816 Mb duplication at 22q11.21 region involving 72 RefSeq genes including 11 OMIM Morbid Map
genes. Maternal FISH confirmation is pending. Father is deceased. Our patient does not show many overlapping features of
DGS/VCFS.
Poster Session
The probable diagnosis of EDS-hypermobility type was made on the basis of hip dislocation, torn ligaments, polyarthralgia,
easy bruising, high myopia and joint hypermobility (beighton score of 6/9).
Although joint hypermobility and myopia have been previously reported in patients with 22q11.2 microduplication, while
the severity of joint laxity and other features suggestive of EDS-hypermobility type in our patient may suggest that she
has two common genetic conditions, it is possible that her EDS-like phenotype is a part of the phenotypic spectrum of the
22q11.2 microduplication syndrome. Future studies on the function of the genes involved in this region will shed more light
on phenotypic features of the 22q11.2 microduplication syndrome.
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Poster Session
Clinical Genetic Testing
Mon(2)-P-189
Title Prevalence of the JAK2 V617F mutation in Srinagarind hospital between June 2013 - June 2014
Kanokon Chaicom 1 ，Chitima Sirijerachai 1 ，Kanchana Chansung 1 ，Pinsuda Klangsang 1 ，Boonpeng Palaeng 1 ，
Prachub Chaimanee 2 ，Pimjai Ananta 2
1:Department of Medicine, Medicine Faculty, Department of Medicine, Medicine Faculty KhonKaen University, Thailand、2:Central
Laboratory Srinagarind Hospita
The mutations of JAK2 are association with chronic myeloproliferative disorders (CMPDs) has been described as a frequent
genetic event in majority of patients with polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofi-
brosis (IMF). Its frequency varies in different populations but there are no data from Khon Kaen,Thailand. We therefore,
looked for JAK2 V617F mutation in Khon Kean, Thailand. This study is a retrospective descriptive research, Mutation
screening for JAK2 V617F in patients was performed in 83 patients attending Hematology clinic in a Srinagarind hospital
in Khon Kaen, Thailand, by Allele Specific-PCR (AS-PCR) assay and analyzed by SPSS for Windows using descriptive
statistics. JAK2V617F mutation was found in 21 of 83 cases (25.30%), 33.33 percent in PV, 38.10 percent in ET and 19.04
Poster Session
percent of IMF. The presence of JAK2V617F mutation was associated with a higher hemoglobin level, a higher white blood
cell count and higher age. The findings will be used as reference statistics. And guide the development of diagnostics and
treatment plan provides the most effective.
Mon(2)-P-190
A case of chromosome 9 trisomy mosaicism not detected by conventional karyotyping or standard aCGH
analysis method
Tomonari Awaya 1 ，Kanako Maizuru 1 ，Atsushi Yokoyama 1 ，Minako Ide 1 ，Takeo Kato 1 ，Tohsio Heike 1 ，
Hironao Numabe 1,2
1:Department of Pediatrics, Kyoto University Hospital, Japan、2:Department of Genetic Counselling, Ochanomizu University
[Introduction] Chromosome 9 mosaic is a rare condition associated with variable features, and is difficult to diagnose by
conventional karyotyping. We present a case whose trisomy was not detected by intensive karyotyping or standard aCGH
analysis method, and discuss the pitfalls in mosaic detection. [Case] An 18-month-old dysmorphic female patient was referred
to our hospital. She had a history of severe IUGR, and suffered from respiratory and feeding difficulty due to central hypopnea,
gastro-esophageal reflux, and recurrent pneumonia. Subtle seizures were noted during early infancy. She also showed severe
psychomotor retardation. Clinical investigation revealed bilateral hearing loss, and small infarction at the left ventricle wall.
[Cytogenetic testing] Karyotype: 46,XX [20 counts at neonate, 1,000 counts at 18 months]; Array CGH (Agilent CGH+SNP
180K): Complete 9 chromosome amplification [AverageLogRatio: 0.21*]; Interphase FISH for ABL gene (9q34.1): 3 signals
in 24.0% [240/1,000] on buccal samples, and 28.6% [20/70] on blood samples. *This aberration was not detected by standard
analysis method CGH+SNP v2 provided by Agilent due to the cut-off AverageLogRatio value of <0.25. [Discussion] We
experienced a female patient whose trisomy mosaic was not detected by intensive karyotyping or standard aCGH. However,
aCGH signals slightly shifted to the patient-side throughout chromosome 9. The re-calculated LogRatio of chromosome 9 was
0.21 (approximately 31% trisomy). Subsequent interphase FISH analysis revealed 24-29% trisomic cells, which confirmed the
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diagnosis. We speculate that trisomy 9 cells have some growth disadvantage during blood cultivation using PHA stimulation,
and the cut-off LogRatio value of 0.25 can only allow the detection of more than 38% trisomic cells. These practical pitfalls,
and the limitations of conventional karyotyping and standard aCGH analysis in mosaic detection should be noted.
Mon(2)-P-191
Genetic heterogeneity in 26 infants with a hypomyelinating leukodystrophy
Natsuko Arai-Ichinoi 1 ，Mitsugu Uematsu 1 ，Atsuo Kikuchi 1 ，Ryo Sato 1 ，Hiroki Kudo 1 ，Tasuku Suzuki 1 ，
Naomi Hino-Fukuyo 1 ，Mitsuyo Matsumoto 2,3 ，Kazuhiko Igarashi 2 ，Kazuhiro Haginoya 4 ，Shigeo Kure 1
1:Pediatrics, Tohoku University School of Medicine, Japan、2:Biochemistry, Tohoku University Graduate School of Medicine、3:Integrative
Genomics, Tohoku Medical Megabank Organization, Tohoku University、4:Pediatric Neurology, Takuto Rehabilitation Center for Children
T2 hyperintensity of brain white-matter lesions detected by magnetic resonance imaging (MRI) are characteristic of a het-
erogeneous group of diseases. Persistent T2 high intensity in combination with T1 iso- or high intensity of white matter in
infants indicates a lack of normal myelination, that is, hypomyelination. However, the precise diagnosis of hypomyelinating
leukodystrophy based solely on MRI findings can be difficult, especially in the early stage of the disease. We studied 26
patients who were diagnosed with hypomyelinating leukodystrophy according to MRI findings and clinical features to uncover
their genetic etiology through chromosomal analyses, targeted gene analyses, and an array comparative genomic hybridization
(aCGH) assay. Then, for the 17 patients with unexplained hypomyelination by traditional analyses, whole-exome sequencing
(WES) was performed. The presumptive diagnoses were confirmed in 58% of the enrolled patients (15/26) and involved 9
different genetic backgrounds. The most frequent backgrounds were 18q deletion syndrome and Pelizaeus-Merzbacher disease,
Poster Session
with an incidence of 12% (3/26) for both. The diagnostic rate of chromosomal analyses, targeted gene analyses, and aCGH
was 31% (8/26), and one patient was clinically diagnosed with Cockayne syndrome. Using WES, the following causative genes
of hypomyelination were identified in six individuals (35%, 6/17): TUBB4A, POLR3B, KCNT1 , and MCOLN1 , and some
of those genes were pathogenic for not only hypomyelination but also dysmyelination or delayed myelination. Our findings
suggested heterogeneous genetic backgrounds in patients with persistent white matter lesions. These data also indicate that
WES may be a rapid and useful tool for identifying the underlying genetic causes of undiagnosed leukodystrophies.
Mon(2)-P-192
Genome Sequencing Carrier Testing in Preconception Women: Lessons Learned from the First Two
Years of the NextGen Study
J A Reiss 1 ，B Wilfond 2,3 ，F Lynch 1 ，T L Kauffman 1 ，J Schneider 1 ，C McMullen 1 ，M C Leo 1 ，J Davis 1 ，
M Gilmore 1 ，P Himes 1 ，E Morris 1 ，C S Richards 4 ，S Punj 4 ，G P Jarvik 5,6 ，L Amendola 5 ，D Nickerson 6 ，
K AB Goddard 1
1:Center for Health Research, Kaiser Permanente Northwest, USA、2:Department of Pediatrics, Division of Bioethics, University of
Washington, Seattle, WA、3:Truman Katz Center for Pediatric Bioethics, Seattle Childrens Hospital, Seattle, WA、4:Department of
Molecular and Medical Genetics, Knight Diagnostic Laboratories, Oregon Health & Science University, Portland, OR、5:Department of
Medicine University of Washington, Seattle、6:Department of Genome Sciences, University of Washington, Seattle
Introduction: Rapidly decreasing costs of genome sequencing are making clinical application of expanded carrier testing more
feasible in a general clinical setting. However, the impact on patients has not been empirically assessed.
Methods: As part of the Clinical Sequencing Exploratory Research consortium, Kaiser Permanente Northwest is conducting
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the NextGen study, a randomized trial of preconception genetic carrier screening that compares genome sequencing (GS) to
prior testing. Women who received carrier testing and are not pregnant are eligible. Male partners of women who are carriers
are enrolled to identify at-risk couples. Women in the GS arm have750 gene/condition pairs analyzed. They can select five
categories of carrier gene/disease pairs: shortened lifespan, serious, mild, unpredictable, and adult onset. Pathogenic and
likely pathogenic variants for carrier status are disclosed. Information is optional for variants for about 100 genes associated
with medically actionable conditions.
Results: The study has enrolled 229 subjects, while 457 declined participation. Most (89%) chose to receive results from all
disease categories. Sequencing has been completed for 82 participants. Of those 82, 79% are Caucasian with an average age of
32 for women and 34 for men. Approximately 2/3 of the women randomized to GS had at least 1 variant identified (average
1.8, range 1-5). A total of 99 carrier variants and 2 medically actionable conditions have been disclosed. For two couples,
both partners were carriers for pathogenic variants in the same gene.
Discussion: This presentation focuses on lessons learned from the first 100 sequenced participants. Lessons include: time
needed for genetic counseling for returning results, potential for heightened anxiety for pregnant participants with positive
carrier results, adequately conveying uncertainty surrounding laboratory and clinical validity of results, and reasons women
decline GS for carrier testing.
Poster Session
Mon(2)-P-193
Identification of Novel mutations in SLC20A2 and PDGFB responsible for primary familial brain calcifi-
cation
Shingo Koyama 1 ，Hidenori Sato 1 ，Manabu Wada 1 ，Shigeki Arawaka 1 ，Toru Kawanami 1 ，Takeo Kato 1
1:Yamagata University, Japan
Background
Primary familial brain calcification (PFBC), also known as Fahr’s disease or idiopathic basal ganglia calcification, is a rare
neuropsychiatric disorder. Clinical presentation is characterized by psychosis, cognitive impairment, migraine, parkinsonism;
however, individuals with brain calcification can be clinically asymptomatic. This condition is typically transmitted in an
autosomal dominant fashion and is genetically heterogeneous. So far, mutations in SLC20A2 , PDGFRB, PDGFB, and XPR1
have been reported to be responsible for PFBC. Whole-exome sequencing (WES) is becoming widely adopted as an efficient
strategy to identify disease-causing mutations in genetically heterogeneous diseases.
Methods
Three probands and their relatives of familial cases of PFBC and 6 sporadic patients were enrolled for clinical and genetic
analysis. WES was performed using amplicon-based next-generation sequencing using an Ion AmpliSeq Exome Kit (Life
Technologies, Carlsbad, CA).
Results
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Three novel mutations responsible for PFBC were identified: c.269G>T (p.Gly90Val) and c.516+1G>A in SLC20A2 in
familial cases; c.577-1G>T in PDGFB in a sporadic patient. RT-PCR analysis demonstrated that the c.516+1G>A mutation
results in exon 4 skipping in SLC20A2 , leading to a frameshift and a premature stop codon (p.Val144Glyfs*85). The abnormal
123
findings were demonstrated in I-metaiodobenzylguanidine cardiac scintigraphy and dopamine transporter single photon
123
emission computed tomography using I-ioflupane in patients presenting with parkinsonism.
Conclusions
WES is a powerful clinical tool in the evaluation of genetically heterogeneous conditions such as PFBC. Genetic analysis
should be considered even in apparently sporadic patients due to its incomplete clinical penetrance. Radiological examinations
revealed pre-synaptic dopaminergic deficit and cardiac sympathetic nerve dysfunction in PFBC-associated parkinsonism.
Mon(2)-P-194
Mutational spectrum and genotype-phenotype association in a cohort of Croatian, Serbian and Slovenian
patients with hereditary angioedema due to C1 inhibitor deficiency
Mira Silar 1 ，Mitja Kosnik 1 ，Mihaela Zidarn 1 ，Peter Korosec 1 ，Sladjana Andrejevic 2 ，Ljerka Karadza-Lapic 3 ，
Drasko Cikojevic 4 ，Marko Baresic 5 ，Matija Rijavec 1
1:Laboratory for Clinical Immunology and Molecular Genetics, University Clinic for Respiratory and Allergic Diseases Golnik, Slovenia、
2:Clinic of Allergology and Immunology, Clinical Center of Serbia, Belgrade, Serbia、3:General Hospital Sibenik, Sibenik, Croatia、
4:University Hospital Split, Split, Croatia、5:University Hospital Center Zagreb
Poster Session
Background: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare genetic disorder characterized
by recurrent oedemas and large heterogeneity in clinical presentation. We aimed to determine the spectrum of SERPING1
mutations in Croatia, Serbia and Slovenia and to investigate the possible associations between mutation type and disease
phenotype.
Methods: A cohort of 85 well clinically characterised C1-INH-HAE patients from 46 unrelated families was recruited for
genetic analysis, which included sequencing and multiplex ligation-dependent probe amplification of SERPING1 gene.
Results: We have identified 32 different mutations; 29 in C1-INH-HAE type I, among them 10 missense, 8 nonsense, 6
frameshift, 2 splicing defects, 1 substitution affecting the promoter, 2 large deletions, 1 large insertion, and 2 mutations in
C1-INH-HAE type II both affecting the Arg444. Nine mutations have not been previously described. In one patient only the
homozygous variant c.-21T.C was found while in one patient no causative mutation could be identified. To investigate the
possible correlation between type of mutation and disease phenotype, patients were divided into two mutation groups: group
1 (nonsense, frameshift, large deletions/insertions, splicing defects, and mutations at Arg444) or group 2 (missense, excluding
mutations at Arg444). Since our patient population consisted of related subjects we performed generalized estimating equation,
and found significant differences in clinical severity score (P = 0.03), based on the age of disease onset, organs affected and
long-term prophylaxis ever, between two mutation groups, with milder disease in group 2.
Conclusion: Our study identified 32 different, among them 9 novel, disease-causing mutations in C1-INH-HAE patients,
highlighting the heterogeneity of mutations in the SERPING1 gene. Furthermore, it appears that mutations with clear
impact on the C1-INH function might be responsible for a more severe disease phenotype.
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Mon(2)-P-195
Universal Lynch Syndrome Screening in an Integrated Health Care System: Results of a 5-Year Study
Jacob A Reiss 1 ，Kathleen A Arlond 1 ，Kellene M Bergen 1 ，Jennifer Cook 1 ，James V Davis 1 ，Elizabeth J Esterberg 1 ，
Marian J Gilmore 1 ，Jessica Ezzell Hunter 1 ，Tia L Kauffman 1 ，Cheryl McGinley 1 ，Kristin R Muessig 1 ，
Alan F Rope 1 ，Jennifer L Schneider 1 ，Carol Young 1 ，Jamilyn M Zepp 1 ，Louise S Acheson 2 ，Susan K Peterson 3 ，
Sapna Syngal 4 ，Georgia L Wiesner 5 ，Katrina AB Goddard 1
1:Center for Health Research, Kaiser Permanente Northwest, USA、2:Departments of Family Medicine and Community Health, Reproductive
Biology, and Oncology, Case Western Reserve University, Cleveland, OH、3:Department of Behavioral Science, University of Texas MD
Anderson Cancer Center, Houston, TX、4:Dana-Farber Cancer Institute, Boston, MA、5:Vanderbilt Hereditary Cancer Program, Department
of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN
Background:Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, found in 2-3% of
all new CRC cases. Universal tumor screening (UTS) of newly CRC cases has been proposed to increase identification of
LS cases and to reduce morbidity and mortality in at-risk family members. Microsatellite instability (MSI) testing and
immunohistochemistry (IHC) testing are effective methods for CRC tumor screening for LS. The study is exploring feasibility
of implementing a UTS program for LS in an integrated health care system.
Method:Kaiser Permanente Northwest (KPNW) is an integrated health care system in Oregon and Washington, USA. KPNW
members, who were newly diagnosed with CRC in 2011-2015 were recruited to determine the effectiveness of UTS (via MSI
testing) for LS versus usual practice. Members with MSI-High tumors were followed up by a genetic counselor.
Results:207 eligible participants consented to participate in this study; 138 declined. Of 184 (88.9%) tumors tested for MSI,
36 (19.5%) were MSI-High, 119 (64.7%) were MSI-Stable, and 29 (15.8%) had insufficient material. Of 31 MSI-High tumors
Poster Session
with follow-up IHC completed, 30/31 (96.8%) had abnormal IHC results. In the abnormal IHC group, there was MLH1
hypermethylation in 21 (70%). 9 (29.0%) participants with no hypermethylation were referred for genetic counseling. LS was
diagnosed in 5 (16.7%). 31/143 (21.7%) surveyed with MSI-Stable or MSI-Insufficient results had a positive family history
for CRC. They might benefit from genetic counseling. In this UTS study, LS was diagnosed in 2.7% of CRC patients.
Conclusions:UTS improved the identification of LS over usual care. Among participants with LS, 40% would not have been
identified following existing guidelines. Limitations included not testing colonoscopy specimens, patient refusal to consent
to testing, refusal following consent, and ineligibility from chart review. Barriers and facilitators for implementing UTS at
KPNW will be discussed.
Mon(2)-P-196
From Sanger sequencing to NGS approaches for molecular diagnosis for primary immunodeficiency dis-
eases (PID)
Jing Yang 1 ，Wanling Yang 1 ，Pamela Pui Wah Lee 1 ，Yu Lung Lau 1
1:The University of Hong Kong, Hong Kong
Sanger sequencing of PCR amplicons has been the predominant method for genetic testing of candidate genes for primary
immunodeficiency diseases. Despite largely successful results in finding causal mutations for this group of diseases, the method
is tedious and inefficient, and suffers from false negative and false positive detections under many circumstances. Next
generation sequencing is rapidly becoming applicable to genetic testing in clinical laboratories and has showed advantages in
many aspects. In this report, we showed two real cases in which whole exome sequencing successfully detected the causal
mutations missed by previous tests using Sanger sequencing. In one of the cases, a somatic mutation for which the mutation
allele only accounted for less than 12% of the total chromosomes from peripheral blood mononuclear cells in the NLRP3
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gene in a patient suffering from chronic infantile neurological, cutaneous and articular syndrome (CINCA) was detected by
whole exome sequencing. In another case, a large deletion in DCLRE1C gene, missed previously due to very slight sample
contamination, was detected by whole exome sequencing and analysis using CoNIFER (copy number inference from exome
reads). While whole exome sequencing showed advantages in these cases, we propose two new strategies, a combination of
sequence-specific PCR and smaller scale next generation sequencing, and a combination of targeted region capture and whole
exome sequencing for molecular diagnosis of primary immunodeficiency disease and similar clinical situations.
Mon(2)-P-197
Application of array-based comparative genomic hybridization to pediatric neurologic diseases
Amal M Alhashem 1 ，Brahim Tabarki 1 ，Bashaer Al Bulushi 1
1:Pediatrics, Prince Sultan Military Medical City, Saudi Arabia
PURPOSE:
Array comparative genomic hybridization (array-CGH) is a technique used to analyze quantitative increase or decrease of
chromosomes by competitive DNA hybridization of patients and controls. This study aimed to evaluate the benefits and yield
of array-CGH in comparison with conventional karyotyping in pediatric neurology patients.
MATERIALS AND METHODS:
Poster Session
We included 700 patients from the pediatric neurology clinic with at least one of the following features: developmental
delay/intellectual disability, dysmorphic features, microcephaly, multiple congenital anomalies or refractory epilepsy. Results
are compared with G-band karyotyping. The results were analyzed with findings reported in recent publications and internet
databases.
RESULTS:
Array CGH yielded abnormal (pathogenic) results in 189 of 700 patients (27%), and normal in 511 patients (73%).
CONCLUSION:
Although there were relatively small number of tests in patients with pediatric neurologic disease, this study demonstrated
that array-CGH is a very useful tool for clinical diagnosis of unknown genome abnormalities performed in pediatric neurology
clinics
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Mon(2)-P-198
Diagnostic Utility of Regions of Homozygosity Detected by Chromosome Microarray in Two Cases of
Inborn Errors of Metabolism
Roya M Mostafavi 1 ，Asim F Choudhri 1,2
，Jewell C Ward 2,3
，Eniko K Pivnick 2,3
1:Le Bonheur Children’s Hospital, USA、2:University of Tennessee Health Science Center、3:UT Le Bonheur Pediatric Specialists
Single nucleotide polymorphism chromosome microarray (CMA), in addition to detecting copy number variations, can detect
regions of homozygosity (ROH) indicative of uniparental disomy, consanguinity, or descent from a common ancestor, all of
which increase the risk of autosomal recessive (AR) conditions. AR genes within ROHs, combined with clinical presentation,
can greatly facilitate the diagnostic process. We report 2 patients with ROHs identified by CMA whose phenotype, as well
as review of AR genes within the ROHs, helped direct diagnoses.
Patient 1, a 10 year old male, presented with progressive cognitive decline, joint contractures, seizures, dysphagia and mildly
coarse facial features. He was the product of consanguinity and had inconsistent family and medical care. Brain MRI revealed
generalized cerebral volume loss and cystic cerebellar lesions. Analysis of AR genes within his ROHs included SGSH , the gene
responsible for heparan N-sulfatase enzyme, deficiency of which is associated with Sanfilippo IIIA. Diagnosis was confirmed by
urinary elevation of heparan sulfate and ~ 5% leukocyte heparan-N-sulfatase activity. Patient 2, a newborn female, presented
with hypotonia, dysmorphia, and ventriculomegaly. MRI of the brain showed bilateral perisylvian polymicrogyria, as well
as germinolytic cysts along the lateral margin of the body of both lateral ventricles. CMA detected ROH and analysis of
AR genes identified PEX 12 , one of 12 known genes associated with Zellweger syndrome (ZS). Physical exam suggested ZS
and diagnosis was confirmed by elevated very long chain fatty acids and detection of a homozygous pathogenic frameshift
Poster Session
mutation in the PEX12 gene.
Combining clinical information with ROHs detected by CMA can lead to identification of single AR genes of interest in
genetically heterogeneous conditions and can streamline timely, cost effective diagnostic workup, which may lead to earlier
treatment, enhanced quality of life, and timely genetic counseling.
Mon(2)-P-199
Functional Analysis of Three Novel TSC2 Variants Identified in Taiwanese TSC Patients
1,2
Da-Chang Chu ，Tz-Shiu Tsai 2 ，Jung-Yu Liao 1 ，Ju-Li Lin 3 ，Po-Cheng Hung 4
1:Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taiwan、2:Graduate Institute of Biomedical
Sciences, Chang Gung University, Tao-Yuan, Taiwan、3:Division of Medical Genetics & Neonatology, Department of Pediatrics, Chang Gung
Memorial Hospital, Lin-Kou, Taiwan、4:Department of Pediatric Neurology, Chang Gung Memorial Hospital, Taipei, Taiwan
Tuberous sclerosis complex (TSC, MIM number 191092) is an autosomal dominant genetic disorder frequently encountered
in pediatric genetic clinics in Taiwan. With clinical features commonly observed among other disorders, it is necessary to
explore molecular evidences to assist clinicians making accurate diagnosis. In our lab we use high resolution melting analysis
(HRMA) and next generation sequencing (NGS) to identify TSC genes mutations in patients suspect of suffering from TSC.
However, certain novel missense mutations we found have not been documented in TSC gene mutation database and thus
whether they are deleterious or merely gene polymorphism need to be determined. An in vitro system involving site-directed
mutagenesis and S6K1 protein phosphorylation determination in mTOR pathway was applied to fulfill this purpose. Data
indicated that TSC2 c.1565 A to C and c. 4400 C to G transitions are less likely pathogenic but c.4436 C to T is very
likely pathogenic. In conclusion, we have successfully established a platform to demonstrate the nature of novel TSC2 gene
mutations and these results can be helpful for physicians when making clinical diagnosis.
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Mon(2)-P-200
Identification of a Factor VIII Exon 14 novel frame shift mutation c. 2138 delA, p.(N713Tfs*9) in Saudi
Arabian patient: Genotype-Phenotype Correlation
Faisal A. Allaf 1,2,3 ，Mohiuddin M. Taher 2 ，Zainularifeen Abduljaleel 2 ，Mohammed Athar 2 ，Halah Abalkhail 4 ，
Faisal A. Ba-hammam 2 ，Munir Abdulla 2 ，Abdellatif Bouazzaoui 2 ，Tarek M. Owaidah 4
1:Medical Genetics, Umm-Al-Qura University, Makkah, KSA, Saudi Arabia、2:Science and Technology Unit, Umm Al-Qura University,
Makkah、3:Department of Laboratory Medicine and Blood Bank, King Abdullah Medical City, Makkah、4:Pathology and Laboratory
Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia
Hemophilia-A is a disorder of blood coagulation factor deficiency, affected gene, factor VIII is transmitted by heterozygous
females and the disease phenotype presents exclusively in males. More than 1000 different mutations have been described
in factor VIII gene. Mutations are predominantly point mutations such as missense, nonsense, frame shift mutations, and
splice sites mutations. Exon 14 of factor VIII gene is larger than 3000 bp, many deletions, insertions, and point mutations
were reported in this exon. Here we report the mutations screening in factor VIII gene in Saudi Arabian population. For
factor VIII gene sequencing a cohort of 107 samples from 87 of families undergoing treatment at KFSH&RC (Riyadh) were
collected. All patients were tested for factor VIII coagulant activity that was carried out on Behring Coagulation System.
First, screening for inversion 1, and inversion 22 were performed, and the positives were excluded. PCR products from the
family’s index cases were screened by Sanger method and analyzed on ABI 3500 Genetic analyzer. In one patient in exon14
we have identified a novel frame shift mutation c. 2138 delA, p.(N713Tfs*9). This deletion of A in AAT codon of Aspargine
changes to ACT and codes for Threonine and inturn a frame shift occurs in the coding of 9 amino acids further and a stop
codon (TGA) at 9th amino acid leading to transcriptional termination and truncated protein. This mutation is associated
with sever to moderate form of hemophilia. This patient was a 15 years old male with mild hemophilia symptoms with factor
Poster Session
VIII levels of 5 to 40% . Our In-silico study suggests that this mutation have significant impact on the structure and function
of the factor VIII protein. Genotype-phenotype correlations and computer prediction analysis on the effect of this frame shift
mutation on the secondary structure of the factor VIII protein were performed and the relationships evaluated. (MAARIFAH
Grant Code: 09-BIO920-10).
Mon(2)-P-201
Development of a melting curved-based allele-specific PCR of apoliooprotein E (APOE) genotyping
method for genomic DNA, Guthrie blood spot and whole blood
1,2
Chia-Hsiang Chen
1:Chang Gung University, Taiwan、2:Chang Gung Memorial Hospital-Linkou
Apolipoprotein E (APOE) genotype is associated with various health and disease conditions, especially the APOE4 associated
with Alzheimer’s disease is well documented worldwide across different population. Given the presence of various genotyping
methods for APOE, there is still a need for a fast, accurate, and inexpensive APOE genotyping method with a flexible
throughput in the laboratory that can be used for population research and clinical utility. We develop a melting curve-based
allele-specific PCR method to assess the genotype of two single nucleotide polymorphisms (SNPs) at codon 112 (rs429358)
and 158 (rs7412) of APOE that determine the genotype of APOE2, E3 and E4. For each SNP, two allele-specific forwards
primers tagged with different length of GC-tails and a common reverse primer were generated. PCR and melting curve
analysis were performed using SYBR Green PCR Master Mix and implemented using ABI StepOnePlus. We obtained a
concordance rate of 100% in 300 subjects typed by this method and Sanger sequencing method. We also demonstrated the
method can be reliably applied to DNA template obtained from Guthrie blood spot and whole blood. Thus, we demonstrate
fast, accurate, and inexpensive APOE genotyping method with versatility that can be used in large population research and
clinical laboratory.
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Mon(2)-P-202
Next generation sequencing-based panel analysis for hereditary connective tissue disorders through the
ion PGM™ system
Tomomi Yamaguchi 1 ，Yuki Takahashi 2 ，Masumi Ishikawa 1 ，Emiko Kise 1 ，Motoko Kamiya 1,2,3 ，Kyoko Takano 1,2
，
Katsuya Nakamura 1,2 ，Rie Kawamura 2 ，Keiko Wakui 1,2 ，Yoshimitsu Fukushima 1,2 ，Tomoki Kosho 1,2
School of Medicine、3:Problem-Solving Oriented Training Program for Advanced Medical Personnel: NGSD Project
Hereditary connective tissue disorders (HCTD), such as Marfan syndrome (MFS) and Ehlers-Danlos syndrome (EDS), are
good candidates for next generation sequencing (NGS)-based panel analysis of causative genes, because (1) appropriate
prevention and/or intervention based on early genetic diagnosis would lead to improvement of survival and quality of life; (2)
clinical diagnosis would be sometimes difficult; (3) causative genes are often large; (4) genetic information would be useful in
early diagnosis of at-risk family members. We present current status of an ion PGM™ -based panel analysis for HCTD that we
established. We obtained genomic DNA from 125 patients suspected clinically to have HCTD. Genetic analysis was performed
through the ion PGM™ system: custom primer sets comprising 17 genes known to cause MFS, EDS, Loys-Dietz syndrome,
and Beals syndrome; validation pipeline using wANNOVAR. As a result, 11 mutations, in COL5A1 (4 patients), COL5A2 (5),
COL1A1 (1), TNXB (1), were detected in 20 patients (55%) with suspected classical type EDS; 12 mutations, in COL3A1 (9),
COL5A1 (2), COL1A1 (1), in 38 patients (32%) with suspected vascular type EDS; 2 homozygous/1 compound heterozygous
mutations, in CHST14 , in 4 patients (75%) with suspected musculocontractural type EDS; 2 mutations, in COL1A1 (2), in 3
patients with suspected osteogenesis imperfecta; 9 mutations, in FBN1 (8), COL3A1 (1), in 34 patients (26%) with suspected
MFS; no mutations in 26 patients with suspected hypermobility type EDS, arthrochalasia type EDS, unclassified type EDS,
Poster Session
or Beals syndrome. These results were applied to the management of each patient (surveillance, intervention, evaluation of
at risk family members). Incorrect clinical diagnosis, heterogeneity of the disorders, or undetectable mutations in this system
(e.g. copy number variations) could be related to limited overall detection rate (37/125, 30%). NGS-based panel analysis is
useful in the management of patients with HCTD.
Mon(2)-P-203
Indications for first erythrocyte transfusion in patients with upper gastrointestinal bleedings considering
the genetic constitution
Sergiy Kharchenko 1 ，Sergiy Kobyletskyi 1 ，Igor Duzhiy 1
1:Department of Surgery, Radiology and Phthisiology, Medical Institute of Sumy State University, Ukraine
Background. Today the transfusion practice has a growing trend towards a restrictive management, however, individual
approach to define indications for transfusion therapy is still clinically challenging in every patient with upper gastrointestinal
bleeding.
Aim: to develop indications for first eyrthrocyte transfusion considering the patient genetic constitution based on ESR1
(rs2234693) single nucleotide polymorphism.
Materials and methods. A total of 10 patients with acute upper gastrointestinal bleedings were analyzed. The patient data
were collected from Sumy Regional Clinical Hospital and Sumy State University in 2014. After the in-patient conservative
treatment the polymerase chain reaction-restriction fragment length polymorphism and the post hoc analysis were used.
Results. A new therapy scheme was designed and visualized. The first erythrocyte transfusion was indicated to compensate
nonvariceal and variceal bleedings when the haemoglobin thresholds were =<80 g/L and =<70 g/L, respectively, for patients
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with C/C genotype. Despite the bleeding etiology but during a nonstable haemostasis, the haemoglobin threshold was =<100
g/L for patients with T/T or T/C genotypes and with /without the cardiovascular anamnesis. During a stable haemostasis
for bleedings of different nature, the haemoglobin threshold was =<90 g/L for patients with T/T or T/C genotypes and with
a positive cardiovascular anamnesis, but for patients with a negative cardiovascular anamnesis the haemoglobin thresholds
were within levels of =<80-85 g/L.
Conclusions. Thus, the first erythrocyte transfusion under the haemoglobinemia between =<70 g/L and =<100 g/L should be
clinically effective for patients with upper gastrointestinal bleedings if diagnostics of haemostasis control, patient cardiovascular
history and genotyping information were appropriately considered. More research is needed for further evidence study of this
transfusion strategy.
Mon(2)-P-204
From synaptic architecture to epileptic encephalopathy
Gholamreza Shariati 1 ，Hamid Galehdari 1 ，Mohammad Hamid 1 ，Alihossein Saberi 1 ，Neda Mazaheri 1 ，Tahereh Seifi 1 ，
Mina Zamani 1 ，Javaher Zeighami 1
1:Narges laboratory, Iran
Epileptic encephalopathy is heterogeneous group of neurodevelopmental disorders. These are complex diseases included
Poster Session
multiple inducement factorsincluding genetic factors. The genetic assessmentcan provide certainty in diagnosis,treatment,
prognosis decisions. Indeed, many of these diseases causing genes encode regulator and structural proteins. Changes in any of
these proteins can affect neuronal connectivity in the brain. An important player in the game is gephyrin, a master regulator
of neuronal function.When deleterious mutations occur in these genes, synaptic homeostasismay disrupt.
Here we applied Exome sequencing to a patient with epileptic encephalopathy symptoms; mental retardation, microcephaly,
seizure (daily, from the age of 5 months), growth retardation, speechless, and blindness.
At result we found a single nucleotide variation (g.602775A>G) in HGPN genewith homozygous genotype in the patient and
heterozygous genotype in her unaffected parents. Bioinformatics analysis using mutation taster, PredictSNP (87% deleterious),
MutPred (0.85 probability of deleterious mutation) showed this mutation is diseases causing. Furthermore post translational
modification prediction using MutPred showed loss of glycosylation (p=0.0121) and phosphorylation (p=0.0415) as confident
hypotheses. Notably according to the Exome Aggregation Consortium report this allele frequency is 1.647e-05 .Protein structure
evaluation using swiss-modeling and 3D-JIGSAW showed mutated status of the proteindiffer from wild type.
These findings potentially emphasize a significant role for synaptic disorganization in epileptic encephalopathy. On the other
hand our data shed light on significance of Exome sequencing application as genetic test to identify and characterize the
comprehensive spectrum of genetic variation and classification for the patients with epileptic encephalopathy.
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Mon(2)-P-205
Next Generation Sequencing based detection of NRXN1 gene mutation in an autistic individual from
Southwest Iran
Hamid Galehdari 1 ，Gholamreza Shariati 1 ，Mohammad Hamid 1 ，Alihossein Saberi 1 ，Tahere Seifi 1 ，neda mazaheri 1 ，
Mina Zamani 1 ，Javaher Zeighami 1 ，Alireza Sedaghat 1
1:Narges laboratory, Iran
Autism and related developmental disabilities clinically referred to as autism spectrum disorders which are a neurodevel-
opmental disorder of complex etiology in which genetic factors play a major role. Neurexin 1 gene has been implicated as
gene which its variants are associated with autism or its susceptibility. Neurexin 1 (NRXN1) has two major protein isoforms
using alternative promoters, coding for the alpha-Neurexin 1 (α-NRXN1) and beta-Neurexin 1 (β-NRXN1) genes. Sequence
variants have recently been reported including four novel variants in the β-NRXN1 gene, one variant of six GGC repeats
in exon 1, and three variants at the 5- UTR. Furthermore, five novel variants were identified in the α-NRXN1 gene, four
intronic variants and one missense variant in exon 14 (c.2713T >A or p.F905I).
Next Generation Sequencing based approached revealed in the present study a recurrent homozygous missense changes in
exon 2 (c.325G>C or p.Val109Leu) of the NRXN1 gene from an individual suspected to Autism. Parents were heterozygous
for the detected change.
Mon(2)-P-206
Poster Session
Identification of a rare form of autosomal recessive ataxia by Next Generation Sequencing
1
Alireza Sedaghat
1:Jundishapur University, Iran
Episodic ataxia is a group of related conditions that affect the nervous system and cause problems with movement. Hallmark
of disease is episodic ataxia with recurrent episodes of poor coordination and balance. During this phase, patients also
experience vertigo, nausea and vomiting, migraine headaches, blurred or double vision, slurred speech, and tinnitus. Seizures,
muscle weakness, and hemiplegia may also occur during attacks.
However, we found by NGS a change at codon 225 of the SLC1A3 gene. Mutations in this gene are also the cause episodic
ataxia, type 6 with paroxysmal cerebellar incoordination, episodic ataxia, seizures, migraine, and alternating hemiplegia,
discrete episodes of ataxia and slurred speech, seemingly triggered by a febrile illness. MRI usually shows cerebellar atrophy
and neurologic examination showed mild interictal truncal ataxia. The c.674 C>T change is to date unreported, but regarding
prediction programs pathogenic. Father and mother are both heterozygous and therefore carrier. Affected child is homozygous
for detected change. Healthy individuals were negative for this change.
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Mon(2)-P-207
Comparison of three different methods for heteroplasmy detection of the Mitochondrial DNA 1555A>G
mutation
Shayan Wang 1 ，Hui Gao 1 ，Shanshan Shen 1 ，Linkai Wang 1 ，Ruanzhang Zhang 1 ，Yuhua Hu 1 ，Hui Guo 1 ，Yumei Lin 1
1:Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, China
Objective: Mitochondrial DNA (mtDNA) 1555A>G mutation is an important cause of hearing loss and the proportion of
mutant copies have been associated with diverse phenotypes. The objective of this study was to compare the performances of
TaqMan probe melting curve technology, DHPLC method and Sanger sequencing technology in terms of detecting mtDNA
1555A>G heteroplasmic mutation. Methods: Using the TaqMan probe melting curve technology based on SLAN-96S Real-
Time PCR System, standard curves were built on the mixture of the prepared wild type and the 1555A>G mutation plasmid
DNA with the latter presented at different levels (0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%).The standard
curves were used in statistical analysis to establish a function to quantitate the percentage of mtDNA 1555A>G mutation in
aminoglycoside-induced hearing loss individuals, which were collected by our previous study. The results were compared with
our previous results which have been analyzed by DHPLC method and Sanger sequencing technology. Results: 50 samples of
the heteroplasmy levels of mtDNA 1555A>G mutation were detected by TaqMan probe melting curve technology successfully.
This technology found one more case of heteroplasmic mutation (85.84%) than Sanger sequencing technology, but three less
than DHPLC method (11.90%, 14.80% and 97.90%). Conclusions: The proportions of mutant mtDNA 1555A>G copies
ranged from 19% to 86% were accurately detected by the TaqMan probe melting curve technology in this experiment. Its
sensitivity was higher than Sanger sequencing technology but lower than DHPLC method.
Poster Session
Mon(2)-P-208
Mosaic Ratio Quantification of Isochromosome 12p in Pallister-Killian syndrome using Droplet Digital
PCR
Kosuke Izumi 1 ，Katsunori Fujiki 1 ，Maninder Kaur 2 ，Matthew A Deardorff 2 ，Laura K Conlin 2 ，Katsuhiko Shirahige 1 ，
Ian D Krantz 2
1:Laboratory of Genome Structure and Fuction, The University of Tokyo, Institute of Molecular and Cellular Biosciences, Japan、2:Division
of Human Genetics, The Children’s Hospital of Philadelphia
Pallister-Killian syndrome is a prototypic mosaic aneuploidy syndrome caused by mosaic supernumerary marker isochromo-
some 12p. Cells possessing the isochromosome 12p rapidly diminish after birth in the peripheral blood, often necessitating
a skin biopsy for diagnosis. Therefore, a genomic testing that is capable of detecting low percent mosaic isochromosome
12p is preferred for the diagnosis of Pallister-Killian syndrome. In this study, we report the utility of the droplet digital
PCR (ddPCR) system in quantifying the mosaic ratio of isochromosome 12p in Pallister-Killian syndrome. ddPCR utilizes
a water-oil emulsion droplet technology that compartmentalizes the PCR reaction solution into 15,000 droplets. After the
droplets are generated, PCR amplification occurs in each droplet using fluorescent dyes. The ddPCR system then quantifies
the number of signal positive and negative droplets that allows for the absolute amount of the target genomic region of interest
to be counted precisely. The ability of ddPCR to provide an absolute quantitation of a defined sample makes it a potentially
useful technology to detect low levels of the iso12p and quantify the mosaic ratio as well as serve as a rapid diagnostic tool
for PKS and other mosaic diagnoses.
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Mon(2)-P-209
A Collaborated Study of Fragile X syndrome and Fragile-X-Associated Tremor/ataxia Syndrome (FX-
TAS) for promoting clinical research in Japan
Kaori Adachi 1 ，Tohru Matsuura 2 ，Kazuhiro Ishii 3 ，Yuji Nakayama 1 ，Yu-ichi Goto 4 ，Eiji Nanba 1,5,6
1:Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Japan、2:Division of Neurology,
Department of Medicine, Jichi Medical University, Shimono, Japan、3:Department of Neurology, Clinical Medicine, University of Tsukuba,
Tsukuba, Japan、4:Depart. of Mental Retardation and Birth Defect Research National Institute of Neuroscience, National Institute of
Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan、5:Division of Clinical Genetics, Tottori University Hospital,
Yonago, Japan、6:Center for Promoting Next-Generation Highly Advanced Medicine Tottori University Hospital, Yonago, Japan
Fragile X syndrome (FXS) is caused by expansion of the FMR1 gene CGG repeat (> 200), exhibit symptoms such as
intellectual disability and autism. Many patients are registered in the US and Europe, and clinical study of treatment has
been already started.
We have established a Japanese research group for FXS and its related disorders (FXTAS and POI) from 2010 to 2012
supported by“research on measures for intractable diseases” of the ministry of Health Labour and Welfare in Japan. In this
study, we collected the patient information from more than 3,400 special doctors of child neurology and psychiatry, and the
309 public health center. Also, we analyzed the FMR1 CGG expansion and 42 and 5 patients with FXS and FXTAS were
found respectively. The prevalence of FMR1 premutation among Japanese POI patients was 1.56% (2 of 128) and many of
the Japanese patient was not diagnosed.
Recently, promising pharmacological targets have been reported and the clinical research should be promoted in Japan. We
Poster Session
newly establish a research group of fragile X syndrome and its related disorders for promoting clinical research supported by
Japan Agency for Medical Research and Development (AMED) from 2015. In this study, we examine new diagnostic methods,
going to perform diagnose FXS/FXTAS widely, establish the registration for the clinical research and medical guideline.
Mon(2)-P-210
Evaluation of Digital PCR for Monitoring of Acute Rejection in Kidney Transplantation
Hyeseon Lee 1 ，Young-Mi Park 1 ，Yu-Mee We 1 ，Duck Jong Han 2 ，Sang-Ho Lee 3 ，Jong-Keuk Lee 1
1:1Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea, South、2:Department of Surgery, Asan Medical
Center, University of Ulsan College of Medicine, Seoul, Korea、3:Department of Internal Medicine, Kyung Hee University Hospital at
Gangdong, Seoul, Korea
Early detection and proper management of rejection in transplantation is a crucial for long-term health. The current standard
ways to monitor rejection are biopsy and creatinine measurement in kidney transplantation. Donor-derived cell-free DNA
(cfDNA) from grafts in plasma and urine of recipient is potential biomarker to detect acute rejection in transplant patients.
In this study, we evaluated the digital PCR (dPCR) system to monitor the graft status in kidney transplant patients using
SNP-based donor DNA detection in plasma or urine samples. Initially, we compared the performance of 3 different dPCR
systems (QX200, RainDrop and QuantStudio 3D). We found that Bio-Rad QX200 had best performance to detect DNA in
terms of accuracy and sensitivity. We also tested the several SNPs for sex determination and human identification. At least
24% of SNPs for human identification were useful DNA markers for donor DNA detection in transplant patients between either
related individuals or unrelated individuals. Using SNPs for sex-determination, human identification or mitochondrial DNA
(mtDNA) detection, we assessed whether measurement of donor-derived cfDNA using dPCR system is appropriate in a total
of 34 clinical patients’ plasma (n= 72) or urine (n= 69) DNA samples isolated at multiple time points after transplantation.
We found that donor DNA percentage was almost undetectable in plasma DNA samples due to high background of recipient’
s DNA from recipients’ cells, whereas high donor DNA percentage was measured in urine DNA samples, indicating that urine
DNA is a good source of cfDNA for kidney transplantation monitoring. However, both total positive DNA counts and donor
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DNA percentage could not distinguish the clinical conditions of transplanted patients due to high inter-patient variations.
Our results indicate that noninvasive dPCR system is currently not an accurate screening method to monitor the clinical
conditions in transplant patients.
Mon(2)-P-211
HER-2/neu status in paraffin-embedded tissue from breast cancer patients by immunohistochemistry
(IHC) and fluorescence in situ hybridization (FISH) assays
1
Pitichai Phornsarayuth
1:Pathology, Ramathibodi Hospital Faculty of Medicine, Thailand
Pitichai Pornsarayouth, Veerawat Korkiatsakul, Lucksamee Malee, Takol Chareonsirisuthigul, Sansanee Wongwaisayawan
and Budsaba Rerkamnuaychoke
Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University
Abstract
The combination of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays are useful tools for
breast cancer patients involving HER-2/neu status evaluation. The HER2 test result shall be reported as positive if it is:
Poster Session
(a) IHC 3+ positive; or (b) FISH positive. It shall be reported as equivocal and a reflex test ordered on the same using the
alternative test if the result is: (a) IHC 2+ equivocal; or (b) FISH equivocal (ASCO 2013). Therefore, a combination of
IHC and FISH analysis performed on all 2+ IHC cases can improve the testing result. In this report, we studied HER-2/neu
gene status on paraffin embedded tissues of 818 patients during January 2011 to August 2015. IHC and FISH analysis were
performed for the assessment of HER-2 overexpression. The IHC showed that 366/818 (44.74%) presented 3+ score staining
and 452/818 (55.26%) presented 2+ score. Using FISH technique, the result demonstrated that 497/818 (60.76%) and 321/818
(39.24%) were amplification and no amplification, respectively. Therefore, IHC 2+ cases showed HER2/neu amplification by
FISH in 159/452 cases (35.18%) and no amplification in 293/452 cases (64.82%). In IHC 3+ cases, HER2/neu amplification by
FISH was detected in 338/366 cases (92.35%) and no amplification in 28/366 cases (7.65%). In conclusion, these data suggest
that the combination of IHC assay followed by FISH to analyze the IHC 2+ samples provide a more accurate determination
of HER-2/neu amplification status. Moreover, FISH studies are recommended to evaluate all 3+ and 2+ IHC stained tumors
to avoid inappropriate treatment.
Mon(2)-P-212
Optimal cutoff value for diagnosis G-6-PD-deficient heterozygous female neonates based on molecular
identification of G-6-PD mutations
Suttiphan Kitcharoen 1 ，Supphanan Subin 1 ，Surasak Channara 1 ，Sumalai Dechyotin 2 ，Nappmats Khemtonglang 1 ，
Supawadee Yamsri 1 ，Chanudda Kleesuk 3
1:Clinical Microscopy, Faculty of Associated Medical Sciences, Khon Kaen University, Thailand、2:Graduate School, Khon Kaen University、
3:Diagnostic Microscopy Unit, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University
Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is an X-linked inherited enzyme deficiency that results from G-6-PD
gene mutations. Female heterozygotes exhibit a wide variety of G-6-PD activity, ranging from normal to completely deficient,
and are more difficult to identify by conventional screening test. Quantitative G-6-PD activity assay should improve the
detection of these individuals, but requires an appropriate reference or cutoff value. This study aimed to determine the
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optimal G-6-PD activity cutoff value, using mutation analysis as a gold standard, in order to increase sensitivity in identi-
fying heterozygous female neonates. The cutoff value was determined using Receiver Operating Characteristic (ROC) curve
generated from 126 known samples of our previous studies. Two cutoff values were selected, ≤14.2 U/gHb for differentiation
between non-deficient females and deficient heterozygotes and ≤ 3.3 U/gHb for differentiation between deficient heterozygotes
and deficient homozygotes. The selected cutoffs were validated in 241 unknown samples from female neonates. All samples
were subjected to G-6-PD activity assay and G-6-PD mutation identification. Sensitivity and specificity of the cutoff point
of ≤14.2 U/gHb were 61.7% and 89.1% respectively, meanwhile, 100% sensitivity and 87.2% specificity were achieved for the
cutoff of ≤ 3.3 U/gHb. When compared with other studies, our cutoff values demonstrate the highest sensitivity for detection
of heterozygous female neonates.
Mon(2)-P-213
A novel COL11A1 mutation affecting splicing in a Japanese patient with Stickler syndrome
Takuya Naruto 1 ，Tomohiro Kohmoto 2 ，Haruka Kobayashi 2 ，Miki Watanabe 2 ，Nana Okamoto 3 ，Kiyoshi Masuda 1 ，
Nobuhiko Okamoto 4 ，Issei Imoto 1
1:Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan、2:Student Lab, Fac-
ulty of Medicine, Tokushima University、3:Department of Oral and Maxillofacial Surgery, Kobe University graduate School of Medicine、
4:Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health
Stickler syndrome is a clinically and genetically heterogeneous collagenopathy characterized by ocular, auditory, skeletal, and
orofacial abnormalities commonly occurring as an autosomal dominant trait. We report a novel intronic COL11A1 mutation
Poster Session
affecting splicing in a Japanese patient with Stickler syndrome detected by targeted exome analysis using next-generation
sequencing (NGS).
A 4-year-old girl was born with a cleft palate and short extremities. X-ray imaging at 2 years of age revealed lumbar spine
lordosis, L-1 hypolasia, and metaphyseal widening of long bones. Eardrum tubing was placed to alleviate otitis media with
effusion and hearing loss. Her motor and mental development was normal. Her clinical characteristics of orofacial, ocular,
auditory, and skeletal abnormalities were compatible with those of Stickler syndrome. We performed NGS with a TruSight One
Sequencing Panel (Illumina), and detected a novel heterozygous mutation (NM_001854.3:c.3168+5G>A) within an intronic
sequence (intron 41) of COL11A1 that may impair splicing, which was suggested by various in silico prediction programs.
This prediction was validated by a functional assay using minigenes produced by cloning exon 41 with franking wild type or
mutated sequences. RT-PCR analysis using RNA from minigene-transfected cells detected a small transcript lacking exon 41,
indicating that c.3168+5G>A mutation likely affected mRNA processing and produced a misspliced transcript.
Significant portions of the reads obtained in whole or targeted exome sequencing from outside the targeted regions or complete
genome capture of target genes may enhance the detection of non-exonic variants with uncertain pathogenicity. Integrated
analyses using databases, bioinformatics tools, and functional studies used may be critical for determining the pathogenicity of
variants and facilitating differential diagnosis, appropriate therapy, and genetic counseling for patients with Stickler syndrome
and related diseases.
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Mon(2)-P-214
Filaggrin mutations in early- and late-onset atopic dermatitis
Peter Korosec 1 ，Helena Rupnik 2,3
，Katarina Dezman 1 ，Matija Rijavec 1
1:Laboratory for Clinical Immunology & Molecular Genetics, University Clinic of Respiratory and Allergic Diseases Golnik, Slovenia、
2:Department of Dermatovenereology, University Medical Centre Ljubljana, Slovenia、3:Dermatology Centre Arsderma, Ljubljana, Slovenia
Background: The influence of filaggrin gene (FLG) mutations on early- vs. late-onset development of atopic dermatitis (AD),
allergic contact dermatitis (ACD) and chronic irritant contact dermatitis (CICD) is not completely understood.
Objectives: To assess the association between FLG mutations and development of AD, ACD and CICD.
Methods: This study assessed 241 patients with AD. AD developed during infancy in 85 patients, during childhood in 79
patients (32 early and 47 late) and during adulthood in 77 patients. We also included 100 patients with ACD and 44 with
CICD, as well as 164 healthy controls. Four prevalent FLG loss-of-function mutations were genotyped (R501X, 2282del4,
R2447X and S3247X). We also assess polymorphism rs2303067 in SPINK5, and rs490928 in CHI3L1.
Results: Similarly to other studies from central and eastern Europe the 2282del4 mutation was the most prevalent and
significantly associated with a greater risk of AD in the entire group [odds ratio (OR) 4.33, 95% confidence interval (CI)
1.26-14.96]. However, the 2282del4 mutation was associated only with AD that developed during infancy or throughout early
childhood (≤ 8 years: OR 20.91, 95% CI 2.73-159.9). On the other hand, in patients experiencing AD onset during late
childhood (>8 years) or as an adult, the frequencies of the 2282del4 mutation were low and highly comparable with those of
Poster Session
healthy controls. Similar associations were also observed for the combined 2282del4 or R501X genotype. None of the FLG
mutations were associated with ACD or CICD. Early-onset AD was also associated with rs2303067 in SPINK5, which is
involved in skin barrier functioning, and late-onset with rs4950928 in CHI3L1, which is involved in the immune response.
Conclusions: According to our results the development of late-onset AD is not associated with FLG loss-of-function mutations,
and therefore other susceptibility genes or acquired factors are more likely involved in the manifestation of skin lesions.
Mon(2)-P-215
SUNMAC: A Project for Population Based Screening of Thalassemia and its Mutations in Pakistan
1,2 2,3,4 2,3
Muhammad Imran Qadeer ，Muhammad S Akhtar ，Muhammad Aslamkhan
1:Department of Microbiology and Molecular Genetics, University of the Punjab, Pakistan、2:Sundas Foundation Molecular Analysis Center,
Lahore、3:University of Health Sciences, Lahore、4:Gulab Devi Postgraduate Medical Institute, Lahore
Sundas Foundation is haematological services to more than 5000 thalassemia, haemophilia and blood cancer patients. In
2014, Sundas Foundation started a new project entitled Sundas Foundation Molecular Analysis Centre (SUNMAC) has
primary objectives to find out prevalence of thalassemia in Pakistani Population and identification of families and individuals
with thalassemia or thalassemia trait. It is the first state of the art thalassemia prevention and control laboratory in
Pakistan. SUNMAC has initiated population based thalassemia screening program, as a part of thalassemia prevention
program. Our teams visit various institutes and universities and screen out students for thalassemia using NESTROFT
followed by confirmatory mutational analysis. Screening program is started from Punjab and will be extended.
Naked Eye Single Tube Red Cell Osmotic Fragility Test (NESTROFT) has worldwide acceptance for thalassemia screening
for field studies with sensitivity 95.56% and specificity 84.25%. NESTROFT positive cases are brought to our haematology
lab and are looked for their CBC parameters and Supravital Staining, to determine either it is alpha or beta thalassemia
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or iron deficiency. Thalassemia type determined samples are studied in genetics laboratory for mutational analysis. Genetic
counseling services are being provided to screened carrier population and their families.
Beta thalassemia mutations common in Pakistan include Intervening Sequence 1-5 (IVS 1-5 (G-C)), Frameshift 8-9 (Fr 8-9),
IVS 1-1 (G-T), Codon-30 (Cd-30 (G-C)), Codon-5(Cd-5 (-CT),Deletion 619 base pair (Del 619bp), and Codon-15 (Cd-
15(G>A)) and two Hb variant mutations of HbS and HbF. In response to specific mutation, Hydroxyurea (antineoplastic
drug) is being tried to registered thalassemia major patients to keep them transfusion independent.
Along with above services, prenatal screening of fetus in thalassemia major families is also being provided by leading to
mutational analysis.
Mon(2)-P-216
Relationship between G6PD deficiency and UGT1A1 mutation in neonates with hyperbilirubinemia
Noppmats Khemtonglang 1 ，Suttiphan Kitcharoen 2 ，Pakaphan Kiatchoosakun 3 ，Sumalai Dechyothin 1 ，
Chanudda Kleesuk 4
1:Graduate School, Khon Kaen University, Thailand、2:Department of Clinical Microscopy, Faculty of Associated Medical Sciences, Khon
Kaen University、3:Department of Pediatrics, Faculty of Medicine, Khon Kaen University、4:Diagnostic Microscopy Unit, Faculty of
Medicine, Khon Kaen University, Khon Kaen
Background
Poster Session
Neonatal hyperbilirubinemia is one of the most common problems of neonates. A variation in the coding region and promoter
of the UDP-glucuronosyl transferase 1A1 (UGT1A1) gene were an additive risk factor for neonatal hyperbilirubinemia in
G6PD-deficient neonates. The relationship between these mutations on hyperbilirubinemia has not been investigated in the
northeast Thai neonates.
Objective
To investigated the relationship between G6PD deficiency and UGT1A1 mutation in neonates with hyperbilirubinemia.
Methods
108 G6PD normal and 111 G6PD-deficient neonates were recruited.The UGT1A1 TA(n) and 211G>A were performed. The
neonates were classified into six groups, group I: control group; (G6PD-normal with 211G/G,TA6/6), group II (G6PD-
deficient with 211G/G,TA6/6), group III (G6PD-normal with 211G/A), group IV (G6PD-deficient with 211G/A), group V
(G6PD-normal with TA6/7) and group VI (G6PD-deficient with TA6/7). To assess the association of G6PD deficiency and
UGT1A1 mutations on the severity of hyperbilirubinemia, each group were compared with the peak of total serum bilirubin
with group I.
Results
The peak of total serum bilirubin in group I was 13.8±2.2 mg/dL and 15.5±3.4, 15.4±2.2, 15.9±2.9, 14.8±2.7, 14.6±2.6
mg/dL in group II, group III, group IV, group V and group VI, respectively. The peak of total serum bilirubin was significant
increased than control in group II, group III and group IV (P value = 0.0033, 0.0284 and 0.0009).
Conclusions
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The G6PD-normal, G6PD-deficient neonates with 211G/A mutation and G6PD-deficient neonates with wild type UGT1A1
have the peak total serum bilirubin significantly higher than G6PD-normal with wild type UGT1A1 .However,the neonates
co-inheriting of TA6/7 with neither G6PD deficient nor G6PD normal showed no statistical significant.
Therefore,G6PD deficiency and 211G/A mutation were associated with the severity of neonatal hyperbilirubinemia but TA6/7
is not likely to be associated in this population.
Mon(2)-P-217
An investigation of definite diagnosis rate for monogenic diseases in the order receiving system of genetic
testing
1,2 1,3
Tomohiro Nakayama ，Hiromu Naruse
1:Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, Japan、2:Division
of Companion Diagnostics, Department of Pathology of Microbiology, Nihon University School of Medicine、3:Health Sciences Research
Institute, Inc.
We have established the germline genetic testing system for some monogenic diseases using DNA sequencing. The aim of this
study was to investigate the definite diagnosis rate for monogenic diseases in the order receiving system of genetic testing
in the Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine
during October 2009 and November 2015.
Poster Session
We performed genetic testing for 71 cases from our own facilities and other facilities. There were 17 disorders with 7 autosomal
dominant, 7 autosomal recessive, 2 X-linked recessive diseases and 1 pharmacogenomics testing. Of these cases 27 cases (38.0%)
was made definitive diagnoses. Types of causal mutations were classified into 27 nonsynonymous (missense) mutations, 3
nonsense (stop) mutations, 1 splicing site mutation, 3 insertions and 1 deletion. Twelve novel causal mutations were discovered.
Although genetic testing is useful for definite diagnosis selection of subjects by examining clinical differentiation might be
very important to increase definitive diagnoses rate.
Mon(2)-P-218
Implementation of Genomic Medicine in Sri Lanka
Vajira H.W. Dissanayake 1 ，Nirmala Sirisena 1 ，Dulika Sumathilala 1 ，Kalum Wetthasinghe 1 ，
Nilaksha Neththikumara 1 ，Rohan Jayasekara 1
1:Human Genetics Unit, Faculty of Medicine, University of Colombo, Sri Lanka
Genomic Medicine involves using genomic information about an individual as part of their clinical care. The advances made
in Next Generation Sequencing Technologies have made it possible to implement Genomic Medicine. These advances are
reaching even developing countries such as Sri Lanka where capacity for implementation is limited.
We successfully implemented clinical exome testing for rare disorders and common disorders with unusual coexisting phe-
notypes and gene panel testing for inherited cancer syndromes in our center in Sri Lanka and integrated them into routine
clinical practice.
In this paper we describe our workflow and bioinformatics pipeline; the novel pathogenic variants and their associated
phenotypes that we discovered [e.g. LPL p.Arg270Gly in hyper lipoproteinemia, Type1; MYH p.Asp265Glu in peripheral
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neuropathy]; the advantages of implementing these tests which include rapid diagnosis of difficult to diagnose cases and discov-
ery of novel pathogenic mutations not described before; the challenges for bioinformatics and reporting which include dealing
with variants of unknown significance, non representation of variants found in the Sri Lankan population in public databases,
and dealing with incidental findings; and ethical legal social implications of moving from genetic to genomic counseling and
special issues related to implementing these tests stemming from policy issues related to financing tests and perception about
the usefulness of these tests among policy makers and administrators.
Mon(2)-P-219
Next-generation sequencing approach in skeletal dysplasias with prenatal onset: experience of a tertiary
center in Brazil
Guilherme L Yamamoto 1,2 ，Carolina Malcher 2 ，Wagner AR Baratela 1 ，Rossana Viera 3 ，Marco Antonio Lopes 3 ，
Rachel Honjo 1 ，Chong A Kim 1 ，Maria Rita Passos-Bueno 2 ，Debora R Bertola 1,2
1:Genetica Medica - departamento de Pediatria, Instituto da Crianca do Hospital das Clinicas da Faculdade de Medicina da Universidade
de Sao Paulo, Brazil、2:Genetica e biologia evolutiva, Instituto de Biociencias da Universidade de Sao Paulo、3:Obstetricia, Hospital das
Clinicas da Faculdade de Medicina da Universidade de Sao Paulo
The diagnosis of skeletal dysplasias with prenatal onset is of particular importance both for management of the gestation
and/or delivery due to the possibility of lethal conditions and for an appropriate genetic counseling for the family. The clinical
genetics outpatient clinic in Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São
Poster Session
Paulo evaluated 13 cases with a prenatal-onset skeletal dysplasias/dysostosis in a period of 18 months, between 04/2014
and10/2015, for diagnosis and genetic counseling. In 11 cases, the pregnant women were referred from the obstetrics of the
same center, with a mean gestational age of 30w. The two other cases were evaluated postnatally. DNA analysis by Sanger
(FGFR3) or by next-generation sequencing (panel of 83 genes associated with skeletal dysplasias) allowed the confirmation
of the skeletal dysplasia in 11 cases: tanatophoric dysplasia I (2) and II (2), achondroplasia (1) osteogenesis imperfecta
type II (1), diastrophic dysplasia (2), achondrogenesis II (1), atelosteogenesis I (1) and otopalatodigital II (1). One case
with a ciliopathy and one with limb deficiency were not evaluated molecularly. Non-invasive prenatal testing methods have
been used especially for screening of chromosomal disorders, however testing for monogenic disorders through this method
is not well established so far. We propose to investigate circulating cell-free fetal DNA in maternal plasma as a screen for
prenatal-onset skeletal dysplasias. One of the cases has both maternal blood collected in the third trimester of gestation and
molecular testing in the newborn blood. The possibility of having molecular confirmation before delivery could help decisions
on pregnancy termination or contribute to improved maternal and fetal treatments.
Mon(2)-P-220
Rapid and accurate genetic testing for CHARGE syndrome based on long-range PCR and Next-Gen
high-throughput sequencer
Kumiko Yanagi 1 ，Manami Iso 1,2
，Akira Ganaha 3 ，Tadashi Kaname 1
1:Genome Medicine, Center for National Research Institute for child health and development, Japan、2:Pediatrics and Adolescent Medicine,
Juntendo University School of Medicine、3:Otorhinolaryngology, Head and Neck Surgery, University of the Ryukyus
[Background] CHARGE syndrome is an autosomal dominant disorder, characterized by Coloboma, Heart defects, choanal
Atresia, Retarded growth and development, Genital abnormalities, and Ear anomalies. The occurrence is approximately 1
in 8,500 to 10,000 individuals. Chromodomain helicase DNA binding domain 7 (CHD7 ) have been identified as the cause
of CHARGE syndrome. The gene consisting of 38 exons spanning 189Kb locates on 8q12. Gene testing of CHD7 revealed
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that about 65%-70% of individuals with either typical CHARGE syndrome or a milder phenotype has mutations, i.e. single
nucleotide substitution (63.3%), indels (36.4%) and translocations (0.2%) (Basson and RavenswaaiJ-Arts, Trends in Genetics
Vol.31, 25015). We show here rapid and accurate gene testing method of CHD7 using long-range PCR and benchtop Next-
Gen high-throughput sequencer. [Method and Patients] We have experienced two patients clinically diagnosed as CHARGE
syndrome. The genomic DNA was extracted from blood. Long-range PCRs with several sets of primers were performed
to enrich the CHD7 gene including its promoter. The amplicons were 10-15 kb in length and were pooled at equimolal
concentration. The pooled amplicons were then fragmented and indexed for use in next-generation sequencing. Variations
found in the patients were confirmed by Sanger sequencing and were screened in more than 200 controls by PCR-high resolution
melting analysis or PCR-RFLP. [Results] We have identified two indel mutations in two patients (two bp deletion and one
bp deletion respectively), which were both results in premature stop codons. The two variations were not detected in more
than 200 controls. The loss-of-function mutations in CHD7 are suggested to be cause of CHARGE syndrome. Genetic testing
based on long-range PCR and benchtop Next-Gen high-throughput sequencer is useful for clinical diagnosis of CHARGE
syndrome.
Mon(2)-P-221
Toward Objective Interpretation of Sequence Variants
1
James L. Weber
1:PreventionGenetics, USA
Poster Session
Interpretation of sequence variants is probably the greatest current challenge in clinical genetics. To date, variant inter-
pretation has been highly subjective. In an effort to make interpretation more objective, we have utilized several simple,
quantitative measures of pathogenicity. These measures include allele frequency differences between cases and controls, the
fraction of times a particular variant occurs together with a second plausible pathogenic variant in patients affected with
recessive disorders, and the occurrence of de novo mutations in individuals affected with dominant or X-linked recessive
disorders. All of these approaches have potential pitfalls and therefore must be used with caution. These approaches also
require quantitative definitions of pathogenic, likely pathogenic, likely benign and benign. However, these approaches are
important first steps in transforming sequence interpretation from an art to a science.
Mon(2)-P-222
Identification of genetic alterations in the APC gene by the use of NGS for patients with polyposis of
the colon
Yoichi Furukawa 1 ，Kiyoshi Yamaguchi 1 ，Tsuneo Ikenoue 1 ，Mitsuhiro Komura 1 ，Eigo Shimizu 1 ，Rui Yamaguchi 1 ，
Tetsuo Shibuya 1 ，Seiya Imoto 1 ，Satoru Miyano 1 ，Haruhiko Sugimura 2 ，Satoshi Nagayama 3
1:The Institute of Medical Science, The University of Tokyo, Japan、2:Dept. Tumor Pathology, The School of Medicine, Hamamatsu
University、3:Dept. Gastroenterological Surgery, The Cancer Institute Hospital
Polyposis of the colon is a mixture of diseases caused by a germ line mutation in one of the responsible genes. Among the
polyposis, the most well known disease is the familial adenomatous polyposis of the colon (FAP) that results from a germ
line mutation in the APC gene. Although most of patients with FAP have family history displaying the inheritance of an
autosomal dominant manner, de novo cases are difficult to diagnose since they do not exhibit family history. In addition,
MUTYH-associated polyposis caused by mutations in the MUTYH gene, an autosomal recessive disease, is also difficult to
diagnose by their family history. Furthermore polymerase proofreading-associated polyposis, a new class of polyposis has
been identified, whose characteristics have not been clarified. To perform the genetic diagnosis of adenomatous polyposis of
the colon that had been undiagnosed by the conventional Sanger method, we applied their DNA for whole genome sequencing
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or whole exome sequencing. As a result, we identified two cases with mosaic mutations in APC , and a case with a large
deletion in the promoter region of APC . The case with a mosaic mutation carried a deleterious APC mutation with the
frequency about 12% in their peripheral lymphocytes and the frequencies between 3 and 13% in the non-tumorous mucosa. It
is notable that the mutation was detected more than 20% in all adenomatous polyps examined, suggesting that the polyps had
developed from the epithelial cells carrying the mutation. The large deletion in the APC promoter reduced the transcription
from the mutant APC allele. An additional analysis of his parents disclosed that it was a de novo alteration. These results
indicate that NGS is a useful tool in the clinics of hereditary tumors to identify undiagnosed genetic abnormalities by the
conventional sequencing method.
Mon(2)-P-223
Genomics and precision in variant filtering strategies and phenotypic characterisation for accurate genetic
diagnosis in the retinal dystrophies
1,2,3,4 1,4 1,4 2,3,4 2,3,4
Benjamin M Nash ，Dale C Wright ，Bruce Bennetts ，John R Grigg ，Robyn V Jamieson
1:Sydney Genome Diagnostics, The Children’s Hospital at Westmead, Cnr Hawkesbury Rd and Hainsworth St, Westmead NSW, Australia、
2:Eye Genetics Research Group, Children’s Medical Research Institute, The Children’s Hospital at Westmead, Westmead, Australia、3:Save
Sight Institute, Sydney, Australia、4:Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney, Sydney,
Australia
Retinal Dystrophy (RD) describes a collection of degenerative eye disorders involving the retina that affect approximately
1/3500 people. Due to the high genetic heterogeneity underlying these disorders, prioritisation in examining the >120 genes
where pathogenic mutations are known to occur in RD is challenging. There is currently no test available in Australasia that
Poster Session
examines all associated genes to allow a molecular diagnosis to be reached in a cost-effective and timely manner.
We used a next generation sequencing (NGS) approach on a cohort of 41 sporadic and familial RD patients utilising the
Illumina Trusight and Trusight One targeted exome panels, interrogating ~ 2700 and ~ 4800 OMIM disease-causing genes
respectively. Libraries were sequenced on the Illumina HiSeq 2500. Variants detected in the 127 genes examined were
filtered and prioritised based on in silico allele frequencies, conservation and predicted pathogenicity scores. Novel and
previously described frameshift, missense and premature stop mutations were identified in several genes including BBS1 ,
PDE6B, RPGRIP1 , RPGR, RP1 , SPATA7 and USH2A. In two cases, multiple predicted pathogenic variants were detected
necessitating detailed variant review and segregation analysis. Accurate phenotypic characterisation was critical for result
interpretation in several cases. Molecular diagnosis was achieved in 22/41 (54%) patients, providing new clinical diagnoses and
markedly improved recurrence risk counselling for affected individuals and families. Our NGS approach has been successful
in detecting pathogenic variants in the highly heterogeneous disease RD in a time and cost-effective manner, leading to new
clinical diagnostic and management information.
Mon(2)-P-224
Triaging Patients for Genomic Tests in South Australia: a Multi-disciplinary Team Approach
Janice M Fletcher 1 ，Karin S Kassahn 1 ，Peter A Kaub 1
1:Genetics & Molecular Pathology, SA Pathology, Australia
New genetic testing platforms offer much promise, but are still a relatively limited resource in clinical diagnostic settings.
To maximise clinical utility a systematic approach is required. Our clinical diagnostic service uses a multi-disciplinary team
(MDT) forum, where medical scientists performing genetic testing and analysis interact with primary clinicians and patholo-
gists to determine the most appropriate testing for complex clinical cases.
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We have developed a systematic approach for case presentations, and decision criteria to assist determination of the most
appropriate testing for each case, based on both clinical and laboratory information. We consider the management implica-
tions, evidence supporting genetic testing indication and utility, test availability, service capacity and in-house expertise, as
well as expected turnaround time. A recommendation for each case is formed after open and robust discussion between the
MDT meeting members. Outcomes include recommendations for phenotype-targeted next generation sequencing (NGS) gene
panels, clinical exome, whole exome or whole-genome sequencing, array-based testing and MLPA. Where there are issues of
capacity or lack of expertise, samples have been referred to research colleagues or external laboratories.
In just under one year, this consensus-based, open discussion platform has reviewed more than 65 complex clinical cases. The
majority have been Paediatric patients, with the greatest number referred from Clinical Geneticists, however Immunologists,
Neurologists, Cardiologists, Metabolic, Renal and General Physicians have also been represented. A summary of the MDT
system used, with range of outcomes, phenotypes and results encountered will be presented.
This approach reflects a paradigm shift in clinical review meetings, where embedding medical scientists in an active clinical
conversation is essential to maximising the utility of diagnostic services and assisting best clinical outcome for patients.
Mon(2)-P-225
Alport Syndrome - Interesting Cases and Findings
Poster Session
Evelyn Douglas 1 ，Louisa Sanchez 1 ，Kathy Cox 1 ，Kristian Brion 2 ，Melissa Gurner 2 ，Liam McIntyre 3 ，Paul Henning 4 ，
Sam Crafter 4 ，Chris Barnett 5 ，Karin Kassahn 3 ，Kathie Friend 1
1:Molecular Genetics, Genetics and Molecular Pathology, SA Pathology, Australia、2:National Referral Laboratory, Genetics and Molecular
Pathology, SA Pathology、3:Technology Advancement Unit, Genetics and Molecular Pathology, SA Pathology、4:Department of Nephrology,
The Women’s and Children’s Hospital、5:South Australian Clinical Genetics Service, SA Pathology
Alport syndrome (ATS) is a disorder of the basement membrane, resulting in a glomerulonephropathy causing renal failure
as well as sensorineural hearing loss and ocular anomalies. The majority of cases are X-linked (85%) whilst 15% are auto-
somal recessive, with autosomal dominant forms rarely seen. The COL4A3 and COL4A4 genes have been associated with
recessive form of ATS syndrome whilst variants in the COL4A5 gene, including a large number of multi exon deletions and
duplications, have been associated with X-linked cases. Rarely patients with ATS also have diffuse leiomyomatosis (ATS-DL),
a benign neoplastic condition characterised by aberrant proliferation of well differentiated smooth muscle cells, involving the
gastrointestinal, tracheobronchial and female genital tracts. A contiguous deletion of the 5’ exons of COL4A5 and COL4A6
is commonly detected in patients with this phenotype.
Our laboratory (Genetics and Molecular Pathology, SA Pathology) has recently introduced screening of genes known to be
involved in Alport syndrome using multiplex ligation-dependent probe amplification (MLPA - MRC Holland), in combina-
tion with Next Generation Sequencing using the Illumina TruSight One and NextSeq platform. Variants detected to date
include large duplications or deletions of COL4A5 and COL4A6 and several few novel variants. These include a 51 year old
female presenting with glomerular nephritis and a family history of haematuria (heterozygous duplication of exons 10-24 of
COL4A5 ) and a 10 year old female with familial haematuria and leiomyoma (heterozygous contiguous deletion encompassing
the COL4A5 (exons 1-36) and COL4A6 (exons 1-3) genes). Investigations are currently underway to further evaluate the
extent of the deletion. In this report we will present these cases in detail as well as summarise our overall findings.
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Mon(2)-P-226
Experience of introducing chromosome microarray analysis as a diagnostic tool in a clinical genetics
service in Brasilia, Brazil
Juliana F Mazzeu 1,2 ，Maria Teresa AS Rosa 2 ，Claudiner P Oliveira 3 ，Rafael Bonadio 4 ，Bianca F dos Reis 3 ，
Beatriz R Versiani 2 ，Rosenelle Araujo 2 ，Heloisa PN Safatle 2 ，Mara S Cordoba 2 ，Iris Ferrari 1,2 ，Rinaldo W Pereira 5 ，
Aline Pic-Taylor 4 ，Silviene F Oliveira 4
1:Faculty of Medicine, Universidade de Brasilia, Brazil、2:Hospital Universitario de Brasilia, Brasilia, Brazil、3:Secretaria de Estado de
Saude-DF, Brasilia, Brazil、4:Instituto de Ciencias Biologicas, Universidade de Brasilia, Brasilia, Brazil、5:Universidade Catolica de Brasilia,
Brasilia, Brazil
Intellectual disability and congenital malformations affect more than 3% of the world ´ s population and are a major public
health problem. There are many causes of intellectual disability and malformations and genetic causes contribute to a
significant percentage of cases. The ability of chromosome microarray analysis (CMA) to detect submicroscopic genetic
abnormalities has revolutionized the clinical diagnostic approaches to individuals with intellectual disability, neurobehavioral
phenotypes and congenital malformations. The identification of copy number variations in these patients may allow a better
follow-up, genetic counseling and therapeutic interventions in some cases. However, CMA is still not available as a diagnostic
test in most clinical genetics services in Brazil. The aim of this study was to describe the experience of introducing chromosome
microarray analysis in a public clinical genetics service at Hospital Universitario de Brasíiia, Brasilia, Brazil. A total of 300
patients were screened using a 750k Affymetrix platform. From this total, 36% had non-polymorphic CNVs: 22% of the
patients had pathogenic CNVs related to the phenotype, 12% had variants of unknown significance (VOUS) and 2% had
likely benign CNVs inherited from normal parents. Single stretches >5MB of loss of heterozygosity (LOH) were considered
likely pathogenic and were decisive for the diagnosis in three cases. Therefore, the introduction of CMA significantly increased
Poster Session
the diagnostic yield in our service. This study reinforces the importance of performing chromosome microarray analysis as
a diagnostic tool for patients with intellectual disability/congenital malformations and contributes to the description of rare
and novel chromosome abnormalities.
Mon(2)-P-227
The Medical Genome Reference Bank - Whole genome sequencing of 4,000 healthy elderly individuals
1,2 1,2
Marcel E Dinger ，David T Thomas
1:Kinghorn Centre for Clinical Genomics, Garvan Institute for Medical Research, Australia、2:St Vincents Clinical School, Faculty of
Medicine, UNSW
The advent of low cost, high quality whole genome sequencing (WGS) has revolutionised scientific research, resulting in an
exponential advance our understanding of human biology and disease. This technology is now being adopted in the clinic,
providing rapid and accurate diagnoses of increasing numbers of inherited genetic diseases in both children and adults.
To maximise the efficiency of disease-specific genomic analyses in both the research and clinical setting, whole genome
sequences from ~ 4,000 healthy, elderly Australian individuals will be analysed to create a reference database, depleted of
damaging variants that will act as a powerful filter to distinguish between causal and passenger mutations. The Medical
Genome Reference Bank (MGRB) program has been specifically established to leverage the Illumina Hiseq X Ten sequencing
platform at the Garvan Institute’s Kinghorn Centre for Clinical Genomics (KCCG), to sequence participants of the 45 and
Up and ASPirin in Reducing Events in the Elderly (ASPREE) studies, with the aim of providing a resource for national and
international health and medical researchers. These data are also anticipated to further our understanding of the genetics of
healthy aging.
The MGRB will generate an unprecedented amount of genomic information, promoting and encouraging significant scientific
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discovery by employing a hierarchical data management system, which will maintain participant privacy and confidentiality,
whilst maximizing the utility of the database. This rapidly growing database provides the ideal background for the future of
genomic research in Australia, and will serve to facilitate the transition and effectiveness of WGS in clinical practice.
Mon(2)-P-228
Targeted next-generation sequencing panel assay in a patient with bilateral hands postaxial polydactyly:
Identification of one novel and one reported CENPJ mutations
1,2 1,2,3
Chia-Cheng Hung ，Yi-Ning Su
1:Sofiva Genomics Co., Ltd., Taiwan、2:Phoebus Genetics Co., Ltd.、3:Dianthus Maternal Fetal Medicine Clinic
Background: Targeted next generation sequencing (NGS) testing has emerged as a powerful tool for the diagnosis of causative
mutations in rare Mendelian disease genes. Here we report a prenatal case at 22 weeks of gestation presenting features of
bilateral hands postaxial polydactyly with ultrasound.
Methods: Based on the ultrasound findings, we used amniotic fluid cells to perform karyotyping, oligo array comparative
genomic hybridization (aCGH) and targeted next-generation sequencing panel assay, and try to find out the cause of the
phenotype. For targeted NGS panel, we investigated Ellis-van Creveld syndrome (EVC) and primary autosomal recessive
microcephaly (MCPH) /seckel syndrome panels which included 6 and 5 known causing genes, respectively.
Poster Session
Results: The chromosome analysis showed 46, XX karyotype and aCGH reveal no pathologic gene dosage variation was
detected. NGS genetic diagnosis achieved 1 novel mutation (c.3612_3613 delAA) and 1 previously described pathogenic
mutation (c.2462 C>T) in CENPJ gene, which confirmed by Sanger sequencing.
Conclusion: NGS technologies can be used in combination with multigene panels to generate deep sequencing of target regions
in the clinical diagnostic laboratory. It can provide delivering fast, inexpensive, and detailed genetic information.
Mon(2)-P-229
Retrospective evaluation of rare benign CNVs detected by chromosomal microarray
Keiko Wakui 1,2 ，Tomoki Kosho 1,2,3 ，Kyoko Takano 1,2,3 ，Kenji Shimizu 1,4 ，Yoko Narumi-Kishimoto 1,2 ，Eriko Nishi 3 ，
Seiji Mizuno 5 ，Tomomi Yamaguchi 2 ，Rie Kawamura 1 ，Hirofumi Ohashi 4 ，Yoshimitsu Fukushima 1,2
1:Medical Genetics, Shinshu University School of Medicine, Japan、2:Clinical and Molecular Genetics, Shinshu University Hospital、3:Medical
Genetics, Nagano Children’s Hospital、4:Medical Genetics, Saitama Children’s Medical Center、5:Pediatrics, Central Hospital, Aichi Human
Service Center
We frequently encounter a difficulty to evaluate of rare genomic variants in undiagnosed patients using genome-wide analysis
for determining whether the detected variants have clinically relevant or not. In such situations, the parents’ analyses are
considered, and publicly-available genome databases, such as ClinGen, DECIPHER, DGV and etc. are relied for genomic
interpretation after chromosomal microarray testing. The DGV is the database which only representing structural variation
identified in healthy control samples, and the registered total number of CNV loci is 491,894 in latest DGV (July 2015),
though it was 14,478 in 2010.
In this presentation, we will show retrospective evaluation of the particular rare benign CNVs detected by chromosomal
microarray (PerkinElmer, 135K, Oligo array) in our lab during 2009 to 2011. First, we picked up the rare CNVs which were
determined as variants of uncertain clinical significance (VOUS), because there was no same or larger CNVs in DGV at the
time, however, it was finally concluded as benign on the basis of the confirmation of inheritance from each parent. Then we
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reviewed the registration status about each CNV using latest DGV, and found that about half of those CNV regions are still
unregistered even in latest DGV.
Improving genomic interpretation of undiagnosed patients especially having the rare variants of uncertain clinical significance,
the parents’ analyses are definitely informative. And it is strongly recommend to the re-evaluation of genotype-phenotype
correlation in such variants at occasions of database renewal.
Mon(2)-P-230
Identification of copy number aberration in hereditary cancer susceptibility genes using data from next
generation sequencing
Ja-Hyun Jang 1 ，Taeheon Lee 2 ，Junnam Lee 2 ，Junghoon Park 2 ，Eunhae Cho 2
1:Green Cross Laboratories, Korea, South、2:Green Cross Genome
Background
Recently, various bioinformatics strategies has been attempted to identify copy number aberration (CNA) using next gener-
ation sequencing data. In this study, we investigated the possibility of next generation sequencing data for detection of CNA
in hereditary cancer susceptibility genes using bioinformatics analysis.
Methods
Poster Session
A total of 48 samples including 4 deletion positive samples either in BRCA1 or MSH2 gene were subjected to massively
parallel sequencing; 3 with BRCA1 deletion (ex13-15, ex1-14, ex5-8), 1 with MSH2 (ex6) deletion. CNA had been confirmed
by multiplex ligation probe amplification analysis. Library preparation was performed using TruSight One Panel (Illumina,
USA) based on probe hybridization. Four CNA positive samples were sequenced in 4 different batches. CNA analysis was
performed by both CODEX algorithm and calculation of z-score of the normalized depth per exons.
Results
The CODEX algorithm identified 2 BRCA1 deletions. Prediction of the deleted exons was exact for one sample (ex13-15).
For the ex1-14 deletion, the algorithm predicted the narrow region as being deleted (ex 8-14). Deletions of BRCA1 ex5-8
and MSH2 ex6 were not identified by the CODEX algorithm. No false positive calls were present. With arbitrary cut-off (-2
for BRCA1 and -2.5 for MSH2), calculation of z-score identified deletion at least one exon in four samples. Prediction of the
deleted exons was exact for samples with deletion of BRCA1 ex13-15 and MSH2 ex6. For samples with BRCA1 deletions of
ex1-14 and 5-8, calculation of z-score identified only deletion of 2 exons in both samples. False positive calls for BRCA1 and
MSH2 were present in 16% and 5% of samples, respectively.
Discussions
Z-score identified single exon deletion although it showed limited specificity. The CODEX algorithm showed better specificity
despite of limited sensitivity for small deleted region. Combination of the two algorithms could help to detect CNA from the
NGS data.
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Mon(2)-P-231
Molecular Diagnostics using Genomics: Our Experiences & Success Stories in Inherited Disorders from
Over a Hundred Cases in India
Nandita Mullapudi 1 ，Sudha N Rao 1 ，Gautam Singh 1 ，Honey Reddi 2
1:Dhiti Omics Technologies Private Limited, India、2:Transgenomic Inc.
Dhiti Omics Technologies enables the diagnosis of genetic disorders by testing for the exact genetic marker by microarray,
Sanger or NGS. We have tested over a hundred cases from a vast variety of categories. We have used existing pipelines
and built upon these by customizing them in different ways based on the clinical presentation. We have been successful in
confirming correct diagnosis when other clinical data showed conflicting results, in identifying the marker to enable future
prenatal testing, and in providing accurate diagnosis when the clinical picture was unclear. We will present our experiences
in refinement of these pipelines which enabled us to achieve a high diagnostic yield from panel-based sequencing for inherited
disorders.We will also discuss our approaches to pre and post-test counseling, a rapidly evolving area in India.
Mon(2)-P-232
Fragile X premutation screening in Korean women
Kyung Min Kang 1 ，Ji Eun Park 1 ，Se Ra Sung 1 ，Sun Ok Park 1 ，Sang Woo Lyu 2 ，Dong Hyun Cha 1,2
，
Sung Han Shim 1
1:Genetics Laboratory of Fertility Center, CHA University School of Medicine, Korea, South、2:Department of Obstetrics and Gynecology,
Poster Session
CHA Gangnam Medical Center, CHA University
Fragile X syndrome is one of the most common mental retardation diseases resulting from unusual expansion of (CGG) n
repeat in the 5’ untranslated region of the FMR1 gene. The aim of this study is to know the allelic distribution and to
identify the prevalence of premutation carriers in Korean women. Between March 2010 and August 2015‚ a total of 1‚333
individuals those who were preconceptional or pregnant women were tested for fragile X molecular analyses at CHA medical
center. Genomic DNAs were extracted from peripheral blood samples. The FMR1 CGG repeat region was amplified by PCR
and Southern blot analyses were performed to identify a premutation or full mutation. All procedures and data analysis were
performed by manufacturer’s protocols. Of the 1‚333 samples 1‚315 (98.6%) had two normal alleles of (CGG) repeats. The
other 18 samples had one normal allele and one expanded allele; eight intermediate ranges (0.6%), nine premutation (0.7%)
and one full mutation (0.1%). Of the women in the normal group, 856 were heterozygotes (65%) and 459 were homozygotes
(35%). The number of their CGG repeat was distributed from 16 to 44, of which 27, 28 and 34 repeats accounted for 86.8%
of the total. 4 of the 10 families whose member had premutation or full mutation alleles turned out having FMR1 CGG
expansion. Patient1 was female having premutation allele, and transmitted her daughter to expanded full mutation. Patient 2
was pregnant woman who had a boy with FXS and as a result, a full mutation allele was detected in amniocytes. Patient 3 and
Patient 4 were males having full mutation, and their mothers were carriers having premutation alleles. We observed dynamic
mutation events of the (CGG)n repeat expansion in families with a premutation carrier mother. Females with premutation
carriers have a 50% risk of transmitting the expanded allele to offspring. Thus, it is important to identify premutation carriers
through routine screening.
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Mon(2)-P-233
The clinical utility of whole exome sequencing in clinical practice: detecting mosaic post-zygotic muta-
tions in neonates
John M Taylor 1 ，Tracy Lester 1 ，Jon Williams 1 ，Jenny Taylor 2 ，Jenny Carmichael 3 ，Andrea Nemeth 4 ，Usha Kini 4 ，
Edward Blair 4 ，Hugh Watkins 2,5 ，Anneke Sellar 1
1:Oxford Medical Genetics Laboratory, Oxford University Hospitals NHS Trust, UK、2:Oxford Biomedical Research Centre, Wellcome Trust
Centre for Human Genetics, Oxford、3:Department of Clinical Genetics, Northampton General Hospital, Northampton、4:Department of
Clinical Genetics, Churchill Hospital, Oxford University NHS Hospitals Trust, Oxford、5:Department of Cardiovascular Medicine, University
of Oxford, Oxford
Introduction: Whole exome sequencing (WES) is rapidly becoming an invaluable diagnostic screen for genetically and phe-
notypically heterogeneous conditions. Here we present three cases where WES has detected separate mosaic mutations in
neonates severely affected by epileptic encephalopathy, hypertrophic cardiomyopathy, and an undiagnosed dysmorphic con-
dition with dysponea.
Method: Patients were discussed within a genomic-themed MDT and enrolled in a biomedical research committee funded
local exome programme. Parent-child trio exome sequencing was undertaken on DNA extracted from peripheral blood sam-
ples prepared using the NimbleGen SeqCap EZ Human Exome Library v2.0 in solution-based capture method followed by
paired-end sequencing on the Illumina HiSeq. The initial data analysis targeted specific causative gene panels, followed by
whole exome analysis with appropriate consent.
Results: Targeted analysis of genes associated with epileptic encephalopathy and hypertrophic cardiomyopathy identified de
Poster Session
novo mutations in the WDR45 (X-linked) and PRKAG2 genes with minor allele frequencies of 87.5% and 18% respectively.
Whole exome analysis using ExomeDepth and calculating B-allele frequencies detected a mosaic 6.4Mb deletion of 17q11.2q12
and a mosaic 8.4Mb duplication of 17q12.21.3 within the child with dysmorphic features and dysponea. Each of these vari-
ants are believed to have been a post zygotic event, resulting in low recurrence risk. The latter two neonatal patients had
previously had targeted molecular analysis, which failed to detect the causative variants. Exome analysis in these two cases
has subsequently changed clinical practice.
Conclusion: WES is a very powerful diagnostic tool when applied to severe genetic conditions, presenting in the neonatal
period. Parent-child trio analysis and high read depth can have a significant impact on the molecular diagnosis, current
clinical practice, and patient counselling; especially when addressing reproductive risk.
Mon(2)-P-234
Whole Exome Sequencing as a diagnostic Tool to Identify Novel Mutations in 3M syndrome
Asuman Koparir 1 ，Erkan Koparir 2 ，Omer Faruk Gerdan 3 ，Betul Yuceturk 3 ，Mahmut Samil Sagiroglu 3 ，
Adnan Yuksel 4 ，Mustafa Ozen 1,4,5
1:Istanbul University, Turkey、2:Department of Medical Genetics, Kanuni Sultan Süleyman Research and Training Hospital, Istanbul Turkey、
3:Advanced Genomics and Bioinformatics Research Center, The Scientific and Technological Research Council of Turkey (TUBITAK-
BILGEM), Kocaeli, Turkey、4:Department of Molecular Biology and Genetics, Biruni University, Istanbul, Turkey、5:Department of
Pathology and Immunology, Baylor College of Medicine, Houston, USA
Primordial dwarfism (PD) is used for describing prenatal onset growth failure, which persists postnatally. 3M is normocephalic
form of PD and very rare autosomal recessive disorder. CUL7, OBSL1, and CCDC8 are the causative genes of this syndrome.
In current study, we describe five individuals from two unrelated kindred Turkish families with primordial dwarfism. The
initial clinical diagnosis of the patients was 3M syndrome due to short stature, facial dysmorphism and tall vertebral bodies.
To confirm the clinical diagnosis, we utilized whole exome sequencing (WES), which is time-saving and affordable method
compared to targeted molecular analysis in genetically heterogeneous syndromes. A novel homozygous exonic frameshift
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deleterious mutation in exon 26 of CUL7 in one family and a novel homozygous insertion in exon 2 of OBSL1 in the other
family were detected. These novel variants were confirmed by Sanger sequencing. This molecular results support the benefits
of conducting WES in genetically heterogeneous syndromes. To further investigate the pathogenicity of these mutations, we
analyzed the relative expression levels of CUL7 and OBSL1 in peripheral blood cells of the patients and a control individual
and demonstrated the reduced expression of CUL7 and OBSL1 in the patient samples.
Mon(2)-P-235
Utilisation of Non-invasive prenatal testing to exclude an unbalanced karyotype in a translocation carrier’s
pregnancy: A case study
Alison Yeung 3 ，Nikki Gelfand 1 ，Theresa Boomer 2 ，Nilesh Dharajiya 2 ，Marcos Gonzales 2
1:Monash Genetics, Monash Health, Australia、2:Sequenom Laboratories、3:Vicorian Clinical Genetics Services
This case study aims to illustrate the innovative use of cell free DNA technology for prenatal testing for a 27-year-old
balanced translocation carrier. The patient, G8 P0 had recurrent first trimester miscarriages, and was discovered to carry
a 13;16 balanced reciprocal translocation: t(13;16)(q14.1;q22.3). She attended genetic counselling to discuss the potential
reproductive outcomes of her specific translocation, and the testing options available in an ongoing pregnancy.
Poster Session
The patient and her husband declined invasive testing for prenatal detection of a potentially unbalanced karyotype during
pregnancy, due to the associated risks of miscarriage. Given the two chromosomes involved in her translocations were both
being analysed using cell free DNA technology in Australia at the time, the US based laboratory (Sequenom) were able
to report whether they detected any copy number variants around the specific translocation breakpoints. The patient was
counselled that this testing was not diagnostic, but rather utilised as an adjunct screening method with ultrasound, in lieu
of invasive prenatal diagnosis. The report indicated no abnormalities and the patient went on to deliver a healthy baby girl,
confirmed postnatally to have a 46,XX karyotype.
Requests to use cell free DNA for assessment of chromosomes other than 21, 18, and 13 have increased over time. To meet this
need, MaterniT ™ GENOME, a whole-genome cell free DNA test that analyses each chromosome, was developed for patients
known to be at-risk for chromosome anomalies other than the common trisomies. This laboratory-developed test (LDT) is
able to identify chromosome gains and losses (suggestive of unbalanced translocations) ≥ 7 Mb and becomes another tool
available to clinicians in prenatal risk assessment. We believe patients with balanced reciprocal translocations could benefit
greatly by further development and accreditation of NIPT technology for this purpose in Australia.
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Mon(2)-P-236
Diagnostic Application of Targeted Exome Sequencing for Skeletal Dysplasia
Eun Kyung Cho 1 ，A Ram Yang 1 ，Jinsup Kim 1 ，Young Bae Sohn 2 ，Su Jin Kim 3 ，Sung Won Park 4 ，
Sung Yoon Cho 1 ，Dong-kyu Jin 1
1:Department of Pediatrics, Samsung Medical Center, Korea, South、2:Department of Medical Genetics, Ajou University School of Medicine、
3:Department of Pediatrics, Myongji Hospital, Seonam University College of Medicine、4:Department of Pediatrics, Jeil Hospital, Dankook
University College of Medicine
Identification of causative genes for skeletal dysplasia (SD) is important to provide an exact diagnosis and decide treatment
modalities and to counsel the patients. Due to the genetic heterogeneity in SD, the high throughput method can be adapted
for the efficient diagnosis. To this end, a new diagnostic pipeline were designed to screen 260 reported candidate genes
for SD. A total of 22 patients diagnosed with skeletal dysplasia, or suspected to have it were recruited over one year.
Their clinical diagnosis were hypochondroplasia, osteogenesis imperfect type I, Sticker syndrome, pseudohypoparathyroidism,
osteopetrosis. pycnodysostosis, spondyloepiphyseal dysplasia strudwick type, and ischiospinal dysostosis. We applied targeted
exome sequencing (TES) on 260 genes in the 22 probands with SD. Potential causative variants determined using TES
were confirmed by filtering steps. These variants were then filtered out with clinical features, inheritance pattern and a
co-segregation study in the family and allele frequency in normal 197 control subjects. Finally, we detected 18 causative
variants, and these variants were in the FGFR3, GANS, COL1A1, COL1A2, COL2A1, LRP5, CLCN7, CTSK, BMPER, and
TNFSF11 genes bringing the total detection rate in all the patients to be 68.2% (15/22). These variants were validated using
Sanger sequencing. Despite the advent of whole genome and whole exome sequencing, we propose TES as a screening and
diagnostic tool at least for SD to find mutations based upon its efficacy and cost-effectiveness.
Poster Session
Mon(2)-P-237
Prenatal clinical and molecular (epi-) genetic diagnosis of Beckwith-Wiedemann syndrome: time to shift
gears?
Maria Paola R. Lombardi 1 ，Suzanne C.E.H. Sallevelt 2 ，Audrey B.C. Coumans 3 ，Ingrid Witters 3 ，
Kim J.A.F. van Kaam 2 ，Salwan Al-Naseri 3 ，Yvonne H.J.M. Arens 2 ，Christine E.M. de Die-Smulders 2 ，
Mariëlle Alders 1 ，Merryn V.E. Macville 2 ，Marcel M.A.M. Mannens 1 ，Suzanna G.M. Frints 2
1:Department of Clinical Genetics, University of Amsterdam, Netherlands、2:Department of Clinical Genetics, Maastricht University
Medical Center+, Maastricht, The Netherlands、3:Department of Gynecology & Obstetrics, Maastricht University Medical Center+,
Maastricht, The Netherlands
Beckwith-Wiedemann syndrome (BWS) is an overgrowth (epi)genetic disorder with prenatal clinical onset, which can be
inherited but usually develops de novo. Prenatal ultrasound abnormalities of BWS are omphalocele, overgrowth, large (poly-
cystic) kidneys with/-out hydronephrosis, body asymmetry and/or polyhydramnios or rarely an embryonic tumor. Agreement
on minimal diagnostic ultrasound criteria and indication for DNA analysis for BWS does not exist. As a result BWS is prob-
ably underdiagnosed.
We report on four prenatal cases with clinical presentations of BWS. In all cases BWS was diagnosed by molecular investiga-
tion of the 11p15.5 locus on both prenatal and postnatal derived cell material.
Fetal DNA was obtained from amniotic fluid for microarray analysis and molecular diagnosis of BWS. Methylation analysis
(fetus, mother and once the father) of the 11p15.5 locus was performed using High Resolution Melting Analysis (HRMA)
and/or quantitative Methylation-Sensitive (MS-MLPA). Control samples from normal individuals were used to calculate the
average methylation index (MI) for each of the assays. Fetuses with a MI more or less than three standard deviations from
the mean of normal controls were categorized as hyper- or hypomethylated, respectively. In one familial case methylation
levels of both the KCNQ1OT1 and H19 genes were normal but sequence analysis of the CDKN1C gene revealed the presence
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of a pathogenic c.635delC mutation in fetuses and their mother.
These prenatal cases illustrate a strategy for fast and reliable prenatal diagnosis of BWS based on one BWS ultrasound abnor-
mality through targeted genetic investigations. A prospective validation study has to be performed to calculate the positive
and negative predictive value of genetic investigation in case of one BWS ultrasound abnormality such as omphalocele. In
our opinion, it is nearly time to shift gears from postnatal to prenatal molecular diagnosis of BWS.
Mon(2)-P-238
A method for large scale screening of sex chromosome aneuploidies at birth
Marisol Ibarra-Ramirez 1 ，Luis D Campos-Acevedo 1 ，Jose J Lugo-Trampe 1 ，Michelle Zamudio-Osuna 1 ，
Iris Torres-Munoz 1 ，Viviana M Gomez-Puente 1 ，Gloria B Garcia-Castaneda 1 ，Patricia Arredondo-Vazquez 2 ，
Iram P Rodriguez-Sanchez 2 ，Isabel Moreno-Vega 1 ，Jesus Z Villarreal-Perez 2 ，Laura E Martinez-Garza 1
1:Genetics, Medicine School Of Universidad Autonoma de Nuevo Leon, Mexico、2:Secretaria de salud de Nuevo Leon
Introduction: Sex chromosome aneuploidies (SCA) are defined as numerical abnormalities of the X or Y chromosomes. These
disorders are the most frequent chromosomal abnormalities in humans. SCA are not associated with obvious features at birth,
and only a small percentage of phenotypes are detected in a timely manner. This may hinder early interventions that could
improve the quality-of-life of individuals with such disorders. The aim of the present study was to develop a feasible and
practical molecular diagnostic tool for newborn screening of SCA by quantifying the gene dosage of the SHOX, VAMP7 and
SRY genes by quantitative polymerase chain reaction. Materials and methods: We collect dried blood spot into FTA Elute
Poster Session
Micro Cards (Whatman, UK) for 8732 newborns for neonatal screening program. DNA from FTA Elute cards was used to
measure the dosage of SHOX, VAMP7 and SRY genes with the StepOne Plus System (Applied Biosystems) and TaqMan
Genotyping (Applied Biosystems). Relative quantification (RQ) values were obtained using the δδ CT. The diagnosis of
newborns showing abnormal RQ values was confirmed by GTG band karyotype. Results: Out of 8732 samples (4485 male and
4247 female) we detected 16 with abnormal RQ. These results were confirmed by karyotyping: 3 patients presented Turner
syndrome, 5 newborns presented Klinefelter syndrome, 6 males with 47,XYY and 1 newborn with 47,XXX. The guardians
for one patient with probable Klinefelter syndrome diagnosis refused the confirmatory test. Discussion and conclusion: The
delay in SCA diagnosis presents a significant problem to the appropriate, timely treatment of preventable symptoms. We
demonstrated that gene dosage analysis is a viable, effective method for identifying patients with sex chromosome aneuploidy.
Interestingly, the incidence of patients with SCA is similar to that reported in the literature, except for Turner syndrome
(1:1415 female newborn) and polysomy X (1:4247 female newborn).
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Poster Session
Cardiovascular Genetics
Mon(2)-P-240
Molecular genetic risk scale of coronary artery disease (CELERA, USA) and sudden cardiac death: a
case-control study
Anastasiya A. Ivanova 1 ，Vladimir N. Maksimov 1,4
，Pavel S. Orlov 1,2
，Divara E. Ivanoshchuk 1,2
，
Sergey V. Savchenko 3,4 ，Mikhail I. Voevoda 1,2
1:Federal State Budgetary of Scientific Institution Institution of Internal and Preventive Medicine, Russia、2:Institute of Cytology and
Genetics, Siberian Branch under the Russian Academy of Sciences、3:Novosibirsk Regional Office of Forensic Medical Examination、
4:Novosibirsk State Medical University
Objectives: Single nucleotide polymorphisms (SNPs) rs3900940 gene MYH15 , rs1010 gene VAMP8 , rs7439293 gene PALLD,
rs2298566 gene SNX19 , rs20455 gene KIF6 were effectively used in large study of corporation CELERA (USA). The aim
of that project was creating new informative molecular genetic risk scale of coronary artery disease (CAD). Sudden cardiac
death (SCD) is one of the forms of CAD. The risk factors, pathogenesis in SCD and CAD are rather similar. We assumed
that the SNPs associated with the development of CAD might also contribute to SCD development. So the aim of this work
is investigate the association of rs3900940, rs1010, rs7439293, rs2298566, rs20455 with SCD.
Poster Session
Methods and Algorithms: A sample of SCD cases (n=379) was formed using the WHO criteria; the control sample (n=377)
was selected from the DNA bank of HAPIEE and MONICA international projects. DNA was isolated by phenol-chloroform
extraction from the myocardial tissue of SCD cases and blood of control cases. The groups were genotyped for the selected
SNPs by real-time PCR using TaqMan probes (Applied Biosystems, United States). The data were statistically processed
using chi-square test according to Pearson, two-sided Fisher’s exact test.
Results: No statistically significant differences in the genotype and allelic frequencies of rs7439293, rs2298566, rs3900940
between SCD cases and control were detectable. Genotype GG of rs20455 is associated with protective effect against SCD in
the group over 50 years old (p=0.009, OR=0.46, 95%CI 0.26-0.81). In the men over 50 years old genotype CC of rs1010 is
associated with protective effect against SCD (p=0.002, OR=0.33, 95%CI 0.16-0.68) and genotype CT of rs1010 is associated
with an increased SCD risk (p=0.025, OR=1.73, 95%CI 1.08-2.76).
Conclusion: The association of selected polymorphisms with SCD was studied for the first time. Polymorphisms rs20455,
rs1010 are associated with SCD.
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Mon(2)-P-241
Detection and Putative Functional Effect of Variants in Congenital Heart Defects -Related Genes
Alaaeldin G Fayez 1 ，Nora N Esmaiel 1 ，Ghada S Nor El deen 1 ，Arwa A El Darsh 1 ，Mona O El Ruby 1
1:Molecular Genetics and Enzymology, National Research Centre, Egypt
Despite the many advanced therapies currently available for a number of heart defects, significant morbidity and mortality
are still associated with some types of congenital heart defects (CHDs). Therefore improved understanding of possible genetic
causes, allows identification of disease risk factors and establish a proper genetic therapy protocol. Patients: We examined 155
patients with CHDs referred from Genetics Clinics at the National Research Centre (NRC), out of them 66 syndromic and 89
nonsyndromic. Methods: All patients were subjected to full clinical evaluation. Genomic DNA was extracted from peripheral
blood and subjected to PCR followed by direct sanger sequencing. The predicted function effect of the novel variants was
done by a variety of a proper bioinformatics tools. Results: We detected totally 24 variants as two variants (one novel and
one reported) in PTPN11 gene, three variants (two novels and one reported) in HAND2 gene, three variants (two novels and
one reported) in Tbx5 gene, seven variants (two novels and five reported) in GATA4 gene, nine variants (six novels and three
reported) in Nkx2-5 gene. In silico analysis for the detected novel variants postulated 11 out of 14 have significant predicted
effect on splicing site, DNA binding, protein conformation and mRNA folding. Conclusion: we detected 24 variants in a
studied CHD patients. By standing the relationship between the variant site and presented phenotype, we concluded that (1)
despite that Tbx5 is known as Holt-Oram syndrome (HOS) candidate gene, but the variants in N-terminal end of the T box
domain of Tbx5 gene might lead to cardiac septal defects with mild or no HOS, (2) Nkx2-5 gene variants in N-terminus before
and outside homeobox domain (HD) might lead to cardiac septal defects without AV conduction disturbance, (3) 3’-UTR
Poster Session
variants in GATA4 gene could lead to fauty mRNA folding faulty and heterozygote G/T genotype for rs867858 could increases
the risk for the VSD more than homozygote G/G.
Mon(2)-P-242
Genetics and Environment: Impact of Ethnicity, Age and Sex on Heritability of Cardiometabolic and
Inflammatory Risk Traits
Enkhmaa Byambaa 1 ，Anuurad Erdembileg 1 ，Wei Zhang 1 ，Kyoungmi Kim 2 ，Lars Berglund 1,3
1:Internal Medicine, University of California - Davis, USA、2:Public Health Sciences, University of California - Davis、3:Veterans Affairs
Northern California Health Care System, Sacramento, USA
Despite recent declining trend seen in mortality rate, cardiovascular disease (CVD) remains as the leading cause of death in
the U.S. Many factors contributing to CVD development are under genetic and environmental influences. To gain insights
into the role of genetic vs. environmental influences on CVD risk traits, we estimated heritability of four anthropometric,
seven metabolic and eight inflammatory risk traits in 82 Caucasian and African-American nuclear families. Heritability (h2 )
was estimated by relative contribution of the genetic component of variance responsible for parent-offspring resemblance.
Overall, there was a large variation in heritability for many of the studied traits. In both ethnicities, total cholesterol, LDL
cholesterol, apoB-100, serum amyloid A (SAA), α-acid glycoprotein, and sICAM-1 were heritable (h2 =0.27 to 1.00). Of note,
a pronounced >2-fold higher heritability was seen in African-Americans vs. Caucasians for LDL cholesterol, apoB-100 and
SAA (p<0.05 for race difference). To investigate whether heritability differs by age, we stratified families by mean age of
parents (47 yrs). In Caucasians, heritability of many traits were higher in older vs. younger families with marked differences
for apoB-100 (7-fold, p=0.044) and fibrinogen (8-fold, p=0.002). Heritability patterns were similar in African-Americans for
most of the traits, although lower heritability estimates in older vs. younger families were found for body weight, BMI, blood
pressure, triglycerides and sICAM-1. Sex-specific heritability estimates were similar. Our results demonstrate a moderate to
high heritability for many of the studied traits albeit differences between ethnic groups. Age influenced heritability of some
risk factors differently in Caucasians and African-Americans, suggesting that these risk traits evolve over the lifespan due to
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variable contribution of the environment.
Mon(2)-P-243
The First Genetic Epidemiological Study of North Cyprus: Genetic Mapping of Cardiovascular Diseases
and Using Those Variants as a Biomarker
1,2
Mahmut Cerkez Ergoren ，Esra Ozerkan 2 ，Arda Gursel 2 ，Aysegul Bostanci 2 ，Meral Kizilkanat 2
1:Medical Genetics, Near East University, Cyprus、2:Medical Genetic Laboratory, Near East University Hospital
Genetic variation is a rich source of knowledge for cardiovascular disease because many, if not all, cardiovascular disorders
are highly heritable. Genetic risk scores are a useful tool for examining the cumulative predictive ability of genetic variation
on cardiovascular diseases (CVDs). Important considerations for creating genetic risk scores include the choice of genetic
variants, biochemical parameters, and ethnicities.
The questions still remain until today about the ultimate clinical utility of the genetic risk score, further investigation in
high-risk populations and new ways to combine genetic risk scores with traditional risk factors may prove to be fruitful.
To investigate the CVD genetic risk score profile, we compared 144 subjects with a cardiac problem and 180 without; we
based on HapMap, 1000 genome and dbSNP datas and picked previously identified 36 different SNPs on 24 different genes
that are suggested to have association with CVDs for different populations. This study is the first analysis of the highest
Poster Session
SNP coverage that shown the association of genetic variants with CVDs in North Cyprus.
Our data is the first data shown the association of all 24 gene and 36 polymorphism to CVD and thus these data are
demonstrating the cardio-genetic profile of North Cyprus. North Cyprus has a unique mixture of allele distribution for each
SNP to the other close by country neighbors. Thus, SNP-SNP interactions and also their relation with biochemical pathways
might play critical role for developing genetic related diseases like CVD, metabolic syndromes etc. To conclude, this study will
help for understanding the genetic profile of CVDs in the Island and also will be great source and useful tool for prevention
of CVDs.
Mon(2)-P-244
Incidence of homozygous familial hypercholesterolaemia (hoFH) in New Zealand
Andrew D Laurie 1 ，Peter M George 1,2
，Nicola Reid 2
1:Molecular Pathology, Canterbury Health Laboratories, New Zealand、2:Lipid Disorders Clinic, Christchurch Public Hospital
Familial cholesterolaemia (FH) is a genetic disorder characterized by high cholesterol levels in circulating plasma, specifically
very high levels of low-density lipoprotein (LDL), and early-onset cardiovascular disease. FH is caused by mutations in the
LDLR gene, and is inherited as an autosomal co-dominant trait. The frequency of heterozygous FH in Caucasian populations
is estimated to be 1:500, and the frequency of homozygous FH (hoFH), which includes those patients who are compound
heterozygous for two LDLR mutations, is estimated to be 1 per million. Patients with hoFH have a very severe phenotype,
typically with total cholesterol of 17-20 mmol/L and LDL >15 mmol/L. They do not respond to statin therapy, leaving plasma
apheresis as the only effective treatment option. At Canterbury Health Labs, where LDLR mutation screening is performed
primarily for patients attending the Christchurch Hospital Lipid Disorders Clinic, but also for other patients as requested,
we have identified seven cases of hoFH since 2004. This is significantly higher than the number of hoFH cases expected to
be observed in New Zealand, which has a population of 4.5 million. The high number of observed hoFH cases may suggest a

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heterozygous frequency of more than 1:500 in the New Zealand population, or may simply reflect immigration from countries
with a high FH rate due to founder effects. Our laboratory is also currently developing a preimplantation genetic diagnosis
(PGD) assay for a couple at risk of having a hoFH child.
Mon(2)-P-245
Analysis of genotype-phenotype correlations for desmoplakin mutations
Wanling Yang 1 ，Jing Yang 1 ，Pamela Pui-wah Lee 1 ，Yu Lung Lau 1
Desmoplakin(DSP) is the major linker in desmosomes in epithelia and myocardium, anchoring intermediate filaments through
its C-terminus to plakoglobin and plakophilin in the desmosomal plaque through its N-terminus. There is a diverse range
of various manifestations caused by mutations in this gene in both recessive and dominant modes, including arrhythmogenic
cardiomyopathy, skin fragility and palmoplantar keratoderma. The exact genotype-phenotype correlations are far from clear.
Many heterozygous carriers of the mutations for this gene have late onset, often asymptomatic cardiac problems that can
lead to arrhythmias and sudden cardiac death. Not having a clear understanding of the genotype-phenotype correlation
causes difficulties in patient counseling and disease prevention. Here we reviewed the literature on DSP mutations, especially
the manifestations for heterozygous carriers and conclude that missense mutations in the N-terminus and the Rod domain
of the protein, or nonsense mutations when coupled with incomplete nonsense mediated decay, are probably the cause of
cardiac manifestations through dominant negative effect. Mutations in the C-terminus, however, usually cause phenotypes in
Poster Session
a recessive mode. Furthermore, the ever increasing population genetics data allow us to revisit some of the reported causal
mutations for this gene and identify a number of potentially disease-causal mutations in the general population.
Mon(2)-P-246
Investigation of Pathogenic Genes in Chinese sporadic Hypertrophic Cardiomyopathy Patients by Whole
Exome Sequencing
Jing Xu 1 ，Zhongshan Li 2 ，Xianguo Ren 3 ，Ming Dong 1 ，Jinxin Li 1 ，Xingjuan Shi 1 ，Yu Zhang 1 ，Wei Xie 1 ，
Zhongsheng Sun 2,4 ，Xiangdong Liu 1 ，Qiming Dai 5
1:Insititute of Life Science, Southeast University, Nanjing, China、2:Genomic Medical Institute, Wenzhou Medical University, Wenzhou, P.
R. China、3:General Hospital of Nanjing Military Command, P. R. China、4:Beijing Institutes of Life Science, Chinese Academy of Sciences,
Beijing, P. R. China、5:ZhongDa Hospital, Southeast University, Nanjing, P. R. China
Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease with high heterogeneity. Limited knowledge concerning
the genetic background of nearly 40% HCM cases indicates there is a clear need for further investigation to explore the
genetic pathogenesis of the disease. In this study, we undertook a whole exome sequencing (WES) approach to identify
novel candidate genes and mutations associated with HCM. The cohort consisted of 74 unrelated patients with sporadic
HCM (sHCM) previously determined to be negative for mutations in eight sarcomere genes. The results showed that 7 of 74
patients (9.5%) had damaging mutations in 43 well established HCM disease genes. Furthermore, after analysis combining
the Transmission and De novo Association (TADA) program and the ToppGene program, 10 putative genes gained priority.
A thorough review of public databases and related literature revealed that there is strong supporting evidence for most of
the genes playing roles in various aspects of heart development. Findings from recent studies suggest that the putative
genes converge on three functional pathways: (i) sarcomere function; (ii) calcium signaling; and (iii) a substrate and energy
metabolic pathway. This study illustrates the benefit of WES, in combination with rare variant analysis tools, in providing
valuable insight into the genetic etiology of a heterogeneous sporadic disease.
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Mon(2)-P-247
Interaction of maternal age and MTHFR C677T polymorphism increases the risk of co-occurrence of
Down syndrome and congenital heart disease
S. Justin Carlus 1 ，Lama M El-Attar 1,2 ，Sahar AF Hammoudah 1,3
，Atiyeh M Abdallah 1 ，Lvks Bhaskar 4 ，
Ibrahim S. Almuzainy 5 ，Khalid M Al Harbi 1
1:Cardiogenetics team- Pediatric Cardiology, College of Medicine, Taibah University, India、2:Department of Human Genetics, Medical
Research Institute, Alexandria University, Egypt、3:Department of Clinical Pathology, School of Medicine, Tanta University, Egypt、4:Sickle
Cell Institute Chhattisgarh, JNM Medical College, Raipur (C.G.), India、5:Department of Pediatric Cardiology, Maternity and Children
Hospital, Madina, Kingdom of Saudi Arabia
Congenital heart diseases (CHD) are the most common birth defect in the world. About 40 to 50 percent of babies with
Down syndrome (DS) have congenital heart defects. Advanced maternal age and consanguinity proved to be risk factors for
CHD and DS. In Saudi Arabia the prevalence of consanguinity is 56%. Highest prevalence of consanguinity was recorded
in Madina with 67.2%. Methylenetetrahydrofolate reductase (MTHFR) polymorphism C667T has been associated with
congenital malformation; this common missense mutation in the MTHFR gene may reduce enzymatic action, and may be
involved in the etiology of congenital heart defects (CHD). The aims of the present study were to assess (i) the frequency of
MTHFR C677T polymorphism in CHD and CHD in DS individuals in the Saudi Arabian population; (ii) the relationship
between paternal, maternal, consanguinity and MTHFR polymorphism in CHD and CHD-affected DS children.
Method: DNA sequencing was used to detect genotype MTHFR C677T in 99 patients (73 CHD, 26 CHD-DS) and 126
ethnically similar controls collected from Madina, Saudi Arabia.
Poster Session
Results: The presence of CHD in general was not significantly associated with the MTHFR C677T polymorphisms in this
study. But the distribution of MTHFR C677T genotypes and other risk factors revealed that the maternal age increased
the risk of CHD-DS (OR= 5.32; 95% CIs 1.43-19.82; p=0.013) and consanguinity decreased the risk of CHD-DS (OR=0.25;
95% CIs 0.09-0.75; p=0.013). Mantel-Haenszel analysis provides evidence of significant heterogeneity between in the effect of
maternal age on CHD-DS among different genotypes of the C677T polymorphism (OR=0.322; 95% CIs 0.128-0.814; p=0.027),
indicated the presence of confounding effect of MTHFR C677T genotype on the relationship between DS and maternal age.
Conclusion: These results suggest that the MTHFR C677T genotypes interact with the maternal age in increasing the risk
of co-occurrence of Down syndrome and congenital heart disease.
Mon(2)-P-248
IL10 promoter polymorphisms are associated with rheumatic heart disease in Saudi Arabian patients
Khalid M Al Harbi 1 ，Atiyeh M Abdallah 1 ，Abdulhadi H Al-Mazroea 1 ，Amr E Eldardear 1 ，Yousef Almohammadi 2 ，
S. Justin Carlus 1
1:Cardiogenetics Team- Department of Pediatrics, College of Medicine, Taibah University, Saudi Arabia、2:Security Forces Medical Centre,
Madinah, Saudi Arabia
Rheumatic heart disease (RHD) is an inflammatory disease that develops following streptococcal infections. IL-10 helps to
balance immune responses to pathogens. IL10 polymorphisms have been associated with RHD, although results remain
inconclusive. Our aim was to investigate the association between IL10 polymorphisms and RHD in Saudi Arabian patients.
Method: IL10 promoter polymorphisms (-1082A/G, -829C/T, and -592C/A) were genotyped in 95 RHD patients and 146
matched controls using the TaqMan allelic discrimination assay. Result: There was a significant difference in IL10 -1082
genotype frequency between patients and controls (p=0.01). -1082G allele carriage (GG+GA vs. AA) and the (−1082,
-819, -592) GCC haplotype carriage were associated with an increased risk of RHD (p=0.004, OR=2.1, 95% CIs 1.7-3.4 and
p=0.004, OR=2, 95% CIs 1.3-3.4, respectively). The ACC haplotype was associated with a decrease in RHD risk (p=0.015,
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OR=0.6, 95% CIs 0.4-0.9). Discussion: IL10 promoter polymorphisms may play an important role in the development of
RHD and provide an opportunity for therapeutic stratification.
Mon(2)-P-250
Targeted Resequencing of 174 Genes in Patients with Inherited Cardiovascular Diseases for Future Clinical
Utility
Akiyoshi Ogimoto 1 ，Mareomi Hamada 2 ，Shuntaro Ikeda 2 ，Kiyotaka Ohshima 2 ，Hideaki Shimizu 2 ，
Haruhiko Higashi 1 ，Naohito Tokunaga 1 ，Jun Suzuki 1 ，Katsuji Inoue 1 ，Kazuhisa Nishimura 1 ，Takayuki Nagai 1 ，
Jun Aono 1 ，Teruyoshi Uetani 1 ，Chiharuko Iio 1 ，Tamami Kono 1 ，Fumiyasu Seike 1 ，Hiroshi Kawakami 1 ，
Yasuharu Tabara 3 ，Jitsuo Higaki 1
1:Ehime University Graduate School of Medicine, Japan、2:Uwajima City Hospital、3:Kyoto University Graduate School of Medicine
Background: Thousands of mutations in more than 150 genes have been reported in inherited cardiovascular diseases. Using
next-generation sequencing (NGS), the enormous scanning of candidate genes has become a feasible approach to genetic
testing in patients with inherited cardiovascular diseases. The aim of this study was to assess the performance characteristics
and cost of a 174-gene-NGS assay in patients with inherited cardiovascular diseases. METHODS and RESULTS: We targeted
and sequenced the coding regions and splice junctions of 174 genes associated with inherited cardiovascular diseases in 36
Japanese patients with inherited cardiovascular diseases by using TruSight Cardio Sequencing Kit (illumina). We utilized
bioinformatics analyses pipelines based on commercially available software (VariantStudio). Thirty-six patients (multiplexing
12 samples per sequencing run) resulted in a mean region coverage depth of 229.9, of which 96.9% had >20 coverage, mean
Poster Session
detected single nucleotide polymorphisms (SNPs) of 297.4 and 96.0% were concordant with known heterozygous SNPs. We
found mean 5.9 variants per patient as candidate mutations by filtering with the frequency less than 1% in Asian Population.
Total run time was 5 days at an approximate cost of 34,000 yen per patient. CONCLUSIONS: This study suggested that
the targeted resequencing of 174 genes in patients with inherited cardiovascular diseases provides a highly efficient and cost-
effective approach for routine genetic diagnosis of cardiomyopathies. Genetic classification of inherited cardiovascular diseases
might lead to better treatment.
Mon(2)-P-251
Tight junction gene CLDN8 were associated with plasma chemokine IP-10 level in methadone mainte-
nance patients
Sheng-Wen Liu 1 ，Hsiang-Wei Kuo 1 ，Sheng-Chang Wang 1 ，Chia-Lung Shih 1 ，Yu-Li Liu 1,2
1:Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan、2:Graduate Institute of Clinical Medical
Science, China Medical University, Taichung, Taiwan
Methadone-induced cardiac QT prolongation is a potentially lethal side effect for heroin dependent patients under its main-
tenance therapy. This severe adverse reaction has been reported as context dependence with the causes of high dosage
methadone, CYP3A4 inhibitor in co-medication, hepatic failure and pre-existing heart disease. In our previous study, we
have reported that the plasma chemokine interferon gamma-inducible protein 10 (IP-10) were elevated in methadone mainte-
nance therapy (MMT) patients with either HIV or HCV infection. The IP-10 showed positive correlation with the corrected
current QT-interval. To evaluate the mechanism regulating IP-10 level in MMT patients, we used the genomewide genotyped
database of the 344 MMT patients for further pathway-based association analyses. We found a significant pathway in tight
junction interactions significantly associated with plasma IP-10 (P=1.01x10-5 ), where the claudin 8 (CLDN8 gene) had the
highest significance (P=6.8x10-5 ). There were 3 out of 5 single nucleotide polymorphisms (SNPs) on CLDN8 , including
rs686364 (exon 1) (P=0.001), rs2832657 (promoter) (P=0.001) and rs670864 (promoter) (P=0.025), associated with plasma
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IP-10 level. These 3 SNPs were also showed significant associations with plasma IP-10 in urine morphine test positive patients,
but not in urine morphine test negative patients. The minor genotype carriers had higher IP-10 than the major allele carriers
(P<0.025). These results indicated that the tight junction protein encoding gene CLDN8 may play a role in the plasma IP-10
level regulatory mechanism
Mon(2)-P-252
Among RyR2 carriers, sinus bradycardia is more frequent in CPVT than other types of phenotype
Seiko Ohno 1 ，Minoru Horie 1
1:Shiga University of Medical Science, Japan
Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by ma-
lignant arrhythmias and sudden cardiac death in young people. The main cause of CPVT is mutations in RYR2 encoding
cardiac rhyanodine receptor. Recently, RYR2 mutations have been reported to cause another arrhythmic disorder called short
coupled variant of torsade de point (SCTdP) characterized by short coupling time of ventricular contract leading to TdP.
Although CPVT patients with RYR2 mutations show bradycardia, the frequency of sinus bradycardia in patients with other
arrhythmia syndromes has not been clarified yet.
Purpose: This study aimed to evaluate the sinus bradycardia in RYR2 mutation carriers in primary arrhythmia syndromes.
Poster Session
Methods and Results: We identified 92 RYR2 mutation carriers (male n=51) with primary arrhythmia syndrome; 69 CPVT,
9 long QT syndrome (LQTS), 4 Brugada syndrome (BrS), 3 SCTdP, 3 idiopathic ventricular fibrillation (IVF) and 4 other
entities. We excluded variants of which minor allele frequency (MAF) in Japanese were more than 0.005. The definition of
sinus bradycardia is less than 60 bpm in 9 y.o. and over patients. In patients less than 9 y.o., the definition is based on
the report published in 2001. Among the CPVT patients, 24 patients showed bradycardia, 23 were normal range in heart
rate (HR) and 22 could not be evaluated HR due to the beta blocker therapy. In contrast, the HRs of 7 from 8 LQTS
patient without beta-blocker therapy, 3 from 4 BrS patients and all SCTdP and IVF patients were within normal range. Sinus
bradycardia is more frequent in patients with CPVT than other arrhythmia syndromes (51% vs 17%, p=0.002).
Conclusions: Among RYR2 mutation carriers, sinus bradycardia was highly identified in patients with CPVT though the HR
of other arrhythmia syndromes was mostly normal range. The difference would be useful to distinguish malignant CPVT
from other arrhythmic syndrome related with RYR2 mutations.
Mon(2)-P-253
Analysis of Moyamoya disease associated genetic variant RNF213 c.14576G>A in various cerebrovascular
diseases
Satoru Miyawaki 1 ，Hideaki Imai 1 ，Masahiro Shimizu 2 ，Shinichi Yagi 2 ，Hideaki Ono 1 ，Akitake Mukasa 1 ，
Hirofumi Nakatomi 1 ，Tsuneo Shimizu 2 ，Nobuhito Saito 1
1:Department of Neurosurgery, The University of Tokyo, Japan、2:Kanto Neurosurgical Hospital
(Background and Purpose) The c.14576G>A variant in ring finger protein 213 (RNF213 ) was recently identified as a suscep-
tibility gene variant for moyamoya disease (MMD). We assumed that the c.14576G>A variant could be the cause of a wide
spectrum of phenotypes of intracranial major artery stenosis/occlusion (ICASO). In this study, the occurrence of c.14576G>A
variant was evaluated in various phenotypes of cerebrovascular diseases.
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(Methods) Study participants were recruited from The University of Tokyo Hospital and Kanto Neurosurgical Hospital. The
occurrence rate of c.14576G>A variant was investigated in 868 patients, 111 with definite MMD, 20 with unilateral MMD, 11
with Quasi-MMD (typical unilateral or bilateral MMD angiographic findings associated with inherited or acquired disorders),
303 atherosclerotic ICASO, 111 with extracranial carotid atherosclerosis, 114 with cerebral aneurysm, 28 with intracerebral
hemorrhage, and 163 control subjects.
(Results) RNF213 c.14576G>A variant was found in 80.1% (89/111) of the definite MMD group, and 74.0% (20/27) of
the unilateral MMD group. Moreover, the variant was found in 25.4% (77/303) of the atheroslerotic ICASO group. On
the other hand, there none in Quasi-MMD group. RNF213 c.14576G>A variant had significant associations with definite
MMD, unilateral MMD, and also with atherosclerotic ICASO (P=4.0 x 10(-13); odds ratio, 18.5; 95% confidence interval,
5.74-59.6). There was no significant association with Quasi-MMD, extracranial carotid atherosclerosis, cerebral aneurysm, or
intracerebral hemorrhage.
(Conclusions) Moyamoya disease and related diseases might be classified by genetic analysis of the RNF213 c.14576G>A
genotype (Miyawaki et al J Stroke Cerebrovasc Dis 2015). A particular subset of patients with atherosclerotic ICASO had
RNF213 c.14576G>A, indicating that RNF213 c.14576G>A variant is a high-risk allele for ICASO (Miyawaki et al Stroke
2012, 2013).
Mon(2)-P-254
Poster Session
A novel de novo mutation in Lamin A/C gene in Emery Dreifuss Muscular Dystrophy: The first clinical
and molecular report of an Indonesian patient
Almira Zada 1 ，Chaerul Ahmad 2 ，Mardlatillah Affani 2 ，Erwan Martanto 2 ，Augustine Purnomowati 2 ，Toni Aprami 2
1:Biochemistry and Molecular Biology, Faculty of Medicine Universitas Padjadjaran, Indonesia、2:Department of Cardiology, Faculty of
Medicine Universitas Padjadjaran
Emery Dreifuss Muscular Dystrophy (EDMD) is a rare genetic disorder, characterized by early contractures, slowly progressive
muscle wasting and cardiac conduction defects. Lamin A/C (LMNA) gene is responsible for autosomal-dominant form of
EDMD (EDMD-AD). We present a 26 year old female Indonesian patient with contracture of elbows, heel cord and pelvic,
muscle wasting and weakness. She was admitted to hospital due to an episode of syncope with history of pre-syncopal
states. Electrocardiography showed persistent junctional arrythmia. High level creatinine kinase was found. She received
dual chamber pace maker due to atrial standstill. She is the only affected family members. Sanger sequencing of all coding
exons and surrounding splice sites of the LMNA gene was performed and a pathogenic heterozygous missense mutation
(NM_170707.3: c.122G>T, p.Arg41Leu) in exon 1 was detected. Subsequent carrier testing in the parents revealed that the
mutation had occurred de novo.
LMNA gene encodes for alternatively spliced lamin A and C which are the component of nuclear envelope and expressed in
skeletal and cardiac muscle. The particular mutation detected in the patient described in this paper has not been reported
before. This mutation is located in α-helical central rod domain of lamin A and C protein structure. Previous study suggested
that mutation in the rod domain of the LMNA gene may cause the full clinical spectrum of EDMD-AD which comparable to
our patient. Conversely, study involved 11 families with autosomal dominant dilated cardiomyopathy and conduction system
defect suggested that missense mutation in the rod domain of LMNA gene cause dilated cardiomyopathy with no skeletal
defect. Therefore, hypothetical domain-specific phenotype is still debatable. In conclusion, we report a novel mutation in
LMNA gene following autosomal dominant form of EDMD. Functional analysis study on specific mutation for the future is
needed to determine genotype-phenotype correlation.
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Mon(2)-P-255
Hypertrophic Cardiomyopathy - Retrospective Analysis 18 Months On
Kathy R Cox 1 ，Evelyn Douglas 1 ，Sin Lay Kang 1 ，Liam McIntyre 2 ，Gemma Correnti 3 ，Eric Haan 3,4
，
Kathryn Friend 1
1:Molecular Genetics, Genetics and Molecular Pathology, SA Pathology at the Women’s and Children’s Hospital, Adelaide, Australia、2:SA
Pathology at Royal Adelaide Hospital, Adelaide, Australia、3:South Australian Clinical Genetics Service, SA Pathology at the Women’s
and Children’s Hospital, Adelaide, Australia、4:School of Medicine, University of Adelaide, Adelaide, Australia
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant condition characterised by unexplained left ventricular
hypertrophy (LVH). Clinical manifestations are highly variable ranging from asymptomatic LVH to progressive heart failure
to sudden cardiac death. HCM commonly presents clinically with shortness of breath, chest pain, palpitations, syncope and
pre-syncope. A number of genes which encode components of the sarcomere are known to be associated with HCM, the most
common being MYBPC3 (40%), MYH7 (40%), TNNT2 (5%), TNNI3 (5%), TPM1 (2%) and MYL3 (1%).
In October 2014, our laboratory (SA Pathology, Genetics and Molecular Pathology) began offering testing for 16 genes known
to be associated with HCM, using the Agilent Haloplex Cardiomyopathy kit on an Illumina MiSeq platform. Currently,
we have detected a pathogenic / likely pathogenic mutation in 36% of samples tested, a variant of unknown significance
(VUS) in 21% and no variant of clinical significance in 43% of samples tested. Of the pathogenic variants detected, 70%
were detected in MYBPC3 , 20% in MYH7 and the remaining 10% in CSRP3 with two variants (1 pathogenic and 1 VUS)
detected in one patient. With the majority of mutations in our cohort detected in MYBPC3 , we will present the spectrum of
mutations observed. To date, 56% of mutations in MYBPC3 affect splice sites, with 22% small deletions and 22% missense
mutations. We have collected clinical information and family history for our cohort and will present our results relative to
Poster Session
this information.
Mon(2)-P-256
DNA copy number and copy-neutral changes in patients with both coronary artery disease and metabolic
comorbidity
Aleksei Sleptcov 1,2 ，Maria S. Nazarenko 1,2 ，Igor N. Lebedev 1,2 ，Nikolay A. Skryabin 1,2
，Anton V. Markov 1,2
，
Aleksei V. Frolov 3 ，Olga L. Barbarash 3 ，Valery P. Puzyrev 1,2
1:Laboratory of Population Genetics, Research Institute of Medical Genetics, Russia、2:Tomsk State University、3:Research Institute for
Complex Problems of Cardiovascular Diseases
The purpose of this study was to investigate whether coronary artery-specific DNA alterations are present in patients with
both coronary artery disease and metabolic comorbidity (hypercholesterolemia, hypertension, obesity, and type 2 diabetes
mellitus). We have collected biopsy samples of right coronary arteries with advanced atherosclerotic plaques (CAP), samples
of intact internal mammary arteries (IMA), and white blood cells derived from the same patient. The arteries samples from
ten patients were screened for genomic imbalances using by Agilent SurePrint G3 Human CGH+SNP Microarray 2x400K
(Agilent Technologies). Identical copy number variations (CNVs) were detected between the matched arteries analyzed, and
the average number of aberrations was 38 per individual. We also identified 8 copy-neutral changes >1.5 Mb in matched
arteries samples in 4 out of 10 individuals. The gain of 10q24.31 (ERLIN1 ) and 12q24.11 (UNG, ACACB) genomic regions
was confirmed by quantitative real-time PCR. The frequencies of these CNVs from an additional 33 match-paired arteries
and white blood cells of patients with coronary artery disease and metabolic comorbidity were evaluated. Two patients were
identified with increased gene copy numbers in 10q24.31 (ERLIN1 ) in all of their tissues studied and one patient had the
gain in the same region that affected only a blood DNA of the tissues studied. Another two patients had the gain in region
12q24.11 (ACACB) in both arteries (CAP and IMA) and white blood cells. In conclusion, the results do not indicate that de
novo pathogenic DNA copy number and copy-neutral changes are common in arteries of patients with both coronary artery
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disease and metabolic comorbidity. The study was supported by the Russian Science Foundation (14-15-00305).
Mon(2)-P-257
Mutations in the BMPR2 Gene in Patients with Heritable Pulmonary Arterial Hypertension
Yuki Aimi 1,2 ，Yuichi Momose 1 ，Tomomi Hirayama 1,2
，Masaharu Kataoka 1,3
，Masae Ono 4,5
，Hideaki Yoshino 1 ，
Toru Satoh 1 ，Shinobu Gamou 2
1:Division of Cardiology, Second Department of Internal Medicine, Kyorin University School of Medicine, Japan、2:Department of Molecular
Biology, Kyorin University School of Health Sciences、3:Department of Cardiology, Keio University School of Medicine、4:Department of
Pediatrics, Kyorin University School of Medicine、5:Pediatrics Department, Tokyo Teishin Hospital
A substantial proportion of patients with pulmonary arterial hypertension (PAH) have mutations in the Bone Morphogenetic
Protein Receptor type-2 (BMPR2 ) gene. PAH due to BMPR2 mutations is inherited as an autosomal dominant trait with
several unique features, including a wide variety of mutations, reduced penetrance, a skewed gender ratio, variable expressivity
and genetic anticipation.
To address the genetic background of these unique features of BMPR2 mutation in Japanese population, we conducted a
systematic analysis for larger gene rearrangements together with conventional mutation analysis in 230 patients including 61
patients diagnosed as having idiopathic PAH (IPAH) and 12 diagnosed as having familial PAH (FPHA).
Analysis of the BMPR2 gene revealed seven nonsense, five frameshift, two missense/pathogenic mutation, and two splice-site
Poster Session
mutations. Three types of genetic rearrangements of BMPR2 were identified in PAH patients as the deletion of one or
more exons of the gene. The deletion break points investigation revealed that two cases with over 200kb deletion and 5kb
deletion were Alu-mediated via non-allelic homologous recombination and non-homologous recombination, respectively. In
another case with a short deletion (>1kb), the break point was not located in an Alu sequence. Among 12 FPAH, 10 families
inherited mutated BMPR2 gene. Combining mutation detection with parental identification, three cases were found as de
novo mutation in the BMPR2 gene in IPAH patients.
Exonic deletions of BMPR2 account for BMPR2 mutations associated with heritable PAH, may be a unique and non-recurrent
rearrangement, and appears to be of a different size from that in each patients. The de novo mutations may account for the
wide variety of mutations in BMPR2 . Taken together with the juvenile onset of the disease, there is possibly some balance
of de novo mutations and untransmittable mutations which keeps the frequency of PAH low in the general population.
Mon(2)-P-258
Polygenic risk score of 45 coronary artery disease risk variants is associated with the progression of
coronary artery calcification - Results of the Heinz Nixdorf Recall Study
Sonali Pechlivanis 1 ，Nils Lehmann 1 ，Amir A Mahabadi 2 ，Raimund Erbel 1,2 ，Per Hoffmann 3,4
，Karl-Heinz Joeckel 1 ，
Markus M Noethen 3 ，Susanne Moebus 1,5 ，Heinz Nixdorf Recall Study Investigative Group
1:Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Germany、2:De-
partment of Cardiology, West-German Heart Centre, University Hospital of Essen, University Duisburg-Essen, Germany、3:Department of
Genomics, Life & Brain Center, University of Bonn, Bonn, Germany、4:Division of Medical Genetics, Department of Biomedicine, University
of Basel, Basel, Switzerland、5:Centre for Urban Epidemiology, University Hospital Essen, Essen, Germany
Introduction
Atherosclerosis is the primary cause of coronary artery disease (CAD) and precedes the onset of most cases of clinically
apparent coronary heart disease by decades. In recent years, 45 single nucleotide polymorphisms (SNPs) associated with
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CAD were identified in genomewide association studies. In our study we hypothesized that the polygenic risk score (PRS)
for CAD associated SNPs influence the progression of CAC.
Methods
We included 2680 participants of the Heinz Nixdorf Recall Study with CAC measured during two time points (five years
apart). CAC progression was defined as described in [1]. To evaluate the effect of 45 SNPs associated with CAD, a PRS for
each individual was constructed by adding up the number of risk alleles (0/1/2) of each SNP and weighing by the natural
log of the reported odds ratio (OR) for CAD. Generalized linear regression models explored the impact of the PRS on the
outcome "rapid vs. expected/slow CAC progression". The models were adjusted for cardiovascular risk factors as well as
stratified by sex.
Results
Prevalence of rapid CAC progression was 19.5%. CAD risk alleles in PRS ranged from 34 to 54. The weighted CAD PRS was
normally distributed within a range from 2.6 to 4.2 (mean±SD: 3.45±0.34). In the crude analysis the weighted CAD PRS
was associated with rapid CAC progression (OR (95%Confidence Interval) per SD: 1.12 (1.02;1.23),p=0.02). Similar effect
was observed in the multivariate analysis (1.11 (1.00;1.22),p=0.05). The sex stratified multivariate analyses did not reveal
differences between men and women (men: 1.12 (0.97;1.30),p=0.12) and women (1.09 (0.95;1.25),p=0.24) respectively.
Conclusion
Poster Session
The polygenic risk score of 45 GWAS identified CAD variants increases the risk of rapid CAC progression in the Heinz Nixdorf
Recall study.
1. Erbel R et al. Progression of coronary artery calcification seems to be inevitable, but predictable-results of the Heinz
Nixdorf Recall (HNR) study. Eur Heart J. 2014 Nov 7;35(42):2960-71.
Mon(2)-P-259
Genome wide array analysis of patients with conotruncal heart defects in the Kingdom of Bahrain
Cristina Skrypnyk 1 ，Neale Kalis 2 ，Sara Al-Othman 1 ，Ghada Al-Kafaji 1
1:Al Jawhara Center for Molecular Medicine, Kingdom of Bahrain, Arabian Gulf University, College of Medical Sciences, Bahrain、2:MK
Cardiac Center, Bahrain Defense Force Hospital, Kingdom of Bahrain
Introduction: Conotruncal heart defects (CHDs) result from disturbance of the outflow tract of the embryonic heart and/or
impaired development of the branchial arch and arteries.Genomic copy number variations were reported to be involved in the
genesis of CHDs.
Objective: The study attempt to identify the genomic imbalances associated with CHDs and evaluate the usefulness of genome
wide array as a genetic diagnostic tool.
Methods: Genome wide array was performed on 47 CHDs patients referred from MK Cardiac Centre, BDF Hospital Bahrain,
using Affymetrix CytoScan HD SNP array platform. Data were analyzed using Affymetrix Chromosome Analysis Suite
(ChAS) software, Genomic Oligoarray and SNP array evaluation tools.
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Results: Genomic causal copy number variations (CNVs) were detected in 17% (8/47) patients: 22q11.2 deletion (6/8), 2q13
deletion (1/8), 7q11.21 deletion (1/8). TBX1 gene haploinsuficiency explained the cardiac phenotype of patients with 22q11.2
deletion. FBLN7 and TMEM87B genes haploinsuficiency are considered responsible for cardiac defects of patient with 2q13
deletion syndrome. Potential significant CNVs, with variable size and containing genes associated with cardiac defects, were
also found: 3q deletion (14/47), 9q34.3 duplication (11/47). Loss of homozygosity (LOH) larger than 10Mb were identified
in 12/47 (26%), 8/12 which were previously known having consanguineous parents.
Conclusions: Genome wide array analysis is useful tool in the genetic investigation of CHDs. The genotype-phenotype
correlation certified the clinical suspicion for 22q11.21 deletion syndrome and elucidated the phenotype for 2q13 deletion.
The study results can assist in the evaluation, management and genetic counseling of the conotruncal heart defects. Further
studies are required for the LOH covering critical genomic regions for conotruncal heart defects as no data are reported about
CHDs and consanguinity.
Keywords: Conotruncal heart defects, genome wide array, CNVs, LOH
Mon(2)-P-260
Exome sequencing in 111 Czech families with inherited cardiovascular diseases
Hana Hartmannova 1 ，Lenka Piherova 1 ，Katerina Hodanova 1 ，Viktor Stranecky 1 ，Anna Pristoupilova 1 ，
Nikola Ptakova 3 ，Alice Krebsova 2 ，Milos Kubanek 2 ，Vojtech Melenovsky 2 ，Tomas Palecek 4 ，Milan Macek 3 ，
Stan Kmoch 1
Poster Session
1:Institute of Inherited Metabolic Disorders, Charles University of Prague, First Faculty of Medicine, Czech Republic、2:Department
of Cardiology, Institute for Clinical and Experimental Medicine-IKEM, Prague, Czech Republic、3:Department of Biology and Medical
Genetics, 2nd Faculty of Medicine, Charles University in Prague, Czech Republic、4:Department of Cardiovascular Medicine, 1st Faculty of
Medicine, Charles University in Prague, Czech Republic
Exome sequencing (ES) facilitates genetic diagnostics of inherited cardiovascular diseases, enables genetic stratification and
may eventually foster individualized therapies. Due to integrated cardio-genetic care, altogether 111 families with ≥ 2 affected
individuals were characterized and ES was carried out in all families (TruSightOne Exome, Illumina, USA). 27 families suffered
from dilated cardiomyopathy (DCM), 23 hypertrophic cardiomyopathy (HCM), 35 arrhythmogenic cardiomyopathy (ACM),
4 restrictive cardiomyopathy (RCM), 19 ion channelopathies and 3 had unexplained cardiac arrest (UCA). Detected variants
were confirmed by Sanger DNA sequencing and by segregation analysis. ES revealed a putative molecular genetic mechanism
in 62/111 (56%) families. The causal mutations were identified in 16/27 (59%) DCM, 18/23 (78%) HCM, 17/35 (49%) ACM,
3/4 (75%) RCM, 6/19 (32%) ion channelopathies and 2/3 families with UCA. The most frequently mutated gene in DCM
was TTN - truncated mutations (25%), in HCM the MYH 7 - missense mutation (28%) and in ACM the PKP2 - missense,
deletions and splicing mutations (40%). Although disease genes were already identified, most mutations were novel. Our
results and mutation distribution are in accordance with other studies. Our model of integrated genetic care of patients with
inherited cardiovascular diseases is the first one in Czech Republic.
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Mon(2)-P-261
Uncoupling associations of the Apolipoprotein B locus alleles with lipids, myocardial infarction, and
survival
Alexander Kulminski 1 ，Yelena Kernogitski 1 ，Irina Culminskaya 1 ，Yury Loika 1 ，Konstantin Arbeev 1 ，Olivia Bagley 1 ，
Matt Duan 1 ，Liubov Arbeeva 1 ，Svetlana Ukraintseva 1 ，Deqing Wu 1 ，Eric Stallard 1 ，Anatoliy Yashin 1
1:Duke University, USA
Genome-wide association studies (GWAS) emphasize the benefits of large samples in the analyses of complex traits rather
than their specifics. We adopted a realistic concept of genetic susceptibility to inherently heterogeneous, complex traits and
re-analyzed in details the associations of rs693 and rs562338 polymorphisms representing the Apolipoprotein B locus with
total cholesterol (TC), high-density lipoprotein cholesterol, myocardial infarction (MI), and survival for MI patients in four
large NHLBI-sponsored longitudinal studies (N=20,748). We show that strong, robust predisposition of rs693 and rs562338
to TC is not translated into predisposition to MI and the survival. The rs693_A allele may protect against MI (relative risk
[RR]=0.84, p=1.1×10-5 ) and increase MI risks (RR=1.16, p=2.8×10-3 ), and mortality for MI patients, additively with lipids,
i.e., antagonistically in different populations. Paradoxically, we show that increased TC concentrations can reduce risks of
MI for the rs693_A allele carriers. All the results are replicated in independent studies. Our results uncouple influence of the
same alleles on lipids and MI despite potential causal relationship among them. Our strategy reveals overall highly significant
association of rs693 with MI (p=5.5×10-8 ) that is contrasted by weak estimate following GWAS strategy (p=0.16) in the
same sample. The results imply that the traditional GWAS strategy should be used with caution and be considered as a
preliminary step to gain insights on genetic predisposition to complex traits.
Poster Session
Mon(2)-P-262
Genetic Analysis using next-generation sequencing in Brugada Syndrome
Yoshinori Katsumata 1 ，Yoshiyasu Aizawa 1 ，Seiji Takatsuki 1 ，Kenjiro Kosaki 2 ，Keiichi Fukuda 1
1:Department of Cardiology, Keio University, Japan、2:Center of Medical Genetics, Keio University
Background
Genetic variations are identified and associated with 30-35% of cases of Brugada Syndrome (BrS), with nearly 20-25%
attributable to variants SCN5A, meaning many cases remain undiagnosed genetically. BrS may actually include heterogeneous
group of disorders with a variety of genetic and clinical phenotypes. Recently, next-generation sequencing (NGS) is beginning
to be applied to arrhythmogenic disease like BrS. The aim of this study was to evaluate the role of genetic variants in BrS
using NGS technology.
Methods and Results
A tolat of 89 BrS (40.6±10.2 y/o, 76 males) Japanese cases were genetically evaluated by means of target resequencing of
more than 4800 genes using commercially available sequencing panel (TruSight One, Illumina). Detection rate of mutations
in BrS by NGS increased from 9% to 46%, compared to conventional method by Sanger sequencing. Mutations in SCN5A,
which were the major causes of BrS, were detected in 10% by NGS. However, NGS identified rare mutations, such as SCN3B,
SCN1A, CACNA1A, PKP2, DSG2, DSC2, which were not identified in previously. These rare mutations were detected in
22% in our BrS cohort. The variant in SCN3B, p.Val110Ile (V110I, c.328G>A), was found in 2 unrelated Japanese patients;
a 44-year-old male, a 40-year-old male. The former had experienced a syncope, and showed saddle-back type ST-segment
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elevation, and pilsicainide administration unmasked coved type ST-segment elevation. His uncle had undiagnosed sudden
death in his 30’s. The latter was asymptomatic patient, and showed spontaneous coved-type ST elevation in ECG. The
family history of sudden death or BrS was negative.
Conclusions
The use of NGS enables a rapid analysis for huge number of genes associated with BrS. Genetic mutation in SCN3B was
also identified in our cohort. The 2 BrS cases carrying identical SCN3B-Val110Ile variant demonstrated different clinical
phenotypes, similar to SCN5A related BrS.
Mon(2)-P-263
A PDE3A mutation in familial hypertension and brachydactyly syndrome
Hidehito Inagaki 1 ，Hiroko Boda 2 ，Hidetoshi Uchida 2 ，Nobue Takaiso 1 ，Yuya Ouchi 3 ，Naoko Fujita 3 ，Asami Kuno 3 ，
Tadayoshi Hata 4 ，Arisa Nagatani 2 ，Yuri Funamoto 2 ，Masafumi Miyata 2 ，Tetsushi Yoshikawa 2 ，Hiroki Kurahashi 1,3
1:ICMS, Division of Molecular Genetics, Fujita Health University, Japan、2:Department of Pediatrics, Fujita Health University、3:Genome
and Transcriptome Analysis Center, Fujita Health University、4:Faculty of Medical Technology, School of Health Science, Fujita Health
University
Poster Session
Hypertension and brachydactyly syndrome (HTNB) with short stature is an autosomal dominant disorder, characteristic with
salt-independent and age-dependent hypertension and death from stroke before age 50 years when untreated. A linkage study
of a family in the first report of HTNB had identified the location of the candidate genes at 12p12.2-p11.2. Mutations in
the PDE3A gene located at 12p12.2-p11.2 were recently identified in HTNB families. Our patient was an 8-year old boy of
short stature (-1.9SD), with short fingers and toes and normal sized palms, and normal balanced bones. He was diagnosed
with myocardial hypertrophy with a systolic and diastolic blood pressure of 120 and 82 mmHg, respectively. His father, and
paternal grandmother were also of short stature with short fingers and toes, and had hypertensions from young adulthood.
His brother had similar characteristic short fingers and toes. Therefore, we looked for the dominant mutation in the patient.
We first performed cytogenetic microarray analysis to detect copy number mutations in the patient, but all of the identified
copy number variations were confirmed to be benign. We then searched for nucleotide changes in the candidate region,
12p12.2-p11.2, by whole exome analysis of the patient. We found a novel heterozygous missense mutation c.1336T>C in exon
4 of the PDE3A gene in a Japanese family with multiple HTNB patients. This mutation was found to be completely linked
to the family members who inherited this condition. The mutation, resulting in p.Ser446Pro, was located within the cluster
region of the mutations recently reported. This mutation may also affect the phosphodiesterase activity of PDE3A to reduce
the cyclic AMP level in the cell, and thereby influencing the development of limbs and the function of the cardiovascular
system.
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Mon(2)-P-264
Functional Characterization of mir-1297 and mir-3179 in ABCA1 and Apo-A1 genes involved in Reverse
Cholesterol Transport (RCT) and Cholesterol Efflux (CE)
Sarah Peñafrancia L Coralde 1 ，Reynado L Garcia 1 ，Arjelle D Agupitan 1
Cholesterol levels within the body are regulated by its uptake and efflux by all cells. Accumulation of cholesterol in blood vessel
walls which may lead to atherosclerosis is prevented through reverse cholesterol transport (RCT) pathway. A critical part
of RCT is cholesterol efflux, in which accumulated cholesterol is removed from macrophages in the subintima of the vessel
wall by ATP-binding membrane cassette transporter A1 (ABCA1), and collected by high-density lipoprotein (HDL) and
apolipoprotein A-1 (ApoA1). Esterified cholesterol in the HDL is then delivered to the liver for excretion. This study reports
the potential downregulation of expression of RCT genes through a miRNA-mediated mechanism. Using pmirGLO vector,
constructs containing wild-type ABCA1 and ApoA1 3’UTR were generated. These were transfected to HepG2 liver cell line,
a model directly involved in reverse cholesterol pathway. Dual luciferase assay data have shown a significant downregulation
of activity in constructs with ABCA1 and ApoA1 3’UTRs compared to empty GLO vector, suggesting regulation by miRNAs
endogenous to hepatocyte. Co-transfection of candidate miRNAs and wild type RT genes 3’UTR constructs demonstrate
that miR-1297 and miR-3179 regulate ABCA1 and ApoA1 expression respectively. Further verification will be made by
monitoring endogenous ABCA1 and APOA1 in the presence of miRNA constructs. Endogenous mRNA and protein copies
of RT genes will be assayed through quantitative real time-PCR and Western blot. Cholesterol efflux assays will then be
analyzed later in the process using commercialized kits to further confirm possible miRNA-regulation of lipoprotein biogenesis
in the liver and cellular cholesterol efflux.
Poster Session
Mon(2)-P-265
20-HETE Regulates the Expression of Nedd4-2 in Kidney via Neddylation
Yanyan Zhao 1 ，Jianzhu Zhao 1 ，Bijun Zhang 1 ，Runhong XU 1
1:Department of Clinical Genetics, Shengjing Hospital of China Medical University, China
Previously, we generated a cytochrome P450 4F2 (CYP4F2 ) transgenic mouse model which showed overproducted 20-
hydroxyeicosatetraenoic acid (20-HETE) in kidney and a hypertensive phenotype. Furthermore, we demonstrated that 20-
HETE and high salt intake synergistically decreased Na+ -K+ -2Cl- cotransporter, isoform 2 (NKCC2) protein via Nedd4-
2-mediated ubiquitin-proteasome pathway. In order to investigate 20-HETE regulation of Nedd4-2, an ubiquination E3
ligase targeting multiple ion channel proteins in kidney, we initially detected Nedd4-2 expression in the kidney of CYP4F2
transgenic mice and 20-HETE-treated HEK293 cell line. Western blot illustrated that 20-HETE increased the Nedd4-2 protein.
Subsequently, Co-immunoprecipitation assay showed Nedd4-2 could be modified by Nedd8, and the level of Neddylation on
Nedd4-2 was lower in the kidney of transgenetic mice compared with wild-type controls. We further detected the expression
of Senp8, a deNeddylation enzyme, found that Senp8 was higher in the kidney of trangenetic mice than wild-type controls.
Aforementioned data indicated that 20-HETE reduced Neddylation of Nedd4-2 by augmentation of Senp8 in kidney. It has
been reported that Neddylation of Smurf1, one member of Nedd4 family, promotes self-ubiquitination. Therefore, we inferred
that decreased Neddylation of Nedd4-2 could result in suppression of self-ubiquitination, thereby, Nedd4-2 was increased by
20-HETE in kidney. In conclusion, 20-HETE plays an important role in regulation of blood pressure. It participates in
Neddylation modification of Nedd4-2 which could modulate ion channel proteins in kidney. Our study provides a new clue
for pathogenesis of hypertension
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Mon(2)-P-266
Apolipoprotein E is Associated with Coronary Artery Disease in Asian-Filipinos
Arielle Kae L Sulit 1 ，Mark Anthony D Luz 1 ，Khristine Amber C Pasion 1 ，William S Chua 2 ，Maria Luisa G Daroy 1 ，
Fabio Enrique B Posas 2 ，The Genomics and Cardiovascular Medicine Initiative Study Group
1:Research and Biotechnology Group, St. Luke’s Medical Center, Philippines、2:Heart Institute, St. Luke’s Medical Center, Philippines
Apolipoprotein-E (ApoE) and its allelic variants may have roles in the development of heart diseases.Generally, e4 is thought
to increase risk and e2 is thought to be protective. This study was conducted on 569 Asian-Filipinos who had undergone
coronary angiography. Associations between the presence of the 3 ApoE alleles and >= 50% stenosis in these patients were
considered. Genotypes were grouped based on the allele of interest - homozygous for the allele, heterozygous for the allele, and
not containing the allele. Age and gender adjusted ORs obtained were 0.56 (95% CI: 0.34-0.94) and 1.71 (95% CI: 1.12-2.62),
for e2 (dominant model) and e3 (recessive model) genotypes, respectively. This indicated that the e2 genotype is somewhat
protective, while the e3 genotype is detrimental. No significant association was found in the e4 genotype. Gender also
appeared to have an association with stenosis development. In the e2 model, being a female appears to be protective against
stenosis regardless of containing the e2 allele with OR 0.21 (95% CI: 0.13-0.35) for females with genotypes not containing e2,
and OR 0.12 (95% CI: 0.06-0.27) for females with e2, both against males not containing the e2 allele. There was no significant
association found between males with the e2 allele and males without the e2 allele. The female gender also appears to confer
protection for individuals containing the e3 allele with ORs 0.24 (95% CI: 0.12-0.50) for females with at most 1 copy of the
e3 allele and OR 0.36 (95% CI: 0.20-0.66) for females homozygous for the e3 allele, both against males with at most 1 copy
of the e3 allele. Being a male homozygous for the e3 allele seems to be detrimental for the disease with OR 1.87 (95% CI:
1.09-3.21) against males with at most 1 copy of the e3 allele. In Asian-Filipinos, the e2 allele is found to be protective while
Poster Session
the e3 allele is detrimental. Females are protected against stenosis, while being an e3/e3 male appears to be detrimental.
Mon(2)-P-267
Associations of the polymorphisms wihtin the CRP and IL1ß genes with acute cardiovascular events in
patients with multivessel coronary artery disease
Anastasiia V. Ponasenko 1 ，Yuliya V. Bayrakova 1 ，Mariya V. Khutornaya 1 ，Yana V. Kazachek 1 ，Olga L. Barbarash 1
1:Russian Academy of Sciences, Research Institute for Complex Issues of Cardiovascular Diseases, Russia
Study Aim. To determine whether the polymorphisms of the IL1ß and CRP genes are associated with the clinicopathological
features of myocardial infarction (MI) and stroke in patients with multivessel coronary artery disease (MCAD).
Materials and Methods. We recruited 303 consecutive patients with stable coronary artery disease, including 52 (17.16%)
with MCAD. Out of these, 188 (62.04%) and 33 (11.00%) suffered from MI and stroke, respectively. Genotyping was per-
formed in 96-well format using the TaqMan SNP genotyping assay.
Results. GG genotype of the rs1143634 polymorphism within the IL1ß gene was associated with 4-fold lower risk of MCAD in
female carriers (p=0.046). CC genotype of the rs1205 polymorphism within the CRP gene was associated with a higher risk
of multivessel coronary artery disease in patients over 65 years of age (OR=4.72, 95%CI=1.27-17.56, p=0.045). Other poly-
morphisms were not significantly associated with MCAD. Item, CACGG haplotype (rs3093077-rs1130864-rs1205-rs1143634-
rs16944) was associated with a 3-fold decreased MI risk (OR=0.34, 95%CI=0.30-0.40, p=0,019). CC genotype of the rs3093077
polymorphism, AG genotype of the rs1130864 polymorphism, and CT genotype of the rs1205 polymorphism within the CRP
gene were associated with a decreased MI risk in females (OR=0.53, 95%CI=0.30-0.95, p=0.0079; OR=0.37, 95%CI=0.16-
0.82, p=0.0027; OR=0.35, 95%CI=0.14-0.84, p=0.0097, respectively). Rs1143634 polymorphism within the IL1ß gene was
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ICHG2016 929
associated with decreased MI risk (OR=0.48, 95%CI=0.29-0.77, p=0.0025) whilstrs16944 polymorphism was associated with
5-fold increased MI risk (OR=5.12, 95%CI=1.82-14.42, p=0.0022).
In addition, CACAG haplotype (rs3093077-rs1130864-rs1205-rs1143634-rs16944) which was detected in 8% of the patients,

was associated with aimost 3.5-fold higher risk of stroke (OR=3.43, 95%CI=1.03-11.40, p=0.045).
Conclusions. Polymorphisms within the L1ß and CRP genes have a role in the development of MI and stroke in patients
with MCAD.
Mon(2)-P-268
Mutations in an actin filament nucleation gene predispose individuals to thoracic aortic aneurysms and
dissections
Alex Y.B Wan 1 ，Michael A Simpson 2 ，Jose A Aragon-Martin 1 ，Bijan Modarai 3 ，Daniel Osborn 4 ，Jaipreet Bharj 4 ，
Anand Saggar 5 ，James F Sneddon 6 ，Elizabeth M Fisher 7 ，Marjan Jahangiri 8 ，Dianna M Milewicz 9 ，Alberto Smith 3 ，
Elijah R Behr 1 ，Anne H Child 1
1:Cardiovascular and Cell Sciences Research Institute, St. George’s Hospital, University of London, United Kingdom, St George’s Univer-
sity of London, UK、2:Genomic Medicine Group, Division of Genetics and Molecular Medicine, Kings College London, United Kingdom、
3:Academic Department of Vascular Surgery, Cardiovascular Division, BHF Centre of Research Excellence, King’s College London、4:Human
Genetics Research Centre, St. George’s Hospital, University of London, United Kingdom、5:Clinical Genetics Unit, St George’s University
of London, United Kingdom、6:Spire Gatwick Park Hospital, Horley, United Kingdom、7:The Park Surgery, Horsham, West Sussex, United
Poster Session
Kingdom、8:Department of Cardiothoracic Surgery, St. George’s Healthcare NHS Trust, London, United Kingdom、9:Department of Internal
Medicine, University of Texas, USA
Over 20 percent of non-syndromic forms of TAAD are inherited, and within kindreds the disorder shows variability in its
penetrance and severity, notably between males and females. The disorder is heterogeneous; 27 genes have been reported as
the site of pathogenic mutation in TAAD and contribute to the genetic aetiology of approximately 30% of TAAD families.
Investigations of the known TAAD genes reveals some common pathways including those relating to TGF-β signaling as well
as smooth muscle cell contraction.
Here we seek to extend the understanding of the genetic basis of TAAD using a whole exome sequencing approach in a large
multigenerational family of British ancestry with autosomal dominant inheritance of TAAD.
The probands presented with soft stretchy skin, wrinkled forehead, down-slanting palpabel fissures, a high arched palate and
small joint hypermobility. His echocardiogram revealed a mildly dilated aortic root at ~ 4.2cm at the age of 50. Full features
suggesting Marfan, Loeys-Dietz and Ehlers-Danlos were not met upon examination and major known genes were excluded by
subsequent Sanger sequencing.
From the family pedigree, the three most distantly related affected individuals were processed for exome sequencing and no
known TAAD gene was found to harbor a causative mutation in all affected individuals.
Initial analysis revealed three rare (MAF<0.0001), protein altering, heterozygous variants in three different genes and each
of these were present in the profiles of each of the sequenced individuals. The three candidate variants were each evaluated
for cosegregation with the trait in the pedigree by Sanger sequencing and only one of the three mutant alleles was carried
by each of the 14 affected individuals in the pedigree. A parametric linkage analysis of the observed segregation of this one
mutant allele and the affection status generated a LOD score of 6.656 given a dominant model with a disease frequency of
0.0001 and penetrance of 0.9.
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Poster Session
Metabolic Disorders
Mon(2)-P-269
Neuronal ceroid lipofucinosis type CLN2: Clinical presentation, Enzyme analysisand Genotype study in
7 cases from India
Jayesh J Sheth 1 ，Riddhi Bhavsar 1 ，Mahesh Kamate 2 ，Raju Shah 3 ，Harshuti Shah 4 ，Sanjiv Mehta 5 ，Mehul Mistry 1 ，
Frenny Sheth 1
1:Dr. Kalam’s centre of excellence for rare disease study, Foundation for Research in Genetics and Endocrinology (FRIGE) and Institute of
Human Genetics, India、2:Child Development Centre, KLES PrabhakarKore Hospital, Belgaum, India、3:Ankur Neonatal Nursery, Nr. Citi
Gold Cinema, Ashram Road, Ahmedabad-India、4:Rajvee Child Neurology Hospital, Ahmedabad, India、5:Usha Deep Neurology Hospital,
Ahmedabad, India
Late infantile neuronal ceroid lipofucinosis (LINCL) or JanskyBielschowsky disease is an autosomal recessive lysosomal storage
disorder with an unknown frequency in India. It has a reported prevalence of 1:100,000 with higher frequency of 1:12500 in
Finish population. Visual impairment is the cardinal feature of the disease observed in affected children at 4 to 6 years of age.
Residual or null activity of Tripeptidyl peptidase 1 (TPP1) enzyme occurs in patients with underlying mutation in CLN2
gene. Presentstudy was undertaken in 7 Indian patients clinically suspected with LINCL in the age range of 4 to 6 years.The
key features were decline in cognitive function, cerebellar atrophy, myoclonus, progressive visual loss and seizures. All patients
Poster Session
had residual TPP1 enzyme activity in the range of 3.5-14.4 nmol/hr/mg protein) in leucocytes. Seven homoallelic (5 known
and 2 novels) mutations were detected. One known pathogenic mutation (c.616 C>T, p.R206C) was observed in 3 patients
from Gujarat, novel mutation (c.1376A>C, p.Y459S) was seen in 2 patients from Karnataka, one known missense mutation
(c.622C>T, p.R208X) and deletion (c.1546_1547delTT, p.F516) was observed in one each from Maharashtra and Karnataka
region, respectively. Our study suggest c.616C>T as a common mutations in patients from Gujarat and c.1376A>C is likely
to be a founder mutation in patients from Karnataka.
Mon(2)-P-270
Extended newborn screening program in Chile (NESPC)
1,2
Silvia Castillo Taucher
1:Seccion Genetica, Hospital Clinico Universidad de Chile, Chile、2:Seccion Citogenetica, Laboratorio Clinica Alemana de Santiago, Vitacura,
Santiago, Chile
Newborn blodspot screening to detect congenital conditions in newborns is a public health measure aimed at the early
identification and management of affected newborns in an effort to reduce infant morbidity and mortality. It is a comprehensive
system of education, screening, follow-up, diagnosis, treatment/management, and evaluation that must be institutionalized
and sustained within public health systems - however often challenged by economic, political, and cultural considerations.
In 1998, the Ministry of Health of Chile launched a national program of neonatal screening for phenylketonuria and congenital
hypothyroidism, extended to the entire country and with almost total coverage. Chile’s government is considering to start
realizing the Extended Newborn Screening Program and through it increase the actual rate of detection of 1 in 21,000
newborns, meaning around 450 new cases a year. The analyzed disorders cause severe mental retardation, illness, or death if
not treated early in life. Numerous studies show that early detection and early intervention can prevent these consequences.
There is need in building support within the medical community, ie, fostering medical and scientific knowledge development,
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collaboration, and consensus treatment strategies. It is important to consider managing the overall screening system, including
obtaining and documenting physician and patient compliance, ie, screening, short-term follow-up, and health outcomes.
NESPC in Chile: infants will benefit from and be protected by newborn screening systems, every newborn will receive
nationwide appropriate and timely services. The newborn screening system will be clinically, socially, and ethically an
important cornerstone in improving the entire health care system in Chile. Chilean population will be investigated to obtain
data on the frequency of these disease and traits. Specialized regional centers will be set up for the study and the management
of patients.
Mon(2)-P-271
9 YEARS OLD GIRL SUFFERING FROM WILSON DISEASE HAS ONLY ONE HETEROZYGOTE
LYS1010THR MUTATION IN ATP7B GENE
Nguyen T.M Huong 1 ，Ngo D Ngoc 1 ，Nguyen T.P Mai 1 ，Tran V Khanh 3 ，Ta T Van 3 ，Nguyen P.A Hoa 2 ，
Phan V Chi 4 ，Le T Hai 1,2
1:Human Genetics Department, National Hospital of Pediatrics, Vietnam、2:Hepatology Department、3:Gene and Protein Center, Hanoi
Medical University、4:Institute of Biotechnology
A case of Wilson’s disease, a rare autosomal recessive disorder of copper metabolism is reported here. The patient, 9
Poster Session
age female, was presented with hepatic symptoms. Slit lamp examination of eye revealed bilateral Kayser-Fleischer ring
with normal visual acuity. Investigations showed that case increased trans-aminase (ALT=140,7 U/L). Ultrasonogram of
hepatobiliary system revealed coarse hepatic tissue echotexture with splenomegaly. Serum ceruloplasmin level was 0,078 g/l;
24 hours urinary copper excretion was 131 µg per day; serum copper was 0,765 mg/l; genetic analysis found that case was
heterozygote of missense mutation Lys1010Thr on ATP7B gene; 7 polymorphisms including V456L, K832R, R952K, A1140V,
P1245S, IVS19+50 G>C, IVS 21delA also were found. Now she was advised for taking Mifros, zinc in a dose of 450 mg/day
and 80mg/day. Her situation is stable. The study hypothesized that the interaction of single heterozygote mutation and
polymorphism could be influence on the phenotype of WD.
Keywords: Wilson disease, ATP7B gene, Mutation analysis
Mon(2)-P-272
Screening of MCAD deficiency in Japan: 15 years’ experience of enzymatic and genetic evaluation
Go Tajima 1 ，Miyuki Tsumura 1 ，Reiko Kagawa 1 ，Satoshi Okada 1 ，Keiichi Hara 2 ，Nobuo Sakura 3 ，Ikue Hata 4 ，
Yosuke Shigematsu 5
1:Department of Pediatrics, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan、2:Department of Pediatrics,
National Hospital Organization Kure Medical Center、3:Suzugamine Nursing House for Sever Motor and Intellectual Disabilities、
4:Department of Pediatrics, Faculty of Medical Sciences, University of Fukui、5:Department of Health Science, Faculty of Medical Sciences,
University of Fukui
[Introduction] Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most representative disorders of fatty
acid oxidation (FAOD). In Japan, pilot study of tandem mass spectrometry-based screening started in 1997. Since the first
patient was found in 2000, the number of patients gradually increased and finally the official nationwide newborn screening
realized in 2014. Correlation between genotype and clinical and biochemical phenotype of Japanese patient has not been fully
clarified.
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[Methods] Newborns and symptomatic patients showing elevation of C8-acylcarnitine in blood were evaluated by measurement
of MCAD activities in lymphocytes and direct sequencing of ACADM gene.
[Results] We enzymatically diagnosed MCAD deficiency in 9 out of 18 symptomatic patients and 33 out of 52 newborns and
asymptomatic siblings of affected patients. Residual activities of symptomatic patients were lower than 3% of the average of
normal control values, except for a patient with 10% activity. On the other hand, 21 of the 33 asymptomatic patients were
left with activities around 10% or lower, while those of the other 12 patients ranged from 13 to 38%. The most prevalent
mutation was c.449-452delCTGA (p.P128X), detected in 19 alleles of 16 patients, which was followed by c.50G>A (p.R17H),
c.1085G>A (p.G362E), c.157C>T (p.R53C) and c.843A>T (p.R281S). These five mutations accounted for approximately
50% of all the alleles examined. Caucasian common mutation c.985A>G (p.K329E) was not detected at all.
[Discussion] As the K329E mutant MCAD has been reprted to retain 10% to 20% of activity, approximatly two thirds of
our asymptomatic patients are associated with actual risk of acute clincal onset, while the rest are not likely to present
any symtom. Further accumulation of data of enzymatic and genetic evaluation is essential to enable appropriate medical
management of Japanese patients with MCAD deficiency.
Mon(2)-P-273
An intergraded tandem mass spectrometry method for the quantitations of disaccharides derived from
dermatan, heparan, and keratan sulfates in urine applied for the diagnosis of mucopolysaccharidosis
Poster Session
Chih-Kuang Chuang 1 ，Hsiang-Yu Lin 2 ，Tuen-Jen Wang 1,3
，Sung-Fa Huang 3 ，Shuan-Pei Lin 1,2
1:Medical Research Department, MacKay Memorial Hospital, Taiwan、2:Pediatrics Department, MacKay Memorial Hospital、3:Department
of Clinical Laboratory Medicine, MacKay Memorial Hospital
Background: Mucopolysaccharidosis (MPS) is a lysosomal storage disease caused by the deficiency of one specific enzyme
activity that catalyzes the stepwise degradation of glycosaminoglycans (GAGs). Accumulation of undegraded GAG metabo-
lites in lysosomes gives rise to distinct clinical manifestations. An intergraded method for the quantitation of disaccharides
derived from dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS) in urine by tandem mass spectrometry
is proposed and feasible for MPS initial diagnosis.
Method: A total of 23 urine samples were collected and analyzed from MPS I, II, IIIB, IVA, and VI patients, and 30 normal
controls. Precipitated urinary GAG was first digested by keratanase II, and then degradation by methanolysis was performed.
The protonated species of predominant disaccharide products were detected using multiple reaction monitoring experiment.
Results: One particular disaccharide of CS, DS, HS, and KS was selected respectively, according to the m/z of definite ion pair
after collision, whereas the dimer derived from individual internal standard was also detected. The results corresponded well
with the two-dimensional electrophoresis method. The quantities of urinary DS and HS were significantly raised in confirmed
MPS I and II patients. Increased levels of DS with absent HS were found in MPS VI patients, whereas the quantities of HS
were elevated only found in MPS IIIB patients. By using this method, MPS IVA patients were identified due to the high
levels of KS detected.
Conclusions: The intergraded tandem mass spectrometry method used for MPS type determination is specific, sensitive, vali-
dated, and applicable for urinary GAG quantifications. This method can be used for first-line examination of MPS diagnosis,
and also for outcome survey after enzyme replacement therapy.
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Mon(2)-P-274
Severe glutathione synthetase deficiency: clinical outcome after a 6-year follow-up
Jirat Chenbhanich 1 ，Rungnapa Ittiwut 2,3
，Vorasuk Shotelersuk 2,3
，Kanya Suphapeetiporn 2,3
1:Faculty of Medicine, Chulalongkorn University, Thailand、2:Division of Medical Genetics and Metabolism, Department of Pediatrics,
Faculty of Medicine, Chulalongkorn University、3:Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, the Thai
Red Cross Society
Purpose: Glutathione synthetase (GSS) deficiency is a rare inborn error of the metabolism affecting glutathione synthesis.
The severe form has poor prognosis and early initiation of vitamin C and vitamin E is crucial. However, treatment with both
antioxidants beginning at the neonatal period is seldom reported.
Methods: A Thai 2-month old boy with severe glutathione synthetase deficiency was identified. Biochemical panels and
mutation analysis of the GSS gene were analyzed. The patient was followed for six years to evaluate metabolic and clinical
outcomes.
Results: A patient was initially hospitalized for 16 days due to fever, tachypnea, and poor feeding. Laboratory investigations
revealed anemia, wide anion gap acidosis and elevated urinary 5-oxoproline. The clinical course was complicated by two
episodes of seizure. Two novel mutations of the GSS gene were detected. After treatment with vitamin C (50 mg/kg/day),
vitamin E (10 mg/kg/day) and bicarbonate supplementation, his symptoms improved. During the six-year follow-up, he had
normal growth and development without any further seizure episodes or metabolic crises.
Poster Session
Conclusions: Patients with glutathione synthetase deficiency can present with sepsis-like and neurological symptoms. Genetic
analysis is needed to confirm the diagnosis. This study suggests that initiation of both antioxidants during the neonatal
period could result in an excellent prognosis and vitamin C can be given in a lower dosage than previously recommended (100
mg/kg/day). Furthermore, this is the first report of glutathione synthetase deficiency in a Thai patient.
Mon(2)-P-275
A newborn patient with carbonic anhydrase VA deficiency presenting with hyperammonemic en-
cephalopathy
Shoko Komatsuzaki 1 ，Dorothea Haas 1 ，Christian Staufner 1 ，Holger Pokisch 2,3
，Tobias Haack 2,3
，Stefan Koelker 1
1:Department of Neuropediatrics and Inherited Metabolic Disorders, University Children’s Hospital Heidelberg, Germany、2:Institute of
Human Genetics, Helmholtz Zentrum Muenchen、3:Institute of Human Genetics, Technische Universitaet Muenchen
Background: CA5A codes a mitochondrial carbonic anhydrase VA (CA-VA) which catalyzes the reversible conversion of
CO2 to HCO3 and provide HCO3 as a substrate in four mitochondrial enzymes, carbamoylphosphate synthetase1, propionyl-
CoA, 3-methylcrotonyl-CoA, and pyruvate carboxylase. The biochemical findings is thus characteried by accumulations of
toxic metabolites in these known inherited metabolic diseases. Recently pathogenic changes in CA5A were identified in four
patients. Here, we report a newborn patient with CA-VA deficiency, who developed hyperammonemic encephalopathy. Case:
A male patient was born to consanguineous Turkish parents weighing 2785 g. At two days of life, he developed lactic acidosis
and hyperammonemia. Biochemical analysis showed elevated levels of glutamine and alanine, and low to normal levels of
citrulline without increased levels of urinary orotic acid. In the further course, he showed transient hyperphenylalaninaemia.
He never showed biochemical features of propionyl-CoA and 3-methylcrotonyl-CoA carboxylase deficiency. At the age of 20
days, he developed seizures. Brain MRI showed edema in pons and signal changes in capsula interna and pyramidal tract. The
transient impairment was explained by noroviral gastroenteritis. No mutations in CPS1, NAGS, and PAH were determined.
BH4 deficiency/atypical phenylketonuria was excluded by normal findings of dihydropterin reductase activities, pterins and
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biogenic amines. Finally, WES revealed a homozygous deletion of exon 1 of CA5A. Conclusion: Homozygous alternations in
CA5A was first reported in 2014 in four patients; missense mutation in two siblings, splice-site mutation, and exon 6 deletion.
The clinical symptoms of patient with exon 6 deletion were similar to the other three patients with point mutations. Our
patient developed the symptoms during the neonatal period and a homozygous deletion of exon 1 was identified. At present,
genotype-phenotype correlation is unknown.
Mon(2)-P-276
Microbial enzymes contaminate urine in newborn urine and alter the results of metabolic screening
1,3
John A. Duley ，Michael G. Henman 2 ，David M. Cowley 3 ，George Marshall 2
1:School of Pharmacy, University of Queensland, Australia、2:Mater Health Services, Brisbane、3:Mater Research Institute, University of
Queensland
HPLC combined with tandem mass spectrometer (LC-MS/MS), in addition to GC-MS/MS, is routinely used to screen urines
for metabolic disorders. We investigated inconsistencies in concentrations of purine and pyrimidine metabolites found in
some urine samples. Methods: Urines were stored at -20C until use. Preservatives were not used. Purines/pyrimidines were
analysed as previously described (for saliva), using an ABI-4000 QTrap with electrospray (1). HPLC peaks were identified
and quantified using SCIEX Multiquant v.2.1 software. Peak areas of isotopic internal standards in all samples were compared
utilising the ’Metric Plot’ function in Multiquant. Results: We noted that approx. 1% of urines, usually dilute urines from
newborns, had low/zero concentrations of either/both of two isotopes: [D2]-uridine and [13C5]-adenosine. There was no
loss of isotopic standards for hypoxanthine, deoxyuridine, thymine, uric acid, creatinine and orotic acid. Centrifuging urines
Poster Session
through a 0.2 micron ultrafilter did not remove degradative activity, but a 50 kD ultrafilter removed most of the activity.
Incubation of deoxy-adenosine with urine that had degraded adenosine produced adenine, not deoxy-inosine. Discussion:
Metabolite changes in urine can be caused by intact bacteria (2). We found nucleoside degradation was not removed by a
0.2 micron bacterial filter, but was filtered at the cut-off for proteins (50 kD). The breakdown of deoxyadenosine to adenine
was consistent with microbial adenosine phosphorylase, presumably secreted into urine by microbes in faecal contamination.
Pseudouridine breakdown to uracil in urine, also commonly observed, may be similar (3). We suggest other metabolites, e.g.
fatty acids, may also be substrates for microbial catabolism. This may bias metabolic screening, including GC-MS.
References: (1) Al-Shehri S, et al, J Chromatogr B 2013, 931:140-7. (2) Saude EJ, Sykes BD, Metabolomics 2007, 3:19-27.
(3) Van Gennip G, et al, Clin Chem 1993, 39:380.
Mon(2)-P-277
Find-GEMS (Gaucher patients in Epilepsy and MyoclonuS): Screening for Gaucher’s disease with enzyme
assay among patients with early-onset seizures
Kimitoshi Nakamura 1 ，Ken Momosaki 1 ，Shirou Matsumoto 1 ，Hiroshi Mitsubuchi 1 ，Fumio Endo 1
1:Pediatrics, Kumamoto University, Japan
Gaucher disease is a lysosome disease, characterized by accumulation of the substrate glucocerebroside in reticuloendothelial
cells due to reduced enzyme activity of glucocerebrosidase. Gaucher disease is classified into 3 types: type 1 with a chief com-
plaint of splenohepatomegaly, anemia, and bone symptoms; type 2 with rapidly progressing neurological symptoms; and type
3 with slowly progressing myoclonus, abnormal eye movement and other symptoms. Recently, enzyme replacement therapy
has become available, prompting establishment of early treatment of Gaucher disease. This has increased the importance of
early diagnosis using clinical symptoms as clue. The objective of this study is to develop effective screening method and verify
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the system in order to establish screening for Gaucher disease with enzyme assay among patients with early-onset seizures.
After obtaining informed consent from subjects, screening test for Gaucher disease was conducted at medical institutions.
The study population consisted of patients with early-onset seizures. Blood will be sampled on filter paper and sent to the
Department of Pediatrics, Kumamoto University Hospital to measure glucocerebrosidase activity. If measurement detects ab-
normally low enzyme activity, suggestive of Gaucher disease, in a patient, the patient was examined for splenohepatomegaly,
neurological symptoms, or bone symptoms and undergo bone marrow test as well as blood acid phosphatase (ACP) and
angiotensin-converting enzyme (ACE) measurement at the medical institution. Glucocerebrosidase genetic analysis was also
be performed with separate consent from the patient. Based on these results, diagnosis of Gaucher disease was confirmed.
Then, by determining the frequency of Gaucher disease diagnosed using seizures as clue, an efficient diagnostic system for
high-risk patients could be established to develop an algorithm for early diagnosis and treatment of Gaucher disease.
Mon(2)-P-278
Unexpected persistent gastrointestinal mucosal infiltration of Gaucher cells in identical twin patients
with non-neuronopathic Gaucher disease despite long-term enzyme replacement therapy
Yoo-Mi Kim 1 ，Dong Hoon Shin 2 ，Su Bum Park 3 ，Su Bum Gu-Hwan Kim 4 ，Chong Kun Cheon 1 ，Han-Wook Yoo 4
1:Department of Pediatrics, College of Medicine, Pusan National University Children’s Hospital,Yangsan, Korea, South、2:Department of
Pathology, College of Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea、3:Department of Internal Medicine, College
of Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea、4:Medical Genetics Center, Asan Medical Center, University of
Ulsan College of Medicine, Seoul, Korea
Poster Session
Gastrointestinal involvement in Gaucher disease is very rare during long-term enzyme replacement therapy (ERT), and it
appears to be unresponsive to ERT. Here, we describe identical twin, splenectomized, non-neuronopathic Gaucher patients on
long-term ERT for 9 years who complained of intractable epigastric discomfort. The pathologic result of biopsies demonstrated
the presence of Gaucher cell infiltration of gastroduodenal mucosa. Long-term ERT seems to modify the evolvement of the
clinical presentation of Gaucher disease.
Mon(2)-P-279
Lysine homocysteinylation inactivates ATR pathway and contributes to colorectal cancer onset
1,2,3
Jian-Yuan Zhao ，Dan Wang 5 ，Shi-Min Zhao 1,2,3,4
1:School of Life Sciences, Fudan University, China、2:State Key Lab of Genetic Engineering, Fudan University、3:Collaborative Innovation
Center for Genetics and Development, Fudan University、4:Institutes of Biomedical Sciences, Fudan University、5:Children Hospital, Fudan
University
Elevated homocysteine (Hcy) levels are established risk factors for colorectal cancer (CRC) with limited underlying mechanism
elucidated. We report that increased protein lysine homocysteinylation (K-Hcy) contributes the CRC onset by suppressing
ataxia-telangiectasia and Rad3-related (ATR) repairing pathway. Increased K-Hcy modification are found in CRC tumors
compared to matched adjacent normal tissues. This led to the identification of overexpression of methionyl-tRNA synthetase
(MARS), the enzyme that converts Hcy to homocysteine thiolactone (HTL), the reactive compound that spontaneously
forms K-Hcy in lysine residues in proteins, in cancer tissues. In cells, MARS interacts with ATR and promotes the K-Hcy
modification of ATR. Increased either Hcy or MARS promotes the K-Hcy of ATR, which destroys the interaction between
ATR and ATR-interacting protein (ATRIP), results in the reduction of the ATR phosphorylation (Ser428) and ATR kinase
activity. ATR inhibition induced by K-Hcy impairs its downstream target in DNA repair response pathway, reflected in
decreased phosphorylation of p53 (Ser15) and checkpoint kinase 1 (CHK1, Ser317 and Ser345). In hydroxyurea treated cells,
increased K-Hcy blocks the activation of ATR, p53 and CHK1 induced by the DNA damage occurrence, diminishes the cell-
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cycle arrest and finally results in increased DNA damage. The critical role of MARS in causing K-Hcy makes it an intervening
target to inhibit K-Hcy and its consequence. Inhibiting MARS production of HTL with either MARS shRNA or Hcy analogs
restores the activity of ATR and its downstream pathway, and decreases the DNA damage in cells and hyperhomocysteinemia
rat model. Furthermore, we observe that accompanied by increased MARS and K-Hcy modification, the phosphorylation of
ATR, p53 and CHK1 decreased profoundly in the CRC tumors. Thus, we elucidated a mechanism by which Hcy induces
CRC and shed lights on its preventive/therapeutic measures by inhibiting HTL production and K-Hcy.
Mon(2)-P-280
Clinical and laboratory evaluation of patients with mucopolysaccharidosis types I, II and VI receiving
Enzyme Replacement Therapy (ERT)
Chong Ae Kim 1,2 ，Lilian M J Albano 2 ，Diogo C Q Soares 2 ，Rachel S Honjo 2 ，Stephanie P Pegler 2 ，
Debora R Bertola 2 ，Jose F S Franco 2
1:Pediatrics, Instituto da Criança, Brazil、2:Pediatrics, Instituto da Crianca
Mucopolysaccharidosis (MPS) are lysosomal storage disorders caused by glycosaminoglycans (GAGs) enzymatic catabolism
deficiencies, leading to mucopolysaccharides organ and tissues deposition. Objective: to describe the clinical and laboratory
data of patients with MPS types I, II and VI receiving ERT. Methods: 27 MPS patients (13- I; 8-II and 6-VI) confirmed
by enzymatic and urinary GAGs measurement. Results: The age of onset symptoms (coarse face, enlarged abdomen, stiff
joints, short stature) varied from 6mo to 8y. The mean age of diagnosis was: MPS I-H (1y6mo), MPS I-HS (4y8mo), MPS
I-S (13y7mo), MPS II (5y) and VI (5y). ERT initiation was since 1y 2mo to 31y 9mo and duration from 40w to 556w
Poster Session
(mean 259w). Approximately 26 weeks after ERT, urinary GAGs decreased to normal levels in 12/27 (44%) and slightly
increased in 15/27 (56%) patients. Before ERT, 24/26 (92%) patients presented echocardiographic abnormalities, which
persisted or worsened in spite of ERT. Polysomnography was performed in 10 patients before ERT and revealed obstructive
sleep apnea in 9 patients (2 MPS I-H, 3 MPS I-HS, 3 MPS II and 1 MPS VI); the apnea/hypopnea index increased after ERT.
Adverse infusion reactions were reported in 55% (15/27) of patients. Most of them were observed during the first weeks of
treatment and were solved with antihistamines, antipyretics and/or reduction of infusion rate. Severe reactions were noted in
2 patients. Regarding clinical complications, arterial hypertension (25%), hypoacusia (37%) and hydrocephalus (15%) were
diagnosed before ERT. After ERT, arterial hypertension (37%), hypoacusia (59%) and hydrocephalus (22%) were reported.
Conclusions: This study showed both inter and intrafamilial clinical heterogeneity. ERT is able to ameliorate but not to
stop the progression of the disease that remains with high mortality rate. Early diagnosis and ERT are critical for a better
outcome and for enhancing the quality of life of these patients.
Mon(2)-P-281
Evaluation of Wilson ｀ s disease in patients with a primary diagnosis other than WD: an inspiration for
reviewing the course of Robert Schumann ´ s illness
Teodor Podskarbi 1 ，Yoon Shin 2
1:Molecular Genetics and Metabolism Laboratory, Germany、2:University of Munich, Lindwurmstr Munich, Germany
Wilson ｀ s disease (WD), an autosomal recessive disorder of copper transport resulting from mutations in the ATP7B gene
expresses a broad range of genotypes and clinical phenotypes. The goal of this study was to evaluate the complexity of the
process one should engage in when attempting to determine the nature of a problem and impact of co-morbidity to establish
the final diagnosis. In addition we have evaluated Robert Schumann ｀ s patient records, autobiographical texts and letters,
since his medical history suggests WD as an underlying cause of the clinical manifestation.
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Methods: Information on clinical history, physical examination, and laboratory parameters of 32 cases was collected. Referrals
to the Molecular Genetics & Metabolism Lab for direct genetic analysis of ATP7B were reviewed.
Results: Five patients and four siblings were diagnosed in the pre-symptomatic stage of WD as well as others with either
hepatic or neurologic/neuropsychiatric disease were confirmed by molecular genetic analysis. The detection frequency of
mutant alleles was 96%; analysis of exons 2, 8, 14, and 18 accounts for 77% of all mutations.
Conclusions: WD should be considered in any patient with unexplained hepatic abnormalities and neuropsychiatric illness.
Tracing back to early histories of patient ｀ s symptoms could improve the diagnosis. Based on test-retest evaluation repeated
over a longer period proper diagnosis could be established. Mutation analysis is an important tool in final diagnosis.
Mon(2)-P-282
Cytokine profile of patients with Gaucher disease type I and its response to enzyme replacement therapy
Filippo Vairo 1,3 ，Fernanda Sperb-Ludwig 2,3
，Kristiane Michelin-Tirelli 1 ，Cristina Netto 1 ，Eurico C Neto 4 ，
Ida V.D. Schwartz 1,2,3,5
1:Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Brazil、2:Post-Graduate Program in Genetics and Molecular Biology,
Universidade Federal do Rio Grande do Sul、3:BRAIN Laboratory, Hospital de Clínicas de Porto Alegre、4:CTN - Centro de Triagem
Neonatal, Porto Alegre、5:Department of Genetics, Universidade Federal do Rio Grande do Sul
Gaucher disease (GD) is a lysosomal disorder that features extensive involvement of the immune system and is caused by the
Poster Session
accumulation of glucocerebroside in macrophages. Although the macrophage is the most thoroughly studied cell type in the
pathophysiology of GD, there is evidence for the involvement of other immunological cells. The chronic pro-inflammatory
status of individuals with GD is thought to be one of the causes of their increased risk of developing malignancies. We
studied the variation of thirty different cytokines in fourteen patients with GD type 1 during imiglucerase shortage and after
restarting enzyme replacement therapy (ERT). We compared the changes in cytokine levels with clinical and biochemical data
and observed correlations for a number of these cytokines. We found a decrease of TNF-α (29.9%), MIP-1 α (46.1%), MIP-1
β (23.2%) and MDC (18.9%) levels after the restart of ERT. There was an increase in GRO (55.3%), PAI-1 (79.8%) and
leptin (21.5%) levels. In addition to corroborating previous findings, we obtained new data regarding inflammatory cytokines
that demonstrated that cytokine profiles might be useful to monitor therapeutic responses and to predict certain disease
features in patients with GD.
Mon(2)-P-283
Molecular and clinical heterogeneity in pyruvate dehydrogenase complex deficiency: the role of high
throughput sequencing approach
Elzbieta Ciara 1 ，Dariusz Rokicki 1 ，Paulina Halat 1 ，Dorota Piekutowska-Abramczuk 1 ，
Agnieszka Karkucinska-Wieckowska 1 ，Johannes Mayr 2 ，Joanna Trubicka 1 ，Edyta Szymanska 1 ，Dorota Jurkiewicz 1 ，
Maciej Pronicki 1 ，Malgorzata Krajewska-Walasek 1 ，Wolfgang Sperl 2 ，Rafal Ploski 3 ，Ewa Pronicka 1
1:The Children’s Memorial Health Institute, Poland、2:Paracelsus Medical University, Salzburg, Austria、3:Warsaw Medical University,
Warsaw, Poland
Pyruvate dehydrogenase complex (PDHc) deficiency is a clinically heterogeneous disorder. The phenotypic variability among
patients results mainly from complex genetic background, skewed lyonization or somatic mosaicism. We assessed the utility of
clinical, biochemical and molecular diagnostic methods in identification and differentiation of PDHc defects. Sanger sequencing
of PDHA1 gene in 21 patients with E1 α subunit expression <50% of reference values and whole exome sequencing in 6
probands with clinical PDHc suspicion was performed. In some patients lactate response to glucose loading was measured. We
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present 12 patients (5 males and 7 females) of Polish origin with eight different PDHA1 pathogenic variants including three
novel changes [c.291G>A (p.?), c.464T>C (p.M155T), c.856_859dupACTT (p.R288Kfs*10)] and one DLD gene mutation.
De novo occurrence has been confirmed for two novel mutations, in addition somatic mosaicism for c.291G>A variant was
observed. Furthermore, in 3 cases with low E1 α level pathogenic FBXL4 mutations were identified. In all patients with
PDHc causing mutations the course of disease corresponded to the literature data. Lactate response to glucose load differed
in the PDHA1 mutated cases (23% increase) comparing to the cases unrelated to the PDHA1 defects (27% decrease). The
study confirmed that PDHA1 is the most frequently mutated gene in PDHc deficiency but it was less prevalent than expected.
The genotype-phenotype profile of our patients mostly correspond to the data reported worldwide. Novel variants expand the
list of pathogenic mutations, including new potentially related (with E1 α dysfunction) molecular changes in FBXL4 gene.
Measuring of lactate response to glucose load and E1 α amount may contribute to disease recognition while the NGS provides
a powerful tool to discover genomic mutations of PDHc defects and becomes a method of choice for PDHc diagnostics.
The research was supported by CMHI projects: 134/13, 136/13, 216/12.
Mon(2)-P-284
Investigation of clinical differences between MODY1 and MODY3 in Japanese
Mayumi Enya 1 ，Yukio Horikawa 1 ，Kenichi Hashimoto 1 ，Jun Takeda 1
1:Gifu university, Japan
Poster Session
Aim:
MODY is a specific form of diabetes with an autosomal dominant genetic inheritance pattern. Defects in the genes HNF-4A
and HNF-1A are the responsible genes of MODY1 and 3, respectively. HNF-4A and HNF-1A are involved in a complex
cross-regulatory network, but the clinical features of MODY1 are not fully elucidated in comparison with MODY3, mainly
because of its rarity in Japan. We have investigated clinical differences between Japanese patients with MODY1 and MODY3.
Method:
We assessed the clinical features of 11 MODY1 and 43 MODY3 patients. Genetic tests were performed by Sanger DNA
sequencing of the gene’s coding region and by multiplex ligation-dependent probe amplification (MLPA).
Results:
The majority of both groups of patients had point mutations. Two types of genomic rearrangement were found in MODY1,
while one type was found in MODY3. In both types of MODY, most patients showed glycosuria in the screening test and
were rarely obese. There was no significant difference in mean age of onset (16.9 years vs 12.8 years; P=0.31), but wider
dispersion was seen in MODY1 compared to MODY3. More than half of the MODY1 patients were treated by insulin, but
there was no significant difference (63.6% vs 43.6%; P=0.24) between the two groups. In the patients treated by insulin, the
mean interval from onset to beginning of insulin treatment was almost the same (5.3 year vs 5.6 year; P=0.37) in the two
groups. One baby who developed hypoglycemia several times from neonate proved to have the HNF4A mutation after her
mother was diagnosed with MODY1.
Conclusion:
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Clinical features of MODY1 patients generally resemble MODY3, but there is a possibility that some MODY1 patients develop
the disease later than MODY3. Family history of both of neonatal hypoglycemia and young onset diabetes without obesity
suggests defects in HNF-4A. Further investigation with larger numbers of patients will be required to elucidate the clinical
differences between MODY1 and MODY3.
Mon(2)-P-285
In search for low excretor genotype in Indian patients with Glutaric Acidemia Type I
Kruthika-Vinod T.P 1 ，Shaik Muntaj 1
1:Neurochemistry, National Institute of Mental Health and Neuroscience, Bangalore, India
Introduction
Glutaric Acidemia type I (GA-I), a metabolic disorder caused due to defective in glutaryl-CoA dehydrogenase gene. There
are few studies on the genetic etiology of GA-I from India. In addition, there is a paucity of data on low excretor GA-I
phenotype from this region.
Objective
In this study, GA-I patients were screened for commonly occurring high excretor mutations (R402W, A421V and A293T),
Poster Session
low excretor mutations (R227P and V400M) and for the possible presence other predominant novel low excretor genotypes
in Indian population.
Materials and Methods
The institutional Human Ethics Committee approved this study. The blood spots were collected from 55 GA-I patients
based on clinical, biochemical or neuroimaging studies. Direct sequencing of PCR products or RFLP was used for genotyping
studies. The presences of mutations in GA-I patients were confirmed by sequencing.
Results
Genotyping results showed that R402W mutation was found in 22% GA-I patients, F236L in 2% and R313W in 2%. Many
novel mutations such as W225X 1 (2%), H403Y1 (2%) and 1606 G>T at 3’UTR 1 (2%) were identified while genotyping.
The genetic screening also showed the existence of a novel low excretor mutation, P286S in 2 (4%) GA-I patients. This low
excretor mutation is a second most prevalent mutation among GA-I patients in India after R402W mutation. Mutation such
as A421V, A293T, R227P and V400M were found to be absent in our population.
Conclusion
In conclusion, R402W is commonest mutation among GA-I patients from India. A novel mutation, P286S, is the predominant
genotype among low excretor GA-I patients in India.
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Mon(2)-P-286
Therapeutic effects of dietary supplementation with glycine, L-carnitine, or both in combination in
isovaleric acidemia
Yasutsugu Chinen 1 ，Inokuchi Takahiro 2
1:Pediatrics, Faculty of Medicine, University of the Ryukyus, Japan、2:Research Institute of Medical Mass Spectrometry, Kurume University
School of Medicine
Isovaleric acidemia (IVA) is an autosomal recessive disorder of organic acid metabolism caused by a deficiency of isovaleryl-
CoA dehydrogenase (IVD). The proposed treatments of IVA comprise of dietary leucine restriction, and supplementation
of L-carnitine and/or glycine to conjugate isovaleric acid resulting in its conversion into non-toxic isovaleryl (C5)-carnitine
(IVC) and isovalerylglycine (IVG) that is excreted in the urine. We have reexamined supplemental therapy from an alternative
viewpoint.
Methods: The patient had an uneventful delivery after a 39 week-gestation with a weight of 3088 g. Ten days after birth he
had anemia and thrombocytopenia. As he exhibited symptoms such as mild mental retardation and repetitive vomiting with
hyperammonemia, he was diagnosed with IVA at the age of five years.
The IVA patient was supplemented with either glycine (250mg/kg/day), L-carnitine (100mg/kg/day), or both glycine and
L-carnitine for four days each. After the meal containing 1600mg leucine, we measured his levels of ammonia, free carnitine,
IVC, and IVG from different body fluid samples.
Poster Session
Results: Three hours after the meal, serum ammonia showed the smallest increase with L-carnitine supplementation, followed
by both agents in combination, and the largest increase with glycine. The increase in urinary IVG with glycine supplemen-
tation was twice that of both agents in combination, and of L-carnitine. The combination of both glycine and L-carnitine
supplementation was associated with an extreme increase in urinary free carnitine. The increase in urinary acylcarnitine was
the highest with L-carnitine supplementation; there was a gradual increase to the concentration observed with L-carnitine
supplementation six hours after the meal when both agents were given.
Discussion: We hypothesized that L-carnitine would conjugate earlier than glycine in IVA, as serum ammonia showed the
greatest reduction with L-carnitine supplementation alone,
Mon(2)-P-287
New indexes of neonatal tandem mass-screening for early detection of citrin deficiency (NICCD)
Hiroko Shigetomi 1 ，Toju Tanaka 1 ，Mayuko Morii 1 ，Masayoshi Nagao 1
1:Center for Pediatric Genetics & Metabolic disorder, Clinical Research, NHO Hokkaido Medical Center, Japan
[Introduction] Citrullinemia, which can be detected by newborn tandem mass-screening (NBS), is the earliest identifiable
biochemical abnormality among patients with neonatal intrahepatic cholestasis due to citrin deficiency (NICCD). However
the detection rate using elevated citrulline (Cit) is 1/80000, which is a quarter of the observed prevalence of NICCD.
[Methods] We examined new indexes to evaluate the NBS data among nine NICCD patients who were considered to be normal
in neonatal period. Diagnosis of NICCD was confirmed by DNA testing.
[Results] Cit values at NBS were below cut-off level (40nmol/ml, mean: 11.7, S.D.: 3) in all cases. However their standard
deviation (S.D.) ranged from +2.2 to +6.3. We therefore compared S.D. of each amino acid (13 species) collected from the
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patients. Cit showed characteristically higher value (4.4±0.5) than others (-1 to +1.2). Although concentrations of amino
acids in total (tAA) tended to be low in NICCD, ratio of Cit to summation of 13 amino acids (Cit/tAA) were always high,
being more informative to detect NICCD. Therefore we set a new cut-off value for each (Cit>20 and Cit/tAA>0.011) and
picked up dual positive cases for screening NICCD. Retrospectively, nine out of eleven cases could have been flagged using
the above role.
[Discussion] Introduction of a new parameter (Cit/tAA) and reconsideration of cut-off value for Cit, will make it possible to
detect in neonatal period. Although it is sometimes difficult to distinguish from other causes of citrullinemia, such as mild
type of ASS deficiency and transient biochemical phenotype, presence of other biochemical abnormalities such as elevation
of galactose and phenylalanine, will help the diagnosis exactly. Even if they were missed by NBS, reference of NBS data at
one-month checkup as mentioned above, in association with screening for congenital bile duct atresia, will reveal the presence
of NICCD.
Mon(2)-P-288
Utility of CCL18/PARC and Heparin Cofactor II - Thrombin for diagnosis and monitoring of Lysosomal
Storage Disorders
Sanjeev Kumar Pandey 1 ，Jyotsna Verma 1 ，Ishwar Chander Verma 1 ，Seema Kapoor 2
1:Biochemical Genetics Division, Sir Ganga Ram Hospital, India、2:Pediatrics Research & Genetic Lab, Maulana Azad Medical College
Poster Session
Background and Objective:
The objectives of the study was to analyze the CCL18 and Heparin-Thrombin II cofactor (HCII-T) of selected lysosomal
storage disorders and focus on studying the efficacy of these biomarkers in diagnosis, and monitoring at various time intervals
in order to shed light on the status of severity of these deadly diseases.
Method:
A total of 36 patient out of that 14 Gaucher Disease (GD), 4 Niemann Pick Disease (NPD) and 18 Mucopolysaccharidoses
(MPS) patients, who had low enzyme activity for GD (< 3.5nmol/hr/mg), NPD (<1.0nmol/hr/mg) and MPS (Type I <
2.0nmol/hr/mg, Type II < 2.5nmol/hr/mg ) has been enrolled in the study. A control group of 60 healthy individuals with
normal enzyme activity and who did not have any evidence of LSDs were inducted in the study.
CCL18 level for Gaucher and Niemann pick disease and Heparin thrombin II cofactor for Mucopolysaccharidoses were exam-
ined as a biomarker over different time intervals.
Results:
The CCL18 was analyzed in all controls with the mean value of 87.5ng/ml where as in GD and NP patients the values were
824 ng/ml and 516.5 ng/ml respectively. These values indicates statistically significance (P<0.05) between healthy controls
and GD and NP patients.
The level of HCII-T in MPS patients were 426.25 ng/ml in type I and 363.18 ng/ml in type II; whereas the observed levels of
this marker in control group was < 60ng/ml. These value also shows statistically significance (p<0.05) between controls and
MPS type I and II patients. There were no significant differences observed in the level of these biomarkers at various time
intervals.
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Conclusion:
The markedly elevated plasma CCL18 levels in symptomatic GD and NP patients and HCII-T levels in MPS patients can
give insights in the diagnosis and monitoring of these disease and warrants further investigations regarding its applicability
in the clinical management as well as its role in the peculiar pathophysiology of these disorders.
Mon(2)-P-289
KLF14 involves in controlling inflammation in the white adipose tissue
Chiharu Tayama 1 ，Rieko Takanashi 2 ，Junko Tomikawa 1 ，Hajime Okita 1 ，Kenichiro Hata 1 ，Tadashi Okamura 2 ，
Kazuhiko Nakabayashi 1
1:National Research Institute for Child Health and Development, Japan、2:National Center for Global Health and Medicine
KLF14 is imprinted in both mice and humans. eQTL and GWA studies have suggested that KLF14 acts as a master regulator
of key metabolic genes in adipose tissue, and demonstrated that cis-regulatory SNPs in the KLF14 locus are associated with
susceptibility to multiple metabolic diseases including T2D. We revealed by qRT-PCR analyses that Klf14 was highly expressed
in the embryos at 9.5pdc or later and only in the white adipose tissue (WAT) among 15 adult tissues examined. Maternal
allele-specific expression of Klf14 in WAT was consistently maintained in all adult stages examined. We obtained a Klf14
Poster Session
knock-out mouse line from KOMP. Klf14 -/- mice showed no morphological and growth abnormalities. We fed Klf14 -/- mice
(n=11) and wild-type littermates (n=7) with a high-fat diet for 8 weeks (from 9 to 16 weeks of ages) and examined their
metabolic phenotypes. No significant difference was observed in the items inspected such as body weight, GTT, and ITT. We
subsequently subjected the WAT samples from Klf14 -/- and WT mice with high-fat diet treatment to a gene expression array
analysis (n=5 each). Both of GO and GSEA analyses for differentially expressed genes, 1033 up- and 1441 down-regulated
genes with t-test P-value < 0.05, revealed that only the latter was enriched with genes related to inflammation and immune cell
activation, indicating that obesity-induced inflammation characterized by macrophage infiltration was alleviated in Klf14 -/-
WAT. The expression levels of key pro- and anti-inflammatory adipokines were also altered in Klf14 -/- WAT. Our results
suggest that KLF14 involves in controlling inflammation in WAT possibly through transcriptional regulation of adipokine
genes.
Mon(2)-P-290
POLG-related disorders in Polish population - a comprehensive study
Dorota Piekutowska-Abramczuk 1 ，Magdalena Kaliszewska 2 ，Katarzyna Tonska 2 ，Anna Sulek 3 ，Marketa Tesarova 4 ，
Joanna Pera 5 ，Joanna Trubicka 1 ，Elzbieta Ciara 1 ，Dorota Jurkiewicz 1 ，Magdalena Pelc 1 ，Pawel Kowalski 1 ，
Paulina Halat 1 ，Dariusz Rokicki 6 ，Rafal Ploski 7 ，Malgorzata Krajewska-Walasek 1 ，Ewa Pronicka 1,6
1:Medical Genetics, The Children’s Memorial Health Institute, Poland、2:Institute of Genetics and Biotechnology, Faculty of Biology,
Warsaw, Poland、3:Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland、4:Department of Pediatric and
Adolescent Medicine, First Faculty of Medicine, Charles University in Prague, Czech Republic、5:Department of Neurology, Jagiellonian
University Medical College, Krakow, Poland、6:Department of Pediatrics, Nutrition and Metabolic Diseases, The Children’s Memorial
Health Institute, Warsaw, Poland、7:Department of Medical Genetics, Medical University in Warsaw, Poland
The spectrum of POLG-related diseases inherited in autosomal recessive or dominant manner includes the main phenotypes of:
Alpers-Huttenlocher syndrome (AHS), myocerebrohepatopathy spectrum, myoclonic epilepsy myopathy sensory ataxia, ataxia
neuropathy spectrum, and progressive external ophthalmoplegia, often comprising a continuum of overlapping phenotypes
presenting from early childhood to late adulthood.
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We assessed the frequency of POLG mutations in a large cohort of Polish (Caucasian) patients consisted of 1150 individuals
(including 480 children) that previously had been molecularly tested for mitochondrial pathology and/or spinocerebellar ataxia
background with negative results. Genotyping of the samples was performed by targeted mutation analysis [TaqMan allele
discrimination assays for recurrent c.1399G>A (p.A467T), c.2542G>A (p.G848S), and c.2243G>C (p.W748S) mutations]
and/or entire POLG gene sequencing (Sanger/NGS technique). Seventeen pathogenic molecular variants including novel:
R290C, A518T, R869X, A880D, Q968E, S998P, T1053Rfs*6, V1106A, and known: T251I, R309L, A467T, P587L, W748S,
R807C, A979G, L1191N, Y1210X changes were identified. POLG disease was identified in 21 cases: seven children presenting
with AHS/AS phenotype (disease onset: 2-20 months) and fourteen adolescents/adults with sensory-motor neuropathy,
ophtalmoplegia and/or mtDNA multiple deletions (disease onset: 13-74 years).
Our findings are in line with the literature data and confirm: 1/ AHS as probably the most frequent presentation of POLG
diseases in infants and young children; 2/ regional predominance of W748S mutation (45.2% of all alleles); 3/ POLG mutations
as relatively rare cause of neurological involvement in adults, that should be excluded in each case of sensory-motor neuropathy,
ophthalmoplegia and multiple mtDNA deletions.
The study was financed by NSC projects 2012/05/B/NZ2/01627, 2857/B/P01/2010/39, and CMHI project S136/12.
Mon(2)-P-291
A long term follow-up study of 8 individuals with asymptomatic propionic acidemia
Poster Session
Yoriko Watanabe 1,2 ，Kaori Fukui 1 ，Naomi Harada 1 ，Kyoko Tashiro 2 ，Go Tajima 3 ，Toru Yorifuji 4 ，
Yosuke Shigematsu 5 ，Yasuhiro Maeda 6 ，Yoko Nakajima 7 ，Takahiro Inokuchi 2 ，Naohisa Uchimura 2
1:Pediatrics and Child Health, Kurume University, Japan、2:Research Institute of GC/MS, Kurume University、3:Pediatrics, Hiroshima
University、4:Ped Endo Metab Osaka City Gen Hosp、5:Dept. Health Science, Fukui University、6:Lab Hosp Pharm, Nagoya City University、
7:Dept. Pediatrics, Fujita Health University
Background: Prevalence of the mild form of propionic academia (PA) is thought to be high in Japan. After recent introduction
of newborn screening by tandem-mass spectrometry the number of new cases of mild PA is expected to increase. Studying
clinical/laboratory findings as well as outcomes in the known cases of mild PA is important in establishing better clinical
management of mild PA.
Methods: Acylcarnitines in blood spots on filter paper and in plasma, and urine organic acids were analyzed in 8 individuals
(age: 4 months to 14y) at multiple points during the observation period. The specimens from each individual obtained as
newborn were also analyzed. These values were compared to the ones in patients with classic PA.
Results: (1) C3 carnitine levels and C3/C2 ratios in dried blood spots in newborn screening as well as methylcitrate and
3-hydroxypropionate levels in the urine from the neonatal period showed lower values in the asymptomatic PA individuals. (2)
Plasma C3 carnitine and urine methylcitrate levels in asymptomatic PA were lower than the lowest values of these analytes
in classic PA.
Conclusion: A retrospective study of biochemical analytes and clinical outcomes in 8 cases of mild PA was conducted.
A longitudinal study of biochemical analytes in 8 individuals with asymptomatic propionic acidemia (PA) was conducted.
Higher residual activities in propionyl-CoA carboxylase and the common mutation (Y435C) in PCCB in Japanese are known in
individuals with asymptomatic PA. All of them remained asymptomatic on regular diet during the observation period (mean:
67 months). Our objectives were to study and compare the biochemical characteristics in individuals with asymptomatic PA
to classic PA. Distinguishing asymptomatic PA from classic PA may be possible based on the biochemical analytes.
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Mon(2)-P-292
Mutation Spectrum of Japanese Patients with Fabry Disease- Correlation between genotype and pheno-
type
Masahisa Kobayashi 1 ，Toya Ohashi 2 ，Yoshikatsu Eto 3 ，Hiroyuki Ida 1
1:Department of Pediatrics, The Jikei University School of Medicine, Japan、2:Division of Gene Therapy, Research Center for Medical
Sciences, The Jikei University School of Medicine、3:Advanced Clinical Research Center and Institute of the Treatment of Genetic Diseases,
Institute of Neurological Diseases
Objective: Fabry disease is an X-linked lysosomal disorder resulting from mutations of the alpha-Galactosidase A (GLA)
gene. The clinical phenotype of Fabry disease comprises classic form and later-onset form. Although enzyme replacement
therapy has been approved for Fabry disease, it is difficult to predict the clinical phenotype and to determine the therapeutic
approach from genetic information. The aim of this study is to clarify the correlation between genotype and phenotype in
Fabry disease.
Material and Method: The study patients were 157 Japanese patients (male: 81, female 76) from 102 families with Fabry
disease. We directly sequenced the each exon flanking intronic sequence of GLA gene. We classified clinical phenotypes in
classical form, later-onset form with end-stage renal disease (ESRD group) and later-onset form without ESRD (no-ESRD
group), and studied the correlation between mutation and phenotype.
Results: In 95 out of 102 families, 65 different mutations (including 17 novel mutations) were detected and in 7 families
(6.8%), disease-causing mutations were not detected in GLA gene. Forty-eight mutations were private mutations and 17
Poster Session
mutations were common to some families. Although various type mutations (missense, nonsense, deletion and splicing defect)
were detected in classic form (52 families) and ESRD group (5 families), no-ESRD group (7 families) had only missense and
intronic mutations. Three mutations (missense, deletion, splicing defect) were common to classic form and ESRD group. In
7 out of 102 families (6.9%), they were confirmed as de novo cases by parents gene analysis.
Conclusion: It may be possible to distinguish classic form from no-ESRD group, however it is difficult to differentiate between
classic form and ESRD group from genetic information. In genetic point of view, ESRD group is thought to resemble classic
form. The frequency of de novo case was 6.9% and parents diagnosis should be made by gene analysis.
Mon(2)-P-293
Analysis of ABCG2 allelic variants in primary gout
1,2
Blanka Stiburkova ，Pavel Simek 1 ，Pavel Cepek 1 ，Jakub Zavada 1 ，Lenka Petru 1 ，Karel Pavelka 1
1:Molecular Biology and Immunogenetics, Institute of Rheumatology, Czech Republic、2:Institute of Inherited Metabolic Disorders, First
Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
The cohort consisted of 100 individuals: 21 primary hyperuricemics and 79 primary gout. We analyzed 15 exons of ABCG2
by PCR amplification and sequenced directly. The definition of hyperuricemia was as follows: >420/>360 µmol/l at two
repeated measurements at intervals of at least 4 weeks in men/women, respectively. Gouty arthritis was diagnosed according
to the American college of rheumatology criteria. The functional analysis of identified allelic variants is in process (Xenopus
oocyte, HEK cells).
In the ABCG2 gene, 16 intronic sequence variants and seven exon sequence variants were detected. From these 16 intronic
variants, 14 were previously reported as polymorphisms and two were unpublished: three-nucleotide deletion c.690-19_690-
17delTGT and c.689+1G>A nucleotide change at exon/intron boarding region. In the case of nucleotide heterozygous intron
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ICHG2016 945
variant c.689+1G>A, related to an individual with severe gouty phenotype, two abnormal splicing variants were identified:
r.[532_689del] and r.[532_689del], identified deletions lead to frameshift and premature stop codon introduction.
From the seven exon sequence variants detected, there were five non-synonymous: rs2231137 , rs2231142 , rs753759474 ,
rs752626614 and rs34783571 . Heterozygous p.V12M allelic variant was detected in genome of six individuals. Each of
non-characterized allelic variants p.T153M, p. F373C and p.D620N were detected once in heterozygous state. The p.Q141K,
previously functionally characterized allelic variant with an effect on uric acid secretion impairment, was in cohort of
hyperuricemic/gout patients presented with higher frequency (28 heterozygotes/3 homozygotes, allele frequency 0,17) than
in population of European origin (MAF=0,09) and world-wide population (MAF=0,12).
Our results strongly suggest a relationship between the allelic variants of the ABCG2 gene and a primary hyper-
uricemia/primary gout phenotype.
Support: AZV 15-26693A, 00023728.
Mon(2)-P-294
PNPLA4 is a novel causative gene for mitochondrial respiratory chain disorder presenting with apparent
life-threatening event
Hiromi Nyuzuki 1,2 ，Yoshihito Kishita 1 ，Yoshimi Tokuzawa 1 ，Masakazu Kohda 3 ，Kei Murayama 4 ，Akihiko Saitoh 2 ，
Akira Ohtake 5 ，Yasushi Okazaki 1,3
Poster Session
1:Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Japan、2:De-
partment of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences、3:Division of Translational Research, Research
Center for Genomic Medicine, Saitama Medical University、4:Department of Metabolism, Chiba Children’s Hospital、5:Department of Pe-
diatrics, Saitama Medical University
Mitochondrial respiratory chain disorders (MRCD) have the highest incidence among congenital metabolic disorders charac-
terized by biochemical respiratory chain complex deficiencies with phenotypic and genetic heterogeneity. It is particularly
difficult to diagnose patients with MRCD at the molecular level because of the massive numbers of potentially involved nu-
clear genes and genes not yet linked to human disease. Therefore, identification of the causative genes and an understanding
of the pathogenic mechanisms of MRCD remain unsolved challenges. Here we identified a novel causative gene for MRCD
presenting with apparent life-threatening event (ALTE). A boy who presented with ALTE at the age of one month was
diagnosed as MRCD with complex IV deficiency by enzyme analysis of mitochondrial respiratory chain complexes in cul-
tured fibroblasts. Exome analysis and sanger sequence revealed that he inherited a hemizygous nonsense variant c.559C>T
(p.R187X) in PNPLA4 (NM_001142389) from his mother. PNPLA4 mRNA and protein expression levels were apparently
decreased in patient’s fibroblasts. We confirmed the localizations of the endogenous PNPLA4 and the lentiviral-mediated
exogenous expression of PNPLA4-V5 in mitochondria by confocal microscopic observation. We found reduced complex I,
III and IV assemblies of patient’s fibroblasts under low glucose medium conditions and complementation with PNPLA4
could restore them. Although PNPLA4 is known to encode a calcium-independent phospholipase A2η that exhibits great
lipase and transacylase activity, the precise functions are not completely understood. PNPLA4 has never been reported to
associate with the mitochondria nor be linked to human disease. We assume that PNPLA4 is required for mitochondrial
phospholipid metabolism affecting the functions of respiratory chain complexes. We need further investigation to elucidate
PNPLA4 function in mitochondria, which might help to clarify the pathogenic mechanisms of MRCD.
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Mon(2)-P-295
Spectrum of AGL mutations in Chinese patients with glycogen storage disease type III: identification of
31 novel mutations
Chaoxia Lu 1 ，Zhengqing Qiu 2 ，Miao Sun 1,3
，Wei Wang 2 ，Min Wei 2 ，Xue Zhang 1
1:McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, China、2:Department
of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College、3:Institute
for Fetology, the First Affiliated Hospital of Soochow University
Glycogen storage disease type III (GSD III), a rare autosomal recessive disease characterized by hepatomegaly, fasting hypo-
glycemia, growth retardation, progressive myopathy and cardiomyopathy, is caused by deficiency of the glycogen debranching
enzyme (AGL). Direct sequencing of human AGL cDNA and genomic DNA has enabled analysis of the underlying genetic
defects responsible for GSD III. To date, the frequent mutations in different areas and populations have been described in
Italy, Japan, Faroe Islands and Mediterranean area, while little has been performed in Chinese population. Here we report a
sequencing-based mutation analysis in 43 Chinese patients with GSD III from 41 families. We identified 51 different mutations,
including 15 splice-site (29.4%), 11 small deletions (21.6%), 12 nonsense (23.5%), 7 missense (13.7%), 5 duplication (9.8%)
and 1 complex deletion/insertion (2.0%), 31 of which are novel mutations. The most common mutation is c.1735+1G>T
(11.5%). The association of AGL missense and small in-frame deletion mutations with normal creatine kinase (CK) level was
observed. Our study extends the spectrum of AGL mutations and suggests a genotype-phenotype correlation in GSD III.
Mon(2)-P-296
Poster Session
Two Filipino siblings with Glutaric Aciduria Type 1
Barbra Charina V. Cavan 1 ，Dubhe Prescila O. Sanchez 1
1:Pediatrics, Cebu Doctors’ University Hospital, Philippines
We present two siblings, a 9 year old female and a 4.5 year old male, who both had macrocephaly since infancy, developmental
delay, dystonic dyskinetic movements, and spasticity. The older child had been referred for metabolic work-up at 7 months
of age but was lost to follow-up and labeled as cerebral palsy. The younger child presented with sensorial changes and
anisocoria at our Emergency Room at 4.5 years of age, leading to an urgent brain scan. Imaging findings showed bilateral
subdural bleed, parenchymal volume loss, perisylvian cortical dysplasia, and abnormal signals from the basal ganglia. Urine
organic acid analysis showed grossly increased glutarate and trace 3-hydroxyglutarate and glutaconate, which were highly
supportive of the diagnosis of Glutaric Aciduria Type 1 (GA1).Treatment with dietary restriction of protein, L-carnitine
administration, adequate calories, and drugs to control dystonia were initiated. Management plans for intercurrent illness
were also formulated. Increased awareness of this rare but treatable metabolic condition, as well as the advent of expanded
NBS in the Philipines (which includes GA1), will hopefully prevent similarly affected patients from ending up with severe
neurologic sequelae such as an encephalopathic crisis.
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Mon(2)-P-297
Biochemical and molecular characteristics of Korean children with citrin deficiency
Jae-Min Kim 1 ，Beom Hee Lee 1,2
，Seak Hee Oh 2 ，Gu-Hwan Kim 1 ，Jin-Ho Choi 2 ，Kyung Mo Kim 2 ，Han-Wook Yoo 1,2
1:Medical Genetics Center, Asan Medical Center, Korea, South、2:Department of Pediatrics, Asan Medical Center Childrens Hospital,
University of Ulsan College of Medicine
Purpose/background: The purpose of the study is to investigate the genotypes of Korean patients with citrin deficiency as well
as their biochemical characteristics. Methods: Between 2006 and 2014, patients with citrin deficiency had genetic sequencing
on SLC25A13 at Asan Medical Center and long PCR was performed in order to screen large, transposal insertions. The
patients’ clinical data were retrospectively collected from our medical records. The biochemical data of children with NICCD
were compared to those of patients with idiopathic neonatal hepatitis (INH). Results: A total of 68 alleles were identified
among 34 patients with citrin deficiency (29 NICCD and 5 CTNL2). The most common pathogenic allele on SLC25A13
was IVS16ins3kb (34%) followed by c.851_854del (29%), c.1177+1G>A (13%), and c.674C>A (9%). Three novel variants
(p.Ser74Phe, p.Gln549*, and p.Aeg558Pro) were identified on SLC25A13. INH had higher aspartate aminotransferase, alanine
aminotransferase, and direct bilirubin. On amino acid profiles, Citrulline, threonine, methionine, tyrosine, and arginine were
higher in the NICCD group. Conclusion: The genetic ethnicity of Korean patients with citrin deficiency was characterized
by the high frequency of IVS16ins3kb. We identified three, novel mutations of SLC25A13 .
Mon(2)-P-298
Diverse clinical phenotypes of mitochondrial trifunctional proteindeficiencyaccording to mutations in
Poster Session
HADHA and HADHB
Gu-Hwan Kim 1 ，Eungu Kang 2 ，Beom Hee Lee 1,2
，In Hee Choi 1 ，Jin-Ho Choi 2 ，Han-Wook Yoo 1,2
Purposes: Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency or mitochondrial trifunctional protein
(MTP) deficiencies are the fatty acid oxidation defects caused by HADHA or HADHB mutations. This study was performed
to investigate clinical and biochemical features according to the genotypes of either gene.
Methods: Seven patients (2 boys and 5 girls) were diagnosed as LCHAD or MTP deficiencies. Their clinical findings with
respective genotypes were reviewed.
Results: MTP deficicncy of three patients presented in their neonatal periods. One patient manifested severe cardiomyopathy
at first day of life and and subsequently died of lactic acidosis at age 4 days. She was homozygous for c.1793_1794del
(p.H598Rfs*33) of HADHA. Another patient identified by tandem mass spectrometry but died at age 49 days as sudden
infantile death syndrome. Mutation analysis of HADHA identified homozygous mutations of c.1689+2T>G, leading to
deletion of exon 16. A female compound heterozygous for p.H379R/p.G404fs*2 presented with cardiomyopathy at age 5 days
and died at 9 days of age. The other 4 patients manifested rhabdomyolysis at age 2.4 ± 1.3 (0.8 - 4) years and had missense
mutations in the HADHB gene. Despite avoidance of prolonged fasting with supplementation of medium chain triglyceride,
recurrent rhabdomyolysis and sensorimotor polyneuropathy developed during the follow-up period of 7.7 ± 4.0 ( 2.0 - 11.0)
years.
Conclusion: Patients with truncating mutations in HAHDA or HAHDB experienced severe neonatal phenotype, while those
with missense mutations presented with recurrent rhabdomyolysis at later ages. These results indicate the different phenotypic
severity according to a mutation type.
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Mon(2)-P-299
A Nationwide Survey on Fabry disease in Korea
In Hee Choi 1 ，BeomHee Lee 1,2
，Eungu Kang 2 ，JaHyang Cho 2 ，Gu-Hwan Kim 1 ，Jin-Ho Choi 2 ，Han-Wook Yoo 1,2
Fabry disease is caused by a deficiency of the lysosomal enzyme, alpha-galactosidase A (GLA). The natural long-term course of
untreated Fabry disease is complicated by renal, cardiac or cerebrovascular diseases. Since the introduction of two recombinant
enzymes in 2001, their beneficial effects on renal, cardiac, and cerebral complications have been reported. However, for the
optimum therapeutic efficacy, early diagnosis and treatment are important. The current study was done to evaluate the
current status of diagnosis and treatment of Fabry disease in Korean populations in order to improve the patients’ care in
this population.
A total of 14 institutions joined this survey and as of Oct in 2015, 94 patients from 46 different Korean families were affected
including 38 adult male, 46 symptomatic female, and 10 pediatric Fabry patients. All patients were diagnosed based on the
biochemical and genetic studies. Overall age at symptomatic presentation was 24(5-65) years but diagnosis was delayed by
21±19 years. All male and pediatric patients have been on enzyme replacement therapy (ERT), while 75 % of symptomatic
female patients on ERTfor 4.2±3.6 years. When we evaluated the renal outcomes of patients who received ERT longer than 5
years, amount of proteinuria, age at diagnosis, and glomerular filtration rate before ERT were the important factors affecting
renal outcome. In addition, the renal pathological findings such as global glomerular sclerosis, interstitial fibrosis or tubular
atrophy that suggests the chronic kidney injuries were noted in the patients whose renal function deteriorated significantly.
Poster Session
These results indicate that early diagnosis and treatment is very important for a patient’s prognosis.
Mon(2)-P-300
Combined Effect of Celastrol and Chemical Chaperone on glucocerebrosidase (GBA) activities of skin
fibroblasts from Gaucher patients
Sun Hee Heo 1 ，Beom Hee Lee 1,2
，Gu-Hwan Kim 2 ，In Hee Choi 2 ，Han-Wook Yoo 1,2
1:Asan Institute for Life Sciences, Asan Medical Center, Korea, South、2:Medical Genetics Center, Asan Medical Center Childrens Hospital,
University of Ulsan College of Medicine, Seoul, Korea
Gaucher disease (GD) is one of the most common lysosomal disorders. It is caused by glucocerebrosidase (GBA) deficiency,
and is characterized by accumulation of glucosylceramides in reticuloendothelial systems. According to neurological system
involvement, this condition is divided into non-neuronopathic and neuronopathic GD. Most Caucasian patients are affected
by non-neuronopathic GD, whereas up to half of the East Asian patients are suffering from neuronopathic GD. Importantly,
because recombinant enzyme cannot cross blood-brain barrier, neurological manifestations cannot be treated in patients with
neuronopathic GD. Ambroxol (ABX) and N-(n-nonyl)deoxynojirimycin (NN-DNJ), the brain-penetrating chemicals, have been
suggested as the chemical chaperones to treat neuronopathic GD. However, very high doses should be administered to reach
a therapeutic level to increase the residual activity of GBA. Recently, one proteastasis regulator, celastrol has been shown to
improve the efficacy of chaperone. In the current study, we evaluated the combined effect of celastrol and ABX/NN-DNJ. The
fibroblasts from GD patients whose genotypes were G46E/D399N, N188S/R257Q, F213I/L444P, N188S/P171fsX21 (603delC)
and L444P/L444P, were treated by 10uM ABX, 10uM NN-DNJ or 0.4uM ~ 0.8uM celastrol. Under single chemical treatment,
the enhancement of residual activity was different among the genotypes. N188S/R257Q responded to ABX, F213L/L444P
and N188S/P171fsX21 responded to NN-DNJ, whereas F213I/L444P and L444P/L444P responded to celastrol. Significant
increase of residual GBA activity was noted in F213L/L444P and L444P/L444P fibroblasts under combined treatment of
10Um ABX and 0.4uM celastrol. The results of our study indicate that the response to chemical chaperone is different
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ICHG2016 949
according to genotypes, and combined therapy of ABX and celastrol might help to enhance the therapeutic effect of ABX in
GD, especially in L444P genotype.
Mon(2)-P-301
Clinical And Molecular Updates Of Infantile Systemic Hyalinosis In Arab Populations
Sahar AF Hammoudah 2 ，Lama M.A. El-Attar 1
1:Human Genetics Department, Medical Research Institute, Saudi Arabia、2:Department of Clinical and Chemical Pathology, Tanta Uni-
versity
Infantile Systemic Hyalinosis (ISH) is a rare autosomal recessive disorder belonging to the heterogeneous genetic group of
fibromatosis. ISH is diagnosed clinically by hyperpigmented skin over bony prominences with papulonodular lesions scattered
all over the body, congenital progressive joint contactures associated with severe pain on passive movement and gingival
hypertrophy. However, children with ISH are found to be intellectually normal. Clinical manifestations are present at birth
or early infancy with a fatal progressive course in which failure to thrive is common and most affected children are died
from recurrent chest infection and/or chronic diarrhea in infancy or early childhod. Mutations in Anthrax Toxin Receptor
2(ANTXR2) gene which previously was called Capillary Morphogenesis gene 2(CMG2) are currently known to be associated
with ISH.Several muataions have been identified in exon 1 to exon 15, and exon 13 was found to be a hot spot. Specific
treatment or prenatal diagnosis in subsequent pregnany are not available for ISH. ISH has been recognized in families from
different ethnic backgrounds.The incidence among arabs is uncertain. some reports suggest it is rare while others suggest
that ISH is a common disorder.We beleive that many cases are missed and the disease is undiagnosed as affected children
Poster Session
die before establishing an accurate diagnosis due to paucity of genetic information and poverty in molecular fascilities.In this
reveiw, we are trying to evaluate and analyze reported data regarding ISH in order to identify the actual incidence among
arab countries with special emphasis on the genotype/phenotype correlation between clinical manifestations and molecular
results. Proper identification of the disease will help in the planning of strategies for the prevention and management of ISH
by offering accurate diagnosis and genetic counseling for familes of affected children
Mon(2)-P-302
Analysis of inverted chromosome from phosphoglucomutase 1 deficiency patient
Tamae Ohye 1 ，Haruna Mizukami 1 ，Yohei Katsuragawa 1 ，Naoko Fujita 2 ，Yoko Nakajima 3 ，Hidehiko Akiyama 1 ，
Tetsuya Ito 3 ，Hiroki Kurahashi 2
1:Department of Clinical Hematology, Faculty of Medical Technology, Fujita Health University, Japan、2:Division of Molecular Genetics,
Institute for Comprehensive Medical Science, Fujita Health University、3:Department of Pediatrics, Fujita Health University School of
Medicine
Phosphoglucomutase 1 (PGM1) deficiency is the congenital metabolic disorder, showing a diverse clinical manifestations,
such as cleft palate, hepatic insufficiency, hypoglycemia and growth delay. These symptoms reflect the central role of the
enzyme in glucose metabolism. PGM1 deficiency is autosomal recessive in inheritance, and associated with various types of
mutations, including frameshifts, aberrant splicing, and missense variants. We analyzed a case of PGM1 deficiency having a
chromosomal inversion.
The patient shows a cleft palate, hypoglycemia and hepatic insufficiency in a newborn period, and PGM1 activity was
markedly diminished in liver biopsy. To identify the mutation of PGM1 , the Sanger sequencing was carried out. c.1258T>C
was detected in PGM1 , but it was reported as a common polymorphism in the database. The patient karyotype was
determined as to be 46,XY,inv(1)(p31.1p32.3), of which inv(1) as a homozygous. The parents of the patient were the first
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ICHG2016 950
cousins marrying.
PGM1 is located on 1p31.1, which corresponded to one of the inversion breakpoints. We performed FISH analysis using a BAC
probe containing the entire regions of PGM1 . A single signal for PGM1 was observed on the short arm of chromosome 1 in
a normal karyotype individual. In contrast, the two distinctive signals were detected on the arm in the patient’s chromosome
1. To narrowed down the breakpoint region in DNA level we carried out long PCR with several sets of primers on PGM1 .
Since only the primer pairs within intron 1 failed to amplify the products in the patient DNA, the breakpoint was identified
to be located on intron 1. It indicates that the inversion disrupts the patient’s PGM1 gene between the exons 1 and 2 and
lost its function completely.
We conclude that the homozygous inv(1) inherited from first cousin parents disrupts both PGM1 genes in the patient leading
to the PGM1 deficiency.
Mon(2)-P-303
Mutational Analysis of Egyptian Morquio Patients
Ekram M.A. Fateen 1 ，Mona L Essawy 2 ，Mona Sabry 3 ，Mona I Mahmoud 4 ，Hanan A Attia 5 ，Nora R Essa 6
1:Biochemical Genetics, National Research Centre, Egypt、2:Medical Molecular Genetics, National Research Centre, Egypt、3:Clinical Genet-
ics, National Research Centre, Egypt、4:Biochemical Genetics, National Research Centre, Egypt、5:Faculty of Pharmacy, Alazhar University,
Egypt、6:Medical Molecular Genetics, National Research Centre, Egypt
Poster Session
Morquio disorder( MPS IV A) is a rare autosomal recessive lysosomal storage disease, due to N-acetylgalactosamine-6-sulfatase
(GALNS) deficient activity.
Objective : Mutational analysis of Morquio Patients in Egypt.
Subjects and Methods : 17 Morquio patients from 15 families were diagnosed by low GALNS activity. They are 10 (58.8%)
males and 7 (41.4%) females . 80% of the parents were consaguinous .7 of the 14 GALNS exons ( 1, 2, 4,7,8,11 and 130 )
were sequenced.
Results : pathologic mutations were found in 9 patients from nine different families . Five novel mutations in exons 1, 2, 7
and 8 and three previously reported mutations in exons 1,2,and 13 ( c.120+1 G-A ;c.239C-T ; c.1438G-T ). All nine patients
were homozygous for the detected mutations . All patients showed polymorphism in exons 2, 4, 7, 8, 11 and 13 .The common
two polymorphisms are a silent mutation c.1431G-A at codon 477 in exon 13 found in 21 allele (61.8 %) . And an intronic
variation in intron 4 c.422+117 C-A ( IVS4 + 117C-A) found in 20 allele ( 58.8%) .
Conclusions: five novel mutations were detected among the nine patients with pathologic mutations . Although exons 1, 2,4,
7, 8, 11 and 13 are known to harbor the mutations of the GALNS gene, 8 patients showed no mutations in these exons .
Accordingly, the other 7 exons must be sequenced to detect the pathologic mutations.
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Mon(2)-P-304
NEWBORN SCREENING FOR MUCOPOLYSACCHARIDOSES: DETERMINATION OF SENSITIVITY,
SPECIFICITY AND CUTOFF VALUES
Adriana M Montano 1,6 ，Katherine E. Foerster 1 ，Qi Gan 1 ，Mary Campbell 2 ，Shunji Tomatu 3 ，Tadao Orii 4 ，
Yasuyuki Suzuki 4 ，Seiji Yamaguchi 5
1:Pediatrics, Saint Louis University, USA、2:CWHM, Saint Louis University、3:Alfred I. Dupont Children’s Hospital、4:Gifu University、
5:Shimane University、6:Biochemistry and Molecular Biology, Saint Louis University
Introduction: Mucopolysaccharidoses (MPS) are inherited lysosomal storage disorders caused by deficiency of the lysosomal
enzymes needed to degrade glycosaminoglycans (GAGs), which include chondroitin sulfate (CS), heparan sulfate (HS), keratan
sulfate (KS), dermatan sulfate (DS) and hyaluronan. Lysosomal accumulation of GAG molecules result in cell, tissue and
organ dysfunction. Most MPS patients are asymptomatic at birth with subsequent onset of clinical signs and symptoms.
Currently some therapeutic options are available for most MPS. Thus early diagnosis by newborn screening (NBS) is critical
to achieve better treatment outcomes. Here we describe an accurate and sensitive method for measuring DS, HS and KS
levels simultaneously in dried blood spots (DBS) using LC-MS/MS.
Methods: DBS of 3,256 de-identified newborns were digested with chondroitinase B, heparitinase and keratanase II, and
analyzed using API-4000 LC-MS/MS at Saint Louis University. Concentrations of HS subtypes (HS-6S, HS-0S, and HS-NS),
KS, and DS were determined for each newborn. Cutoff levels of mean+2(SD) (97.5th percentile) and mean+3(SD) (99.85th
percentile) were compared.
Poster Session
Results: The coefficient of variation was ranked as follows: NS>6S>0S>KS>4S. DiHS-NS had the greater variation or
dispersion and δ Di4S had the lowest variation among all the analytes. Overall there was very small intra-sample variation.
54% of newborns had HS-6S levels above the low level of quantitation (LLOQ), while 98.5%, 98.46%, 98.53%, and 98.40%
of newborns had HS-0S, HS-NS, KS, and DS-4S levels above the LLOQ, respectively. The cutoff values (mean+2(SD)) were
determined to be: 167.97ng/mL, 108.44ng/mL, 50.72ng/mL, 155.43ng/mL, and 62.77ng/mL for HS-6S, HS-0S, HS-NS, KS,
and DS-4S, respectively.
Conclusion: This methodology provides high sensitivity and accuracy for simultaneous measurement of three disaccharides
(DS, HS, and KS) in DBS.
Mon(2)-P-305
Development of a Less Immunogenic Protein for Enzyme Replacement Therapy of Morquio A Disease
1,2
Adriana M Montano ，Alexandria Lee 1 ，Catalina Sosa 1 ，Michael Flanagan 1 ，Qi Gan 1
1:Pediatrics, Saint Louis University, USA、2:Biochemistry and Molecular Biology, Saint Louis University
Immune response against proteins used for enzyme replacement therapy (ERT) has been characterized as one of the main
limitations in the treatment effectiveness. Preclinical trials of enzyme replacement therapy (ERT) in Mucopolysaccharidosis
IVA (Morquio A disease, MPS IVA) have shown to reduce accumulation of glycosaminoglycans, but are accompanied by a
large immune response that significantly decreases the efficacy of this treatment. The aim of this study is to bioengineer a
human GALNS protein with reduced immunogenicity without affecting the biological activity for effective ERT of MPS IVA.
The original GALNS amino acid and cDNA sequences were compared to the corresponding altered sequences in a variety
of in silico programs. We evaluated predictions of the immunogenicity, post-translational modifications, physico-chemical
properties, and 3D structural evaluation of molecular docking. In silico analyses were performed in the new sequences
harboring various combinations of substitutions on various immunodominant peptide regions within the whole GALNS protein.
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ICHG2016 952
In vitro experiments were conducted on HEK 293 cells to determine enzyme activity of the mutated GALNS proteins.
324 mutated sequences were created and narrowed to 7 sequences after analyzing (1) the immunogenicity predictions, (2)
the predictions of phosphorylation sites, N-glycosylation sites, and physico-chemical properties, and (3) three-dimensional
visualization of molecular docking. Three out of seven mutated GALNS sequences had 80% or more enzyme activity compared
to the wild type GALNS protein in vitro. In conclusion, a less immunogenic GALNS would improve the efficacy of ERT,
remove the two to three year period in which the patient develops tolerance to the protein, and ultimately eliminate the need
for immunosuppressive protocols of ERT.
Mon(2)-P-306
Age-dependent gene expression profile analysis in Morquio cartilage tissue
1,2
Adriana M Montano ，Shane Grace 1 ，Shiragi Patel 1 ，Catalina Sosa 1 ，Qi Gan 1
1:Pediatrics, Saint Louis University, USA、2:Biochemistry and Molecular Biology, Saint Louis University
Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by a deficiency of lysosomal enzymes respon-
sible for the degradation of glycosaminoglycans (GAGs). Mucopolysaccharidosis type IVA (MPS IVA, Morquio syndrome A)
is caused by a variety of mutations in the GALNS gene on chromosome 16q24, which encodes the galactosamine-6-sulfate
sulfatase (GALNS) enzyme that is directly involved in the lysosomal degradation of keratan sulfate (KS) and chondroitin-6-
sulfate (C6S). Accumulation of undegraded GAGs results in impairment of multiple organ systems, manifesting in distinct
clinical manifestations. Patients with Morquio A syndrome have variable clinical course with manifestations ranging from
Poster Session
mild skeletal involvement to progressive bone deformities, namely kyphoscoliosis, pectus carinatum and genu valgum, result-
ing in complete growth arrest. Early-onset osteoarthritis is known to affect MPS IVA patients, but the underlying reactive,
physiological response of the cartilage tissue secondary to GAG accumulation is not completely elucidated. Here we compare
the expression of autophagic and apoptotic genes in cartilage tissue of GALNS knockout mice to age-matched wild type
controls at 1, 3, 6, 9 and 12 months. We observed an age-dependent variability in autophagic and apoptotic gene expression,
which could correlate with KS blood levels. These data concur with the theory that a change in autophagic flux and apoptosis
could underlie the proposed chondrocyte phenotypic change that leads early-onset osteoarthritis in MPS IV patients
Mon(2)-P-307
Evaluation of Homocysteine Levels in Cuban Patients with Homocystinuria and Methylmalonic Aciduria
by HPLC
Alina Concepcion 1 ，Ivette Camayd 1 ，Lauro Nuevas 1
1:Laboratory of Biochemical Genetics, National Center of Medical Genetics, Cuba
Introduction. Homocysteine (Hcy) is a nonessential amino acid that links the methionine and the folate cycle. Hcy levels are
increased in genetic disorders such as classical homocystinuria and homocystinuria combined with methylmalonic aciduria.
The diagnosis of classic homocystinuria in Cuba is routinely carried out by a qualitative test. The aim of this work is to validate
a High Performance Liquid Chromatography (HPLC) method to quantify Hcy and to introduce it in the assessment in patients
with high urine methylmalonic acid levels or clinically suspected to have classic homocystinuria.Material and Methods. A
method to quantify Hcy levels in plasma by HPLC was developed and validated. We determined the following validation
parameters: specificity, linearity, precision, accuracy, limit of detection and quantification. The method was applied in 14
patients with suspicion of homocystinuria and MA in a period of two years.Results. The method allowed the identification
and quantification of Hcy. A lineal behavior was observed with an r2 = 0.9967. In the precision and accuracy studies the
coefficients of variation obtained were below 5%. The limits of detection and quantification obtained were 3.12 µM and
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ICHG2016 953
6.25 µM, respectively. Of the 14 studied patients, one of them showed elevated Hcy levels suggesting a homocystinuria. In
addition, three out of five patients with MA, showed elevated Hcy levels, indicating the presence of a MA combined with
homocystinuria. In one of these patients after starting treatment, a decrease of Hcy levels was observed, which was correlated
to a successful evolution after starting the treatment. The remaining two patients had normal Hcy levels and were described as
isolated MA.Conclusions. The method validated for the quantification of Hcy in plasma fulfills the requirements for analytical
validation of methods in clinical chemistry. Its use allowed the diagnosis and follow-up of patients with homocystinuria and
methylmalonic acidurias.
Mon(2)-P-308
Galsulfase hypersensitivity and desensitization of mucopolysaccharidosis VI patients
Ana Maria Martins 1 ，Vania D’Almeida 1 ，Carolina Aranda 1 ，Carmen Mendes 1 ，Luis Felipe Ensina 1 ，Dirceu Sole 1
1:Pediatrics, Universidade Federal de Sao Paulo, Brazil
Mucopolysaccharidosis VI or Maroteaux-Lamy Syndrome (MPS VI) is a lysosomal storage disorder caused by deficiency of
arylsulfatase B. The enzyme replacement therapy (ERT) with galsulfase is so far the only specific treatment for MPS VI.
Infusion-related reactions (IRR) to ERT can occur and can be severe, precluding further ERT. However, the interruption
of ERT can accelerate the disease progression and precipitate earlier death. The aim of this study is to report similar IRR
to galsulfase in two Brazilian patients with MPS VI, and treatment restablishing after desensitization. Patient 1: male,
7y-old, began presenting symptoms in 44th infusion as dyspnea and itch without improvement using premedication such as
Poster Session
corticosteroids and antihistamines. Patient 2, female, 13y-old, began presenting hives unwieldy in 7th infusion. ERT were
stopped for four weeks and patients underwent skin tests (prick and intradermal). Skin prick test was performed using the
straight concentration of galsulfase and Intradermal tests with progressive dilutions. Skin tests were also performed in 10
healthy subjects and in a MPS VI patient without IRR, to rule out a skin irritant effect, since skin tests with galsulfase
have not been standardized. The two patients presented positive tests. This result infers IgE-mediated reactions. Therefore,
a dose specific rapid desensitization protocol was generated. Three solutions (each 250 mL of water with 5% dextrose -
1:100, 1:10 and 1:1 respectively) were delivered in 12 consecutive steps at increasing infusion rate. There were used various
pre medications to block different pathways allergy. We were the first group in the world to adapt desensitization protocol
for galsulfase desensitization and it has been shown to be safe and effective for both patients are receiving enzyme in the
recommended dose. Management of these reactions with desensitization can provide first line therapy and permit continued
ERT.
Mon(2)-P-309
The little things that matter: A qualitative study of the disease management experiences of caregivers
of children with inherited metabolic diseases
Beth K Potter 1 ，Shabnaz Siddiq 1 ，Brenda J Wilson 1 ，Ian D Graham 1 ，Monica Lamoureux 2 ，Sara D Khangura 1 ，
Kylie Tingley 1 ，Laure Tessier 2 ，Sarah Wafa 3 ，Natalia Yuskiv 4 ，Pranesh Chakraborty 2 ，Anne-Marie Laberge 5 ，
Chitra Prasad 6 ，John J Mitchell 3 ，Kathy N Speechley 6 ，Komudi Siriwardena 7 ，Yannis Trakadis 3 ，Rebecca Sparkes 8 ，
Alette Giezen 4 ，Jagdeep Walia 9 ，Robin Hayeems 10 ，with Shailly Jain, Alberta Children’s Hospital; Cheryl R. Green-
berg, University of Manitoba; and on behalf of the Canadian Inherited Metabolic Diseases Research Network
1:University of Ottawa, Canada、2:Children’s Hospital of Eastern Ontario、3:Montreal Children’s Hospital、4:BC Children’s Hospital、
5:CHU, Hopital Sainte-Justine、6:Western University、7:University of Alberta、8:Alberta Children’s Hospital、9:Queen’s University、10:The
Hospital for Sick Children
Objectives: We sought to understand the experiences of parents/caregivers of children with inherited metabolic diseases
(IMD), regarding the management of disease, its impact on child and family life, and interactions with the health care system.
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ICHG2016 954
Design and Methods: At four centres participating in the Canadian Inherited Metabolic Diseases Research Network, we
invited caregivers of children with an IMD to participate in a semi-structured telephone interview. Participants were selected
with the aim of achieving a diverse sample with respect to treatment centre, IMD, and child’s age. Interviews explored par-
ticipants’ experiences, emphasizing impacts of the disease and its treatment on the child and family and explicitly querying
perceptions of interactions with the health care system. Data were analyzed inductively to identify emerging themes.
Results: We completed 21 interviews with caregivers of children with 13 different IMDs. Participants described their adap-
tation to their child’s diagnosis: daily disease management protocols that were often complex were noted to have become
routine through the use of proactive coping strategies. Caregivers often expressed concerns about social challenges faced by
their children, particularly for those where dietary restrictions were part of treatment. Participants described mainly positive
interactions with their child’s most involved health care providers within the metabolic clinic. However, they frequently
reported stress resulting from interactions with the health care system outside of the speciality metabolic clinic, for example,
related to care received in the emergency department or with services from the pharmacy or blood laboratory.
Conclusions: As described by one participant, "it’s very, very small things that make a massive difference in overall patient
care".
Mon(2)-P-310
Altered pre-mRNA splicing due to novel intronic mutation c.1443+5G>A in the dihydropyrimidinase
(DPYS) gene
Poster Session
Yoko Nakajima 1 ，Judith Meijer 2 ，Chen Zhang 3 ，Xu Wang 4 ，Tetsuya Ito 1 ，Andre B.P. Van Kuilenburg 2
1:Pediatrics, Fujita Health University School of Medicine, Japan、2:Laboratory Genetic Metabolic Diseases, Academic Medical Center,
Amsterdam、3:Research and Development, MILS International, Kanazawa、4:Beijing Children Hospital, Beijing, China
Dihydropyrimidinase (DHP) deficiency is an autosomal recessive disease caused by mutations in the DPYS gene and patients
present with strongly elevated levels of dihydrouracil and dihydrothymine in urine, blood and cerebrospinal fluid. The analysis
of the effect of mutations in DPYS on pre-mRNA splicing is hampered by the fact that DHP is primarily expressed in liver and
kidney cells. We have used a minigene-based approach to analyze the effects of a presumptive pre-mRNA splicing mutation in
two newly identified Chinese pediatric patients with DHP deficiency. Mutation analysis of DPYS showed that both patients
were compound heterozygous for a novel intronic mutation c.1443+5G>A in intron 8 and a previously described missense
mutation c.1001A>G (p.Q334R) in exon 6. Wild type and the mutated minigene constructs, containing exon 7, exon 8 and
exon 9 of DPYS, yielded different splicing products after expression in HEK293 cells. The c.1443+5G>A mutation resulted
in altered pre-mRNA splicing of the DPYS minigene construct with full skipping of exon 8. Thus, the minigene analysis
suggests that the c.1443+5G>A mutation results in aberrant splicing of the pre-mRNA encoding DHP underlying the DHP
deficiency in two unrelated Chinese patients.
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Mon(2)-P-311
A novel, hybrid method of blue and clear native polyacrylamide gel electrophoresis (BCN-PAGE): a
minimally invasive method to detect electron transport chain abnormalities in cultured skin fibroblasts
in patients with mitochondrial disease
Christopher Newell 1 ，David Sinasac 2 ，Floyd Snyder 2 ，Stacey Hume 3 ，Rebecca Sparkes 2,4
，Aneal Khan 2,4
，
Iveta Sosova 5
1:Department of Medical Science, Cumming School of Medicine, University of Calgary, Calgary, Canada、2:Department of Medical Genetics,
Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada、3:Department of Medical Genetics, University of Alberta,
Edmonton, Alberta, Canada、4:Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada、
5:Departments of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
Mitochondrial disease affects 1:5000 people and can be caused by either nuclear or mitochondrial (mt) DNA mutations.
Approximately 20-30% of cases are due to mtDNA mutations. Muscle-extracted mtDNA provide the highest sensitivity
for mutation detection but is an invasive method and low-level deletions can accumulate simply with aging. Cultured skin
fibroblasts, collected from a less invasive skin biopsy, can be a potential source to detect defects in the mitochondrial electron
transport chain (ETC). A novel, hybrid method combining both blue and clear native polyacrylamide gel electrophoresis (BCN-
PAGE) was developed to perform in-gel activity stains on the mitochondrial ETC complexes in skin fibroblasts. The results
of skin BCN-PAGE were compared to commercial BN-PAGE or CN-PAGE assays performed on muscle in the same patient.
Four patients aged 46 to 65 years of age were seen in the Metabolic Clinic at Alberta Children’s Hospital and investigated
for mitochondrial disease. Muscle and skin biopsies were performed as part of standard-of-care diagnostic procedures. Muscle
BN-PAGE or CN-PAGE identified incomplete assembly of complex V in each patient. Long-range polymerase chain reaction
performed on muscle tissue successfully identified four unique mtDNA deletions spanning the ATP6 gene of complex V. To
Poster Session
distinguish between deletions that may be acquired with aging in muscle, skin fibroblasts were analyzed using the hybrid
BCN-PAGE method. In all 4 cases, the results confirmed the presence of the mtDNA deletion. Our results, showing the
presence of the same deletion in two different tissue types, suggest that the mtDNA mutations are more likely inherited than
de novo age-related accumulations. Potentially acquired somatically in early gametogenesis, these results show that skin
fibroblasts can be a less invasive source of ETC complex electrophoresis as a diagnostic test for mitochondrial disease due to
mtDNA mutations.
Mon(2)-P-312
Plasma cell-free mitochondrial DNA: A novel and non-invasive method to detect mutations in mito-
chondrial DNA
Christopher Newell 1 ，Stacey Hume 2 ，Steven C Greenway 3,4,5
，Aneal Khan 4,5,6
1:Department of Medical Science, Cumming School of Medicine, University of Calgary, Calgary, Canada、2:Department of Medical Genetics,
University of Alberta, Edmonton, Alberta, Canada、3:Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary,
Calgary, Alberta, Canada、4:Departments of Paediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada、
5:Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada、6:Department of Medical Genetics,
Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
Mitochondrial disease is a heterogeneous disease affecting 1 in 5000 people caused by either nuclear DNA or mitochondrial
DNA (mtDNA) mutations. Muscle biopsy is considered the gold standard for the detection of mtDNA mutations but is
invasive and can be difficult in small infants. The most common non-invasive method involves using peripheral blood DNA
extracted from bone marrow-derived leukocytes but has 2 major limitations: 1) it only represents one tissue source and 2)
negative selection of cells with mutant mtDNA load can yield false negative results.
During cellular apoptosis small 150-200 base pair fragments of mitochondrial and nuclear DNA are released from all cell types
and persist in the circulation as cell-free DNA (cfDNA). Due to the presence of cell-free mitochondrial DNA (cf-mtDNA) in
the blood, a plasma sample could provide the necessary DNA to make a diagnosis of mitochondrial disease non-invasively.

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ICHG2016 956
Furthermore, as cf-mtDNA represents all replicating cells, there is the potential to detect mtDNA mutations from any tissue
source.
To test this hypothesis, blood samples from patients with known mitochondrial disease have been collected and their cfDNA
isolated. To demonstrate the presence of the mitochondrial genome within these samples, we amplified custom PCR primers
that were specific to large overlapping fragments of the mitochondrial genome. Confirmation of the mitochondrial DNA was
made, demonstrating that the full mitochondrial genome is in fact present within cell-free DNA isolated samples.
Further work will involve sequencing the cfDNA isolates for mitochondrial DNA and to determine if the non-invasive cell-free
DNA collection yields the same diagnosis as sequencing from muscle or buccal DNA sources.
Mon(2)-P-313
Sulfated disaccharides improve the iduronate-2-sulfatase function in fibroblasts from patient with mu-
copolysaccharidosis type II
Hiroo Hoshina 1,2 ，Yohta Shimada 2 ，Takashi Higuchi 2 ，Hiroshi Kobayashi 1,2
，Yoshikatu Eto 1,3
，Hiroyuki Ida 1,2
，
Toya Ohashi 1,2
1:Department of Pediatirics, Jikei Univ Sch of Med, Japan、2:Div of Gene Thera, Res Cent for Med Sci, Jikei Univ Sch of Med、3:Adv Clin
Res Cent, Insti of Neur Dis
Mucopolysaccharidosis type II (MPS II) is an inherited metabolic lysosomal storage disorder that caused by a deficiency of
Poster Session
iduronate-2-sulfatase (IDS). In recent years, pharmacological chaperone (PC) therapy has attracted considerable concern as
potential treatment for lysosomal storage disorders such as Fabry disease and Gaucher disease. However, because candidate
chemical of PC for MPS II has not been found, PC therapy for this disease has not been developed yet. In this study,
we focused on the degradation products of heparin that is one of the substrates for IDS, and analyzed the utility of the
oligosaccharides as chemical chaperone for MPS II.
When sulfated disaccharides from heparin were incubated with recombinant human IDS (rhIDS), sulfate groups were cleaved
from a part of the oligosaccharides. Addition of sulfated disaccharides to rhIDS solution significantly prevented the thermal
degeneration of IDS. Sulfated disaccharides also increased the IDS activity in the fibroblasts from patient with MPS II.
Furthermore, sulfated disaccharides improve the accumulation of GAGs in patient fibroblasts.
These results suggest that disaccharides from heparin have a potential application for the PC therapy of MPS II.
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ICHG2016 957
Mon(2)-P-314
Expert recommendations for the laboratory diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2
disease): diagnostic algorithm and best practice guidelines for a timely diagnosis
Emanuela Izzo 1 ，Moeenaldeen AlSayed 2 ，Derek Burke 3 ，Jessica Cohen-Pfeffer 1 ，Jonathan D Cooper 4 ，
Lenka Dvorakova 5 ，Michael Fietz 6 ，Roberto Giugliani 7 ，Helena Jahnova 5 ，Zoltan Lukacs 8 ，Sara Mole 9 ，
Ines Noher de Halac 10 ，David Pearce 11 ，Angela Schulz 12 ，Nicola Specchio 13 ，Winnie Xin 14 ，Nicole Miller 1
1:Scientific Affairs, BioMarin Pharmaceuticals Inc, USA、2:Department of Medical Genetics, Alfaisal University and King Faisal Specialist
Hospital and Research Center, Riyadh, Saudi Arabia、3:Chemical Pathology, Camelia Botnar Laboratories, Great Ormond Street Hospital,
London, UK、4:Institute of Psychiatry, Psychology, Neuroscience, Kings College London, London, UK、5:Institute of Inherited Metabolic
Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic、
6:Department of Diagnostic Genomics, PathWest Laboratory Medicine WA, Nedlands, Australia、7:Servico de Genetica Medica HCPA,
Departamento de Genetica UFRGS, Porto Alegre, RS Brazil、8:Newborn screening and Metabolic Diagnostics unit, Hamburg University
Medical Center, Hamburg, Germany、9:Molecular Cell Biology, MRC Laboratory for Molecular Cell Biology, University College London,
London, UK、10:Universidad Nacional de Cordoba, Facultad de Ciencias Medicas, Cordoba, Argentina、11:Sanford Children Health
Research Center, Sioux Falls, USA、12:Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany、
13:Department of Neuroscience, Bambino Gesu; Children Hospital, Rome, Italy、14:Neurogenetics DNA Diagnostic Lab, Massachusetts
General Hospital, Harvard Medical School, Boston, USA
Neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of lysosomal storage disorders that include the rare autosomal
recessive neurodegenerative disorder CLN2 disease (CLN2). CLN2 is caused by mutations in the TPP1/CLN2 gene, resulting
in tripeptidyl peptidase-1 (TPP1) enzyme deficiency. Classic late-infantile CLN2 phenotype has a pediatric onset with initial
symptoms of language delay and seizures, followed by progressive dementia, motor and visual deterioration and early death.
Variant phenotypes of CLN2 occur more rarely. Diagnosis of CLN2 is based on laboratory testing following clinical suspicion;
however, delays in diagnosis are common due to low disease awareness, non-specific initial symptoms and limited diagnostic
testing access in some regions. With advent of new therapies, early CLN2 diagnosis is key to ensure optimal clinical care and
outcomes.
Poster Session
In May 2015, a panel of international experts met to recommend best laboratory practices for early diagnosis of CLN2.
When NCL is suspected due to the presence of suggestive clinical signs, TPP1 activity test should be the first diagnostic
test performed (along with PPT1 enzyme to exclude CLN1). However, since initial suspicion of CLN2 and NCLs is often
challenging, where available, the use of epilepsy gene panels for the investigation of unexplained seizures in childhood is
endorsed. These panels should include TPP1/CLN2 as well as genes for NCLs that lack diagnostic biochemical tests.
Diagnostic TPP1 enzyme test in leucocytes is well established and robust and in DBS is considered diagnostic if followed
by molecular confirmatory testing. Future methods to measure TPP1 activity via MS/MS may improve DBS-based TPP1
testing sensitivity allowing also future newborn screening. Experts recommend that to confirm specific clinical suspicion of
CLN2, the gold standard for laboratory diagnosis is demonstrating deficient TPP1 enzyme activity and/or detecting causative
mutations in each allele of TPP1/CLN2 gene.
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ICHG2016 958
Poster Session
Cancer Genetics 2
Tue., April 05, 2016 17:30-18:30 Event Hall (1F)
Tue(3)-P-1
Reducing genotoxicity emitted from diesel engines fueled with diesel/biodiesel/butanol blends
1,2 2,3 2,3
Yuan-Chung Lin ，Chia-Chi Wang ，Ying-Chi Lin ，Po-Ming Yang 1 ，Syu-Ruei Jhang 1 ，Li-Jung Lin 4
1:Institute of Environmental Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan、2:Ph.D. Program in Toxicology, College of
Pharmacy, Kaohsiung Medical University, Taiwan、3:School of Pharmacy, Kaohsiung Medical University, Taiwan、4:Department of Biomedical
Engineering, Oregon Health and Science University, USA
This study investigated the genotoxic effects of particulate matter (PM) emitted from diesel engine under steady-state con-
ditions. The potential mutagenicity and genotoxicity of PM10 generated from various blends on mammalian cells were
determined by conducting in vitro micronucleus and comet assays. CHO-K1 cells were treated with the PM10 extracts pre-
pared from B10W20 (10% butanol + 20% biodiesel + 70% diesel), B10W40, and D100. All samples induced the formation
of a micronucleus in the CHO-K1 cells at a concentration of 20 µg/mL. The mutagenicity of PM10 generated from B10W40
was lower than that of PM10 generated from B10W20 or D100. Evidence indicates that long-term exposure to diesel exhaust
substantially increases the risk of lung cancers. To further determine the genotoxic effects of biodiesel-blend-induced PM10 on
human lung cells, A549 cells were treated with 10 µg/mL of PM10 extracts, and the alkaline comet assay was then conducted
Poster Session
to detect DNA damage. The genotoxic effects of PM10 generated from B10W20 and B10W40 on A549 cells were significantly
lower than that of the diesel control sample. Collectively, the biodiesel-butanol-diesel blend is a potential alternative fuel for
reducing diesel-induced genotoxicity.
Tue(3)-P-2
Ultra-sensitive droplet digital PCR for detecting a low-prevalence somatic GNAQ mutation in Sturge-
Weber syndrome
1,2
Yuri Uchiyama ，Masakazu Miyajima 3 ，Masataka Taguri 4 ，Mitsuko Nakashima 1 ，Naomichi Matsumoto 1
1:Human Genetics, Yokohama City University Graduate School of Medicine, Japan、2:Medicine and Clinical Science, Gunma University
Graduate School of Medicine、3:Neurosurgery, Juntendo University Graduate School of Medicine、4:Biostatistics, Graduate school of Medicine,
Yokohama City University
Droplet digital PCR (ddPCR), a method for detecting DNA quantity, is useful for determining somatic mutation rates utilizing
TaqMan probes. In this study, the detection limit of copy numbers of genomic DNA by ddPCR was determined based on
Poisson distribution. Peptide nucleic acid (PNA), which strongly hybridizes to target lesions, can inhibit target amplification
by PCR. Therefore by combination of PCR with PNA and ddPCR (PNA-ddPCR), detection limit could be lowered. We
revisited a somatic GNAQ mutation (c.548G > A) in patients with Sturge-Weber syndrome (SWS) using ddPCR and PNA-
ddPCR. Importantly among three mutation-negative patients by previous next generation sequencing, two patients had the
GNAQ mutation with less than 1% of mutant allele frequency. This data clearly indicates that ultra-sensitive method should
be utilized in detecting the low-prevalence somatic GNAQ mutation in SWS.
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ICHG2016 959
Tue(3)-P-3
MiR-200a, miR-200b, and miR-429 Are Onco-miRs That Target PTEN Gene in Endometrioid Endome-
trial Carcinomas of The Uterus
Koichi Yoneyama 1 ，Osamu Ishibashi 2 ，Rieko Kawase 3 ，Akihito Yamamoto 3 ，Keisuke Kurose 3 ，Toshiyuki Takeshita 3
1:Obstetrics and Gynecology, Nippon Medical School Musashi Kosugi Hospital, Japan、2:Laboratory of Biological Macromolecules, Graduate
School of Life and Enviromental Sciences, Osaka Prefercture Unuversity、3:Obstetrics and Gynecology, Nippon Medical School Hospital
Endometrioid endometrial carcinoma (EEC) is a common malignancy of the female genital tract. However, no good biomarker
has been available so far to predict prognosis of this cancer. Recent studies have revealed that expression of some microRNAs
(miRNAs), which are called “onco-miRs”, is dysregulated in a variety of cancer tissues; thus they could be promising
prognostic biomarkers of cancer progression and/or metastasis. In this study, to search for onco-miRs and their possible targets
involved in the occurrence of EECs, we performed microarray-based integrative analyses of miRNA and mRNA expression in
specimens excised from EEC lesions and adjacent normal endometrial tissues. By integrated statistical analyses, we identified
miR-200a, miR-200b, and miR-429 as highly upregulated onco-miRs in EECs. Conversely, we found that expression of a
tumor-suppressor gene, PTEN, which was predicted to be an in silico to target of the three miRNAs using a miRNA-targeting
mRNA prediction algorithm, was downregulated in EECs. Furthermore, these miRNAs were experimentally validated to target
PTEN by luciferase assay and real-time PCR. These results suggest that occurrence of EEC is, possibly in part, mediated by
miRNA-medaited suppression of PTEN expression.
Tue(3)-P-4
Poster Session
Furin, a pro-protein convertase, is a novel molecular target for c-Myc driven ovarian cancers
Junko Minato 1 ，Masafumi Toyoshima 1 ，Masumi Ishibashi 1 ，Shogo Sigeta 1 ，Toshinori Usui 1 ，Kazuyuki Kitatani 1 ，
Nobuo Yaegashi 1
1:Tohoku University, Japan
[Objective] The proto-oncogene c-Myc regulates cell proliferation, differentiation and apoptosis, and its over-expression and
gene amplification are observed in many cancers including ovarian cancers. In fact, c-Myc gene amplification is reportedly
found in approximately 20% to 30% of ovarian cancers. Since c-Myc is an essential transcription factor which is also expressed
in normal tissues, it is difficult to make this molecule a therapeutic target. Focusing on c-Myc, Wwe aimed to searchhave
been searching for the therapeutic target gene which showsing synthetic lethal interaction with an aberrant c-Myc expres-
sion.[Method] We carried out a high-throughput functional siRNA screening utilizing a library of 7000 genes. Two ovarian cell
lines, TOV112D (high c-Myc) and CAOV3 (low c-Myc), were employed for screening, and their cell viabilities were assessed.
The primary screening identified 94 hits genes conferred differential lethality to high c-Myc cell versus low c-Myc cell line.
We conducted a database analysis and a network analysis for 94 hits genes and selected 31 genes for the secondary screen-
ing.[Results] We conducted validation assays using different sequences of siRNA for those 31 genes. The pairs of other high and
low c-Myc cell lines, IGROV and HFF-c-Myc (high c-Myc), DOV13 and HFF-pBabe (low c-Myc) were adopted and we chose
to focus on FURIN, a pro-protein convertase, based on validation assays and bioinformatics analysis.[Conclusion] Through
this large scaled functional screening, we have identified FURIN as a novel potential target which shows synthetic lethal
interaction with c-Myc overexpressing ovarian cancers. These results will also indicate rational combination of treatments
and biomarkers to aid therapeutic choices for molecularly defined patient populations.
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ICHG2016 960
Tue(3)-P-5
An Incidental Finding of Indolent T-PLL During a Routine Fertility Screen: A Case Study
1
Charmaine E Pollock
1:Cytogenetics, Sullivan Nicolaides Pathology, Australia
T-prolymphocytic leukaemia (T-PLL) is a rare malignancy with a rapidly progressive and aggressive clinical course and
a median survival of 7.5 months. It is usually associated with distinct morphological, immunophenotypical and complex
cytogenetic abnormalities with symptoms including hepatosplenomegaly and lymphadenopathy. However, T-PLL can behave
in an indolent manner for a variable time, with patients remaining otherwise asymptomatic. We report a case of T-PLL, with
the most complex subclone having the karyotype: 44,X, del(X)(q26), add(1)(q42), der(8)(p21) add(8)(q11.2), add(11)(p13),
add(12)(p11.2), add(14)(p11.2), inv(14)(q11.2q32),-16, der(17)t(16;17)(q11.2;p13),-20, add(20)(p13),+mar. This result was
found incidentally on peripheral blood chromosome studies when the asymptomatic patient was referred as part of a routine
fertility screen.
Tue(3)-P-6
Comprehensive genetic analysis of a pediatric pleomorphic myxoid liposarcoma reveals near-
haploidization and loss of the RB1 gene
Jakob P Hofvander 1 ，Vickie Y Jo 2 ，Iman Ghanei 3 ，David Gisselsson 1 ，Emma Martensson 1
1:Department of Clinical Genetics, Lund University, Sweden、2:Department of Pathology, Brigham and Womens Hospital、3:Department of
Poster Session
Orthopedics, Skane University Hospital
Aims: Pleomorphic myxoid liposarcoma (PML) is an exceptionally rare and poorly studied subtype of liposarcoma, typically
occurring in children and adolescents. The few previous genetic studies have shown that PML lacks the gene fusions and
amplifications that characterize myxoid liposarcoma, atypical lipomatous tumor, and dedifferentiated liposarcoma. To learn
more about its pathogenesis, we performed a comprehensive genetic analysis, including chromosome banding, fluorescence in
situ hybridization, single nucleotide polymorphism (SNP) array analysis, deep sequencing of the exome (WES) complemented
by targeted sequencing of hotspot regions of selected cancer-associated genes, and transcriptome sequencing (RNA-seq), of a
PML in a 10-year-old boy.
Methods and results: Banding analysis revealed a hyperdiploid/hypotriploid karyotype that at SNP array analysis could be
shown to derive from a near-haploid ancestral clone. Structural imbalances were few, but included homozygous loss of the
RB1 locus; no fusion transcripts were identified at RNA-seq, no somatic mutations were seen at gene panel analysis, and the
only mutation detected at WES that might be pathogenetically important involved KMT2D.
Conclusion: The results support the notion that PML is a distinct type of liposarcoma, associated with a spectrum of
somatic mutations that is different from that in other liposarcoma subtypes. The findings in the present case, combined with
previous data, suggest that PML develops through combinations of numerical chromosome aberrations, possibly initialized
by haploidization. The results also suggest that inactivation of RB1 is pathogenetically important.
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Tue(3)-P-7
RNA-seq analysis of lung adenocarcinomas reveals different gene expression profiles between smoking
and nonsmoking patients
Yafang Li 1 ，Xiangjun Xiao 1 ，Xuemei ji 1 ，Bin Liu 2 ，Christopher Amos 1
1:Dartmouth College, USA、2:MD Anderson Cancer Center
Introduction: Lung adenocarcinoma is caused by the combination of genetic and environmental effects, and smoking plays an
important role in the disease development. Exploring the gene expression profile and identifying genes that are shared or vary
between smokers and nonsmokers with lung adenocarcinoma will provide insights into the etiology of this complex cancer.
Methods: We obtained RNA-seq data from paired normal and tumor tissues from 34 nonsmoking and 34 smoking patients
with lung adenocarcinoma (GEO: GSE40419). R Bioconductor, edgeR, was adopted to conduct differential gene expression
analysis between paired normal and tumor tissues. A generalized linear model was applied to identify genes that were differ-
entially expressed in nonsmoker and smoker patients as well as genes that varied between these two groups.
Results: We identified 2273 genes that showed differential expression with FDR < 0.05 and logFC >1 in nonsmoker tumor
versus normal tissues; 3030 genes in smoking group; and 1967 genes were common in both groups. 68% and 70% of the identi-
fied genes were down regulated in nonsmoking and smoking groups, respectively. The top 20 significant genes including SPP1,
SPINK1, CYP24A1, etc., with largest fold change are identified in smoking and nonsmoking patients. We also identified 175
genes that were significantly different between nonsmoker and smoker patients.
Poster Session
Conclusion: Gene expression profile varied dramatically between smoker and nonsmoker patients with lung adenocarcinoma.
Smoking patients overall showed far more complicated disease mechanism and have more dysregulation in their gene expres-
sion profiles.
Impact: Our study reveals pathogenesis and epigenetics differences in smoking and nonsmoking patients with lung adeno-
carcinoma from transctiptome analysis. We provided a list of candidate genes for further study on disease prevention and
treatment in both smoking and nonsmoking patients with lung adenocarcinoma.
Tue(3)-P-8
Clinicopathological factors of breast cancer in women under 35 years: A retrospective statistical analysis
Masahiro Kitada 1 ，Nana Takahashi 1 ，Shyunsuke Yasuda 1 ，Kei Ishibashi 1 ，Satoshi Hayashi 1
1:Department of Breast Disease Center, Asahikawa Medical University, Japan
Background: The percentage of breast cancer patients who are young is high compared to that of young patients with other
cancers. Breast cancer in young women also recurs frequently, and the prognosis is poor in a substantial proportion of this
particular patient population. Treatment planning requires consideration of issues such as fertility, early menopause, and
hereditary predisposition. To that end, we investigated the characteristics of breast cancer in young women treated at our
institution. Material and Methods: Early-onset breast cancer was defined as occurring in women under 35 years of age. Of
2,271 patients who underwent surgery for breast cancer during the period from January 2000 to October 2014, 51 young
women (2.24%) were included in this study. The clinicopathological factors of these patients were compared to breast cancer
patients aged 35 years or older; these included tumor size, presence or absence of lymph node metastasis, nuclear grade,
vascular invasion, presence or absence of hormone receptor, expression of human epidermal growth factor receptor type 2, and
10-year disease-free and overall survival rates. Result: Incidences of 4 or more metastatic lymph nodes, grade III cases, and
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triple negative cases were significantly more frequent in young patients than in older patients (p = 0.002, 0.025, and 0.0174,
respectively). There was no significant difference in the rate of breast-conserving surgery between the two age groups. The
10-year disease-free survival rate was 54.8% in young patients and 87.4% in older patients (p = 0.001); the 10-year overall
survival rates in these patients were 80.2% and 93.2%, respectively (p = 0.03). Conclusions: The prognosis of breast cancer
was poorer in patients under 35 years of age than in those aged 35 years or older. Improving the prognosis requires drug
therapy planning with a better understanding of the details of the underlying pathological conditions, including the use of
genetic analysis.
Tue(3)-P-9
A competing endogenous RNA (ceRNA) network regulates KRAS gene expression in human colorectal
cancer cells
Marian Abigaile N Manongdo 1 ，John Paul T Rigor 1 ，Liezel U Tamon 1 ，Joshua Reginald P Malapit 1 ，
Robert Lorenz C Chua 1 ，Jose Paulo E Lorenzo 1 ，Reynaldo L Garcia 1
KRAS sits upstream of the Raf-MEK-ERK and the PI3 kinase-AKT cellular pathways. Its constitutively activating mutants
are known to be oncogenic. Recently, an interplay among RNA species, including protein-coding and non-coding RNAs,
which share miRNA response elements (MREs), has been described. Termed as competing endogenous RNAs (ceRNAs),
these transcripts co-regulate each other by competing for shared miRNAs, and have implications in cancer. We posit that
the oncogene ONECUT2, tumor suppressor gene ZNF148, and pseudogene KRAS1P, which share MREs with KRAS, can act
Poster Session
as ceRNAs of KRAS. To assess the potential ceRNA interactions among them, the 3’UTR of each gene was co-transfected
with its cognate miRNA in HCT 116. Dual-luciferase assays revealed the downregulation of KRAS and ONECUT2 by
hsa-miR-181a-5p and hsa-miR-15a-3p, KRAS and ZNF148 by hsa-miR-365a, and KRAS and KRAS1P by hsa-miR-143 and
hsa-miR-206. Overexpressing these miRNAs in HCT 116 altered the endogenous expression levels of their putative gene targets
as measured through semi-quantitative RT-PCR. These results show the regulation of KRAS and its potential ceRNAs by the
same miRNAs, providing a basis for the proposed ceRNA network. To explore the possibility of ceRNA crosstalk among these
genes, the 3’UTR of each gene was overexpressed in HCT 116. Semi-qRT-PCR showed the upregulation of the endogenous
KRAS in KRAS1P, but not in ONECUT2 and ZNF148 overexpression. In turn, KRAS overexpression resulted to differential
regulation of endogenous expression of its candidate ceRNAs. Furthermore, preliminary Western blot analyses provided
information on KRAS regulation at the protein level. These findings hint at the possible cross-regulation between KRAS and
its ceRNAs by competing for shared miRNAs endogenous in HCT 116. Understanding this novel miRNA-dependent crosstalk
may further our knowledge on gene regulatory networks and disease pathology, opening new avenues for the development of
therapeutics.
Tue(3)-P-10
Enhancing SHP-1 and PRG2 expression by 5-Azacytidine may inhibit STAT3 activation and confer
sensitivity in Lestaurtinib (CEP-701) resistant FLT3 -ITD positive Acute Myeloid Leukemia
Muhammad Farid Johan 1 ，Hamid AN Al-Jamal 1 ，Siti Asmaa Mat Jusoh 1 ，Shaharum Shamsuddin 2
1:Department of Haematology, Universiti Sains Malaysia, Malaysia、2:School of Health Sciences, Universiti Sains Malaysia
Tumor-suppressor genes (TSG) are inactivated by methylation in several cancers including acute myeloid leukemia (AML).
PRG2 gene functions as TSG and maybe methylated in leukemic and pancreatic cells. Transcriptional silencing of SHP-1
plays a critical role in the development and progression of cancers through STAT3 activation. 5-Azacytidine (5-Aza) is a

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DNA methyltransferase inhibitor that causes DNA demethylation resulting in re-expression of silenced SHP-1 . CEP-701
is a multitargeted tyrosine kinase inhibitor (TKI) that potently inhibits FLT3 tyrosine kinase and induces hematological
remission in AML patients. However, majority of AML patients in developed resistance to CEP-701. Therefore, this study
was aimed to assess the effect of re-expression of SHP-1 on sensitivity to CEP-701 in AML.
Resistant FLT3 -ITD cell line (MV4-11R) was developed by overexposure of MV4-11 to CEP-701 and treated with 5-Aza.
Apoptosis and cytotoxicity of CEP-701 were determined using Annexin V and MTS assays. Gene expression was performed
by quantitative real-time PCR. STATs activity was examined by Western blot and methylation profiling by pyrosequencing.
Repeated measure ANOVA and Kruskal Wallis tests were used for statistical analysis.
The cytotoxic dose of CEP-701 on MV4-11R was significantly higher than MV4-11 and MV4-11R+5-Aza (p=0.004). MV4-
11R showed significant higher viability and lower apoptosis compared to MV4-11 (p<0.001). Expression of SHP-1 and
PRG2 was 7 and 56 folds higher in MV4-11R+5-Aza compared to MV4-11 (p=0.011) and MV4-11R (p=0.002). STAT3 was
activated in MV4-11R but silenced in MV4-11R+5-Aza. Methylation of SHP-1 and PRG2 was significantly decreased in
MV4-11R+5-Aza.
The restoration of SHP-1 and PRG2 expression and STAT3 inactivation by DNA methyltransferase inhibitor may induce
sensitivity towards CEP-701 and other TKI. Thus, SHP-1 and PRG2 provide suitable candidates for mechanisms underlying
the development of CEP-701 resistant in AML with FLT3 -ITD positive.
Poster Session
Tue(3)-P-11
Correlation between MGMT promoter methylation and hMSH2 mRNA expression in primary frontal
high grade anaplastic glioma (HGAG)
Jeru Manoj Manuel 1 ，Chetan Ghati K 1 ，Narasinga Rao K V L 2 ，Venkatesh H N 1
1:Human Genetics, National Institute of Mental Health and Neurosciences (NIMHANS), India、2:Neurosurgery, National Institute of Mental
Health and Neurosciences (NIMHANS)
Background & Aim: HGAG [WHO 2007-grade III] are highly infiltrating CNS tumors with poor prognosis (PFS) and overall
survival (OS). Epigenetic silencing of direct DNA repair gene MGMT by hypermethylation of the 5′-CpG islands of promoter
region leads to accumulation of O6-MeG:T and O6-MeG:C mispairs. During physiological state, MutS α mismatch repair
(MMR) protein coded by hMSH2 and hMSH6 has to be recruited to recognize the damage. This process plays a key role in
gliomagenesis as well as treatment response. We explored the probable correlation between MGMT methylation and hMSH2
expression, their effect on PFS and OS.
Methods: Post surgery excised primary frontal lobe HGAG tumors, pre-operative blood from 40 patients and non-tumor brain
tissue from 8 non-glioma patients (control) were collected in RNAlater. Nucleic acids were extracted from tissues having >95%
tumor cells. Promoter methylation status of MGMT was detected by quantitative MS-PCR and mRNA expression of hMSH2
was performed by TaqMan relative quatification using comparative Ct method.
Results: MGMT CpG island promoter region methylation was observed in 29/40 (72.5%), mean percentage of methylation
being 13.35±5.38. MGMT methylation, patient age <40years, gross total resection and post-surgery RT+CT therapy were
found to be useful predictive markers of PFS and OS (p<0.05). hMSH2 was significantly up-regulated with median fold
change of 2.74 relative to non-glioma tissue (p=0.006) and has inverse correlation with OS (ρ =-0.292, p=0.06). Association
between the percentage of MGMT methylation and expression of hMSH2 was inverse (ρ =- 0.112, p=0.493), indicating
dysregulation of these two repair mechanisms.
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Conclusion: We hypothesize that, this aberrant correlation between these two genes could lead to accumulation of mutations,
thereby increasing replication errors and genomic instability, therefore may be an early event for gliomagenesis.
Keywords: HGAG,DNA repair, Methylation, MGMT, MMR, hMSH2
Tue(3)-P-12
Cytotoxic effects of Palladium (II) Complex on Prostate Cancer Cells
Hale Samli 1 ，Murat Samli 2 ，Nazlihan Aztopal 1 ，Buse Vatansever 1 ，Ozlem Sigva 1 ，Deniz Dincel 1 ，Cumhur Gunduz 3
1:Department of Genetics, Uludag University, Turkey、2:Department of Urology, Acibadem University、3:Department of Medical Biology,
Ege University
Prostate cancer is among the most common cancers in male reproductive system. The drugs derived from palladium were
showed to be effective in cancer therapy and the palladium complexes caused cell death by means of apoptosis. In our
study, cytotoxic/apoptotic effects of Palladium(II) complex (Pd(II)),[PdCl(terpy)](sac)·2H2 O(terpy=2,2’:6’,2”-terpyridine
and sac=saccharinate anion), which was synthesized by Yılmaz et al, in PC-3, DU-145, VCaP, PNT1A cell lines were
investigated. Pd(II) complex was dissolved in culture media with different molar dilutions (0,1-100µM) and treatment of
cell lines with these dilutions were done in 24, 48 and 72 hour periods. The IC50 values, detected with SRB/MTT viability
test, showed that Pd(II) complex suppressed the growth of cells, depending on exposure time and molar concentration of
the complex. IC50 results of the cell lines were given as follows respectively for 24, 48 and 72 hours; 77.38, 19.99, <1.56 in
Poster Session
PC-3 cell line; 81.58, 4.14, <1,56 in DU-145 cell line; 81.95, 24.01, 18.49 in VCaP cell line and >100, 19.36, 1.56 in PNT1A
cell line. Hoechst33342 and Annexin-V-FITC fluorescence method were used to determine the mode of cell death. Not only
the presence of pyknotic nuclei and nuclear fragmentation that was typically observed in apoptosis process, but also both
early apoptotic cells (Annexin-V-FITC+/PI-) and late apoptotic cells (Annexin-V-FITC+/PI+) were demonstrated. Also
effect of Pd(II) complex on miRNA expression profile was investigated and used to explain the differences of expression of
miRNAs among the groups. Considering the potential cytotoxic and apoptotic effects of Pd(II) complex on prostate cancer
cells, we believe that this compound is a promising anti-cancer agent. It is planned to carry out genomic studies to clarify
the mechanism of action of these compounds. Note: This study is supported by Scientific Research Project Unit of Uludag
University, project number OUAP(V)-2013/3.
Tue(3)-P-13
Detection of p53 gene polymorphisms in patients with Hepatocellular Carcinoma in India
Subramaniam Mohana Devi 1 ，Vellingiri Balachandar 2 ，Keshavarao Sasikala 1
1:Human Molecular Genetics Laboratory, Department of Zoology, Bharathiar University, India、2:Department of Human Genetics and
Molecular Biology, Bharathiar University, India
Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Polymorphism in p53
gene was associated with increased risk of early-onset HCC. However the status of this mutations in South Indian HCC had
not been studied, we aim to analyze these polymorphisms in South Indian population.
Methods: In the present study 92 HCC patients and 92 control subjects were analyzed for known polymorphisms in the p53
gene.
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Results: In the Arg194Trp polymorphism of p53 gene, we found 17.19% with Arg399Trp (heterozygous variant) genotype
and 1.1% with 399Trp (homozygous variant) in comparison to controls who exhibited 85.12% with wild type genotype. This
polymorphic incidence revealed significant association with advanced stages of the HCC and also well differentiated tumor.
Conclusions: Thus the results of our study provide the genetic variations of p53 which may contribute to the susceptibility
to HCC in South India. The results suggest that, these genes could play a significant role in HCC and the combined effect of
these variants may interact to increase the susceptibility to HCC.
Key words: Gene polymorphism, p53 gene, Hepatocellular carcinoma.
Tue(3)-P-14
High Mutation Detection Rate and Novel Mutations Identified in Major and Minor- Risk Cancer Genes
by Applying Multigene Panels in Hereditary Cancer Clinic
Poster Session
Guy Rosner 1,2 ，Sivan Aharon Caspi 1,2
，Merav Ben-Yehoyada 1,2
，Dani Bercovich 3,4
，Zamir Halpern 1,2
，
Erwin Santo 1,2 ，Revital Kariv 1,2
1:Gastroenterology, Tel-Aviv Sourasky Medical Center, Israel、2:Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel、3:Human
Molecular Genetics and Pharmacogenetics, Migal - Galilee Bio-Technology Center, Kiryat Shmona, Israel、4:Tel-Hai Academic College,
Kiryat Shmona, Israel
Background: Multigene panels testing are being used more frequently in hereditary cancer cases. However, results obtained
are sometimes challenging due to detection of variants of unknown significance.
Methods: Results of the first twenty cases of multigene panels testing in a cancer genetic clinic at a tertiary referral academic
center are reported. Tests have been performed in three different genetic labs analyzing a panel of up to 100 cancer-related
genes.
Results: Cohort included 12 females and 8 males with cancers of: colorectal (7), small bowel (3), gastric cancer (3), pancreatic
(2), ovarian (1), thyroid (1) and 3 subjects with advanced adenomas. All had family history of cancer in at least one first
degree relative. Five subjects had >1 cancer. Pathogenic mutations were detected in 16 out of 20 subjects tested, and 10
subjects had >1 mutated gene. Ten subjects had mutation in major-risk cancer genes: POLD1, PMS2, MSH2, FANCI,
STK11, CDH1 and RET. Six subjects had mutation in minor-risk cancer genes: ATM, BARD1, RAD50, CHEK2, GALNT12,
BLM, MET, NBN, AR, PTCH1, MSR1 and KDS. Ten out of the 16 had >1 pathogenic mutated gene detected: 7 subjects
had major and minor-risk cancer genes mutated and 3 subjects and two minor-risk cancer genes mutated. Novel mutations
were detected in three major-risk cancer genes (POLD1, MSH2, FANCI).
Conclusions: High rate of pathogenic mutations detection is achieved by selection of subjects with both personal and family
history of cancer. Combined mutations in minor-risk cancer genes seem to play a substantial role in cancer susceptibility.
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Tue(3)-P-15
The importance of multidisciplinary approach to HBOC patients ~ the experience in a general hospital ~
Daisuke Takabatake 1 ，Kazuyuki Oishi 1
1:Breast Oncology, Kochi Health Science Center, Japan
Background:With increasing social recognition of HBOC, taking family history or and genetic counseling for breast cancer
patients are becoming routine practice. Nonetheless, there are still not many institutions which provide multidisciplinary
approach to HBOC patients. In this study, a patient with HBOC who underwent collaboration treatment, is reported.
Case presentation:31y.o woman with rapidly progressive breast tumor consulted our hospital. She was diagnosed with
T2N0M0 triple negative breast cancer. Although neoadjuvant chemotherapy was performed, tumor was remained progressive.
Mastectomy was then performed .There were plural number of breast and pancreas cancer patients within second degrees of
relatives. Therefore HBOC was suspected, and the result of genetic test identified BRCA1 mutation. Although Platinum
and Taxane containing chemotherapy was postoperatively administrated, mediastinal lymphadenopathy was emerged after
7months later. In spite of chemotherapy containing Bevacizumab or Eribulin performed, liver metastasis emerged, as well
as mediastinal lymphnode metastasis progressed. At present, collaboration with other institution, she is participating with
Phase3 randomized controlled study of PARP inhibitor for BRCA mutation carrier. Discussion:With the recognition of
HBOC among medical stuff and patients, multidisciplinary approach to HBOC patients containing genetic counseling is
now becoming essential even in the general hospitals. Moreover, it seems that large number of patients have missed their
diagnosis. In future, management of these increasing patients may overload among cancer specialized hospital. In order to
provide better treatment option, it is thought that collaboration treatment with various institutions, the accumulation of
Poster Session
database and creating clinical evidence are very important.
Tue(3)-P-16
Hedgehog signaling and genetic diseases
Yoshiro Nakano 1 ，Kazuma Noguchi 2 ，Hideaki Chiyo 3,4
，Ritsuko Pooh 3 ，Hiromitsu Kishimoto 2 ，
Tomoko Hashimoto-Tamaoki 1,4
1:Genetics, Hyogo College of Medicine, Japan、2:Oral Maxillofacial Surgery, Hyogo College of Medicine、3:CRIFM Clinical Research
Institute of Fetal Medicine、4:Clinical Genetics, Hyogo College of Medicine
Hedgehog signaling plays pivotal roles in animal development and the control of adult organ homeostasis by regulating
stem cell differentiation and maintenance. Mutations in hedgehog signaling components induce Gorlin, Pallister-Hall, Greig
cephalopolysyndactyly syndromes or holoprosencephaly, characterized by specific morphological anomalies.
Keratocystic odontogenic tumor (KCOT) is the most frequent benign neoplasm observed in Gorlin syndrome patients. How-
ever, these Gorlin syndrome-associated KCOT lesions differ from sporadic KCOT, and the mechanisms underlying their
development are poorly understood. In order to understand the nature of KCOTs, we established two KCOT cell lines,
KCOT2 (sporadic type) and NS11 (inherited type), and found that both cell lines exhibited parakeratosis and nodule forma-
tion by increasing calcium concentration. We also conducted 3D culture using the 3D Life Hydrogel system. Both cell lines
formed spheroid structures in the presence of RGD-peptides and low calcium conditions. Cells adopted a cyst-like structure
under high calcium conditions, with nuclei of cells at the center being small and condensed. Stem cell related genes were
expressed in these cell lines. The character and possible origin of KCOTs will be discussed.
Greig cephalopolysyndactyly syndrome (GCPS) is a rare autosomal dominant disorder characterized by abnormalities in
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limb (such as preaxial polydactyly) and craniofacial (such as hypertelorism, a broad forehead, and macrocephaly) develop-
ment. The zinc-finger transcriptional factor gene GLI3 has been identified as responsible for GCPS. We identified a missense
R625W mutation in a Japanese family clinically diagnosed with GCPS. This mutation corresponded to the conserved residue
in zinc-finger domain 5 and was also reported in a Belgian family. The Japanese family showed the novel symptom of dental
hypoplasia. Possible roles of GLI3 will be discussed.
Tue(3)-P-17
Genomic copy number changes in CML patients with the Philadelphia chromosome (Ph+): an update
Yuan Ren 1,2 ，Young Mi Kim 1 ，Xianfu Wang 1 ，Xianglan Lu 1 ，Yue Gu 1 ，Mingran Sun 1 ，Yunpeng Shi 1 ，
Jianqin Zhang 1 ，Shibo Li 1 ，Lijun Zhang 2
1:Pediatrics, The university of Oklahoma Health Science Center, China、2:Hematology, The First Affiliated Hospital of China Medical
University
In our previous pilot study of 19 chronic myeloid leukemia (CML) patients with sole Philadelphia chromosome using whole
genomic oligonucleotide array CGH analysis, we demonstrated that subtle genomic copy changes were relatively common.
To expand our study, we have collected additional t(9;22) positive 47 CML patients without secondary chromosomal changes
by G-banded chromosomal analysis and performed array CGH to identify subtle acquired genomic copy number changes
(CNCs). Twelve of the 47 patients had somatic segmental CNCs, including both deletions and duplications. Some of patients
had one or two CNCs, and others had 8 - 10 CNCs. Five out of 12 patients had a deletion of 9q33.3-34.12 region with
molecular size ranging from 106 Kb to 4.1 Mb. Two of these five cases had a deletion of the ASS gene. Other CNCs were
Poster Session
randomly distributed on different autosomes. Our findings further confirmed that CNCs were common in CML patients with
sole Philadelphia chromosome and these CNCs were randomly distributed in autosomes, except 9q33.3-q34.12 region, which
was detected in 5 out of 12 CML patients.
Tue(3)-P-18
Exploring clinicians’ attitudes about using aspirin for risk reduction in people with Lynch Syndrome with
no personal diagnosis of colorectal cancer
Yanni Chen 1,3 ，Bettina Meiser 2 ，Rajneesh Tim 2 ，Michelle Peate 4 ，Judy Kirk 5 ，Robyn Ward 4 ，Annabel Goodwin 6 ，
Finlay Macrae 4 ，Janet Hiller 7 ，Alison Trainer 8 ，Gillian Mitchell 9
1:School of Medicine, University of Sydney, Singapore、2:University of New South Wales、3:National Cancer Centre Singapore、4:University of
Melbourne、5:Westmead Millennium Institute、6:Concord Cancer Centre、7:Swinburne University of Technology、8:Peter MacCallum Cancer
Centre、9:British Columbia Cancer Agency
Background: Recent research has shown that aspirin reduces the risk of cancers associated with Lynch syndrome. However,
uncertainty exists around the optimal dosage, treatment duration and whether the benefits of aspirin as a risk-reducing
medication (RRM) outweigh the adverse risks. Little is known about clinicians’ attitudes, current practice and perceived
barriers to recommending aspirin as a RRM.
Aim: To explore the attitudes of Australian clinicians who discuss risk management options with patients with Lynch syndrome
towards using aspirin as a RRM.
Materials and methods: Clinicians were invited to complete an online survey. Topics included their clinical experience with
Lynch Syndrome, views and practice of recommending aspirin as a RRM, and knowledge about clinical risk management
guidelines for Lynch syndrome. Comparison of attitudes was made between three professional groups.
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Results: 144 respondents were included in the analysis: 41 genetics professionals, 44 gastroenterologists and 59 colorectal
surgeons. Most clinicians considered aspirin to be an effective RRM and were confident about discussing it; however, majority
considered that further research was needed around dose and toxicity. Many clinicians also felt that there was a need for patient
educational materials and clinical guidelines. There were significant differences between professional groups’ perception of
aspirin’s efficacy, confidence about their knowledge of literature and attitudes about aspirin’s prescription. The reasons are
unclear but could stem from the lack of clear clinical guidelines resulting in varying practices.
Conclusion: Development of clinical guidelines and patient information materials is needed and will likely improve consistency
in patient care and facilitate communication.
Tue(3)-P-19
Genetic and epigenetic alterations of netrin-1 receptors in gastric cancer
Takeshi Nagasaka 1 ，Yoshiko Mori 1,2
，Kunitoshi Shigeyasu 1 ，Shinichi Toyooka 2,3
，Toshiyoshi Fujiwara 1
1:Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan、2:Clinical
Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences、3:General Thoracic Surgery,
Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Background: The gene expressions of netrin-1 dependence receptors, DCC and UNC5C, are frequently downregulated in
many cancers. We hypothesized that downregulation of DCC and UNC5C has an important growth regulatory function in
gastric tumorigenesis.
Poster Session
Results: In the present study, a series of genetic and epigenetic analyses for DCC and UNC5C were performed in a Japanese
cohort of 98 sporadic gastric cancers and corresponding normal gastric mucosa specimens. Loss of heterozygosity (LOH)
analyses and microsatellite instability (MSI) analysis was applied to determine chromosomal instability (CIN) and MSI
phenotypes, respectively. More than 5% methylation in the DCC and UNC5C promoters were found in 45% (44/98) and
32% (31/98) gastric cancers, respectively, and in 9% (9/105) and 5% (5/105) normal gastric mucosa, respectively. Overall,
70% (58 of 83 informative cases) and 51% (40 of 79 informative cases) of gastric cancers harbored either LOH or aberrant
methylation in the DCC and UNC5C genes, respectively. In total, 77% (51 of 66 informative cases) of gastric cancers showed
cumulative defects in these two dependence receptors and were significantly associated with chromosomal instability. Both
DCC and UNC5C were inactivated in 97% of CIN-positive gastric cancers and in 55% of CIN-negative gastric cancers.
Conclusions: Defect in netrin receptors is a common feature in gastric cancers. DCC alterations are apparent in the early
stages, and UNC5C alterations escalate with the progression of the disease, suggesting that the cumulative alterations of
netrin-1 receptors was a late event in gastric cancer progression and emphasizing the importance of this growth regulatory
pathway in gastric carcinogenesis.
Tue(3)-P-20
Functional characterization of RNAi-mediated regulation of the tumor suppressor gene Neurofibromin 2
(NF2 )
Krizelle Mae M. Alcantara 1 ，Pixie Dale S. Alvarez 1 ，Reynaldo L. Garcia 1
1:Disease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular Biology and Biotechnology, Philippines
The neurofibromin 2 (NF2 ) gene expresses the protein Merlin, a member of the protein 4.1 family that functions in actin-
plasma membrane linkage. Germline loss-of-function mutations in Merlin underlie the cancer predisposition syndrome neurofi-
bromatosis type 2 (NF2), characterized by benign tumors of the nervous system. Merlin also functions as a tumor suppressor
by regulating contact-dependent inhibition of cell proliferation. Somatic mutations in NF2 have been documented in cancer,
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but its direct role in disease progression has not been clearly elucidated despite its established involvement in cancer signalling
pathways such as the MAPK, PI3K/Akt, and Rac/PAK pathways. In silico analysis posits the 3’UTR of NF2 mRNA as a
strong potential target of hsa-miR-7 and hsa-miR-92a, microRNAs (miRNAs) that are also aberrantly expressed in cancer.
Luciferase assays performed using a reporter construct containing a partial sequence of NF2 -3’UTR suggest that the gene is
negatively regulated by endogenous miRNAs via its 3’UTR in normal (NIH3T3) and cancer (HCT116) cells. To demonstrate
that NF2 gene expression is directly regulated by endogenous miRNAs and to compare and contrast its functional sequelae
versus direct NF2 knockdown via siRNA, parallel experiments in NIH3T3 and HCT116 cells was performed. Sequence-specific
RNA interference was done by transfection of an NF2 short hairpin RNA (shRNA) construct in cultured cells. The effect of
overexpression of the candidate miRNAs and of siRNA-directed NF2 knockdown on endogenous mRNA and protein levels of
NF2, as well as of other tumorigenic biomarkers such as E-cadherin and vimentin was analyzed by semi-quantitative RT-PCR
and Western blotting, respectively. Phenotypic effects of RNAi-mediated regulation of NF2 on cell morphology, cell adhe-
sion, migration potential, apoptosis, and cellular senescence were also characterized through live-cell fluorescence imaging,
time-lapse microscopy, and cell-based assays.
Tue(3)-P-21
CpG island methylator phenotype is associated with the efficacy of chemotherapy for metastatic colorectal
cancer
Hideki Shimodaira 1,2 ，Xiaofei Zhang 1 ，Keigo Komine 1,2
，Shin Takahashi 1,2
，Masanobu Takahashi 1,2
，
Chikashi Ishioka 1,2
1:Department of Medical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Japan、2:Department of Clinical
Poster Session
Oncology, Tohoku University Hospital
Background: The CpG island methylator phenotype (CIMP) with multiple promoter methylated loci has been widely ob-
served in human colorectal cancer (CRC). CIMP status tightly associated with special clinicopathological and molecular
characteristics has been referred to a potential epigenetic predictive marker or biomarker. However, the effect of standard
chemotherapy and anti- epidermal growth factor receptor (EGFR) antibody therapy based on CIMP status is not fully known.
Methods: In 125 metastatic colorectal cancer (mCRC) patients, we analyzed the relationship between clinical outcome of
mCRC therapy, CIMP status detected by methylation-specific PCR (MSP), and genetic status in 5 EGFR related genes
(KRAS, BRAF, PIK3CA, NRAS, and AKT1 ) detected by direct sequencing.
Results: CIMP-positive status was significantly associated with proximal tumor location, lung and peritoneum metastasis (all
P values < 0.05). The progression free survival of the sequential first- and second-line therapy with irinotecan-based regimen
followed by FOLFOX (median = 15.2 months) was superior to the reverse sequence (median = 6.6 months) in CIMP-positive
tumors (P = 0.043). Furthermore, CIMP-positive tumors showed higher frequency of mutation in any of 5 EGFR related
genes than CIMP-negative tumors.
Conclusion: Sequential irinotecan-based regimen followed by FOLFOX is favorable in CIMP-positive tumors than the reverse
sequence.
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Tue(3)-P-22
BRCA1/2 Mutation Dependent Effect on Survival of Advanced Stage Ovarian Cancer
1,2
Ramunas Janavicius ，Vilius Rudaitis 3 ，Dovile Janulynaite 1 ，Laimonas Griskevicius 1
1:Hematology, Oncology and Transfusion Medicine Center, Vilnius University Santariskiu Hospital Clinics, Lithuania、2:State Research
Innovative Medicine Center、3:Oncogynecology Unit, Vilnius university Santariskiu Hospital Clinics
The aim of this study was to evaluate BRCA1 and BRCA2 mutation impact on prognosis of advanced-stage (III-IV) ovarian
cancer patients after standard treatment.
Methods: A total of 521 patients with advanced-stage (primary) epithelial ovarian cancer (EOC) were identified from a clinical
database during year 1998-2014 and enrolled in a prospective, single-center study. All cases with available germline DNA were
screened for BRCA1 and BRCA2 gene mutations using combination of methods (HRM, Sanger/Next Generation Sequencing,
MLPA). Progression-free survival (PFS) and overall survival (OS) was assessed between BRCA1/2 mutation carriers and
BRCA1/2 wild-type patients. Various clinical risk factors for PFS and OS were assessed by univariate and multivariate Cox
regression analysis with stepwise model selection process.
Results: For selected patients, an older age (HR, 1.032; 95% confidence interval [CI], 1.010-1.055; P=0.0047), nonoptimal
cytoreduction (HR, 3.170; 95% CI, 1.986-5.060; P=0.0001), and BRCA1/2 wild type (HR, 1.625 [1.003-2.632]; P=0.0486)
were significantly associated with shorter PFS in multivariate Cox regression analysis. Nonoptimal cytoreduction (HR, 2.684;
95% CI, 1.264-5.701; P=0.0102) and BRCA1/2 wild type (HR = 1,612 (95% CI 1,16 - 2,23; P=0.0002) were statistically
significant risk factors for shorter OS. The overall 5-year survival for the hereditary case patients was better than that of the
Poster Session
nonhereditary patients, however after that time no survival advantage was apparent. Unexpectantly, carriers of Baltic founder
BRCA1 c.4035delA mutation had median OS significanlty shorter than carriers of other BRCA1/2 mutations (p = 0,0139)
(HR 2,716; 95% CI of 1,225 - 6,023).
Conclusions: Advanced ovarian cancer patients harboring BRCA1/2 mutation treated with debulking surgery and platinum-
based adjuvant chemotherapy have a longer PFS and OS not longer than 5-years. Our date suggests that BRCA1 c.4035delA
mutation may be associated with poor survival.
Tue(3)-P-23
Withdrawn

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Tue(3)-P-24
A case with pachydermoperiostosis with gastrointestinal malignancy
Mariko Kakudo 1 ，Hisatomo Ikehara 2 ，Hironori Niizeki 3 ，Kazuhiko Nakabayashi 4 ，Chika Sato 1 ，Hiroko Mimura 1 ，
Tadayuki Oshima 2 ，Jiro Watari 2 ，Seiichi Hirota 5 ，Hiroto Miwa 2 ，Tomoko Hashimoto-Tamaoki 1,6
1:Department of Clinical Genetics, Hyogo College of Medicine, Japan、2:Division of Gastroenterology, Department of Internal Medicine,
Hyogo College of Medicine, Nishinomiya, Japan、3:Department of Dermatology, National Center for Child Health and Development, Tokyo,
Japan、4:Department of Reproductive Biology, National Research Institute for Child Health and、5:Department of Surgical Pathology, Hyogo
College of Medicine, Nishinomiya, Japan、6:Department of Genetics, Hyogo College of Medicine, Nishinomiya, Japan
The case of pachydermoperiostosis, a rare autosomal recessive disease (OMIM #614441), was 51-year old male with no family
history of skin and bone hypertrophy nor cancers with young onset. He developed mild anemia at 10. He underwent plastic
surgery for hypertrophic skin at 20 and 43. At his regular check-ups at 50, multiple high-uptake regions in the abdomen and
tumors in paraspinal regions were detected by PET-CT. He was referred to our hospital, and a tumor was detected in the
pylorus with no malignant cells. Paraspinal tumors were determined as extramedullary-hematopoiesis regions. Other region
of stomach and duodenum were free from tumors. Nine months later, a duodenal adenocarcinoma was found with multiple
metastasis in the liver and lung. He received chemotherapy, but deceased five months later due to multiple metastasis and
cachexia. While on hospital, he was found to have clubbed fingers, pachydermia, and periostosis, and was clinically diagnosed
as pachydermoperiostosis.
Genetic testing showed a frameshift mutation in the SLCO2A1 gene with homozygous 1-bp insertion in exon 7 (c.940+1G>A).
This causes truncation in the fourth intracellular domain, downstream of the sixth transmembranous domain, resulting in loss
of six transmenbranous domains and a large extracellular domain in the C-terminal region. This mutation has been reported
Poster Session
in Japan, China and Korea, suggesting that it is common in East Asia. No similar phenotypes were observed in any of his
four sister (42-51 yo) although one shows slightly broad fingertips.
Castori et al. (2005) reported that beside of skin and bone lesions, this disease is accompanied by gastrointestinal (GI)
disease (11%, ulcers and Crohn disease), growth retardation (4.8%) and myelofibrosis (4.8%). However, there have been no
reports on the association with malignancy, showing that our case may be the first with malignancy. The relationship between
pachydermoperiostosis and GI malignancy requires further investigation.
Tue(3)-P-25
Integrated analysis of whole-exome and transcriptome sequencing in signet ring cell carcinoma of col-
orectum
1,2
Jae-Yong Nam ，Je-Gun Joung 2 ，Hye Kyung Hong 4 ，Joon Seol Bae 2 ，Yong Beom Cho 4 ，Woong-Yang Park 2,3
1:Department of Health Sciences and Technology, SAIHST, Seoul, Korea, South、2:Samsung Genome Institute, Seoul, Republic of Korea、
3:Department of Molecular Cell Biology, Sungkyunkwan University of Medicine, Seoul, Republic of Korea、4:Department of Surgery, Samsung
Medical Center, Seoul, Republic of Korea
Signet ring cell carcinoma (SRCC) is a rare subtype (less than 1%) of colorectal cancer, in which abundant intracytoplasmic
mucin displaces the nucleus to the periphery. SRCC of colorectal has been reported that it is usually associated with advanced
stage and a poor prognosis. However, comprehensive molecular analysis of SRCC has not been fully yet. Here, we analyzed the
whole-exome and transcriptome of matched normal and tumor of five SRCCs. Mutation profile of whole-exome sequencing
was almost similar with non-hypermutated colorectal adenocarcinoma except for low APC mutation rate. Interestingly,
recurrent somatic copy number amplifications of two genes were found in all the five SRCCs of which gene expressions were
also significantly elevated in tumor samples. Functional enrichment analysis revealed that cell-cell adhesion, tight junction
and extracellular matrix-related genes were significantly differentially expressed in tumor samples. Also, cadherin and integrin
signaling pathways were significantly altered in SRCC tumors. In conclusion, somatic changes associated with dysregulation
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of cell-cell adhesion and the over production of mucin may trigger the subsequent EMT-like process in SRCCs.
Tue(3)-P-27
Revealing hidden complexity of the cancer genome with the aid of RNA sequencing
Sarah Moore 1 ，Wendy Parker 2 ，Jeffrey M Suttle 1 ，Mario Nicola 1 ，Joel Geoghegan 2 ，Chris Fraser 3 ，Heather Tapp 4 ，
Andreas W Schreiber 2,5,6 ，Hamish S Scott 1,6,7,8,9
1:Genetics and Molecular Pathology, SA Pathology, Australia、2:Australian Cancer Research Foundation Cancer Genomics Facility、3:Lady
Cilento Children’s Hospital, Brisbane、4:Haematology Directorate, SA Pathology、5:School of Biological Sciences, University of Adelaide、
6:Centre for Cancer Biology、7:School of Medicine, University of Adelaide、8:School of Biological Sciences, University of Adelaide、9:School
of Pharmacy and Medical Science, University of Adelaide
Identifying the presence of fusion genes in acute leukaemia can be of critical importance to patient management since they
provide diagnostic and prognostic information. Targeted therapies are becoming available for some of these fusions, which
often yield better response rates than conventional chemotherapy alone. There are limitations to many of daignostic pathology
methods and cytogeneticists have long understood that, while a positive result is truly positive, a negative result may simply
imply that the abnormality is not detectable by the particular method in use. We have explored the use of RNA sequencing
(RNAseq) to identify unexpected or novel gene fusions in the clinical setting of acute leukaemia (ALL). In two cases fusion
genes were identified for which specific interphase FISH analysis, with break apart probes, had yielded a negative result.
Both were paediatric patients who were diagnosed with acute lymphoblastic leukaemia. One showed a normal karyotype and
a normal FISH result with our standard probe set (CRLF2, CEP4,10&17, BCR-ABL1, ETV6-RUNX1, KMT2A, TCF3).
RNAseq revealed a TCF3-HLF fusion gene. The second patient showed a complex abnormal karyotype and an unexpected
Poster Session
FISH result of three ABL1 signals. SNP-microarray demonstrated normal copy number of the ABL1 gene and so further
investigations were carried out to identify the fusion gene partner. ETV6 was considered to be the most likely candidate, but
a break apart probe yielded a negative FISH result. RNAseq demonstrated a ETV6-ABL1 gene fusion. TCF3-HLF positive
ALL may respond to the BCL2 inhibitor ABT-199 and ETV6-ABL1 positive disease is usually responsive to tyrosine kinase
inhibition. Therefore RNA sequencing identified fusion genes of potential therapeutic action in these patients.
We suggest that RNA sequencing is an appropriate technology to use in the investigation of patients with suspicious or
complex cytogenetic results or those who have failed initial induction therapy.
Tue(3)-P-28
Targeted semiconductor sequencing of 409 cancer-related genes for somatic mutations and copy number
variations in multiple myeloma
Hisayo Fukushima 1,2 ，Hiroshi Ikeda 3 ，Kazuya Ishiguro 3 ，Tetsuyuki Igarashi 3 ，Yuka Aoki 3 ，Tadao Ishida 3 ，
Miyuki Tamura 2 ，Yasushi Sasaki 2 ，Akihiro Sakurai 1 ，Takashi Tokino 2
1:Departmant of medical genetics, Sapporo medical University, Japan、2:Department of Medical Genome Sciences, Research Institute
for Frontier Medicine, Sapporo Medical University、3:Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo
Medical University
<Background>Although introduction of novel therapies such as bortezomib, thalidomide, and lenalidomide have remarkably
improved the treatments for multiple myeloma (MM), the prognosis of patients with relapse and refractory MM remains poor,
and novel therapies are needed.
<Methods>DNA was extracted from magnetic bead-enriched bone marrow CD138-positive malignant plasma cells from 8
cases of MM, and CD138-negative cells were used as matched non-tumor cells. Forty nanograms of DNA were used for
multiplex PCR amplification with an Ion Ampliseq Comprehensive Cancer Panel that offers targeted coverage of all exons
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in 409 tumor suppressor genes and oncogenes frequently cited and frequently mutated in human cancers. (covered regions:
95.4% of total). We sequenced 15,992 regions which obtained more than 1.5 megabases of target sequence.
<Results>Each sample underwent on average 7.5 million sequencing reads after quality filtering. The mean read depths were
486x, and >96% of targeted bases were represented by at least 20 reads. The average number of non-synonymous mutations
detected per patient was 4.8 (range 0-11). We also detected copy number variations in which segments of the genome can
be duplicated or deleted from sequencing data. We found several genetic alterations that may have been associated with the
poor prognosis and poor response to chemotherapy of MM patients. Pathway assessment has shown that somatic aberrations
within MM genomes are mainly involved in several important pathways, including cell cycle regulation, RTK-MAPK-PI3K
and NF-kB.
<Conclusion>We performed targeted next-generation sequencing for rapid (2 days), standardized, and cost-effective gene
analysis of malignant plasma cells from patients with MM. This study demonstrates the utility of using this approach to
efficiently identify genetic alterations in human cancer.
Tue(3)-P-29
Variants of uncertain significance in BRCA: Experience from the Japanese HBOC consortium trial survey
Junko Yotsumoto 1,2 ，Shiro Yokoyama 2 ，Mayuko Inuzuka 2 ，Reiko Yoshida 2 ，Chie Watanabe 2,3
，Masami Arai 4 ，
Seigo Nakamura 2 ，The registration committee of The Japanese HBOC consortium
Poster Session
1:Natural Science Division, Faculty of Core Reserch, Ochanomizu University, Japan、2:Showa University,Breast Center、3:Sophia University,
Faculty of Human Sciences、4:Cancer Institute Hospital, Division of Clinical Genetic Oncology
Background: Patients who receive a genetic test that identifies a variant of uncertain significance (VUS) do not know if their
mutation is benign or deleterious and associated with hereditary cancer risk. This lack of clarity is emotionally difficult and
confusing for patients who are making medical decisions. Recent studies indicate VUS results are challenging for clinicians
and patients, often resulting in negative patient outcomes. In Japan, current practices regarding BRCA VUS results are
unknown. To explore Japanese clinical situation related to disclosing BRCA VUS results, we are reporting the result of the
Japanese HBOC consortium trial survey.
Methods:This study utilizes a data of the Japanese HBOC consortium trial survey of Japanese breast and/or ovarian cancer
patients and their family, from 2009 to Aug 2015. We reviewed data from 827 patients who had underwent BRCA1/2 testing,
and the incidence of VUS among Japanese patients, and their options, after having received BRCA VUS results.
Results: The proportion of pathogenic BRCA1/2 mutations was 20%, 10.6% for BRCA1 (88/827), 9.2% for BRCA2 (76/827),
and VUS rate was 6.6%(in 54 patients). VUS rate was high and similar to the frequency of VUS reported by Myriad for Asian
patients (7.8%,2012).Ten patients (38%) selected mastectomy, 14 patients (54%) selected breast-conserving surgery, among
26 VUS patients who had received BRCA1/2 testing prior to surgery. And four patients selected RRM and/or RRSO.
Conclusion: Japanese VUS rate is high, referring western database like Myriad. Most VUS may not be associated with a high
risk of cancer, but later some of VUS will turn to be a deleterious mutation. To improve this situation, there is a real need
for national database of HBOC. A misinterpreted VUS has the potential to lead to mismanagement of the patient and their
family. We need to recognize the more importance of adequate genetic counseling and the communication for VUS results.
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Tue(3)-P-30
Reduction of physiologic endogenous DNA double strand breaks advances genomic instability in chrono-
logical aging yeast
Maturada Patchsung 1 ，Jirapan Thongsroy 2 ，Monnat Pongpanich 3 ，Apiwat Mutirangura 4,5
1:Biomedical Sciences, Chulalongkorn University, Thailand、2:Schoolof Medicine, Walailak University, Nakhon Si Thammarat, Thailand、
3:Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Bangkok, Thailand、4:Department of
Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand、5:Center for Excellence in Molecular Genetics of Cancer and
Human Diseases, Chulalongkorn University, Bangkok, Thailand
Genomic instability is one of the hallmark characters of aging. However, how senescence genome of non-dividing cell become
unstable is yet to be explored. Previously, we discovered a new type of Endogenous DNA Double Strand Breaks (EDSBs),
namely replication independent EDSBs (RIND-EDSBs). Unlike commonly known pathologic DSBs, such as replication
dependent EDSBs or radiation induced EDSBs, RIND-EDSBs may possess physiologic function. The physiologic RIND-
EDSBs present ubiquitously in cells, independently from DNA replication, are not associated with γ H2AX, and are localized
within heterochromatin. In human, DNA sequences around physiologic EDSBs are hypermethylated. In yeast, the EDSBs
are localized non-randomly and occur after the sequence “ACGT”. In this study, we show that physiologic-EDSBs may
help to prevent genome’s physical stress and decrease in physiologic-EDSBs promotes genomic instability of chronological
aging Saccharomyces cerevisiae. First, we found reduction of physiologic-EDSBs, accumulation of mutations and decrease
viability in chronological aging yeast. Induction of global DSB repair process by HO endonuclease reduced physiologic-EDSBs.
Interestingly, the reduced physiologic-EDSBs cells increased pathologic-EDSBs, accumulated more mutation and reduced
cellular viability. We hypothesized that the reduction of physiologic EDSBs in turn increases DNA tension and consequently
causes genomic instability. Our experiment may be the first to explain how genomic instability occurs in chronological aging
Poster Session
cells. Further understanding how to maintain physiologic EDSB level in aging cells will be a way to prevent senescence of
non-dividing cells.
Tue(3)-P-31
ß -catenin controls the expression profiles of KCNQ1OT1/LIT1 long noncoding RNA
Hiroyuki Kugoh 1,2 ，Takahito Ohira 1 ，Daigo Inaoka 1 ，Miki Kataoka 1 ，Hideyuki Tanabe 3 ，Mitsuo Oshimura 2 ，
Yuji Nakayama 4 ，Naohiro Sunamura 1
1:Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori
University, Japan、2:Chromosome Engineering Research Center, Tottori University, Japan、3:Department of Evolutionary Studies of
Biosystems Science, School of Advanced Sciences, SOKENDAI (The Graduate University for Advanced Studies), Japan、4:Division of
Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Japan
The KCNQ1OT1/LIT1 long noncoding RNA, itself the product of an imprinted gene, is involved in cis-limited silencing
within an imprinted cluster on human chromosome 11p15.5. We have identified KCNQ1OT1/LIT1 using the library of hu-
man monochromosomal hybrids Furthermore, we showed that targeted deletion of the maternally methylated CpG island
at the human KCNQ1OT1/LIT1 locus causes loss of silencing of the paternal allele of several genes that are normally re-
stricted to maternal expression, including KCNQ1/KvLQT1, KCNQ1DN and CDKN1C/p57KIP2 . These data suggest that
KCNQ1OT1/LIT1 RNA is required for silencing of these genes, and may contribute in cis as an imprinting center (IC) to
bring about coordinate imprinting at the 11p15.5 region. In addition, aberration of its transcription was observed with a high
frequency in colorectal cancer. However, the underlying mechanisms of the transcriptional regulation and the functional role
of KCNQ1OT1/LIT1 in colorectal cancer remain unknown.
An aberrant Wnt signaling pathway is implicated in the multistep processes for colorectal cancer development. In partic-
ular, nuclear accumulation of the key oncogenic factor β-catenin indicates activation of its target genes, which facilitate
cancer promoting functions such as cell proliferation. Transient overexpression of β-catenin induced a significant increase in
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KCNQ1OT1/LIT1 transcription level. Interestingly, KCNQ1OT1/LIT1 long noncoding RNA-coated territory was contracted
by downregulation of β-catenin. Moreover, β-catenin can promote KCNQ1OT1 transcription through direct binding to the
KCNQ1OT1/LIT1 promoter. Thus, our results indicate that β-catenin signaling may contribute to development of colorectal
cancer by functioning as novel long noncoding RNA regulatory. This result provides important information for elucidation of
the regulatory mechanisms of KCNQ1OT1 lncRNA in colorectal cancer cells.
Tue(3)-P-32
KRAS mutations and intratumoral heterogeneity in rectal adenomas and early carcinomas
Natalia Pospekhova 1 ，Yuri Shelygin 1 ，Olga Maynovskaya 1 ，Evgeny Rybakov 1 ，Stanislav Chernyshov 1 ，
Sergey Frolov 1 ，Vitaly Shubin 1
1:State Scientific Centre of Coloproctology, Russia
The aim of the study was to determine the frequency of somatic mutations in KRAS, quantification of gene mutant copies
and detection of intratumoral heterogeneity. Materials for the study were 74 rectal tumors obtained by transanal endoscopic
microsurgery. Specimens were undergone routine pathological examination. Detection of mutations was performed by capillary
sequencing - exons 2-4 and digital droplet PCR (ddPCR) on QX200 instrument - mutation p.G12D, p.G12V, p.G13D.
Pathological investigation of 74 specimens demonstrated 36 villous or tubulo-villous rectal adenomas (AD), 14 carcinomas
in situ (Tis) and 24 carcinomas pT1-2 (AC). Capillary sequencing detected 57 mutations in 54 tumors (73%). Two different
Poster Session
mutations were detected in 3 samples. The number of 3 most frequent mutations, i.e. p.G12D, p.G12V, p.G13D was 45 in
42 samples. All these 45 mutations were confirmed by ddPCR. In addition, 5 mutations with low amount of mutant allele
(0.66-2.8%) were discovered. As a result, the number of mutant tumors was 56 (75.7%), tumors with multiple mutations - 5
(6.8%).
The number of mutant allele varied in the range of 32-90.6%. Six tumors showed the mutant allele prevalence (59.6-90.6%).
Amplification of the mutant gene seems to be in these cases.
Most frequently mutations were detected in AD - 86.1% (31/36) comparing to Tis - 78.6% (11/14). For AC mutation rate was
54.2% (13/24) (p=0.006). Difference in the frequency was observed for p.G12V: 38.7% in the AD, 31.5% in Tis and 24.4% in
AC.
High frequency of somatic mutations in the KRAS gene was detected in rectal adenomas and early carcinomas. In addition,
mutations were found in almost each of adenoma. Some rectal adenomas and carcinomas have intratumoral heterogeneity
and consist of at least two different subclones. Amplification of KRAS mutant copy takes place in some tumors. ddPCR
method is more sensitive comparing to capillary sequencing and can detect the somatic mutations existing in a small amount
of tumor cells.
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Tue(3)-P-33
Action of the hereditary breast cancer ovarian cancer syndrome practice cooperation in Kochi
Fuminori Aki 1,2 ，Sueyoshi Ito 1 ，Takeki Sugimoto 2 ，Syuin Taro 2 ，Mari Tashiro 2 ，Koki Hirano 3 ，
Daisuke Takabatake 2,4 ，Kazuyuki Oisi 2,4 ，Ryuhei Nagai 2,4 ，Yusei Nakata 2,4 ，Ichiro Yamasaki 2 ，Nobuo Ikenoue 2 ，
Chiaki Izumiya 2 ，Kenji Matsushita 2 ，Toru Kubo 2
1:Ito Breast Surgery Clinic, Japan、2:Hospital Heredity Practice Part Attached to the Kochi University School of Medicine、3:Kochi Red
Cross Hospital Obstetrics and Gynecology Department、4:Kochi Medical Center
It is said that 5-10% of all breast cancer are genetic and approximately 70,000 people have breast cancer in Japan in one year
and the 3,500-7,000 race requires genetic counseling for one year.In Japan, the genetic screening of the BRCA1/2 mutation
is not performed by a medical service under health insurance now.We cannot examine BRCA1/2 mutation in the gene by
the common practice.Also, the screening and preventive therapy of the person with BRCA1/2 mutation in the gene positive
non-onset are not provided by a medical service under health insurance.It is necessary to make the system that can access
the heredity practice of heredity breast cancer ovarian cancer (HBOC) at each place to decrease death for HBOC.We report
actions of the HBOC practice cooperation in Kochi of a population of 75,000 people.We conduct a pickup in the breast
surgery of each medical institution.We perform monthly conference and do information sharing in hospital clinic heredity
practice part attached to the Kochi University School of Medicine.We treat the screening of the patient with breast cancer
and the family member of the HBOC family with multiple medical institutions and share information.We screened it based on
NCCN guidelines and the patients with the foreign medical examination were covered in October, 2015 from April, 2014.322
people (24.9%) became screening-positive in a hospital attached to the Kochi University School of Medicine.61 people (28.0%)
became screening-positive at Ito breast surgery clinic.Around hospital heredity practice part attached to the Kochi University
School of Medicine, we are discussing that we make the systems that the screening and risk reduction treatment can perform
Poster Session
for non-onset mutation carrier in breast surgery and the obstetrics and gynecology department of each medical institution.
Tue(3)-P-34
Genomic and epigenetic changes underlying retinoblastoma tumors
Poh-San Lai 1 ，Swati Tomar 1 ，Raman Sethi 1 ，Gangadhara Sundar 2
1:Paediatrics, National University of Singapore, Singapore、2:Ophthalmology, National University of Singapore
Retinoblastoma (RB) is a malignant intraocular tumor affecting children. Biallelic mutations in RB1 gene initiate tumor
development. However, it has been suggested that tumor progression in RB may be driven by other cumulative genetic
alterations. In this study, 40 RB tumors were investigated for epigenetic changes as well as copy number (CNVs) and structural
variations (SVs) in MGMT , TNF α, KIF13A, MYCN , BCOR, FNDC3A, OTX2 , NOTCH1 , DEK and E2F3 genes. These
genes belong to key pathways including DNA repair, pRB and p53 signalling, transcriptional regulation, cell cycle regulation,
cell-cell interaction, etc. Recurrent focal gains and losses have also been reported in genomic regions harbouring some of these
genes. Hypermethylation at MGMT locus was seen in 25% (9/36) retinoblastoma tumours, of which 55% showed increased
gene dosage for both KIF13A and TNF α. Increased copy numbers of TNFa and KIF13a were observed in 48.6% (18/37)
and 40% (15/37) tumors, respectively. A significant association existed between increased dosage of RBKIN and TNF α
(p = 0.001). We observed a 7.7kb frameshift deletion in BCOR gene spanning 3 exons, while large intronic variations were
seen in NOTCH1 , MGMT , KIF13A. Recurrent focal gains in OTX2 gene, which encodes bicoid subfamily of homeodomain-
containing transcription factors required for retinal photoreceptor development, and losses in FNDC3A, which is involved
in poly(A) RNA binding, have previously been observed in 3.2% and 5.3% of RB tumours respectively. The mechanisms
that enable retinoblastoma cells to acquire the additional hallmarks of cancer still remain unknown. It is speculated that
overexpression of TNF α and KIF13A as a result of increased copy number, may play a potentially supportive role in the
multistep process of tumorigenesis and cancer progression. This study contributes towards overall knowledge of tumorigenesis
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in retinoblastoma by confirming the involvement of molecular defects in genes additional to RB1 .
Tue(3)-P-35
Identification of driver gene mutations and fusion events in patients with Sezary Syndrome
Aparna Prasad 1,2,3 ，Raquel Rabionet 1,2,3 ，Anna Puiggros 4 ，Luis Zapata 1,2,3 ，Carme Melero 4 ，Anna Puig 1,2,3
，
Yaris Sarria Trujillo 1,2,3 ，Blanca Espinet 4 ，Fernando Gallardo 5 ，Ramon Pujol 5 ，Xavier Estivill 1,2,3
1:Centre for Genomic Regulation, Spain、2:Universitat Pompeu Fabra (UPF), Barcelona, Spain、3:CIBER in Epidemiology and Public
Health (CIBERESP), Barcelona, Spain、4:Laboratory of Molecular Cytogenetics, Pathology Service, Hospital del Mar, Barcelona, Spain、
5:Dermatology Service Hospital del Mar, Barcelona, Spain
Sezary syndrome (SS) is a leukemic form of cutaneous T-cell lymphoma (CTCL) with an aggressive clinical course. It is
characterized by erythroderma, lymphadenopathy and high number of clonal circulating neoplastic T-cells in the peripheral
blood. The genetic etiology of the disease is poorly understood with chromosomal abnormalities and mutations in some genes
being involved in the disease. The goal of our study is to understand the genetic basis of the disease by looking for driver
gene mutations and fusion genes in a matched tumor and normal pair of 17 SS cases. We have undertaken a whole-exome,
RNA and small RNA sequencing approach. We have discovered novel genes that could be involved in the pathogenesis of SS.
Some of the genes that are affected by somatic point mutations include ITPR1 , ITPR2, DSC1 , RIPK2, IL6, and RAG2 with
some of them mutated in more than one patient. We have observed several somatic copy number variations that were shared
between patients including deletions and duplications of large segments of chromosome 17. Genes with potential function
in T-cell receptor signaling pathway and tumorigenesis were observed to be disrupted in SS patients, e.g. CBLB, RASA2
Poster Session
and RAMP3 . Furthermore, we have discovered several fusion events. Of particular interest are the ones involving RASA2,
BCR, FASN and SGMS1 genes due to their function as well as relevance in a variety of human cancer types. Our work has
potential implications for the development of novel potential therapeutic approaches for this aggressive disease.
Tue(3)-P-36
Early development of rare tumors in individuals with congenital malformation syndrome
Mari Minatogawa 1 ，Fuminori Iwasaki 2 ，Kunio Fukuda 2 ，Chihiro Hatano 1 ，Takayuki Yokoi 1 ，Yumi Enomoto 1 ，
Kazumi Ida 1 ，Yoshinori Tsurusaki 1 ，Noriaki Harada 1 ，Toshiyuki Saitou 1 ，Junichi Nagai 1 ，Hiroaki Goto 2 ，
Kenji Kurosawa 1
1:Medical Genetics, Kanagawa Children’s Medical Hospital, Japan、2:Hemato-Oncology and Regenerative Medicine, Kanagawa Children’s
Medical Center
Background: The risk of tumorigenesis in patients with congenital malformation syndromes is higher than that of the normal
population. Based on the previous literatures, each malformation syndrome is liable to get the specific cancers in the specific
sites at some specific ages. Major examples are as follows: Leukemia in children with Down syndrome, embryonal tumors in
children with the overgrowth syndromes like Sympson-Golabi-Behmel syndrome (SGBS), Beckwith-Wiedemann syndrome,
Sotos syndrome, and Perlman syndrome, lympho-hematological tumors in adolescence with Sotos syndrome. Nevertheless,
we encounter the unexpected tumors associated with malformation syndromes during a long term follow up of patients with
congenital anomalies at our children medical hospital. Case Report: One of the case we describe is a male with clinical and
molecular diagnosis of SGBS during infancy. At the age of 7 years, acute lymphoblastic leukemia was detected at the annual
medical checkup. In addition, we report on Kabuki syndrome and Smith-Magenis syndrome with tumors which have not been
reported till today. Conclusion: We reported on several cases of unexpected tumors in children with malformation syndromes.
SGBS is caused by the germline mutations in the GPC3 , in which somatic loss of function mutations have detected in the
various tumor tissues. While KMT2D (MLL2 ) is one of the responsible gene of the Kabuki syndrome, its rearrangements
are observed in various types of pediatric and adult leukemia. These indicate that not only somatic mutations but germ
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line mutations may contribute to developing tumors. Also, observation of atypical oncogenesis in patients with congenital
anomalies might be as a hint of finding new functions of the genes.
Tue(3)-P-37
The Role of SLURP-1 in melanoma promoting microenvironment
1,3
Pei-Jung Lin ，Ting Kuang Yeh 2 ，Wei-Shiung Yang 1 ，Shiou-Hwa Jee 3,4
1:National Taiwan University College of Medicine, Graduate Institute of Clinical Medicine, Taiwan、2:Science Education Center, National
Taiwan Normal University、3:National Taiwan University Hospital, Department of Dermatology、4:Cathay General Hospital, Department
of Dermatology
Our previous works have demonstrated that patients with Mal de Meleda (MDM), a rare autosomal recessive form of
palmoplantar keratoderma caused by lymphocyte antigen6/urokinase-type plasminogen activator receptor related protein-1
(SLURP-1) G86R mutation, are prone to develop cutaneous melanoma. The comparing human peripheral blood mononuclear
cells (PBMCs) revealed that loss-of-function SLURP-1 mutation also caused impaired T-cell activation under anti-CD3/anti-
CD28 stimulation in MDM patients.
Based on these findings, we hypothesize that MDM provides an inflammatory microenvironment facilitating melanoma de-
velopment, possibly through an immunosuppressive microenvironment that inhibit T cell activation.
In our studying, the cancer stem cell markers Oct4 and Nanog expressed by analyzing mRNA of PBMCs in 3 of 3 MDM
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patients. The 11 melanoma non-MDM patients of PBMCs and FFPE sections, 3 MDM-ALM PBMCs and FFPE sections
and 24 MDM family members successfully completed targeted next generation sequencing (NGS). In the 14 melanoma cohort
consisted of 9 men and 5 women. For arcal lentiginous melanoma (ALM) subtype, there were 6/11 (54.54%) non-MDM and
3/3 (100%) MDM patients. Comparing the two ALM groups (non-MDM and MDM), the percentage of patients with tumor
thinkness > 4 mm and lymph node metastasis in ALM were higher in MDM-ALM (66.67%) than in non-MDM patients
(18.18%).The TP53, KIT and HRAS heterozygous mutations were detected in PBMCs and FFPE sections of MDM-ALM
and melanoma patients by NGS. Furthermore, the KIT gene variant calls rate was higher in MDM-ALM (47.87%).
The data revealed that mutation of the SLURP-1 plays a role in melanoma carcinogenesis and the function of SLURP-1
in melanoma-associated microenvironments.The KIT gene might be the driver associated with melanoma development from
MDM melanoma. There may be used to the development of novel treatments for melanoma.
Tue(3)-P-38
SNPs in MEG3 lncRNA could alter its tumor suppressive capacity
Martin Daniel C Qui 1 ，Andrea S Estuart 1 ，Reynaldo L Garcia 1
Maternally expressed 3 (MEG3) is the first lncRNA to be classified as a tumor suppressor, and is downregulated in many
human cancers and cancer cell lines characterized to date. As a tumor suppressor, it must maintain and preserve its structure
to carry out a consistent function across populations. Despite this, in silico analysis has displayed numerous MEG3 SNP
variants that are predicted to drastically alter its structure, potentially affecting its stability and role in oncosuppression. We
have characterized 8 MEG3 SNP variants, which exhibit primary or secondary structure changes that may alter (1) post-
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transcriptional processing via miRNA-binding sites, (2) functional domains, or (3) overall folding. To show that SNP variants
may alter MEG3 stability, we looked into its potential regulation by miRNA, which has not been explored prior to this study.
Using a luciferase reporter as an analogue for expression, co-transfection with miRNAs predicted to bind MEG3 are shown to
target MEG3 for degradation. On the other hand, a SNP (MEG3n.850C>T) that alters the secondary structure encompassing
predicted miRNA-binding sites permits post-transcriptional silencing of MEG3. We further investigated the other SNPs
generated by site-directed mutagenesis by cloning them into pTARGET ™ for overexpression studies in HCT116. Here, we
also provide preliminary data on the effect of SNPs on MEG3’s tumor suppressive function through cell proliferation, scratch
wound, and other assays. With this, it seems that MEG3 SNPs have a strong potential for use as a novel prognostication
marker.
Tue(3)-P-39
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Tue(3)-P-40
Poster Session
Preliminary Investigations on the Putative PIK3CA-ZNF148 ceRNA Network
Alvin B. Bello 1 ，Reynaldo L. Garcia 1 ，Disease Molecular Biology and Epigenetics Laboratory
The PIK3CA gene encodes a catalytic subunit of PI3-kinase which lies upstream of the AKT-mTOR cell growth and survival
pathway. Mutations in or dysregulation of this gene may lead to many types of cancer including breast, colorectal, and liver
cancers. Recently, the role of microRNAs in PIK3CA regulation was demonstrated with miR-375 able to inhibit colorectal
cancer cell growth by binding to the 3’ untranslated region of PIK3CA. Here we hypothesize that genes sharing microRNA
response elements (MREs) with PIK3CA may regulate its expression and thus lead to cancer progression, similar to other
cancer-implicated competitive endogeous RNAs (ceRNAs). By in silico analysis, we identified ZNF148, a tumor suppressor
gene, as a likely ceRNA of PIK3CA, which may act as a molecular decoy able to sequester shared miRNAs and upregulate
the expression of PIK3CA. We cloned the 3’UTR of both genes downstream of a luciferase reporter in the vector pmirGLO
and show that both may be subject to endogenous miRNA regulation. We also identified a putative miRNA, miR-506, and
cloned it in the miRNA expression vector pmRZsGreen. Cotransfection of miR-506 with target constructs and luciferase
assays showed that it can negatively regulate both genes. Semi-quantitative and real-time PCR showed a significant decrease
in the levels of endogenous PIK3CA and ZNF148 upon transfection of miR-506. To elucidate the mechanism of the putative
PIK3CA-ZNF148 ceRNA network, we over-expressed the 3’UTR of PIK3CA and measured the level of ZNF148 transcripts.
Semi-quantitative and real-time PCR showed that over-expression of PIK3CA 3’UTR increased the level of ZNF148. Lastly,
HCT116 cells over-expressed with PIK3CA 3’UTR showed reduction on cell survival and proliferation, suggesting the possible
sequestration of miR-506 and the consequent upregulation of the tumor suppressor gene ZNF148. Knockdown assays will
further verify the existence of a putative PIK3CA-ZNF148 ceRNA network.
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Tue(3)-P-41
Model comparison of cancer genetics practice in Japan: How to provide genetic counseling, genetic
testing, cancer surveillance, and risk-reducing options for people who may have high cancer risks
Chieko Tamura 1,2,3 ，Yukiko Tsunematsu 2 ，Miki Kimura 2 ，Kohji Tanakaya 3 ，Keiko Matsuda 3,4
，Chikako Nishida 3 ，
Hiromi Sanai 3,5 ，Hiromi Arakawa 1 ，Yasushi Nakamura 1
1:Medical Information & Genetic Counseling Division, FMC Tokyo Clinic, Japan、2:Juntendo University Hospital、3:National Hospital
Organization Iwakuni Clinical Center、4:Osaka Medical Center and Research Institute for Maternal and Child Health、5:Yamaguchi Grand
Medical Center
[Objectives and Methods]
Consideration of the hereditary aspects of cancer is a critical component of medical practice. However, in Japan, genetic
testing for hereditary cancer syndromes, as well as related genetic counseling, cancer surveillance, and risk-reducing medication
and surgeries for people who have high cancer risks have not been covered by health insurance. Despite this difficult situation,
some have tried to establish several models of cancer genetics practices. In this presentation, we would like to describe and
compare three different models we have developed in Japan.
[Results]
Model A is at a local medical center where genetic counseling sessions are held every 3-4 months to see 4-5 cases by inviting
experienced genetic counselors from outside. Model B is at a university hospital in Tokyo, and cancer genetic counseling clinic
is held every two weeks with a part-time genetic counselor. Model C is a private genetics clinic which only provides genetic
Poster Session
counseling and genetic testing. Model C is used by cancer patients and families who are treated in hospitals where there is no
genetics services. With model A and B, all patient care is conducted in the same hospital, but, doctors in the hospital need
to know what to do in the absence of genetic counselors. With a large center like model B, how to share patients’ genetic
information with different departments should be carefully considered. With model C, genetic counselors are always there
and easy to be contacted, and patients’ privacy can be easily controlled in the clinic, but, collaboration with doctors of other
hospitals, where patients come from, is essential.
[Discussion]
Cancer genetics practice can be done in many different ways, but each model has its advantages and disadvantages. It would
be important for Medical professionals to be aware of those issues to better facilitate these practices in the future.
Tue(3)-P-42
The new subcellular role of BRCA2 involved in FIP3-dependent endosome function
Miho Takaoka 1 ，Akira Nakanishi 1 ，Yoshio Miki 1
1:Molecular genetics of Med. Res., Tokyo Medical & Dental university, Japan
We already reported that BRCA2 is involved in the abscission between two daughter cells during cytokinesis. Many common
proteins are known as having some role in the both events between cytokinesis and endocytosis pathway. Besides, some
of these proteins are reported the interaction with BRCA2 like as ESCRT associated proteins, so we made hypothesis that
BRCA2 might have some role in endosome.
At first, we tried to validate the existence of BRCA2 in endosome. We isolated endosome lysates from HeLa S3 cells and
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analyzed the lysates by mass spectrometry or immunoblotting using anti-BRCA2 antibody. The results indicated the existence
of BRCA2 in the endosome lysates. Next, we tried the fractionation of endosome lysates by iodixanol centrifugation to clear
which steps of endocytosis BRCA2 is involved in. BRCA2 was detected in one of the early endosome fraction from the result
of immunoblotting using anti-BRCA2 antibody. We observed the co-localization of BRCA2 and GFP-Rab5, which was over-
expressed in U2OS cells as a marker of early endosome, by immunofluorescence microscopy. However, the interaction of both
proteins are still unclear from the immunoprecipitation using total whole cell lysates. Then, we tried the mass spectrometry
analysis of the anti-BRCA2 immunoprecipitates from the early endosome fraction which contains BRCA2. This results
suggested the possibility of the interaction between BRCA2 and many recycling endosome proteins. We selected Rab11-
FIP3 (Rab11-family interacting protein3) as a candidate of BRCA2 partner in endosome from the list of mass spectrometry
analysis. Rab11-FIP3 is known as a Rab11, the marker of recycling endosome, effector protein and involved in recycling
endosome, cytokinesis and spindle formation. In this time, we investigate the new function of BRCA2 at endosome through
the interaction of Rab11-FIP3.
Tue(3)-P-43
Can surgeon provide early BRCA gene counseling for advanced ovary cancer?
Min Kyu Kim 1 ，Yoo Min Kim 2 ，Soo Hyun Kim 2
1:Obstetrics and Gynecology, Sungkyunkwan University of Medicine,Samsung Changwon Hospital, Korea, South、2:Sungkyunkwan University
of Medicine,Samsung Medical Center
Objective: BRCA testing and genetic counseling is recommended for women among ovarian cancer with regard to survival
Poster Session
benefit and prevention of cancer including patient and mutation carrier among family members. We undertook this study to
investigate whether advanced staging can be a barrier in BRCA testing and genetic counseling.
Materials and Methods: Early (I-II) and advanced (III-IV) ovary carcinoma patients . Total 34 patients were evenly divided
between them. After complete surgical staging and pathology result, single gynecologic oncologist offered genetic counseling
about risk assessment based on pathology, family history and immunohistochemistry. BRCA1/2 gene sequencing was done
for approved patient.
Results: Advanced stage group was a little bit older than early stage group, median age were 57.77(45-75) vs 52.53(20-73)
(p>0.05). In contrast to early stage group, advanced stage group had high proportion of serous carcinoma (15/17 (88.2%) vs
6/17(35.3%)) (p<0.05) and short DFI (10.87 vs 22.27 months) (p<0.05). Among 34 patients, only 2 patients refused BRCA
testing and gene counseling at each group. Patient with cancer related family history is 1(5.9%) in early stage and 3(17.6%)
in advanced stage. In early stage group, BRCA testing period after the operation (126.38(6-981 days) vs 50.69(6-315 days)
(p>0.05)) was longer than advanced group. BRCA1 was found by three patients in advanced stage group only and BRCA2
was not detected in all groups.
Conclusion: Genetic counseling even at advanced stage of ovary cancer by gynecologic oncologist is feasible. Comprehensive
cancer care including treatment, prevention and early detection of BRCA mutation of ovary carcinoma is equally important.
Therefore, advanced staging patient may not be an obstacle for early counseling by surgeon about BRCA mutation
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Tue(3)-P-44
Overexpression of miR-127 and miR-375 in Medullary Thyroid Carcinoma Tumors
Marjan Zarif Yeganeh 1 ，Sara Sheikholeslami 1 ，Mahsa Rahmani Samani 2 ，Atefeh Mehrabi 2 ，Samira Ehyaei 3 ，
Mehdi Hedayati 1
1:Cellular and Molecular Research Centre, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences,
Tehran, Iran、2:Islamic Azad University Tehran Medical Branch Faculty of Modern Science、3:Clinical Biochemistry Research Center,
Medical Faculty, Shaherekord University of Medical Sciences
Background: Medullary thyroid cancer (MTC), an neuroendocrine tumor, is derived from parafollicular C-cells and accounts
for 5-10% of all thyroid cancers. 75% of MTC cases are sporadic and 25% are heredity forms. Mutations in RET gene are
responsible for the most cases of MTC. MicroRNAs (miRNAs) represent a class of small, non-coding RNAs that control
gene expression by targeting mRNA and triggering either translational repression or RNA degradation. They have been
implicated in the pathogenesis of many cancers. The main goal of this study was to evaluate the expression of miR-127,
miR-154, miR-183, miR-375, miR-224, and miR-10a in the MTC formalin-fixed paraffin-embedded (FFPE) tissues.
Methods: In this case-control study, total RNA was extracted from FFPE tissue of 15 MTCs and 15 non-tumor thyroid
gland. The expression of miR-127, miR-154, miR-183, miR-375, miR-224, and miR-10a were quantitated by real-time PCR
method.
Results: Data analysis showed that the expression of miR-127 and miR-375 were significantly overexpressed in MTC tumor
tissues compared to the control group, but the increased expression of miR-154, miR-224, and miR-183 were not significant
between two groups. The expression of miR-10a was decreased in tumor tissues in comparison with the none-tumoral tissues,
Poster Session
but it was not significant.
Conclusion: This data indicate that the differential expression of miR-127, miR-375 can be important for tumor development
their overexpression may play a role in pathogenesis of MTC. Understanding of miRNA expression patterns and their effects
on gene expression may provide a better understanding of tumor development and progression.
Tue(3)-P-45
Germline Mutational Analysis of RET Proto Oncogene in Iranian Medullary Thyroid Carcinoma Patients:
a 14-year Study
Sara Sheikholeslami 1 ，Marjan Zarif Yeganeh 1 ，Mehdi Hedayati 1
1:Cellular and Molecular Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Iran
Introduction: Medullary thyroid carcinoma is one of the most malignant thyroid tumors which occurs in hereditary and
sporadic forms. RET proto oncogene plays potential role in MTC development. This study is investigated the spectrum of
germline mutations of RET exons 3, 5, 8, and 10-18 in both forms of MTC patients and their relative.
Materials and Methods: 445 participants, including 259 patients (198 sMTC, 42 FMTC, eight MEN2A, four MEN2B, and
six Pheochromocytoma) and 186 relatives were studied since 2001 up to now. Genomic DNA was extracted by the standard
Salting Out/ProteinaseK method and mutation detection was performed through direct DNA sequencing.
Results: Seventeen different mutations were detected in 92 participants in RET main exons, 10, 11, and 13-16. The most
frequent mutation was C634R (3.37%; 15/445) in exon11 whereas C618R, C618S, and C620G mutations had rare allele
frequency (0.2%; 1/445) in exon 10. R886Q (exon15) and L790L (exon13) mutations were detected in two separate probands
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and one of their relatives. As we expected, M918T were detected in all MEN2B patients. The frequency of haplotype
G691S/S904S was 56.37 (146/259) in patients and 54.83 (102/186) in their relatives. Conclusion: Exon 11 and after that
exon 10 were the most frequently mutated exons of RET proto-oncogene in MTC patients in Iranian population. As about half
of patients with the hot spot mutations had the G691S/S904S haplotype simultaneously, further analysis needs for clarifying
the effect of multiple risk alleles in MTC development.
Tue(3)-P-46
Genome-wide DNA copy number analysis of primary head and neck squamous cell carcinoma (HNSCC)
and second primary esophageal squamous cell carcinoma (ESCC)
Meng-Shin Shiao 1 ，Sacarin Bunbanjerdsuk 2 ，Tanjitti Pongrujikorn 2 ，Tanadech Dechaphunkul 3 ，
Somkiat Sunpaweravong 4 ，Natini Jinawath 1,2
1:Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand、2:Graduate Program in Translational
Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, Bangkok, Thailand、3:Department of
Otorhinolaryngology Head and Neck Surgery, Faculty of Medicine, Prince of Songkla University, Songkla, Thailand、4:Department of
Surgery, Faculty of Medicine, Prince of Songkla University, Songkla, Thailand
The prognoses of HNSCC and ESCC are poor, especially when two primary tumors occurred at the same time. Understanding
the genetic characteristics of these two types of primary tumors should help establish an early detection strategy resulting
in better outcomes. Therefore, we aim to analyze somatic DNA copy number alterations (CNAs) in HNSCC and ESCC
using genome-wide SNP arrays in 21 patients who developed both primary HNSCC and second primary ESCC within 12
months. Comparing CNAs of each cancer type with common copy number variations (CNVs) of approximately 3,000 general
Poster Session
Thai populations from Thai CNV database, we categorized CNAs into somatic allelic imbalance (including duplications and
deletions, denoted as AI hereafter) and copy-neutral loss of heterozygosity (LOH). Based on our results, AIs were found along
the entire chromosome arm 3p and spanning both arms of chromosome 17 in more than 50% of the patients with HNSCC.
In addition, AIs were found in small regions of 5q, 9p, 11q, 18q and 21q and LOH was found in 1p in HNSCC. In ESCC, AIs
were found mostly in 3p, 5q and chromosome 9, and LOH were identified in small regions of 2p, 2q, 3q, 8q 12q and 16q in
more than 50% of the patients. CNAs in chromosome 3 and 5 were among the most common changes in the two types of
cancer, which was in line with previous reports. We further performed pathway analyses of genes associated with HNSCC
and ESCC within regions showing CNAs. Interestingly, we found that alterations, particularly deletions, of pathways related
to cancer signaling were enriched in HNSCC. We also observed the enrichment of pathway alterations related to immune
systems in HNSCC, which was not seen in ESCC. Taken together, we identified common and unique CNAs and alteration of
different pathways in two primary cancers, it may contribute to the improvement of diagnostic strategies and identification
of novel therapeutic target in the future.
Tue(3)-P-47
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Tue(3)-P-48
Clinical utility of genomic SNP microarrays in hepatosplenic γδ T-cell lymphoma
1,2 1,2
Reha M Toydemir ，Bo Hong
1:Pathology, University of Utah, USA、2:ARUP Institute for Clinical and Experimental Pathology
Hepatosplenic T-cell lymphoma (HSTL) is an extranodal neoplasm arising from cytotoxic T-cells usually of γδ T-cell re-
ceptor type and associated with aggressive course of systemic disease and poor response to treatment. The pathogenetic
mechanisms leading to HSTL is poorly understood, most likely due to the low incidence of this disorder. Conventional
cytogenetic studies have shown that isochromosome of the long arm of chromosome 7 and trisomy 8 as recurrent findings.
However, these findings do not appear to be specific, and large cohorts with detailed genetic and clinical characterization of
the patients are not available.
We report the clinical utility of genomic SNP microarrays in HSTL on two HSTL patients with multiple cytogenetic abnormal-
ities. The first patient is 42-year-old male presenting with a complex karyotype including isochromosome 7q and tetrasomy
8. The second patient is a 31-year-old female with either normal karyotypes or failed cultures within the 4 years of being
diagnosed with HSTL.
In both patients, the genomic SNP microarray showed isochromosome 7q and gain of extra copies of chromosome 8, in addition
Poster Session
to other findings. Some of the other findings include deletion on the short arm of chromosome 9 involving the CDKN2A and
CDKN2B genes seen in both patients; various copy number changes as well as long contiguous stretches of homozygosity.
This study, although limited in size, shows the clinical utility of the genomic SNP microarrays in further characterization of
the genetic alterations in HSTL which will potentially lead to better targeted treatment protocols.
Tue(3)-P-49
Roles of Tyrosine Phosphorylation of histone H4 in Breast Cancer
Ruey-Hwang Chou 1 ，Ying-Nai Wang 2 ，Wei-Chao Chang 1 ，Ling-Chu Chang 3 ，Weiya Xia 2 ，Yung-Luen Yu 1 ，
Mien-Chie Hung 1,2
1:Graduate Institute of Cancer Biology, China Medical University, Taiwan、2:Department of Molecular and Cellular Oncology, The
University of Texas MD Anderson Cancer Center、3:Graduate Institute of Pharmaceutical Chemical, China Medical University
Post-translational modifications (PTMs) on histones, such as methylation, acetylation, phosphorylation, and ubiquitination,
play the important roles in chromatin dynamics and different biological functions. Unlike serine/threonine phosphorylation,
it is rarely understood about tyrosine phosphorylation on histones and its functions. We have identified several novel tyrosine
phosphorylation sites on histones and elucidated some of their biological functions. For instance, we found that EGFR
phosphorylates histone H4 at Y72 and results in enhancing the recruitment of histone methyltransferases (HMTases), SET8
and SUV4-20H, via non-SET domain to facilitate its K20 methylation and consequently promotes DNA synthesis and repair.
Furthermore, EGFR expression clinically correlates with histone H4-Y72 phosphorylation, H4-K20 mono-methylation, and
the Ki-67 proliferation marker. Based on the finding, we synthesized the cell penetrative polypeptide (CPP) derived from
histone H4Y72 to interrupt the interaction between EGFR and histone H4 for potential cancer treatment. Disrupting the
interaction between EGFR and histone H4 by Y72 peptide significantly reduced tumor growth in a xenograft mouse model of
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breast cancer. Here, we uncover a mechanism by which EGFR transduces signal to chromatin to regulate DNA synthesis and
repair via phosphorylation of histone H4-Y72 and provide a potential therapeutic strategy for breast cancer by disrupting the
interaction.
Tue(3)-P-50
Targeted Single Cell Sequencing for Accurate Mutation Detection in Heterogeneous Cellular Populations
1
Ryoko Shimada
1:QIAGEN K.K., Japan
Genomic analyses at the single-cell level shed light on the genes and their functions in each individual cell and give valuable
information on the fundamental mechanisms of cellular functions.
Recent developments in single cell sequencing technologies have enabled single-cell genomic analysis at single nucleotide
resolution and revealed the cellular heterogeneity among presumably homogeneous cell populations. Single-cell sequencing
has become a powerful tool in cancer research (for early detection and monitoring of rare non-identical circulating tumor
cells), in immunology, stem cell research, and preimplantation diagnosis.
Targeted sequencing, the selective enrichment and sequencing of a panel of genes of interest, is a sensitive and cost-effective
method to analyze functionally relevant genes. The targeted sequencing at single-cell level is especially useful in cancer
Poster Session
research, due to the high heterogeneity of the tumor cells and relatively small numbers of significantly mutated genes (SMGs)
in all cancer types. This poster describes an optimized workflow for streamlined targeted sequencing at the single-cell level
that combines reliable, multiple displacement amplification (MDA)-based, single-cell whole genome amplification (WGA),
multiplex PCR-based targeted enrichment, and a fast one-step sequencing library construction protocol. We demonstrated
that this method can be used to sensitively and reliably detect oncogene mutations in a heterogeneous cellular population.
Tue(3)-P-51
Global nuclear radial distribution of chromosome territories in various cancer cell lines
1
Hideyuki Tanabe
1:Department of Evolutionary Studies of Biosystems, School of Advanced Sciences, SOKENDAI (The Graduate University for Advanced
Studies), Japan
Spatial radial positioning of chromosome territories (CTs), in other words, global nuclear radial distribution of CTs from
center to nuclear rim was related to their gene densities and physical sizes in normal cells as well as several tumor cell lines,
and this observation was previously well studied (Croft et al., 1999, Cremer et al., 2003). Particularly the gene-poor human
18 CTs are located toward the nuclear periphery but the gene-dense human 19 CTs are arranged near the nuclear interior.
Comparative analyses of nuclear arrangements of 18 and 19 CTs between normal and tumor cell lines suggested that such a
topology is a common feature in both normal and tumor cell types, but is less conserved in the tumor cell lines compared
with that of the normal cell lines.
In the present study using the originally developed periphery (P) and interior (I) pooled DNA probes consisting of chro-
mosome specific paints, global nuclear radial distribution of P and I probes in various tumor cell lines including lymphoma,
adenocarcinoma, fibrosarcoma, neuroblastoma, and glioblastoma was analyzed by 3D-FISH technique. The results suggested
that the disturbance of P and I probes was observed in the specific cell lines showing the dynamic nuclear architecture. The
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reason for this phenomenon will be considered in relation to Lamin Associated Domains (LADs) as well as Topologically
Associating Domains (TADs). LADs are located near the nuclear rim, which are tethering mainly gene-poor chromosomal
regions corresponding to G/C-bands roughly consisting of heterochromatin (Lieberman-Aiden et al., 2009). TADs can be
defined as linear units of chromatin that fold as discrete 3D structures tending to favor chromatin interactions within the single
CT (Dekker and Heard, 2015). In addition, Actin related protein 6 (Arp6, ubiquitous components of chromatin remodeling
complexes) will be discussed whether regulating global radial distribution of CTs in tumor cell lines.
Tue(3)-P-52
Nonclonal chromosome abnormalities in hematologic malignancies
1,2
Ma. Luisa D. Enriquez
1:Biology, De La Salle University, Philippines、2:Research and Biotechnology, St. Lukes Medical Center
The prevailing notion that cancer is characterized by a stepwise accumulation of specific clonal aberrations is challenged by
clinical findings with cancer cases exhibiting high degree of genetic heterogeneity following a nonlinear pattern and random
genomic (chromosomal) changes.In the past, we considered nonclonal chromosome abnormalities (NCCAs) also as “non sig-
nificant background”. However, recent reevaluation of its role in genomic instability and cancer progression has prompted
us to pay more attention to these genomic changes. We present 77 nonclonal chromosome abnormalities (NCCAs) seen in
65 Filipinos with hematological malignancies for a three period (2012-2015). Based on clinical diagnosis, these cases are
distributed as follows: 16 (25%) leukemia, 17 (26%) myelodysplastic syndrome, 3 (5%) multiple myeloma, 4 (6%) myelopro-
Poster Session
liferative neoplasms and 25 (39%) other hematologic diseases. There are 32 (49%) males and 33 (51%) females; 50 (77%)
patients are >40 years old and 15 (23%) ≤ are 40 years old. Median age is 57 years old and ages ranged from <1 year to 88
years old. Analysis of G-banded chromosomes from lymphocytes of these patients the nonclonal abnormalities are described:
8 cells with additional chromosomal segments, 12 with segment deletions,11 cells each carrying 2 chromosome abnormalities
(structural and/or numerical), 26 cells have reciprocal translocations and 20 are complex karyotypes. Among the 26 (34%)
cells with reciprocal translocation, 4 (15%) have a t(7;14). Aberrant chromosome 7 was seen in 13 (17%) karyotypes and
abnormal chromosome 3 was seen in 13 (20%). Eleven cases 11 (17%) have more than one NCCAs. A competent clinical
follow up paralleled with subsequent cytogenetic tests in these patients can provide defining evidence on the role of NCCAs
in cancer progression as well as its dynamic relationship with clonal chromosomal abnormalities (CCAs).
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Poster Session
Complex Traits and Polygenic Disorders 2
Tue(3)-P-53
Replication of 49 type 2 diabetes associated risk variants in Punjabi Pakistani population
Asima Zia 1 ，Xingbin Wang 2 ，Attya Bhatti 1 ，F. Y Demirci 2 ，Wei Zhao 3 ，Asif Rasheed 4 ，Maria Samuel 4 ，
Aysha K Kiani 1 ，Muhammad Ismail 5 ，Jamal Zafar 6 ，Peter John 1 ，Danish Saleheen 4,7 ，M I Kamboh 2
1:Atta ur Rahman School of Applied Biosciences (ASAB), National University of Science and Technology (NUST), Pakistan、2:Department
of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA, USA、3:Institute of Translational Medicine and Human
Genetics, Department of Medicine, University of Pennsylvania, PA, USA、4:Center for Non-communicable Diseases, Karachi, Pakistan;
5Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan、5:Institute of Biomedical and Genetic Engineering
(IBGE), Islamabad, Pakistan、6:Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan、7:Department of Biostatistics and
Epidemiology, University of Pennsylvania, PA, USA
Objective: The burden of type-2 diabetes is alarmingly high in South Asia, a region that has many genetically diverse ethnic
populations. Genome-wide association studies (GWAS) conducted largely in European populations have identified a number
of loci predisposing to T2D risk, however the relevance of such genetic loci in many South Asian sub-ethnicities remain elusive.
The aim of this study was to replicate 49 SNPs previously identified through GWAS in Punjabis living in Pakistan.
Poster Session
Methods: We examined the association of 49 SNPs in 853 T2D cases and 1,945 controls using additive logistic regression
models after adjusting for age and gender.
Results: Of the 49 SNPs investigated, 8 showed nominal association (p<0.05) that also remained significant after controlling
for false discovery rate. The most significant association was found for rs7903146 at the TCF7L2 locus. For a per unit
increase in the risk score comprising of all the 49 SNPs, odds ratio in association with T2D risk was 1.16 (95% CI 1.13-1.19,
P<2.0E-16).
Conclusion: These results suggest that a large number of T2D susceptibility loci are shared between Europeans and Punjabis
living in Pakistan.
Tue(3)-P-54
Copy number variations play important roles in heredity of common diseases: a novel method to calculate
heritability of a polymorphism
1
Yoshiro Nagao
1:Department of Pediatrics, Takashimadaira Chuo General Hospital, Japan
“Missing heritability” in genome wide association studies, the failure to account for a considerable fraction of heritability
by the variants detected, is a current puzzle in human genetics. For solving this puzzle the involvement of genetic variants
like rare single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) has been proposed. Many papers have
published estimating the heritability of sets of polymorphisms, however, there has been no paper discussing the estimation of
a heritability of a single polymorphism. Here I show a simple but rational method to calculate heritability of an individual
polymorphism, hp 2 . Using this method, I carried out a trial calculation of hp 2 of CNVs and SNPs using published data. It
turned out that hp 2 of some CNVs is quite large. Noteworthy examples were that about 25 % of the heritability of type 2
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diabetes mellitus and about 15 % of the heritability of schizophrenia could be accounted for by one CNV and by four CNVs,
respectively. The results suggest that a large part of missing heritability could be accounted for by re-evaluating the CNVs
which have been already found and by searching novel CNVs with large hp 2 .
Tue(3)-P-55
Determination of IFIT1 Gene Polymorphisms on Human Cerebral Malaria in Thai Population
Pornlada Nuchnoi 1 ，Hathairad Hananantachai 2 ，Jun Ohashi 3 ，Izumi Naka 3 ，Jintana Patarapotikul 2
1:Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Thailand、2:Faculty of Tropical Medicine, Mahidol
University、3:Department of Biological Science, Graduate School of Science, The University of Tokyo, Tokyo, Japan
Background Malaria infection caused by Plasmodium falciparum remains the major challenge for disease protection and
treatment in developing countries. Human cerebral malaria is responsible for severe and fatal cases in both children and
adults infected with P.falciparum. There are accumulating evidences supporting that host genetics play important role
for controlling the malaria severity predisposition. Interferon-induced protein with tetratricopeptide repeat (IFIT) played
important role as neuro-inflammation in cerebral malaria susceptible mice. Herein, we examined the association between four
tag single nucleotide polymorphisms (SNPs) of IFIT1 gene and malaria severity in Thai patients infected with P.falciparum.
Material and Methods A total of (109 cerebral malaria and 203 mild malaria) were genotype for four IFIT1 SNPs. Allele and
genotype frequencies were compared among mild malaria and cerebral malaria group using the chi-square test. Result Allele
and genotype frequencies of four IFIT1 SNPs show no association with cerebral malaria (P-value > 0.05). Conclusion IFIT1
SNPs show no influence on cerebral malaria outcome in Thai population.
Poster Session
Tue(3)-P-56
Genome-wide association studies (GWAS) for adult height and body mass index in the Japanese popu-
lation using the JPDSC database
Daisuke D. Ikeda 1 ，Satoshi Nagasaka 2 ，Toshihide Ono 1 ，Masatoshi Masuda 2 ，Tsutomu Fujiwara 2 ，
Haretsugu Hishigaki 1
1:Biomedical Technology Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Japan、2:Clinical Pharmacology,
Headquarters of Clinical Development, Otsuka Pharmaceutical Co., Ltd.
Japan PGx Data Science Consortium (JPDSC), which was founded by 6 pharmaceutical companies in Japan, built a control
DNA database for the Japanese in order to develop drugs with high efficacy and safety. This database stores the information
of genotypes and 121 clinical traits of 3,000 healthy Japanese people.
Otsuka Pharmaceutical Co., Ltd. started to participate in the Genetic Investigation of Anthropometric Traits (GIANT)
consortium last year, which is an international collaboration that seeks to identify genetic loci that modulate human body
size and shape. We conducted genome-wide association studies (GWASs) for gender-specific adult height and BMI in the
JPDSC cohort. After quality control of ~ 2.4 million SNPs, ~ 1.3 million SNPs were retained. Through the genotype
imputation with 1000 genome reference panel (phase3, v5) and Minimac3, we gained ~ 7.7 million high-quality (Rsq >0.7)
SNPs. As for trait values, residuals of linear regression analyses were transformed into z-scores (for height) or by the inverse
normal transformation (for BMI). We utilized MACH2QTL for the association study.
As a result, none of SNP reached genome-wide levels of significance (p<5x10-8 ). We focused SNPs with p<10-5 and found
that they included novel loci as shape-related traits, in addition to SNPs located in the regions of shape-associated genes such
as the FTO, fat mass and obesity associated gene.
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Tue(3)-P-57
Mutation identification of ABCA1 gene in subjects with low level of high-density lipoprotein
Nani Maharani 1,2 ，Udin Bahrudin 1,3 ，Hesty Wahyuningsih 1 ，Isna R Fara 1 ，Ferdy K Cayami 1 ，Sodiqur Rifqi 3 ，
Sultana MH Faradz 1 ，Ichiro Hisatome 1,2
1:Center for Biomedical Research, Faculty of Medicine, Diponegoro University, Semarang, Indonesia, Japan、2:Division of Regenerative
Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical
Science, Yonago, Japan、3:Departement of Cardiology and Vascular Medicine, Faculty of Medicine, Diponegoro University, Semarang,
Indonesia
Background: The crucial part of high density lipoprotein cholesterol (HDL-C) metabolism for protection against development
of atherosclerosis is attributed to its role in reverse cholesterol transport, and ABCA1 gene is a key element in this process.
Mutation in ABCA1 is the most common among genes involved in the HDL-C metabolism. The purpose of this study was
to identify predicted pathogenic mutation of ABCA1 gene in subjects with low level of HDL-C.
Methods: Blood samples were taken from 42 subjects with low HDL-C level (<40mg/dl). Identification of gene variant was
done in the translated region of exon 2 to 49 and their flanking regions, by using high resolution melting (HRM) technique.
The aberrant samples were confirmed by DNA sequencing. Alamut software was used to predict pathogenic mutation.
Results: Subjects were consisted of 24 (57.1%) males and 18 (42.9%) females. Nine polymorphisms of ABCA1 gene were
identified. One variant found in 5’UTR was c.-76dup. Three variants were identified in intron, i.e., c.+378G>C, c.814-
14dup, and c.1892+24T>A. Four variants found as synonimous substitutions were c.936C>T, c.948G>A, c.2040C>A, and
c.5586G>A. A variant c.2311G>A was predicted deleterious. The c.5586G>A was a novel variant, while the rest have been
Poster Session
reported in the SNP database. Polymorphism in exon 2 and 14 were found in 52% and 100% of subjects, respectively.
Conclusion: This study identified 9 polymorphisms of ABCA1 gene in subjects with low HDL level. Among them, one
polymorphism is novel and another polymorphism is predicted pathogenic. The predicted deleterious mutation of ABCA1
may contribute to the low level of HDL and clinical presentation of the patient.
Tue(3)-P-58
Leveraging Compartmental Modeling to Assess the Pathophysiologic Effect of Genetic Variation Under-
lying Risk for Type 2 Diabetes
1,2,3
Richard M Watanabe ，David Conti 1 ，Anny H Xiang 5 ，Hooman Allayee 1,3
，Thomas A Buchanan 2,3,4
1:Preventive Medicine, Keck School of Medicine of USC, USA、2:Physiology & Biophysics, Keck School of Medicine of USC、3:USC Diabetes
and Obesity Research Institute、4:Medicine, Keck School of Medicine of USC、5:Research and Evaluation, Kaiser Permanente Southern
California
Hundreds of loci underlying type 2 diabetes (T2D) risk or variation in T2D-related traits have been identified; less is known
about their pathophysiologic effects. We hypothesized integrating genetic effects into compartmental models (CM) of glucose
metabolism can dissect biology underlying genotype-phenotype relationships. Our CM links validated models of glucose
(GLU) and insulin kinetics into a single model able to simulate GLU and insulin profiles from clinical protocols, e.g., oral
glucose tolerance test (OGTT). Each parameter in the CM denotes a specific biologic function, so “genes” can be assigned
to one or more model parameters and simulations performed to assess genetic effects on glucoregulation. We simulated the
effect of PPARG P12A by imposing it on a parameter (p3) determining insulin signaling transduction. Genotype-specific p3
values were drawn from a literature-derived non-diabetic population distribution, constrained by gene frequencies assuming
an additive genetic model. 1,000 OGTTs were simulated by randomly selecting a p3 value from the population distribution.
OGTT GLU profiles for AA genotypes tightly clustered in the normal range while those for PA and PP genotypes show
considerable variability; 3% of PA and 11% of PP genotypes having 2-hour GLU >140 mg/dl. Power analysis based on 3,000
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replicates of 1,000 OGTTs showed 60 min OGTT GLU having best power to detect association with P12A. We validated CM-
based simulation results by testing association between P12A and OGTT GLU, adjusting for covariates in 1,621 individuals
from Mexican American families (BetaGene study). Evidence for association with P12A was strongest for OGTT 60 min
GLU (p=0.036), compared to fasting (p=0.55), 30 (p=0.10), 90 (p=0.06) or 120 min (p=0.39), consistent with model-based
power analysis. This study demonstrates a physiologically-based CM can be used to better understand the pathophysiologic
implications of genetic variation.
Tue(3)-P-59
Location, Loci or Lifestyle? Dissecting Health-Associated Regional Variation in Scotland
Carmen Amador 1 ，Charley Xia 1 ，Archie Campbell 1 ，David Porteous 1 ，Generation Scotland 3 ，Nick Hastie 1 ，
Veronique Vitart 1 ，Caroline Hayward 1 ，Pau Navarro 1 ，Chris S Haley 1,2
1:MRC IGMM, University of Edinburgh, UK、2:Roslin Institute, University of Edinburgh、3:A collaboration between the University Medical
Schools and NHS in Aberdeen, Dundee, Edinburgh and Glasgow Scotland
Regional differences in health-related phenotypes and diseases have been detected between and within countries. Regions in
Scotland differ for health-related traits, such as obesity, and display differences in mean lifespan of up to 7.5 years in men
and 4.9 years in women. Both genetics and environmental differences are possible causes of these differences. In this study,
we explored a data set of 11,000 individuals from the Generation Scotland’s Scottish Family Health Study (GS:SFHS), with
genome-wide genetic information and measures of health-related traits and of lifestyle and socioeconomic factors. There was
significant variation between regions in our sample for obesity related traits. We used mixed model analyses to disentangle
Poster Session
the causes of the observed regional differences, fitting a set of genetic and environmental similarity matrices and covariates
to explore the influence of genetics, lifestyle and socioeconomic variables (broadly environmental variables) on the traits.
For most of the traits explored, the regional variation in our sample is not associated with genetic stratification. Regional
variation was however correlated with some environmental variables related to lifestyle and socioeconomic status, such as
smoking status, alcohol intake, area deprivation and dietary variables. We also observed that genes and environment are not
confounded, since the heritability estimates are robust and not biased by the inclusion or exclusion of the extended set of
environmental covariates. Our results show that, although genetic variation makes an important contribution to variation
between individuals, regional differences in health-related traits are attributable mostly to environmental differences between
the regions. These results suggest that regional inequalities could be tackled with appropriate social and economic policies
and interventions.
Tue(3)-P-60
Effects of HLA-DPB1 genotypes on HBV-related diseases in Japanese population
Nao Nishida 1,2 ，Jun Ohashi 3 ，Masaya Sugiyama 1 ，Takayo Tsuchiura 1 ，Mayumi Ishii 1 ，Katsushi Tokunaga 2 ，
Masashi Mizokami 1
1:The Research Center for Hepatitis & Immunology, National Center for Global Health and Medicine, Japan、2:Department of Human
Genetics, Graduate School of Medicine, University of Tokyo、3:Department of Biological Sciences, Graduate School of Science, The
University of Tokyo
Associations of variants located in HLA class II region with chronic hepatitis B (CHB) infection have been identified in Asian
populations. To date, no published report has documented a clear effect of HLA genotype on chronic hepatitis B (CHB)
infection; therefore, we used the HLA genotype data from the 929 Japanese individuals in our previous study and acquired
HLA genotype data from an independent set of 1,653 Japanese samples representing 892 HBV patients and 761 healthy
controls; we used the data from these 2,582 individuals to assess the effects of HLA genotype on CHB infection.
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Significant associations between CHB infection and five DPB1 alleles (two susceptibility alleles, DPB1*05:01 and *09:01 ,
and three protective alleles, DPB1*02:01 , *04:01 , and *04:02 ) were confirmed in a population comprising 2,582 Japanese
individuals. Odds ratios for CHB were higher for those with both DPB1 susceptibility alleles than for those with only one
susceptibility allele; therefore, effects of susceptibility alleles were additive for risk of CHB infection. Similarly, protective
alleles showed an additive effect on protection from CHB infection. Moreover, heterozygotes of any protective allele showed
stronger association with CHB than did homozygotes, suggesting that heterozygotes may bind a greater variety of hepatitis
B-derived peptides, and thus present these peptides more efficiently to T cell receptors than homozygotes. Notably, compound-
heterozygote of DPB1*04:02 (protective) and DPB1*05:01 (susceptibility) was significantly associated with protection against
CHB infection, which indicated that one protective HLA-DPB1 molecule can provide dominant protection.
Identification of the HLA-DPB1 genotypes associated with susceptibility to and protection from CHB infection is essential for
future analysis of the mechanisms responsible for immune recognition of hepatitis B virus antigens by HLA-DPB1 molecules.
Tue(3)-P-61
Associations between the orexin (hypocretin) receptor 2 gene polymorphism Val308Ile and nicotine
dependence in genome-wide and subsequent association studies
Daisuke Nishizawa 1 ，Shinya Kasai 1 ，Junko Hasegawa 1 ，Naomi Sato 2,3 ，Hidetaka Yamada 3 ，
Fumihiko Tanioka 4 ，Makoto Nagashima 5 ，Hiroshi Ujike 6,18 ，Ryota Hashimoto 7,8 ，Tomio Arai 9 ，
Seijiro Mori 10 ，Motoji Sawabe 11 ，Makiko Naka-Mieno 12 ，Yoshiji Yamada 13 ，Miki Yamada 14 ，Noriko Sato 14 ，
Masaaki Muramatsu 14 ，Masashi Tanaka 15,16 ，Masakazu Hayashida 17 ，Haruhiko Sugimura 3 ，Kazutaka Ikeda 1,18 ，
Poster Session
Japanese Genetics Initiative for Drug Abuse (JGIDA)
1:Addictive Substance Project (Department of Psychiatry and Behavioral Science), Tokyo Metropolitan Institute of Medical Science, Japan、
2:Department of Clinical Nursing, Hamamatsu University School of Medicine、3:Department of Tumor Pathology, Hamamatsu University
School of Medicine、4:Department of Pathology, Iwata City Hospital、5:Department of Surgery, Toho University Sakura Medical Center、
6:Ujike Nishiguchi Clinic、7:Department of Psychiatry, Osaka University Graduate School of Medicine、8:Molecular Research Center for
Childrens Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu
University, Chiba University, and Fukui Univ.、9:Department of Pathology, Tokyo Metropolitan Geriatric Hospital、10:Center for Promotion
of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital、11:Molecular Pathophysiology, Department of Molecular-genetic Sciences,
Division of Biomedical Laboratory Sciences, Graduate School of Health Care Sciences, Tokyo Medical and Dental University、12:Department
of Medical Informatics, Center for Information, Jichi Medical University、13:Department of Human Functional Genomics, Life Science
Research Center, Mie University、14:Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental
University、15:Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology、16:Department of Clinical
Laboratory, Tokyo Metropolitan Geriatric Hospital、17:Department of Anesthesiology & Pain Medicine, Juntendo University School of
Medicine、18:Japanese Genetics Initiative for Drug Abuse (JGIDA)
Background: Many genetic and environmental factors are involved in the etiology of nicotine dependence. Although suscep-
tible gene variations have been reported by candidate gene or genome-wide association studies (GWASs) to be associated
with smoking behavior and the vulnerability to nicotine dependence, such studies have been mostly conducted with subjects
with European ancestry. However, genetic factors have rarely been investigated for the Japanese population as GWASs. To
elucidate genetic factors involved in nicotine dependence in Japanese, the present study comprehensively explored genetic
contributors to nicotine dependence by using whole-genome genotyping arrays with more than 200,000 markers in Japanese
subjects.
Results: The subjects for the GWAS and replication study were 148 and 374 patients, respectively. A two-stage GWAS was
conducted using the Fagerström Test for Nicotine Dependence (FTND), Tobacco Dependence Screener (TDS), and number
of cigarettes smoked per day (CPD) as indices of nicotine dependence. For the additional association analyses, patients
who underwent major abdominal surgery, patients with methamphetamine dependence/psychosis, and healthy subjects with
schizotypal personality trait data were recruited. Autopsy specimens with various diseases were also evaluated. After the
study of associations between more than 200,000 marker single-nucleotide polymorphisms (SNPs) and the FTND, TDS, and
CPD, the nonsynonymous rs2653349 SNP located on the gene that encodes orexin (hypocretin) receptor 2 was selected as
the most promising SNP associated with FTND. This association was replicated for the remaining 374 samples. This SNP
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was also associated with postoperative pain, the initiation of methamphetamine use, schizotypal personality traits, and sus-
ceptibility to goiter.
Conclusion: The rs2653349 SNP (Val308Ile) may be a genetic factor for nicotine dependence and possibly pain, schizotypal
personality traits, and goiter in the Japanese population.
Tue(3)-P-62
Meta-analysis of GWAS followed by replication identifies new susceptibility genes on X chromosome for
SLE in cross-ethnic populations
Yan Zhang 1 ，Yong Cui 2 ，Timothy J Vyse 3 ，Xuejun Zhang 2 ，Wanling Yang 1 ，Yulung Lau 1
1:The University of Hong Kong, Hong Kong、2:Anhui Medical University、3:King’s College London
Objective:To make the best use of existing GWAS data on X chromosome that would lead to a better understanding of the
female preference of this disease.
Subject:612 SLE patients and 2193 controls from Hong Kong, 1044 SLE patients and 1201 controls from Anhui, China, 6959
SLE patients and 4036 controls from United Kingdom with GWAS data were used for preliminary evaluation based on meta-
Poster Session
analysis. Further replication was preceded on the X-chromosome prominent association signals.
Method: Based on the existing GWAS data in three cohorts, we adopted METAL, an algorithm for meta-analysis, to examine
additional X-linked genetic susceptibility variants to SLE. More samples from Hong Kong, Anhui and Thailand were used in
the replication stage in Asians to further identify association signals, considering gender as a covariate.
Results: One new X-linked susceptibility locus was confirmed on SLE, reaching genome-wide significance.
Significance: Understanding the X-linked susceptibility genes of this complex disease would help elucidate the disease mecha-
nisms. In the long run, the ever increasing awareness of genetic impact on different clinical manifestations of SLE, will move
us closer to using genetics to predict disease risks and disease outcomes, and guiding clinical treatment according to patient’s
genetic makeup.
Tue(3)-P-63
The power of family: Linkage Analysis vs GWAS in family-based cohorts
Reka Nagy 1 ，Pau Navarro 1 ，Caroline Hayward 1 ，James F Wilson 1,2
，Christopher S Haley 1,3
，Veronique Vitart 1
1:Institute of Genetics and Molecular Medicine, University of Edinburgh, UK、2:Centre for Population Health Sciences, University of
Edinburgh、3:Roslin Institute and Royal (Dick) School of Veterinary Studies
Genome-wide association studies (GWAS) have identified many single-nucleotide polymorphisms (SNPs) affecting complex
traits. The success of GWAS depends on strong linkage disequilibrium at the population level between individual SNPs and
trait variants. In contrast, linkage analyses utilise associations between SNPs and trait variants within families instead of at
the population level.
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Our family-based cohorts from Croatia, the Orkney Islands and the general Scottish population have extensive pedigree infor-
mation, making them ideal for linkage analysis. Some of these cohorts are also population isolates, which means individuals
share longer haplotypes derived from common ancestors. Additionally, variants that are absent, or at a very low frequency,
in the general population may have drifted to higher frequencies in these isolates.
Here, we performed variance components linkage analysis and GWAS on quantitative traits of public health importance (e.g.
blood biochemical traits, anthropometric traits) in several isolated and cosmopolitan family-based populations. We compared
using known pedigree structures and population-based estimates of identity by descent sharing to perform our linkage anal-
yses. We identified promising linkage peaks (LOD scores of 4-6) for several traits, in individual populations.
One of these peaks was in educational attainment in the Orkney population (2000 individuals), with the highest-LOD SNP,
a missense variant predicted to be deleterious, being in complete linkage disequilibrium with a suggestively significant SNP
identified by a GWAS done on 126000 individuals. This SNP was not picked up by GWAS done in our population, suggest-
ing a more complex association of inherited haplotypes rather than single SNPs and showcasing the additional information
provided when integrating family into genetic analysis.
Tue(3)-P-64
Decreased Severity of Experimental Autoimmune Arthritis in Peptidylarginine Deiminase Type 4 Knock-
out Mice
Poster Session
Akari Suzuki 1 ，Yuta Kochi 1 ，Hirofumi Shoda 2 ，Keishi Fujio 2 ，Kazuhiko Yamamoto 1,2
1:RIKEN, Japan、2:Graduate School of Medicine, The University of Tokyo
Rheumatoid arthritis (RA) is well-known as an autoimmune disease and is a chronic inflammatory disorder characterized by
the destruction of multiple joints. Many genome wide association studies were performed and multiple RA-susceptibility loci
and autoimmune-susceptibility loci have been identified. These studies suggested that multiple genes and its functions were
related with disease causing and development.
Previouly, peptidylariginine deiminase type 4 (PADI4) was identified as a susceptibility gene for RA in a Japanese population
by case-control association study (Ref 1). PADI4 is a member of the PADI gene family and converts arginine residue (peptidy-
larginine) to citrulline residue (peptidylcitrulline). PADI4 is highly expressed in bone marrow, macrophages, neutrophils and
monocytes. Peptidylcitrulline is an interesting molecule in RA, because it is an antigen of ACPA and only PADs (translated
protein from PADI genes) can provide peptidylcitrullines, via modification of protein substrates. To evaluate the importance
of PADI4 gene in the progression of RA, we generated Padi4 -/- DBA1J mice. We used Padi4-/- mice to show that PAD4
is significantly affected to progress of collagen induced arthritis (CIA), well known as an RA model animal. Expression of
various inflammatory cytokines and Padi genes in immune cells was detected by real-time TaqMan assay. Cytokine concen-
trations in sera were measured by enzyme-linked immunosorbent assay. We demonstrated that Padi4 expression was induced
by CII immunization. In Padi4−/− mice, inflammatory cytokine levels were significantly decreased compared with those in
wild-type mice. Interestingly, Padi2 expression was induced in immune cells of Padi4-/- mice in compensation for the defect
in Padi4.
1) Suzuki, A. et al Nat. Genet.34, 395-402 (2003)
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Tue(3)-P-65
A replication study of four candidate loci for sex hormone levels previously identified by genome-wide
association studies
Youichi Sato 1 ，Atsushi Tajima 2 ，Motoki Katsurayama 1 ，Issei Imoto 3 ，Aiko Yamauchi 1 ，Teruaki Iwamoto 4
1:Pharmaceutical Information Science, Biomedical Sciences, Tokushima University Graduate School, Japan、2:Bioinformatics and Genomics,
Graduate School of Medical Sciences, Kanazawa University、3:Human Genetics, Biomedical Sciences, Tokushima University Graduate School、
4:Center for Infertility and IVF, International University of Health and Welfare Hospital
Recently, six genome-wide association studies (GWASs) revealed that several single nucleotide polymorphisms (SNPs) were
significantly associated with levels of sex hormones. Of these, rs2075230 was found to be associated with levels of testosterone
and sex hormone-binding globulin (SHBG), and rs2414095 was found to be associated with levels of follicle-stimulating
hormone (FSH) in 3495 Chinese men. In addition, rs6259 and rs727428 were found to be associated with levels of testosterone
in 3225 men of European ancestry. In the present study, we performed a replication study to assess whether these four SNPs
are associated with sex hormone levels in Japanese men. Cohort 1 (20.7 ± 1.7 years old) consisted of 901 male university
students, and cohort 2 (31.2 ± 4.8 years old) consisted of 786 partners of pregnant women. Associations between each SNP and
sex hormone levels were evaluated by meta-analysis of the two cohorts. We found that rs2075230 was significantly associated
with levels of testosterone (β STD = 0.15, P = 7.2 × 10-6 ) and of SHBG (β STD = 0.22, P = 3.4 × 10-12 ), and rs2414095 was
significantly associated with levels of FSH (β STD = 0.15, P = 9.7 × 10-5 ). On the other hand, rs6259 and rs727428 were
not associated with levels of testosterone (β STD = 0.082, P = 0.017; β STD = 0.17, P = 0.071, respectively) after adjusting
for multiple testing in the combined analysis of the two Japanese male cohorts. However, rs6259 and rs727428 were found to
be significantly associated with levels of SHBG (β STD = 0.23, P = 6.5 × 10-6 ; β STD = 0.21, P = 3.4 × 10-10 , respectively)
after adjusting for multiple testing in the combined analysis of the two Japanese male cohorts. Overall, our results from the
Poster Session
Japanese male population reflect those of the previous GWASs for rs2075230 and rs2414095, but not for rs6259 and rs727428.
Tue(3)-P-66
Genome-wide Association Studies on Immunoglobulin G Glycosylation Patterns
Annika Laser 1,2 ，Lucija Klaric 3,4,5 ，Elisa Benedetti 6 ，Marija Pezer 4 ，Marian Beekman 7 ，Joris Deelen 7 ，
Anton J.M. de Craen 8 ，Manfred Wuhrer 9 ，Rosina Plomp 9 ，Harald Grallert 1,2,10 ，Jan Krumsiek 6,10 ，
Konstantin Strauch 11,12 ，Annette Peters 2 ，Thomas Meitinger 13 ，P. Eline Slagboom 9 ，Gordan Lauc 4,14 ，
Christian Gieger 1,2
1:Institute of Epidemiology 2, Research Unit Molecular Epidemiology, Helmholtz Zentrum Muenchen - German Research Center for
Environmental Health, Neuherberg, Germany、2:Institute of Epidemiology 2, Helmholtz Zentrum Muenchen - German Research Center for
Environmental Health, Neuherberg, Germany、3:MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of
Edinburgh, Edinburgh, United Kingdom、4:Glycobiology Laboratory, Genos, Zagreb, Croatia、5:Centre for Population Health Sciences,
School of Molecular, Genetic and Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom、6:Institute of Computa-
tional Biology, Helmholtz Zentrum Muenchen - German Research Center for Environmental Health, Neuherberg, Germany、7:Department of
Molecular Epidemiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands、8:Department of Gerontology and Geriatrics,
Leiden University Medical Center (LUMC), Leiden, The Netherlands、9:Center for Proteomics & Metabolomics, Leiden University Medical
Center (LUMC), Leiden, The Netherlands、10:German Center for Diabetes Research (DZD), Neuherberg, Germany、11:Institute of Genetic
Epidemiology, Helmholtz Zentrum Muenchen - German Research Center for Environmental Health, Neuherberg, Germany、12:Institute of
Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universitaet, Munich, Germany、
13:Institute of Human Genetics, Helmholtz Zentrum Muenchen - German Research Center for Environmental Health, Neuherberg, Germany、
14:University of Zagreb, Faculty of Pharmacy and Biochemistry, Zagreb, Croatia
Immunoglobulin G (IgG), a glycoprotein produced and secreted by B-cells, plays a major role in the human immune response.
IgG glycosylation patterns affect the Fc binding receptors which, being activated, prompt the immune response. To analyze
the genetic influence on glycosylation in IgG, we performed a genome-wide association study (GWAS) on LC-MS measured
IgG glycans on plasma of about 1600 individuals in the KORA (Cooperative Health Research in the Augsburg Region) study
cohort. Additionally, we performed GWAS on ratios of glycans within IgG subclasses in order to elucidate genetic factors
determining single steps in the glycosylation pathways. We replicated the results from all GWAS in the Leiden Longevity
Study (LLS) of about 1842 individuals. The results indicate that in addition to genes encoding for enzymes known to be
contribute to IgG glycosylation (ST6GAL1 (chr.3), B4GALT1 (chr.9), FUT8 (chr.14), MGAT3 (chr.22)), other genes have a
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strong influence on the IgG glycosylation patterns. Interestingly, associations were found with SNPs on chromosome 17 in
the region of IKZF1, a gene encoding for a DNA-binding transcription-factor. This is of particular interest as its non-binding
isoforms are suggested to alter the progression of B-cell malignancies in humans.
Tue(3)-P-67
The crispld2 story: From gene function to new NSCLP candidate gene identification
Jacqueline T Hecht 1,2 ，Brett Chiquet 1 ，Qiuping Yuan 2 ，Lorena Maili 2 ，Robert Plant 2 ，Ariadne Letra 1 ，
Susan H Blanton 3 ，Eric C Swindell 2
1:The University of Texas Health Science Center at Houston School of Dentistry, USA、2:The University of Texas Health Science Center at
Houston Medical School、3:John P. Hussman Institute for Human Genomics, University of Miami Health System
We and others have shown that variation in the cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2 ) gene
is associated with nonsyndromic cleft lip with or without cleft palate (NSCLP) and that expression of Crispld2 is detected
in the craniofacies of mice and oropharynx of zebrafish during development. Additional evidence that CRISPLD2 is involved
in craniofacial development comes from zebrafish morpholino (MO) studies, which show that knockdown of Crispld2 causes
1) severe craniofacial abnormalities of the jaw and palate, 2) altered expression of neural crest cell (NCC) marker genes,
and 3) altered NCC migration during orofacial development. Further analysis in the crispld2 morphant shows that p53-
independent apoptosis is increased, indicating increased cell death as contributing to the phenotype, while cell proliferation
is unchanged. To identify NSCLP candidate genes that might interact with CRISPLD2 , zebrafish crispld2 morphants and
uninjected controls were subjected to RNA profiling studies. RNA-seq identified 349 differentially expressed genes, and in
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silico analysis identified a novel pathway involving 8 genes previously implicated in orofacial development: bag3, casp8, fgfr1,
fos, hoxb1b, jag2, kif1B, and mmp2 . Quantitative mRNA analysis confirmed differential expression for six of these transcripts.
Single nucleotide polymorphism (SNP) genotyping for these genes in our NSCLP families found the strongest associations with
FOS and MMP2 (p<0.002). Gene-gene interaction analysis revealed 22 interactions within this novel pathway with p<0.002.
Importantly, our results demonstrate that genes identified in human studies can be functionally assessed in zebrafish to define
biological processes that underlie complex birth defects. The results of our animal data are now being used to investigate
pathways in our NSCLP families. This novel approach can be used with other craniofacial developmental genes to dissect the
genetic contributions to NSCLP.
Tue(3)-P-68
Combined genome-wide linkage and association analysis of depressive symptomes point to CTNNA3
gene
Irina V. Zorkoltseva 1 ，Nadezhda M. Belonogova 1 ，Najaf Amin 2 ，Tatiana I. Axenovich 1 ，Cornelia M. van Dujin 2
1:Institute of Cytology & Genetics, Russia、2:Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
Despite a long search for genetic variants associated with major depressive disorder (MDD), a little success has been achieved
due to both heterogeneity and complexity of the genetic architecture of the disorder.
We analyzed a quantitative trait of depressive symptoms based on the Center for Epidemiological Studies Depression Scale
(CES-D) (N = 2203). We performed a genome-wide linkage and association analyses in Dutch genetically isolated population
(the Erasmus Rucphen Family Study). One significant linkage peak at the chromosome 13 (LOD score = 3.87) and three
suggestive peaks at chromosomes 3, 5 and 10 (LOD score = 2.09, 2.99 and 3.00, respectively) were found. No association
signals reached a genome-wide significance. To improve the power of association analysis we applied the weighted p-value
method (Roeder et al., 2006). The weights were estimated based on values of linkage tests. This procedure highlighted 10q22
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region. To reduce the risk of false discoveries, we calculated q-value for each p-value in this region using QVALUE software
(Storey and Tibshirani 2003). A strong association signal (FDR q-values < 0.05) was obtained for three SNPs located in the
catenin alpha-3 (CTNNA3 ) gene.
CTNNA3 encodes catenin alpha-3, a key protein of the adherens junctional complex playing a crucial role in cellular adherence.
This gene is located within a common fragile site, epigenetically regulated, transcribed through multiple promoters, and
alternately spliced. Both CTNNA3 and its nested gene LRRTM3 (encoding the Leucine-rich repeat transmembrane neuronal
protein 3) have previously been found associated with Alzheimer’s disease and autism spectrum disorder.
The combination of genome-wide linkage and association analyses allowed us to identify novel genetic association for depression
symptoms. Although further studies in other populations are needed to confirm these finding, the result presented here will
improve our understanding of MDD.
Tue(3)-P-69
Shared and unique genetic determinants between pediatric and adult celiac disease
1,2
Sabyasachi Senapati ，Thelma B.K 2 ，Ajit Sood 3 ，Vandana Midha 3
1:Centre for Human Genetics and Molecular Medicine, Central University of Punjab, India、2:Department of Genetics, University of Delhi
South Campus, New Delhi、3:Department of Medicine, Dayanand Medical College, Ludhiana, Punjab
Methods: A retrospective analysis of children (n=531) and adult (n=871) patients with celiac disease (CD) between January
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2001 and December 2010 was done. The database included basic demographic characteristics, clinical presentations, asso-
ciated diseases and complications, if any. The genotype dataset was acquired for children (n= 217) and adult CD patients
(n=340) and controls (n=736) using Immunochip. Association analysis was performed using logistic regression model to
identify susceptibility genetic variants.
Results: The predominant form of CD was classical CD in both pediatric and adult CD groups. There was remarkable
similarity between pediatric and adult CD except for quantitative differences between the two groups such as female pre-
ponderance, nonclassical presentation, co-occurrence of other autoimmune diseases being more common amongst adult CD.
HLA-DQ2 and -DQ8 haplotypes were the major risk factors in both types of CD. In addition, a few non-HLA markers were
associated with the two age categories but only ANK3 (rs4948256-A; rs10994257-T) was shared.
Conclusions: This present study is the first comparative study based on genetic markers to suggest that CD in pediatric age
group and in adults are the spectrum of the same disease with novel and shared genetic risk determinants.
Tue(3)-P-70
The role of regulatory single-nucleotide genetic polymorphisms of placental tissue in the development of
preeclampsia in different ethnic groups
Victoria Serebrova 1 ，Ekaterina Trifonova 1 ，Vadim Stepanov 1
1:Research Institute of Medical Genetics SB RAMS, Russia
Preeclampsia (PE) is one of the most serious pregnancy complications and the leading cause of maternal and perinatal
morbidity and mortality. The incidence of this pathology is approximately 2-8% of pregnancies worldwide. Despite decades of
research, the mechanisms underlying the cause and progression of PE remain poorly understood. The placenta is pivotal for
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the development of PE. Presently as promising approach for the characterization of the molecular mechanisms PE can consider
the research of differentially expressed genes placental tissue and mechanisms of this regulation. In this work we analyzed 48
regulatory single-nucleotide polymorphisms (rSNPs) in 23 new candidate genes, associated with PE according to the analysis
of the transcriptome in 519 patients with preeclampsia and 718 women with uncomplicated pregnancies of Russian, Buryat and
Yakut populations using MassArray iPLEX (Sequenom). We have detected significant associations of PE with 15 rSNPs in 12
genes: BHLHE40, PLIN2, CORO2A, SYDE1, LHB, HK2 , INHA, NDRG1, SASH1, ZNF175, CEBRA, PPP1R12C . These
results demonstrate the significant role of allelic variations of the regulatory single-nucleotide polymorphisms (rSNPs) new
candidate genes, which are associated with PE in the formation of this pathology in different ethnic groups. Interestingly,
frequently occurring category of "Gene Ontology" (GO) genes which associated with PE in this work are DNA binding,
sequence-specific DNA binding transcription factor activity, protein heterodimerization activity, receptor binding, hormone
activity, contributes to protein binding and protein binding. These categories characterize biological processes that occur
in placental tissue and hypothetically are involved in the molecular mechanisms development of preeclampsia. The clinical
significance of these findings remains to be determined. This work was supported by the Russian Foundation for Basic
Research (grant 14-04-01467).
Tue(3)-P-71
Genetic Association of HLA-C Region with Kawasaki Disease in the Korean Population
Jae-Jung Kim 1 ，Hye-Seon Lee 1 ，Jong-Keuk Lee 1 ，Korean Kawasaki Disease Genetics Consortium
1:Asan Institute for Life Sciences, University of Ulsan College of Medicine, Korea, South
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Kawasaki disease (KD) is an acute self-limited vasculitis of infants and children, manifested by fever and signs of mucocuta-
neous inflammation. Coronary artery aneurysms develop in approximately 15 to 25% of untreated children and have made
KD the leading cause of acquired heart disease in developed countries. Although its etiology is largely unknown, epidemiologic
data suggest the importance of genetic factors in susceptibility to KD. To identify genetic variants influencing KD suscepti-
bility, we performed a genome-wide association study (GWAS) in 249 Korean KD patients and 1,000 controls. Six genomic
regions with one or more sequence variants were associated with KD (P < 1 × 10-5 ). Of these, only one locus was replicated
in our previous GWAS data set consisting of 165 children with KD and 600 controls (odds ratio (OR) = 1.49, 95% confidence
interval (95% CI) = 1.08-2.05, P = 0.01459), and thus selected for further validation. This SNP in HLA-C locus was also
replicated in independent 550 children with KD and 569 normal controls (OR = 1.33, 95% CI = 1.06-1.66, P = 0.01342).
Further fine-mapping of the candidate gene is needed to identify causative variants for KD susceptibility in HLA-C region.
Tue(3)-P-72
Dissecting the unexpected role of PAG1 in asthma
Cristina M.T. Vicente 1 ，Jason P. Lynch 2 ，Simon Phipps 2 ，Manuel A.R. Ferreira 1
1:Genetics & Computational Biology, QIMR Berghofer Medical Research Institute, Australia、2:School of Biomedical Sciences, The University
of Queensland
The gene(s) whose expression is regulated by allergy risk variants is unknown for many loci identified through genome-wide
association studies. Addressing this knowledge gap might point to new therapeutic targets for allergic disease. Our studies
suggest that the risk-associated allele of rs2370615 on chromosome 8q21 predisposes to allergic disease by increasing PAG1
expression - a gene highly expressed in the immune system (T and B cells) that encodes for a transmembrane adaptor protein
localized to lipid rafts. Challenging the current paradigm that PAG1 overexpression has an anti-inflammatory effect, our
results suggest that increased PAG1 expression might activate B-cells and have a pro-inflammatory role instead. Therefore, we
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hypothesize that inhibition of PAG1 expression or function might attenuate allergen-induced airway inflammation or prevent
asthma symptoms. To test this possibility, we are currently characterizing the immune and inflammatory responses triggered
in the airways by allergen challenge of wildtype (WT) and PAG1 knockout (KO) mice, in an acute model of experimental
asthma. Results from these experiments, which will be presented at ICHG, provide the first assessment of the role of PAG1
in asthma pathophysiology.
Tue(3)-P-73
Gene-gene interaction for markers in 16p13.3 may contribute to the risk of non-syndromic cleft lip with
or without palate in Chinese population
Dongjing Liu 1 ，Holger Schwender 2 ，Ingo Ruczinski 3 ，Jeffrey C. Murray 4 ，Mary L. Marazita 5 ，Ronald G. Munger 6 ，
Ping Wang 1 ，Richard J. Redett 7 ，Yah Huei Wu-Chou 8 ，Samuel S. Chong 9 ，Vincent Yeow 10 ，Hong Wang 1 ，
Ethylin W. Jabs 7,11 ，Bing Shi 12 ，Sun Ha Jee 13 ，Tao Wu 1,3 ，Alan F. Scott 7 ，Terri H. Beaty 3
1:School of Public Health, Peking University Health Science Center, Beijing, China、2:Mathematical Institute, Heinrich Heine University
Duesseldorf, Duesseldorf, Germany、3:Johns Hopkins University, School of Public Health, Baltimore, Maryland, United States of America、
4:University of Iowa, Children’s Hospital, Iowa City, Iowa, United States of America、5:Center for Craniofacial and Dental Genetics, School
of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America、6:Utah State University, Logan, Utah,
United States of America、7:Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America、8:Chang Gung
Memorial Hospital, Taoyuan, Taiwan、9:National University of Singapore, Singapore, Singapore、10:KK Women’s & Children’s Hospital,
Singapore, Singapore、11:Mount Sinai Medical Center, New York, New York, United States of America、12:State Key Laboratory of Oral
Disease, West China College of Stomatology, Sichuan University, Chengdu, China、13:Yonsei University, School of Public Health, Seoul,
Korea
Background: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common, complex human congenital birth
defect. A recent genome-wide association study (GWAS) among Chinese populations has identified a new region 16p13.3
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associated with NSCL/P, which still requires further replication. Here, we attempted to validate and further clarify the
genetic association between this region and NSCL/P and to test for potential gene-gene (G×G) and gene-environment (G×E)
interaction. Methods: We conducted transmission disequilibrium tests on 97 single nucleotide polymorphisms (SNPs) mapping
to 16p13.3 explicitly among 806 Chinese case-parent trios ascertained through an international consortium which conducted
a GWAS of oral clefts. G×G as well as G×E interaction involving maternal environmental tobacco smoke (ETS) and
multivitamin supplementation were explored based on conditional logistic regression model. We applied Cordell’s method
which implemented in the R package TRIO to perform the interaction analysis. Results: While no SNP showed evidence
of linkage and association with the disease after Bonferroni correction, we found signals of SNP-SNP interactions between
markers in 16p13.3. Three pairs of SNPs between ADCY9 and a nearby non-coding region attained GWAS statistical
significance (p<10-8 ), among which the most significant interaction was found between rs7197403 (ADCY9 ) and rs2283484
(non-coding region, p<2.2x10-16 ). Linkage disequilibrium (LD) analysis revealed only low level of LD between these markers.
Tests for GxE interaction failed to show significant results. Conclusion: This study fails to confirm the prior association
between markers in 16p13.3 and NSCL/P, but underlines the importance of taking into account potential G×G interactions
for genetic association analysis in NSCL/P.
Tue(3)-P-74
Association of serum biotin and total/specific IgE levels and a common locus for biotin and cedar
pollen-specific IgE levels
Yoichi Suzuki 1 ，Yoichi Mashimo 2 ，Mika Yageta-Sakurai 1 ，Naoki Shimojo 3 ，Yoshitaka Okamoto 4 ，Akira Hata 2
1:Education and Training, Division of Genetic Epidemiology Research Support, Tohoku Medical Megabank Organization, Tohoku University,
Japan、2:Department of Public Health, Graduate School of Medicine, Chiba University, Chiba, Japan、3:Department of Pediatrics, Graduate
School of Medicine, Chiba University, Chiba, Japan、4:Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School
of Medicine, Chiba University, Chiba, Japan
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Biotin is a coenzyme of several carboxylases. It is well known that nutritional biotin deficiency and mutations of holocarboxy-
lase synthetase and biotinidase cause eczema-like dermatitis. Molecular mechanism of this condition has not been studied
well. Physiological roles of biotin other than coenzyme are largely unknown and there is no report about association of biotin
metabolism with allergic sensitization or allergic diseases in humans.
We investigated prevalence of allergic diseases, serum total and 8 specific IgE levels, environmental factors, and genetic back-
grounds in 411 Japanese school children (age 6 to 12). Serum biotin levels were assayed with Biotin ELISA Kit. We found that
significant associations of biotin level with total IgE(P=0.0030)and several specific IgE levels (cedar pollen (P=0.00036), cat
dander (P=0.0085), egg white (P=0.00013)). The mean biotin level of cedar pollinosis patients (mean=154.8 ng/L, Number
(N) =85) was significantly (P=1.9 x10-4 ) higher than that of the non-atopic control subjects (mean=127.9 ng/L, N=105).
To our knowledge, these data are the first demonstration of correlation between biotin metabolism and allergic sensitization
and an allergic disease.
To investigate the mechanism of biotin in regulation of IgE production, as a first step, we have tried to identify loci to affect
serum biotin level. We genotyped 233 children in a first screening. Of 485k SNPs tested, 91 SNPs showed a coefficient with
P<0.001 in a linear regression model, which were tested in the rest of the children as a second screening. Six SNPs with
P<0.1 showed the same direction of effect as in the first. The significance levels of the entire subjects of the SNPs were
4.43×10-4 to 7.81×10-8 . One SNP showed association also with cedar pollen-specific IgE level (P=4.40×10-4 ), suggesting
Poster Session
that this locus may be common to allergic sensitization and biotin level and may at least in part explain the association
between these phenotypes.
Tue(3)-P-75
Genome-wide association study identified new susceptible genetic variants in HLA class I region for
hepatitis B virus-related hepatocellular carcinoma
Hiromi Sawai 1 ，Nao Nishida 1,2
，Masaya Sugiyama 2 ，Seik-Soon Khor 1 ，Masashi Mizokami 2 ，Katsushi Tokunaga 1
1:Department of Human Genetics, The University of Tokyo, Japan、2:The Research Center for Hepatitis and Immunity, National Center for
Global Health and Medicine
Recent genome-wide association studies (GWAS) using chronic HBV (hepatitis B virus) carriers with and without HCC
(hepatocellular carcinoma) in Chinese populations reported that SNPs in KIF1B, HLA-DQA1/DRB1 , GRIK1 , STAT4 and
HLA-DQ were associated with HCC susceptibility. In this study, we performed a GWAS using 473 Japanese HBV-positive
HCC patients and 516 HBV carriers including CH (chronic hepatitis) and ASC (asymptomatic carrier) individuals in order
to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations.
After quality control, there were 110 SNPs with P value < 10-4 with 65 and 4 SNPs located within the HLA class I and II
region, respectively. In a subsequent replication analysis, 3 SNPs in HLA class I region were genotyped in 4 independent
population-based replication sets (Japanese, Korean, Hong Kong Chinese, and Thai). The meta-analysis with the combined
Japanese samples and 3 other replication sample sets confirmed the association for the SNPs (SNP1: OR = 1.63, P = 7.34
x 10-11 ; SNP2: OR = 1.70, P = 6.72 x 10-13 ; and SNP3: OR = 1.71, P = 5.63 x 10-9 ). We performed four-digit HLA
genotype imputation for 5 HLA locus (HLA-A, B, DRB1, DQB1 and DPB1 ) using GWAS SNP typing data to investigate
the association of HLA alleles. HLA alleles association test detected a particular HLA class I allele was significantly associated
with disease progression to HCC (OR = 1.97, P = 4.58 x 10-4 ). Conditioning analysis of each of the 3 SNPs on HLA class I
region abolish the association of the HLA allele (P > 0.05). On the contrary, conditioning the HLA allele could not eliminate
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the association of the 3 SNPs (SNP1: OR = 1.67, P = 6.53 x 10-4 ; SNP2: OR = 1.72, P = 2.49 x 10-4 ; and SNP3: OR = 1.48,
P = 1.02 x 10-2 ), suggesting that additional genetic factor seems to exist in HLA class I region. Additional conditional
analyses were needed to find other genetic factor(s) in HLA class I region.
Tue(3)-P-76
Metabolomic and transcriptomic fingerprints of menopausal hormone therapy in 3479 Finnish women
Anni Joensuu 1,2 ，Johannes Kettunen 2,3,4 ，Matti Jauhiainen 2 ，Antti J Kangas 3 ，Pasi Soininen 3,4 ，Antti Jula 5 ，
Veikko Salomaa 2 ，Johan Eriksson 6 ，Mika Ala-Korpela 3,4,7,8 ，Markus Perola 1,2,9 ，Kirsi Auro 1,2,10
1:Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland、2:Department of Health, National Institute for Health and Welfare,
Helsinki, Finland、3:Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland、4:NMR Metabolomics Laboratory,
School of Pharmacy, University of Eastern Finland, Kuopio, Finland、5:National Institute for Health and Welfare, Turku, Finland、
6:Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland、7:Oulu University Hospital, Oulu,
Finland、8:Computational Medicine, School of Social and Community Medicine & Medical Research Council Integrative Epidemiology Unit,
University of Bristol, Bristol, United Kingdom、9:University of Tartu, Tartu, Estonia、10:Helsinki University Central Hospital, Department
of Gynecology and Obstetrics, Helsinki, Finland
Background: Menopause (MP) influences the health of all middle-aged women. Hormone therapy (HT) is commonly used to
treat menopausal symptoms, but the effect of HT on cardiovascular disease (CVD) risk is under strong debate. The analysis
of metabolic and transcriptomic profiles of HT users and non-users introduces novel information on factors affecting disease
risk.
Methods: We studied 3479 non-pregnant, non-lipid medicated 40-70-year-old women from four Finnish population cohorts,
Poster Session
FINRISK97, DILGOM, HBCS and Health2000. Levels of 70 serum metabolites were defined using an NMR platform.
Metabolites were individually treated as dependent variables in linear regression corrected for age, BMI and fasting. HT
users (N=1017) were studied against a) premenopausal and b) postmenopausal women. The transcriptomic effects of HT
were analyzed similarly in 176 DILGOM women.
Results: The metabolic profiles of preMP women and HT users are very similar: p<0.05 Bonferroni corrected differences
were seen in only three metabolites; monounsaturated, total and saturated fatty acids. On the contrary, a clear atherogenic
shift was seen when comparing HT users and postMP women: levels of 21 of the 70 studied metabolites differed. The lowest
p-value (2.8*10-13) was seen in the level of total cholesterol in LDL. Levels of LDL and IDL subclasses were higher and HDL
subclasses lower in postMP women. Also levels of serum total cholesterol, apoB, glycine and glycoprotein acetylation were
clearly higher in postMP. Results from the transcriptomic and metabolomic analyses are somewhat contradictory; levels of
510 transcripts differed (p<0.01) between preMP and HT users, whereas levels of only 164 transcripts differed between HT
and postMP women.
Conclusions: Our results provide the first metabolome-wide population-based knowledge on using HT. The data demonstrate
that change from HT usage to postmenopausal non-usage causes a clear atherogenic metabolic shift possibly contributing to
the risk of CVD.
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Tue(3)-P-77
Genome-wide association study on cephalic form in Japanese
Kyoko Yamaguchi 1 ，Tsuyoshi Ito 2 ，Akira Kawaguchi 2 ，Takehiro Sato 3 ，Chiaki Watanabe 2 ，Ken Yamamoto 4 ，
Hajime Ishida 2 ，Ryosuke Kimura 2
1:School of Natural Sciences and Psychology, Liverpool John Moores University, UK、2:Graduate School of Medicine, University of the
Ryukyus、3:Graduate School of Medical Sciences, Kanazawa University、4:Kurume University School of Medicine
Human skull size increases as the brain grows inside during infancy, hence, head circumference has been used as a proxy index
for brain development. However, the biological process including genetic basis of normal variation in size and morphology of
head has not been revealed yet. Therefore, we conducted a genome-wide association study (GWAS) for human cephalic form
based on analyses using DNA microarrays with 767 Japanese individuals living in Okinawa Island of Japan. A single nucleotide
polymorphism (SNP) located within LOC284825 on chromosome 21q21.3 was associated with head circumference measured
with a tape-measure at a conventional genome-wide significant level (P<5.0x10-8 ) after controlling for sex, height, BMI, and
population groups. We then conducted a replication study to confirm the results. In addition to the SNP in LOC284825 , we
genotyped two SNPs located in CNTNAP2 , a gene related to neuropsychological traits, that showed associations at suggestive
levels (P<1.0x10-5 ) in the GWAS with head circumference and head breadth measured using an anthropometer. We used
computed tomography images of 194 individuals in Okinawa Island to obtain the head morphology measurements that are
similar to the GWAS. One of the two SNPs located in CNTNAP2 was associated with head circumference with marginal
significance after Bonferroni correction for multiple testing. The result of the replication study reinforced the findings in the
GWAS that the region of CNTNAP2 is involved in determining head size in humans. Further studies examining a variety of
factors that determine head size, including brain size or thickness of soft and hard tissue, are needed to elucidate the detailed
Poster Session
pathway in which CNTNAP2 affects head circumference.
Tue(3)-P-78
Identification and Replication of Height Loci in African Ancestry Populations
Maggie C.Y. Ng 1 ，Mariaelisa Graff 2 ，Anne Justice 2 ，Ying Chang Lu 3 ，Poorva Mudgal 1 ，Ching-Ti Liu 4 ，
Kristin Rand 5 ，Qing Duan 2 ，Brian E. Cade 6 ，Jennifer Brody 7 ，Mary K. Wojczynski 8 ，Mary F. Feitosa 8 ，
Lisa R. Yanek 9 ，Michael A. Nalls 10 ，Leslie Lange 2 ，Sailaja Vedantam 11 ，Xiuqing Guo 12 ，Christopher A. Haiman 5 ，
Ruth J.F. Loos 3 ，Kari E North 2 ，the African Ancestry Anthropometry Genetics Consortium
1:Wake Forest School of Medicine, USA、2:University of North Carolina at Chapel Hill, Chapel Hill, NC、3:Icahn School of Medicine at
Mount Sinai, New York, NY、4:Boston University School of Public Health, Boston, MA、5:University of Southern California, Los Angeles,
CA、6:Brigham and Women’s Hospital, Boston, MA、7:University of Washington, Seattle, WA、8:Washington University School of Medicine,
St. Louis, MO、9:Johns Hopkins University School of Medicine, Baltimore, MD、10:National Institute on Aging, Bethesda, MD、11:Boston
Childrens Hospital, Boston, MA、12:Harbor-UCLA Medical Center, Torrance, CA
Height is a classic polygenic trait with >80% heritability. Genome-wide association studies (GWAS) have identified >400
height loci primarily in European ancestry populations. Here, we performed meta-analyses of GWAS for height in individuals
of African ancestry from 16 discovery (n=41,402) and 7 replication (n=11,364) studies.
In each study, height was stratified by sex and adjusted for age and principal components. Imputation was performed using
the cosmopolitan 1000 Genomes Phase 1 reference panel. Single variant association test was performed under an additive
model. For stage 1, we combined study specific association results using fixed-effects inverse variance weighted meta-analysis,
both stratified and combined across sexes. Variants reaching P<1E-4 (576 loci) were brought forward for replication in stage
2. We also performed meta-analysis of our data with summary statistics from European ancestry populations at the GIANT
consortium (n= 253,252).
In the meta-analyses of stages 1 and 2 results, we observed genome-wide significant signals (P<5E-8) in 37 established and
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10 novel loci (near MIR4268 , NCOA2 , ECD, TGFB3 , CA10 , KIF2B, CUEDC1 , C17orf64-APPBP2 , MRC2 and PRKCA)
in African ancestry individuals. Sex-stratified analyses identified 2 additional novel loci (near CRB1 and LINC00704 ) in
women. Combining association results from individuals of African and European ancestry identified 8 additional novel loci
near UGGT1 , COL6A3-MLPH , ZNF318 , PTPN9 , RCCD1 , G6PC3 , ITGB3-EFCAB13 and CEP95 . Among 686 lead
variants previously reported in Europeans, 565 variants showed directionally consistent effects (binomial P=2E-16) and 24
were replicated at P<7E-5 in our samples.
Our findings suggest the presence of ancestry-specific variants associated with height. In addition, many loci are shared
between populations of African and European ancestry. The differences in linkage disequilibrium across populations may
improve the localization of causal variants in these shared loci.
Tue(3)-P-79
The h4 curse of genomic prediction
1,2
Xia Shen ，Zheng Ning 1 ，Youngjo Lee 3 ，William G. Hill 2 ，Chris S. Haley 2 ，Yudi Pawitan 1
1:Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden、2:University of Edinburgh、3:Seoul National Uni-
versity
Geneticists have spent plenty of efforts trying to predict human complex traits using individual genotypes. For instance, one
of the popular methods is to construct so-called polygenic scores based on variants effects estimates from large genome-wide
association study meta-analyses. However, there is surprisingly a huge gap between the estimated narrow-sense heritability
Poster Session
of each complex trait and the predicted proportion of variance using polygenic scores in an independent sample. This gap is
mostly considered to be caused by limited sample size and imperfect linkage disequilibrium between causal and genotyped
variants. Here, we define the predictive ability of a clone to be “h 4 ”, i.e. the squared heritability, and we show theoretically
how the h 4 value becomes a natural limit of high-dimensional genomic prediction. We conclude that, with a polygenic
architecture, genomic prediction of a complex trait heritability is cursed to be difficult and can even be practically impossible
to achieve.
Tue(3)-P-80
Frequent Potential Mutations in 378 Candidate Genes of Glaucoma Identified by Whole Exome Sequenc-
ing of 257 Patients with Glaucoma
1
Xiaobo Huang
1:State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, China
Purpose: Glaucoma is a leading blindness-inducing disease with great inherited tendency. At least seven glaucoma genes have
been identified. However, mutations of all known glaucoma genes account for only 5-7% percent of patients with glaucoma.
The aim of this study is to evaluate variants of candidate glaucoma genes in a cohort of patients with glaucoma.
Methods: Whole exome sequencing was performed in the genomic DNA samples of 257 Chinese patients with primary
glaucoma. Variants in all known glaucoma genes and 378 candidate genes were filtered through multi-step bioinformatics
analysis.
Results: Totally, 19 pathogenic mutations in known glaucoma genes were detected in 7.8% (20/257) patients with glaucoma.
In addition, 160 potential mutations in 71 candidate genes were detected in 56.8% patients, including 26.5% (68/257), 19.5%
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(50/257), and 10.9% (28/257) patients with mutations in genes associated with optic neuropathy, hereditary retinal dystrophy
genes, or eye development (anterior segment dysgenesis, microphthalmia or microcornea), respectively.
Conclusions: The similarity between mutation frequency of known glaucoma genes in our patients and previous studies
suggests that whole exome sequencing is a reliable technique for mutation screening. The unexpected frequent mutations in
genes associated with optic neuropathy, hereditary retinal dystrophy, or eye development in patients with glaucoma implies
that mutations in these genes may be risk factors for glaucoma. These novel findings are expected to be validated in different
ethnic groups.
Tue(3)-P-81
Functional annotation of chronic pancreatitis-associated intronic variants in the SPINK1 gene
Wen-Bin Zou 1,2,3,4 ，Arnaud Boulling 1,3 ，Emmanuelle Masson 1,5
，David N. Cooper 6 ，Zhuan Liao 2,4
，Zhao-Shen Li 2,4
，
Claude Ferec 1,3,5,7 ，Jian-Min Chen 1,3,7
1:U1078, Institut National de la Sante et de la Recherche Medicale (INSERM), France、2:Department of Gastroenterology, Changhai Hospi-
tal, the Second Military Medical University, Shanghai, China、3:Etablissement Francais du Sang (EFS); Bretagne, Brest, France、4:Shanghai
Institute of Pancreatic Diseases, Shanghai, China、5:Laboratoire de Genetique Moleculaire et Histocompatibilite, Centre Hospitalier Univer-
sitaire (CHU) Brest, Hopital Morvan, Brest, France、6:Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, United
Kingdom、7:Faculte de Medecine et des Sciences de la Sante, Universite de Bretagne Occidentale (UBO), Brest, France
SPINK1 is one of the best studied genes predisposing to chronic pancreatitis. It encodes pancreatic secretory trypsin inhibitor,
an important defense mechanism against prematurely activated trypsinogen within the pancreas. Whereas the pathological
Poster Session
relevance of large deletions and nonsense, frameshift and splice site mutations is generally self-evident, that of missense and
regulatory variants has to be deduced by functional analysis. We and others have previously functionally established the
pathogenicity of various SPINK1 missense mutations and promoter variants. Here we performed a systematic functional
annotation of SPINK1 intronic variants, including those already known (N = 15, 8 of which have been classified as being of
unknown clinical significance) and those newly identified (>10) from deep resequencing of the SPINK1 gene in 39 unrelated
French patients with familial chronic pancreatitis (none of these patients had been found to harbor pathogenic variants
within the coding regions or exon/intron boundaries of the PRSS1, SPINK1, CTRC and CPA1 genes). We succeeded
in cloning all these variants (with one exception), in the context of the entire genomic sequence of the SPINK1 gene (as
opposed to a minigene system) into the pcDNA3.1/V5-His-TOPO vector, either by means of site-directed mutagenesis or
by PCR amplification of the entire SPINK1 genomic sequence from their respective carriers. RT-PCR analyses of mRNAs
from subsequently transfected HEK293T cells corroborated previous conclusions with respect to the two known pathogenic
variants and all 5 presumed non-pathogenic variants, and established that 7 previously reported variants of unknown clinical
significance and all newly identified intronic variants were of no pathogenic significance. Importantly, we failed to confirm
the functional defect predicted by Alamut software in several cases, highlighting the need for functional analysis in precisely
determining the clinical significance of intronic variants.
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Tue(3)-P-82
Multi-trait GWAS method comparison and application of summary statistic methods to publicly available
data
Heather F Porter 1 ，Samir De Marchi 1 ，Paul F O’Reilly 1
1:SGDP Centre, IoPPN, King’s College London, UK
There is growing interest in performing genetic analyses on multiple phenotypes jointly. We present a simulation framework
to model the complex networks underlying multivariate genetic epidemiology, enabling the vast model space of genetic effects
on multiple correlated traits to be explored systematically. We exploit our simulation framework to perform a comprehensive
comparison study of the leading multi-trait GWAS methods (both those based on individual-level data, and those that utilise
GWAS summary statistics), finding: (1) method performance is highly sensitive to the specific combination of genetic effects
and phenotypic correlations, (2) the individual-level data methods have remarkably similar, seemingly optimal, statistical
power, and (3) multivariate methods offer an estimated 103% increase in discovery of genetic variants over the standard
univariate approach. However, for studies that can utilise much larger summary statistic data sets than individual-level data,
applying a summary data method may optimise statistical power. Motivated by this, we perform multi-trait analyses on
the latest publicly available GWAS summary statistics on more than 20 phenotypes. We use methods that aim to detect
heterogeneous and homogeneous genetic effects, and identify novel genome-wide significant associations.
We provide a web application (www.MultiTraitGWAS.kcl.ac.uk) and open-source software program implementing our simula-
tion framework for: (i) further benchmarking of multivariate GWAS methods, (ii) power calculations for multivariate genetic
studies, and (iii) generating data for testing any multivariate method in genetic epidemiology or quantitative fields.
Poster Session
Tue(3)-P-83
Systems Genetics of Plasma 1 H Nuclear Magnetic Resonance Metabotypes Associated with Car-
diometabolic Diseases in a Lebanese Cohort
Andrea Rodriguez-Martinez 1 ，Michael Kyriakides 1 ，Nikita Gandhi 1 ，Jean-Baptiste Cazier 2 ，Joram M. Pasma 1 ，
Jeremy.K Nicholson 1 ，Dominique Gauguier 3 ，Pierre Zalloua 4 ，Marc-Emmanuel Dumas 1
1:Surgery and Cancer, Imperial College London, UK、2:Centre for Computational Biology, University of Birmingham、3:NSERM, UMRS872,
Centre de Recherche des Cordeliers, Paris, France、4:Lebanese American University, School of Medicine, Beirut, Lebanon
Coronary artery disease (CAD) has a multifactorial aetiology, combining environmental and genetic factors. Epidemiolog-
ical studies have shown that a number of metabolic conditions are associated with increased risk of CAD. These so-called
CardioMetabolic Diseases (CMDs) consist of a cluster of disorders including: type II diabetes mellitus, hypertension, hyper-
lipidaemia, and visceral obesity. The comprehensive evaluation of the metabolic perturbations observed in CMDs represents
a major challenge for accurate diagnosis and personalised healthcare. High-throughput metabolic phenotyping (ie metabo-
typing) by 1 HNMR targets low molecular weight compounds from biofluids or biopsies and has proved to be very successful
in diagnosis of CAD, and in the prediction of drug toxicity. Mapping disease-associated metabolites onto the human genome
brings new insights in the molecular basis of CMDs and CAD. In order to achieve this, we focussed on a cohort of 1,949
genotyped patients with CAD and CMDs selected from previously studied collection of 8,709 Lebanese subjects with detailed
clinical, biological, behavioural and social data available. The geographic location of Lebanon, at the crossroad of Europe,
Africa, Asia Minor and the Middle East, and its unique genetic characteristics, makes our study an excellent opportunity to
identify novel alleles regulating metabolite abundance in blood.
We profiled 1,949 plasma samples from the cohort by 1 H NMR and metabolome-wide association studies were implemented
taking into account risk factors. We identified several metabolites associated with CMDs, including alanine, histidine, pro-
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line, branch chain aminoacids (leucine, isoleucine, valine), lactate, myo-inositol, mannose, glucose, N -acetylated compounds,
creatinine, and specific lipoproteins subfractions. These disease-associated metabolites are currently being mapped onto the
genome to provide new insights in the genetic landscape of CMD-associated plasma metabolites.
Tue(3)-P-84
Transcriptomic analysis to identify biological markers for antibody production introduced by seasonal
influenza vaccination
Maiko Narahara 1 ，Toby Hocking 2 ，Guillaume Bourque 2 ，Mark Lathrop 2 ，Fumihiko Matsuda 1
1:Medicine, Kyoto University, Canada、2:McGill University
Influenza vaccines reduce the risks of serious outcomes of influenza infections. However, the efficiency of the vaccines is
limited. We conducted a multi-omics study that includes a wide range of omics data from genomes to phenomes of vaccinated
human subjects to elucidate molecular mechanisms under the protection induced by the vaccines. Here we will report present
the results of the transcriptomic analysis as a part of the multi-omics study.
We obtained samples at four time points from each of 302 individuals who were vaccinated with trivalent inactivated influenza
vaccines; immediately before vaccination (day0), day1, day7, and day90 after vaccination. Transcriptomic profiles were
obtained from whole blood samples at day0 and day7 by microarrays.
Poster Session
We defined binary outcomes, responders (Rs) and non-responders (NRs), based on influenza-specific antibody levels in the
serum; and we obtained 153 Rs and 141 NRs at day7, and 185 Rs and 93 NRs at day90. First, we performed the differential
expression (DE) analysis of day7 expression between Rs and NRs. We identified 143 DE probes for day7, and 318 DE probes
for day90 by separate models. However, an interaction model indicated that all the DE genes were associated with day90
outcomes rather than day7 outcomes. Second, we employed an L1-regularized logistic regression to generate a predictive
model for the outcomes from transcriptomic profiles and clinical phenotypes. Given the results of the DE analysis, we
applied the method to the day90 outcomes. The most frequently selected variables (>80%) included expressional changes
of immunoglobulin genes and past vaccinations. Repeated cross-validation demonstrated that the mean accuracy and mean
AUC of generated models were 77%±8.8 and 0.88±0.07, respectively.
In conclusion, transcriptomic profiles can predict the outcomes effectively. Extending the analyses to other omics profiles can
improve the predictive performance of the model.
Tue(3)-P-85
Characterizing the genetic architecture of ocular biometrics in an untested south Asian population: the
Jirels of eastern Nepal (Jiri Eye Study)
Matthew P Johnson 1 ，Suman S Thapa 2 ，Kent L Anderson 3 ，Sandy Laston 1 ，Mohan K Shrestha 2 ，Bradford Towne 4 ，
Janardan Subedi 5 ，John Blangero 1 ，Sarah Williams-Blangero 1
1:South Texas Diabetes & Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, USA、2:Tilganga Institute of
Ophthalmology, Kathmandu, Nepal、3:Department of Ophthalmology, School of Medicine, University of Texas Health Science Center at San
Antonio, San Antonio, TX, USA、4:Department of Community Health, Boonshoft School of Medicine, Wright State University, Kettering,
OH, USA、5:Department of Sociology and Gerontology, College of Arts and Science, Miami University, Oxford, OH, USA
Approximately 90% (n=660 million) of the world’s visually impaired reside in developing countries. Combating ocular-related
health problems in these countries is critical if we are to reduce the global burden associated with visual impairment (VI).
An objective of a new study established in eastern Nepal and focused on the Jirel ethnic group is to characterize the genetic
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architecture of ocular-trait measures known to influence VI prevalence. Nepal is a developing country where the prevalence of
VI across regions ranges from 7% to 42%. Our family-based study design is recruiting 2,000 members of the Jirel population to
undergo an eye examination to document, in part, optic disc characteristics such as vertical cup-to-disc ratio (VCDR), a known
risk factor for glaucoma. We will use a variance components method for pedigree data (SOLAR) to determine the underlying
genetic architecture (heritability, pleiotropy) of all measured ocular-related traits (e.g., VCDR) and disease end-points (e.g.,
glaucoma). The Jirels, a genetic isolate, belong to a single extended pedigree containing >62,000 pair-wise relationships that
are informative for genetic analysis. The Jirel pedigree has 80% power to detect an additive genetic heritability as low as
6.5% and a genetic correlation between two traits as low as 4.4%. To date, 229 Jirel members have been recruited to the
study. Their mean (range) age at exam was 45.7 (13-85) years. Mean (median) VCDR for the right and left eyes were 0.55
(0.59) and 0.56 (0.60), respectively. Approximately 800 Jirels will be recruited to the study by March 2016 allowing us to
then perform and present initial heritability and plieotropy estimates to explain the basic underlying genetic architecture
of these clinically important ocular measures. Evaluating the genetic architecture underlying ocular biometry, especially in
under-studied populations from the developing world, is an important step to help aleviate the global burden associated with
VI.
Tue(3)-P-86
Functional variants in a clinical setting: an example using APOC3 R19X and extreme triglyceride levels
extracted from electronic health records
1,2
Dana C. Crawford ，Kirsten E. Diggins 3 ，Nicole A. Restrepo 1,2
，Eric Farber-Eger 4 ，Quinn S. Wells 5,6
Poster Session
1:Institute for Computational Biology, Case Western Reserve University, USA、2:Department of Epidemiology and Biostatistics, Case Western
Reserve University、3:Cancer Biology, Vanderbilt University Medical Center、4:Vanderbilt Institute for Clinical and Translational Research,
Vanderbilt University Medical Center、5:Department of Medicine, Vanderbilt University Medical Center、6:Department of Pharmacology,
Vanderbilt University Medical Center
In a personalized or precision medicine setting, patients with extreme triglyceride (TG) levels may be flagged for further
evaluation for cardiovascular disease risk assessment (TG ≥200 mg/dL) or for the presence of hyperthyroidism, malnutrition,
or malabsorption disease (TG ≤10 mg/dL). We hypothesize that the addition of functional genetic variants such as APOC3
R19X, a variant (rs76353203) associated with low TG levels and cardioprotection, can further facilitate the triage process in
assessing disease risk among flagged patients. To test this approach, we surveyed BioVU, the Vanderbilt University Medical
Center’s biorepository linked to de-identified electronic health records (EHRs), for adult European American patients (>45
and >55 years of age for men and women, respectively) with the lowest percentile of TG levels. The initial search identified
262 patients with the lowest TG levels in the biorepository; among these, 184 patients with sufficient DNA and the lowest
TG levels were chosen for Illumina ExomeChip genotyping. The average first mentioned TG level for these patients was 39.3
mg/dL. A total of two patients were identified as heterozygotes of APOC3 R19X for a minor allele frequency (MAF) of 0.55%
in this patient population. Both heterozygous patients had only a single mention of TG in the EHR (31 and 35 mg/dL,
respectively), and one patient had evidence of previous cardiovascular disease. In this patient population, the inclusion of
APOC3 R19X genotypes in the EHR did not assist in assessing hyperthyroidism, malnutrition, or malabsorption given no TG
levels ≤10 mg/dL were identified in the EHR. Among the two patients that were carriers of a null variant strongly associated
with cardioprotective lipid profiles, only one lacked evidence of disease highlighting the challenges of inclusion of functional
genetic variation in clinical risk assessment.
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Tue(3)-P-87
Genetic variants of FTO, LEPR, MC4R, PON1, SCL6A4, DRD2, MAOA and COMT , associated to the
genetic risk for overweight and obesity in children from Yucatan, Mexico
Lizbeth Gonzalez-Herrera 1 ，Maria Jose Lopez Gonzalez 1 ，Ruvy Alvarado-Vargas 1 ，Zenda Cardena-Carballo 1 ，
Didier May-Hau 1 ，Gerardo Perez-Mendoza 1 ，Doris Pinto-Escalante 1 ，Guadalupe Garcia-Escalante 1 ，
Fernando Herrera-Sanchez 2 ，Rodrigo Rubi-Castellanos 1
1:Laboratorio de Genetica. Centro de Investigaciones Regionales, Universidad Autonoma de Yucatan, Mexico、2:Facultad de Medicina.
Unidad Cardiometabolica. UADY
Childhood obesity is a major health problem in Mexicans, particularly in Yucatán overweight and obesity is the first cause
of morbidity in children. GWAS have shown several obesity susceptibility genes that predispose to increased body weight,
body mass index (BMI)or body fat percentage, such as FTO, LEPR, and MC4R genes. Individuals possessing these obesity
susceptibility genes associated with extreme obesity and body fat percentage may either posses more than de average number
of other common obesity susceptibility genes. Moreover, dopamine release in the dorsal striatum is involved with regulation
of feeding behavior, and correlates with the degree of pleasure experienced while eating. COMT, MAOA, SCL6A4, DRD2
genes govern dopamine and serotonin metabolism or transport. In this study, we evaluated the association of variants in
candidate genes to obesity, analyzing 12 SNPs of 8 genes: rs9939609, rs8057044, rs1421085 of FTO, rs1137101 of LEPR,
rs17782313 of MC4R, rs705379, rs854560, rs662 of PON1, VNTR-MAOA, 5’HTTLPR- SCL6A4, Taq1A- DRD2 and rs4680
of COMT, with the risk for overweight and obesity in children from Yucatan, Mexico. We included 319 children with BMI
Pc >85, and 303 children with BMI Pc<85>10 adjusted by age and gender, on a case-control association study. SNPstats
and STATA software were used for statistical analysis. Genotype and allele frequencies were distributed according to Hardy-
Weinberg expectations (p>0.05). Significant differences were found for the heterozygous genotype of the SNP rs1421085-FTO
Poster Session
(p= 0.003), rs1137101-LEPR (p=0.029), and rs705379-PON1 (p=0.012) between obese and non-obese children, suggesting an
associated genetic risk factor for child obesity; whereas the homozygous genotype of the SNP rs854560-PON1 was significantly
associated with overweight (p=0.026). Interestingly, the SNP rs4680-COMT showed significant association with the risk for
both overweight and obesity in females only (p=0.02) of the studied population.
Tue(3)-P-88
Improved imputation accuracy using population-specific SNP array and haplotype reference panel
Yosuke Kawai 1 ，Takahiro Mimori 1 ，Kaname Kojima 1 ，Naoki Nariai 1 ，Kazuharu Misawa 1 ，Yumi Yamaguchi-Kabata 1 ，
Yukuto Sato 1 ，Inaho Danjoh 1 ，Rumiko Saito 1 ，Fumiki Katsuoka 1 ，Jun Yasuda 1 ，Masayuki Yamamoto 1 ，
Masao Nagasaki 1
1:Tohoku Medical Megabank Organization, Tohoku Univeristy, Japan
Genotype imputation is crucial step on genome-wide association studies . The accuracy and coverage of imputed genotype
are largely affected by the choice of SNP array and the haplotype reference panel. Tohoku Medical Megabank Organization
(ToMMo) has been conducting a prospective genome cohort study in Miyagi prefecture in Japan. Upon this project, we
have recently constructed the haplotype reference panel (the 1KJPN panel) from the whole genome sequences of Japanese
individuals to get better imputation accuracy with Japanese population. To facilitate this approach, we have developed the
new SNP array - Japonica array that is optimized for the genotype imputation using the 1KJPN panel. We have conducted
the imputation using the 1KJPN panel and the international 1000 genomes project panel with using Japonica array and
the existing SNP arrays. The better imputation performance was obtained for the Japonica array with the 1KJPN panel
compared with other combinations of SNP array and reference panel. The genomic coverage of imputed genotypes (r2 >0. 8)
with the Japonica array reached around 97% and 67% for common (MAF > 5%) and low-frequency SNPs (0. 5% < MAF ≤
5%), respectively.
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Tue(3)-P-89
Allelic imbalance in regulation of ANRIL through chromatin interaction at 9p21 endometriosis risk locus
Hirofumi Nakaoka 1 ，Aishwarya Gurumurthy 1 ，Takahide Hayano 1 ，Somayeh Ahmadloo 1 ，Waleed Omer 1 ，
Kazuyoshi Hosomichi 1 ，Ituro Inoue 1
1:Division of Human Genetics, National Institute of Genetics, Japan
Genome-wide association studies (GWASs) have discovered numerous single nucleotide polymorphisms (SNPs) associated with
human complex diseases. However, functional characterization of the disease-associated SNPs remains a formidable challenge.
Here we explored regulatory mechanism of a SNP on chromosome 9p21 associated with endometriosis by leveraging “allele-
specific” functional genomic approaches. By re-sequencing 1.3 Mb of 9p21 region and scrutinizing DNase-seq data from
the ENCODE project, we prioritized a SNP as a candidate functional variant that was in perfect linkage disequilibrium
with the original GWAS SNP and located on DNase I hypersensitive site. Chromosome conformation capture followed
by high-throughput sequencing revealed that the protective allele of the SNP exerted stronger chromatin interaction with
the promoter of ANRIL. We demonstrated that the protective allele exhibited preferential binding affinities to TCF7L2
and EP300 by bioinformatics and chromatin immunoprecipitation (ChIP) analyses. ChIP assays for histone H3 lysine 27
acetylation and RNA polymerase II reinforced the enhancer activity of the SNP site. The allele specific expression analysis
for eutopic endometrial tissues and endometrial carcinoma cell lines showed that the SNP was a cis-regulatory variant where
the protective allele was associated with increased the expression level of ANRIL. Motivated by the fact that TCF7L2
was a key transcription factor of Wnt signaling pathway, we demonstrated that the induction of Wnt signaling activated
expressions of ANRIL and G1 cell-cycle inhibitors (CDKN2A and CDKN2B). Our work illuminates the allelic imbalances in
a series of transcriptional regulation from factor binding to gene expression mediated by chromatin interaction underlie the
Poster Session
molecular mechanism of 9p21 endometriosis risk locus. Functional genomics on common disease will unlock functional aspect
of genotype-phenotype correlations in the post-GWAS stage.
Tue(3)-P-90
Stability profiling of HLA class II protein for disease association studies
1,2
Hiroko Miyadera ，Jun Ohashi 3 ，Katsushi Tokunaga 2
1:Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Japan、2:Department of Human Genetics,
Graduate School of Medicine, The University of Tokyo、3:Department of Biological Sciences, Graduate School of Science, The University of
Tokyo
Among many disease-susceptibility loci, human leukocyte antigens (HLA) provide the strong genetic risks for autoimmune
and variety of immune disorders, but underlying mechanisms have not been fully explained. We hypothesized that functional
variation of HLA in addition to the well-known variation in the peptide binding spectrum might also contribute to genetic
association of HLA with diseases. We investigated whether the protein stability of HLA class II (HLA-DQ) might vary among
the alleles and if so, whether the stability of HLA is associated with genetic risk for autoimmunity. We measured the stability
of DQ proteins for the major HLA-DQ alleles, including 10 alleles of DQA1 and 14 alleles of DQB1 , and found over 100-fold
of stability differences among the HLA-DQ allele products. Polymorphic residues that regulate the intrinsic stability of DQ
protein have been identified and some of these variants are found to be associated with susceptibility to type 1 diabetes
(Miyadera, et al. J Clin Invest 2015). Using the cell-surface expression assay, we also analyzed the stability of HLA-DR and
-DP. In this presentation, we show the stability profiles for the entire HLA class II loci and discuss potential mechanistic basis
of HLA class II associations with autoimmune and other immunological disorders.
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Tue(3)-P-91
SNP-set Kernel Association Tests (SKAT) of the association between interleukin (IL) polymorphisms
and risk of H. pylori infection and related gastric atrophy
Asahi Hishida 1 ，Kenji Wakai 1 ，Mariko Naito 1 ，Hideo Tanaka 2
1:Nagoya University Graduate School of Medicine, Japan、2:Aichi Cancer Center Research Institute
Helicobacter pylori (HP) still remains a threat as a pathogen causing gastric cancer in Japanese. Human interleukins (ILs)
are implicated in HP persistent infection and development of gastric precancerous lesions including gastric atrophy by some
studies. We conducted the analysis of the association of IL polymorphisms and risk of H. pylori persistent infection as well
as related gastric atrophy (GA) using the SNP-set Kernel Association Tests (SKAT). The data from the 1,307 participants
of J-MICC Daiko Study were analyzed, among whom 500 were tested positive for urine HP antibodies. Presence of GA was
diagnosed in 196 HP positive subjects by the serum pepsinogen levels, and the genotyping was conducted using the Illumina
SNP array. The associations between IL genes and risk of HP infection as well as GA were tested using SKAT. The statistical
analyses were conducted by R. Among all the participants, 65 subjects were diagnosed as having GA. As a result of SKAT,
IL-17RD, IL-18R1, IL-1R1 and IL-6R genes were detected as significantly associated with HP infection genes with the IBS
Kernel (P = 0.049, 0.031, 0.005 and 0.049, respectively), whereas the IL-18RAP gene was significantly associated with GA
when using the IBS Kernel (P = 0.039). The present study results indicated the potentially important roles of ILs with the
risk of HP infection as well as that of related GA.
Poster Session
Tue(3)-P-92
Assessment of somatic DNA methylation profiling and copy number variations in atherosclerosis
Maria S. Nazarenko 1,2 ，Anton V. Markov 1,2 ，Aleksei A. Sleptcov 1,2
，Igor N. Lebedev 1,2
，Nikolay A. Skryabin 1,2
，
Aleksei V. Frolov 3 ，Olga L. Barbarash 3 ，Valery P. Puzyrev 1,2
1:Research Institute of Medical Genetics, Russia、2:Tomsk State University、3:Research Institute for Complex Problems of Cardiovascular
Diseases
We hypothesize that somatic epigenetic and genetic heterogeneity of arteries can contribute to regional vascular bed differences
in susceptibility to atherosclerosis. However, the DNA methylation and copy number variations (CNVs) of affected and healthy
vascular tissues of patients with atherosclerosis had not been investigated in detail. The Illumina HumanMethylation27
BeadChip and Agilent SurePrint G3 Human CGH+SNP 2×400K microarrays were used for DNA testing from right coronary
arteries in the area of advanced atherosclerotic plaques (CAP) and atherosclerotic-resistant internal mammary arteries (IMA)
of six patients with coronary artery disease. A total 358 CpG sites showed significant differences in DNA methylation
(FDR adjusted P<0.05), defined as a mean methylation difference of at least 20% between CAP and IMA samples. Forty
differentially methylated genes have previously been linked to atherosclerosis in candidate-gene based association studies, but
most of the loci were not previously connected to the disease. The most representative terms in KEGG included neuroactive
ligand-receptor interaction (16 genes; FDR adjusted P=0.02). There were not high confidence coronary artery specific copy
number variations. We identified 90 high-confidence CNVs that were present in matched arteries studied. Fifteen chromosomal
regions contained CNVs that are candidates for genes previously associated with cardiovascular diseases and their risk factors.
KEGG pathway analysis revealed enrichments in the olfactory transduction and metabolic pathways. There was not overlap
between both DNA methylation and copy number changes in arteries. In conclusion, although DNA methylation differences
do not appear to be linked to the copy number changes in arteries of patients with coronary heart disease both mechanisms
may be important in the disease. The study was supported by the Russian Science Foundation (14-15-00305).
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Tue(3)-P-93
Predictive utility of a genetic risk score of common variants associated with type 2 diabetes in a black
South African population
Tinashe Chikowore 1 ，Tertia Van Zyl 1 ，Karin R Conradie 1
1:Center of Excellence, North West University, South Africa
Type 2 diabetes (T2D) is a complex disease with a polygenic etiology. Its global prevalence is increasing rapidly and there
is an urgent need to develop early screening strategies to curb its growing burden. Limited evidence exists regarding the
predictive utility of the common variants associated with T2D alone or in combination with other risk factors in the black
South African population. We set out to evaluate the genetic risk score (GRS) associated with T2D and its predictive utility
alone and in combination with other risk factors. Our study was a case-control nested in the Prospective Urban and Rural
Epidemiological (PURE) study of 178 males and females cases, matched for age and gender with 178 controls. The Illumina
GoldenGate Assay was used for genotyping 77 selected SNPs using the BeadXpress platform. Association tests were done
using the Plink software and the GRS was computed using the unadjusted additive count method. Three types of GRS were
developed which consisted of beta cell related variants (GRSb), four variants which had significant associations with T2D in
our study (GRSn) and all the SNPs (GRSt).The GRSs association with T2D was evaluated using logistic regression while
adjusting for age, sex and BMI. Of the GRSs only GRSn was associated with increased risk of T2D as indicated by an OR
(95CI) of 1.26 (1.05-1.51) p value =0.015. The residual probabilities of the logistic models of T2D and risk factors of age, sex
and BMI alone and with GRSn were evaluated using the receiver operating (ROC) curves. The area under the ROC curve of
the T2D risk factors alone was 0.662 (p value < 0.001) and 0.684 (p value < 0.001) with the addition of GRSn. The common
variants associated with T2D in the black South African population have limited predictive utility in addition to other risk
Poster Session
factors in the black South African population as has been reported in other ethnicities. More studies are required to identify
variants of significant predictive utility.
Tue(3)-P-94
Studies of Genetics & Environment interaction and health longevity in Bama population
Ze Yang 1 ，Chenguang Zheng 2 ，Zeping Lv 2 ，Caiyou Hu 2 ，Liang Sun 1
1:Institute of Geriatrics, Beijing Hospital, Chinese Ministry of Public Health, China、2:Jiangbin hospital, Guangxi province, China
Objective To explore the causation of nuclear and mitochondrial genome variation and the health longevity. Result 1 )
This study collected 814 CCP longevity of the elderly ( aged ≥ 90 years) and 1136 without a family history of longevity, the
local general population control group ( aged 30-65 years), male to female ratio of 2:1, which Red River area Zhuang 1012
total population of 938 people who Yongfu Han population . 2 ) total phenotypic correlation screening, where the elderly
live longer, compared with the control group had a statistically difference in phenotype (SBP, DBP, FBG, TC, TG and
LDL-C), although these indicators are in the normal range the high limit. 3) The mitochondrial genome sequencing in Red
River area longevity of the elderly found 225 mutations (mtSNPs), and construct a sequence of mitochondrial haplogroups
based on the results . 4 ) that: where F haplogroups associated with longevity, there is a significant difference (21.0% vs
13.5% in the frequency distribution of longevity group and the control group, p = 0.01), haplotype group F increased health
and longevity effects ( OR: 1.703, 95% CI: 1.153-2.514). 5 ) Further analysis revealed that haplotype group F in three
mtSNPs (m.3970C> T, m.13928G> C, m.10310G> A) is associated with health and longevity longevity (p = 0.009, OR:
1.602, 95% CI: 1.134-2.262; p = 0.021, OR: 1.507, 95% CI: 1.075-2.114, and p = 0.01, OR: 1.703, 95% CI: 1.153-2.514). 6)
by comparison with mitomap, found m.13928G> C non-synonymous mutations cause changes in MT-ND5 protein of one
amino acid (Ser531Thr). Further MT-ND5 protein secondary structure prediction and analysis showed that the hydrophobic
amino acid change Ser531Thr located 7 and 8 of the transmembrane helix loop structure and makes ND5 protein localized
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hydrophilic increased. Conclusions We found that F mtDNA haplogroups associated with health and longevity may be a
protective factor .
Tue(3)-P-95
Analysis of the regulatory role of fifty-two genetic loci influencing human electrically active myocardial
mass on epigenetic human heart data
Daiane Hemerich 1,2 ，Vinicius Tragante 1 ，Jaiyi Pei 3 ，Jessica van Setten 4 ，Magdalena Harakalova 1 ，Michal Mokry 5 ，
Pim van der Harst 6 ，Folkert W. Asselbergs 1,7,8
1:Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands、2:CAPES Foundation,
Ministry of Education of Brazil, Brasília, Brazil、3:Department of Nephrology and Hypertension, DIGD, University Medical Center Utrecht,
Utrecht, the Netherlands、4:Laboratory of Experimental Cardiology, Department of Cardiology, Division Heart & Lungs, UMC Utrecht,
The Netherlands、5:Division of Pediatrics, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands、
6:University of Groningen, Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands、7:Durrer Center
for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, the Netherlands、8:Institute of Cardiovascular Science, Faculty of
Population Health Sciences, University College London, London, United Kingdom
BACKGROUND: Identifying tissue-specific regulatory elements assaying epigenetic chromatin marks can help understand
effects of non-coding loci identified by genome-wide association studies (GWAS). Abnormal amplitude and prolonged duration
of the QRS complex on the electrocardiogram (ECG) are associated with (pre)clinical cardiovascular disease such as cardiac
hypertrophy and hypertrophic heart failure. GWAS meta-analyses of 4 QRS traits (Sokolow-Lyon, Cornell, 12-lead-voltage
duration products and QRS duration) identified 52 genomic loci associated with QRS phenotypes at P<1×10-8 .
Poster Session
AIM: To assess whether epigenetic factors influence QRS voltage, we tested the overlap of these 52 SNPs with H3K27ac peaks
across 67 datasets of cardiac cell-types (septum, left and right ventricles) in 7 different stages of cardiac hypertrophy (healthy,
normal, remodeling, LVH, decompensation, DCM and HCM).
METHODS AND RESULTS: We mapped H3K27ac peaks to the 52 SNPs and vicinity (r2 >0.8) and tested for enrichment
within each tissue. Forty-six SNPs were mapped to 10,357 H3K27ac peaks in 67 datasets. The most significant enrichment was
in left ventricle (LV) tissue with DCM condition (p=0.0028) and septum tissue with HCM condition (p=0.0032). Statistical
significance was evaluated by permuting 10,000 matched sets of SNPs not associated with the phenotype to calculate a 95th -
percentile threshold as cell type specificity score. In LV DCM sample, we found 9 SNPs mapped to tissue-specific H3K27ac
peaks, with specificity of 0.23 or greater. In the septum hypertrophic sample, we found 6 SNPs overlapping the cell type
specific chromatin mark (0.13 of specificity).
CONCLUSION: These preliminary results point to an enrichment of QRS-voltage related SNPs with regulatory regions
highlighted by H3K27ac peaks. Further analyses may help clarify the mechanisms through which 52 QRS-related SNPs affect
genes, identify the causal variants and their influence in regulatory regions.
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Poster Session
Clinical Genetics and Dysmorphology 2
Tue(3)-P-96
Waardenburg Syndrome Type IIE in a Japanese Patient Caused by a Novel Missense Mutation in the
SOX10 Gene
Tamio Suzuki 1 ，Ken Okamura 1 ，Naoki Oiso 2 ，Gen Tamiya 3 ，Satoshi Makino 3 ，Daishi Tsujioka 4 ，Yutaka Hozumi 1 ，
Yoshikazu Shimomura 5 ，Yuko Abe 1
1:Department of Dermatology, Yamagata University, Japan、2:Department of Dermatology, Kinki University、3:Tohoku Medical Megabank
Organization, Tohoku University、4:Department of Ophthalmology, Sakai Hospital Kinki University、5:Departments of Ophthalmology, Kinki
University
Waardenburg syndrome (WS) is characterized by piebald leukoderma, white forelock, characteristic facial features, hete-
rochromia irides, and sensorineural deafness. The phenotype is variable, and affected individuals may exhibit only one or a
combination of several features. WS is classified into four subtypes (1-4) based on the clinical characteristics. WS2, which is
inherited as an autosomal dominant condition, is classified into five forms (A-E). WS2E is the result of mutation in SOX10 ,
which has been also observed in WS types 4 as well as neurologic variants. Here, we report a case of WS2E caused by a novel
missense mutation in SOX10 .
Poster Session
A 20-year-old Japanese man with mild mental retardation visited us with photophobia caused by congenital bilateral blue
iris and bilateral sensorineural hearing loss. The patient showed a slight presence of white hair on the scalp, however, piebald
leukoderma, white forelock, dystopia canthorum, broad nasal root, limb anomaly, and Hirschsprung disease (HSCR) were
absent. Fundoscopy showed a bilateral view of the entire hypopigmentation and peripheral degeneration.
MITF and SOX10 were subjected to mutational screening, and a novel heterozygous missense mutation, c.391A>G, p.N131D,
was detected in SOX10 . The amino acid altered by this novel mutation was confirmed to be conserved among all known
species. The newly identified mutation was not observed in 106 unrelated, normally pigmented Japanese adults, and was not
identified in the 1000 Genomes Project and dbSNP (build 141) databases.
In addition, the rs2435357 polymorphism, located in an intronic RET enhancer and associated with HSCR susceptibility in
the Asian population was genotyped, and the patient was discovered to be homozygous for the C allele, which is not the
statistical risk allele for HSCR.
Tue(3)-P-98
A novel HSF4 missense mutation in Iranian siblings causes autosomal recessive congenital cataract
Eri Imagawa 1 ，Mahdiyeh Behnam 2 ，Ahmad R Salehi 3 ，Firooze Ronasian 2 ，Mansoor Salehi 4 ，Noriko Miyake 1 ，
Naomichi Matsumoto 1
1:Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan、2:Medical Genetics Center of Genome、
3:Department of Medical Genetics, School of Medical Sciences, Tarbiat Modares University、4:Division of Genetics and Molecular Biology,
School of Medicine, Isfahan University of Medical Sciences
Cataract is a common ocular disorder with lens opacities or cloudiness. It is classified into congenital (occurring within 1
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year after birth), juvenile (occurring from 1 to 10 years of age), presenile (before 45 years), and age-related (after 45-year-old)
forms based on the onset ages. To date, mutations in at least 86 genes have been reported in cataract, and among them,
more than 50 genes have been reported in congenital cataract (CC). Here, we report Iranian male siblings presenting CC and
nystagmus. They were born to consanguineous healthy parents. To identify the genetic cause of them, we performed genetic
analysis using whole exome sequencing. Based on the hypothesis of autosomal recessive and X-linked recessive models, we
identified one homozygous missense mutation in HSF4 (c.521T>C, p.Leu174Pro; NM_001040667.2) in both affected siblings.
Heterozygous change of this mutation was identified in their parents and healthy sibling. HSF4 at 16q22.1 encodes a heat-
shock transcription factor which forms the homotrimer repressing and/or activating downstream target genes required in
lens development. The HSF4 protein is composed of three functional regions of DNA-binding domain (DBD), hydrophobic
repeats (HR-A/B), and downstream of hydrophobic repeat (DHR). Interestingly, Interestingly. HSF4 mutations are known
to cause autosomal dominant and recessive CC, and the inheritance patterns is depend on their mutational positions of the
HSF4 mutations: all dominant mutations reported are located in DBD close to the N-terminal region of HSF4, whereas the
recessive mutations reside within HR-A/B or DHR. The present mutation (c.521T>C) was also identified in HR-A/B, which
might support the previous finding.
Tue(3)-P-99
Tatton-Brown-Rahman syndrome due to 2p23 microdeletionTatton-Brown-Rahman syndrome due to
2p23 microdeletion
Kimiko Ueda 1 ，Nobuhiko Okamoto 1 ，Yasuhisa Toribe 2 ，Keiko Shimojima 3 ，Toshiyuki Yamamoto 3
Poster Session
1:Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Japan、2:Toribe Clinic、
3:Tokyo Women’s Medical University Institute for Integrated Medical Sciences
Tatton-Brown-Rahman syndrome is a new overgrowth syndrome due to DNMT3A (DNA cytosine 5 methyltransferase 3A)
mutation. Mutation carriers show a distinctive facial appearance, intellectual disability (ID), and increased height. We expe-
rienced an overgrowth patient with submicroscopic deletion of chromosome 2p23 including DNMT3A.
A 5-year-old male propositus was the second-born child of a 39-year-old mother and a 40-year-old father, both healthy and
nonconsanguineous. After an uncomplicated pregnancy, he was born at 42 weeks of gestation with a weight of 3,980 g (+2.4
SD), a length of 52.3 cm (+1.5 SD), and OFC of 36.2 cm (+1.3 SD). His development had been retarded since early infancy.
He started to walk independently at 2 and a half years of age. He showed moderate ID.
He was clinically diagnosed with Sotos syndrome in other hospital and visited our institution for further investigations. His
height (121.2 cm (+2.5 SD)), weight (24.3 kg (+2.1 SD)) and OFC (56.5cm (+3.1 SD)) were enlarged. Physical examination
identified dysmorphic features including heavy, horizontal eyebrows, narrow, down-slanting palpebral fissures, epicanthal folds,
low set ears, and a high arched palate, which were consistent with those of Tatton-Brown-Rahman syndrome. Neuroradiologi-
cal studies were normal. His bone age was not advanced. His karyotype by G-banded analysis was 46,XY. We considered that
his features were distinct from Sotos syndrome. Array-CGH analyses were performed, revealing submicroscopic chromosomal
aberrations, and identified loss of the genomic copy numbers in the region of 2p23.3, which included DNMT3A. FISH analyses
confirmed the deletion. His parents did not have the deletion. The patient had a de novo 1.5-Mb deletion of 2p23.3 : arr
2p23.3(24,012,152-25,552,894)X1 dn.
We suggest that 2p23 microdeletion including DNMT3A may cause similar symptoms in patients with DNMT3A mutations
and should be considered in overgrowth patients.
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Tue(3)-P-100
Mutational Analysis of TSC1 and TSC2 in Japanese Patients with Tuberous Sclerosis Complex Revealed
Higher Incidence of TSC1 Patients than Previously Reported and unique TSC1 mutational pool
Yo Niida 1 ，Mamoru Ozaki 1 ，Akiko Wakisaka 2 ，Takanori Tsuji 2 ，Mondo Kuroda 3 ，Yusuke Mitani 3 ，Ayano Yokoi 3
1:Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Japan、
2:Department of Pediatrics, National Hospital Organization Iou Hospital、3:Department of Pediatrics, Kanazawa University Graduate School
of Medical Science
Objective: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by multiple hamartias and
hamartomas involving throughout the body. To date, many TSC1 and TSC2 mutations have been reported all over the world,
however, few mutation studies have been performed and genetic characteristics of Japanese TSC patients are not yet clear. In
this study, we performed national mutational cohort study in Japanese patients with TSC. Methods: 100 Japanese patients
from 98 families suspected with TSC were evaluated their phenotypes and genotypes. These patients were clinically diagnosed
according to established criteria (Roach et al. 1998), and 82 patients (from 80 families) diagnosed as definite TSC. TSC1 and
TSC2 point mutations were screened by CHIPS (CEL endonuclease mediated heteroduplex incision with polyacrylamide gel
electrophoresis and silver staining) and confirmed by direct sequencing. Large deletion and insertion were analyzed by long
PCR and DNA microarray. Results: We identified 55 mutations among 80 definite TSC families (68.8%), including 17 TSC1
mutations and 38 TSC2 mutations. Detected mutation types of TSC1 /TSC2 were frame shift 6/10, in-frame deletion 0/5,
missense 1/12, nonsense 5/2, splicing 2/6, stop codon mutation 0/1 and large deletion or duplication 3/2 respectively. No
differences emerged in mutation distributions and types in precedent studies. Comparing clinical manifestations, the incidence
of developmental delay and/or mental retardation was significantly lower in TSC1 patients than TSC2 patients (p = 0.023)
as previously reported. As a new discovery, our study demonstrates significantly higher incidence of TSC1 mutations among
Poster Session
TSC patients in the Japanese population compared to US and European studies (P = 0.005). Also 10 mutation s of 14 TSC1
point mutations were new mutations. Conclusions: Japanese patients with TSC have unique mutational pool and higher
incidence of TSC1 mutations comparing to US and European patients.
Tue(3)-P-101
WDR62/MCPH2 mutations identified in patients with primary microcephaly by a combined approach
of exome sequencing and genome editing technology
Yoshinori Masatsuna 1 ，Silvia Natsuko Akustu 1 ，Kosuke Hosoba 1 ，Hiroyuki Morino 2 ，Hideki Kawakami 2 ，
Takashi Yamamoto 3 ，Kenji Simizu 4 ，Hirofumi Oohashi 4 ，Tatsuo Miyamoto 1 ，Shinya Matsuura 1
1:Department of Genetics and Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan、2:Depart-
ment of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University、3:Department of Mathematical and
Life Sciences, Graduate School of Science, Hiroshima University、4:Saitama Children’s Medical Center
Primary microcephaly (MCPH) is an autosomal recessive neurodevelopmental disorder characterized by congenital reduction
of head circumference. So far twelve underlying genes have been identified. It was reported that WDR62 gene, which protein
product localizes to mitotic centrosomes to control mitotic spindle assembly, is responsible for MCPH2 gene locus (Nature
2010, Nat Genet 2010). Here we identified compound heterozygous mutations c.731 C>T (p.Ser 244 Leu) and c.2413G>T
(p.Glu 805 X) in the WDR62/MCPH2 gene of the two siblings in a Japanese microcephalic family using whole exome
sequencing.
The molecular and cellular pathology of WDR62/MCPH2 mutation-caused microcephaly remains unclear. In this study,
we generated human WDR62/MCPH2 c.731 C>T (p.Ser 244 Leu) missense mutation knock-in cell lines using single strand
oligonucleotide (ssODN) and CRISPR/Cas9-mediated genome editing technology in order to elucidate the physiological role
of WDR62. In the normal metaphase, mitotic spindle forms parallel to the substratum to ensure symmetric cell division.
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WDR62/MCPH2 mutated cells showed randomized spindle orientation caused by the impaired microtubule assembly activity.
During early neurogenesis, neural stem cell expands its population by symmetric cell division, and the following asymmetric
cell division produces neurons to determine the proper size of brain. Our results suggest that WDR62/MCPH2 mutations
disrupt symmetric cell division of neural stem cell through the instability of spindle orientation to lead to microcephaly.
Tue(3)-P-102
Dyschromatosis symmetrica hereditaria complicated by intracranial hemangiomas and Parry-Romberg
syndrome
Kazuyoshi Fukai 1 ，Saki Yanagihara 1 ，Daisuke Tsuruta 1 ，Toshiyuki Seto 2 ，Taro Shimono 3 ，Ken Okamura 4 ，
Yutaka Hozumi 4 ，Tamio Suzuki 4
1:Dermatology, Osaka City University, Japan、2:Pediatrics, Osaka City University、3:Diagnostic and Interventional Radiology, Osaka City
University、4:Dermatology, Yamagata University
Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominant cutaneous disease characterized by hyper- and
hypopigmented macules on the dorsal aspects of the extremities. Here, we report a case of DSH complicated by intracranial
hemangiomas and Parry-Romberg syndrome. The patient was a 5-year-old girl. She had several seizures and presyncopal
episodes. She had a small area of circumscribed scleroderma on the skin of the right wing of the nose, and linear depressions
on the right frontal region. Small hyper- and hypopigmented macules were present mainly on the face and the dorsal aspects
of the extremities. Her mother and grandmother also had the same pigmentary changes. Brain computed tomography showed
calcifications in the right frontal lobe. Brain magnetic resonance imaging disclosed thinning of the right frontal bone and
Poster Session
atrophy of the cerebral cortex in the right frontal lobe. Intracranial hemangiomas and white matter hyperintensities on
T2-weighted images in the right cerebral hemisphere were also found. Mutation analysis of the ADAR1 gene revealed the
heterozygous frameshift mutations c.2398_2399insG and p.E800fsX842. Her mother had the same mutations. Therefore,
the patient was diagnosed as DSH complicated by Parry-Romberg syndrome and intracranial hemangiomas. It is possible
that the phenotype of intracranial hemangiomas and Parry-Romberg syndrome is worsened by dysregulated ds-RNA in the
developmental phase of the brain.
Tue(3)-P-103
Clinical features and outcomes for infants with an antenatal/ perinatal diagnosis of Tuberous Sclerosis
Clara WT Chung 1 ，John A Lawson 2 ，Sean E Kennedy 3 ，Stephen Cooper 4 ，Vanessa Sarkozy 5 ，Orli Wargon 6 ，
Jacqueline Robinson 1 ，Harry King 1 ，David R Mowat 1
1:Department of Medical Genetics, Sydney Children’s Hospital, Australia、2:Department of Neurology, Sydney Children’s Hospital、
3:Department of Nephrology, Sydney Children’s Hospital、4:Department of Cardiology, Sydney Children’s Hospital、5:Sydney Children’s
Community Child Health Centre, Sydney Children’s Hospital、6:Department of Dermatology, Sydney Children’s Hospital, High St,
Randwick NSW Australia 2031
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic condition caused by mutations in the TSC1 or TSC2
gene with a birth incidence between 1 in 6,000 and 1 in 10,000. It may lead to neurocognitive deficits, autism and epilepsy
as well the development of benign tumours in various organs at different times of life, including brain, skin, kidneys, heart,
lungs and eyes. The age of presentation and the severity of clinical manifestations can be quite variable between individuals.
Based on the current literature approximately 17% of cases are diagnosed antenatally and the majority of these are diagnosed
through the discovery of cardiac rhabdomyomas on routine antenatal ultrasound. Neurodevelopmental sequelae, such as
epilepsy, intellectual disability, autism and neuropsychiatric manifestations, affect 90% of patients and are the major cause
of morbidity and mortality. Of note, early intervention and management of seizures can improve the neurodevelopmental
outcome of patients. This means that the earlier identification of infants with TSC may allow interventions that improve
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outcome. Early diagnosis may occur in families with known TSC, antenatal detection of cardiac rhabdomyomas or a variety
of features that may lead to a diagnosis prior to the onset of clinical seizures.
We commenced a multidisciplinary TSC clinic in 2005 and have strong links with a co-located maternal fetal medicine unit.
We will present the proportion of TSC cases identified at or soon after birth over three 5 year periods (2000-2005, 2005-2010,
2010-2015) and look at the range of presentation and clinical outcomes. These cases will be compared with those that present
with seizures in the first year of life.
We will also describe the counselling recommendations for couples where a single or multiple cardiac rhabdomyomas are
detected antenatally.
Tue(3)-P-104
Clinical and genetic diagnosis of HPT-JT syndrome
Yoshiko Matsumoto 1 ，Shinya Uchino 1 ，Akiko Ito 2 ，Shin Watanabe 1 ，Syouichi Kikuchi 1 ，Shirou Noguchi 1
1:Department of Surgery, Noguchi Thyroid Clinic and Hospital Foundation, Japan、2:Department of Genetic Testing, Noguchi Thyroid Clinic
Poster Session
and Hospital Foundation
Hyperparathyroidism jaw tumor syndrome (HPT-JT) is rare autosomal dominant by inherited multiple tumor syndrome.
Penetrance in HPT-JT is estimated at 80-90%. Primary hyperparathyroidism, the main finding of HPT-JT occurs in more than
70% of affected individuals, onset is typically in late adolescence or older. HPT-JT associated primary hyperparathyroidism
is usually caused by a single parathyroid adenoma, but multiple adenomas can develop either simultaneously or at different
times. In approximately 10-15% of cases, primary hyperparathyroidism is caused by parathyroid carcinoma. Ossifying
fibromas of the mandible and/or maxilla occur in 30-40% of patients. Approximately 20% of individuals with HPT-JT have
kidney lesions, most commonly cyst. Moreover, 75% of female patients have benign or malignant uterine tumors. The tumor
suppressor gene HRPT2/CDC73 was shown to be responsible for the development of HPT-JT. HRPT2/CDC73 is located
in the autosomal chromosome locus 1q25-q32 and encodes parafibromin, which is a 17-exon and 531-amino acid protein,
and mainly expressed in the parathyroid glands and kidney. Diagnosis is based on the biochemical findings of primary
hyperparathyroidism, identification of ossifying fibroma of the maxilla and/or mandible on imaging studies, family history,
and detection of a heterozygous germline HRPT2/CDC73 pathogenic variant on molecular genetic testing. The patients who
have HRPT2/CDC73 gene mutation are only 50% of them.
We experienced 5 patients (1 male, 4 females) of HPT-JT. pHPT occurred at a young age, and 40% (2/5) of patients have
family history of pHPT. Recurrence rate of pHPT was 40% (2/5). Half of female patients (2/4) have kidney and uterine tumors.
The age at operation was between 17 and 25. HRPT2/CDC73 gene mutation analysis by PCR-based direct sequencing using
DNA from peripheral blood leukocytes was performed. Mutations were found between exons 5 and 8, and all of them were
nonsense or frameshift mutation.
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Tue(3)-P-105
De novo DNM1 mutations in two cases of epileptic encephalopathy
Mitsuko Nakashima 1 ，Takeshi Kouga 2,3 ，Charles Marques Lourenco 4 ，Masaaki Shiina 5 ，Tomohide Goto 3 ，
Yoshinori Tsurusaki 1 ，Satoko Miyatake 1 ，Noriko Miyake 1 ，Hirotomo Saitsu 1 ，Kazuhiro Ogata 5 ，Hitoshi Osaka 2 ，
1:Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan、2:Department of Pediatrics, Jichi
Medical University, Tochigi, Japan、3:Division of Neurology, Kanagawa Children’s Medical Center, Yokohama, Japan、4:Department
of Medical Genetics, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil、5:Department of Biochemistry,
Yokohama City University Graduate School of Medicine, Yokohama, Japan
Dynamin 1 (DNM1) is a large guanosine triphosphatase involved in clathrin-mediated endocytosis. In recent studies, de
novo mutations in DNM1 have been identified in five individuals with epileptic encephalopathy. In this study, we report two
patients with early-onset epileptic encephalopathy possessing de novo DNM1 mutations. Using whole exome sequencing, we
detected the novel mutation c.127G>A (p.Gly43Ser) in a patient with Lennox-Gastaut syndrome and a recurrent mutation
c.709C>T (p.Arg237Trp) in a patient with West syndrome. Structural consideration of DNM1 mutations revealed that both
mutations would destabilize the G domain structure and impair nucleotide binding, dimer formation, and/or GTPase activity
of the G domain. These and previous cases of DNM1 mutations were reviewed to verify the phenotypic spectrum.
Tue(3)-P-106
Renal tubular dysgenesis and intellectual disability with uniparental disomy of chromosome 1
Hiroshi Yoshihashi 1 ，Shiho Ito 2 ，Mami Niida 3 ，Tomu Kuchikata 1
Poster Session
1:Department of Medical Genetics, Tokyo Metropolitan Children’s Medical Center, Japan、2:Department of Nursing, Tokyo Metropolitan
Children’s Medical Center、3:Division of Pediatrics, Tama-Hokubu Medical Center
Renal tubular dysgenesis (RTD: MIM#267430) is a severe disorder of renal tubular development characterized by oligohy-
dramnio, perinatal death due to pulmonary hypoplasia and chronic renal failure, not necessarily involving developmental
delay(DD) and intellectual disability(ID). The prognosis in survivors with RTD remains unknown. RTD is caused by ho-
mozygous or compound heterozygous mutation in genes encoding components of the rennin-angiotensin system, including
REN (1q32.1), AGT （1q42.2）, AGTR (3q24), ACE (17q23.3). Herein, we report a young girl with RTD and DD/ID. Case:
6-year-old female. The clinical manifestations included chronic renal failure, generalized tonic seizure, dental crowding, tube
feeding and severe developmental delay in infancy. Conventional chromosomal study showed normal female karyotype. At the
age of 5 year old, genetic counseling for recurrence risk was required. Methods and Results: Direct sequencing detected the
homozygous frameshift deletion in exon 5 of the AGT . Analysis for the parents revealed that the one parent was a heterozy-
gous carrier of the same mutation but the other parent was not. SNP microarray for the patient showed uniparental disomy of
chromosome 1(UPD1) and no clinically significant CNVs. In addition, whole exome sequencing revealed the homozygosity of
uniparental gene mutations suggestive of the cause of neurological impairments. Discussion: The previous cases with UPD1
were rarely reported. In our knowledge, the patient was the first case of UPD1 concomitant with AGT mutation in RTD.
Subsequent analysis demonstrated only one parent of the patient to be a heterozygous carrier in AGT and the presence of
UPD1 as the cause leading to the homozygous mutations in the autosomal recessive disorder, regarding not only RTD but
also DD/ID. The present observation indicated the utility of genetically exhaustive analysis for the underlying mechanism
and the precise genetic counseling in RTD with DD/ID.
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Tue(3)-P-107
Novel mutation in the COL1A1 gene causes severe scoliosis and valvular heart disease in a Japanese
family with osteogenesis imperfecta
Toshiyuki Seto 1 ，Toshiyuki Yamamoto 2 ，Keiko Shimojima 2 ，Haruo Shintaku 1
1:Department of Pediatrics, Graduate School of Medicine, Osaka City University, Japan、2:Institute for Integrated Medical Scinences, Tokyo
Women’s Medical University
Osteogenesis imperfecta (OI) is a heterogeneous disorder characterized by bone fragility and systemic complications caused
by mutations in the genes encoding collagen, mainly COL1A1 and COL1A2 . Here we identified a novel mutation in COL1A1
in members of a Japanese family clinically diagnosed with OI.
Patient 1 (P1) was an adult male reporting a normal daily life who was clinically diagnosed with OI Type I based on a history
of broken long bones (approx. 30 breaks before adolescence) leading to deformities of the bones and joints of his extremities.
He also had blue sclera, a short stature, and severe scoliosis. He had undergone previous mitral valve repair and aortic valve
replacement.
His father had no history of OI. His mother (P2), aunt, and grandfather were suspected of having OI from their history of
long bone fractures, blue sclera, and short stature; they did not have scoliosis or heart disease. The apparent severity of OI
in this family was increased through the grandfather to P1, and was more severe in P1 than in P2.
We used next-generation gene sequencing (TruSight One sequencing panel v1.0; Illumina) to analyze the genetic cause of OI
Poster Session
in P1 and P2 and detected a novel candidate mutation (c.750+2T>A) in COL1A1 of P1. To confirm this mutation was the
genetic cause of OI, direct sequencing of the mutation was performed and the same mutation was identified in P1 and P2 but
not in the father. Mosaicism was also ruled out.
The severity OI of P1 was possibly the result of phenotypic penetrance causing weakening of the connective tissue of the
heart, and of the ligaments and muscles supporting the spine and long bones. P1 also reported a more active life than P2
at school and work, so environmental factors (e.g., exercise load) will have increased the risk of bone fracture and may have
accelerated the development of valve regurgitation and scoliosis. The novel mutation in COL1A1 presented here furthers our
understanding of the pathological mechanisms of OI.
Tue(3)-P-108
Clinical utility of medical exome analysis in a tertiary pediatric referral center
Rika Kosaki 1 ，Masaya Kubota 2 ，Tadashi Kaname 3 ，Kenjiro Kosaki 4
1:Division of Medical Genetics, National Center for Child Health and Development, Japan、2:Division of Neurology,National Center for
Child Health and Development、3:National Research Institute of Child Health and Development、4:Keio University, School of Medicine
Many of the rare diseases in childhood are caused by single gene defects. Hence, genetic testing represents an objective
way of delineating pathological basis of the patient. Here we report clinical utility of medical exome analysis in a tertiary
pediatric genetic center in Japan. We tested a cohort of 57 patients with a presumptive monogenic disorders of which
diagnosis was made on clinical findings. The patients were analyzed by medical exome analysis that selectively targets coding
regions of known human disease-causing genes. Targeted hybridization enrichment was performed prior to next-generation
sequencing (TrusightOne panel, Illumina). Single nucleotide substitutions and small indels were detected by BWA-GATK
standard pipeline. Single nucleotide substitutions and indels detected by next-generation sequencing was confirmed by sangner
sequencing. Copy number variants were detected by XHMM and Fishing CNV. Definitive molecular diagnosis was achieved in
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30 patients (52.6%). In of the 30 patients, medical management plan was modified based on the molecular diagnosis. Critical
information for precise genetic counseling was obtained in all the 30 patients. The present data demonstrate clinical utility of
a single-assay system for medical exome analysis in a tertiary pediatric referral center setting. This study has been approved
by institutional review board of the participating institutions. The authors declare that there are no conflicts of interest.
Tue(3)-P-109
Gross insertion in FBN1 causes Marfan syndrome
Takayuki Yokoi 1 ，Chihiro Hatano 1 ，Yoshinori Tsurusaki 1 ，Yumi Enomoto 1 ，Takuya Naruto 2 ，Kenji Kurosawa 1
1:Division of Medical Genetics, Kanagawa Children’s Medical Center, Japan、2:Department of Stress Science, Tokushima University Faculty
Poster Session
of Medicine
<Background>Marfan syndrome (MS) is a disorder that affects the connective tissue in many parts of the body. Mutations
in the FBN1 encoding fibrillin-1 cause MS. This condition is inherited in an autosomal dominant pattern. The signs and
symptoms of MS vary widely in severity, timing of onset, and rate of progression. Similar to the clinical variability, we detect
genetic variability in MS by Next Generation Sequencing (NGS). In this report, we show a case of MS which has a mutation
unlike conventional patterns of MS such as single nucleotide variant or small insertion/deletion.
<Case report>The patient is 36-year-old female with no family history. She is tall and slender. She had annuloaortic
ectasia, mitral valvular prolapse and funnel chest. She was clinically diagnosed with MS. However, we could not detect any
conventional mutations of FBN1 in her by High resolution melting and subsequent target sequencing.
<Method>Using the patient’s DNA from peripheral blood, we performed Mendelian disorders related gene-based NGS
(TruSight One, 4813 genes) on the Illumina Miseq.
<Results>At first, we could not detect any pathogenic variants of FBN1 in her. However, she has a gross insertion (49bp)
in FBN1 although the NGS data of it was low quality score in our algorithm. We could verify it by Sanger sequencing.
<Discussion>This case indicates that MS is variable not only in phenotype but also pathogenic variant of FBN1 . We show
that NGS is useful tool for detecting such a mutation. This result suggests that clinical diagnosis and information are essential
for the analysis for NGS data.
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Tue(3)-P-110
Identified novel FBN1 gene mutation in neonatal/infantile Marfan syndrome
Yoo-MI Kim 1 ，Ji-Na Kim 1 ，Gil-Ho Ban 1 ，Young-Mi Han 1 ，Shin Youn Byun 1 ，Seung Kook Son 1 ，Yeon Joo Lee 1 ，
Chong Kun Cheon 1 ，Gu-Hwan Kim 2 ，Han-Wook Yoo 2 ，Hyung-Doo Lee 1
1:Pediatrics, Pusan National University Children’s Hospital, Korea, South、2:Medical Genetics Center, Asan Medical Center, University of
Ulsan College of Medicine, Seoul, Korea
Marfan syndrome is an autosomal dominant disorder caused by mutations in the fibrillin 1 gene (FBN1). Neonatal form of
MFS is rare and is associated with severe phenotype and a poor prognosis. Here, we report two neonatal/infantile Marfan
syndrome having novel mutations in the FBN1 . A female neonate was born at gestational age 29 weeks 5 days by emergency
C-sec due to maternal aortic dissection. This subject had arachnodactyly, malar hypoplasia, loose skin and large VSD and
dilated both great arteries. Molecular genetic studies revealed a novel intronic c.4399_4400del mutation in the FBN1 gene
inherited from mother. Mother had also long face, malar hypoplasia, tall stature and pectus excavatum and took an operation
for aortic dissection during pregnancy. There were two sudden death in family members, grandmother and mother’s younger
brother. She has been on ARB, beta-blocker and sildenafil. Recent EchoCG revealed improving valsava sinus dilatation
from Z-score 5.64 to 3.91. A 26-months-old girl was presented with chest pain and EchoCG revealed dilated aortic arch and
mitral valve prolapse and showed malar hypoplasia, pectus carinatum, and tall stature. Her molecular sequencing revealed a
novel c.663_664del mutation inherited from mother. This subject’s mother had tall stature (180cm) and performed repair
of pectus carinatum during adolescent period. Our study reports two novel mutations in FBN1 gene in neonatal/infantile
Marfan syndrome and also suggest phenotypic heterogeneity within family members.
Poster Session
Tue(3)-P-111
Oro-dental phenotypes associated with rare monogenic disorders
Emilia Severin 1 ，Octavian Dinca 1 ，Cristian Vladan 1 ，Dana Bodnar 1 ，Cristina Dragomir 2 ，Alexandru Bucur 1
1:Genetics, Carol Davila University of Medicine and Pharmacy, Romania、2:Genetic Lab
Background: Previous published studies revealed that odontogenesis is under genetic control. Dental anomalies are frequent
or occasional associated with genetic syndromes suggesting that the same genes that regulate the dental morphogenesis are
also active in the development of other organs and tissues. The present study describes and compares the known patterns
of oral and dental manifestations with some cases investigated by us. Subjects and Methods: Based on clinical evaluation
patients suspected of having a genetic syndrome were referred for genetic evaluation and diagnosis. An initial examination
was undertaken, followed by a personal and familial anamnesis, clinical and radiological examinations. Chromosome or
molecular testing was performed. Results: Permanent tooth anomalies were found in all patients with Fabry’s disease,
Osteogenesis imperfecta, Cherubism, Cleidocranial dysplasia and Charcot-Marie-Tooth disease. Tooth agenesis was the most
common anomaly observed, followed by hyperdontia. More severe expression of both hypodontia and oligodontia were noticed
comparing with non-syndrome tooth agenesis. Number tooth anamalies were found in conjunction with other dental anomalies
(reduction in tooth dimensions and morphology, delays of development, root anomalies, abnormal positions and also enamel
hypoplasia). In many genetic syndromes there is a typical pattern of dental anomalies. Comparative analysis of tooth
abnormalities patterns revealed common, rare and individual dental findings. Conclusions: Clinical characterization of the
patterns of tooth abnormalities in genetic syndromes is of major importance both for understanding the molecular processes
controlled by a specific gene or group of genes, and for the medical practice by predicting and preventing the functional
complications at oral /dental level. Interceptive treatment stops occlusal, aesthetic and psychological problems of the patient
affected by a genetic syndrome.
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ICHG2016 1021
Tue(3)-P-112
Haddad Syndrome due to PHOX2B Gene Mutation in a Filipino Infant
April Grace D. Berboso 1 ，Maria Melanie Liberty B. Alcausin 1,2
1:University of the Philippines, Manila, Institute of Human Genetics, National Institutes of Health, Philippines、2:Philippine General Hospital
Haddad syndrome is a rare congenital disorder in which congenital central hypoventilation syndrome (CCHS) occurs with
Hirschsprung’s disease. It is extremely rare with only more than 60 cases reported in the worldwide literature. This is a
report on a Filipino term newborn male infant who presented with signs and symptoms of progressive abdominal enlargement,
bowel obstruction and recurrent hypoventilation. An early diagnosis is necessary to avoid the harmful effects of hypoxemia,
hypercapnia and acidosis on the neurocognitive and cardiovascular functions of affected individuals. The diagnosis of Haddad
syndrome and CCHS was made based on a high index of clinical suspicion. The disorder was confirmed by sequence analysis
of the PHOX2B gene which showed a 27-repeat heterozygous expansion of the polyalanine-coding region. The finding of
PHOX2B gene mutation assists in the diagnosis and warrants parental testing to determine if the mutation is segregating in
the family or is a novel mutation.
Tue(3)-P-113
The Management of Pregnancy in Two Japanese Sisters who Developed Deep Vein Thrombosis with
Congenital Antithrombin Deficiency
Yukiko Mikami 1 ，Sumiko Era 1 ，Yoshihisa Ono 1 ，Masahiro Saito 1 ，Yasushi Takai 1 ，Kazunori Baba 1 ，Hiroyuki Seki 1 ，
Poster Session
Keiko Shinozawa 2 ，Katsuyuki Fukutake 2,3
1:Department of Obstetrics and Gynecology, Saitama Medical Center, Saitama Medical University, Japan、2:Department of Molecular
Genetics of Coagulation Disorders, Tokyo Medical University、3:Department of Laboratory Medicine, Tokyo Medical University
Introduction: We report the management of pregnancy in two Japanese sisters who developed deep vein thrombosis (DVT)
and were diagnosed with congenital AT deficiency.
Case presentation:
Propositus was a 26-year-old Japanese female who developed DVT at 10 weeks of gestation. At onset, her plasma AT
activity was 62%. The patient was initially treated with continuous intravenous heparin infusion at therapeutic doses and AT
replacement therapy. This treatment was continued throughout the pregnancy. The patient delivered, assisted by forceps,
at 36 weeks and 6 days of gestation; after delivery, she was treated with warfarin. We analyzed her AT gene and detected
a heterozygous point mutation IVS6-5T>A in SERPINC1 . Two years and three months after delivery, the patient stopped
treatment with warfarin. Four months later, she developed pulmonary thromboembolism. She has now restarted treatment
with warfarin.
Patient 2 was the 25-year-old younger sister of propositus, who developed DVT at 7 weeks of gestation. At onset, her plasma
AT activity and antigens were 72% and 18.4mg/dl, respectively. The patient was initially treated with continuous intravenous
heparin infusion at therapeutic doses and AT replacement therapy. Treatment with subcutaneous or intravenous heparin and
AT replacement therapy was continued throughout pregnancy. The patient delivered vaginally at 39 weeks and 4 days of
gestation. Postpartum, she was treated with warfarin, and this treatment continues to date. We analyzed her SERPINC1
gene and confirmed the splicing mutation same as that of her sister.
Discussion: We identified the same mutation in SERPINC1 in both sisters who developed DVT during pregnancy, which may
contribute to pathogenesis of inherited AT deficiency.
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Tue(3)-P-114
Natural history of motor function changes in childhood-onset spinal muscular atrophy
1,2
Kaori Kaneko ，Reiko Arakawa 2 ，Kayoko Saito 1,2
1:Affiliated Field of Genetic Medicine, Division of Biomedical Engineering and Science, Graduate Course of Medicine, Graduate School of
Tokyo Women’s Medical University, Japan、2:Institute of Medical Genetics, Tokyo Women’s Medical University
Spinal muscular atrophy (SMA) is a hereditary disorder characterized by degeneration and drop-out of motor neurons in
the ventral horn of the spinal cord, which shows progression of predominantly proximal muscular atrophy and depression.
SMA is classified into four types depending on the onset age, highest motor functional ability and clinical course. The
gene for SMN1 (survival motor neuron1 ) was mapped to chromosome region 5q13 for SMA. In addition, SMN2 and NAIP
(neuronal apoptosis inhibitory protein) were reported as possible candidate genes modifying SMA phenotypes. Fundamental
therapeutic strategies for SMA have not as yet been established. However, new approaches such as genetic-based therapy
have been tested in clinical trials. We aimed to determine the natural history of SMA patients in Japan, to investigate their
clinical conditions, and to contribute to assessing the therapeutic value of interventions in this study. We also clinically
classified the SMA patients and analyzed the roles of SMN1, SMN2 and NAIP in relationships between clinical forms and
genetic analysis results. There is a significant difference at the time of introducing ventilation support between whether or
not head control was obtained, in type 1 cases (p=0.0025). In type 2 as well, the time that sitting without support was
acquired until it become impossible to maintain the sitting position, also differs significantly between the group that acquired
sitting alone within eight months and those that did not (p=0.0409). A positive correlation was seen between copy number
and SMA phenotype.
Poster Session
Tue(3)-P-115
Homozygous 4-bp deletion in the DDHD1 gene, resulting the complete deletion of DDHD domain, as a
causative variant in a SPG28 patient
Takuya Morikawa 1 ，Shiroh Miura 1,2 ，Kohei Yamada 1 ，Gohsuke Hattori 3 ，Kengo Kosaka 1 ，Ryuta Fujioka 4 ，
Manabu Motomura 5 ，Takayuki Taniwaki 2 ，Hiroki Shibata 1
1:Division of Genomics, Medical Institute of Bioregulation, Kyushu University, Japan、2:Dvision of Respirology, Neurology and Rheuma-
tology, Department of Medicine, Kurume University School of Medicine、3:Department of Neurosurgery, Kurume University School of
Medicine、4:Department of Food and Nutrition, Beppu University Junior College、5:Department of Internel Medicine, Nagasaki Yurino
Hospital
Spastic paraplegia (SPG) type 28 is an autosomal recessive hereditary SPG caused by mutations in the DDHD1 gene. We
examined a Japanese 54-years-old male patient with SPG. His parents are first cousins. He needed a wheelchair for transfer due
to spastic paraplegia. There was a history of operations for bilateral hallux valgus, thoracic ossification of the yellow ligament,
bilateral carpal tunnel syndrome, bilateral ankle contracture, and lumbar spinal canal stenosis. He noticed gait disturbance at
age 14. He used a cane for walking in his 40s. On neurological examination, he showed hyperreflexia, spasticity, and weakness
in the lower extremities. Urinary dysfunctions and impaired vibration sense in the lower limbs were observed. By the exome
sequencing analysis using Agilent SureSelect and Illumina MiSeq system, we identified 17248 homozygous nucleotide variants
in the patient. Through the examination of 49 candidate genes known to be responsible for autosomal recessive SPG, we
identified a novel homozygous 4-bp deletion c1144_1147del,Ser305Ilefs*2 in exon2 of the DDHD1 gene encoding phosphatidic
acid-preferring phospholipase A1 (PA-PLA1 ). The mutation is expected to cause a frameshift generating premature stop
codon at 3-bp downstream from the deletion. In consequence, the DDHD domain that is known to be critical for PLA1
activity is completely depleted in the mutated DDHD1 protein, resulting the practically a null mutation of the DDHD1 gene.
By Sanger sequencing, we confirmed that both parents are heterozygous for the mutation. This variation was not detected
in 474 Japanese control subjects. We conclude that the novel mutation in DDHD1 is the causative variant for the SPG28
patient that is the first record of the disease in Asian population.
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Tue(3)-P-116
Simultaneous detection of both single nucleotide variations and copy number alterations by next-
generation sequencing in Gorlin syndrome
Kei-ichi Morita 1,2,3 ，Takuya Naruto 4 ，Kousuke Tanimoto 2,5,6 ，Chisato Yasukawa 1 ，Yu Oikawa 1 ，Kiyoshi Masuda 7 ，
Issei Imoto 7 ，Johji Inazawa 2,3,6 ，Ken Omura 1,3,8 ，Hiroyuki Harada 1
1:Oral and Maxillofacial Surgery, Tokyo Medical and Dental University, Japan、2:Bioresource Research Center, Tokyo Medical and Dental
University、3:Hard Tissue Genome Research Center, Tokyo Medical and Dental University、4:Department of Stress Science, Institute of
Biomedical Sciences, Tokushima University Graduate School、5:Genome Laboratory, Medical Research Institute, Tokyo Medical and Dental
University、6:Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and
Dental University、7:Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School、8:Oral
Cancer Center, Tokyo General Hospital
Gorlin syndrome (GS) is an autosomal dominant disorder that predisposes affected individuals to developmental defects
and tumorigenesis, and caused mainly by heterozygous germline PTCH1 mutations. Despite exhaustive analysis, PTCH1
mutations are often unidentifiable in some patients; the failure to detect mutations is presumably because of mutations
occurred in other causative genes or outside of analyzed regions of PTCH1, or copy number alterations (CNAs). In this study,
we subjected a cohort of GS-affected individuals from six unrelated families to next-generation sequencing (NGS) analysis
for the combined screening of causative alterations in Hedgehog signaling pathway-related genes. Specific single nucleotide
variations (SNVs) of PTCH1 causing inferred amino acid changes were identified in four families (seven affected individuals),
whereas CNAs within or around PTCH1 were found in two families in whom possible causative SNVs were not detected.
Through a targeted resequencing of all coding exons, as well as simultaneous evaluation of copy number status using the
alignment map files obtained via NGS, we found that GS phenotypes could be explained by PTCH1 mutations or deletions in
all affected patients. Because it is advisable to evaluate CNAs of candidate causative genes in point mutation-negative cases,
Poster Session
NGS methodology appears to be useful for improving molecular diagnosis through the simultaneous detection of both SNVs
and CNAs in the targeted genes/regions.
Tue(3)-P-117
Mutation in the genes encoding eukaryotic translation initiation factor 2B in Japanese patients with
vanishing white matter disease
Shino Shimada 1 ，Keiko Shimojima 2 ，Toshiyuki Yamamoto 2 ，Satoru Nagata 1
1:Department of Pediatrics, Tokyo Women’s Medical University, Japan、2:Tokyo Women’s Medical University Institute for Integrated Medical
Sciences
Objective:Vanishing white matter disease (VWM) in a chronic, progressive leukoencephalopathy associated with episodes of
rapid deterioration following minor stress events such as head traumas or infectious disorders. The white matter of the patients
with VWM exhibits characteristic radiological findings. Method: The genes encoding all five subunits of eukaryotic translation
initiation factor 2B (EIF2B) were analyzed in patients, who were tentatively diagnosed with VWM, by Sanger sequencing.
Results: Seven mutations were homozygous, and the other four patients were compound heterozygous. Conclusions: All
patients showed white matter abnormalities with various degrees. One patients showed manifestations of end stage VWM
disease. Some patients showed late onset and slow progression associated with brain magnetic resonance imaging displaying
T2 high intensity only in the deep white matter. These were clinical heterogeneity among patients with VWM.
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Tue(3)-P-119
Clinical courses and experiences of seven patients with Ehlers-Danlos syndrome caused by
CHST14/D4ST1 deficiency
Masumi Ishikawa 1 ，Emiko Kise 1 ，Fukushima Yoshimitsu 1,2
，Tomoki Kosho 1,2
School of Medicine
Ehlers-Danlos syndrome (EDS) caused by CHST14/ D4ST1 deficiency, also called as EDS, musculocontractural type 1
(MIM#601776), is a disorder, molecularly-identified and delineated in 2009−2011, which is characterized by multiple con-
genital malformations (craniofacial features, multiple congenital contractures) and progressive multisystem fragility-related
complications (skin hyperextensibility and fragility, recurrent dislocations and progressive talipes or spinal deformities, large
subcutaneous hematomas). To date, 38 patients from 25 families have been described. However, information about detailed
and longitudinal clinical courses as well as psychosocial burden of patients and their families are lacking. In our hospital,
follow-up care for the disorder has been given to seven unrelated patients, which would be one of the largest cohort. Their
ages ranged 4−28 years old at the first visit. Six patients developed large subcutaneous hematomas from early childhood
to school ages, for the prevention of which three started to have intranasal administration of 1-desamino-8-D-arginine vaso-
pressin (DDAVP) after trauma. Four patients had severe scoliosis or kyphoscoliosis, which was surgically corrected in one but
complicated by intractable surgical site infections. One died from intestinal perforation. For five patients and their families,
we prepared chances to communicate each other at their visits, where they exchanged information about daily lives, school
lives, and medical treatment and felt sympathy for what they had difficulty in. Patients’ and families’ narratives obtained
at the clinics showed that medical professionals didn’t understand what the families felt something wrong with before the
Poster Session
diagnosis of the disorder. For the better management, follow-up care should include not only surveillance and intervention of
complications, but also psychosocial support through the clinics as well as the patient-family connection.
Tue(3)-P-120
Next-generation sequencing identifies novel ARID1B mutations in patients with Coffin-Siris syndrome
Yoshinori Tsurusaki 1 ，Yumi Enomoto 1 ，Takayuki Yokoi 2,3
，Chihiro Hatano 2 ，Kazumi Ida 2 ，Kenji Kurosawa 2
1:Clinical Research Institute, Kanagawa Children’s Medical Center, Japan、2:Division of Medical Genetics, Kanagawa Children’s Medical
Center、3:Department of Pediatrics, The Jikei University of School of Medicine
Coffin-Siris syndrome (CSS; MIM 135900), first described by Coffin and Siris in 1970, is a congenital disorder characterized by
intellectual disability, growth deficiency, microcephaly, coarse facial features, and hypoplastic or absent fifth fingernails and/or
toenails. The majority of affected individuals represent sporadic cases. We previously reported that five genes (SMARCB1 ,
SMARCA4 , SMARCE1 , ARID1A, and ARID1B) are mutated in CSS patients, all of which encode subunits of the Brahma-
associated factor (BAF) (also known in yeast as the SWI/SNF) ATP-dependent chromatin-remodeling complex. In addition,
we have identified SOX11 mutations in two CSS patients. Sox11 was recently shown to form a transcriptional cross regulatory
network downstream of the Pax6-BAF complex. The network drives neurogenesis and converts postnatal glia into neurons.
We examined newly recruited CSS-suspected patients by targeted resequencing using a HaloPlex Target Enrichment System
with oligonucleotide probes targeting 437 genes related to epigenetics or TruSight One Sequencing Panel. DNA libraries
were sequenced using MiSeq with 151-bp paired-end reads. Mapping to human genome hg19 was performed using Burrows-
Wheeler Alignment (BWA). Variants were called using the Genome Analysis Toolkit (GATK), and annotated by ANNOVAR.
We found that ARID1B were mutated in four CSS patients. All mutations in ARID1B were truncating mutations (nonsense
or frameshift deletion/insertion). Our data further support that CSS is a BAF complex related disorder and the diagnostic
utility of next-generation sequencing technologies is obvious.
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ICHG2016 1025
Tue(3)-P-121
The comprehensive genetic analysis of Rubinstein-Taybi syndrome (RSTS)
Yumi Enomoto 1 ，Takayuki Yokoi 2 ，Chihiro Hatano 2 ，Ikuko Ohashi 2 ，Yukiko Kuroda 2 ，Yoshinori Tsurusaki 1 ，
Kazumi Ida 1 ，Takuya Naruto 1 ，Kenji Kurosawa 2
1:Clinical Research Institute, Kanagawa Children’s Medical Center, Japan、2:Division of Medical Genetics, Kanagawa Children’s Medical
Center
Rubinstein-Taybi syndrome (RSTS) is characterized by dysmorphic facial features, short stature, broad thumbs and first toes
and moderate-severe intellectual disability. They have common facial features involving downward slanting palpebral fissures,
arcuate eyebrow, high-arched palate and grimacing smile. RSTS is autosomal dominant disease and arise in rate of about
1/100,000-125,000. Most cases of RSTS are sporadic case. Haploinsufficiency and loss of function of CREBBP and EP300
have been reported as causative mechanisms in RSTS. Both genes have similar functions as histone acetyltransferase that
regulates transcription via chromatin remodeling. 50-70% of patients have mutation in CREBBP and 3% have mutation in
EP300 .
To elucidate the causative variants for these patients, we performed comprehensive genetic analysis of CREBBP and/or
EP300 in 8 patients with RSTS. 6 cases were clinically typical cases whereas 2 cases were atypical cases. Here we reported
causative mutations and clinical features in patients. Various causative mutations were detected, which included frameshift
mutations of CREBBP, a deletion including several exons of CREBBP, a micro-deletion in intron of CREBBP which result
in splicing aberrations and a partial deletion of EP300 . The detection rate of causative mutation was 62.5%(5/8). These
results showed that identification of causative mutations in patients with RSTS often need comprehensive molecular analysis.
Poster Session
Tue(3)-P-122
A case of mandibulofacial dysostosis with microcephaly presenting with epilepsy
Mari Matsuo 1 ，Masako Sakauchi 2 ，Akemi Yamauchi 1 ，Yasushi Ito 2 ，Toshiyuki Yamamoto 3 ，Nobuhiko Okamoto 4 ，
Yoshinori Tsurusaki 5 ，Noriko Miyake 5 ，Naomichi Matsumoto 5 ，Kayoko Saito 1
1:Institute of Medical Genetics, Tokyo Women’s Medical University, Japan、2:Department of Pediatrics, Tokyo Women’s Medical University、
3:Institute for Integrated Medical Science, Tokyo Women’s Medical University、4:Department of Medical Genetics, Osaka Medical Center
and Research Institute for Maternal and Child Health、5:Department of Human Genetics, Yokohama City University Graduate School of
Medicine
Mandibulofacial dysostosis with microcephaly(MFDM) is an autosomal dominant congenital anomaly syndrome characterized
by microcephaly, malar hypoplasia, micrognathia, malformed ears, deafness, and developmental delay(DD). Most affected
individuals have a de novo heterozygous EFTUD2 pathogenic mutation or deletion. At least 70 cases have been reported to
date. Although epilepsy is occasionally reported in MFDM, the details remain unknown yet. We report an additional case
with epilepsy, and review the literature.
A 5-year-old boy was the first child of a healthy non-consanguineous Korean couple. He was born at 40 weeks gestation,
showing microcephaly. DD was diagnosed at 9 months of age. MRI of the head revealed lateral ventricle dilatation, small
frontal lobe volume. Sensorineural deafness was noted. G-banded chromosomal analysis and chromosome microarray analysis
results were normal. He developed febrile seizures at age 21 months, and then recurrent febrile / afebrile seizures (complex
partial seizure evolving to secondarily generalized tonic clonic seizure). EEG revealed occasional spike discharges from the
right temporo-parietal area. His seizures were well controlled by sodium valproate and topiramate. At age 3 years, he showed
microcephaly (-3.8SD), malar hypoplasia, malformed ears, and micrognathia. We performed whole exome sequencing. A de
novo flame shift mutation c.2698_2701 del in the EFTUD2 gene was detected.
In the prior 11 reported MFDM cases with epilepsy, seizure details were described for only three cases; one with partial and two
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ICHG2016 1026
with generalized seizures. The brain malformations, which may cause epilepsy, were reported in three cases; simplified gyrus,
lateral ventricles dilatation, heterotopias; abnormal white matter; and delayed myelination. EFTUD2 encodes a spliceosomal
GTPase and is expressed in the ventricular zone of the forebrain in the mouse fetus. The splicing process abnormality may
play an important role in the brain malformations of MFDM.
Tue(3)-P-123
Long-term clinical feature of West syndrome with a de novo mutation in NR2F1 : A case report
Naomi Hino-Fukuyo 1,2 ，Atsuo Kikuchi 2 ，Natsuko Arai-Ichinoi 2 ，Tetsuya Niihori 3 ，Ryo Sato 2 ，Tasuku Suzuki 2 ，
Hiroki Kudo 2 ，Ryo Funayama 4 ，Keiko Nakayama 4 ，Yoko Aoki 3 ，Shigeo Kure 2
1:Center for Genomic Medicine, Tohoku University Hospital, Japan、2:Department of Pediatrics, Tohoku University School of Medicine、
3:Department of Medical Genetics, Tohoku University School of Medicine、4:Division of Cell Proliferation, United Centers for Advanced
Research and Translational Medicine, Tohoku University Graduate School of Medicine
[Background] The NR2F1 gene encodes a conserved nuclear receptor protein that regulates transcription. Mutations and a
deletion in NR2F1 , including mutations at the DNA-binding domain, are the cause of Bosch-Boonstra-Schaaf Optic Atrophy
syndrome (MIM#615722). Recently, we provide additional evidence for NR2F1 as a causative gene for West syndrome. There
has been no report described clinical course of West syndrome with NR2F1 mutation.
[Case] A 23-year-old female was born after an uncomplicated pregnancy to a healthy non-consanguineous Japanese couple.
She developed infantile spasms occurring in clusters with hypsarrhythmia on EEG at 4 months of age. A cerebral MRI scan
Poster Session
showed normal results. A pediatric ophthalmologist noted bilateral optic atrophy. Her spasms responded to ACTH. She
subsequently developed generalized tonic seizures, which responded to valproic acid and clonazepam. In the following years,
the patient acquired some motor skills, such as the ability to sit in her own at 2 years and 6 months and the ability to walk
on her own at 20 years of age. However, she had uttered no meaningful word at 23 years of age.
[Genetic analysis] We performed whole-exome sequencing in this patient after confirmation no copy number variations using
array CGH. We identified a de novo mutation, c.403C>T (p.R135C), in NR2F1 (NM_005654) in this patient. P.R135C
is not present in dbSNP137, the ExAC database, or HGVD and is predicted to be damaging by both SIFT (score=0) and
Polyphen2 HVAR (score=1).
[Discussion] A mutation located at identical position, c.403C>A (p.R135S), was also recently reported in a patient with
infantile spasms. The identification of de novo NR2F1 mutations in the same position in two unrelated patients strongly
suggests that NR2F1 is a novel causative gene for infantile spasms.
[Conclusion] We report a long-term clinical feature of a patient of NR2F1 mutation with West syndrome.
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ICHG2016 1027
Tue(3)-P-124
Two Japanese patients with two genes mutations, showing congenital sensorineural hearing loss
Kotaro Ishikawa 1 ，Shin-ya Nishio 2 ，Shin-ichi Usami 2
1:Hospital, Department of Otolaryngology, National Rehabilitation Center for Persons with Disabilities, Japan、2:Department of Otolaryn-
gology, Shinsyu University, School of Medicine
Objectives
To determine the genes responsible for deafness in Japanese patients with idiopathic congenital sensorineural hearing loss
(SNHL).
Methods
Clinical tests included pure tone audiometry and computed tomography of the temporal bone for one patient, and conditioned
orientation response audiometry, auditory brainstem response, and auditory steady-state response for another patient. Genetic
analysis was performed by four genetic tests, including Invader assay, Sanger sequencing for the GJB2 and SLC26A4 genes,
TaqMan genotyping assay, and targeted exon sequencing using massively parallel DNA sequencing.
Results
A 11-year-old girl with severe congenital SNHL and large vestibular aqueduct carried p.H723R and p.V659L mutations in
Poster Session
the SLC26A4 gene and p.R1939Q mutation in the OTOF gene. Based on the genotype and phenotype of her parents,
compound heterozygous mutations in the SLC26A4 gene were associated with congenital SNHL. We also identified c.235delC
and p.R143W mutations in the GJB2 gene and p.L3160F mutation in the MYO15A gene of the 2-year-old boy with profound
congenital SNHL. We suspected that the compound heterozygous mutations in the GJB2 gene induced congenital SNHL,
and a cochlear implant was performed.
Conclusions
Two mutations in the SLC26A4 gene and one mutation in the OTOF gene of one Japanese patient with severe congenital
SNHL, carrying large vestibular aqueduct, and two mutations in the GJB2 gene and one mutation in the MYO15A gene of
another patient with profound congenital SNHL were idetified. Hearing loss demonstrates profound genetic heterogeneity;
therefore, the genes that induce congenital SNHL for each patient should be carefully decided.
Tue(3)-P-125
Brain morphology in children with nevoid basal cell carcinoma syndrome
Tadashi Shiohama 1 ，Katsunori Fujii 1 ，Toshiyuki Miyashita 2 ，Hideki Uchikawa 1,3
，Hiromi Mizuochi 1,3
，
Hajime Ikehara 1 ，Tomoyuki Fukuhara 1 ，Naoki Shimojo 1
1:Department of Pediatrics, Chiba University Graduate School of Medicine, Japan、2:Department of Molecular Genetics, Kitasato University
School of Medicine、3:Department of Pediatrics, Eastern Chiba Medical Center
Background: Mutations in PTCH1 , a member of hedgehog signaling, are responsible for nevoid basal cell carcinoma syndrome
(NBCCS), which is characterized by developmental defects and tumorigenicity. The clinical findings of NBCCS enlighten
us about what the activation on hedgehog signaling cause on human development. Enhancement of hedgehog signaling,
associated with brain development of mice, has been reported to lead proliferation of cerebellar granular cell and mild
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cerebellar enlargement. However, the impact of increased hedgehog signaling on human brain development has still been
unknown. Here, we firstly presented the brain morphologic characteristics of NBCCS children.
Methods: We evaluated brain magnetic resonance images of 9 NBCCS children (7 boys and 2 girls) and 15 age-matched
normal controls (NC) (9 boys and 6 girls) (mean [standard deviation], 12.2 [2.8] vs 11.6 [2.3] years old). All NBCCS children
were fulfilled with diagnostic criteria of NBCCS by Kimonis et al. The diameters in cerebrum, corpus callosum, brain stem,
and cerebellar volume were compared by unpaired t-test with Welch’s correction, and a p value less than 0.05 was considered
significant.
Results: The transverse diameters of cerebrum (150.4 [9.9] vs 136.0 [5.5] mm, p 0.002), longitudinal diameters of cerebrum
(165.4 [8.0] vs 151.3 [8.7] mm, p 0.0007), cross section area of cerebellar vermis (18.7 [2.6] vs 11.8 [1.7] cm2 , p 0.0001) and
cerebellar volume (185.1 [13.0] vs 131.9 [10.4] cm3 , p 0.0001) were significantly larger in NBCCS children than those in normal
controls. The thinning in corpus callosum and ventricular enlargement were also confirmed in NBCCS children.
Conclusion: We firstly reported the brain morphology of children with NBCCS. Our findings that sizes of cerebrum, cerebellum
and cerebral ventricular in NBCCS were larger than normal controls suggest that the constitutive active hedgehog signaling
can also affect human brain morphology as well as mice brain.
Poster Session
Tue(3)-P-126
Genetic evaluation of patients with intellectual disability (ID) using chromosomal microarray and targeted
next-generation sequencing at the "ID clinic"
Kyoko Takano 1,2 ，Tomoki Kosho 1,2 ，Keiko Wakui 1,2 ，Motoko Kamiya 2,3,4 ，Mitsuo Motobayashi 4 ，Naoko Shiba 4 ，
Tetsuhiro Fukuyama 5 ，Noboru Fueki 6 ，Shinichi Hirabayashi 5 ，Eriko Nishi 7 ，Masumi Ishikawa 2 ，Emiko Kise 2 ，
Tomomi Yamaguchi 2 ，Rie Kawamura 1 ，Yuji Inaba 4 ，Yoshimitsu Fukushima 1,2
1:Department of Medical genetics, Shinshu University School of Medicine, Japan、2:Division of Clinical and Molecular Genetics, Shinshu
University Hospital、3:Problem-Solving Oriented Training Program for Advanced Medical Personnel: NGSD Project、4:Department of
Pediatrics, Shinshu University School of Medicine、5:Division of Neurology, Nagano Children’s Hospital、6:Division of Rehabilitation
Medicine, Nagano Children’s Hospital、7:Division of Medical Genetics, Nagano Children’s Hospital
Intellectual disability (ID) results from significant limitations in both intellectual functioning and adaptive behavior and starts
before the age of 18. ID is one of the most frequent developmental disorders in children, and its prevalence is 1-3% in the general
population. However, more than half of ID was of unknown etiology due to its clinical and genetic heterogeneities. Recently,
genome-wide approaches, such as chromosomal microarray (CMA) and next-generation sequencing (NGS) have improved the
diagnostic yield of ID. The "ID clinic" was established at the Division of Clinical and Molecular Genetics, Shinshu University
Hospital in April 2014. We provide clinical diagnosis, genetic evaluation, and genetic counseling to patients with ID or global
developmental delay (GDD). Genetic evaluation includes CMA and targeted NGS using the "ID panel" (49 ID-related genes).
To date, 59 patients have visited the "ID clinic" and genetic causes were identified in 7 patients (11.9%). Two patients were
found to have de novo pathogenic copy number variations: 9q34.3 deletion and 17p13.3 deletion. Five patients were found
to have de novo disease causing single-gene mutations in 4 genes: UBE3A (1), SHANK3 (1), WDR45 (2), and MECP2 (1).
Genetic evaluation in the "ID clinic" is thought to be useful in providing definitive diagnosis, expected clinical course, and
recurrence risk to patients and their family.
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Tue(3)-P-127
A nationwide survey on genetically confirmed Danon disease in Japan
Kazuma Sugie 1 ，Hirofumi Komaki 2 ，Nobuyuki Eura 1 ，Ikuya Nonaka 2 ，Satoshi Ueno 1 ，Ichizo Nishino 2
1:Department of Neurology, Nara Medical University, Japan、2:National Center of Neurology and Psychiatry, Tokyo, Japan
Introduction
Danon disease, an X-linked dominant vacuolar cardiomyopathy and skeletal myopathy, is caused by primary deficiency of
lysosome-associated membrane protein-2 (LAMP-2). However, the clinical features and the prevalences of Danon disease have
not been well established.
Patients and Methods
We sent questionnaires on Danon disease to 2,617 hospitals in Japan that have departments of neurology, cardiology, or
pediatrics. We reviewed clinical histories and muscle specimens provided by hospitals with Danon disease patients. In
addition, we performed genetic analyses of the LAMP-2 gene.
Poster Session
Results
We identified 28 Danon disease patients (16 men and 12 women) from 13 families. Cardiomyopathy and ECG abnormalities
were evident in all patients with Danon disease. Hypertrophic cardiomyopathy (HCM) was documented in most men, while
dilated cardiomyopathy was more common among women. WPW syndrome was noted at a relatively higher incidence of
38%. Permanent pacemakers were placed in four men and five women. Heart transplantation, the most effective therapy,
was performed in only one man. Pathologically, autophagic vacuoles with sarcolemmal features (AVSF). AVSF expressed
virtually all sarcolemmal proteins on their vacuolar membranes in all Danon disease patients. All Danon disease patients had
LAMP-2 gene mutations. Half of the probands showed de novo mutations.
Conclusion
Danon disease is a very rare muscular disorder and may be primarily caused by lysosomal dysfunctions. Cardiomyopathy is
the most important prognostic factor and the main cause of death among Danon disease patients. Danon disease may be
overlooked in patients with HCM, since other clinical features including myopathy can be mild, particularly in women.
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Tue(3)-P-128
Mental and physical development study of long-term survival patients of thanatophoric dysplasia
Hideaki Sawai 1 ，Mariko Ushioda 1 ，
Study group of thanatophoric dysplasia by grant-in-aid of Ministry of Health, Labour and Welfare
1:Obstetrics and Gynecology, Hyogo College of Medicine, Japan
Thanatophoric dysplasia (TD) is the most frequent form of neonatal lethal skeletal dysplasia. Thanatophoric dysplasia show
remarkable shortening of the limbs, and narrow thorax. In the past the patients had been regarded as complete perinatal
lethal disorder. However, in recent years, some cases are capable of long-term survival by breathing management after birth
and these cases are often reported. To investigate the mental and physical development of children that have survived
over the first year of life we went to investigate these patients. The study was investigated through nationwide pediatric
institute in 2012-2014. We conducted a survey cooperation request to facilities 137 facilities, obtained consent from the
attending physician and the patient family. We surveyed 16 cases to date, i.e. the patient himself (or herself) or the attending
physician. We got the information by family, and visited each institute. we investigated course at the time of birth, respiratory
management method, mental development, I motor development etc. Ages of patients 1-5 years 8 cases, 6 -year-old to 10
years old 5 cases, 11 years 15 years old 1 case, 16 -20 years 0, more than 20 -year-old 2 case, we have noticed all cases are
in respiratory management. Six cases are managed at home. Complications of various diseases were observed in most cases.
Motor developmental delay is the most frequent symptom, in these cases limbs were only moving slightly. Patients look laugh
occasionally and mental development is inevitable. the development of patients seems to be corresponding 1 -year-old from
3 months. Conventionally, at present, not only most of patients are lethal, but long-term survival is possible by adequate
respiratory management. However, in these cases respiratory management is required and inevitable, it needs to be addressed
Poster Session
to a variety of complications, especially we should be reminded of occurrence of mental retardation in all cases
Tue(3)-P-129
Microform holoprosencephaly with bilateral congenital elbow dislocation; a further case of Steinfeld
syndrome related to a CDON mutation?
George A. Tanteles 1 ，Gabriela E. Jones 2 ，Lisa Robertson 3 ，Amit Maniyar 4 ，Christos Shammas 5 ，Marie M. Phelan 6 ，
Pradeep C. Vasudevan 2
1:Department of Clinical Genetics, The Cyprus Institute of Neurology and Genetics, Cyprus、2:Clinical Genetics Department, University
Hospitals Leicester NHS Trust, Leicester, United Kingdom、3:North of Scotland Clinical Genetics Service, Aberdeen, United Kingdom、
4:Department of Radiology, University Hospitals Leicester NHS Trust, Leicester, United Kingdom、5:Department of Molecular Genetics,
Function & Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus、6:NMR Centre for Structural Biology, Institute of
Integrative Biology, University of Liverpool, Liverpool, United Kingdom
Steinfeld syndrome (MIM #184705) was initially reported in 1982. It is typically characterized by holoprosencephaly (HPE)
coupled with limb defects. Other anomalies such as cleft lip and palate, cardiac, renal and genitourinary anomalies may also
be present. Following the initial description, to date three further cases have been reported in the literature. Transmission
appears autosomal dominant. We report on a 23 year old female with features of microform HPE and bilateral congenital
elbow dislocation in association with hypoplastic radial heads. Mutation analysis by Sanger and next generation sequencing
of FGF8 , GLI2 , GLI3 , PTCH1 , SHH, SIX3 , TGIF1 , ZIC2 , and MLPA analysis of GLI3 , ZIC2 , TGIF1 , SIX3 , SHH , GLI2 ,
PTCH1 was negative. The proband was heterozygous for the c.2757G>C(p.Met919Ile) missense variant in exon 15 of the
CDON gene. The mutation was also present in her father who had minimal clinical features. We discuss the clinical features
of Steinfeld syndrome, and broaden the phenotypic spectrum of this condition. Structural analysis suggests that this mutation
could lead to destabilization of binding of CDON with hedgehog proteins. This indicates that mutations in the CDON gene
may be the cause of at least a proportion of Steinfeld syndrome cases.
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Tue(3)-P-130
Novel compound heterozygous mutations in ISPD gene from two cases of Japanese Walker-Warburg
syndrome identified by whole-exome sequencing
Yonehiro Kanemura 1,2 ，Fuyuki Miya 3,4 ，Tomoko Shofuda 5 ，Ema Yoshioka 5 ，Daisuke Kanematsu 1 ，Kyoko Itoh 6 ，
Shinji Fushiki 6 ，Takeshi Okinaga 7 ，Haruhiko Sago 8 ，Rika Kosaki 9 ，Kyoko Minagawa 10 ，Nobuhiko Okamoto 11 ，
Tatsuhiko Tsunoda 3,4 ，Mitsuhiro Kato 12 ，Shinji Saitoh 13 ，Kenjiro Kosaki 14 ，Mami Yamasaki 15
1:Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Japan、
2:Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Osaka, Japan、3:Department of Medical
Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan、4:Laboratory for Medical Science
Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan、5:Division of Stem Cell Research, Institute for Clinical
Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan、6:Department of Pathology and Applied Neurobiology,
Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan、7:Department of Pediatrics, Bell Land
General Hospital, Sakai, Japan、8:Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health
and Development, Tokyo, Japan、9:Division of Medical Genetics, National Center for Child Health and Development, Tokyo, Japan、
10:Department of Pediatrics, Hyogo College of Medicine, Nishinomiya, Japan、11:Department of Medical Genetics, Osaka Medical Center
and Research Institute for Maternal and Child Health, Osaka, Japan、12:Department of Pediatrics, Showa University, School of Medicine,
Tokyo, Japan、13:Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan、
14:Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan、15:Department of Pediatric Neurosurgery, Takatsuki
General Hospital, Osaka, Japan
PURPOSE
Walker-Warburg syndrome (WWS) is an autosomal recessive multisystem disorder clinically characterized as severe forms
of congenital muscular dystrophy (CMD) with a variety of eye and brain malformations such as cobblestone malformation
(COB). Recently, the ISPD (isoprenoid synthase domain containing) gene was newly identified as disease-causing gene of
WWS. Here we report two cases of Japanese WWS having compound heterozygous mutations in ISPD.
Poster Session
CLINICAL REPORT
Case 1 (B001). The fourth male fetus was detected having severe ventriculomegaly (VM) at 19 gestational weeks (GW).
The first male child was terminated at 21GW due to severe hydrocephalus, and the second one were stillbirth at 28GW with
severe VM. No mutations in L1CAM were found in the second child. Parents wanted to terminate the pregnancy and post
mortem autopsy. The autopsy findings revealed COB and agenesis of corpus callosum.
Case 2 (I075). The proband is the second male fetus with occipital encephalocele and VM. After Caesarean delivery at 38GW,
he had neurosurgical treatment on the second day of his life. As the serum CPK value was elevated, the muscle biopsy was
performed. Muscle pathology revealed the muscle dystrophy. He showed severe intellectual and physical retardation.
METHODS
With the approval of the institutional ethics committee, we performed whole exome sequencing on the probands and their
parents. Results were validated by Sanger sequencing.
RESULTS
We identified the same two heterozygous mutations, splicing defect in intron 1 (c.258-1G>C) and missense mutation in exon
3 (c.656T>G, p.K219C) of ISPD as compound heterozygous mutation, from two families.
DISCUSSION AND CONCLUSION
It is reported compound heterozygosity of a missense mutation and a loss-of-function mutation affecting one of the first five
exons of ISPD results in a CMD phenotype. Our novel compound heterozygous mutations in ISPD fulfill this condition, and
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ICHG2016 1032
are supposed to be disease-causing mutations of WWS.
Tue(3)-P-131
The Myhre syndrome: report of a Japanese Female Case
Aki Ishikawa 1 ，Yumi Asakura 2 ，Koji Muroya 2 ，Kenji Kurosawa 3 ，Gen Nishimura 4 ，Akihiro Sakurai 1
1:Medical Genetics, Sapporo Medical University, Japan、2:Endocrinology and Metabolism, Kanagawa Childrens Medical Center, Kanagawa,
Japan、3:Genetics, Kanagawa Childrens Medical Center, Mutsukawa, Kanagawa, Japan、4:Pediatric Imaging, Tokyo Metropolitan Childrens
Medical Center, Tokyo, Japan
Myhre syndrome (MS,OMIM 139210) is a rare disorder characterized by abnormal growth of the skeleton, muscles, and joints.
A heterozygous mutation in the mothers-against-DPP homolog 4 (SMAD4,OMIM 600993) gene has been reported to cause
MS [Caputo et al. 2012; Le Goff et al. 2012]. We reports the first case of a Japanese adult female with molecularly confirmed
MS. The patient was 40 years old at her first visit, and she had been diagnosed with unknown skeletal dysplasia and mental
retardation. Her phenotype fulfilled the clinical and radiological criteria for MS, such as typical facies with prognathism,
conductive and sensorial hearing loss, short stature, square body shape, and limited joint mobility. The thick calvarium
and thick skin were clues to the clinical diagnosis of MS. We sequenced SMAD4 using standard PCR-based technique and
identified a recurrent mutation (p.Ile500Val). This is the first case of a Japanese adult, it is recognized as a valuable case.
We discuss the complications that occur in adulthood and the natural history of MS.
Poster Session
Tue(3)-P-132
The minor nasopharyngeal anomaly in a family of Hypoparathyroidism, Deafness, and Renal dysplasia
(HDR) syndrome
1,2 2,4
Makoto Kita ，Takeshi Usui ，Yasuhiro Kuwata 3 ，Yuichi Akiyama 1 ，Akira Shimatsu 2,4
1:Pediatrics, National Hospital Organization Kyoto Medical Center, Japan、2:Clinical Research Institute, National Hospital Organization
Kyoto Medical Center、3:Neurology, National Hospital Organization Kyoto Medical Center、4:Endocrinology and Metabolism, National
Hospital Organization Kyoto Medical Center
Background
The HDR syndrome is a rare autosomal dominant disorder due to mostly haploinsufficiency of GATA3 located at chromosome
10p15. The triad of hypoparathyroidism, deafness, and renal dysplasia is well known in HDR syndrome. Here, we report
a Japanese family who accompanied by nasopharyngeal malformation, congenital choanal atresia, primary in this HDR
syndrome.
Case presentation
A 6-year-old girl with 3-year history of antiepileptic medication, showed hypocalcemia after she had switched valproate sodium
to carbamazepine (CBZ). As the iPTH level was low, she had diagnosed as primary hypoparathyroidism. In addition, as
she had hearing difficulty, pure tone audiometry was performed and revealed that she had bilateral sensorineural deafness.
Bilateral multicystic dysplastic kidney was also detected by ultrasonography. She had diagnosed as HDR syndrome. Genetic
analysis of GATA3 showed c.708_709insC mutation, which cause a loss of dual zinc finger domains and a premature stop
at codon 302. The mother also had not only sensorineural deafness and renal malformation, but unilateral choanal atresia.
Although genetic testing have not done for all members, we identified the same GATA3 mutation in three out of five in this
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ICHG2016 1033
family, including proband’s mother. And at least these members have same nasopharyngeal anomaly. Although further
study is necessary, GATA3 mutation might be contributed in the minor nasopharyngeal malformation.
Conclusion
The hypocalcemia induced by CBZ can be a clue to diagnose HDR syndrome in infant. This is the first human report with
nasopharyngeal anomaly in HDR syndrome. It suggest that GATA3 heterozygous mutation might cause nasopharyngea
disorder. More attention should be paid to this condition for early diagnosis and clinical screening.
Tue(3)-P-133
SATB2-associated syndrome presenting with Rett like phenotype identified by whole exome sequencing
Jin Sook Lee 1 ，Yongjin Yoo 2 ，Jae So Cho 3 ，Hyewon Woo 3 ，Woojoong Kim 3 ，Byung Chan Lim 3 ，Ki Joong Kim 3 ，
Murim Choi 2 ，Jong-Hee Chae 3
1:Pediatrics, Gachon University Gil Hospital, Korea, South、2:Department of Biomedical Sciences, Seoul National University College of
Medicine, Seoul Korea、3:Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children Hospital, Seoul National
University College of Medicine, Seoul Korea
The SATB2 gene was initially discovered to be associated with isolated cleft palate. There are only two patients carrying
the nonsense mutation (p.R239*) in the SATB2 gene reported to date. More recently a case with the missense mutation
has been reported, who had just intellectual disability even without cleft palate. Here we describe two, novel, de novo
Poster Session
mutations in two unrelated patients presenting Rett like phenotype: one with nonsense mutation and the other missense.
We performed trio-exome sequencing in a 17-month-old girl presenting with Rett like phenotype and her unaffected parents.
Exome sequencing revealed a de novo missense mutation in the SATB2 gene (p.E396Q), which were validated with Sanger
sequencing. Additionally targeted sequencing of the SATB2 gene was performed in a 2-year-old girl with severe delayed
development, facial hypotonia, and cleft palate, who also had some features of Rett syndrome. A novel, de novo, nonsense
mutation of the SATB2 gene was identified (p.R459*). Two cases expanded the clinical and genetic spectrum of SATB2
mutations. Reporting the third patient with nonsense mutation in SATB2 gene, we support the hypothesis that the SATB2
gene might be very important for neurodevelopment as well as craniofacial patterning. SATB2 mutations should be considered
in the cases with developmental delay alone, regardless of the presence of cleft palate, and furthermore in any cases with Rett
like phenotype.
Tue(3)-P-134
Mismatch repair cancer syndrome caused by homozygous deletion of exons 13-14 of PMS2 gene
Fedor A Konovalov 1 ，Ilya V Kanivets 1 ，Denis V Pyankov 1 ，Alexandr A Pushkov 2 ，Vladimir G Solonichenko 3 ，
Sergey A Korostelev 1
1:Federal State Budgetary Institution Research Centre for Medical Genetics, Russia、2:Federal State Bugetary Institution "Scientific Center
of Children’s Health"、3:Filatov’s Children Clinical Hospotal, Moscow
Presence of "cafe au lait” spots (CAL spots) is a common cause for genetic counseling in order to exclude neurofibromatosis
type 1. However, using only a single clinical diagnostic criterion may lead to misdiagnosis and wrong prognosis.
We examined a 7-months old boy born from nonconsanguineous parents. At birth he had 3 CAL spots on the left hip and
sacral region. At the time of examination we noted 8 irregularly shaped CAL spots up to 1cm size located on the skin of the
back and hips. The child showed no facial dysmorphism or developmental delay.
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ICHG2016 1034
The proband’s brother was operated at the age of 8 months for a brain tumor which was classified as pilocytic astrocytoma
grade I. At the time of examination (at 7 years) he had particular facial phenotype and developmental delay, but no CAL
spots. Based on clinical features we suggested a differential diagnosis between phakomatoses accompanied by tumors of the
central nervous system.
A search for pathogenic mutations was performed in the proband by clinical exome sequencing (Illumina TruSight One panel).
No significant variants relevant to clinical features were identified by standard mutation calling procedure. However, a read-
depth analysis performed against a reference panel of 59 unrelated samples suggested a presence of a homozygous deletion of
exons 13-14 in PMS2 gene (Z-score < -3). Homozygous mutations in PMS2 were described earlier in patients with mismatch
repair cancer syndrome MMRCS (OMIM: 276300); notably, CAL spots and astrocytoma have been reported among the main
clinical features, corresponding well to our case. The presence of deletion in proband was confirmed by qPCR.
Thus, the diagnostic protocol for patients with CAL spots and first degree relative with CNS tumors should include an extended
analysis of genes associated with hereditary cancer. Copy number variation analysis enabled by specialized bioinformatics
algorithms proves to be a valuable addition to exome sequencing.
Tue(3)-P-135
Clinical and genetic characterization of patient with SOX5 haploinsufficiency caused by de novo balanced
chromosomal translocation
Poster Session
Nobuaki Wakamatsu 1 ，Daisuke Fukushi 1 ，Kaoru Suzuki 1 ，Noriko Nomura 1 ，Yasuyo Suzuki 1 ，Kenichiro Yamada 1 ，
Mie Inaba 2 ，Seiji Mizuno 2
1:Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Japan、2:Department of Pediatrics, Central
Hospital, Aichi Human Service Center
Objective: Characterization of breakpoints in de novo chromosomal rearrangements is a useful tool for identifying the molec-
ular mechanisms of a disease. We report a 2-year-old boy with a de novo balanced translocation, 46,XY,t(12;20)(p12;p12),
presenting with mild intellectual disability, characteristic facial appearance, and autistic features. To identify the causal gene
in the patient, we analyzed the breakpoints of the chromosomal translocation cytogenetically.
Methods: Fluorescence in situ hybridization (FISH) experiments using RP11 BAC clones were performed to determine the
breakpoints of each chromosome.
Results: The translocation breakpoint in 12p12.1 is located within SOX5 , between RP11-760E23 and RP11-578B11. The
breakpoint in 20p12.3 has been narrowed down to the overlapping 50 kb of the intergenic region between RP11-378C2 and
RP11-204K14.
Conclusion: The patient presented with a very rare case of SOX5 haploinsufficiency caused by a de novo translocation,
t(12;20)(p12;p12). Loss-of-function mutations of SOX5 , including deletions and nonsense mutation in one allele, are reported
to cause intellectual disability. The most common symptoms in all reported patients with SOX5 haploinsufficiency are de-
velopmental delay, mild to moderate intellectual disability, speech delay, hypotonia, strabismus, behavioral abnormalities,
and dysmorphic features. However, there is considerable clinical variability among the patients with genomic alterations
involving only SOX5 , due to locations and sizes of deletions. To clarify the clinical features of the presented patient with
SOX5 haploinsufficiency, detailed studies, including determination of the breakpoint in SOX5 and characterization of SOX5
in the patient’s cells, are necessary.
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ICHG2016 1035
Tue(3)-P-136
A Novel Mutation in the Flavin-Containing Monooxygenase 3 Gene (FMO3) of a Korean Family Causes
Trimethylaminuria
Ji Hyun Kim 1 ，Jong Bin Lee 2
1:Pediatric Endocrinology, Dongguk University Ilsan Hospital, Korea, South、2:Otorhinolaryngology, College of Medicine, Konyang University
Trimethylaminuria also known as the “fish odor syndrome” is a congenital metabolic disorder characterized by a fishy odor
resembling that of rotting fish that results from excess excretion of trimethylamine (TMA) in the urine, breath, sweat, and
body secretion. Patient present, usually in childhood or early adulthood, complaining of the body odor. Trimethylaminuria
is an autosomal recessive disorder and flavin-containing monooxygenase 3 (FMO3) is the only gene known to be associated
with. The primary genetic form of the disease comprise the majority of the reported cases, and clinical symptoms confirmed
genetically as due to inactivating mutations and less severe polymorphisms in the FMO3 gene reported from populations in
the USA, Canada, UK, Spain, Italy, Korea, Japan, Australia, Norway and Thailand. Affected individuals appear normal
and healthy; however, the unpleasant odor often results in social and psychological problems. More than 90 mutations have
been reported to cause trimethylaminuria. Most are missense mutations, but nonsense mutations have been reported. Here
we describe the identification in a family of a novel causative mutation of FMO gene. A 3-year-old girl who presented with
a strong corporal scent after ate fish. Sequence analysis of genomic DNA revealed that she has compound heterozygous
mutation. One is missense mutation for p.Val58Ile in exon 3 and the other is nonsense mutation for p.Ser364X in exon 7 of
the FMO3 gene. Familial genetic analysis showed that the p.Val58Ile derived from the same allele from the mother, and the
p.Ser364X was derived from the father. p.Ser364X is novel mutation
Poster Session
Tue(3)-P-137
Delineation of the molecular basis of borderline hemoglobin A2 in Chinese individuals
Yanhui Liu 1 ，Jiwu Lou 1 ，Yi He 1 ，Manna Sun 1
1:Prenatal Diagnosis Center, Dongguan Maternal and Children Hospital, China
BACKGROUND:
The "gray zone" of borderline hemoglobin A2 (Hb A2) may be present in a large section of the population, especially in
countries where thalassemia is common. However, very little is currently known of the molecular basis of borderline Hb A2
in Chinese individuals.
METHOD:
In this study, we performed a comprehensive analysis of the globin genotypes and KLF1 gene mutations associated with
borderline Hb A2 in 165 Chinese subjects.
RESULT:
Fifteen (9.1%) were positive for a molecular defect in the α-, β-globin genes, of whom, α-thalassemia mutations and α
-globin gene triplication were found in eleven cases, accounting for about 73.3% of these globin gene defects. Twenty (12.1%)
were positive for a molecular defect in the KLF1 gene. Eight different mutations were identified, six of which are here reported
for the first time. The most common is the G176AfsX179 mutation, accounting for 50% of the total.
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CONCLUSIONS:
The molecular characterization of borderline Hb A2 in Chinese individuals is significantly different than in Italian population.
Our data is conductive to provision of genetic counseling for Chinese individuals with borderline Hb A2.
Copyright © 2014 Elsevier Inc. All rights reserved.
Tue(3)-P-138
Monochorionic Diamniotic Twins With 45,X/46,XY Mosaic Who Showed Different External Genitals
Due To Different Rates of Mosaicism: A Case Report
1,3 2,3 1,3
Taisuke Sato ，Ken Takahashi ，Yuki Ito ，Aiko Sasaki 2 ，Aikou Okamoto 3 ，Kenichiro Hata 1 ，Haruhiko Sago 2
1:Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Japan、2:Center of Maternal-Fetal,
Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan、3:Department of Obstetrics and
Gynecology, Jikei University School of Medicine, Tokyo, Japan
[OBJECTIVES] We describe clinical findings, cytogenetic and molecular analyses of a rare case of 45,X/46,XY mosaic in
monozygotic/monochorionic diamniotic twins with different external genitals. We discuss the etiology of this rare case.
[CASE and METHODS] A 37-year-old primigravida was referred to our hospital at 12 weeks gestation. She was pregnant
with monochorionic diamniotic twins, and severe cystic hygroma was detected in one of the fetuses. Chorionic villi sampling
Poster Session
revealed a 45,X[17]/46,XY[3] karyotype. After sufficient genetic counseling with the patient and her partner, she opted an
abortion at 18 weeks gestation. Autopsy revealed that one fetus had a normal penis and testes, whereas the other fetus with
severe cystic hygroma had a normal vagina, uterus, and ovaries. For genetically validation, DNA was collected from each
umbilical cord to compare the single nucleotide polymorphisms (SNPs) using SNP-array analysis. The numbers of 46,XY
cells and 45,X cells were counted in the internal genitals, liver, spleen, heart, lungs, adrenal glands, bone marrow, and spine
using Fluorescence in Situ Hybridization with XY probes (XY-FISH).
[RESULTS] The SNP array analysis showed that all SNPs were the same in the autosomal chromosomes of the umbilical cord
DNA. Cell counting using XY-FISH showed that the abundance rate of 45,X cells in almost all of the organs of the male fetus
was calculated to be about 20%, whereas that of the female fetus was caluculated to be about 80%. These results show that
the fetuses were genetically monozygotic twins and the different mosaic rates were the main causal factors for their differing
genital phenotypes.
[CONCLUSIONS] Here, we present a rare case of 45,X/46,XY mosaic in monozygotic twins with different genital phenotypes.
Different rates of mosaicism contributed the difference of external genitalia in monozygotic twins. The difference of external
genitalia in twins would not exclude monozygotic twins.
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Tue(3)-P-139
Multisystem involvement and progressive course in Woodhouse-Sakati syndrome: from detailed, com-
prehensive, and longitudinal observation of the first East Asian patient
Motoko Kamiya 1,2,3,4 ，Tomomi Yamaguchi 1 ，Kyoko Takano 1,2 ，Masanori Yamazaki 1,5 ，Masanori Yasuo 6 ，
Maiko Miyagawa 7 ，Shin-ichi Usami 7 ，Akane Minagawa 8 ，Jun Takahashi 9 ，Masafumi Kanai 10 ，Kazuki Hirabayashi 11 ，
Katsuya Nakamura 1,2 ，Masumi Ishikawa 1 ，Emiko Kise 1 ，Keiko Wakui 1,2 ，Yoshimitsu Fukushima 1,2 ，Tomoki Kosho 1,2
School of Medicine、3:Department of Pediatrics, Shinshu University School of Medicine、4:Problem-Solving Oriented Training Program
for Advanced Medical Personnel: NGSD Project、5:Department of Diabetes, Endocrinology and Metabolism, Shinshu University School
of Medicine、6:The First Department of Internal Medicine, Shinshu University School of Medicine、7:Department of Otorhinolaryngology,
Shinshu University School of Medicine、8:Department of Dermatology, Shinshu University School of Medicine、9:Department of Ortho-
pedics, Shinshu University School of Medicine、10:Department of Cardiology, Shinshu University School of Medicine、11:Department of
Ophthalmology, Shinshu University School of Medicine
Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive disorder, characterized by alopecia, diabetes mellitus,
hypogonadism, dystonia, intellectual disability, and deafness. It is caused by mutations in DCAF17 (C2orf37 ), encoding a
nucleolar protein of unknown function. To date, 39 patients from 11 families have been molecularly identified, most of whom
were from Middle East and some from Europe, India, and Pakistan. We encountered a 20-year-old Japanese woman with
WSS. She was born to apparently non-consanguineous parents from the same village. In infancy, she had intractable eczema.
Psychomotor development was not delayed. At age 2−3 years, she suffered from purulent skin disease, and was diagnosed
with leukocyte dysfunction and treated with antibiotics. From her higher classes of elementary school, she had difficulty in
learning. In her high school days, she developed hearing impairment and loss of hair, and had primary amenorrhea. At age 18
years, she had progressing hearing impairment and had a weaker grip. At age 19 years, she was referred to our hospital, and
was found to have craniofacial features (sparse and curly hair, hypertelorism, a depressed nose, a protruding jaw), skeletal
Poster Session
features (torticollis, scoliosis, chubby fingers, and joint rigidity), atrophic skin, moderate hearing impairment, severe myopia,
and endocrinological (hypothyroidism, hypergonadotrophic hypogonadism), neurological (writer’s cramp, dystonia), and
cardiovascular abnormalities (mitral valve regurgitation). Genetic investigation using the TruSight One sequencing panel,
targeting 4,813 genes associated with known clinical phenotypes, on the MiSeq revealed a novel nonsense mutation “c.G796
T; p.G266X” in DCAF17 homozygously. Thus, she was diagnosed with WSS, the first reported patient in East Asia. Her
detailed, comprehensive, and longitudinal clinical information suggest fundamental role of the nucleolus with multisystem
involvement.
Tue(3)-P-140
Caffey disease (CD) or infantile cortical hyperostosis: a novel mutation in COL1A1 detected in a Chilean
patient evidences the locus heterogeneity of the disease
1,2 1,3 1,3 1,4 1,3,5 1,3,5
Fanny Cortes ，Karla Moenne ，Ximena Ortega ，Alejandro Baar ，Alejandro Veloz ，Takeshi Asahi
1:Rare Diseases Center, Clinica Las Condes, Chile、2:Pediatrics Department, Genetics Unit, Clinica Las Condes、3:Radiology Department,
Clinica Las Condes、4:Orthopedics Department, Clinica Las Condes、5:Laboratory for Advanced Medical Image Processing. Clinica Las
Condes
CD is a rare dominant disorder, with an unknown prevalence and <100 cases reported worldwide. Considered an osteosclerotic
dysplasia, is characterized by acute inflammation with massive subperiosteal new bone formation involving the diaphysis of
the long bones, ribs, mandible, scapulae, and clavicles. CD has some unusual features for a hereditary disorder: rarely appears
after 5 months of age and usually resolves spontaneously by the age of 2 years; sometimes is present at birth and it has been
identified in utero.
The COL1A1 mutation c.3040C>T (p.Arg1014Cys) in exon 41 is the defining mutation currently identified in all individuals
with CD. Allelic and/or locus heterogeneity is considered possible, but it has not been observed until now.
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We present a Chilean male patient, product of the second pregnancy of apparently healthy parents, with a classical clinical
and radiological CD phenotype. The disease was suspected during the first week of life, when a deformity of both lower limbs
was observed and a complete radiological skeletal survey showed subperiostal cortical hyperostosis of both tibias, mandible,
and right clavicle.
Sequencing of COL1A1 gene, showed an heterozygote mutation, c.2752C>T (p.Arg928Cys), in exon 39. The change
p.Arg918Cys is located in a highly conserved region of the COL1A1 gene. In silico predictive algorithms used, estimate
that the change p.Arg918Cys would have a deleterious effect. Parental molecular analysis detected the same mutation in the
mother, and the reevaluation of maternal familial medical data revealed that her unique brother had a medical history of
curved lower limbs, between 6-18 months of age, diagnosed and treated as rickets, resolved with no sequela. A reduced pene-
trance, described in CD, may explain the normal maternal phenotype. Complete co-segregation of the mutation in this family
will be presented. To our knowledge, this is the first patient reported with this genotype, evidencing a locus heterogeneity of
the disease.
Tue(3)-P-141
Withdrawn

Poster Session
Tue(3)-P-142
DLX6 , MSX1, AND EDN1 : DIFFERENTIAL EXPRESSION IN HUMAN MANDIBLES THAT POTEN-
TIALLY REGULATE MANDIBULAR SIZE
Rachel BV Cooper 1 ，Donald R Oliver 1 ，Ki B Kim 1 ，Alexander Lin 2 ，Rolf G Behrents 1 ，Adriana M Montano 3
1:Center for Advanced Dental Education, Saint Louis University, USA、2:Plastic Surgery, Saint Louis University、3:Pediatrics, Saint Louis
University
Introduction: An individual’s genes influence the morphological features of the mandible. Mandibular size is important to
orthodontists due to the fact that the mandible is the mechanism by which the lower face influences facial esthetics and dental
function. At this point in time, no biological marker has been identified that is indicative of eventual mandibular size. The
objective of this study was to compare the expression of genes DLX6 , EDN1 , and MSX1 to mandibular size.
Subjects and Methods: Fifty-four individuals older than six years of age undergoing orthodontic treatment who have available
cephalograms were included in the study. Condylion to gnathion was measured for each of the fifty-four individuals to sort
them into groups. mRNA was isolated from saliva and subjected to real time quantitative polymerase chain reaction (RT-
qPCR).
Results: Threshold cycle (Ct) values for subjects with small mandibles (greater than one standard deviation) had the least
amount of expression of DLX6 and MSX1 . Ct values for subjects with large mandibles (larger than the population mean by
greater than one standard deviation) had less expression of DLX6 and MSX1 than individuals within one standard deviation
of the mean, but more than those with small mandibles. Ct values for EDN1 did not show any statistically significant
differences between the groups.
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Conclusions: DLX6 and MSX1 significantly influence mandibular development and size.
Tue(3)-P-143
Neuroblastoma Amplified Sequence (NBAS) mutation in Recurrent Acute Liver Failure: confirmatory
report in a sibship with very early onset, osteoporosis and developmental delay
Jose M Capo-chichi 1 ，Cybel Mehawej 2 ，Valerie Delague 3,4 ，Catherine Caillaud 5 ，Issam Khneisser 2 ，Fadi F Hamdan 1 ，
Jacques L Michaud 1,6 ，Zoha Kibar 1 ，Andre Megabarne 2,7
1:CHU Sainte-Justine Research Center, Canada、2:Unite de Genetique Medicale, Faculte de Medecine, Universite Saint-Joseph, Beirut,
Lebanon、3:Inserm, Marseille, France、4:Aix Marseille Universite, Marseille, France、5:Service de Biochimie Medicale, Hopital, Paris, France、
6:Department of Pediatrics and Department of Neurosciences, Universite de Montreal, Montreal, Canada、7:Institut Jerome Lejeune, Paris,
France
Background: Recently, biallelic mutations in the Neuroblastoma Amplified Sequence NBAS gene have been identified in
ten patients with recurrent acute liver failure (RALF) in early infancy. In addition to severe liver dysfunction, some of
these individuals also presented cardiomyopathy, neurologic phenotypes and gastrointestinal immune defects. Here we report
on a consanguineous Lebanese family with three affected siblings who died of RALF between 4 months and 1 year of age.
Of note, neonatal spontaneous fractures, developmental delay, prominent eyes, generalized hirsutism, gingival hypertrophy,
and splenomegaly were also present. Liver dysfunction was also observed and led to the early death of these patients.
Methods: Whole-genome SNP genotyping in all the patients, followed by exome sequencing was performed in one affected
sibling. Results: A homozygous c.409C>T (p.Arg137Trp) missense mutation in NBAS was identified in all three patients.
Conclusion: Overall, our findings confirm the involvement of NBAS in the pathogenesis of this condition characterized by
Poster Session
severe liver dysfunction and help expand its phenotypical spectrum.
Tue(3)-P-144
A novel TTN mutation causing Tibial Muscular Dystrophy in a Turkish patient
Evren Gumus 1 ，Huseyin Aslan 1 ，Oguz Cilingir 1 ，Muhsin Ozdemir 1 ，Beyhan Durak Aras 1 ，Halime Onur Kucuk 1 ，
Sevilhan Artan 1
1:Medical Genetics, Eskisehir Osmangazi University, Turkey
Tibial muscular dystrophy (TMD) is an autosomal dominant late-onset distal myopathy caused by the mutations in TTN ,
located on chromosome 2q31, which encodes the central sarcomeric protein, titin. The phenotype manifests as muscle weakness
which onsets on early 30s and remains confined to the tibial anterior muscles. Histopathological changes are compatible with
muscular dystrophy, with the rather common yet exceptional finding: rimmed vacuoles.
In this paper, we present a 60-year-old male whose symptoms started at the end of his fourth decade as leg muscle weakness
and difficulty in foot dorsiflexion which later progressed into feet muscle atrophy and stepping difficulty.
MRI examinations of crural muscles were compatible with muscular dystrophy and heterogeneous fatty degeneration was noted
in the anterior compartment. Prominent diffuse homogenous fatty degeneration found on the medial and lateral gastrocnemius
muscles bilaterally and medial compartment of left soleus muscle.
Molecular analysis revealed a novel heterozygous mutation in TTN , c.75313A/C (p.Asn25105His). The mutation was found
to be highly a disease causing mutation by in silico assessment tools and confirmed by Sanger sequencing.
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Tue(3)-P-145
Analysis of mitochondria-related gene from clinically suspected Charcot-Marie-Tooth patients by using
whole exome sequencing
Yu Hiramatsu 1 ，Yuji Okamoto 1 ，Akiko Yoshimura 1 ，Junhui Yuan 1 ，Yujiro Higuchi 1 ，Akihiro Hashiguchi 1 ，
Hiroshi Takashima 1
1:Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Japan
Background
Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous disorder that causes inherited distal sym-
metric peripheral neuropathy. In spite of more than 50 causative genes linked to CMT till now, the unexpected low detection
rate suggests more undiscovered genes that could result in CMT phenotype. Mitochondria-related gene like MFN2 and
GDAP1 are well known CMT disease-causing genes, and a third patients with mitochondrial disorders could develop periph-
eral neuropathy.
Methods
We enrolled 399 clinically suspected CMT patients, who were mutation-negative in the pre-screening of target genes using
DNA microarray (Affymetrix; 27 genes) or targeted resequencing (Illumina MiSeq; 40 genes). All of these patients underwent
a whole exome sequencing (WES). On the basis of their inheritance pattern, 247 CMT patients grouped as autosomal recessive
(AR) or sporadic were selected for a further analysis with 167 mitochondria-related genes.
Poster Session
Results
In 9 patients, we detected seven novel mutations in SUCLA2 , MTPAP, PHKA1 , PYGM, HADHB, PDHB, and C12orf65
genes, respectively. Electrophysiological findings of these patients were predominantly sensorimotor axonal polyneuropathy,
except the patients harboring mutation in PYGM (mild demyelination) or C12orf65 (intermediate). In addition, we also
found other neurological abnormalities, comprising encephalopathy, mental retardation, optic atrophy, and hearing loss.
Conclusions
Using WES, we revealed seven novel mitochondria-related gene mutations from a cohort of patients with CMT disease. Since
mitochondrial dysfunction frequently leads to polyneuropathy, it is essential to check the mitochondria-related genes in patients
with a CMT phenotype, particularly for the patients accompanied with additional neurological findings like encephalopathy
or optic atrophy.
Tue(3)-P-146
Mulibrey Nanism in an Omani girl with Primary ovarian failure
1
Adila M. AlKindy
1:Department of Genetics, Sultan Qaboos University Hospital, Sultanate of Oman, Oman
MULIBREY (MUscle-LIver-BRain-EYe) Nanism (MIM#253250) is an autosomal recessive disorder characterized by growth

retardation of prenatal onset. Failure of sexual maturation and hypergonadotrophic premature ovarian failure was reported
in all 110 cases of females with mulibrey nanism worldwide. Though all the patients with mulibrey nanism in this study had
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ICHG2016 1041
spontaneous puberty by 14.7 yrs, they all had incomplete breast development and premature ovarian failure 1.5 yrs. after
the menarche with subsequent infertility. Here we report a 16 yr old Omani girl with mulibrey nanism with primary ovarian
failure. She failed to develop secondary sexual characteristics and no spontaneous menarche by 14.5yrs age when she was
then started on sex hormonal replacement therapy. In addition, she was on Thyroxine for hypothyroidism and on Vitamin D
replacement therapy. This is the first report of an Omani girl with mulibrey nanism confirmed by novel homozygous mutation
c.181C> in TRIM37 (reported as homozygous variant likely to be causal due to the fact it leads to premature STOP codon)
but showed no spontaneous menarche and in addition was noted to be hypothyroid.
Poster Session
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ICHG2016 1042
Poster Session
Development
Tue(3)-P-147
Genetic analysis of 30 families with Joubert syndrome and related disorders
Toshifumi Suzuki 1,2 ，Noriko Miyake 1 ，Mitsuko Nakashima 1 ，Hirotomo Saitsu 1 ，Satoru Takeda 2 ，
1:Human Genetics, Yokohama City University Graduate School of Medicine, Japan、2:Department of Obstetrics and Gynecology, Juntendo
University Faculty of Medicine
Joubert syndrome (JS) and related disorders (JSRDs) are rare recessive neurodevelopment disorders characterized by cere-
bellum vermis hypoplasia and neurological findings including hypotonia, ataxia, abnormal eye movement, neonatal recurrent
breathing pattern, and intellectual disability. Hypoplasia of the superior cerebellar vermis with elongation and thickening of
the superior cerebellar peduncles at brain axial MRI is known specific neuroradiological finding called a molar tooth sign.
Most cases show additional broad multiorgan features including retinal dystrophy, coloboma, cystic kidney disease, liver
fibrosis, encephalocele, and polydactyly. To date, at least 24 mutant genes are found in JS and JSRDs. Considering broad
phenotypic features and extreme genetic heterogeneity in JS/JSRDs, whole-exome sequencing (WES) is a practical choice
as genetic analysis. We performed WES in 30 families who were clinically diagnosed as JS or JSRDs. Genome partitioning
Poster Session
was performed using the SureSelectXT Human All Exon 50 Mb library or V4 (51Mb) library and partitioned DNA was
analyzed either on a Genome AnalyzerIIx sequencer with 108 bp paired-end reads, a HiSeq 2000 or a HiSeq2500 platform
with 101 bp paired-end reads. Candidate variants considered as pathogenic were validated by Sanger sequencing, and their
familial segregation was checked when familial samples were available. We could successfully identify causative mutations
in 25 out of 30 families (83.3%). The mutation detection rate in our study was higher than any other studies (41-62%). In
Japanese families with mutant genes found (n=23), CEP290 (6/23, 26.1%) and TMEM67 (7/23, 30.4%) mutations were most
frequently mutated. Interestingly, 9 out of 12 CEP290 mutant alleles turned out to be c.6012-12T>A (75.0%), while it has
never been reported in patients with other ethnic backgrounds. This finding indicates that c.6012-12T>A in CEP290 is a
founder mutation in Japanese population.
Tue(3)-P-148
The first Japanese patients with genetically definite Bardet-Biedl syndrome
Makito Hirano 1,2 ，Wataru Satake 3 ，Kenji Ihara 4 ，Ikuya Tsuge 5 ，Yutaka Suzuki 6 ，Yusaku Nakamura 1 ，
Susumu Kusunoki 2 ，Tatsushi Toda 3
1:Department of Neurology, Sakai Hospital Kindai Universtiy, Japan、2:Department of Neurology, Kindai University Faculty of Medicine、
3:Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine、4:Department of Pediatrics, Faculty of
Medicine, Oita University、5:Department of Pediatrics, Fujita Health University、6:Department of Computational Biology, Graduate School
of Frontier Sciences, The University of Tokyo
Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by central obesity, mental impairment, rod-cone
dystrophy, polydactyly, hypogonadism in males, and renal abnormalities. The causative genes have been identified as BBS1-
19 . In Western countries, this disease is often reported, but remains undiagnosed in many patients until later in life, while
only a few patients with no mutations identified have been reported in Japan. We previously conducted the first nationwide
survey of BBS in Japan by sending questionnaires to 2,166 clinical departments with board-certified specialists and found 7
patients with clinically definite BBS. We performed exome analyses combined with analyses of mRNA and protein in these
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ICHG2016 1043
patients. We identified 2 novel mutations in the BBS5 gene (p.R89X and IVS7-27 T>G) in 2 sibling patients. We also found
3 previously reported mutations in the BBS2 (p.R413X and p.R480X) and BBS7 (p.C243Y) genes in 2 patients. This is the
first study to identify genetic alterations in Japanese patients with BBS. Our results indicate that BBS in Japan is genetically
heterogeneous and at least partly shares genetic features with BBS in other countries. Future treatments developed in other
countries are thus likely to be applicable in Japan, and vice versa.
Tue(3)-P-149
Placental epigenome vary in relation to inadequate gestational weight gain
Tomoko Kawai 1 ，Takahiro Yamada 4 ，Kosei Abe 1 ，Kohji Okamura 2 ，Hiromi Kamura 1 ，Rina Akaishi 4 ，
Hisanori Minakami 4 ，Kazuhiko Nakabayashi 3 ，Kenichiro Hata 1
1:Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Japan、2:Department of Systems
BioMedicine, National Research Institute for Child Health and Development、3:Division of Developmental Genomics, National Research
Institute for Child Health and Development、4:Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine
A lot of studies suggest that in utero environments might add long-lasting effects to foetus through epigenetic modifications.
However, few human studies have investigated the associations between these two. To elucidate this hypothesis, we focused on
in utero nutritional environment and human postpartum placental epigenome. We report genome-wide methylation profiles for
33 postpartum placentas from pregnancies of normal and foetal growth restriction with various extents of maternal gestational
weight gain. Epigenetic alterations accumulate in the placenta under adverse in utero environments, as shown by application
of Smirnov-Grubbs’ outlier test. Moreover, hypermethylation occurs frequently at the promoter regions of transcriptional
Poster Session
regulator genes, including polycomb targets and zinc-finger genes, as shown by annotations of the genomic and functional
features of loci with altered DNA methylation. Aberrant epigenetic modifications at such developmental regulator loci, if
occurring in foetuses as well, will elevate the risk of developing various diseases, including metabolic and mental disorders,
later in life.
Tue(3)-P-150
Differentiation of iPS cells into cranial neural crest cells to model congenital disorder that arises from
defects in the development of the embryonic cranial neural crest cell lineage
Hironobu Okuno 1 ，Francois -Mihara Renault 1 ，Shigeki Ohta 1 ，Kenji Kurosawa 2 ，Kimiko Fukuda 3 ，
Wado Akamatsu 4 ，Takao Takahashi 5 ，Kenjiro Kosaki 6 ，Hideyuki Okano 1
1:Department of Physiology, Keio University Schoo of Medicine, Japan、2:Department of Medical Genetics, Kanagawa Children’s Medical
Center、3:Depertment of Biological Science, Tokyo Metropolitan University、4:Center for Genomic and Regenerative Medicine, Juntendo
University School of Medicine、5:Department of Pediatrics, Keio University School of Medicine、6:Center for Medical Genetics, Keio
University School of Medicine
iPS cell technology, invented by Shinya Yamanaka in 2006, enables us to convert somatc cells into pluripotent cells.
Before that, it is impossible to make models of congenital disorders that arises from defects in the development of the embryonic
cranial neural crest cell lineage. But now using these iPS cells technologies, we can generate the disease specific differentiated
cell. Then now it is possible to investigate complicated questions of cell biology, transcriptome, and in vivo transplantation
analysis related to the pathogenesis of the disease in ways not before possible. And we can also perform pharmacological
study.
Here we invented the way to differentiate iPS cells into cranial neural crest cells and characterize those iPS-derived neural
crest cells. By applying these protocol we can reveal pathophysiologies of cranial Neurocristopathy.
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ICHG2016 1044
Tue(3)-P-151
Nutrigenomic aspects of adaptive responses to maternal high-sucrose feeding in rat models of metabolic
syndrome
Lucie Sedova 1 ，Elena Skolnikova 1 ，Frantisek Liska 1 ，Ludmila Kazdova 2 ，Drahomira Krenova 1 ，Vladimir Kren 1 ，
Pavel Hamet 3 ，Johanne Tremblay 3 ，Ondrej Seda 1
1:Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University in Prague, Czech Republic、2:Department of
Metabolism and Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic、3:Research Centre CHUM, Montreal,
Quebec, Canada
We aimed to investigate the nutrigenomic aspects of maternal high-sucrose diet feeding using 2 distinct inbred rat models
of metabolic syndrome. Rat dams of genetically defined inbred models of metabolic syndrome, the polydactylous (PD) and
congenic BN.SHR4 rat strains were fed 2 weeks before breeding, during pregnancy and till weaning) high-sucrose (HSD) or
standard (STD) diets. The 5-month-old male offspring were then divided into 2 groups that were fed either HSD or STD
for 2 weeks. The hepatic transcriptome (Affymetrix Rat Exon 1.0ST Array validated by qPCR) profiles were assessed in
all strain*maternal diet*offspring diet combinations. Metabolic profile data were analyzed by general linear model ANOVA,
network analysis was performed using Ingenuity Pathways Analysis.
We identified several siginificant interactions between genetic background and metabolic programming, e.g. for triglyc-
erides,free fatty acids (FFA:PD from HSD dams 0.25±0.01, PD-STD dams 1.22±0.10, BN.SHR4-HSD dams 0.68±0.06 and
BN.SHR4-STD dams 0.37±0.04 mmol/l for HSD-fed offspring) and AUC of oral glucose tolerance test (no difference in
BN.SHR4, significantly lower values in offspring of PD-HSD dams). 355 transcripts showed significant interaction between
genomic background*maternal diet*offspring diet after correcting for multiple comparisons (FDR < 0.05). Major canonical
Poster Session
pathways showing overrepresentation included fatty acid beta oxidation and insulin receptor signaling (both p = 0.0006).
This was corroborated by differences of FFA concentrations in the serum of the respective groups. Network analysis further
revealed specific upstream regulators and network nodes distinguishing the effect of maternal HSD in the PD vs. BN.SHR4
strains.
The strain-specificity of complex reaction to the identical environmental stimulus provides evidence for existence of nutrige-
nomic interaction between the high-sucrose diet and the genomic background of the“metabolically programmed” offspring.
Tue(3)-P-152
Assessment of EGF gene and EGF-R expression following verification of 2-cell and blastocysts mouse
embryos
Saima Abbaspour 1 ，Parvaneh Keshavarz 1 ，Mojhgan Eskandari 1 ，Alireza Sharafshah Rostami 1
1:Cellular and Molecullar Research Center, Faculty of Medicine, Guilan University of Medical Science, Iran
Nowadays, verification is used for the protection of surplus embryos in ART, but genetic effects of this method are unclear.
However, it is not appear that thawed embryos that they are morphologically normal, also be genetically normal. This study
was designed in order to evaluate of cryopreservation effect on expression of EGF and EGFR genes in mouse 2-cells and
blastocysts. To stimulate ovulation in mice, HCG was injected. After 44-46 and 86-88 hours, 2-cells and blastocysts were
collected, respectively. These embryos were divided into case and control groups, 2-cells and blastocysts of control group
were immediately stored in nitrogen tank for future studies. 2-cells and blastocysts of case group were cryopreserved by using
cryotop and after 2-4 mounts were thawed. 2-cells which were normal based on their morphology were selected and extraction
of RNA was performed. Quantitative expression of EGF and EGFR genes in both groups was investigated by using Real-time
PCR. Statistical analyses were performed by SPSS (ver. 13). The results of Real-time PCR quantitative analysis showed
that expression level of EGF and EGFR genes has diminished in case group than control group. This study showed that
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ICHG2016 1045
cryopreservation by cryotop has negative effect on expression amount of EGF and EGFR genes in these embryos.
Tue(3)-P-153
Lgr4 plays as an anti-testis gene of fetal gonads in mice
Masae Koizumi 1 ，Kazunori Oyama 2 ，Akihiro Nawa 3 ，Katsuhiko Nishimori 2
1:Department of Obstetrics and Gynecology, Ehime University School of Medicine, Japan、2:Laboratory of Molecular Biology, Graduate
School of Agricultural Science, Tohoku University、3:Department of Obstetrics and Gynecology, Nagoya University School of Medicine
Leucine-rich repeat-containing G protein-coupled receptor 4 (Lgr4 ) is a type of membrane receptor with a seven-
transmembrane structure. Lgr4 is homologous to gonadotropin receptors such as follicle stimulating hormone receptor (Fshr)
and luteinizing hormone/choriogonadotropin receptor (Lhcgr). Recently, it has been reported that LGR4 is a membrane
receptor for R-spondin ligands, which mediate Wnt/beta-catenin signaling. Defects of R-spondin homolog (Rspo1 ) and
wingless-type MMTV integration site family, member 4 (Wnt4 ) cause masculinization of female gonads. Lgr4 was expressed
in female somatic cells of the ovaries during the embryonic and neonatal periods. Rspo1-3 were expressed in neonatal ovaries.
We observed that Lgr4-/- female mice exhibited pseudo hermaphroditism similar to that observed in Rspo1-deficient mice.
We found no Anti-Mullerian Hormone (AMH) in Lgr4-/- female mice. In Lgr4-/- ovarian somatic cells, the expression levels
of lymphoid enhancer binding factor 1 (Lefl), axin2 (Axin2 ) and trans-acting transcription factor 5 (Sp5 ) which are target
genes of Wnt/beta-catenin signaling, were lower than they were in wild-type mice. The levels of androgen in Lgr4-/- female
mice was not elevated. In KGN cells, the expression of androgen receptor had relation to Wnt3a and RSPO1. This study
suggests that Lgr4 is critical for the specialization of female reproduction organs via the cooperative signaling of Rspo1 and
Poster Session
Wnt/beta-catenin.
Tue(3)-P-154
VA10, an immortalized broncho-epithelial cell line, as a tool for in vitro lung developmental studies
Partha Sen 1 ，Debra Salvi 1 ，Sofya Peysakhovich 1 ，Aaron Hamvas 1
1:Pediatrics, Northwestern University, USA
Background: In vitro lung developmental studies have been minimal due to lack of a proper model system. However,
development of such a system shall lead to beneficial discoveries that may ultimately help towards treatment of deadly
childhood and adult lung disorders. Earlier reports of VA10 cells, an immortalized broncho-epithelial cell line, showed that
co-culturing them with human umbilical vascular endothelial cells (HUVECs) in 3 dimensional (3D) cultures in Matrigel,
result in their differentiation into branches and tube like structures. However, studies with these structures are difficult since
they must be separated from the endothelial cells to fully understand the gene expression patterns during branching and tube
formation. We hypothesized that growth of VA10 cells in Matrigel without the HUVEC supporting layer would result in
similar morphologic characteristics and facilitate gene expression studies.
Methods: Cells were grown in BEGM medium plated with a density of 2000 cells/well in 50% Matrigel in 24-well plates.
Once plated, the cells were incubated at 37o C for 20 days
Results: When grown in liquid medium, the VA10 cells form a monolayer. However, when grown in 3D Matrigel culture, they
form extensive branches and tube like structures along with sac like structures at the termini of the branches. The cells first
grow into small clusters and differentiation starts around day 9 and the fully differentiated structures are observed by day 15.
We have further fine-tuned the growth conditions of these cells and show that the VA10 cells start branching on day 3 when
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ICHG2016 1046
layered on the Matrigel instead of being embedded into it.
Conclusions: VA10 cells can be cultured in 3D medium without HUVECs to differentiate into branches and tubular structures.
This will make downstream studies of lung differentiation much easier and will provide the tools for analyzing the roles of
specific genes in the process of lung development and also a model for testing gene mutations.
Tue(3)-P-155
A Boolean network model of normal gonadal sex determination in human and related disorders of sex
development
Leda Torres 1 ，Osiris Rios 1,2
，Alfredo Rodriguez 1,4
，Susana Kofman 5 ，Horacio Merchant 3 ，Luis Mendoza 3,6
，
Sara Frias 1,3
1:Human Genetics, Instituto Nacional de Pediatria, Mexico、2:Posgrado en Ciencias Biologicas, UNAM、3:Instituto de Investigaciones
Biomedicas, UNAM、4:Doctorado en Ciencias Biomedicas, UNAM、5:Facultad de Medicina, UNAM, Hospital General de Mexico,、6:Centro
de Ciencias de la Complejidad, UNAM
In human the sex development occurs in three steps: 1) Chromosomal sex determination established at conception with the
complement of sex chromosomes, XX or XY. 2) Gonadal sex determination (GSD) takes place in early stages of development
when bipotential gonadal primordium (BGP) differentiates to testes or ovaries, and 3) phenotypic sex differentiation that
involves the development of internal and external genitalia in response to the hormones secreted. The interactions and
Poster Session
dynamics of the elements that constitute the GSD network are poorly understood; our group is interested in inferring the
general architecture of this network as well as modeling the behavior of genes associated to this process under wild-type and
mutant conditions. We reconstructed the regulatory network of GSD with a set of genes directly associated with the process
of differentiation towards Sertoli or granulosa cells as: EMX2, LHX1, PAX8, CBX2, NR5A1, GATA4, WT1, NR0B1, SRY,
SOX9, FGF9, PGD2, DHH, AMH, DKK1, DMRT1, CTNNB1, WNT4, FOXL2, RSPO1 . These genes are well-characterized
and the effects of their deficiency have been reported. We modeled this as a synchronous Boolean network model (BNM)
and characterized its attractors under wild-type and mutants to resemble some disorders of sex development (DSD). Three
attractors with biological meaning were found; one corresponds to the expression pattern in Sertoli cells, the second correlates
to the granulosa cells and, the third with a disgenetic gonad. The BNM of GSD that we present summarizes the experimental
data on the pathways for Sertoli and granulosa, sheds light on the behavior of a population of cells that differentiate in the
developing gonad. With this model we propose a set of regulatory interactions needed to activate the SRY or the WNT4
pathway as well as their downstream targets, which are critical for sex differentiation. In addition, we observed a pattern of
altered regulatory interactions and their dynamics that lead to some DSD.
Tue(3)-P-156
Identification and characterization of non-coding RNAs associated with chromatin in pluripotency
Alessandro Bonetti 1 ，K Kashi 1 ，Kosuke Hashimoto 1 ，Alexandre Fort 1 ，Piero Carninci 1
1:RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa, Japan
Although mammalian genomes contain less than 25,000 protein-coding genes, the non-coding RNA (ncRNA) transcription
constitutes their most unexplored and prevalent part. Despite such abundance only in the past few years we have started to
appreciate their functions in cells. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are increasingly
being used for drug screening as well as for cell-based models of numerous pathologies and regenerative medicine. For such
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models, understanding the mechanisms that maintain stemness and promote differentiation is critical.
We recently used four complementary high-throughput sequencing technologies to characterize the non-coding transcriptome
of mouse pluripotent stem cells. We have identified over 6000 stem cell-specific non-annotated transcripts predominantly
expressed in the nucleus. Here we present our latest findings regarding the characterization of these ncRNAs and their
intimate association with the chromatin.
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Poster Session
Evolutionary and Population Genetics
Tue(3)-P-157
Fingerprint Pattern and Blood Groups in Twins- A Genetic Perspective
1
Fawaz Pullishery
1:Public Health, Educare Institute of Health Sciences, India
Introduction : The distinguishing nature of physical characteristics of a person is due to both the inherent individual genetic
diversity within the human population as well as the random processes affecting the development of the embryo. The focus
of this study is to quantitatively determine the similarity of fingerprint pattern and blood groups in identical twins as well as
in non identical twins.The village, kodinhi, draw attention from many international experts and others after a survey done
by locals found an unusually large number of twin births in the region.
Material and Methods: A total of 24 pair of identical twins and 33 pairs of non-identical twins were selected for the study.
The fingerprints of the thumb, index, middle, ring and little fingers of both hands of 57 pairs of twins were scanned. Due to
differences in paper quality and degradation of the print over time, several of these fingerprints are of poor quality and we
selected only 51 pairs. The blood groups of the study population were identified using ABO System of Blood Grouping .
Poster Session
Results: The results showed that ’Arch’ type was the most common type of finger print pattern present in both identical
(42.04%) and non-identical twins (53.10%). The Loop type was 26.59% and 22.24% in identical and non-identical twins
respectively.All the identical twins shared the same blood group as their respective co-twin except one pair where they had a
different type of B+ and O+.
Conclusion: The similarity in finger print pattern among identical twins were very high than non-identical twins and it was
statistically significant. Rh+ blood type was the common blood group in twins than Rh-.
Tue(3)-P-158
Oral Health Related Habits and Oral Hygiene Practices among Identical and Non-Identical-A Genetic
Perspective
1
Fawaz Pullishery
1:Public Health, Educare Institute of Health Sciences, India
Background: The advantage of twin studies is that it allows disentanglement of the shared genetic and environmental factors
for the trait of interest. Researchers can estimate the proportion of variance in a trait attributable to genetic variation, versus
the proportion that is due to shared environment or unshared environment. This study was conducted to assess the oral
hygien habits and practices among a twin population.
Methodology: : A structured questionnaire was used for collection of sociological data, oral health related habits and oral
hygiene practices.The study was conducted in twins living in the village of Kodhini in the state of Kerala in India which has
drawn attention from many international experts and others after a survey done by locals found an unusually large number
of twin births in the region
RESULTS: 58 percent of the participants brushed their teeth at least twice daily, while 17 percent reported irregular tooth
brushing. When the tooth brushing method was seen between identical and non-identical twins the results were not statistically
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significant (p=0.162).
CONCLUSION: Identical twins had a similarity than non-identical twins to some extent in the oral health practices and
habits. It may be concluded that the similarity is due to the same genetic traits among them.
Tue(3)-P-159
Genetic Analysis Provides Evidence for Increased Disease Prevalence of Systemic Lupus Erythematosus
in Chinese Populations compared to Europeans
Yongfei Wang 1 ，Yan Zhang 1 ，Yu Lung Lau 1 ，Wanling Yang 1,2
1:Paediatrics & Adolescent Medcine, The University of Hong Kong, Hong Kong、2:Centre for Genomic Sciences, LKS Faculty of Medicine
and Queen Mary Hospital
Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with strong genetic contribution and ethnic differ-
ences, characterized by recurrent inflammatory response and multiple-organ damage. Worldwide epidemiology studies have
showed that the prevalence of SLE in Asians is about 2-3 times higher than that in European ancestry. We have conducted a
trans-ethnic meta-analysis using Genome Wide Association Study (GWAS) datasets from Chinese and Europeans, and identi-
fied 10 novel SLE risk loci, bringing the total to more than Sixty. In this study, we compared those established risk loci between
Asians and Europeans, and observed a significant increase in population frequency of SLE risk alleles in Chinese, providing
strong evidence that genetics explains the discrepant population prevalence. In addition, we integrated multi-dimensional
biologically annotation to prioritize SLE risk genes and demonstrated that these genes are more likely to be the interactors of
targets for the approved drugs for SLE, supporting the role of genetic studies in drug discovery. Through scanning the drug
Poster Session
databases, we suggest that those approved drugs for other diseases may be repositioned for SLE treatment. In summary, on
the basis of genetic findings, our analysis sheds light on the pathways and cell types that contribute to SLE pathogenesis,
and provides genetic evidence for the discrepant population prevalence and supports the role of association studies in drug
discovery.
Tue(3)-P-160
First Report of Hemophilia-A Point Mutation Detection in Egypt: AMean for Providing Proper Genetic
and Prenatal Counseling
Rehab Mostafa Mosaad 1 ，Heba Ahmed 2 ，Naglaa Omar 3 ，Sonia Adolf 4 ，Ghada Youesf El-Kamah 2
1:Molecular Genetics and Enzymology, National Research Centre, Egypt、2:Clinical Genetics, National Research Centre、3:Paediatrics, Kasr
AlAiny School of Medicine, Cairo University、4:Paediatrics, National Research Centre
Background: Hemophilia A is a common inherited recessive X-linked disorder caused by deficiency of factor VIII in the
coagulation cascade and affects approximately 1 in 5000 males world-wide.Aim: we focused on exon 14 of the F8 gene as it is
the largest exonic coding sequence which makes it more prone to mutations compared to the other exons. Patients & methods:
30 patients from 30 unrelated families were attending the Hereditary Blood Disorder Clinic at the National Research Centre .
Clinical evaluation coagulation and immunologic assays to measure FVIII activities were performed .Patients were classified
according to the FVIII activity. Patients gave informed consent for molecular studies.DNA extraction was performed by
salting out . Polymerase Chain Reaction (PCR) was done using 6 primers to target three fragments in exon 14 (14A 14D
and 14F) . Amplified exons were sequenced in both directions. Sequence was compared with the FVIII gene reference
sequence NM_000132.3 in the GeneBank database. Results: patients age ranged between 2 to 50 years (mean age = 11.7).
Positive consanguinity was observed in (50%) and other affected family member was observed in (37.5%).Patients were
classified according to FVIII activity into mild: 10 (33.3%), moderate: 12 (40%) and severe: 8(26.7%).Of the 30 patients
four exhibited sequence mismatch when compared to the reference sequence. Sequence analysis of exon 14A PCR product
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showed a point mutation. This mutation due to codon change CGA > TGA at B domain at codons (c.2440C>T) causes
Arginin amino acid change to stop codon (p.Arg814*) that is associated with sever haemophilia A. This mutation was
recorded in the Haemophilia A Mutation Database however this is the first report of the aforementioned mutation in the
Egyptian hemophilia a patients.Conclusions:We report the first molecular characterization of point mutation among Egyptian
hemophilia-A patients
Keywords: Hemophilia A; Mutation, Missense
Tue(3)-P-161
Signatures of geographically restricted adaptation in the Sea Island Gullah African Americans
Paula S Ramos 1 ，Satria Sajuthi 2 ，Jasmin Jasmin Divers 2 ，Uma Nayak 3 ，Wei-Min Chen 3 ，Kelly J Hunt 1 ，
Diane L Kamen 1 ，Gary S Gilkeson 1 ，Jyotika K Fernandes 1 ，Ida J Spruill 1 ，W T Garvey 4 ，Michele M Sale 3 ，
Carl D Langefeld 2
1:Medical University of South Carolina, USA、2:Wake Forest School of Medicine、3:University of Virginia、4:University of Alabama,
Birmingham
Differences in historical selective pressures may partially explain differences in allele frequencies and thereby disease prevalences
among ethnic groups. Relative to other African-Americans (AA), the Gullah population has lower European admixture and
higher ancestral homogeneity from the Sierra Leone (SL) area in Far-West Africa. We sought to capitalize upon the relative
closeness between the Gullah and SL to identify regions with evidence of population differentiation that may resulted from
Poster Session
geographically restricted selective pressure.
Using genome-wide genotype data on 277 healthy Gullah, 400 SL, and 203 YRI from the HapMap3 Project, we computed the
Weir and Cockerham’s (1984) FST (in VCFTOOLS) and the Hudson estimator for FST (in EIGENSOFT) between Gullah
and SL, and Gullah and YRI. A total of 582,100 autosomal SNPs met standard GWAS quality control.
The FST estimates were similar between Gullah and SL (FST =0.003), and Gullah and YRI (FST =0.003), and slightly higher
in SL and YRI (FST =0.004), reflecting higher allele frequency differences between these African populations. Despite the
similar FST estimates, the loci in the top 0.01% of highest FST were different between Gullah and SL, and Gullah and YRI.
Of the 6 regions with multiple SNPs showing population differentiation between Gullah and SL, and 8 regions between Gullah
and YRI, only the HLA region, known to be under balancing selection, was common.
Here, we identified several regions that show evidence of selection in the Gullah. The best confirmation that a region is
under selection comes from consistent reports using multiple methods (such as the HLA region). Moreover, further analyses
are required to elucidate if the population differentiation is the result of selection pre- or post-admixture. Identification of
functional regions that might be under selection in the Gullah contributes to a better understanding of the natural history
and disease risks in AA.
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Tue(3)-P-162
Molecular Characterization of G6PD Deficient Variants in Karen and Lao populations in Thailand
Chalisa L. Cheepsunthorn 1 ，Kanjanawadee Prasittisa 2 ，Arparkorn Kanchanavithayakul 2 ，
Petcharat Kittiwatanasarn 3 ，Issarang Nuchprayoon 4
1:Biochemistry, Faculty of Medicine, Chulalongkorn University, Thailand、2:Medical Biochemistry Program, Faculty of Medicine, Chu-
lalongkorn University、3:Department of Pediatrics, Buriram Hospital、4:Department of Pediatrics, Faculty of Medicine, Chulalongkorn
University
Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is highly prevalent in Southeast Asia. Mutations of the
G6PD gene are often ethnic-specific. Karen is an ethnic minority of Myanmar and resides in Myanmar and Thailand. The
comprehensive molecular characterization of Karen associated G6PD mutants is unclear. Moreover, heterogeneity of G6PD
mutation in Laotian had never been defined. Here, we performed G6PD deficiency screening and molecular studies of G6PD
variants in Skaw Karen and Laotian in Thailand.
Methods: Cord bloods from 127 Laotian newborns and peripheral bloods from 80 Skaw Karens and 103 migrant Laotians were
tested for G6PD deficient using fluorescent spot test (FST) and G6PD activity assay. G6PD mutations and their haplotypes
were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing.
Results: In Skaw Karen, 27.8% (10/36) males and 2.3% (1/44) females were G6PD deficient. In Laotian newborns, G6PD
deficiency was found in 30.8% (20/65) of males and 8.1% (5/62) of females. Among migrant Laotian, 6.6% (5/76) males
and 3.7% (1/27) females were G6PD deficient. PCR-RFLP and sequencing of G6PD deficient subjects revealed that G6PD
Mahidol (rs137852314) was the most dominant mutation in Skaw Karen (allele frequency 0.278), whereas G6PD Viangchan
Poster Session
(rs137852327) was the predominant in Laotians (allele frequency 0.026, 0.169). The other three Chinese variants, G6PD
Canton (rs72554665), G6PD Union (rs398123546), G6PD Kaiping (rs72554664) were occasionally in both populations. All
G6PD Mahidol Karen subjects shared haplotype C, T (rs2230037, rs2071429) similar to that of Burmeses and Mons. While
Laotian G6PD Viangchan carried haplotype T, C similar to that of Cambodians and Thais.
Conclusions: Our study suggests that Karen co-evolve with Burmese and Mon, whereas Laotian share ancestor with Cambo-
dian which influenced by gene flow from Thai and Chinese.
Tue(3)-P-163
Allelic imbalance of mRNA transcription in α 2-HS glycoprotein (fetuin-A) gene
Motoki Osawa 1 ，Eriko Ochiai 1 ，Yu Kakimoto 1 ，Fumiko Satoh 1
1:Department of Forensic Medicine, Tokai University School of Medicine, Japan
Alpha 2-HS glycoprotein (AHSG), also designated as fetuin-A, exhibits polymorphism in population genetics consisting of
two major alleles of AHSG*1 and *2. The serum level in the AHSG*1 homozygote is significantly higher than that of the
*2 homozygote. SNPs in the AHSG gene are demonstrated to have phenotypic characteristics such as the association with
myocardial infarct and ischemic stroke in a large European cohort. This study examined the molecular mechanism for the cis-
regulatory expressional difference. To quantitate allele-specific mRNA in intra-assays of the heterozygote, RT-PCR method
employing primers that were incorporated to the two closely located SNPs was developed. The respective magnitudes of
AHAG*1 to *2 in the liver tissues and hepatic culture cells of PLC/PRF/5 were determined quantitatively as 2.5-fold and
6.2-fold. The mRNA expressional difference of two major alleles was observed, which is consistent with that in the serum
level. The culture cells carried heterozygous genotypes in rs4917 and rs4918, but homozygous one in rs2248690. It was
unlikely that the imbalance were derived from the rs2248690 SNP located in the promotor site. Furthermore, to investigate
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the effect of mRNA degradation, RNA synthesis in the cell culture was inhibited potently by the addition of actinomycin-D.
No marked change was apparent between the two alleles. The results indicated that the cis-regulatory expressional difference
was expected to be directly originated from the two major SNPs that are accompanied by amino acid substitutions, not
from the linked SNP in the promotor region, which has been predicted previously. The mechanism should be derived from
differences in transcriptional activity or splicing of mRNA.
Tue(3)-P-164
Mitochondrial DNA variation at the Sindh population of Pakistan
Shahzad Bhatti 1 ，Muhammad Aslamkhan 1 ，Sana Abbas 1 ，Marcella Attimonelli 2 ，Hakan Aydin 3
1:Human Genetics, University of Health Sciences Lahore, Pakistan、2:Department of Biosciences, Biotechnologies and Biopharmaceutics,
University of Bari, Bari, Italy、3:Department of Medical Biochemistry, Ege University School of Medicine, Bornova Izmir, Turkey
The present study was undertaken to investigate the control region of mitochondrial DNA for forensic discrimination and
explore the ethno-linguistic affiliations among ethnic groups of Sindh, province of Pakistan. A total of 115 individuals from 6
major ethnic / isonym groups, viz., Bijarani, Chandio, Ghallu, Khoso, Nasrani and Solangi have been studied. We scrutinized
88 haplotypes, defined by particular set of nucleotides; of these 70 haplotypes were unique in the investigated population.
Besides, 82% sequences were observed once, 12% twice and 5.2% thrice. The most common South Asian haplogroup was
assigned: M (42%) and R (6.9%), whereas West Eurasian haplogroups were N (6.9%), W (6.9%), J (1.7%), U (23.4%), H
(9.5%), and T (0.86%), in the six Sindhi ethnic groups. A random match probability between two unrelated individuals was
found to be 0.06%, while genetic diversity ranged from 0.991 to 0.998. The high nucleotide diversity and low random match
Poster Session
probability of mtDNA control region makes it a useful tool for forensic discrimination as well as to evolutionary biologist. It
has important contribution to establish a mitochondrial DNA database in Pakistan.
Keywords: mtDNA haplogroups, control region, Pakistan, Sindh, ethnicity
Tue(3)-P-165
Detection of population specific signals of positive election in Mongolians
Kazuhiro Nakayama 1 ，Jun Ohashi 2 ，Lkhagvasuren Munkhtulga 3 ，Sadahiko Iwamoto 1
1:Jichi Medical University, Japan、2:The University of Tokyo、3:Health Science University of Mongolia
Modern humans in East and Southeast Asia were generally agriculturalist but nomadic lifestyle was more common in ethnic
groups in Central, Northern, and inland East Asia. It is still unclear whether nomadic groups in Asia continents have
undergone genetic adaptation to the nomadic lifestyle. To address this issue, the selection landscape of a nomadic ethnic
group was investigated. Genome wide single nucleotide variation (SNV) genotypes of 96 Mongolians in Ulaanbaatar (MGU)
were obtained by using HumanOmni 2.5 BeadChips. SNV data of the East and Southeast Asians (EA-SEA), was downloaded
from public database (1000 Genome Project, Phase III) and used as reference. Signatures of natural positive selection
were detected using haplotype homozygosity based-tests (iHS, nSL, and XP-EHH), and fixation index (Fst). A total of 133
SNVs with MGU specific signature of selection was identified. The strongest signature of the MGU-specific positive natural
selection was found in 2.25 mega base region of the short arm of chromosome 3, which was previously reported to harbor
association signals for cognitive function, obesity, and onset of menarche. MGU-specific natural selection was also found in
genomic regions containing loci relevant to energy metabolism including DEC1 , ELOVL7, NDUFAF2, and ZIC1/ZIC4 . On
the other hand, 206 SNVs showed strong signals of positive natural selection in EA-SEA but not in MGU. Several selection
signals that were previously found in East and Southeast Asians (the ADH cluster and ALDH2 , for instance) were absent in
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Mongolians. Further genetic epidemiological and cellular biological studies are required to know the evolutionary significance
of the Mongolian specific positive natural selection.
Tue(3)-P-166
Adaptive patterns of genetic diversity in native Siberian populations
Vadim Stepanov 1,2 ，Vladimir Kharkov 1,2
，Anton Markov 1,2
，Andrey Marusin 1 ，Anna Bocharova 1 ，
Kseniya Vagaitseva 1,2
1:Institute for Medical Genetics, Russia、2:Tomsk State University
Adaptation to cold continental and Arctic climate during migrations of modern humans to North Asia probably played the
substantial role in shaping the genetic structure of modern native Siberian populations. We have investigated the distribution
of SNPs, correlated with climatic and geographic parameters, in native Siberians comparing to worldwide human populations.
Our data obtained from genome-wide SNPs genotyping and whole exome sequencing in native Siberian populations (Buriat,
Yakut, Tuva, Khants, Kets, Evenk) were pooled with data on worldwide populations and analyzed by means of positional
search of association of allele frequencies with climatic and geographic parameters and search for signals of natural selection.
Top signals were subjected to bioinformatic analysis of disease associations, biological processes, pathways, and molecular
functions of corresponding genes. About 1000 SNPs were found very significantly correlated with key climatic parameters and
absolute latitude. Major clinical phenotypes associated with these regions are metabolic traits, immune and infectious diseases,
neuro-psychiatric disorders, behavioral traits, response to xenobiotics, and chemo-dependency traits. Some top genomic
Poster Session
regions were found under positive or balancing selection according to haplotype homozygozity and Tajima tests. Examples of
regions subjected to selective pressure in Siberian natives include UDP-Glucuronosyltransferase-2B7 (UGT2B7 , metabolism
of xenobiotics), uncoupling proteins (UCP2-3 , thermoregulation), and interferon lambda (IFNL4 , modulation of immune
response) genes. We suppose that genetic diversity in in native Siberian populations were partially shaped by adaptation
to cold climate. The adaptive pattern of genetic diversity may contribute to common diseases, and may be explained by
the hypothesis of decanalization of genotype-environment relationships under the pressure of natural selection.This work was
supported by RFBR grant 15-04-02442.
Tue(3)-P-167
Analysis of polymorphisms associated with skin pigmentation in Oceanic populations
Izumi Naka 1 ，Nao Nishida 2 ，Ryosuke Kimura 3 ，Kyoko Yamaguchi 4 ，Takuro Furusawa 5 ，Taro Yamauchi 6 ，
Kazumi Natsuhara 7 ，Yuji Ataka 8 ，Takafumi Ishida 1 ，Tsukasa Inaoka 9 ，Yasuhiro Matsumura 10 ，Ryutaro Ohtsuka 11
，
Jun Ohashi 1
1:Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Japan、2:International Medical Center of Japan
Konodai Hospital, Ichikawa, Japan、3:Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan、4:School of Natural
Sciences and Psychology Liverpool John Moores University, U.K.、5:Graduate School of Asian and African Area Studies, Kyoto University,
Kyoto, Japan、6:Department of Health Sciences, Hokkaido University School of Medicine, Sapporo, Hokkaido, Japan、7:The Japanese
Red Cross Akita College of Nursing, Akita, Akita, Japan、8:School of Policy Studies, Kwansei Gakuin University, Sanda, Hyogo, Japan、
9:Department of Human Ecology, Faculty of Agriculture, Saga University, Saga, Saga, Japan、10:Faculty of Health and Nutrition, Bunkyo
University, Chigasaki, Kanagawa, Japan、11:Japan Wildlife Research Center, Sumida, Tokyo, Japan
The Oceania is geographically classified into three areas: Melanesia, Micronesia and Polynesia. Although Oceanic people are
genetically close to Asians, their skin color is darker than Asians. In Oceania, people living in Melanesian have the darkest
skin color, which is comparable to that of people living in Sub-Saharan Africa. To understand the genetic basis of skin
pigmentation in Oceanic people, we investigated eight SNPs previously reported to be associated with self-reported tanning
ability in European ancestry using Digitag2 and TaqMan assay in five Oceanic populations. The genotype data of YRI
(African), CEU (European ancestry), JPT (East Asian), and CHB (East Asian) populations were obtained from the HapMap
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database. All the alleles associated with tanning ability were ancestral ones. The Fst analysis showed that some SNPs were
highly differentiated between Melanesian and HapMap-YRI populations. We further calculated the tanning ability associated
allele count and the tanning ability score (Σ β i xij ) for each individual. The number of allele counts was the highest in YRI
and the lowest in CEU. Of particular interest, the mean of the tanning ability score is lower (i.e., lighter skin color) in Tongan
(Polynesian) and Rawaki (Micronesia) populations than in HapMap-JPT and CHB (East Asian) populations. The present
results suggest that the genetic variation that produces darker skin color of Oceanians is different from that of Asians.
Tue(3)-P-168
GENETIC TESTING OF HERODOTUS’ THEORY ON THE ORIGIN OF ARMENIANS
Anahit Hovhannisyan 1 ，Ashot Margaryan 1 ，Hrant Hovhannisyan 1 ，Zaruhi Khachatryan 1 ，Armine Khudoyan 1 ，
Levon Yepiskoposyan 1
1:Institute of Molecular Biology NAS RA, Armenia
The origin of Armenians is a controversial subject for scholars of various disciplines. Among the several hypotheses on this
issue, one prevails. The ancient Greek historian Herodotus described the Armenians as Phrygian colonists, who resembled
them by their language and clothing. Here, Herodotus ｀ hypothesis was genetically tested applying specific Y chromosome
and genome-wide SNP markers.
We used a total of 1215 high-resolution Y-chromosomal genotyping results of 10 Armenian geographic groups roughly covering
the extent of historical Armenia. The Greek (n=171) and Bulgarian (n=808) groups, representing the Balkan region, were used
Poster Session
as candidate source populations for Armenians. As possible signals of Balkan influence, distribution patterns of the relatively
young and the most frequently encountered Balkan lineages, E-V13, I2-M438, J-M12, and R-M417, were considered. For
more thorough analysis, we additionally processed the genome-wide SNP data of Armenians (n=16), Bulgarians (n=13) and
Greeks (n=20).
We detected a negative frequency cline for the haplogroups observed from the Balkans via the Armenian Highland to the Near
East. In contrast, their genetic diversity and mean age values in the Armenian population are significantly higher than those
for the Balkan groups. The ADMIXTURE analysis reveals weak (14% for 3 kya) genetic signals of the Balkan contribution to
the Armenian gene pool and indicates much higher genetic influence of the Near East, which contradicts the Balkan hypothesis
of the Armenians origin. Moreover, the comparison of F st genetic distances based on variation of genome-wide SNPs revealed
close genetic affinity of Armenian and Levant populations, while Armenian and Balkan ones were significantly different.
Our results allow excluding essential genetic contribution of the Balkan populations to the Armenian genetic legacy, and, in
contrast, provide further support for the ancient human migrations from the Armenian Highland and the Levant to Europe.
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Tue(3)-P-169
Colour-blindness: Impact of Consanguinity and Environment
1,2,3
Muhammad Shoaib Akhtar ，Muhammad Aslamkhan 1 ，Muhammad Imran Qadeer 3 ，Mian Sahibzar 4
1:Human Genetic and Molecular Biology Department, University of Health Sciences Lahore, Pakistan、2:Gulab Devi Postgraduate Medical
Institute, Lahore、3:Sundas Foundation Molecular Analysis Center, Lahore、4:Department of Forensic Biology, University of Health Sciences,
Lahore
Colour-blindness is most common type of vision impairment as well as X-linked recessive disorder worldwide. It is present
in 5-7% males and 0.2-0.75% females worldwide. A study was conducted to screen male and female higher secondary school
students for colour-blindness in the district of Chiniot, Punjab, Pakistan. Pseudoisochromatic Ishihara Plates for Colour
Vision Deficiency (38 Plates Edition) were used to screen students for colour-blindness. The results revealed 2.98% colour-
blindness in the district, which is divisible into 5.29% males and 0.6% females. District Chiniot has three tehsils i.e., Bhowana,
Chiniot and Lalian. Colour-blindness, in Bhowana, Chiniot and Lalian, is 3.76%, 2.29% and 2.92% respectively. Gender wise
percentage of colour-blindness among males and females in Bhowana is 6.19% and 1.58%, in Chiniot is 4.58% and 0.00%
and in Lalian is 5.21% and 0.00%. Students with colour-blindness are also classified into its subgroups i.e., Strong and
Mild Protan and Deutan. Six cases were found that couldn’t be classified into subgroups using Ishihara Plates. Students
with colour-blindness were counselled by genetic counsellor. We found very high consanguinity in the district also, which
is 84.82+2.4%. Consanguinity in three tehsils is: Bhowana 87.45%, Chiniot 84.67% and Lalian 81.95%. It appears that
there is a direct impact of consanguinity on colour vision because Bhowana with highest consanguinity has also the highest
percentage of colour-blindness. However, in Lalian with minimum consanguinity, colour-blindness is not the lowest, as is
found in Chiniot. It appears that a bigger thickly populated area, as Chiniot, offers more choice of mate selection than a
Poster Session
smaller, sparsely populated area. Another factor is the natural selection and adaptation for which there is Post and Pickford
Hypothesis, which is not applicable in this study because agriculturists of Bhowana have highest percentage and the town
residents of Chiniot have lowest percentage.
Tue(3)-P-170
BCL11A erythroid-specific enhancer and fetal hemoglobin levels among Sickle Cell Disease Patients in
Cameroon: Implications for future therapeutic interventions
Gift D Pule 1 ，Valentina JN Bitoungui 2 ，Bernard C Chemegni 3 ，Stylianos Antonarakis 4 ，Ambroise Wonkam 1
1:Pathology, Division of Human Genetics, University of Cape Town, South Africa、2:Faculty of Medicine and Biomedical Sciences, University
of Yaoundé, Cameroon、3:Non-Communicable Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa、
4:Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Switzerland
Variants in BCL11A were previously associated with fetal hemoglobin (HbF) levels among Cameroonian Sickle Cell Disease
(SCD) patients, however explaining only ~ 2% of the variance. In the same patients, we have investigated the relationship
between HbF and two SNPs in a BCL11A erythroid-specific enhancer (N = 626). Minor allele frequencies in rs7606173
and rs1427407 were 0.42 and 0.24, respectively. Both variants were significantly associated with HbF levels (p = 3.11e-08
and p = 6.04e-06) and explained 8% and 6.2 % variations, respectively. These data have confirmed a stronger effect on
HbF of genomic variations at the BCL11A erythroid-specific enhancer among patients with SCD in Cameroon, the first
report on a West African population. The relevance of this finding is of prime importance because the disruption of this
enhancer would alter BCL11A expression in erythroid precursors and thus HbF expression, while sparing the induced various
functional challenges of any alterations on the expression of this transcription factor in non-erythroid lineages, thus providing
an attractive approach for new treatment strategies of SCD.
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Tue(3)-P-171
Population genetics analysis of Negrito groups in Southeast Asia
Timothy A. Jinam 1 ，Katsushi Tokunaga 2 ，Keiichi Omoto 3 ，Naruya Saitou 1
1:Division of Population Genetics, National Institute of Genetics, Japan、2:Dept. of Human Genetics, Graduate School of Medicine, The
University of Tokyo、3:Dept. of Anthropology, Faculty of Science, The University of Tokyo
Southeast Asia has been inhabited by humans at least 40 thousand years ago, following the Out-of-Africa migration. Within
the Malay Peninsula, Andaman and Philippine islands, there are several indigenous groups called the Negritos that are tra-
ditionally associated with short stature, dark skin, frizzy hair and a nomadic lifestyle. They are thought to have a common
ancestry tracing back to the earliest settlers in the region.
We generated approximately 800,000 autosomal SNP in four Negrito groups from the Philippines using the Affymetrix 6.0
genechip. The genotype data was analysed together with available data from Malaysian and Andaman Negrito groups as well
as with other neighboring populations in Southeast Asia.
Principal Component Analysis and ADMIXTURE analysis shows that the Philippine Negritos experienced substantial ad-
mixture with their non-Negrito neighbors. Phylogenetic analysis showed that the Andamanese are basal to the Malaysian
and Philippine Negritos. Reticulations in the NeighborNet networks suggest that there may be genetic links between these
three Negrito groups. Ongoing analysis of shared haplotypes between the Negritos will hopefully shed more light into genetic
loci that contribute to their unique phenotype.
Poster Session
Tue(3)-P-172
Geographical and Cultural Influences on Genetic Diversity: Patterns of the Y-Chromosomal Variation in
Populations with Patronymic Tradition
Maxat Zhabagin 1,2 ，Yuldash Yusupov 3 ，Zhaxylyk Sabitov 6 ，Roza Shalyakho 2,4
，Anastasiya Agdzhoyan 2,4
，
Zhaxybay Zhumadilov 5 ，Elena Balanovska 2,4 ，Oleg Balanovsky 4
1:Population genetics, Center for life sciences, National Laboratory Astana, Nazarbayev University, Kazakhstan、2:Vavilov Institute of
General Genetics, Russian Academy of Sciences、3:Institute of Humanitarian Research of the Republic of Bashkortostan、4:Research Centre
for Medical Genetics, Russian Academy of Sciences、5:National Laboratory Astana, Nazarbayev University、6:L.N. Gumilov Eurasian
National University
Many Turkic speaking Central Asian populations are subdivided into patrilineal groups, typically called in English as "clans"
or "lineages". Members of such groups claim their common ancestry from a legendary founder and carry his name. The
common male ancestor of such group could be a myth but in many cases it was real biological person. We studied two large
Central Asian groups, Kazakhs and Bashkirs. 1893 Kazakh individuals genotyped by 40 Y-SNP haplogroups were classified
into 19 regional populations and the same individuals were also attributed to 14 clans. Similarly, 627 Bashkirs were attributed
to 15 regions and to 15 clans. In both, Kazakh and Bashkirs, AMOVA revealed that genetic differentiation between clans is
1.5 times higher than among geographic subpopulations. This observation proves that clan structure shapes gene pool more
evidently than even geographical distance.
The clan could be considered as a reliable quasigenetic marker - the (culturally) inherited non-genetic trait. One may consider
existence of the clan affiliation as existence of a "locus" and concrete clans as "alleles". Thus, we calculated frequencies of
different clans ("alleles") in every geographic population. These frequencies allowed us to compute the "quasigenetic" distances
between populations. The genetic distances between the same populations were computed from haplogroup frequencies and
geographic distances between populations were also estimated. The Mantel test demonstrated that genetics correlates with
quasigenetics strongly than with geography. This again indicates the pivotal role of clan structure in structuring the Y-
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chromosomal pool in populations with patronymic tradition.
The genetic and quasigenetic distances from each regional subpopulation were further plotted on a map by using the GeneGeo
software. For most subpopulations, the areas of genetic similarity followed the areas populated by clan which is predominant
in a given subpopulation.
Tue(3)-P-173
Prognostic role of Interleukin-1 α and β gene polymorphisms in preterm birth
Monika Pandey 1 ，Shally Awasthi 1 ，Shally Awasthi
1:Department Of Pediatrics, King George ｀ s Medical University, India
Background: Increasing evidence supports a role for pro-inflammatory cytokine IL-1 gene in preterm birth.
Aim: The aim of this study is to assess the role of IL-1 with the risk of preterm birth.
Subjects and Methods: This case -control study was conducted at King George ｀ s Medical University, a tertiary care
hospital. Cases (n=559) were defined as mothers (age 18-40 y) of singleton live preterm. Controls (n=350) were mothers who
delivered a singleton neonate, consecutive to enrolled case, after completing 37 weeks of gestation. Four polymorphisms of
IL1 α (-889C/T, +4845 C/T) and IL1 β genes (-31T/C and -511C/T) were typed from genomic DNA. Allelic frequencies
Poster Session
were compared between cases and control subjects and haplotypic analysis was carried out.
Results: Haplotype analysis demonstrated significant association between preterm birth and genotype frequency of both the
genes (p<0.05). Significant association was found in CT haplotype (OR=1.36, 95%CI (1.14-1.62), p= <0.001) of first block
and CT (OR=1.29, 95%CI (1.01-1.64),p= 0.039) and TT (OR=1.20,95%CI(1.00-1.43), p= 0.044) haplotype of second block.
We observed higher frequency of IL-1 haplotype distribution (CTTC, CTTT, TTCT, CCTC and CCCT) among cases (P =
0.03- 0.001, OR = 1.57-1.97).
Conclusion: Our findings suggest that the polymorphisms and haplotypes in the IL1 gene contribute as a risk factor to PTB
in North Indian population.
Tue(3)-P-174
An update to the distribution of allele frequencies and forensic parameters for 15 autosomal STRs in
the Mestizo population from Península of Yucatán, Mexico
Javier Sosa-Escalante 1 ，Maria Josse Lopez-Gonzalez 1 ，Rocio Rivera-Guzman 3 ，Lizbeth Gonzalez-Herrera 1,2
1:DIMYGEN Laboratorio SCP, DIMYGEN Laboratorio SCP, Mexico、2:Universidad Autonoma de Yucatan. Centro de Investigaciones
Regionales、3:Genomelab, Mexico
People from the Península of Yucatan, are a mixed population mainly composed with Mayan ethnic, European, and Asian
ancestry at Southeastern, Mexico. Short tandem repeat (STR) polymorphisms are mainly used in forensic fields, for paternity
tests and individual identity. Since, Yucatan databases are based on a limited sample size, we updated the allelic frequencies
and forensic parameters for 15 autosomal STR, including the CODIS core, in a sample of 300 Mestizo subjects from the
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Yucatán, Peninsula, Mexico. Fifteen STR autosomal loci included in the Power Plex 16 Promega kit (D3S1358, THO1,
D21S11, D18S51, Penta E, D13S317, D7S820, D16S539, CSF1PO, Penta D, VWA, D8S1179, TPOX and FGA) were PCR-
typed. Genotype distribution by locus was in agreement with Hardy-Weinberg expectations for all fifteen STRs (p>0.01).
We found 48 different alleles in the studied population. The most highly polymorphic loci were Penta E and D18S51,
showing 19, and 18 alleles, respectively. Heterozygosity index ranged from 63.7 for D3S1358 to 94.0 for Penta E. For each
locus, allele frequencies were obtained, ranging from 0.0033 to: 0.4600 for D3S1358; 0.3730 for THO1, 0.2666 for D21S11,
0.2032 for D18S51, 0.1833 for penta E, 0.4883 for D5S818, 0.2484 for D13S317, 0.3167 for D7S820, 0.3183 for D16S539,
0.3650 for CSF1PO, 0.2533 for penta D, 0.3750 for VWA, 0.3566 for D8S1179, 0.4816 for TPOX, 0.1867 for FGA. The most
discriminating loci were Penta E (PD = 0.982) and FGA (PD = 0.967). The combined power of exclusion was 0.9999999 in
the studied population. The random match index in the population was 9.01 x 1016 . Our results suggest that this system
provide powerful discrimination and remarck the importance of the generation of local databases for STRs when these markers
are being currently used in forensic casework
Tue(3)-P-175
Whole genome sequence analysis of fetal hemoglobin in a sickle cell disease cohort
Evadnie Rampersaud 1 ，Guolian Kang 1 ，Yasui Yutaka 1 ，Jiao Yunnian 1 ，Wang Shuoguo 1 ，Palmer Lance 1 ，
Feng Ruopeng 1 ，Estepp Jeremie 1 ，Zhang Jinghui 1 ，Hankins Jane 1 ，Wu Gang 1 ，Weiss J Mitchell 1
1:St Jude Children’s Research Hospital, USA
Although sickle cell disease (SCD) is a monogenic disorder caused by a single point mutation (E6V) in the β-globin gene,
Poster Session
disease severity and mortality varies among patients. One of the strongest modifiers of this variability is fetal hemoglobin
(HbF). HbF normally decreases with gestational age and is almost completely replaced by adult hemoglobin by 6 months
of age. In patients with SCD, higher HbF correlates with better clinical outcomes. Quantitative trait analysis of HbF has
identified several genes including the extended β-globin locus, KLF1 , BCL11A, and the HBS1L-MYB region as important
components of a genetic network that regulates the switch from fetal to adult hemoglobin. Together, variants in these loci
explain up to 50% of the HbF heritability. Importantly, variants responsible for modulating HbF reside in predicted enhancer
regions, defined by characteristic epigenetic marks and binding of erythroid transcription factors such as GATA1 and TAL1.
Our goal is to identify additional genetic modifiers of HbF through genomic studies.
In amplicon-based sequence analysis of 94 SCD patients, we confirmed published associations between variants in BCL11A
(minFDRp=5.2x10-6 ) and HBS1L-MYB (minFDRp=0.01) with HbF by using linear regression methods. Additionally, rare
variant (RV) locus-based tests for HBS1L-MYB non-coding enhancer regions were statistically significant (SKAT-Op=0.03).
Further investigation using Boolean regression analysis revealed that a specific combination of HBS1L-MYB non-coding SNPs
was found among individuals with increased HbF (27.0% vs. 11.7%, permutation-test p=0.001).
We are in the process of extending our findings by performing whole genome sequence analysis of HbF in a cohort of 800
sickle cell disease patients. We aim to confirm our HbF association findings in BCL11A and HBS1L-MYB, to validate our
Boolean-based combinatorial analyses, and to identify additional modifiers of HbF. Preliminary results from these analyses
will be presented.
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Tue(3)-P-176
Molecular-genetic evaluation of G2956A (rs112287730) alteration of FBN1 gene in Russian Marfan
patients
Aleksandr V. Polyakov 1 ，Olga L. Mironovich 1 ，Tagui A. Adyan 1 ，Alla N. Semyachkina 2
1:Research Centre of Medical Genetics, Russia、2:Research Institute for Clinical Pediatrics, Pirogov National Research Medical University
Marfan syndrome (MFS) is an autosomal dominant inherited systemic disorder of connective tissue with many clinical man-
ifestations in the cardiovascular, skeletal, and ocular systems. MFS is cased by mutations in the fibrillin-1 (FBN 1) gene.
Currently about 3000 FBN 1 pathogenic variants that cause MFS or related phenotypes have been described. Most of muta-
tions distributed along the whole gene.
The c.2956G>A, p.Ala986Thr substitution (exon 25) of FBN1 gene is described in the SNP database as rs112287730 with
allele frequencies of 0.02%. The clinical significance of this variant is unknown. Some studies identify this substitution as
probably pathogenic mutations, the other - as polymorphism.
Among 85 Russian Marfan patients heterozygous c.2956G>A substitution has been identified in three probands, two of them
had family history. To determine the clinical significance of this substitution a study of DNA samples of affected and unaf-
fected family members was conducted. In the first case it was shown segregation of the c.2956G>A substitution with disease
in the family: this substitution was associated with the disease phenotypes in the three affected members, but not in the
one unaffected member. However, in the second familial case the segregation was not found: three affected members hadn’t
c.2956G>A substitution, whereas it was found in one unaffected members. In addition, the molecular genetic testing of 110
Poster Session
ethnically unrelated and healthy controls was performed. The c.2956G>A substitution was identified in two of 220 examined
chromosomes (allele frequencies 0,9%).
Thus, it was established that the substitution c.2956G>A is polymorphism (nonpathogenic variant) and cannot lead to MFS.
Tue(3)-P-177
Mutational complexity of a classic founder disease: tyrosinaemia in Quebec
Francis Rossignol 1 ，Hao Yang 1 ，Walla Al-Hertani 2 ，Fernando Alvarez 1 ，Mouna Ben-Amor 4 ，
Catherine Brunel-Guitton 1 ，Daniela Buhas 2 ，Josee Dubois 1 ，Daphna Fenyves 3 ，Paul Goodyer 2 ，
Rachel Laframboise 4 ，Jean Larochelle 5 ，Bruno Maranda 6 ，Aicha Merouani 1 ，Grant A Mitchell 1 ，John Mitchell 2 ，
Guy Parizeault 5 ，Luc Pelletier 4 ，Veronique Phan 1 ，Jean-Francois Soucy 1 ，Quebec NTBC Study Group
1:Ste-Justine University Hospital Centre, University of Montreal, Canada、2:Montreal Children’s Hospital, McGill University Health Centre,
McGill University、3:University of Montreal Hospital Centre, University of Montreal、4:Laval University Hospital Centre, Laval University、
5:Integrated Health and Social Services University Centre of Saguenay-Lac-St-Jean、6:Integrated Health and Social Services University
Centre of Estrie, University of Sherbrooke Hospital Centre, University of Sherbrooke
Introduction: Hepatorenal tyrosinaemia (HT1) is a classic autosomal recessive founder disease in Quebec (Laberge, PMID
16143014). The French Canadian (FC) founder mutation c.1062+5G>A in FAH (Grompe, PMID 8028615) has a 1/66 carrier
rate in Quebec. Newborn blood screening with succinylacetone (SA) in Quebec and referral to Quebec NTBC Study (QNS)
centres is felt to provide full ascertainment and a unique opportunity to describe all causal mutations.
Methods: Chart review of all 95 QNS patients (86 probands of nuclear families), February 1994 - June 2015.
Results: All mutant alleles were identified. 78 FC families showed 9 mutations: c.1062+5G>A (85.3%), c.1090G>T (p.E364*;
5.1%), c.606+1G>A (2.6%), c.1069G>T (p.E357*; 1.9%), c.974C>T (p.T325M; 1.3%), c.1141A>G (p.R381G; 1.3%), 8.93
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kb deletion (exons 13-14; 1.3%), c.47A>T (p.N16I; 0.6%) and c.786G>A (p.T262*; 0.6%). c.606+1G>A recurred in 3 FC
patients, suggesting an other mild FC founder effect. 72 patients (92.3%) have at least 1 c.1062+5G>A allele; 62 (79.5%) are
homozygotes. Interestingly, 2 SA-positive FC subjects were compounds of the“pseudodeficient” c.1021C>T allele (p.R341W,
Rootwelt, PMID 7977370) and a splice mutation in trans, and had mild but sustained asymptomatic elevation of SA. 8 non-FC
families had 10 mutations: c.1062+5G>A (18.8%), 8.93 kb deletion, and 8 other mutations: c.1A>G (p.M1V), c.424A>G
(p.R142G), c.456G>A (p.W152*), c.709C>T (p.R237*), c.742G>A (p.G248R), c.782C>T (p.P261L), c.1025C>T (p.P342L),
c.1180+1G>A. 4 mutations are described for the first time: c.606+1G>A and c.1180+1G>A alter known consensus splice
sites; c.424A>G and c.742G>A are predicted to be pathogenic by MutationTaster, and c.424A>G alters a known substrate-
binding site.
Conclusion: We identified all mutant FAH alleles in 95 Quebec patients. At least 18 mutations underlie HT1 in Quebec.
Substantial genetic diversity exists even in this classical example of a historic genetic founder effect disease.
Tue(3)-P-178
AIMs and Ascertainment Bias in Genomic Datasets: Considerations for Personalized Medicine
Sara D Niedbalski 1 ，Jeffrey C Long 1
1:Anthropology, University of New Mexico, USA
It is well established that genotype may be used to infer ancestry, however, in order for ancestry to predict underlying genetic
Poster Session
architecture, there must exist high frequency ancestry informative markers (AIMs). For the purpose of this study, we define
these AIMs as a SNP occurring at >30% frequency in one ancestry group, and <1% elsewhere. Our research examines the
global pattern of highly informative AIMs, and draws important conclusions for the future of personalized medicine.
First, we compare the proportion of AIMs found in race-based ancestry groups to groups defined by major founder events. We
resolve this empirically using the CEPH-HGDP, HAPMAP, and 1000 Genomes samples. In these datasets, ancestry groups
defined by race categories did not contain AIMs, thus suggesting that predictable genetic architectures underlying complex
diseases will not likely be found under this grouping scheme. However, when large founder events, such as the out of Africa
migration, were used to define ancestry groups, a substantial amount of AIMs were identified. These results are supported by
original simulations which show a lack of evolutionary opportunity for high frequency, unique variation to evolve in classical
race groups.
Next, we examined the extent to which the identified Non-African AIMs are affected merging datasets. We combined the
HAPMAP and CEPH-HGDP sets to produce a common denominator sample of those loci typed in both sets. In this combined
sample, all previously identified AIMs were excluded. Thus ascertainment bias necessarily precludes the type of markers that
constitute a highly informative AIM. These findings provide important considerations for researchers aiming to study this
type of variation. Our results indicate, both theoretically and empirically, that health scientists will be more successful
in identifying genetic architectures related to disease disparity when using groups defined by founder events and unbiased
genomic samples.
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Tue(3)-P-179
Where is Brazil located at? A study on 100 Alu insertion polymorphisms
Ana C. Arcanjo 1 ，Jerilyn A. Walker 2 ，Mark A. Batzer 2 ，Silviene F. Oliveira 1
1:Biological Sciences Institute, University of Brasilia, Brazil、2:Department of Biological Sciences, Louisiana State University
The Brazilian population is one of the most admixed populations in the world. From late 1500’s to early 1800’s, not only was
Brazil the destination to European migrators, but the main route for slavery from Africa, not to mention Native Americans
that already lived there. Strong documentation of the admixture of those three main ancestry groups and several studies
with Ancestry Informative Markers (AIMs) in this population exists. Employing AIMs, the proportion of each ancestry in
Brazilian populations were described, but Brazilian populations was not pinpointed in a world scenario. This work aimed
to locate Brazilian populations in a global context of genetic variability based on 100 Alu insertion polymorphisms. 162
samples from two Brazilian populations (Brasilia, the capital of Brazil and Kalunga, an afro-derived Brazilian population)
were genotyped for 100 Alu insertion polymorphisms, and their allelic frequencies were compared to 963 samples from Africa,
Europe, India, Middle-East, and Asia. There were no departures from Hardy-Weinberg’s Equilibrium. Structure analysis
showed 5 different clusters of populations, relative to the main groups listed above. Brasilia shows the greatest admixture,
with high proportion of Europe and Middle-East, median Africa and small proportions of Asia and India. Kalunga shows less
admixture than Brasilia, with great proportions of Africa, followed by Middle-East and small proportions of Asia, Europe and
India. The other groups show distinct and homogeneous groups with little to no admixture. Kalunga showed no population
differentiation from Zulu populations (FST =0.007). Brasília showed no population differentiation from Iberian (FST =0.012),
Basque (FST =0.009), Jordan (FST =0.004), Syria (FST =0.003) and Egypt (FST =-0.012). We can conclude that Kalunga can
Poster Session
be placed in the African group, with little admixture, whereas Brasilia can be grouped with the Middle-Eastern, but with
high admixture with Africa and Europe.
Tue(3)-P-181
A frequent mutation in the DYSF gene in the Avar’s population from northern Caucasus
Alexander V. Polyakov 1 ，Mariya V. Bulakh 1 ，Oxana P. Ryzhkova 1
1:Research Centre of Medical Genetics, Russia
The dysferlinopathies are a group of autosomal recessive disorders caused by mutations in the DYSF gene on chromosome 2p13
and includes two main common phenotypes: limb girdle muscular dystrophy 2B [OMIM:253601] with predominantly proximal
weakness and Miyoshi myopathy type 1 [OMIM:254130] with calf muscle weakness and atrophy. A unique six-generation,
highly consanguineous family with an identical mutation c.200_201delinsAT (p.Val67Asp) was previously described by Illar-
ioshkin S.N. et al in 2000. All family members are ethnic Avars originating from an isolated mountainous village which is
located in the northern Caucasus (province of Daghestan, Russian Federation). Thus, we supposed that this mutation repre-
sents a common cause of muscular dystrophy within ethnic Avars. To test our hypothesis we analyzed 311 DNA-samples in a
cohort of unexamined healthy Avars for the mutation c.200_201delinsAT in the DYSF gene. Noteworthy, that all individuals
of this population characterizes by high consanguinity due to inbreeding. The mutation c.200_201delinsAT was founded in
14 subjects in the heterozygous state (4,5 %). Than we calculated the incidence of the dysferlinopathies in our cohort based
on an observed quantity of heterozygous careers of the c.200_201delinsAT mutation. The incidence of the dysferlinopathies
in the Avar’s population is 1:2000 with 95% confidence intervals of 1:6024 to 1:690. In the result of our study we found out
that Avars, like Libyan Jews and Japanese, is one of the populations characterized by high prevalence of the dysferlinopathies.
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Tue(3)-P-182
Y chromosome haplogrouping using the next generation sequencing system
Eriko Ochiai 1 ，Keiko Miyashita 1 ，Kiyoshi Minaguchi 1 ，Yu Kakimoto 1 ，Fumiko Satoh 1 ，Motoki Osawa 1
1:Department of Forensic Medicine, Tokai University School of Medicine, Japan
The Y chromosome haplogroup of SNP combination is a valuable marker to study male phylogeny and ethical distribution in
anthropology. The next generation sequencing has been developed for a wide variety of genetics fields. In the present study,
we demonstrate Y-SNP typing that was employed the Ion PGM system (Life Technologies) to determine the haplogroup.
Methods: DNA was available from a total of 60 male subjects including six pairs of parent and child, and 12 pairs of full
siblings. DNA libraries were constructed using the Ion AmpliSeq Library Kit 2.0 (Life Technologies) combined with the
HID-Ion AmpliSeq Identity Panel. Emulsion PCR was performed, then DNA sequences were analyzed on chip. Sequencing
data was analyzed using the HID SNP Genotyper v4.3 plugin on the Torrent Suite Software v4.4.2. This project has been
approved by the ethical committee of Tokai University School of Medicine. Results and Discussion: The HID-Ion AmpliSeq
Identity Panel contains 34 Y-SNPs. Y haplogroup was successfully determined for all sample as follows; O2 (42%), D (40%), C
(7%), O3 (5%), N (3%) and O (3%). Those were the common haplogroups among the Japanese individuals, except for group
O relatively specific to the Chinese population group. No inconsistencies in inheritance were observed. However, we found a
couple of difficulties in analytical procedures. Uneven coverage between forward and reverse strands was observed at several
SNPs. Minor misreading coverage was apparent at the SNP of rs2032631. At rs2032599, the nucleotide was not determined
completely in twelve samples. A very low number of coverage, less than 0.7 of the other average, was observed at M479.
These events might be caused by primers or flanking sequence. The next generation sequencing provides a comprehensive
Poster Session
result with convenient procedures in comparison with the conventional Sanger method, but it remains to be improved further.
Tue(3)-P-183
The genetic landscape of Dagestan from Y-chromosome markers: phylogeny and phylogeography of J1
haplogroup and territorial subdivision of native populations
Vladimir Kharkov 1 ，Magomed Radzhabov 2 ，Eugenia Glazunova 1 ，Vadim Stepanov 1
1:Institute of Medical Genetics, Russia、2:Institute of History, Archeology and Ethnography
The Republic of Dagestan in Russian Caucasus is an unique region of the world. Today about 26 nationalities live in Dagestan.
Languages of the peoples living in Dagestan are very highly differentiated - this is the evidence of constant linguistic end
genetic evolution in the region. We have investigated the structure of the gene pool in indigenous population of Dagestan
belonging to Nakh-Dagestani language family using 65 biallelic and 36 STR Y-chromosome markers. We used DNA samples
from local populations representing Lezgin, Dido and Andes language groups (more than 1000 male samples). As a result
of analysis of Y-haplogroups frequencies in the investigated samples, 21 Y-chromosome haplogroups were revealed. J1 was
identified as the most frequent haplogroup in all populations, typical for the peoples of Dagestan. J1 amounted to more
than 70% of the total sampling. In addition haplogroups J2, G2a, G2a3, R1a1, R1b1a2, Q1b1a and L3 were also identified.
Most populations belonging to different linguistic groups demonstrate significant differences in pairwise comparisons, while
no significant differentiation within linguistic groups was found. Lezgian group of populations demonstrated the highest
haplogroup diversity (H = 0.706 Tsakhurs). In populations of Dido and Andean linguistic groups extremely low genetic
diversity was found due to the predominance of haplogroup J1 (H=0.2-0.3). Native populations of the mountain areas of
Dagestan were characterized by significantly lower levels of genetic diversity on the Y-chromosome haplogroups as compared
to other North Caucasian populations. At the same time a huge diversity of haplotypes within J1 was observed, which meant
a considerable age of J1 in Dagestan. Strong founder effects were observed in different haplogroups. The data set obtained on
the structure of the haplogroups indicates the presence of significant regional differences on the background of the common
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gene pool in populations of Dagestan.
Tue(3)-P-184
Genomic relationships using DNA fractals rather than sequence alignments
1,2,4 2,3
Nike Dattani ，Haran Jackson
1:Kyoto University, Japan、2:Oxford University、3:Nanyang Technological University、4:Cambridge University
Every nucleic acid sequence has a unique“chaos game representation”, which can be used as a rigorous genomic signature. This
representation is a self-repeating fractal image for each sequence, and an image processing technique assesses the structural
similarity between these images. Since alignments have no role in this procedure, the method can be used for studies across
broad phylogenetic ranks, for species between which very few alignments are possible, or for organisms that have undergone
periods of extremely rapid evolution. The image distances are in excellent agreement with established genetic distances
between the corresponding organisms, and even perform better, in all cases we have observed so far. We have been able to
resolve discrepancies in the literature, where morphological studies classified organisms differently from molecular studies.
Using our genetic distances, we use Multi-dimensional scaling to create “genome distance maps” which have advantages over
phylogenetic trees.
Tue(3)-P-185
Poster Session
Withdrawn

Tue(3)-P-186
Population Structure, Divergence and Admixture of Han Chinese, Japanese and Korean Populations
1,3,4
Shuhua Xu ，Yuchen Wang 1 ，Dongsheng Lu 1 ，Yeun-Jun Chung 2
1:Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology, China、
2:Department of Microbiology, The Catholic University Medical College、3:School of Life Science and Technology, ShanghaiTech University、
4:Collaborative Innovation Center of Genetics and Development
The three major ethnicities of East Asia, Han Chinese, Japanese and Korean people share many similarities in characteristics,
language and culture, but their genetic relationships, divergence times and subsequent gene flow have not been well studied
or quantitatively estimated. Here, we conducted a genome-wide study and evaluated the population structure of 182 Han
Chinese, 90 Japanese and 100 Korean individuals, and compared with 663 individuals representing 8 world-wide populations.
Our analyses revealed that Han Chinese, Japanese and Korean populations have distinct genetic makeup and can be well
distinguished based on either the genome wide data or a panel of ancestry informative markers (AIMs). Interestingly, genetic
structure corresponds well to the geographical distributions of the three populations, indicating that geographical isolation
played a critical role in driving population differentiation. The three populations trace their common ancestry back to 3,000
to 3,600 years ago. On the other hand, our analysis revealed substantial admixture which occurred subsequent to initial
splits of populations. Especially, we identified a cline of north/south admixture, which we theorized have been resulted from
isolation by distance (IBD) or that of north/south migrations. In addition, we also discovered distinct gene introgression
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from surrounding populations, of which northern ancestry is dominant in Han Chinese (41.4% ~ 45.7%), Japanese (19.7%)
and Korean (38.8%), while southern ancestry is also frequent in the three groups (27.7% ~ 41.1%). The recent population
admixture might partially explain the significant increase of effective population size in the three East Asian groups in recent
15,000 years as we estimated, although population expansion occurred as well at the same time. These estimations and
findings facilitate to understanding population history and mechanism of human genetic diversity in East Asia, and also have
implications for medical studies.
Tue(3)-P-187
MITOCHONDRIAL GENETIC DIVERSITY OF THE PRE-HISPANIC MEXICAN MAYA POPULATIONS
FROM PALENQUE AND EL REY
Mirna Isabel I.O. Ochoa Lugo 1 ，Gerardo G.P. Pérez Ramírez 1 ，Javiera J.C. Cervini-Silva 2 ，
Miguel M.M. Moreno Galeana 1 ，Eduardo E.R. Ramos 3 ，Arturo A.R. Romano-Pacheco 4,5 ，
María de Lourdes d.L. M. Muñoz 1,6
1:Department of Genetics and Molecular Biology, Center for Research and Advanced Studies of IPN, Mexico、2:Universidad Autónoma
Metropolitana Unidad Cuajimalpa、3:Earth Sciences Division, Lawrence Berkeley National Laboratory、4:Department of Physical
Anthropology, Instituto Nacional de Antropología e Historia (INAH)、5:Universidad del Claustro de Sor Juana、6:Laboratory of Biological
Anthropology, University of Kansas, Lawrence, KS, USA
The Mayan population is known as one of the most advanced ancient civilizations of America due to the development of
Architecture, Calendar, Astronomy, Mathematics, Writing, Arts, and agriculture. The Mayan civilization covered all of the
Yucatan Peninsula, part of the Mexican states of Tabasco and Chiapas, Guatemala, Belize and the western of Honduras and
Poster Session
El Salvador. Palenque, Chiapas was one of the most important Mayan civilizations in the Classic Period (200-900 CE), where
they exerts political and economic control of the region. The Mayan of El Rey, Quintana Roo had its peak in the post-classical
period (1300-1550 CE). Since it is unknown the origin of these populations, the aim of this study was to determine their
genetic diversity and origin through Network analysis of mtDNA Hypervariable Region I partial sequences. This study showed
frequencies for haplogroup A2 of 50% and for haplogroup C1 50%. However, for most of the contemporary Mexican Mayans
the frequencies for haplogroup A are the highest. The Mayan populations from Tojolobal (58.1%) have been reported to
display the highest frequencies for haplogroup B; and the ancient population of Tipu from Belize showed the higher frequency
for haplogroup C (64%) followed by D (28%) and B (8%). The comparative analysis of the sequences of ancient Mayan
from Palenque and El Rey of this study with the contemporary Mayan sequences and populations from Asia, Bering, North
America, Central America and South America Network analysis indicated that the ancient Mayan haplogroup A2 sequences
were more related with Asia, Bering, North America and Central America; while haplogroup C1 sequences were grouped with
sequences from some contemporary Mayans and South American individuals. In conclusion, we suggest that the prehispanic
Mayan population of this study origin is from Asia and it was dispersed to the region and to South America. This study will
be improved by increasing the number of samples.
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Poster Session
Molecular Basis of Mendelian Disorders 1
Tue(3)-P-188
Japanese male twins with Leber congenital amaurosis possibly caused by the GUCY2D gene mutation
Katsuhiro Hosono 1 ，Shinsei Minoshima 2 ，Yuko Harada 1 ，Kentaro Kurata 1 ，Akiko Hikoya 1 ，Miho Sato 1 ，
Yoshihiro Hotta 1
1:Department of Ophthalmology, Hamamatsu University School of Medicine, Japan、2:Department of Photomedical Genomics, Basic
Medical Photonics Laboratory, Medical Photonics Research Center, Hamamatsu University School of Medicine
Leber congenital amaurosis (LCA), a genetically and clinically heterogeneous disease, is the earliest onset retinitis pigmentosa
(RP) and is the most severe of hereditary retinal dystrophies. In most cases, LCA shows an autosomal recessive inheritance.
Twenty-one causative genes for LCA have been identified. This study was conducted to investigate genetic and clinical features
of LCA in a set of Japanese male twins with LCA. To identify causative mutations, 74 genes known to cause RP or LCA
were examined by targeted-next generation sequencing (NGS). This study was approved by the Institutional Review Board
for Human Genetic and Genome Research at Hamamatsu University School of Medicine. All the procedures conformed to
the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patients’ parents before any
study procedure or examination was performed. A custom target-enrichment library of the 74 genes was designed using the
Poster Session
Agilent SureDesign online tool. Targeted NGS was performed by using custom designed Agilent HaloPlex target-enrichment
kit with the Illumina MiSeq sequencer. Identified potential pathogenic mutations were confirmed using Sanger sequencing.
Clinical analyses were based on ophthalmic examination, fundus photography, and electroretinography (ERG). Compound
heterozygous GUCY2D mutations of novel splicing mutation c.2113+2_2113+3insT and novel missense mutation p.L905P
were detected in both twins. Their father and mother were heterozygous for c.2113+2_2113+3insT and p.L905P, respectively.
The twins had phenotypic features similar to those previously reported in patients with GUCY2D mutations. This included
early childhood onset of visual loss, nystagmus, unrecordable ERG, photophobia, and hyperopia. To the best of our knowledge,
this is the first report of genetic and clinical features of Japanese LCA twins with GUCY2D mutation, which were detected
using targeted-NGS.
Tue(3)-P-189
Low-prevalence somatic TSC2 mutations in sporadic lymphangioleiomyomatosis identified by deep-
sequencing
Atsushi Fujita 1 ，Katsutoshi Ando 2 ，Etsuko Kobayashi 2 ，Keiko Mitani 3 ，Koji Okudera 4 ，Mitsuko Nakashima 1 ，
Satoko Miyatake 1 ，Yoshinori Tsurusaki 1 ，Hirotomo Saitsu 1 ，Kuniaki Seyama 2 ，Noriko Miyake 1 ，
1:Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan、2:Division of Respiratory Medicine,
Juntendo University Faculty of Medicine and Graduate School of Medicine、3:Division of Human Pathology, Juntendo University Faculty
of Medicine and Graduate School of Medicine、4:Department of Pathology, Yokohama City University Graduate School of Medicine
Lymphangioleiomyomatosis (LAM) (MIM #606690) is a rare lung disorder presenting progressive dyspnea, pneumothorax
and chylous pleural effusions, affecting predominantly women of childbearing age. It characterized by the proliferation of
abnormal smooth muscle-like cells (LAM cells), leading to progressive cystic destruction in the lung. LAM can occur with
tuberous sclerosis complex (TSC-LAM) or without TSC (sporadic-LAM, S-LAM). TSC is autosomal dominant disorder which
caused by a germline heterozygous mutation in either TSC1 or TSC2. TSC-LAM is thought to occur as a result of a somatic
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mutation as second hit in addition to a germline mutation of TSC1 or TSC2 . S-LAM is also thought to occur by the two-hit
of a somatic mutation and/or loss of heterozygosity in TSC2, while no somatic TSC1 alterations have been reported until
now.
To identify TSC1 or TSC2 somatic mutation in S-LAM patients, we performed deep-sequencing in the two genes using genomic
DNA derived from blood leukocytes (n=9), LAM lung tissue (n=7), LAM cultured cells (n=4), or a LAM cell cluster (n=1).
We detected 19 candidate somatic variants in eight out of nine LAM samples. Of these, nine were confirmed by targeted
deep-sequencing in six of nine S-LAM patients (67%) and the mutant allele frequencies were 1.7-46.2%. Three of these patients
had two mutations with mutant allele frequency of 1.7-28.7%. In addition, at least five mutations with mutant allele frequency
<20% were also detected by droplet digital PCR (ddPCR). Furthermore, possible regions of loss of heterozygosity in TSC2
were detected in two patients with TSC2 mutation by allelic imbalance of heterozygous variants using deep-sequencing data.
The mutant allele frequencies in LAM tissues were very low and LAM cells may have different mutations even in one patient.
Therefore, suitable methods for detecting the low prevalence mutation, such as deep-sequencing, ddPCR, or laser capture
microdissection, should be applied.
Tue(3)-P-190
First report of compound heterozygous mutations in the TRAPPC9 gene showing clinical features of
autism and intellectual disability in a Thai family
Pornprot Limprasert 1 ，Areerat Hnoonual 1 ，Thanya Sripo 1 ，Tasnawat Sombuntham 2
Poster Session
1:Pathology, Faculty of Medicine, Prince of Songkla University, Thailand、2:Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol
University
The trafficking protein particle complex subunit 9 gene (TRAPPC9 ) encodes for the NIK- and IKBKB-binding protein
(NIBP). To date, only homozygous mutations in the TRAPPC9 gene have been identified in patients with intellectual disability
(ID) of autosomal recessive 13 locus. We herein report the first compound heterozygous mutations in the TRAPPC9 gene in
two Thai siblings, a brother with ID and a sister with autism. The two siblings presented with normal head circumference
and unilateral cleft lip at birth. They both were recognized as having microcephaly at approximate 18 months of age. Brian
MRI of both cases showed delayed myelination at anterior and posterior limbs of both internal capsules and diffuse white
matter abnormalities at periventricular and subcortical matter. Non-verbal IQ tests for both indicated moderate impairment.
Whole exome sequencing was performed in the autistic sister using the SureSelect Human All Exon V4 kit on an Illumina
Hiseq2000. Two heterozygous mutations in the TRAPPC9 gene, a splice site mutation (c.3349+1G>A) and an insertion
mutation (c.2415-2416insC), were identified. The c.2415-2416insC results in changing histidine to proline at codon 806 and
premature termination at codon 814 (p.H806PfsX9) of the TRAPPC9 protein. The splice site mutation and frameshift
mutation were transmitted from the unaffected mother and unaffected father, respectively. These two mutations were also
identified in the brother. The frameshift mutation was not reported in the dbSNP137, 1000 Genomes Project, Exome Variant
Server (EVS), Exome Aggregation Consortium (ExAC) nor 156 Thai unrelated individuals in this study. However, a splice
site mutation was reported in one case in the 1000 Genomes Project (MAF = 0.0002). In conclusion, herein we report the
first compound heterozygous mutations in the TRAPPC9 gene in two siblings with ID and autism, suggesting that clinical
manifestations of TRAPPC9 mutations may be broader than previous reports have indicated.
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Tue(3)-P-191
Novel GDAP1 mutations in Japanese patients with Charcot-Marie-Tooth disease
Akiko Yoshimura 1 ，Junhui Yuan 1 ，Yujiro Higuchi 1 ，Akihiro Hashiguchi 1 ，Yuji Okamoto 1 ，Shoji Tsuji 2 ，
Hiroshi Takashima 1
1:Department of Neurology and Geriatrics, Kagoshima University, Japan、2:University of Tokyo
Objective We aim to describe the clinical and genetic spectrum of Japanese patients with Charcot-Marie-Tooth disease
(CMT), and to investigate new disease-causing genes and molecular mechanisms. Specifically, we would like to summarize
the clinical features of patients with GDAP1 mutations.
Methods With a preliminary exclusion of PMP22 duplication mutation using fluorescence in situ hybridization, we collected
1022 DNA samples of CMT, from April 2005 to May 2014. Accompanied by the development of technology, mutation screen-
ing was carried out on custom DNA microarray (Affymetrix; 27 genes) and Miseq amplicon sequencing (Illumina; 40 genes),
successively. In addition, 399 cases proceeded to whole exome sequencing using Illumina HiSeq2000.
Results We identified pathogenic mutations or likely pathogenic variants in GDAP1 from 10 patients, comprising two homozy-
gous, three compound heterozygous, and five heterozygous variants. Three genotypes have been described previously, while
the others were novel. In these patients (half male, half female), the mean age and onset age was 30.7 years (range, 7 ~ 52
years) and 6.2 years, respectively. Herein, the mean onset age of patients with homozygous/compound heterozygous variants
was younger than single heterozygous variants with statistical significance (3 years vs. 10.3 years; p<0.05). All patients
developed distal predominant muscle weakness. Sensory disturbance was found in all 8 cases with a detailed clinical record,
Poster Session
and no autonomic dysfunction was noted except hyperhidrosis from one patient with a homozygous mutation (p.A247V).
Conclusions We detected GDAP1 mutations in 10 CMT patients (less than 1%) in our Japanese cohort of CMT, and the ma-
jority (7 genotypes) had never been described before. The onset age and clinical phenotype were comparable to the previous
reports from other species.
Tue(3)-P-192
Whole Exome Sequencing revealed a nonsense mutation in STAB2 Gene associated with intellectual
disability and oligodontia
Huoru Zhang 1 ，Yong-Fei Wang 1 ，Houyan Xia 3 ，Tony MF Tong 2 ，Ho Ming Luk 2 ，Jing Yang 1 ，Yu Lung Lau 1 ，
Wanling Yang 1
1:Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong、2:Clinical Genetic Services, Department of
Health, Government of Hong Kong SAR、3:Department of Obstetrics and Gynecology, Huolinguole Hospital, Inner Mongolia Autonomous
Region, P.R.C.
SATB homeobox 2 (SATB2) is a highly conserved gene, encoding a nuclear matrix-attachment region (MAR) binding protein.
Functional studies and animal models have shown that satb2 plays an important role in neuronal and craniofacial development.
Patients with abnormalities involving SATB2 exhibit a variety of symptoms including facial dysmorphism, cleft palate, and
severe intellectual disability. Only two patients with nonsense mutation in STAB2 have been reported to date. Here we
report a girl with severely delayed language development who carries the exactly same nonsense point mutation as the two
previous reported patients. Whole Exome Sequencing (WES) of the patient and her parents identified a de novo mutation
in SATB2 gene (c.715C>T; p.R239*), which is then confirmed by Sanger sequencing. Our finding confirms that this gene
is important in mental development and craniofacial patterning. The fact that our patient doesn’t have cleft palate (CP)
suggests incomplete penetrance for this feature. In the meantime, since all of the three patients, while coming from three
different populations, carry the exactly same point mutation (c.715C>T), this position might be a mutation “hot spot”.
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We suggest this gene, particular this position be included in genetic screening involving intellectual disabilities, especially for
patients with delayed mental development, cleft palate and abnormal dentition.
Tue(3)-P-193
Whole Exome Sequencing helps characterize the mysterious skeletal disorder of a village in Jammu and
Kashmir, India
Swarkar Sharma 1 ，Ekta Rai 1 ，Ankit Mahajan 2 ，Parvinder Kumar 3 ，Arshia Angural 1 ，Manoj K Dhar 2 ，
Sushil Razdan 4 ，Kumarasamy Thangaraj 5 ，Carol Wise 6 ，Shiro Ikegawa 7 ，Kamal K Pandita 8
1:School of Biotechnology, Shri Mata Vaishno Devi University, India、2:School of Biotechnology, University of Jammu, J&K, India、3:Human
Genetic Research cum Counselling Centre, University of Jammu, J&K, India、4:7, Bhagwati Nagar, Jammu, J&K, India、5:Centre for
Cellular and Molecular Biology, Hyderabad, A.P, India、6:Texas Scottish Rite Hospital for Children, Dallas, Texas, USA、7:Laboratory for
Bone and Joint Diseases, SNP Research Center, RIKEN, Tokyo, Japan、8:Department of Internal Medicine, ASCOMS & Hospitals, Jammu,
J&K, India
Patients suffering from rare disorders are often misdiagnosed due to lack of specific clinical resources, especially in underde-
veloped or developing countries. A severe mysterious skeletal disorder, that rendered affected physically diabled for life, has
been reported in a geographically isolated remote village of Jammu and Kashmir, India. Population residing in the region is
highly consanguineous. Lack of information about the disorder has led to huge increase in number of affected in the region.
In our survey of the region, 70 affected people were reported, showing similar phenotype, in the village with a population of
approximately 5000 individuals.
We collected familial information of most of the affected and found two multi-generational extended pedigrees. This all aided
Poster Session
in characterizing the disorder as a skeletal dysplasia, with an autosomal recessive inheritance. We further performed whole
exome sequencing (WES) in one of the family and identified a rare WISP3 (WNT1 Inducible Signaling Pathway Protein
3) variation, c.156C>A [p.Cys52*], perfectly segregating with the disease of the family. However, this variation was ab-
sent in other family. We Sanger sequenced WISP3 in the second family and found a novel splice site mutation of WISP3 :
c.643+1G>A, perfectly segregating with the disease. Conclusion: Exploiting WES and putting different evidences together
(familial histories and genetic data, available clinical, radiological and biochemical tests findings), the disease has finally been
diagnosed as a "Spondyloepiphyseal dysplasia tarda with progressive arthropathy". The genetic diagnosis will aid in genetic
counseling and management critically required to curb this otherwise rare disorder that has turned rampant in the population.
Tue(3)-P-194
Exome sequencing identifies pathogenic mutations in the patient with severe combined immunodeficiency
Hui-Wen Yu 1 ，Cheng-Yu Liao 1 ，Chi-Chang Shieh 1 ，Peng-Chieh Chen 1
1:National Cheng Kung University, Institute of Clinical Medicine, College of Medicine, Taiwan
Patients with severe combined immunodeficiency (SCID), which is caused by genetic defects in immune-related genes, died
in infancy due to severe infections. Although improvement in diagnosis had been achieved by newborn screening on the
expression of T cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC), the genetic
basis of most of the patients was unknown. We performed whole exome sequencing (WES) and identified a novel frameshift
mutation of IL7R, which rendered truncated IL7R that is likely to be the underlying genetic cause of SCID in a patient. The
patient received stem cell transplantation from peripheral blood (PB) of unrelated donor and her general condition is well
after the treatment. We showed that WES could aid in genetic diagnosis of SCID following newborn screening in the index
patient without the need to screen the other family members.
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keywords:
Next generation sequencing,Genetic disease,Genetic diagnosis,Congenital immunodeficiency
Tue(3)-P-196
Novel zebrafish models of neuromuscular diseases
Genri Kawahara 1 ，Yukiko K Hayashi 1
1:Department of Pathophysiology, Tokyo Medical School, Japan
Zebrafish disease models are useful to study the mechanism of neuromuscular disorders. They have a number of genes that
are orthologs of muscle disease causative genes, including SIL1, a gene known to be causative for Marinesco-Sjogren syndrome
(MSS). MSS is an autosomal recessive disease characterized by progressive myopathy, cerebellar ataxia, mental retardation,
and congenital cataracta.
We analyzed zebrafish sil1 function using antisense morpholino oligos. To create MSS model fish, we have started to create
MSS knocked-out fish by CRISPR-Cas9 system.
At 4 days post-fertilization (dpf), thirty percent of fish injected with two different morpholino 1 and 2 showed reduced
birefringence compared to embryos injected with a control morpholino. Moreover, co-injection of zebrafish sil1 mRNA
along with the morpholino restored normal development the morphants. Additionally, they were found to have up-regulated
Poster Session
expression of BiP (a ER stress marker protein) and LC3 (an autophagy marker protein) in these morphants.
Using CRISPR-Cas9 system, we successfully identified founders that could pass mutations in sil1 gene through the germline.
Their offspring carried indel mutations, suggesting that these founders carrying heritable mutations.
These findings seem to suggest that it may be feasible to create a MSS model fish for a therapeutic chemical screening.
Tue(3)-P-197
Identification of novel mutations and molecular modelling of novel missense mutations in Pakistani
patients of congenital afibrinogenemia
Tehmina Nafees Sonia Khan 1 ，Arshi Naz 1 ，Arijit Biswas 2 ，Tahir Sultan Shamsi 1
1:Coagulation and Hemostasis, National Institute of Blood Diseases and Bone Marrow Transplantation, Pakistan、2:Institute of Experimental
Hematology and Transfusion Medicine
Background:
Congenital afibrinogenemia (OMIM #202400) is a rare coagulation disorder which was first described in 1920. It is transmitted
as an autosomal recessive trait characterized by absent levels of fibrinogen (factor I) in plasma. Consanguinity in Pakistan
and its neighboring countries has resulted in higher cases of congenital fibrinogen deficiency in their respective populations.
Aims: This study focuses on the detection of mutations in the fibrinogen genes by DNA sequencing and molecular modeling
of missense mutations in all three genes (Fibrinogen gene alpha (FGA), beta (FGB) and gamma (FGG) in Pakistani patients.
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Methods:
This descriptive and cross sectional study was conducted in Karachi and Lahore and fully complied with the Declaration of
Helsinki. Patients with fibrinogen deficiency (tested by fibrinogen functional assay from Laboratoire Stago, Asnieres, France)
were screened for mutations in the fibrinogen gene alpha (FGA), beta (FGB) and gamma (FGG) genes by direct sequencing.
Molecular modelling was performed to predict the putative structure functional impact of the missense mutations identified
in this study.
Results:
Ten patients had mutations in FGA, four have FGB mutations and one mutation was identified in FGG. Thirteen of these
mutations were novel. The missense mutations are predicted to result in loss of stability since they (a) break ordered regions
(b) cause clashes in the hydrophobic core of the protein.
Conclusion:
Congenital afibrinogenemia is a rapid growing problem in countries such as Pakistan where consanguinity is frequently
practiced. This study illustrates the fact that mutations in FGA are relatively more common in our population than those in
FGB where as FGG mutations appear rarer.
Poster Session
Tue(3)-P-198
Refinement of an Autosomal Dominant Hereditary Gingival Fibromatosis Locus on chromosome 2p23
Miao Sun 1 ，Bin Wei 1 ，Zili Ge 1 ，Yingying Zhang 1 ，Xingshun Xu 2 ，Xue Zhang 3
1:The First Affiliated Hospital of Soochow University, China、2:The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu,
China.、3:McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical
Sciences, CAMS & PUMC
Benign and diffuse fibrous hyperplasia of gingival tissues is one of the clinical characteristics of gingival fibromato-
sis/overgrowth, which can be drug-induced or inherited. The pathogenesis of gingival fibromatosis/gingival overgrowth
is still unknown. Previous studies suggested that hereditary gingival fibromatosis displays highly genetic heterogeneity
(GINGF1-4) with many different loci for the disease gene in genome. So far, only a frameshift mutation of SOS1 gene
has been regarded as a possible gene causing GINGF1(OMIM 135300), while most other studies only indicate the location
without finding the disease genes. By using genome-wide linkage analysis, we have mapped a Chinese gingival fibromatosis
to chr2:23876084-34773131, a region known as GINGF3 (OMIM 609955) locus. Combined with all reported GINGF mapping
information, we have further refined the GINGF3 locus to a 7.62Mb region (chr2:23876084-31501119)containing nearly 100
known hypothetical genes. Genome-wide copy number analysis has not revealed any CNV correlated with the gingival
fibromatosis in this candidate region. To date, four separate loci on chormosome 2p13-p23 have been reported to be
responsible for the gingival fibromatosis phenotype, indicating the existence of complex structure changes in this region.
Further whole-exome sequencing/whole genome re-sequencing need to be done to identify the new disease gene for gingival
fibromatosis.
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Tue(3)-P-199
Rare beta-thalassaemia mutation detected in South East Asian population - A dilemma in calling carrier
status
1,2
Hai-Yang Law ，Guek-Peng Tan 2 ，Angeline HM Lai 1 ，Ivy ISL Ng 1,2
1:Department of Paediatric Medicine, Singapore、2:National Thalassaemia Registry, KK Women’s and Children’s Hospital
Thalassaemia is one of the most common inherited disorders worldwide and post a huge medical and social burden in areas
with high prevalence. Individuals who have the most severe form of beta-thalassaemia, the thalassaemia major, require life-
long transfusion and expansive iron chelation therapy to sustain life. With the aim of controlling this disease, The National
Thalassaemia Registry was set up in Singapore to provide subsidised screening and free counselling for carriers and their
families. As there is an increasing number of migrants of other ethnicities, beta-globin gene sequencing has been carried
out to confirm beta thalassaemia carrier status and for prenatal diagnosis purposes. This strategy is efficient in identifing
rare mutations but also novel mutations of unknown significance. Some rare mutations reported to be associated with beta-
thalassaemia have been identified in various ethnic groups. However, family studies of individuals with these mutations did
not always appear to be associated with beta-thalassaemia phenotype. The HBB:c.*233G>C (3’UTR +101G>C) mutation
originally reported in Palestinian population, was identified in at least one family each of Chinese, Malay, Indian and Viet-
namese ethnicity. None but one family presented with a typical beta-thalassaemia phenotype. Another mutation reported
to be associate with beta-thalassaemia in a Chinese family (HBB:c.-100G>A (-50G>A) was identified in many local Chinese
families but did not appear to be associated with beta-thalassaemia phenotype. However, a Malay family with the mutation
present with typical beta-thalassaemia indices. It is possible that these mutations are in linkage disequilibrium with another
beta-thalassaemia causing mutation in the long control region in the beta globin gene cluster. More data need to be collected
Poster Session
from family of different ethnicities, and functional studies need to be carried out to confirm the causal effect of these mutation
and beta-thalassaemia.
Tue(3)-P-200
Novel hearing loss-causative point mutations and copy number variation identified by exon sequencing
Aki Sakata 1,2 ，Akinori Kashio 2 ，Shotaro Karino 2 ，Yu Matsumoto 2 ，Akinobu Kakigi 2 ，Tatsuya Yamasoba 2 ，
Hiroki Ueda 1 ，Shogo Yamamoto 1 ，Kenji Tatsuno 1 ，Hiroyuki Aburatani 1
1:Genome Science Division, Research Center for Advanced Science and Technology, the University of Tokyo, Japan、2:Department of
Otolaryngology, Faculty of Medicine, the University of Tokyo
More than 100 genes were currently reported as causative genes of hearing loss (HL), however, current HL genetic test covered
limited genes and positions. Whole exome sequencing (WES) has been used primary tool for determination of causative genetic
variants, but the cost of sequencing and data analyzing are still expensive. We performed targeted gene sequencing which
was followed by WES to identify uncovered gene mutations with cost effective way.
Target sequence was carried on 82 Japanese NSHL patients and their parents for 18 genes (GJB2 , SLC26A4 , EYA1 , COCH ,
KCNQ4 , MYO7A, TECTA, POU3F4 , CRYM , CDH23 , COL9A3 , KIAA1199 , SIX1 , WFS1 , mitochondrial (Mt) 1555A>G,
Mt 3243A>G, Mt 7445A>G, Mt 8296A>G), that were previously reported HL causative genes in Japanese population, and
13 patients had mutations. Then we performed WES on 38 hearing loss patients who did not have HL causative mutations
in the 18 genes. Variants were called using the Genome Analysis Toolkit. Variants with more than 3% of minor allele
frequency in at least 2 databases among the 1000 Genomes Project, the ESP6500, Human Genetic Variation Database (Kyoto
Univ.), and in-house variation database were removed as non-pathogenic variations. Heritable patterns of these variants
were confirmed Sanger sequence of the patient and their parents. As a result, we identified autosomal dominant mutation
in KCNQ4 and autosomal recessive mutations in BDP1, CDH23, LRTOMT, MYO15A, PCHD15, PDZD7, LOXHD1, and
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USH2A. Additionally, we performed copy number variation (CNV) analysis using WES data and identified copy number loss
in OTOA gene in one case without pathogenic point mutation.
Consecutive targeted and WES analysis could identify the extensive gene variation, including CNV. These sequencing enables
early diagnosis of hearing loss, which help appropriate and timely treatment such as cochlear implant and a selection of
rehabilitation.
Tue(3)-P-201
Withdrawn

Tue(3)-P-202
Utility of a multigene next-generation sequencing panel for molecular diagnosis of Noonan syndrome and
other RASopathies
Maggie Brett 1 ，Eileen Lim 1 ，Siew Peng Lee 1 ，Angeline Lai 2 ，Ee Shien Tan 2 ，Saumya Jamuar 2 ，Ivy Ng 2 ，
Poster Session
Breana Cham 2 ，Jiin Ying Lim 2 ，Ene Choo Tan 1
1:KK Research Centre, KK Women’s & Children’s Hospital, Singapore、2:Department of Paediatrics, KK Women’s & Children’s Hospital
Germline mutations in the genes in the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway cause developmental
disorders known collectively as RASopathies. The RASopathies comprise one of the largest groups of malformation syndromes
and affects approximately 1:1000 individuals. These disorders include Noonan syndrome, Neurofibromatosis, Leopard syn-
drome, Costello syndrome and Cardiofaciocutaneous syndrome. The RASopathies share many overlapping features including
craniofacial dysmorphology, skeletal defects, cardiac defects, cutaneous anomalies, neurodevelopmental delay, and increased
risk of malignancies. The overlapping clinical features make diagnosis difficult, particularly in children. We designed a multi-
gene next-generation sequencing panel for the genes known to be associated with RASopathies: NF1, PTPN11, SOS1 , RAF1,
KRAS, NRAS, BRAF, SHOC2, MAP2K1, MAP2K2, CBL, RASA1, RIT1 and SPRED1 . The panel was designed using the
HaloPlex enrichment technology and sequenced on a MiSeq benchtop sequencer using 250 bp paired-end sequencing. The
MiSeq Reporter software was used for alignment and variant calling. Annotation and variant filtering was carried out using
the web-based GeneTalk or wANNOVAR software. To date, 18 patients with clinical features of RASopathies have been tested
by the multigene panel. The average coverage of the targeted regions of all 14 genes varied from 93x to 255x. A molecular
diagnosis was achieved for 15 patients (83%). Pathogenic variants were detected in PTPN11, NF1 , SOS1, BRAF and RIT1 .
Of particular interest were the co-occurrence of variants in NF1 and SOS1 in two unrelated patients, and the detection of
a somatic mosaic NF1 variant in another patient. Our results show that testing with the RASopathy multigene panel is an
efficient approach which allows prompt diagnosis especially for patients with mild or atypical features. A confirmed molecular
diagnosis will guide patient management, reproductive choices and genetic counselling.
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Tue(3)-P-203
Whole-exome sequencing identifies a novel mutation in primary ciliary dyskinesia from a Chinese con-
sanguinity family
Hong Luo 1 ，Ting Guo 1
1:Department of Internal Medicine, the Second Xiang Ya Hospital of Central South University, China
Primary ciliary dyskinesia is a group of heterogeneous disorders of motile cilia, usually inherited as an autosomal recessive
trait. To date, there are 34 known PCD-causing genes. However, the genetic causes of approximately one-third of PCD cases
still remain to be found. Previous studies have demonstrated that mutations in DNAI1 contribute to PCD. In this study,
we investigate a Chinese consanguinity family of Han nationality with PCD. A novel DNAI1 mutation, c.1562T>G/p.I521S
was identified in this unique family by combining whole-exome sequencing (WES) with bioinformatics strategies. Our finding
expands the spectrum of DNAI1 mutations and provides additional support that WES is beneficial in the genetic research of
midget consanguinity families.
Tue(3)-P-204
Identification and Functional Analysis for Novel Gene Mutation Responsible for Autosomal Dominant
Macular Dystrophy involved Dysfunction of ON-type Bipolar Cells
Yuichi Kawamura 1,2 ，Takuro Fujimaki 2 ，Kazutoshi Yoshitake 1,3 ，Kazushige Tsunoda 1 ，Yukihiro Baba 4 ，Akiko Suga 1 ，
Hiroshi Kuribayashi 4 ，Sumiko Watanabe 4 ，Kazuho Ikeo 5 ，Akira Murakami 2 ，Takeshi Iwata 1
Poster Session
1:Tokyo Medical Center, National Hospital Organization, National Institute of Sensory Organs, Japan、2:Department of Ophthalmology,
Juntendo University Graduate School of Medicine、3:Japan Software Management Corporate、4:Institute of Medical Science, University of
Tokyo、5:National Institute of Genetics
Macular dystrophy is a hereditary retinal disease, which progress to dysfunction and degeneration of central region of the retina
leading to loss of central visual acuity. Number of genes responsible for the disease has been identified including CRX and
LCA5. Here, we identified a novel gene X mutation in Japanese family with autosomal dominant macular dystrophy. Genomic
DNA was isolated from three generation family and whole exome analysis was performed. Consequently, we identified the gene
X mutation and analyzed expression and localization in mouse and monkey retina. Gene X was localized by immunostaining
using anti-protein X antibody in the synapses between outer nuclear layer (ONL) and outer plexiform layer (OPL) where
secondary neurons such as bipolar cells and horizontal cells are located. Further characterization revealed immunostaining in
ON-type bipolar cells, a secondary neuron connected to rod-photoreceptors. Further examination of affected patients with
full-field eletroretinogram (ERG) showed significant decrease of signal from ON-type bipolar cells. This novel phenotype of
macular dystrophy by novel gene X mutation in the Japanese population suggests possibility of unique population of macular
dystrophy in Asian population.
At the time of presentation, name of the gene X will be revealed to the public.
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Tue(3)-P-205
Knockout the ceramide kinase-like gene causes retinal degeneration in zebrafish
Mugen Liu 1 ，Shanshan Yu 1 ，Zhaohui Tang 1 ，Fei Liu 1 ，Jiaxiang Chen 1
1:Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Tech-
nology, China
In humans, CERKL mutations cause widespread retinal degeneration: early dysfunction and loss of rod and cone photore-
ceptors in the outer retina and progressively, death of cells in the inner retina as well. Despite intensive efforts, the function
of CERKL remains obscure and studies in animal models have failed to clarify the disease mechanism of CERKL mutations.
To address this gap in knowledge, we generated a stable CERKL knockout zebrafish model by TALEN technology. These
CERKL-/- animals showed progressive degeneration of photoreceptor outer segments (OS) and increased apoptosis of retinal
cells, including those in the outer and inner retinal layers. Electroretinograms showed that light responses were diminished
by 30% as early as 7 days of age, long before the onset of overt photoreceptor degeneration at 8 weeks. Furthermore, major
proteins of the rod phototransduction cascade decreased by varying degrees before the onset of photoreceptor degeneration;
for example, at 4 weeks, GNAT1 decreased by 10% while significant decreases of rhodopsin, PDE6B, GNB1 and GRK1
occurred at 8 weeks. Structurally, early major signs of degeneration occurred at the rod OS, which seemed to break off from
the cell body as concentric layers of membranes. Collectively, these results point to a novel role of CERKL in maintaining
the structure and function of the rod OS; loss of this function in CERKL-/- animals might be the trigger for the attendant
cellular events that led, ultimately, to rod and cone photoreceptor death.
Poster Session
Tue(3)-P-206
Molecular genetics analysis of Von Williebrand disease type III: studies in Cohort Pakistani patients
Shariq Ahmed 1 ，Arshi Naz 1 ，Hamideh Yadegari 2 ，Julia Driesen 2 ，Johannes Oldenburg 2 ，Nisar Ahmed 3 ，
Shehla Tariq 6 ，Samina Amanat 4 ，Fazale Raziq 5 ，Muhammad Nadeem 1 ，Tahir Sultan Shamsi 1
1:Genomics, National Institute of Blood Diseases & Bone Marrow Transplantation, Pakistan、2:Institute of Experimental Haematology
and Transfusion medicine, University Clinics Bonn, Bonn, Germany、3:Children Hospital Lahore, Lahore, Pakistan、4:Atomic Energy
Commission Islamabad, Islamabad; Pakistan、5:Hayatabad Medical Complex Peshawar, Peshawar; Pakistan、6:Chughtai Lahore Lab,
Lahore, Pakistan
Introduction: Von Willebrand disease (VWD) type III is the second most common inherited bleeding disorder in Pakistan. It
is caused by severe quantitative deficiency of plasma Von Willebrand factor (VWF). Absence of VWF increases the severity
of disease and is caused by homozygous/ compound heterozygous mutations in Von Willebrand factor gene.
Objective: The aim of study is to characterize molecular genetics of von Willebrand type III in Pakistani population.
Material and Methods: In this cohort study of Von Willebrand disease type III, Blood samples of 48 unrelated patients
were collected in different institutes in Pakistan. Genomic DNA was extracted from peripheral blood by QIAamp DNA
Blood mini kit (Qiagen) and Exon specific PCR was done for VWF gene and Direct gene sequenced on automated ABI-
3130 Genetic Analyzer (Applied Biosystems). Sequence Variations in VWF were checked on ISTH-SSC VWD homepage
(http://www.vwf.group.shef.ac.uk/), Ensemble genome browser (http://www.ensembl.org/), VWFdb hemobase and biobase
biological database (http://www.hgmd.cf.ac.uk/ac/index.php).Statistics analysis was done SPSSv20.
Results: Sequence analysis detected mutations in 46 (95.83%) out of 48 samples. VWD type III has led to identification of 28
cases (60.8%) homozygous and 18 (39.1%) were compound heterozygous. We have indentified total 31 Mutations distributed
as 17 missense mutations (54%), 7 nonsense mutations (22%) 2 small deletions (6%), 2 insertion mutations (6%) and 3 splice
site mutations (9%).19 of these were newly mutations in this cohort study. Further method multiplex ligation dependent
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probe amplification (MLPA) is needed for detection of large deletions in two patients. Nonsense c.3931C>T, p. Gln (CAG)
1311 X (TAG) was founder mutation in Pakistani patients.
Conclusion: In cohort study, missense mutations are detected as common in among patients and most of the mutations
identified in this cohort were homozygous due to Consanguinity in the family of the patients.
Tue(3)-P-207
A loss-of-function mutation in JAK1 is associated with epidermodysplasia verruciformis
Rongrong Wang 1 ，Jiawei Liu 2 ，Lili Zhang 1 ，Donglai Ma 2 ，Xue Zhang 1
1:McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences-Peking Union Medical College, China、2:Peking Union
Medical College Hospital, Chinese Academy of Medical Sciences-Peking Union Medical College
Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by persistent and disseminated skin lesions,
and it has a high risk of skin carcinoma that results from an increased susceptibility to a specific group of human beta
papillomavirus. EV is often inherited in an autosomal recessive manner, and approximately 75% of EV patients are caused
by mutations in EVER1 and EVER2 . Recently, we recruited a four-generation Chinese family showing an autosomal dom-
inant transmission of EV. Mutations in EVER1 and EVER2 have been previously excluded by Sanger sequencing. We
performed whole-exome sequencing on four affected individuals, and identified a novel heterozygous donor-splice site mu-
tation (NM_002227.2 c.3258+1 G>A) in the Janus kinase 1 gene (JAK1 ) on chromosome 1p31.3. The splicing variant
co-segregated with the phenotype of all the family members expect III-21.This variant is not present in common databases
Poster Session
and was not detected in chromosomes from 173 control individuals. Sanger sequencing of the cDNA obtained from peripheral
lymphocytes of the affected individuals revealed that the splicing mutation disrupted normal splicing, skipped exon 23,and
led to a premature termination at codon 1050. Quantitative RT-PCR on total RNA isolated from peripheral lymphocytes
of the family members showed that all affected and carrier individuals had significantly reduced JAK1 expression compared
to the unaffected individuals, suggesting that the splicing mutation might destabilize the mRNA transcript via the nonsense-
mediated mRNA decay. Furthermore, Western blot analysis revealed that mutant JAK1 produced a truncated protein and a
reduced expression level compared to the wild-type JAK1. In additional 12 sporadic cases with EV, we also sequenced the
25 exons and their flanking intronic sequences of JAK1 but found no mutation. In summary, we have identified a germline
splicing mutation in JAK1 and provided supportive evidence for its causality in EV.
Tue(3)-P-208
Molecular genetic study of 12 Pakistani families with autosomal recessive sensorineural hearing loss
Rongrong Wang 1 ，Shirui Han 2 ，Amjad Khan 2 ，Xue Zhang 1
1:McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences-Peking Union Medical College, China、2:China Medical
University
Hearing loss is the most common congenital sensorneural disorder affecting about 1.6 in 1000 individuals in Pakistan. To date,
more than100 genes are associated with deafness; and approximately 50% of the families harbor mutations in GJB2 . Here,
a group of 12 families with hearing loss were recruited from Pakistan, and all of them were consanguineous matings. The
probands of 12 families were initially screened for mutations in GJB2 . Subsequently, we applied targeted next-generation se-
quencing (NGS) to identify pathogenic mutations using a custom AmpliSeq panel that contained 64 deafness-associated genes.
This allowed the identification of homozygous causative mutations in eight families (GJB2 (c. 35del G, p. Gly12Valfs*2);
SLC26A4 (c. 679 G>C, p. Ala227Pro); SLC26A4 (c. 1667 A>G, p. Tyr556Cys); LHFPL5 (c. 246del C, p. Gly82Glyfs*3);
ESPN (c. 2519G>A, p. Trp840*); MYO7A (c. 2367+1 G>C); LRTOMT (c. 154C>T, p. Arg52Trp); and PCDH15 (c.
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4726 C>T, p. Gln1576*)), of which, four mutations were novel. Notably, two novel compound heterozygous mutations were
detected in a consanguineous family (MYO7A (c. 1954 T>C, p. Cys652Arg; c. 4184dupA, p. Gln1395Thrfs*9)). All the
mutations co-segregated with the phenotype in all family members. Furthermore, six novel mutations were not detected in
chromosomes from 200 ethnically matched control individuals. Because of the advantage of high efficiency, high accuracy,
and cost-effectiveness, NGS may be clinically adopted to screen pathogenic genes of hearing loss. In addition, we should be
aware of a rare but possible occurrence that compound heterozygous mutations are present in consanguineous families.
Tue(3)-P-209
Gene-based association analysis of familial pulmonary arterial hypertension
Koichiro Higasa 1 ，Aiko Ogawa 2 ，Chikashi Terao 1 ，Masakazu Shimizu 1 ，Shinji Kosugi 3 ，Ryo Yamada 1 ，
Hiroshi Date 4 ，Hiromi Matsubara 2 ，Fumihiko Matsuda 1
1:Center for Genomic Medicine, Kyoto University, Japan、2:Department of Clinical Science, National Hospital Organization Okayama
Medical Center、3:Department of Medical Ethics/Medical Genetics, Graduate School of Medicine, Kyoto University、4:Department of
Thoracic Surgery, Graduate School of Medicine, Kyoto University
Pulmonary arterial hypertension (PAH) is a severe lung disease with little effective treatment available. Familial cases of
PAH are usually recognized as an autosomal dominant disease, but incomplete penetrance of the disease make it difficult to
identify pathogenic variations in accordance with a Mendelian pattern of inheritance. To elucidate the genetic basis of PAH,
we sequenced 17 subjects from 9 families with heritable PAH and applied gene-based association analysis with 320 PAH-free
Poster Session
controls. A burden of rare variants in a well-known gene, bone morphogenetic protein receptor 2 (BMPR2 ), significantly
contributed to the risk of the disease (p = 2.0 × 10-8 ). Eight of nine families carry four previously reported point mutations
and four novel insertion/deletion mutations (indels) in the gene. One of the novel mutations was a large 6.5 kilobase-deletion.
In the remaining one family, the patient carried a point mutation in a member of potassium channels, KCNK3, which was
the first replicative finding of channelopathy in an Asian population. The variety of rare pathogenic variations suggests that
gene-based association analysis using comprehensive genome-wide sequencing information with increased number of samples
will be needed to trace the incomplete penetrance, the genetic heterogeneity, and to develop a panel for genetic testing.
Tue(3)-P-210
A de novo mutation of the MYH7 gene in a large Chinese family with autosomal dominant myopathy
Kazuhiro Kobayashi 1 ，Tetsuya Oda 1 ，Hui Xiong 2 ，Wataru Satake 1 ，Tatsushi Toda 1
1:Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Japan、2:Department of Pediatrics, Peking
University First Hospital
Laing distal myopathy (LDM) is an autosomal dominant myopathy that is caused by mutations in the slow/beta cardiac myosin
heavy-chain (MYH7 ) gene. It has been recently reported that LDM presents with a wide range of clinical manifestations. We
herein report a large Chinese family with autosomal dominant myopathy. The affected individuals in the family presented
with foot drop in early childhood, along with progressive distal and proximal limb weakness. Their characteristic symptoms
include scapular winging and scoliosis in the early disease phase and impairment of ambulation in the advanced phase.
Although limb-girdle muscle dystrophy (LGMD) was suspected initially, a definite diagnosis could not be reached. As such,
we performed linkage analysis and detected four linkage regions, namely 1q23.2-24.1, 14q11.2-12, 15q26.2-26.3 and 17q24.3.
Through subsequent whole exome sequencing, we found a de novo p.K1617del causative mutation in the MYH7 gene and
diagnosed the disease as LDM. This is the first LDM case in China. Our patients have severe clinical manifestations that
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mimic LGMD in comparison with the patients with the same mutation reported elsewhere.
Tue(3)-P-211
Cystic Fibrosis in Chinese: Frequent and Novel Mutations in CFTR
Yaping Liu 1 ，Xinlun Tian 2 ，Jun Yang 1 ，Han Wang 1 ，Tao Liu 2 ，Wenbin Xu 2 ，Kai-Feng Xu 2 ，Xue Zhang 1
1:Department of Medical Genetics, McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Insti-
tute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, China、2:Department of Respiratory
Medicine, Peking Union Medical College Hospital, Beijing, China
Background:
Cystic fibrosis (CF), the most common life-threatening autosomal recessive disorder in Caucasians, is caused by mutations
in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most common CFTR mutations have been
well established among Caucasian CF patients. In Chinese, we and others have previously identified CFTR mutations in 20
Chinese patients with CF.
Methods:
In this study, eight Chinese patients with a clinical diagnosis of suspected CF were newly collected and screened for CFTR mu-
tations using a combination of conventional Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA)
Poster Session
analysis. CFTR mutations in Chinese CF patients, reported previously and identified in the present study, were also summa-
rized.
Results:
We identified ten different mutations in eight newly collected Chinese CF patients including p.F508del, the most com-
mon CF-causing mutation in Caucasians, and three novel mutations: c.3635delT, p.V1212Afs*15; c.1997T>G, p.L666* and
c.2907A>C, p.A969A. Most notably, the previously reported mutation p.G970D was found in six patients, making it the
most frequent mutation identified so far with a frequency of16.1% (9/56) in total of 28 Chinese CF patients. Furthermore,
we noticed that another mutation occurring in combination with p.G970D was always Class I or II CFTR mutations, with
only one exception (p.A969A). However minigene assay suggested that c.2907A>C,p.A969A led to skipping of exon 17 and
generation of a premature stop codon after 3 codons.
Conclusion:
We have detected p.F508del for the first time, identified additional novel CFTR mutations and showed a most frequent CF-
causing mutation in Chinese CF patients. Sequencing of the entire CFTR gene followed by MLPA analysis, rather than using
the targeted sequencing-based screening panel for mutations commonly found in Caucasian populations, is recommended for
genetic analysis in Chinese CF patients.
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Tue(3)-P-212
CHCHD2 is novel gene for autosomal dominant Parkinson’s disease
1,2,3 1,2,3
Manabu Funayama ，Nobutaka Hattori
1:Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Japan、2:Department of Neurology, Juntendo
University School of Medicine、3:Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University
Identification of causal genes for Mendelian forms of Parkinson’s disease provides valuable information for understanding the
etiology of PD. Here we show that mutations in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2 ) are a novel
cause of Parkinson’s disease. We found three CHCHD2 mutations in four out of 341 independent families with autosomal
dominant forms of Parkinson’s disease (c.182C>T; p.Thr61Iie, c.434G>A; p.Arg145Gln, and c.300+5G>A) by whole genome
and exome sequencing. Exon 2 skipping caused by the c.300+5G>A mutation was demonstrated using an in vitro splicing
assay. In addition to pathogenic mutations, we also identified several variants within CHCHD2 . The results of this case-
control association study also suggest that CHCHD2 could be a susceptibility gene for developing sporadic Parkinson’s
disease. CHCHD2 has a predicted N-terminal mitochondrial targeting signal and is involved in cytochrome c oxidase activity.
Our results suggest that CHCHD2 plays a critical role in mitochondrial function, and impairment of CHCHD2 may lead to
dopaminergic cell death.
Tue(3)-P-213
Mutations in the patients with Nakajo Nishimura Syndrome - like autoinflammatory diseases
Poster Session
1,2
Akira Kinoshita ，Nobuo Kanazawa 3 ，Noriko Kinjo 4 ，Hiroyuki Mishima 1 ，Ko-Ichiro Yoshiura 1
1:Human Genetics, Nagasaki University, Japan、2:Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (NRGIC),
Nagasaki University、3:Department of Dermatology, Wakayama Medical University、4:Department of Child Health and Welfare(Pediatrics),
Faculty of Medicine, University of the Ryukyu
Proteasome is a large protein complex consisting of ~ 100 subunits, which has the function of eliminating ubiquitinated
proteins from the cells to control cellular activity. Nakajo-Nishimura syndrome (NNS) is an autoinflammatory disease caused
by G201V mutation in PSMB8 encoding the immunoproteasome subunit b5i. This mutation causes the defects in the protea-
some assembly and lowers the total proteasome activity, thus inducing the accumulated ubiquitinated proteins, excess nuclear
localization of phosphorylated p38, and oversecretion of IL6.
Further five NNS-like patients and their family members were recruited to analyze possible mutations using Next Generation
sequencing systems.
In family 1, a novel mutation (T236P) was detected in PSMB8 . In vertebrates, the threonine at 236 is conserved. Computer
based prediction of protein structure revealed that this mutation can affect b5i activity.
In family 2, a de novo mutation (G156D) was detected in PSMB9 encoding another immunoproteasome subunit b1i. The
glycine at 156 is also conserved in vertebrates. This mutation was predicted to be probably damaging by PolyPhen-2. Im-
mortalized B-lymphoblastoid cell lines from the patient and his healthy mother were used for functional analysis. Proteasome
activities in the patient were weaker than those in the healthy mother, and were almost similar to those in the NNS patient.
Defects in the proteasome assembly were observed in this patient like that in the NNS patient.
In families 3 and 4, no causative mutations were detected using the sequencing analyses. In family 5, a known mutation in
ADRM1 was found, but this mutation has been reported to cause a non-autoinflammatory disease known as Aicardi-Goutieres
syndrome.
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Mutations in the proteasome subunit genes participate in the pathogenesis of autoinflammatory diseases. However, further
studies are required to confirm this finding.
Tue(3)-P-214
Expanding the clinical phenotype of the novel connective tissue disorder due to variants in the PLOD3
gene
Lisa J Ewans 1,2 ，Alison Colley 3 ，Mark J Cowley 1,2 ，Ying Zhu 4 ，Velimir Gayevskiy 2 ，Kevin Ying 2 ，Corrina Walsh 5 ，
Eric Lee 5 ，Edwin Kirk 5,6 ，Michael Field 4 ，David Miller 2 ，Paula Morris 2 ，Michael Buckley 5 ，Marcel Dinger 1,2 ，
Tony Roscioli 1,2,7
1:St Vincent’s Clinical School, University of New South Wales, Australia、2:Kinghorn Centre for Clinical Genomics, Garvan Institute of
Medical Research, Darlinghurst, NSW, Australia、3:Clinical Genetics Department, Liverpool Hospital, NSW, Australia、4:Newcastle GOLD
Service, Hunter Genetics, Waratah, NSW, Australia、5:SEALS laboratory, Prince of Wales Hospital, Randwick, NSW, Australia、6:School of
Women’s and Children’s Health, University of New South Wales, Australia、7:Department of Medical Genetics, Sydney Children’s Hospital,
NSW, Australia
Mutations in PLOD3 encoding the enzyme lysyl hydroxylase 3 involved in collagen glycosylation, have been previously
described once in an autosomal recessive novel connective tissue dysplasia (CTD) of skeletal and ocular features, sensorineural
hearing loss and dysmorphisms in two individuals in one family. We report on the second family with mutations in PLOD3
in multiple affected individuals in a consanguineous family with CTD features similar to the initial report. Whole exome
sequencing of two affected individuals in this family identified a homozygous missense variant in PLOD3 , predicted to be
pathogenic on multiple in silico analyses and localised within the previously reported glycosyltransferase domain. We present
Poster Session
the clinical features including myopia and cataracts, sensorineural hearing loss, mild distal arthrogryposis in childhood and
prominence of large joints, Stickler-like facial dysmorphisms and mild skeletal changes. One family member had a spiral
dissection of his left anterior descending coronary artery. We propose this disorder to be a sub-type of Stickler syndrome,
which is important to recognise due to the potential serious adverse vascular outcomes.
Tue(3)-P-215
Genomics in the genetic clinic: An Australian perspective
Lisa J Ewans 1,2 ，Mark J Cowley 1,2 ，Ying Zhu 3 ，Velimir Gayevskiy 2 ，Kevin Ying 2 ，Corrina Walsh 4 ，Eric Lee 4 ，
Edwin Kirk 4,5,6 ，Alison Colley 7 ，Anne Turner 5,6 ，David Mowat 5,6 ，Lisa Worgan 7 ，Mary-Louise Freckmann 5,6 ，
Rani Sachdev 5,6 ，Michael Field 3 ，David Miller 2 ，Paula Morris 2 ，Michael Buckley 4 ，Marcel E Dinger 1,2 ，
Tony Roscioli 1,2,5
1:St Vincent’s Clinical School, University of New South Wales, Australia、2:Kinghorn Centre for Clinical Genomics, Garvan Institute
of Medical Research, Darlinghurst, NSW, Australia、3:Newcastle GOLD Service, Hunter Genetics, Waratah, NSW, Australia、4:SEALS
laboratory, Prince of Wales Hospital, Randwick, NSW, Australia、5:Department of Medical Genetics, Sydney Children’s Hospital, Randwick,
NSW, Australia、6:School of Women’s and Children’s Health, University of New South Wales, Australia、7:Clinical Genetics Department,
Liverpool Hospital, NSW, Australia
Identifying the molecular basis in patients with Mendelian disorders seen through genetics clinics is important for patient
management. As these disorders are often genetically heterogeneous, next generation sequencing (NGS) technologies such
as whole exome sequencing (WES) have significantly improved molecular diagnostics due to the rapid screening of coding
genomic regions for disease-causing mutations.
To assess the utility of WES in a clinical setting, WES was applied to a cohort of 54 patients from 37 families with Mendelian
disorders. Patients were selected from genetics clinics in New South Wales that were previously extensively investigated and
phenotyped. WES data was filtered to exclude common variants based on population polymorphism data and incorporating
impact on protein function, using the GEMINI (Genome MINIng) software. The most likely inheritance model was applied
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to each family based on pedigree analysis and indication for referral. In those families with consanguinity, analysis focused on
homozygous regions. Further filtering was performed using pathogenicity scoring systems such as CADD to assist prioritisation
of disease-causing mutations.
An overview of the workflow, including our experience in translation of exome sequencing results to patients and families will
be presented. Diagnostic success is between 25-30%. In addition, a likely novel disease gene for intellectual disability has
been identified in a consanguineous family, which is known to be involved in neurite growth. We propose that WES would
provide a cost-effective, first-line diagnostic test for Mendelian disorders with diverse or unknown genetic bases.
Tue(3)-P-216
Clinical application of next generation sequencing in a family with undiagnosed genetic conditions
Erina Ozaki 1,2 ，Minenori Eguchi-Ishimae 3 ，Yuko Tezuka 3,4
，Keiro Kagata 4 ，Takuya Naruto 5 ，Issei Imoto 5 ，
Mariko Eguchi 2,3 ，Eiichi Ishi 2,3
1:Total Medical Support Center, Ehime University Hospital, Japan、2:Division of Medical Genetics, Ehime University Hospital、3:Department
of Pediatrics, Ehime University Graduate School of Medicine、4:Division of Pediatrics, Ehime Prefectural Niihama Hospital、5:Department
of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School
Background Next generation sequencing (NGS) has become a powerful tool in unraveling genetic basis of rare diseases.
We report here an undiagnosed Japanese family presenting various phenotypic conditions including epilepsy and mental
retardation (MR). We applied NGS panel on affected family members to identify the possible causal genetic changes. Cases
Poster Session
The mother has short stature, MR, facial dysmorphisms and ptosis. The father was diagnosed as epilepsy at the age of 5.
The eldest daughter is 10 years old presenting MR, short stature and repeated febrile seizure with abnormal EEG findings.
The 5 years old elder son presented fetal intrauterine growth retardation, MR, short stature and ptosis. The second son is 2
years old with developmental delay, macrocephaly and macroglossia. Method Peripheral blood samples were collected from
the family members with written informed consent of themselves or of their parents. The next generation sequencing panel
TruSight One was used to target 4813 gene involved in known Mendelian genetic disorders. Result Genetic analysis revealed
c.C1740G (p.D580K) mutation of PCDH19 gene in the mother and in the eldest daughter, but not in the other affected family
members. Epilepsy and mental retardation limited to female (EFMR, MIM# 300088) is an X-linked disorder due to mutations
in PCDH19 gene and is characterized by seizure with onset in infancy and cognitive impairment. The identical mutation has
not been reported, but it occurred in the extracellular domain of PCDH19 which is commonly affected in EFMR. Discussion
The detected genetic change could not explain the phenotype of the whole family members. Other possible genetic changes
are now being searched. Although panel analysis using NGS can become a powerful tool in clinical diagnosis, the genes that
do not appear on the panel will not be considered, and may subsequently require whole exome analysis when causative gene
could not be detected.
Tue(3)-P-217
Mutational analysis of Usher syndrome in Taiwan
Liang-Hsuan Hu Hu 1 ，Chia-Ying Chien 1 ，Tzu-Yen Hsu 1 ，Wun-Ying Lin 1 ，Shun-Ping Huang 1 ，Yung-Hao Ching 1
1:Department of Molecular Biology and Human Genetics, Tzu Chi University, Taiwan
Usher syndrome is a devastating genetically heterogeneous autosomal recessive diseases with clinical phenotype encom-
passed of hearing loss, balance impairments and retinitis pigmentosa. Currently, no treatments are available. The clin-
ical phenotypes can be further divided into three subtypes according to the disease onset and the severity. The type
I, type II are more common and the type III is relative rare. So far, 15 causative genes have been identified, includ-
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ing: Type I disease genes : MYO7A,USH1C,CDH23,PCDH15,USH1,GCIB2,USH1E,USH1H,USH1K; Type II disease genes:

USH2A,GPR98,WHRN; and Type III: disease genes: ABHD12,CLRN1,HARS. Despite of research efforts conducted world
wild, the causative genes of many USH patients were yet been identified. Further more, the genetic variations in Taiwan are
still largely unknown. Our aim is to identify the disease causing variations among Taiwanese Usher patients. We perform mu-
tational analysis by target PCR amplification followed by Next Generation Sequencing. So fare, we have designed assays with
60 amplicons optimized which covered 235k of genomic regions. If no mutations were found in a given patient, whole - exome
sequence will be performed for novel USH gene discovery.
Tue(3)-P-218
Haplotype analysis combined with whole exome sequencing for the identification of the causative muta-
tion of a X-linked Retinitis Pigmentosa family
Yung-Hao Ching 1 ，Lian-Hsuan Hu 1 ，Chi-Jia Huang 1 ，Chi-hsuan Chung 1 ，Wun-Ying Lin 1 ，Jia-Ling Jiang 2 ，
Shun-Ping Huang 1
1:Molecular Biology and Human Genetics, Tzu Chi University, Taiwan、2:Department of Ophthalmology, Hualien Tzu Chi Medical Center
A three-generation family with five-affected males exhibiting recessive x-linked retinitis pigmentosa (RP) was identified.
Twelve individuals from the family were genotyped using 12 microsatellite markers across X chromosome. Haplotype analysis
were conducted and the critical interval were defined between markers DXS9902 and DXS9898 (located on chrX: 15,305,340-
88,541,734) accounting for 73,236,395 bp. Three additional markers, DXS1068, DXS1039 and DXS986, were used for fine
mapping. Whole exome sequencing of an affected sib-pair within the family were performed using Agilent human V5_UTR,
Poster Session
71Mb capture kit followed by sequencing using HiSeq2000 with minimum coverage of 30X. Total 281,079 genetic variations
were identified which are shared between the affected individual and the obligated carrier but not by the phenotypically
normal males within the sib-pair. Taking into account of the positional information obtained from the haplotype analysis, we
further reduced the potential genetic variations to 270. Among those variations, previously known X-linked RP genes such
so RPGR and RP2 were located within this interval. Validations of identified variations were prioritized based on the gene
expression profile, novelty and predicted severity of the nucleotide changes.
Tue(3)-P-219
Genomics & Social Justice - Diagnosing Cystic Fibrosis in South Africa
Cheryl S Stewart 1 ，Jeanne van Rensburg 1 ，Refiloe Masekela 2 ，Marco Zampoli 3 ，Tamara Kerbelker 3 ，Robin J Green 2 ，
Michael S Pepper 1
1:Immunology, University of Pretoria, South Africa、2:Department of Paediatrics, Steve Biko Academic Hospital, University of Pretoria、
3:Department of Paediatrics, Red Cross War Memorial Children’s Hospital, University of Cape Town
Cystic fibrosis (CF) is the most common autosomal recessive disease globally and is caused by mutations in the cystic
fibrosis transmembrane conductance regulator gene (CFTR). Most CF genetic research has been Eurocentric resulting in
lower mutation detection rates among other ethnicities in the absence of population-specific diagnostics. This is problematic
as delayed diagnosis leads to a poor prognosis.
In order to address this disparity, DNA was isolated from 33 South Africans suspected of having CF but who lacked a
complete genetic diagnosis. Targeted next generation sequencing was used to cover all 27 exons of the CFTR, the exon/intron
boundaries, known deep intronic mutations, the promoter and the 5’ and 3’ UTR. A bioinformatics pipeline was designed
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to identify potentially pathogenic mutations using four variant callers. This list was filtered using pibase and BAYSIC to
conduct an in silico validation. Mutations that passed this initial filtering were confirmed using PCR and Sanger sequencing.
Within our patient cohort, 14 had unknown CF genotypes while 11 had only one mutation identified by the National Health
Laboratory Service (NHLS) CF panel. We identified 34 potentially pathogenic variants that are not present on the NHLS
diagnostic tool - 24 which had not previously been reported, four that have been reported but whose functional significance
is unknown and six that have been characterised and demonstrated to be CF-causing. Of these 24 calls, 11 passed in silico
validation; four were novel, six are known to cause CF (p.Leu206Trp, p.Arg352Gln, p.Glu585X, p.Arg709X, p.Ser945Leu and
p.Arg1158X) and one (p.Leu183Ile) had no associated functional study. The impact of this molecular investigation has been
a reduction of the number of unknown mutations in this cohort by 43.6%. Additional studies in non-European populations
are needed to raise CF mutation detection rates and reduce delayed diagnosis, which will positively affect patient outcomes.
Tue(3)-P-220
Therapeutic research in a mouse model of cardio-facio-cutaneous syndrome
Daiju Oba 1 ，Shin-ichi Inoue 1 ，Mitsuji Moriya 1,2 ，Yusuke Watanabe 3 ，Tetsuya Niihori 1 ，Sachiko Miyagawa-Tomita 4 ，
Shigeo Kure 2 ，Toshihiko Ogura 3 ，Yoichi Matsubara 1,5 ，Yoko Aoki 1
1:Department of Medical Genetics, Tohoku University School of Medicine, Japan、2:Department of Pediatrics, Tohoku University School of
Medicine、3:Department of Developmental Neurobiology, Institute of Development, Aging and Canner, Tohoku University、4:Department of
Poster Session
Veterinary Technology, Yamazaki Gakuen University、5:National Research Institute for Child Health and Development
Cardio-facio-cutaneous (CFC) syndrome is characterized by congenital heart disease, distinctive facial features, intellectual
disability and skeletal/ectodermal abnormalities. Mutations in BRAF have been identified in 50-75% of patients with CFC
syndrome. We have reported that mice expressing the Braf Q241R mutation (BrafQ241R/+ ), corresponding to the BRAF
Q257R mutation in CFC syndrome, showed embryonic lethality because of cardiac defects, skeletal abnormalities and fetal
hydrops. Treatment with a MEK inhibitor, PD0325901 (PD), and a histone H3K27 demethylase inhibitor, GSK-J4 (GSK),
have rescued embryonic lethality in BrafQ241R/+ mice. In this study, we screened additional seven drugs, including ABT-737,
Sunitinib, SAHA, SB203580, Rapamycin, AZD-6244 and MEK162, for ameliorating the embryonic lethality in BrafQ241R/+
mice. Of seven drugs, a MEK inhibitor, MEK162, treatment reduced the embryonic lethality in BrafQ241R/+ mice, suggesting
that single treatment of a MEK inhibitor, PD or MEK162, and co-treatment of PD and GSK ameliorated embryonic lethality
in BrafQ241R/+ mice. To explore the mechanisms of efficacy in PD and GSK co-treatment, we examined the histone H3K27
methylation of heart tissues in control (Braf+/+ ) and BrafQ241R/+ embryos. There were no significant differences in mRNA
expression of histone H3K27 methylases and demethylases in heart tissues from Braf+/+ and BrafQ241R/+ embryos. Histone
H3K27me3 protein levels of heart tissues in BrafQ241R/+ mice were comparable to those of Braf+/+ mice with or without
PD and GSK co-treatment. Then we performed microarray analysis using the heart tissues from Braf+/+ and BrafQ241R/+
embryos at E13.5 and E16.5. The mRNA expression of transcription factors which regulate the RAS/ERK signaling or
extracellular matrix proteins were altered. Further analysis on methylation profiling of H3K27 in each gene will clarify the
mechanisms why co-treatment of PD and GSK rescued the embryonic lethality in BrafQ241R/+ mice.
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Tue(3)-P-221
Expression profile of inflammatory genes in placenta from sickle cell disease patients
Monica B Melo 1 ，Leticia C Baptista 1 ，Regiane Ferreira 2 ，Fernanda GC Surita 3 ，Dulcineia M Albuquerque 2 ，
Mary A Parpinelli 3 ，Kleber Y Fertrin 2 ，Carolina Lanaro 2 ，Fernando F Costa 2 ，Maria Laura Costa 3
1:Center for Molecular Biology and Genetic Engineering, University of Campinas, Brazil、2:Hematology and Hemotherapy Center, University
of Campinas、3:Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas
Background: Sickle cell disease (SCD) results from the pairing of hemoglobin S (HbS) with another abnormal hemoglobin
and is characterized by acute and chronic inflammation. Endothelial, and inflammatory adaptations during pregnancy may
lead to exacerbation of pathophysiologic changes, which can contribute to obstetrical complications, as intrauterine growth
restriction. Due to the increased production of inflammatory cytokines identified in plasma and leukocytes from SCD patients
and lack of information about the mechanisms by which this disease affects placental physiology, the aim of this study was
to evaluate the expression profile of mediators of inflammatory response in the placenta from pregnant women with SCD.
Methods: This is an ongoing case control study that has recruited 7 pregnant patients per group (HbSS, HbSC and control).
Placental villous tissue was collected for total RNA extraction and subsequently to cDNA synthesis. The qPCR Array for
Human Inflammatory Response and Autoimmunity, which contains 84 genes, was used. To validate the results qPCR was
performed and gene expression levels were normalized to ACTB, B2M and GAPDH genes.
Results: For the HbSS group, the genes that showed significant fold changes were: IL1RAP (2.76-fold), BCL6 (4.49-fold),
CXCL10 (-2.12-fold), CXCR1 (-3.66-fold) and C3 (-2.0-fold), while for the HbSC group the genes that showed significant
Poster Session
fold change were: IL1RAP (4.33-fold), CXCL1 (3.05-fold), BCL6 (4.13- fold), CXCL10 (-3.32-fold), C3 (-2.0-fold) and TLR3
(2.38-fold).
Conclusion: This is the first study that assessed the inflammatory response in placentas from pregnant women with SCD.
The results provide novel insights towards more research to be performed in this area in order to understand how the disease
can affect placentation. The knowledge of pathways that may be altered in placentas from women with SCD could contribute
to greater clinical control of these patients.
Tue(3)-P-222
A novel locus for autosomal dominant high hyperopia mapped to chromosomal 11
Xueshan Xiao 1 ，Shiqiang Li 1 ，Xiaoyun Jia 1 ，Xiangming Guo 1 ，Qingjiong Zhang 1
1:State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, China
High hyperopia is a common and severe refractive error associated with blurred vision, asthenopia, amblyopia and strabismus.
An autosomal dominant high hyperopia was identified in five generation family with 16 affected patients. A genome wide
linkage scan on 20 family members (14 affected) was performed by genotyping microsatellite markers at about 10 cM intervals,
together with two-point linkage analysis. In the meantime, analysis of shared novel alleles on data from whole exome
sequencing was used to confirm the linkage region and to search for potential candidate variants. High hyperopia in this
family shows linkage to markers in 27.1cM region on chromosome 11. All ten markers in the linkage interval gave positive
lod scores, with maximum two-point lod scores of 4.68 at theta=0. Analysis of shared alleles identified only one region with
multiple novel variants, which also located in the linkage interval. Analysis of additional families and functional study on
candidate variants may lead to identification of the gene responsible for autosomal dominant high hyperopia.
*This study was supported by the National Natural Science Foundation of China (30971588).
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Tue(3)-P-223
Novel gene discovery across a large cohort of patients with syndromic craniofacial anomalies
1,2
Elizabeth J Bhoj ，Dong Li 2 ，Hakonarson Hakon 2 ，Zackai H Elaine 1 ，Harr H Margaret 1
1:Genetics and Pathology, Children’s Hospital of Philadelphia, USA、2:Center for Applied Genomics
For many complex disorders it can be difficult to identify patients with single-gene disorders suitable for novel gene discovery.
Many such conditions can also result from multigenic and environmental insults, which dilute discovery cohorts for research
sequencing efforts for novel Mendelian genes. We have addressed this issue by creating an international highly-informative
cohort of patients with craniofacial anomalies and at least one other medical condition to enrich for families affected by
single-gene disorders. Additional findings in this cohort include congenital heart disease, brain malformations, seizures,
cardiomyopathy, autism, hypotonia, and anomalies of the limbs, kidneys, liver, genitourinary system ordiaphragm. Over 200
families with an undiagnosed craniofacial syndrome have been carefully screened for known mutations and enrolled in our
study, over 50 have had exome sequencing performed. Initial discoveries from this cohort included SPECC1L mutations in
Teebi Hypertelorism Syndrome, MYRF andHox3B mutations in Hardikar syndrome, and the identification of over a dozen
genes not previously implicated in human disease, including MACF1, SUV420H1, H3F3A, ZNF599, FAT3, CDH18, RRAS2,
MYRF,HOX3B, ZNRF3, RADIL, and DCHS2 . As these genes appear to play a role beyond the craniofacial pathology in
these families, we were able to discover novel candidate genes underlying over twenty separate medical conditions.
Poster Session
Tue(3)-P-224
Next Generation Sequencing in Spinal muscular atrophy syndromes: involvement beyond the anterior
horn cell
Tony Roscioli 1,2,3 ，Hooi LIng Teoh 4,5
，Ying Zhu 6 ，Hugo Sampaio 4,5
，David Mowat 3,5
，MIchael F Buckley 7 ，
Michelle Farrar 4,5
1:Kinghorn Centre for Clinical Genomics, Australia、2:St Vincents Clinical School, University of New South Wales, Darlinghurst, Australia、
3:Department of Medical Genetics, Sydney Childrens Hospital, NSW, Australia、4:Department of Neurology, Sydney Childrens Hospital,
Sydney, Australia、5:Discipline of Paediatrics, School of Womens and Childrens Health, UNSW Medicine, The University of New South
Wales, Sydney, Australia.、6:Royal North Shore GOLD Service, Sydney, NSW, Australia.、7:SEALS haematology and genetics laboratory,
Prince of Wales Hospital, Randwick, NSW, Australia
Non-SMN1 related Spinal muscular atrophies (SMA) are a group of inherited disorders characterized by motor neuron loss in
the spinal cord/ lower brainstem resulting in muscle weakness. While clinical manifestations are typically confined to anterior
horn cells disease, less common phenotypes may include more extensive involvement (SMA plus). Advances in Massively
Parallel Sequencing (MPS) have accelerated the identification of causative genes and been shown to be more comprehensive
and able to provide diagnostic results in a timely fashion. The present study utilized clinical and neurophysiological assess-
ments combined with MPS technologies to investigate seven patients with SMA plus. This study has defined phenotypes and
causative genes, provide pathophysiological insights and guide diagnosis.
Various SMA plus syndromes were identified revealing symptoms beyond the anterior horn cell, including bulbar and/or
cortico-motor neurone dysfunction, visual, hearing or cognitive impairment/degeneration, epilepsy, achalasia and endocrinopa-
thy. Neurophysiological, radiological and pathological investigations were important in defining phenotype and together with
single gene testing and MPS approaches were critical to attaining a molecular diagnosis. We have described novel phenotypes
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in known genes (VRK1, FBX038, ASAH1 ), gained further pathophysiological insights (PLAG26 ) and potentially identified
pathological variants in 2 novel genes. Pathological mechanisms include defects in RNA metabolism and splicing, axonal
transport, as well as motor neuron development and connectivity. Understanding the diverse clinical phenotypes and genetic
heterogeneity of SMA plus syndromes is essential to developing a diagnostic strategy and emphasize the importance of a
multidisciplinary approach to navigate the complexities of molecular diagnosis. Close collaboration between clinicians and
molecular geneticists is essential as we move closer to clinical utility of this technology.
Tue(3)-P-225
The mechanism study of proximal symphalangism induced by p.Leu373Arg variant in the GDF5 proregion
Yang Luo 1 ，Xinxin Zhang 1 ，Xuesha Xing 1 ，Lihua Cao 1 ，Shusen Wang 1 ，Xue Zhang 1
1:The Research Center for Medical Genomics, China Medical University, China
Abstract Proximal symphalangism (SYM1) is an autosomal dominant disorder, mainly characterized by bony fusion of proxi-
mal phalanges in the hands and feet. GDF5 and NOG were identified to be responsible for SYM1. We reported a p.Ler373Arg
mutation in GDF5 proregion in a large Chinese family with SYM1. Here we performed in vitro and in vivo assays to identify
the effects of the mutation on SYM1 and the function of GDF5 proregion. To investigate the effect of expression and secretion
of GDF5 mature protein, wild and mutant vectors were constructed and transfected into COS7, C2C12, HEK293 and ATDC5
cells. Both mature GDF5 protein level and the percentage of mature GDF5 protein in GDF5 proprotein increased in cells
with mutant vectors, indicating a gigher proteolysis efficiency of GDF5 protein. The variant also raised the activation of
Poster Session
SMAD signaling causing upregulation of SMAD1/5/8 phosphorylation and the expressions of target genes SMURF1 and
ID1 , along with COL2 and SOX9 , the factors associated with bone developing. A knockin mouse expressing the Gdf5
p.Leu363Arg (p.Leu373Arg in human) mutant protein was constructed. In accordance with SYM1, forelimb and hindlimb
of heterozygous mice occurred stiffness, adhesion between the proximal phalanx joint, while homozygous mice showed even
more serious effects. Compared with wild mice, both heterozygous and homozygous mice were absent the joint area but
appeared to be hypertrophic chondrocytes in E16.5. Observation for phalangeal zone chondrocytes showed the extension of
endoplasmic reticulum (ER) in the mutant mice and Ddit3 and Grp78 genes, associated with ER stress, were detected to
have a high expression. Expressions of Sox9 and Col2 were increased as well. According to these results we hypothesize that
the missense mutation p.Leu373Arg interfere the expresstion and secretion of mature GDF5 protein, causing the abnormal
bone development and also suggesting the importance of the proregion of GDF5.
Tue(3)-P-226
Mutations spectrum of COL1A1 /COL1A2 in Chinese with osteogenesis imperfecta
Xiuli Zhao 1 ，Jifang Xiao 1 ，Yiyang Wu 1 ，Jingsong Gao 2 ，Xiuzhi Ren 3 ，Chaoxia Lu 1 ，Han Wang 1 ，Yue Sun 2 ，
Xue Zhang 1
1:McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences - Peking Union Medical College, China、2:Peking
Union Medical College Hospital、3:Tianjin Hospital
Osteogenesis imperfecta (OI) is a group of clinically and genetically heterogeneous disorders with an incidence of 1/10000
in live births. The main clinical manifestations in OI include multiple fractures, blue sclera, short stature, dentinogenesis
imperfecta, hearing loss and so on. Up to now, fifteen different forms (OI type 1 ~ OI type 15) have been recognized
and classified, and at least thirteen genes(COL1A1 , COL1A2 , IFITM5 , SERPINF1 , CRTAP, LEPRE1 , PPIB, SERPINH1 ,
FKBP10 , SP7 , BMP1 , TMEM38B and WNT1 )have been reported to relate to OI. Lots of studies have shown that more
than 90% affected individuals have mutations in either COL1A1 or COL1A2 which encode the chains of type I procollagen.
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In this study, we collected 202 OI cases (65 familial cases and 137 sporadic cases) and their family members. All the affected
individuals showed notable OI phenotypes. We focused on mutation identification in COL1A1 /2 in all the 202 probands.
All the coding region and exon/intron boundaries in COL1A1 /2 were amplified using 43 pairs of primers. Next generation
sequencing was carried out to detect the candidate mutations in the probands, and all the mutations were verified by PCR-
Sanger sequencing. The DNA from the unaffected parents of the sporadic cases was also screened to ascertain the absence of
the de novo mutations. Novel mutations were validated in 50 normal unrelated samples by PCR followed by high resolution
melting (HRM). In total, we found 127 mutations in 155 probands, including 79 mutations in COL1A1 and 48 mutations in
COL1A2 . Among them, 63 mutations were novel and haven’t been reported in human gene mutation database (HGMD),
including 36 mutations in COL1A 1 and 27 mutations in COL1A2 . In summary, we have set up a comprehensive platform
including PCR, Sanger/next generation sequencing and HRM to perform genetic diagnosis for the patients with OI. We
extended the mutation spectrum of COL1A1 /2 in Chinese OI cases.
Tue(3)-P-227
Genetic testing of inherited cardiomyopathy by next generation semiconductor sequencing technologies
Chaoxia Lu 1 ，Wei Wu 2 ，Fang Liu 1 ，Kunqi Yang 3 ，Shuyang Zhang 2 ，Xue Zhang 1
1:McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, China、2:De-
partments of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College、
3:Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences & Peking
Union Medical College
Inherited cardiomyopathy is the most common genetic heterogeneity and clinical heterogeneity cardiac disease. It also
Poster Session
causes a significant proportion of sudden cardiac deaths and heart failure in young. The purpose of this study was to
investigate cases of primary cardiomyopathy for potential disease-causing mutations in 64 genes reported to be related to
inherited cardiomyopathy. A total of 107 unrelated patients diagnosed with primary cardiomyopathy including hypertrophic
cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, left
ventricular non-compaction, and undefined cardiomyopathy were collected after informed consent. In these patients, 18 had
family history and 89 are sporadic. A custom AmpliSeq panel, including 64 genes, were screened by Ion Torrent PGM
Sequencing platform. Data from the PGM runs were processed using Ion Torrent Suite 4.0 software to generate sequence
reads and extraction of SNPs and indels. All variants were filtered against dbSNP142 (≥1%). The most likely disease-
causing variants were validated by Sanger sequencing. As a result, 74 variants in 70 patients (65.4%) had been found with
likely functional effects based on conservation, computational prediction, allele-frequency and supportive literature. In these
variants, 23 are reported to be damaging mutations in the Human Gene Mutation Database, 44 are novel and 6 are uncertain
significance variants. Four patients has more than one variants. The mutations were most frequently found in the sarcomere
(MYBPC3, MYH7, TNNI3, TNNT2, MYL2, MYL3,TPM1 and ACTC1) and cytoskeletal (MYPN, DES, VCL and LMNA)
genes. To date, the low cost and highly efficient next generation sequencing strategy is a useful tool in the clinical management
of disease, testing for pathogenic mutations, treatment of patients with inherited cardiomyopathy and may assist in predicting
disease risk for their family members before the onset of symptoms.
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Tue(3)-P-228
Withdrawn

Tue(3)-P-229
ISOLATED OPTIC NERVE HYPOPLASIA IN 5 FAMILY TRIOS - A CLINICAL AND EXOME STUDY
Pierre Bitoun 1,3 ，Anne Boland-Auge 2 ，Delphine Bacq-Daian 2 ，Eva Pipiras 3 ，Brigitte Benzacken 3 ，
Austin Alexander 4 ，Suzanne Kuzbari 5 ，Jean-Francois Deleuze 2
1:Genetique Medicale, France、2:Centre National de Genotypage, Institut de Genomique, CEA, Evry、3:Embryo-Cyto-Genetique et PMA,
CHU Paris-Nord, Hopital Jean Verdier, Bondy、4:GeneUS, Pearlgen, Austin TX, USA、5:Banque d ADN, Hopital Robert Debre, Paris
Optic nerve hypoplasia (ONH) is a rare congenital malformation with severe visual incapacity.Children are often only tem-
porarily blind at birth.ONH is often syndromic ( septo-optic dysplasia / de Morsier syndrome) with MRI pituitary anomalies.
Our purpose is to explore currently unknown genetic causes of isolated ONH.
Material and Methods:
Poster Session
5 Probands (2 females/3 males) with normal MRI and parents were enrolled in genetic study after informed consent. Pe-
diatric, dysmorphologic and ophthalmologic examinations and endocrine work up was performed. Patients had SNP array
CGH and Exome Sequencing.Male patients were genotyped for HESX. DNA was extracted from lymphoblastoid cell lines or
whole blood and with stringent quality control.DNA was sequenced at a mean of 30X in > 92% of samples using an Illumina
platform; Bam file coherence and duplicate elimination used Sam Tools and Picard Tools, QC used house tools and Bedtools,
variant call using GATK, annotation using snpEff and snpSift, variant Filters with de novo dominant hypothesis, absence in
1k, 65k genomes and Exac databases using Gene US from Pearlgen.
RESULTS
Patients had normal intelligence and distance VA around 20/200, 3 had learning difficulties, one severe dyspraxia, and one
had multiple endocrine deficiencies despite normal MRI and treated micropenis and cortisol deficiency. 3 patients had sleeping
disorders treated with melatonin.
No HESX mutations were identified. A single 410,4 kb deletion of the 2p26.1 was identified on SNP array CGH. All parents
were healthy and 3 fathers were unavailable. Candidate genes identified on NGS exome analysis needing further validation
will be presented.
DISCUSSION
A 2p16.1 deletion was identified on array CGH. Complete Exome NGS analysis results on 5 family trios is presented.
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Tue(3)-P-230
New mutations in PLOD1 and COL3A1 in two cases with Ehlers-Danlos syndrome
Hakan Ulucan 1 ，Ugur Gumus 1 ，Emre Kirat 1 ，Alper Gezdirici 2 ，Asuman Koparir 1 ，Adnan Yuksel 3 ，Bert Callewaert 4 ，
Anne De Paepe 4 ，Mehmet Seven 1
1:Cerrahpasa Medical Faculty, Istanbul University, Turkey、2:Kanuni Sultan Suleyman Training Research Hospital Department of Medical
Genetics、3:Biruni University, Istanbul, Turkey、4:Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
Ehlers-Danlos syndrome (EDS) is a large group of connective tissue disorders that represent with skin hyperextensibility, joint
hypermobility and tissue fragility. The incidence of disease totally approximately 1 in 5000. The disease is classified in seven
main group with predominant features which are hypermobility, vascular, kyphoscoliosis, arthrochalasia and dermatosparaxis.
We aim to present two patients with EDS type 4 and 6 by new mutations.
Our first case is a 2-year-old boy of first cousin parents. Growth retardation, delay in wound healing, asthenic posture, minimal
thoracic scoliosis and hyperextensibility of joints and skin were consistent with EDS type VI. Second case was referred to our
clinic for recurrent dislocation of glenoidal joint and aortic aneurysm at the age of 30 years. She was diagnosed as EDS Type
IV with the findings of thin skin with visual veins, aortic aneurism as well as hypermobility of the joints.
At the first case the diagnosis was comfirmed as EDS type VI by MLPA analysis showing deletion of exon 2 in the PLOD1
gene. Clinical picture of the EDS type IV was comfirmed by detection of c.2337G>C splice site mutation in COL3A1 . Here
we report two new mutations with classical clinical findings in EDS.
Poster Session
Tue(3)-P-231
Decreased performance in IDUA knockout mouse mimic limitations of joint function and locomotion in
patients with Hurler syndrome
Eun Kyung Cho 1 ，A Ram Yang 1 ，Jinsup Kim 1 ，Young Bae Sohn 2 ，Su Jin Kim 3 ，Sung Won Park 4 ，
Sung Yoon Cho 1 ，Dong-Kyu Jin 1
1:Department of Pediatrics, Samsung medical Center, Korea, South、2:Department of Medical Genetics, Ajou University School of Medicine、
3:Department of Pediatrics, Myongji Hospital, Seonam University College of Medicine、4:Department of Pediatrics, Jeil Hospital, Dankook
University College of Medicine
BACKGROUND: Mucopolysaccharidosis type I (MPS I) is caused by the deficiency of alpha-L-iduronidase (IDUA), which
is involved in the degradation of glycosaminoglycans (GAGs), such as heparan sulfate and dermatan sulfate in the lysosome.
It has been reported that joint symptoms are almost universal in MPS I patients, and even in the case of attenuated disease,
they are the first symptom that brings a child to medical attention. However, functional tests and biological markers have
not been published for the evaluation of the limitations in joint and locomotion in animal model-mimicking MPS.
METHODS: We generated IDUA knockout (KO) mice to observe whether they present impairment of joint function. KO
mice were characterized phenotypically and tested dual-energy X-ray absorptiometry analysis (DEXA), open-field, rotarod,
and grip strength.
RESULTS: The IDUA KO mice, generated by disruption between exon 6 and exon 9, exhibited clinical and laboratory find-
ings, such as high urinary GAGs excretion, GAGs accumulation in various tissues, and significantly increased bone mineral
density (BMD) in both female and male mice in the DEXA of the femur and whole bone. Remarkably, we observed a de-
crease in grasp function, decreased performance in the rotarod test, and hypo-activity in the open-field test, which mimic the
limitations of joint mobility and decreased motor performance in the 6-min walk test in patients with MPS I.
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ICHG2016 1089
CONCLUSIONS: We generated a new IDUA KO mouse, tested open field, rotarod and grip strength and demonstrated
decrease in grip strength, decreased performance and hypo-activity, which may be useful for investigating therapeutic ap-
proaches, and studying the pathogenesis of joint and locomotion symptoms in MPS I.
Poster Session
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ICHG2016 1090
Poster Session
Epigenetics
Tue(3)-P-232
Aberrant methylation at imprinted DMRs is associated with placental mesenchymal dysplasia
Saori Aoki 1,4 ，Ken Higashimoto 1 ，Hidenori Hidaka 1 ，Hidetaka Watanabe 1 ，Yasufumi Ohtsuka 2 ，Hiroyuki Mishima 3 ，
Koh-ichiro Yoshiura 3 ，Hitomi Yatsuki 1 ，Kenichi Nishioka 1 ，Keiichiro Joh 1 ，Takashi Ohba 4 ，Hidetaka Katabuchi 4 ，
Hidenobu Soejima 1
1:Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Japan、
2:Department of Pediatrics, Faculty of Medicine, Saga University、3:Department of Human Genetics, Graduate School of Biomedical Sciences,
Nagasaki University、4:Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University
Objective: Placental mesenchymal dysplasia (PMD), a morphological aberration of the placenta defined by placentomegaly
and multicystic changes, is often associated with restricted fetal growth and death. A subset of PMDs has been associated
with androgenetic/biparental mosaicism and infants with Beckwith-Wiedemann syndrome, suggesting disrupted imprinting.
However, the etiology of PMD remains unknown.
Methods: To investigate the etiology of PMD, we collected frozen placental tissues from 21 patients with PMD and ge-
Poster Session
netically analyzed them using whole-exome sequencing (WES) and SNP arrays. Epigenetic analysis consisted of bisulfite-
pyrosequencing to quantitate DNA methylation of 52 imprinting-associated differentially methylated regions (DMRs).
Results: WES identified no disease-associated variants. SNP array analysis identified 5.8 ± 8.6 copy number variations
(CNVs) with copy number gain (average size 3.4 ± 9.8 Mb) and 3.3 ± 4.2 CNVs with copy number loss (average size 7.2 ±
23.1 Mb); however, all CNVs had already been registered in the Database of Genomic Variants, suggesting these were not
pathogenic. SNP array analysis also revealed androgenetic/biparental mosaicism in 15 PMD cases, while the remaining 6
had normal biparental inheritance. As expected, almost all DMRs in androgenetic/biparental mosaic cases showed a paternal
methylation pattern. In biparental cases, 19 DMRs were aberrantly methylated. Of these, 17 normally maternally methylated
DMRs showed hypomethylation, indicating a maternal-to-paternal epigenotype switch. Several DMRs were also aberrantly
methylated in cord blood or peripheral blood of fetuses with normal biparental inheritance.
Conclusion: Genetic abnormalities, such as gene mutations and copy number abnormalities, may not cause PMD. Aberrant
methylation, especially a maternal-to-paternal epigenotype switch, at certain DMRs may explain pathogenesis of PMD. The
environment of pregnancy with PMD may affect methylation of DMRs in fetuses.
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Tue(3)-P-233
H2A.Z genetically interacts with DRG2 which physically associates with RWDD1 and Nup107
1,2
Masahiko Tanabe
1:Department of Breast Oncology, Juntendo University, Japan、2:Kyoundo Hospital
Background) Epigenetic changes are critical for development and progression of cancers. In addition to DNA methylation and
histone modification, histone variant H2A.Z plays an essential role in epigenetic regulation of gene expression. Recently, it was
reported that high expression of H2A.Z was significantly associated with breast cancer progression and lymph node metastasis.
It is speculated that underlying biology of this clinical observation is associated with the molecular mechanism in which H2A.Z
positively regulates estrogen receptor (ER) α-dependent transcription and estrogen stimulation of cell proliferation. However,
biological impact of H2A.Z in breast cancer has yet to be revealed.
Methods and Results) We conducted a screening by use of Drosophila genetics to identify new genes which could reveal
a biological function of H2A.Z, and identified DRG2 (developmentally regulated GTP binding protein 2) gene. However,
it was not enough to explain a biological function of H2A.Z, because function of DRG2 protein is not well known, either.
Next, we conducted protein purification assay to identify associated protein directly with DRG2. We identified several
interactants with this assay. One protein was RWDD1 (RWD domain containing 1), which had been already reported as a
binding partner of DRG2. Additionally, RWDD1 was reported to interact with androgen receptor and to activate androgen-
dependent transactivation. Another protein was nuclear pore complex protein Nup107 in a member of the nucleoporin family.
Furthermore, in order to confirm these three proteins exist as one complex, we conducted glycerol density gradient assay.
Poster Session
This assay revealed that they formed one protein complex.
Perspectives) We speculate that H2A.Z, DRG2, and Nup107 might corporately function at nuclear pore complex.
Tue(3)-P-234
MicroRNA promotes the decidualization of eutopic and ectopic endometrium
Kentaro Kai 1 ，Yoko Aoyagi 1 ，Kaei Nasu 1 ，Tomoko Hirakawa 1 ，Kanetoshi Takebayashi 1 ，Hisashi Narahara 1
1:Department of Obstetrics and Gynecology, Oita University Faculty of Medicine, Japan
Objective: To elucidate the molecular pathways of decidualization in eutopic and ectopic endometrium.
Methods: Under the approval of our institutional review board and with the patients’ written informed consent, we isolated
normal endometrial stromal cells (NESCs) and endometriotic cyst stromal cells (ECSCs) and cultured them with dibutyryl
cyclic-AMP and dienogest for 12 days. We analyzed the expression patterns of microRNA (miRNA) and mRNA by microarray
and an ingenuity pathway analysis. Insulin-like growth factor binding protein 1 (IGFBP1) and prolactin (PRL) were used as
representative markers of in vitro decidualization.
Results: Enhanced expression of miR-30 family members was observed in both decidualized NESCs and decidualized EC-
SCs, whereas miR-210 was upregulated in decidualized ECSCs only. We found three candidate pathways involved in the
decidualization. The miR-30 downstream pathways were the Kruppel-like factor 9-IGFBP1 pathway and the tolloid-like
(TLL) 1/TLL2/paired-like homeodomain 1/Period circadian clock (PER) 2/PER3-PRL pathway. The miR-210 downstream
pathways were the tyrosine-protein phosphatase non-receptor type 1-growth hormone receptor-IGFBP1 pathway and the E2F
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transcription factor 3-thymidine kinase 1-PRL pathway.
Conclusions: Our results revealed that aberrantly expressed miRNA is involved in decidualization. We suggested that the
miR-30 family members are novel signaling molecules conserved in both NESCs and ECSCs, and that the miR-210 family is
conserved in only ECSCs.
Tue(3)-P-235
Epigenetic regulator, Uhrf1, is a positive regulator in chondrocyte differentiation
1,2
Michiko Yamashita ，Kazuki Inoue 1 ，Iori Sakakibara 1 ，Akari Murakami 2 ，Yoshiaki Kamei 2 ，Yuuki Imai 1,2
1:Division of Integrative Pathophysiology, Proteo-Science Center, Ehime university Graduate School of Medicine, Japan、2:Department of
Hepato Biliary Pancreatic and Breast Surgery
<Introduction>
Recently, it has been unveiled that the epigenetic regulator, Ubiquitin-like with PHD and ring finger domains 1 (UHRF1),
plays a significant role in both physiological and pathological condition. However, the function of UHRF1 is completely
unknown in the skeletal tissue. Here, we analyzed the function of Uhrf1 in skeletal tissue using limbs specific Uhrf1 knockout
mice.
<Method>
Poster Session
Limb mesenchymal cell specific Uhrf1 KO mice (cKO) have generated by crossing limb mesenchymal cell-specific expressing
Cre recombinase (Prx1-Cre) mouse with Uhrf1 flox mouse, and harvested skeletal tissues were analyzed by radiological and
histological examinations. In addition, we used the chondrocyte differentiation system by micromass culture of undifferen-
tiated mesenchymal cell line, C3H10T1/2 cells, with or without gene knockdown using shRNA for Uhrf1 . The chondrocyte
differentiation marker gene expression was analyzed by real time RT-PCR.
<Result>
The conditional Uhrf1 knockout mice (cKO) exhibited remarkably short limbs when compared with control mice. The soft
X-ray showed that long bone length of cKO mice were significantly reduced and were approximately 31-40% shorter than
that of control group. In addition, bone mineral density of cKO male femur at 6 weeks of age was about 20% lower than that
of control group. Furthermore, the histological analysis showed that the columnar structures of cells in growth plate of cKO
mice were disturbed and the area of growth cartilage was decreased in cKO mice.
The expression levels of cartilage differentiation marker genes are reduced in 10T1/2 cells with Urhf1 knockdown.
<Discussion>
The results suggested that Uhrf1 is a positive regulator and has an essential function in cartilage differentiation. In the future,
the detailed molecular mechanism in cartilage differentiation would be revealed using a genome-wide analysis, such as RNA
sequence or MeDIP-seq.
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Tue(3)-P-236
Altered levels of epigenetic marks/factors on regulatory regions of sperm chromatin condensing genes
in testicular biopsies infertile men
Maryam Shahhoseini 1 ，Raha Favaedi 1 ，Mohammad Ali Sadighi- Gilani 2
Iran、2:Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR,
Tehran, Iran
Chromatin structure is tightly regulated by various epigenetic factors/marks which affect different cellular mechanisms through
development. One of the best characterized epigenetic regulations occurs during development of sperms (spermatogenesis),
via replacement of histones of sperm chro matin by transition proteins (TNPs) and protamines (PRMs), which finally leads
to chromatin condensation. In this study we tried to evaluate the epigenetic profile TNPs and PRMs genes in testis tissues
of infertile men referred to Royan Institute. For this respect, based on spermogram and presence/absence of sperm in TESE
(testicular sperm extraction) process, the samples were collected as two groups of TESE+ and TESE- . Consent was obtained
from patients according to local ethical approval. Messenger RNA expression of TNPs and PRMs as well as two epigenetic
modifiers JMJD1A (as a testis specific histone demethylase) and CDY1 (as a highly expressive testis histone acetyltransferase)
were evaluated by qRT-PCR quantitatively. Also, chromatin immunopercipitation (ChIP) coupled with real time-PCR was
performed to evaluate the incorporation of JMJD1A and CDY1 factors into regulatory regions of TNPs and PRMs genes,
parallel to acetylation/methylation levels of these promoters. Results showed significant decrease in expression of TNPs,
PRMs, JMJD1A and CDY1 in TESE negative compared to TESE positive group. These results were also confirmed by
ChIP data which revealed significant hypoacetylation and hypermethylation of the candidate genes in analyzed samples. The
Poster Session
finding implies association of altered levels of epigenetic marks/factors with a differential expression profile of sperm chromatin
condensing genes and impairment of spermatogenesis.
Keywords: Epigenetic, TNPs, PRMs, Chromatin condensation.
Tue(3)-P-237
Is the association between sweet and bitter perception due to genetics?
1,2 3,4
Liang-Dar Hwang ，Paul AS Breslin ，Danielle R Reed 3 ，Gu Zhu 1 ，Nicholas G Martin 1 ，Margaret J Wright 1,5
1:Genetic Epidemiology Lab, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia、2:School of Medicine, University
of Queensland, Brisbane, Australia、3:Monell Chemical Senses Center, Philadelphia, USA、4:Department of Nutritional Sciences, School of
Environmental and Biological Sciences, Rutgers University, New Brunswick, USA、5:Queensland Brain Institute, University of Queensland,
Brisbane, Australia
Perceived intensities of sweetness and bitterness are associated and both are partially influenced by genetics. However, the
extent that this association is due to shared genetic factors has not been investigated.
Here, in a sample of 1901 adolescent and young adults (53.8% female; 243 MZ and 452 DZ twin pairs, 511 unpaired individuals;
age 16.2±2.8 years), we used multivariate genetic modelling to estimate the covariance between the perceived intensities of
four bitter compounds (6-n-propylthiouracil (PROP), sucrose octa-acetate (SOA), quinine HCl, and caffeine) and a sweetness
factor (weighted mean ratings of glucose, fructose, neohesperidine dihydrochalcone, and aspartame).
Sweetness was moderately correlated with SOA, quinine, and caffeine (rp =0.35-0.40). This was largely due to a shared genetic
factor (rg =0.46-0.51) that accounted for 46-94% of the genetic variance in the three bitter compounds (h2 =0.35-0.40) and 23%
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of the genetic variance in sweetness (h2 =0.36). An association between sweetness and PROP (rp =0.31) was only evident after
adjusting for the TAS2R38 genotype. This PROP genetic factor accounted for all of the genetic variance in PROP, 11-22% in
SOA, quinine, and caffeine, and 13% of the genetic variance in sweetness. We hypothesized that these taste common factors
might be mediated by intelligence or personality but, while significant, only a small amount of the observed genetic covariance
could be accounted for by these behavioral factors.
This study supports an overlap of genetic variance between the perception of sweet and bitter tastes and further provides
evidence for two separate common genetic pathways when considering the TAS2R38 genetic influence. The finding facilitates
further investigations for the common transduction and perceptual mechanisms in humans.
Tue(3)-P-238
Clinical and molecular findings in a patient with 46,XX/47,XX,+14 mosaicism caused by postzygotic
duplication of a paternally derived chromosome 14
Nobuhiro Suzumori 1 ，Masayo Kagami 2 ，Kyoko Kumagai 1 ，Shinobu Goto 1 ，Keiko Matsubara 2 ，Shinichiro Sano 2 ，
Mayumi Sugiura-Ogasawara 1
1:Department of Obstetrics and Gynecology, Nagoya City University, Graduate School of Medical Sciences, Japan、2:Department of Molecular
Endocrinology, National Research Institute for Child Health and Development
Trisomy 14 mosaicism is a rare chromosomal disorder typified by several congenital anomalies, and only 30 patients with
the disorder have been reported in the medical literature. A 38-year-old gravida 2, para 1 Japanese woman was referred
Poster Session
to our hospital because of fetal hydrops at 23 weeks’ gestation. Fetal ultrasound findings suggested transposition of the
great arteries, pleural effusion, and skin edema. Amniocentesis was performed at 26 weeks’ gestation, and the result of the
G-banding was 46,XX[12]/47,XX,+14[3]. At 37 weeks’ gestation, a 2,696 g female infant was delivered by Cesarean section
because of fetal breech presentation. Due to severe asphyxia immediately after birth, intubation was repeatedly attempted,
but failed due to congenital tracheal atresia. Finally, the infant died soon after birth. Congenital tracheal atresia, atrial septal
defect, and transposition of the great arteries type II were confirmed at autopsy.
The karyotypes of umbilical vein blood and neonatal peripheral blood were 46, XX[23]/47, XX,+14[7] and /46, XX[25]/47,
XX, +14[5], respectively. The microsatellite analysis showed that the patient’s chromosome 14 was of biparental origin,
and an extra copy of chromosome 14 in trisomy 14 cells was of paternal origin. The absence of a bell-shaped thorax and
abdominal wall defects in the patient may be explained by the similarity of the ratio of trisomy 14 cells caused by paternal
duplication of chromosome 14 cells in the ribs, abdominal wall, and blood. The ratio of the trisomy 14 cells in the blood was
about 20% on the chromosome test and 44.5% in calculations using the AUC of the microsatellite data.
This patient showed congenital tracheal atresia, which has not previously been reported in patients with trisomy 14 or
upd(14)pat. When trisomy 14 mosaicism is detected in a fetus, precise radiological assessment of congenital tracheal atresia
is recommended for pregnant women.
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Tue(3)-P-239
Assessment of the oral health status of monozygotic and dizygotic twins - a comparative study
1
Delfin Lovelina Francis
1:Public Health Dentistry, Tamil Nadu Dr MGR Medical University, Chennai, India
Purpose:
To assess the oral health status and concordance between monozygotic and dizygotic twin pairs.
Materials and methods:
After obtaining prior consent, a cross-sectional descriptive study was conducted among 9 monozygotic and 21 dizygotic twin
pairs who were reared together. Perception towards oral health practices was assessed using a pre-tested questionnaire.
The WHO oral health assessment form (1997) was employed to assess the oral health status. Zygosity determination was
determined using the medical records, dermatoglyphics and details about chorionicity and number of placental cords. Pearson’s
correlation was calculated to determine the correlation among the monozygotic and dizygotic twin pairs.
Results:
The monozygotic twin pairs showed a greater correlation compared to the dizygotic twin pairs in dental caries, periodontal
Poster Session
disease and malocclusion.
Conclusion:
In the present study, monozygotic twin pairs showed a higher correlation rate than the dizygotic twin pairs, suggesting
considerable evidence that genes play a significant role in the aetiology of dental caries, periodontal disease and malocclusion.
Tue(3)-P-240
Association of epigenetic role of BRDT in spermatogenesis and male infertility
1,2
Fereshteh Kohandani ，Seyed Mohammad Moshtaghioun 1 ，Maryam Shahhoseini 2
1:Biology Department, Faculty of Sciences, Yazd University, Yazd, Iran、2:Department of Genetics, Reproductive Biomedicine Research
Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
Post-meiotic stages of spermatogenesis are consisted of many epigenetic events leading to sperm chromatin condensation.
Many factors are involved in this epigenetic process such as BRDT. BRDT is a regulatory protein which binds to hyper-
acetylated histones and facilitates their replacement by protamines to induce chromatin condensation. This study aimed to
consider the expression and epigenetic role of BRDT in testis tissues of infertile men referred to Royan Institute. Testicular
biopsies were collected from 45 infertile men and distributed into 3 groups: obstructive azoospermia (OA) as positive control
group, complete maturation arrest at second spermatocyte/spermatid level (CMA) and Sertoli cell only syndrome (SCO) as
negative control group. Real-time PCR was performed on synthesized cDNA, to identify the expression of BRDT . Also, chro-
matin immunoprecipitation (ChIP) coupled with real-time PCR was performed to evaluate incorporation of histone marks of
H3K9ac/me2/me3 and H3K4/27me3 into regulatory region of BRDT . The expression of BRDT in OA group was significantly
higher than the other groups. The promoter of BRDT is associated with different epigenetic marks. In OA group, levels of
epigenetic marks of H3K9ac and H3K4me3 are higher than the H3K9me2/me3 and H3K27me3 marks. While the levels of
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H3K9me2/me3 and H3K27me3 marks are higher than the H3K9ac and H3K4me3 in 2 groups with spermatogenesis defect
(CMA and SCO). The finding in this study declared an association between failure in epigenetic regulation of BRDT and
defective spermatogenesis and male (in)fertility.
Key words: Epigenetics, Histone modification, Spermatogenesis, BRDT .
Tue(3)-P-241
Differential histone modification of marker genes involved in stemness and differentiation in human
pluripotent and differentiated cells
Raha Favaedi 1 ，Maryam Shahhoseini 1 ，Sepideh Mollamohammadi 2 ，Hossein Baharvand 2
Iran、2:Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and
Technology, ACECR, Tehran, Iran
Besides being involved in DNA packaging, nucleosome organization plays an important role in cell fate. There is much
debate about the major determinants of the nucleosome architecture and chromatin structure in pluripotency. Chromatin of
pluripotent cells has special epigenetic features which impact cellular function by acting as key regulators in the maintenance
and remodeling of chromatin, thus affecting transcription regulation. In this study we tried to compare changes of histone
modifications of (H3K9ac/me2) in regulatory regions of 6 marker genes involved in stemness (NANOG, OCT4 and SOX2 )
and fibroblast differentiation (VIM, COL1A1, THY1 and DES), in a human ES cell line before and after differentiation to
Poster Session
fibroblast cells and an iPS cell line reprogrammed from these fibroblast cells. Also a human dermal fibroblast cell line as
a completely and natural differentiated cell line was used in this study as well as an iPS line originated from it to gain an
overall understanding of dynamic regulation of chromatin structure in balancing of pluripotency and cell fate. Chromatin
data revealed hyperacetylation and hypomethylation on H3K9 in regulatory regions of stemness genes vs. fibroblast marker
genes in ES and two iPS lines. While in fibroblasts differentiated from ES cells and dermal fibroblast, hyperactylation of
H3K9 was the dominant mark on regulatory regions of fibroblast marker genes compares to stemness genes.
This study declared the dynamic association of histone modifications on the upstream regulatory regions of marker genes in
regulation of pluripotency, differentiation and reprogramming state of cells.
Key words: Epigenetic, ESC, iPSC, Fibroblast.
Tue(3)-P-242
Discovering site-specific changes in 5-hydroxymethylcytosine in suicide completers through next-
generation sequencing
Jeffrey A. Gross 1 ，Alain Pacis 2 ，Gary G. Chen 1 ，Megan Drupals 1 ，Pierre-Eric Lutz 1 ，Luis B. Barreiro 2 ，Carl Ernst 1 ，
Gustavo Turecki 1
1:McGill University and the Douglas Hospital Research Centre, Canada、2:University of Montreal and the CHU Sainte-Justine Research
Centre
The recent discovery that methylated cytosines (5mC) are converted to hydroxymethylated cytosines (5hmC) by the family of
ten-eleven translocation enzymes has sparked significant interest on the genomic location, the abundance in different tissues,
the putative functions, and the stability of this cytosine modification. 5hmC plays a key role in the brain, where it is
particularly abundant and dynamic during development, and has been previously associated with several psychiatric illnesses.
Using AbaSI-Seq, which utilizes a restriction enzyme that recognizes 5hmC, we comprehensively characterize 5hmC in the
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prefrontal cortices of 19 individuals that died by suicide and 19 matched controls that died by natural or accidental causes. We
show that, although there is inter-individual variability in 5hmC content among unrelated individuals, approximately 8% of all
CpGs on autosomal chromosomes contain 5hmC, while sex chromosomes contain far less. Across groups, genome-wide levels
of 5hmC do not differ, however, there exist differentially hydroxymethylated regions (dhMRs) within gene bodies of genes
previously associated with psychiatric disorders. To validate these findings, we used targeted oxidative bisulfite sequencing
to interrogate both 5mC and 5hmC levels in these dhmRs, and assessed their impact on gene expression. Collectively, these
results offer an important reference for the growing number of studies that are interested in the investigation of the role of
5hmC in brain and mental disorders. Understanding the differences in the genomic locations of 5hmC will shed light on the
growing debate as to whether 5hmC represents a novel epigenetic mark or whether it is simply an intermediate product of
active DNA demethylation.
Tue(3)-P-243
DNA Methylation Reflects Early Life Chronic Stress Environment: A Biomarker for Childhood Cortisol
Evan Gatev 1,2 ，Mina Park 2 ，Rachel Edgar 2 ，Lisa McEwen 2 ，Julia MacIsaac 2 ，Sarah Goodman 2 ，Nicole Bush 5 ，
W. Thomas Boyce 5 ，Michael Kobor 1,2,3,4
1:Bioinformatics, University of British Columbia, Canada、2:Centre for Molecular Medicine and Therapeutics、3:Child and Family Research
Institute、4:Department of Medical Genetics、5:University of California
Cortisol is a measure of stress reactivity, capturing chronic stress during childhood development, e.g. from growing up in
a low socio-economic status (SES) environment, that is associated with disease later in life. Persistent DNA methylation
Poster Session
(DNAm) signature of childhood basal cortisol level would be useful as biomarker for early-life chronic stress environment.
The typical small size of cohorts with DNAm data pose several challenges to the statistical construction of biomarkers, includ-
ing over-fitting, performance assessment and interpretability of the results. To address these, we offer a novel bioinformatic
construction of a DNAm biomarker for childhood cortisol.
Our 3-stage pipeline includes selection of a small number of phenotype-relevant DNAm sites and genotypes, and their inte-
gration and further selection for a biomarker model that allows for Gene-Environment Interactions.
We apply our method in a cohort of 166 individuals whose DNAm was measured at age 12, while cortisol was measured at
age 6. Despite the small size of the cohort used for statistical training, our 34-site DNAm biomarker prediction has adjusted
R-square of 65% in 5-fold cross-validation, with actual childhood cortisol. The DNAm biomarker model is validated in an
independent cohort of 138 individuals whose DNAm is measured at age 18.
Tue(3)-P-244
Epigenetic role of the nuclear factor NF-Y on ID family genes in endometrial tissues of women with
endometriosis
1,2
Shirin Amirteimouri ，Maryam Shahhoseini 2 ，Fariba Ramezanali 3 ，Parvaneh Afsharian 2 ，Reza Aflatoonian 3 ，
Raha Favaedi 2
1:Faculty of Basic Sciences and Technologies, University of Science and Culture, ACECR, Tehran, Iran、2:Department of Genetics,
Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran、3:Department of
Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR,
Tehran, Iran
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Endometriosis is a benign endometrial proliferation which is associated with both infertility and pelvic pain and it is charac-
terized by the presence of endometrial cells outside the uterine cavity. Recent studies have revealed that endometriosis can
be considered as an epigenetic disorder.
Epigenetic mechanisms such as incorporation of histone substitutes have been shown to play key roles in regulation of gene
transcription. Among them, NF-Y is a transcription factor which specifically binds to the CCAAT box of the target genes
and causes their regulation. The CCAAT box is one of the elements present in eukaryotic promoter regions of numerous genes
such as basic helix-loop-helix ID (Inhibitor of DNA binding) factors. ID proteins are transcriptional regulators that regulate
the two major cellular processes of differentiation and proliferation. ID family genes are ID1,ID2, ID3 , ID4 .
Regarding the critical roles of NF-Y in regulation of cellular proliferation, in this study the epigenetic role of NF-Y on ID
genes was aimed in endometrial tissues of women with endometriosis.
In this study, the chromatin immunoprecipitation coupled with realtime PCR was performed using anti-NF-Y antibody, on
chromatin extract from ectopic, eutopic and endometrial tissues, to monitor incorporation levels of NF-Y on the regulatory
regions of ID genes and samples obtained from 20 patients with endometriosis in reproductive age with normal menstrual
cycle. Control samples were surgically checked for the absence of endometriosis. Informed consent was obtained from patients
according to local ethical approve.
The results of ChIP real-time PCR analysis showed significant increase incorporation of NF-Y complex on the regulatory
regions of ID2 and ID3 genes in endometrial tissues compared to normal endometrium.
Poster Session
Our findings imply an association between altered levels of histone substitutes in regulation of proliferation genes and en-
dometriosis.
Keywords: Epigenetic, NF-Y, ID Genes, Endometriosis
Tue(3)-P-245
Monozygotic twins concordant for ICR2 hypomethylation in different tissues but discordant for Beckwith-
Wiedemann syndrome phenotype
Dorota Jurkiewicz 1 ，Monika Kugaudo 1 ，Elżbieta Ciara 1 ，Dorota Piekutowska-Abramczuk 1 ，
Magdalena Pelc 1 ，Joanna Trubicka 1 ，Matthias Begemann 2 ，Thomas Eggermann 2 ，Krystyna Chrzanowska 1 ，
Małgorzata Krajewska-Walasek 1
1:Department of Medical Genetics, Children’s Memorial Health Institute, Warsaw, Poland、2:Institute of Human Genetics, RWTH Aachen,
Germany
Beckwith-Wiedemann syndrome (BWS) is characterized by overgrowth, macroglossia, abdominal wall defects and tumor
predisposition. It is caused by various 11p15 genetic or epigenetic mutations leading to defective expression of imprinted
genes. The most frequent abnormality resulting in BWS phenotype is loss of methylation at ICR2, in some of patients with
this defect other imprinted loci are also affected leading to multi-locus imprinting disturbance (MLID). In very rare cases of
MLID trans-acting mutations have been identified.
We report 3 years old female monozygotic twins discordant for BWS. One of the twins presents BWS phenotype (macroglossia,
omphalocele, neonatal hypoglycemia, diastasis recti, ear lobe creases, characteristic face) whereas the second twin has only
a characteristic face. Methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) performed in twins’
DNA extracted from blood, buccal swabs, and urine sediment revealed hypomethylation at ICR2. The presence of the
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epimutation in both probands was confirmed by multilocus methylation-specific single nucleotide primer extension (MS-
SNuPE), the analysis was performed in DNA extracted from blood and buccal swabs. MS-SNuPE additionally revealed
hypomethylation in IGF2R locus on chromosome 6q25 indicating the presence of multi-locus imprinting disturbance (MLID).
Mother of the twins had a normal phenotype and epigenotype, father was not investigated.
Up to now several monozygotic twins discordant for BWS with ICR2 hypomethylation in blood have been reported. However,
when other tissues were examined only the affected twin presented loss of methylation. To our knowledge this is a first
report on monozygotic twins discordant for BWS with ICR2 hypomethylation in blood and other investigated tissues in both
individuals. This finding together with MLID suggests a presence of a trans-acting genetic factor leading to epigenetic changes
in both twins and needs further investigations.
Tue(3)-P-246
Exploration of hydroxymethylation in Kagami-Ogata syndrome caused by hypermethylation of imprinting
control regions
Kazuki Yamazawa 1,2 ，Keiko Matsubara 2 ，Masayo Kagami 2 ，Kazuhiko Nakabayashi 3 ，Kenichiro Hata 3 ，
Maki Fukami 2 ，Tsutomu Ogata 2,4
1:Clinical Genetics Center, NHO Tokyo Medical Center, Japan、2:Department of Molecular Endocrinology, National Research Institute for
Child Health and Development、3:Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development、
4:Department of Pediatrics, Hamamatsu University School of Medicine
Background: 5-hydroxymethylcytosine (5hmC), converted from 5-methylcytosine (5mC) by Tet enzymes, has recently drawn
Poster Session
attention as the ‘sixth base’ of DNA since it is considered an intermediate of the demethylation pathway. Nonetheless, it
remains to be addressed how 5hmC is linked to the development of human imprinting disorders. In this regard, conventional
bisulfite (BS) treatment is unable to differentiate 5hmC from 5mC. It is thus hypothesized that BS conversion-derived
‘hypermethylation’ at imprinting control regions (ICRs), which may cause imprinting disorders, would in fact be attributable
to excessively increased levels of 5hmC as well as 5mC. To test this hypothesis, we applied the newly developed oxidative BS
(oxBS) treatment to detect 5hmC in blood samples from Kagami-Ogata syndrome (KOS14) patients caused by an epimutation
(hypermethylation) of two differentially methylated regions (DMRs) functioning as ICRs, namely, IG-DMR and MEG3 -DMR.
Findings: oxBS with pyrosequencing revealed that there were few amounts of 5hmC at the hypermethylated IG-DMR and
MEG3 -DMR in blood samples from KOS14 patients. oxBS with genome-wide methylation array demonstrated that global
levels of 5hmC were very low with similar distribution patterns in blood samples from KOS14 patients and normal controls.
We also confirmed the presence of large amounts of 5hmC in the brain sample from a normal control.
Conclusions: 5hmC is not a major component in abnormally hypermethylated ICRs or at a global level, at least in blood from
KOS14 patients. As the brain sample contained large amounts of 5hmC, the neural tissues of KOS14 patients are promising
candidates for analysis in elucidating the role of 5hmC in the neurodevelopmental context.
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Tue(3)-P-247
ANALYSIS OF CHROMOSOMAL ABNORMALITIES AND DNA METHYLATION AT SNRPN GENE
IN PRADER WILLI SYNDROME - COIMBATORE POPULATION
Padmavathi Vijaykumar 1 ，Balachandar Vellingiri 1 ，Sasikala Keshavrao 1
Prader-willi syndrome (PWS) is a neurogenetic disorder characterised by developmental delay, hypotonia and feeding diffi-
culties, hyperphagia, obesity, short stature and small hands and feet, almond shaped eyes, Temper tantrums and obsessive
compulsive. Many of the characteristic features of PWS result from the distinct genetic conditions caused by unusually turn
off (inactive) genes of paternal copy at the 15q11-13 imprinted region. The aim of study was to analyze cytogenetics and DNA
methylation of SNRPN gene of PWS patients in Indian population. We carried out 10 PWS patient and parent samples,
based on the detailed DSM - IV questionnaire, and equal number of controls were selected to investigate the chromosomal
abnormalities and to determine methylation at the promoter of the differentially methylated SNRPN gene locate within the
PWS. In our study chromosomal alterations were frequently observed in chromosomes 15q11.2-q13 and identified 75-80% of
all individuals with the PWS syndrome, including those with cytogenetic deletions, imprinting center defects and maternal
uniparental disomy. In the present study, chromosomal aberrations showed confirm higher degree in experimentals compared
to controls (P<0.001) and we investigated Methylation analysis of the parental samples revealed normal methylation levels
at all the imprinted loci. In conclusion, we observed that the identification of cytogenetic abnormalities is not only important
for providing a cause for the PWS in a single individual but is also critical for accurate counselling regarding recurrence risks
to parents and family members. We suggest that SNRPN might represent a major susceptibility gene for PWS.
Poster Session
Tue(3)-P-248
Meta-Analysis of Epigenome-wide Association Studies on Serum Urate Levels including 7600 individuals
Christian Gieger 1,2 ，Annika Laser 1,2 ，Benjamin C Lehne 3 ，Stefan Gustafsson 4 ，Tao Zhang 5 ，Sonja Kunze 1,2 ，
Dianjianyi Sun 5 ，Shengxu Li 5 ，Gerald Berenson 5 ，Fabian Theis 6 ，Annette Peters 2 ，Gabi Kastenmueller 7 ，
Erik Ingelsson 4 ，Wei Chen 5 ，Lars Lind 4 ，John Chambers 3 ，Melanie Waldenberger 1,2
1:Research Unit of Molecular Epidemiology, Helmholtz Center Munich, Germany、2:Institute of Epidemiology, Helmholtz Center Munich、
3:Department of Epidemiology and Biostatistics, Imperial College London、4:Department of Medical Sciences, Molecular Epidemiology and
Science for Life Laboratory, Uppsala University, Uppsala、5:Department of Epidemiology, School of Public Health and Tropical Medicine,
Tulane University, New Orleans、6:Institute of Computational Biology, Helmholtz Center Munich、7:Institute of Bioinformatics and Systems
Biology, Helmholtz Center Munich
Hyperuricemia is a major risk factor for gout. Serum urate concentrations are highly sex-specific and heritable. However,
SNPs discovered by genome-wide association studies can only explain up to 7% of the heritability and do not reveal clear
insight on the source of the sex-differences in serum urate levels and the prevalence of gout. In order to integrate both
the genetic and environmental influences, we conducted an epigenome-wide meta-analysis including around 7,600 individuals
from four cohorts. We identified ten methylation sites on nine independent loci being significantly associated with serum
urate levels. Two of these are located on the gene SLC2A9 which has been determined as the main genetic contributor to
differences of serum urate levels. Other significant CpG-sites are located on genes encoding for transporters of the solute
carrier family, SLC1A5 and SLC7A11 respectively. A sex-stratified meta-analysis on the same data suggests that the relation
of DNA methylation and urate levels is highly dependent on sex, thus helping to understand the reasons underlying the
sex-specificity of the disease.
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Tue(3)-P-249
Effect of butylated hydroxytoluene (BHT) on BDNF gene methylation, learning and memory in male
wistar rats
Parvaneh Keshavarz 1 ，Mahsan Maleki 1 ，Parvin Babaei 1 ，Alireza Sharafshah Rostami 1 ，Ali Albonaim 1 ，
Vahid Omarmeli 1
1:Cellular and Molecular Research center, Faculty of Medicine, Guilan University of Medical Science, Iran
Brain-derived neurotrophic factor (BDNF) is a small secreted protein that is a member of the neurotrophin family of growth
factors. It has been found that BDNF has important roles in the development of the nervous system and neuronal plasticity-
related processes such as memory and learning. A lot of studies have demonstrated that BHT can play as an epigenetic
factor in human and other species. The aim of current study is to investigate the way it can affect the methylation status
of BDNF gene, learning and memory. In current study, 21 male Wistar rats weighting 190-210 gr were used. Animals were
divided in to tree groups: 1-control group (received sesame oil with the same volume as experimental group), 2-experimental
group (received BHT 60 mg/kg/day), and 3-intact group (without injection). BHT was administrated by IP injection for
14 days. Learning and memory were assessed by passive avoidance shuttle-box. The percentage of BDNF gene methylation
were assessed by msPCR. Data were analyzed by one way anova, tucky ｀ s post-hoc test, fhisher ｀ exact test. The learning
ability and memory did not show statistically significant difference between three groups in first day(p=0.139). However,
they represented statistically significant difference between three groups in second day (p=0.0001). The frequency rate of
methylation did not statistically demonstrate significant difference between groups (intact vs BHT, control vs BHT and
control vs intact). We concluded that BHT can affect the learning ability and memory of male Wistar rats. However, it not
able to create methylation in the BDNF gene. For future studies, we recommend to investigate the methylation rate of all 12
Poster Session
CpG sites located in one CpG island of BDNF promoter region in Wistar rats underwent different dosage of BHT levels.
Tue(3)-P-250
Multilocus methylation defects in a patient presenting with both clinical phenotype of pseudohy-
poparathyroidism type Ib and Beckwith-Wiedemann syndrome
Shinichiro Sano 1 ，Keiko Matsubara 1 ，Keisuke Nagasaki 3 ，Akie Nakamura 1 ，Kazuhiro Nakabayashi 2 ，
Kenichiro Hata 2 ，Maki Fukami 1 ，Tsutomu Ogata 4 ，Masayo Kagami 1
1:Molecular Endocrinology, National Research Institute for Child Health and Development, Japan、2:Maternal-Fetal Biology, National
Research Institute for Child Health and Development, Tokyo、3:Division of Pediatrics, Department of Homeostatic Regulation and
Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata、4:Department of Pediatrics, Hamamatsu
University School of Medicine, Hamamatsu
Context: Pseudohypoparathyroidism type Ib (PHP-Ib) is rare endocrine disorder caused by loss of imprinting (LOI) at
maternally inherited GNAS differentially methylated regions (DMRs). Beckwith-Wiedemann syndrome (BWS) is also one of
the imprinting disorders (IDs) caused by epigenetic or genetic alterations of two imprinting control regions on chromosome
11p15. It has become apparent that a subset of ID patients carries multilocus methylation defects (MMD) not only at an ID-
specific locus but also at other imprinted DMRs. Objectives: To report a MMD patient presenting with both clinical phenotype
of PHP-Ib and BWS. Patient and methods: A female patient was born with overgrowth and presented clinical phenotype
of BWS, such as macroglossia, umbilical hernia, and hemihyperplasia. At 14 years of age, she was diagnosed as PHP-Ib
because of hypocalcemia, hyperphosphatemia and elevated serum PTH level without Albright’s hereditary osteodystrophy
features. Methylation patterns of PHP-Ib and BWS related loci were evaluated with pyrosequencing analysis and MS-
MLPA. Furthermore, a genome-wide methylation status was investigated using the Illumina Infinium HumanMethylation450
BeadChip array. Results: Loss of methylation (LOM) at Kv-DMR, A/B-DMR, XLas-DMR, AS-DMR and gain of methylation
(GOM) at NESP55 -DMR were identified by pyrosequencing and MS-MLPA. The genome-wide methylation analysis revealed
nine aberrant DMRs: LOM at DIRAS3 -DMR, FAM50B-DMR, PEG1/MEST -DMR, Kv-DMR, RB1 -DMR, A/B-DMR,
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XLas-DMR, AS-DMR and GOM at NESP55 -DMR. Conclusion: We presented a MMD patient with clinically diagnosed as
PHP-Ib and BWS carrying broad methylation defects at GNAS DMRs as well as LOM at Kv-DMR. The both impaired ID
related regions affected the patients’ clinical phenotypes.
Tue(3)-P-251
The Transcriptome and DNA Methylome Landscapes of Human Primordial Germ Cells
Fan Guo 1 ，Liying Yan 1 ，Hongshan Guo 1 ，Lin Li 1 ，Fuchou Tang 1 ，Jie Qiao 1
1:Biodynamic Optical Imaging Center and Department of Obstetrics and Gynecology, College of Life Sciences, Third Hospital, Peking
University, China
Germ cells are vital for transmitting genetic information from one generation to the next and for maintaining the continuation
of species. Here, we analyze the transcriptome of human primordial germ cells (PGCs) from the migrating stage to the gonadal
stage at single-cell and single-base resolutions. Human PGCs show unique transcription patterns involving the simultaneous
expression of both pluripotency genes and germline-specific genes, with a subset of them displaying developmental-stage-
specific features. Furthermore, we analyze the DNA methylome of human PGCs and find global demethylation of their
genomes. Approximately 10 to 11 weeks after gestation, the PGCs are nearly devoid of any DNA methylation, with only
7.8% and 6.0% of the median methylation levels in male and female PGCs, respectively. Our work paves the way toward
deciphering the complex epigenetic reprogramming of the germline with the aim of restoring totipotency in fertilized oocytes.
Poster Session
Tue(3)-P-252
Investigation of maternal effects, maternal-fetal interactions and parent-of-origin effects (imprinting),
using mothers and their offspring with schizophrenia
1
Byung Dae Lee
1:Pusan National University Hospital, Korea, South
Introduction: Many complex genetic effects, including epigenetic effects, may be expected to operate via mechanisms in
the inter-uterine environment. A popular design for the investigation of such effects, including effects of parent-of-origin
(imprinting), maternal genotype, and maternal-fetal genotype interactions, is to collect DNA from affected offspring and their
mothers (case/mother duos) and to compare with an appropriate control sample. We investigate the effects of estimation of
maternal, imprinting and interaction effects using multimodal modeling using parents and their offspring with schizophrenia
in Korean population.
Subjects and Methods: We have recruited 27 probands(with schizophrenia) with their parents and siblings whenever possible.
We analyzed 96 SNPs of 17 functionally only relevant genes and 21 neuronal genes relevant to schizophrenia for DNA samples
that was checked for the data quality and genotype error. We used EMIM analysis program for the estimation of maternal,
imprinting and interaction effects using multimodal modeling
Results: Of analyzed 96 SNPs functionally and positionally relevant to schizophrenia, very significant SNP ( rs 324420 )
was suggested in EMIM analysis for child genetics effects. ( p= 1.5 * 10-4 ) rs 324420 was also significant for child genetic
effects allowing for maternal genetic effects. ( p = 5.3 * 10-4 ) with very stringent multiple comparison Bonferroni correction.
Additionally, no significant SNP was presented in the analysis results for maternal genetic effects and maternal genetic effects
allowing for child genetic effects.
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Discussion: Epigenetics and gene-environment interactions are represented underlying statistical genetics. Our results are the
pilot study for epigenetic study in mental disorder and help to understanding and use of EMIM statistical genetics analysis
program with many limitations including small pedigree numbers
Tue(3)-P-253
Telomere Length and Epigenetics, TERRA Transcript Level and Telomerase Expression as Dynamic
Genetic Parameters in Poly Cystic Ovary Syndrome
Narges Ghobadi 1 ，Maryam Shahhoseini 1 ，Poopak EftekhariYazdi 2 ，Raha Favaedi 1 ，Fatemeh Hassani 2 ，
Bahar Movaghar 2 ，Leyli Karimian 2
Iran、2:Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR,
Tehran, Iran
There are conserved structures at the end of all eukaryotic chromosomes named telomere which composed of TTAGGG tandem
repeats. This structure protects the end of linear chromosomes against genome instability. Despite the heterochromatin entity
of telomere, some parts of this region are transcribed into a non coding RNA named TERRA. This RNA transcript is involved
in regulation of telomere length and structure, through modulation of telomerase expression and heterochromatin state which
is mostly characterized by epigenetic modifications. In this investigation, we focused on finding possible correlation between
telomere length, TERRA, telomerase expression and epigenetic modification with Poly Cystic Ovary Syndrome (PCOS)
appearance which is a common cause of annovulatory infertility among women in reproductive age.
Poster Session
For this respect, blood samples were collected from PCOS patients and healthy women with male factor infertility as a control
group. Telomere length, TERRA level and telomerase expression were measured by real time PCR and epigenetic alterations
were studied via chromatin immunopercipitation(ChIP) technique coupled with real time PCR.
In the current study we did not find a remarkedable difference in telomere length of samples between patients and control
group. However, the expression of TERRA and telomerase genes were increased in patients compared to control group. On
the other hand, epigenetic data showed increased level of H3K9me3 mark in PCOS patients vs. control group.
Based on our data, although there was no difference in telomere length between two groups, but significant increased level
of TERRA transcript implies a strong correlation between TERRA and PCOS appearance. Also, by considering the profile
of telomerase expression and epigenetic alteration outcome, we speculate an association among these parameters with PCOS
etiology.
Key words: Epigenetics, Telomere, TERRA, Telomerase, PCOS.
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Tue(3)-P-254
LRRC37A2 and SNORD42B methylation analysis in gastric cancer tissues using next-generation se-
quencing
Fernanda Wisnieski 1 ，Leonardo Caires Santos 1 ，Mariana Ferreira Leal 1 ，Jaqueline Geraldis Cruz 1 ，
Ana Carolina Anauate Pereira 1 ，Danielle Queiroz Calcagno 2 ，Carolina Oliveira Gigek 1 ，Elizabeth Suchi Chen 1 ，
Samia Demachki 2 ，Ricardo Artigiani 3 ，Paulo Pimentel Assumpção 2 ，Laércio Gomes Lourenço 4 ，
Rommel Rodríguez Burbano 5 ，Marília Cardoso Smith 1
1:Morphology and Genetics, UNIFESP, Brazil、2:Nucleu of Research in Oncology, UFPA、3:Department of Pathology, UNIFESP、
4:Department of Surgical Gastroenterology, UNIFESP、5:Human Cytogenetics Laboratory, UFPA
Despite the fact that overall rates of gastric cancer (GC) continue to decline worldwide, the majority of patients are still
diagnosed with advanced disease in Western countries. New strategies for early diagnosis and new therapeutic methods in
GC continue to be explored. Epigenetic control using inhibitors of DNA methylation, such as decitabine, may offer new
possibilities in GC therapy. Our research group previously identified 86 differentially expressed genes (DEGs) by microarray
analysis comparing decitabine-treated GC cells lines and untreated cells. Among the upregulated DEGs identified, LRRC37A2
and SNORD42B were selected for further analyzes. This study aimed to evaluate, compare and correlate the mRNA and
methylation levels of LRRC37A2 and SNORD42B in GC and adjacent non-tumor samples from 40 patients with primary
gastric adenocarcinoma. The mRNA and DNA methylation levels were assessed by qRT-PCR and by the Ion Torrent PGM
sequencer, respectively. A total of 8 and 24 CpG sites were evaluated in LRRC37A2 and SNORD42B promoter regions,
respectively. Reduced LRRC37A2 mRNA was detected in early staging GC compared with adjacent non-tumor samples
(p<0.01) and was associated with the absence of lymph node metastasis (p=0.02). Reduced percentage of LRRC37A2
methylation was observed in GC compared with adjacent non-tumor samples (p<0.01) and was associated with absence of
Poster Session
lymph node metastasis (p=0.02). In addition, reduced SNORD42B mRNA was detected in GC compared with adjacent
non-tumor samples (p<0.01). This gene did not show methylation in the evaluated samples. No significant correlations
between mRNA and methylations levels were detected. Our study demonstrated, for the first time, the applicability of the
Ion Torrent PGM sequencer for promoter DNA methylation analysis in GC tissues. Although different mechanisms may be
involved in the downregulation of LRRC37A2 and SNORD42B, LRRC37A2 methylation seems to play an important role in
gastric carcinogenesis.
Tue(3)-P-255
A fluorescence polarization-based method with methyl-sensitive one-label extension for quantification of
single CpG dinucleotide methylation
Cunyou Zhao 1 ，Shufen Li 1 ，Zhongju Wang 1 ，Lin Zhou 1 ，Fu Luo 1
1:Department of Medical Genetics, Southern Medical University, China
To rapid quantitation of methylation at individual CpG dinucleotide sites from a great quantity of biological or clinical
sample, we have developed a methyl-sensitive one-label extension (Ms-OLE) method, visualized by fluorescence polarization
(FP) based measurement of single CpG site methylation. Genomic DNA was treated with sodium bisulfite to convert
unmethylated cytosine to uracil while leaving 5-methylcytosine unaltered, followed by methyl-sensitive PCR to generate a
DNA template containing target CpG sites for methylation analysis using Ms-OLE. Ms-OLE is performed with a methyl-
sensitive primer hybridized immediately upstream of the target CpG site being examined, and then fluorescent dCTP or
dUTP will be incorporated into the methylated or unmethylated form of the target CpG site through single-nucleotide
chain extension, yielding an FP-ratio between the fluorescent dCTP- and dUTP-incorporated products as a measure of
methylation. Ms-OLE provided stable estimates of methylation level of human genomic DNA, and of a 250-bp plasmid
DNA segment containing a single TaqI restriction site (TCGA) in accord with determination by COBRA method. Ms-OLE
was also applied to measure dose-dependent DNA hypomethylation in human embryonic kidney 293T cells treated with the
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DNA-methyltransferase inhibitor 5-aza-dC.
Tue(3)-P-256
Comprehensive methylation microarray analysis for placental genomic DNA in abruption cases
Jun Konno 1 ，Akizawa Yoshika 1 ，Ogawa Masaki 1 ，Matsui Hideo 1
1:Obstetrics and Gynecology, Tokyo Women’s Medical University, Japan
Introduction Placental abruption has both genetic risk factor(familial, race, prior abruption) and environmental risk fac-
tor(age, smorking, cocaine). From these risk factors, epigenetic factor which acquired DNA modification influenced by age,
enviroment and lifestle may be associated with placental abruption. So, we undertake a systematic analysis of DNA methy-
lation patterns by microarray between placental abruption cases and controls matched for gestational ages.
Methods Five placental abruption cases and five controls who were matched for gestational ages were collected at the depart-
ment of Obstetrics and Gynecology, Tokyo Women’s Medical University, Japan. Genomic DNA were extracted from placental
villous which were obtained from placenta after cesarean section or vaginal delivery. Microarray analysis which evaluated the
comprehensive methylation status was conducted at TaKaRa Bio Inc in Japan. We defined statistically significant differences
in methylation level of each CpG sites when two criteria were satisfied, 1) difference of average methylation level between
cases and controls > 15%, 2) P value < 0.01. This study was approved by the institutional review boards in our institution.
Poster Session
Results Of 485,577 probes, 6,425 probes were removed from analysis because of vacant data in more than one sample, so
total 479,152 probes were analysed. 45 CpG sites showed statistically significant differences in methylation level. 8 CpG sites
were hypomethylated and 37 CpG sites were hypermethylated. Among 37 hypermethylated sites, three CpG site included in
promotor region of KLHL34 gene.
Conclusion Comprehensive methylation analysis showed that epigenetic factor might be associated with mechanism of on set
of placental abruption. Additional studies including the expression of gene were needed.
Tue(3)-P-257
Maternal undernutrition alters DNA methylation profiles in rat embryonic kidney
1
Mariko Hida
1:Neonatology, Yokohama Rosai Hospital, Japan
Maternal undernutrition leads to low nephron number. We found that ureteric bud branching, a crucial factor in determining
nephron number, is reduced by maternal undernutrition in rats. The reduced nephron number is transmitted to the second
generation. Furthermore, maternal undernutrition alters global methylation in the baboon kidney. We therefore investigated
the effect of maternal undernutrition on genome-wide DNA methylation in the rat embryonic kidney. The embryonic day
18 kidneys of dams given food ad libitum (CON) and those subjected to 50% food restriction throughout pregnancy (NR)
were examined. The DNA methylation landscape around promoter CpG islands was analyzed using methylated DNA im-
munopreciitation (MeDIP) coupled with microarray (NimbleGen Rat ChIP-chip 385K Promoter array) comparing methylated
fractions of CON and NR. MeDIP probe significances were generated using the Kolmogorov-Smirnov test as implemented by
NimbleScan. These values were transformed (−log10) to give peak scores, which reflect the probability of methylation at a
p-value of less than 0.01. Glomerular number was determined by acid maceration at 3 weeks. Glomerular number of NR
was significantly reduced by 20%. Of 15911 promoter regions included in the array, 7330 regions were hypomethylated and
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6310 regions were hypermethylated in NR compared with CON. In NR, nearest genes to methylated regions were categorized
as, in descending order of frequency, G-protein coupled receptor signaling pathway, detection of chemical stimulus involved
in sensory perception of smell, transcription, transport, apoptosis, development, and others. Most of these are critical for
ureteric branching. Maternal nutrient restricition changes DNA methylation of genes involved in ureteric branching, which
may contribute to reduced nephron number and transgenerational transmission.
Tue(3)-P-258
The epigenetic impact of a 6 month lifestyle intervention programme on women aged 18-40
Michelle C Thunders 1 ，Victoria Chinn 1 ，Rachel Page 1
1:College of Health, Massey University, New Zealand
Many strategies employed to improve health through diet and exercise are relatively unsuccessful. A possible reason for this
is a ‘one size fits all’ approach does not consider the individual’s need or the expectation to committing to a long term
lifestyle change to achieve and maintain healthy body shape goals. The aim of this project is to explore the molecular impact
of a 6 month diet and exercise intervention program designed to optimise and maintain health and healthy body shape in
women aged 18-40. Variation in health is determined by our inherited non-changeable genome as well as our modifiable
environmental and lifestyle factors.This helps us to understand how our environment in the broad sense, including exercise,
nutrition, toxins and even behaviour, contribute to the regulation of gene expression and hence to our resulting health
phenotype. In this pilot study epigenetic analysis is carried out by exploring changes in gene methylation status. Methylation
Poster Session
status in peripheral blood is compared pre and post intervention using reduced representation bisulfite sequencing (RRBS) and
Differential Methylation Analysis Package (DMAP) for comparative high resolution DNA methylation analysis.This allows
an overall picture of genomic methylation and how lifestyle intervention affects gene regulation. Initial data is reported on
the first 20 women through the study, findings on the short-term impact of lifestyle changes on epigenetic control mechanisms
will be discussed. This study is at the cutting edge of gene-environment interaction and has the potential for being successful
where other strategies have failed. The goal is to empower women to be proactive in achieving healthy body goals through
understanding how lifestyle impacts on the molecular functioning of the body so they can make sustainable lifelong decisions
concerning their health.
Tue(3)-P-259
Skewed pattern of X chromosome inactivation in Brazilian women without familial history of X-linked
intellectual disability
1,2
Silviene F de Oliveira ，Diana LM Brandao 2 ，Aline PicTaylor 1,2
，Juliana F Mazzeu 3
1:Genetica e Morfologia, Universidade de Brasilia, Brazil、2:Programa de Pos-graduacao em Biologia Animal, Universidade de Brasilia、
3:Area de Clinica Medica, Faculdade de Medicina, Universidade de Brasilia
Mammal X chromosome inactivation is a female biological phenomenon which has as consequence the balancing male and
female X chromosome genetic material. A skewed pattern of X chromosome inactivation, i.e., when the genomic occurs in
at least in 95% of the body cells, can represent structural variation or pathogenic mutations in the silenced chromosome X.
Pathogenic mutations in certain genes and genomic regions located in the X chromosome can be associated to intellectual
disabilities, which are more frequently found in men than women. Here we aim to establish the incidence of skewed X
chromosome inactivation in a sample of Brazilian women (n = 102) with no reported family background of X-linked mental
impairment. The inclusion criteria eligibility was: a) woman above 35 years old, b) at least one biological male child with
normal mental health; c) no family record of X-linked mental impairment. Aiming to access proportion of each parental
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X-chromosome inactivation, we analyzed a STR located in the AR gene, one of the X methylated genes. We observed skewed
X-inactivation in four women (3%), considering full skewed inactivation as ≥95:5 or ≥5:95, and 26 women (25.5% of the
sample) considering full and partially skewed inactivation (≥80:20 or ≥20:80). These are the highest values ever described
for a population. Karyotype analysis and Cytoscan Affymetrix microarray showed no structural variation in the four full
skewed X chromosome. On the other side, three of the four women had family background of cancer. While this sample
showed that 46% of these women have cancer history in at least one family member, this number is higher among the skewed
X chromosome inactivation women - 65%. Further studies are necessary, specially comparing the X chromosome inactivation
pattern in mothers of intellectual deficient males and people with cancer.
Acknowledgment: CNPq and FAPDF.
Tue(3)-P-260
Functional analysis of Xist long noncoding RNA using mouse artificial chromosome (MAC)
Daigo Inaoka 1 ，Naohiro Sunamura 1 ，Miki Kataoka 1 ，Yuji Nakayama 2 ，Mitsuo Oshimura 3 ，Hiroyuki Kugoh 1,3
1:Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori Uni-
versity, Japan、2:Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Japan、3:Chromosome
Engineering Research Center, Tottori University, Japan
The non-coding RNA (ncRNA) genes, which did not encode proteins, produce functional RNA molecules that play an
important role of gene regulation, including X chromosome inactivation (XCI) and RNA interference (RNAi). Xist long
Poster Session
noncoding RNA, which is specifically expressed from X inactivation center (XIC) in the inactive X chromosome, plays an
essential role in XCI. Xist RNA coats and sequentially spreads along the X chromosome, and eventually establishes XCI by
induction of heterochromatin formation. However, it was incompletely defined how Xist RNA actually affects on XCI.
We have developed mouse artificial chromosome (MAC) as an ideal gene delivery vector, including stable episomal maintenance
and the capacity to carry large genomic loci with their regulatory elements, thus allowing the physiological regulation of the
introduced gene in a manner similar to that of native chromosomes. In addition, MI-MAC, which multiple acceptor sites were
introduced into the MAC, enables to introduce various large genes or genomic loci.
To investigate functional Xist long noncoding RNA, we established NIH/3T3 and HeLa cells containing mouse MAC that
express Xist RNA by a doxycycline (Dox). As a result, Xist RNA territories were observed on MAC by Dox-dependent Xist
expression. However, genes that contain selectable marker located on MAC were expressed despite on cis-accumulation of
Xist RNA on MAC. These results suggest that the establishment of XCI by Xist RNA may play an important role in a
specific chromatin region as elements for cis-silencing on chromosome.
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Poster Session
Health Services Research
Tue(3)-P-261
Breast cancer, genetics or bad karma: Meanings and experiences of Thai women living with breast
cancer in southern Thailand
Pranee Liamputtong 1 ，Dusanee Suwankhong 2
1:Public Health, La Trobe University, Australia、2:Public Health, Thaksin University
In this paper, we discuss the lived experiences and meaning making of breast cancer among women in southern Thailand.
We conducted in-depth interviews with 20 women living with breast cance and invited them to take part in a drawing
method. Our data revealed that the diagnosis of breast cancer generated numerous emotional responses. Most women did
not associate their breast cancer with genetics but believed that their own bad karma was the cause of breast cancer. This
was even apparent among women with a history of cancer in the family. After the intitial shock, most women started to
accepte their reality. The acceptance of their breast cancer played an essential role in the meaning making discourse because
it assisted the women to be able to sustain the equilibrium of their emotional wellbeing. Meaning making and the Buddhist
belief about bad karma was a prominent theme. The belief that adversities in life were the result of bad deeds that one had
Poster Session
committed to others in the past not only helped the women to accept their fate but also to deal with their life situations
better. Our findings suggest that these women act in their own agencies to counteract any negativiity they might encounter
from their breast cancer trajectory. Our findings provide a theoretical understanding about the ways Thai women deal with
their breast cancer which can be adopted as a means to provide culturally sensitive care for women with breast cancer in
Thailand and elsewhere. The findings can also be used for the provision of education about genetics and breast cancer to
women who live with the illness in Thailand and elsewhere.
Tue(3)-P-262
Breast Cancer and Genetical Belief: Barriers to Screening Programmes amongst Thai Migrant Women
in Australia
Dusanee Suwankhong 1 ，Pranee Liamputtong 2
1:Public Health, Thaksin University, Thailand、2:Department of Public Health, School of Psychology & Public Health, College of Science,
Health & Engineering La Trobe University, Bundoora, Victoria, Australia
Breast cancer is a feared disease among women worldwide. Breast cancer screening is seen as the best practice to detect
breast cancer. However, there are circumstances that prevent immigrant women from attending screening programmes. Little
is known about Thai migrants and the barriers to their seeking breast cancer screening in Melbourne, Australia. This paper
discusses the barriers to their attending screening services. Basing on the Health Belief Model, the women did not perceive
that they were at risk of breast cancer. They did not believe that genetics played an important part in breast cancer risk.
This belief was strong even among women with a history of cancer in their family. Additionally, despite seeing breast cancer
screening as important, Thai migrant women rarely paid attention to breast cancer screening and used the mammography
services provided by the Australian health care system. The barriers included the non-belief in genetical risk, location of the
services, unfamiliar patterns of health care provision and language difficulties. The findings has implications for the provision
of health education about genetics and breast cancer risk for Thai migrant women as well as the design of health services to
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be more sensitive to the socio-cultural contexts of Thai migrant women in particular and other migrant women in general.
Tue(3)-P-263
The relationship between the social competence of children and adults with Down’s syndrome and
caregivers’ burden
Kanako Morifuji 1 ，Hideyuki Nakane 2 ，Tatsuro Kondoh 3 ，Akira Imamura 4
1:Department of Nursing, Nagasaki University Graduate School of Biomedical Sciences, Japan、2:Department of Psychiatric Rehabilitation
Sciences, Unit of Rehabilitation Sciences, Nagasaki University Graduate School of Biomedical Sciences、3:Division of Developmental Dis-
ability, the Misakaenosono Mutsumi Developmental, Medical and Welfare Center, Nagasaki, Japan、4:Department of Neuropsychiatry, Unit
of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences
Aim To clarify the factors that affect the social competence of the persons with Down’s syndrome, as well as the burden
placed on caregivers and their mental health.
Method Self-completion surveys were sent by mail to patients and family members, comprising 226 individuals. The contents
of the survey for children and adults with Down’s syndrome included Denver Developmental Screening Test, Japanese Autism
Screening Questionnaire, and for their caregivers, GHQ-12, Zarit Caregiver Burden Interview, and WHOQOL. A statistical
analyses were performed by using SPSS Ver.18.
Results Data from 100 at-home patients were selected for our analysis. The average age of the patients was 20.4 years old,
while the average age of the caregivers was 54.7 years old. Regarding sex of the patients, 57.0% were male. 95.7% of the
Poster Session
respondents were mothers.
The risk of“Regression of Social and Communication Skills” was significantly more prevalent among older participants and
females, and the average ASQ score was significantly higher for those at risk than not (p = 0.034). There were significant
differences in the frequency of caregivers’ responses to items on the GHQ-12: intellectual degree of the patients (p = 0.049),
degree of independence with excretion (p = 0.001), and economic conditions (p = 0.019).
There was a significant correlation between the Caregiving Burden and WHOQOL scores (r = -0.309, p = 0.004), and with
the ASQ scores (r = 0.358, p = 0.001).
Conclusions We found that the factors that increase the burden of caregivers are influenced by their inability to anticipate the
reactions of patients with Down’s syndrome, and by the particular obstinacy characteristic of Down’s syndrome. Reduced
physical ability and economic circumstances were indicated as causes of caregivers’ burden. As a country that promotes the
participation of handicapped people in community life, it is important for Japan to respond sensitively to these issues.
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Tue(3)-P-264
CD44, ALDHI, E-cadherin and Snail gene protein analysis in ameloblastoma
Chong Huat Siar 1 ，Zainal Ariff Bin Abdul Rahman 1 ，Nurharnani Binti Harun 2 ，Hidetsugu Tsujigiwa 3 ，
Hitoshi Nagatsuka 4 ，Kok Han Ng 5
1:Oro-Maxillofacial Surgical and Medical Sciences, University of Malaya, Malaysia、2:Department of Oral & Maxillofacial Diagnostics &
Medcine, MARA Universitiy of Technology、3:Department of Life Sciences, Okayama University of Science、4:Department of Oral Pathology
and Medicine, Okayama University、5:Unit of Stomatology, Insitute for Medical Research
Background: Ameloblastoma, the most common and clinically significant odontogenic epithelial neoplasm of the jawbones,
remains challenging to treat because of its locally-invasive behavior and high recurrence rate. Limited research into the
regulatory genes underlying this biological aggressiveness prevented the development of adjunctive treatment modalities to
mitigate tumour growth.
Method: Study sample consisted of 87 ameloblastoma of different subtypes. These were subjected to immunohistochemistry for
cancer stem cell (CD44 and ALDHI), and epithelial-to-mesenchymal transition (E-cadherin and Snail) gene protein markers.
Results: Colocalization of CSC and EMT gene proteins was significantly higher along the tumor-host interface compared to
tumor centre for all ameloblastoma subsets (P<.05 ). Solid/multicystic ameloblastoma tends to show higher expression levels
compared to the unicystic variant (P<.05 )
Conclusions: Findings suggest that growth signals mediated by CD44, ALDHI, E-cadherin and Snail contribute to the
differential growth characteristics of ameloblastoma subtypes. However given the limitation of immunohistochemistry, the
human genetic aspects of these regulatory molecules need to be further explored.
Poster Session
Tue(3)-P-265
Community Genetics in Cuba
1
Beatriz Marcheco-Teruel
The application of knowledge gained from the characterization of the human genome holds considerable potential for the
development of new health care innovations over the next years, but we still have a challenge and it will be how to achieve
access to these benefits for most of the population. In the last 35 years the Cuban health system has implemented a national
program for diagnosis, management and prevention of genetic diseases based in a nationwide network with 17 centres, 38
laboratories and 621 services of medical genetics and genetic counseling all over the country. 1 200 researchers, physicians and
technicians including genetic counselors and clinical geneticists, are working in the national network, from the primary care
attention level to the tertiary level. The National Centre of Medical Genetics, placed at the Medical University of Havana,
coordinates the entire network. It is the national reference centre for diagnosis of genetic diseases focused on developing
genetics approach for health promotion. Several national genetic registers for clinical and research purposes are conducted
by the centre, such as: the Cuban registry for congenital malformations (more than 3 million births indexed in 30 years, the
twins registry (59 400 twin pairs), and the familial registry for complex disorders with more than 75 000 families and 170
000 affected members (diabetes, hypertension, cancer, depression, schizophrenia, bipolar disorder, dementia, asthma, alcohol
addiction, etc.). The center also runs several training programs to guarantee human resources for medical genetic services,
genetic education of health professionals and the entire population as well as for developing local researches. At the beginning
of this program, the Cuban infant mortality rate due to birth defects was 3.8 per 1000 live births and it has decreased until
0.9 per 1000 in 2014. As far as we know, there is no other developing country with a similar strategy.
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Tue(3)-P-266
Using Quality Improvement Methods and Time-Driven Activity Based Costing to Improve Value-Based
Cancer Care Delivery at a Cancer Genetics Clinic
Ryan Tan 1 ，Marie Met-Domestici 1 ，Ke Zhou 2 ，Alexis B Guzman 3 ，Soon Thye Lim 2 ，Khee Chee Soo 2 ，
Thomas W Feeley 3,4 ，Joanne Ngeow 1,2
1:Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, Singapore、2:Oncology Academic Clinical
Program, Duke-NUS Graduate Medical School, Singapore、3:Institute for Cancer Center Innovation, The University of Texas MD Anderson
Cancer Center, Houston, Texas、4:Institute for Strategy and Competitiveness, Harvard Business School, Boston, Massachusetts
Purpose:
To meet increasing demand for cancer genetic testing and improve value-based cancer care delivery, National Cancer Centre
Singapore restructured the Cancer Genetics Service in 2014. Care delivery processes were redesigned to improve access by
increasing the Cancer Genetics Service’s clinic capacity by 100% within a year without increasing direct personnel costs.
Methods:
Process mapping and Plan-Do-Study-Act (PDSA) cycles were used in a Quality Improvement (QI) project for the Cancer
Genetics Service clinic. The impact of interventions was evaluated by tracking the weekly number of patient consultations and
access times for appointments from April 2014 to May 2015. The cost impact of implemented process changes was calculated
Poster Session
via the Time-Driven Activity Based Costing (TDABC) method.
Results:
Our study completed 2 PDSA cycles. An important outcome was achieved after the first cycle: the inclusion of a genetic
counsellor increased clinic capacity by 350%. The number of patients seen per week increased from 2 in April 2014 (range 0-4)
to 7 in November 2014 (range 4-10). Our second PDSA cycle showed that manual pre-appointment call reminders reduced the
variation in the non-attendance rate and contributed to a further increase in patients seen per week to 10 in May 2015 (range
7-13). The access times to first clinic appointment remained at a median of 26 days (range 7-49). There was a concomitant
decrease in costs of the patient care cycle by 18% after both PDSA cycles.
Conclusion:
This study shows how QI methods can be combined with TDABC to demonstrate improved value. In this example, we
improved access while reducing care delivery costs.
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Tue(3)-P-267
Cost is a barrier to accept germline mutation testing for known cancer syndrome in Japan
Koji Matsumoto 1 ，Saki Hinoshita 2
1:Department of Medical Oncology, Hyogo Cancer Center, Japan、2:Division of Nursing, Hyogo Cancer Center
Background; Germline mutation testing (GMT) for known cancer syndrome can improve client ｀ s length and quality of life
by appropriate interventions. Although cost effectiveness of GMT is already proven, Japanese medical insurance system does
not yet cover GMT. The effect size of this lack of coverage among Japanese clients is not known.
Method: Retrospective survey for records of genetic counseling clinic in Hyogo Cancer Center has been done. Acceptance of
GMT, and cost of test was studied. Cost of test was free for patients enrolled into clinical trials. Otherwise, clients had to
pay about 30,000 JPY (for siblings of founders), 80,000 JPY (for TP53), 100,000 (for MLH1/MSH2), and 200,000 JPY (for
BRCA 1/2) by their own.
Result: From Feb. 2011 to Oct. 2015, 66 clients came to genetic counseling clinic. Among them, 37 clients accepted GMT.
For clients free of charge for GMT (n = 22), all of them accepted GMT (100 %). For clients with charge for GMT (n = 44),
15 clients (34 %) accepted GMT.
Discussion: Cost is a significant barrier for clients to accept GMT for known cancer syndrome in Japan, although the effect of
other confounding factors had to be taken into account. If Japanese medical insurance system cover GMT for known cancer
Poster Session
syndrome, annual testing and positive results may increase three times more.
Tue(3)-P-268
Fulfilling the promise of personalised medicine - prioritising our investment
1,2,4 2,3 2,5,6 2,6
Deborah J Schofield ，Brett Doble ，Tony Roscioli ，John S Mattick
1:The University of Sydney, Australia、2:Garvan Institute of Medical Research、3:Centre for Health Economics, Monash Business School,
Monash University、4:Murdoch Childrens Research Institute, Royal Children’s Hospital、5:Department of Medical Genetics, Sydney Children’s
Hospital、6:St. Vincent’s Clinical School, UNSW Australia
Numerous first world countries are beginning to make substantial investments in next generation sequencing (NGS) and
genomic medicine with a view to delivering improved health outcomes to its citizens. But with so many promising applications
of genomics, potentially very large costs and many countries struggling under the weight of sovereign debt, it is crucial that
we make prudent early investments that are both effective and deliver value for money to fulfil the promise of personalised
medicine.
We examine evidence for a framework for investment in improving population health using (NGS) and genomic medicine.
We analysis data on genetic testing and its effects in terms of incidence reduction of a range of conditions, and based on this
evidence, provide guidance on where the greatest benefits from genomic medicine might be initially be achieved. We conclude
that the individuals who are uniquely placed to gain immediate benefit from personalised genomic medicine are those who
can be identified as being at high risk of imminent, serious, preventable, penetrant, and costly disorders.
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Tue(3)-P-269
The social and economic impacts of childhood syndromes of suspected genetic origin
1,2,3
Deborah J Schofield ，Khurshid Alam 2 ，Susan M White 2,4
，Clara Gaff 4,5
1:The University of Sydney, Australia、2:Murdoch Children’s Research Institute, Royal Children’s Hospital、3:Garvan Institute of Medical
Research、4:University of Melbourne、5:Melbourne Genomics Health Alliance
As part of a prospective study on the“Integration of genomic sequencing into clinical care”at the Royal Children’s Hospital,
Melbourne Australia, we undertook a detailed survey of the social and economic impacts of childhood syndromes of suspected
monogenetic origin. In this study, infants aged 0 to 2 years undertook diagnostic testing using whole exome sequencing
in parallel with standard diagnostic care. In this paper, we report on the first wave of our survey including quality of life
impacts for the child, and for the primary carer, the impacts on family planning, the parental marital relationship and social
connectedness. We also report on maternal plans to return to the workforce following the birth of their child and the current
labour force participation and income for both the mother and father.
Tue(3)-P-270
Cost effectiveness of whole exome sequencing compared with standard diagnostic care
Zornitza Stark 1 ，Deborah Schofield 1,2,3 ，Khurshid Alam 1 ，William Wilson 4 ，Nessie Mupfeki 1,6 ，Ivan Macciocca 1 ，
Rupendra Shrestha 2 ，Susan M White 1,5 ，Clara Gaff 1,5,6 ，Melbourne Genomcis Health Alliance
1:Murdoch Childrens Research Institute, Australia、2:University of Sydney, Australia、3:Garvan Institute of Medical Research, Sydney,
Australia、4:CSIRO, Australia、5:University of Melbourne, Australia、6:Melbourne Genomics Health Alliance, Australia
Poster Session
Background: To determine the optimal timing of whole exome sequencing (WES) as a diagnostic tool by (1) prospectively
evaluating the cost-effectiveness of singleton WES in comparison to standard diagnostic care in infants with suspected mono-
genic disease, and (2) examining the impact of integrating singleton WES at various points in the diagnostic trajectory.
Methods: We collected cost data for a cohort of 40 infants with suspected monogenic disorders who had undergone singleton
WES as a first-tier sequencing test in parallel with standard investigations. Comparisons were made using counterfactual
diagnostic pathway models to determine the impact of integrating WES at different points in the diagnostic trajectory, for
example after all other investigations are exhausted (’last resort’) or replacing some or most other investigations (’first-tier’).
Results: The mean duration of the diagnostic trajectory was 13 months. A molecular diagnosis was achieved in 7 out of 40
infants (17.5%) through standard diagnostic care, with an average cost per patient of AU ＄ 4,734. By contrast, a molecular
diagnosis was achieved in 25 out of 40 infants (62.5%) using singleton WES at a cost of AU ＄ 3,154.79 per patient. Integrat-
ing singleton WES after exhaustive standard investigation results in an incremental cost per additional diagnosis of AU ＄
8,111.82, whereas integrating WES as a first-line test results in an incremental cost savings per additional diagnosis of AU ＄
2,182.
Conclusions: This is the first study to evaluate the cost-effectiveness of WES in the clinical setting. We demonstrate that
when used as a first-tier test in infants with a suspected monogenic disorder, singleton WES not only outperforms standard
diagnostic care in terms of diagnostic utility, but is also cost-effective, with more diagnoses reached and the potential to
decrease per patient diagnostic expenditure below current levels.
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Tue(3)-P-271
How do people feel on knowing their disease risks by genetic testing? -Attitudinal Study for 4,000
Japanese Respondents: Behavior Change after knowing their disease Risks and Impact of Communication
Ways of Disease Risk-
Takashi Kido 1 ，Minae Kawashima 2
1:Rikengenesis, Japan、2:Tokyo University
Personal Genome Services, predicting personal disease risk, has been a growing interest in Japan. While some studies have
been done on informatics analyses for predicting disease risks, there are little studies on interpretation of the personal genetic
test results in social psychological context.
We have been conducted more than 4,000 scales of web surveys on psychological attitudes on personal genome services over
past four years. We report some new findings on people’s attitudes on knowing genetic risks by PGS.
First, we investigated how people change their behaviors after knowing their disease risks for ten diseases. We found that
behavior change patters depend on the diseases. For example,“Getting the information on the diseases” is the most popular
action for 7 diseases including Alzheimer’s disease, Stomach cancer and Pancreatic Cancer. “Pay more attention to nutritional
balance” is the most popular action for Type 2 Diabetes and Obesity, and “Go to the hospital” is the most popular action
for Colorectal cancer.
Second, we investigated the effect of ways of communicating on risk information and compared the four different ways to let
Poster Session
people know the disease risk for ten actions and ten diseases. We found that communicating ways are significantly influence
the“ Go to the hospital” action (p-value = 5.87 E-09) and “Do nothing special” action (p-value = 0.037). “Go to the
hospital” action increases from 12.2 % to 18.5 % by changing the statements.
We discuss the reasons of the survey results and potential applications of these results on PGS.
Tue(3)-P-272
A prospective evaluation of whole exome sequencing as a first-tier molecular test in infants with suspected
monogenic disorders
Susan M White 1,2 ，Zornitza Stark 1 ，Tiong Y Tan 1,2 ，Belinda Chong 1 ，Gemma Brett 1,5 ，Patrick Yap 1 ，Maie Walsh 1 ，
Alison Yeung 1 ，Shannon Cowie 1 ，George McGillivray 1 ，Heidi Peters 1,2,4 ，Paul G Ekert 1,2 ，Christiane Theda 1,2,3 ，
Ivan Macciocca 1 ，Katrina Bell 1 ，Alicia Oshlack 1,2 ，Simon Sadedin 2 ，Peter Georgeson 2 ，Charlotte Anderson 2 ，
Natalie Thorne 1,2,5 ，Clara Gaff 2,5 ，Melbourne Genomics Health Alliance
1:Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia、2:University of Melbourne, Melbourne, Australia、
3:Royal Womens Hospital, Melbourne, Australia、4:Royal Childrens Hospital, Melbourne, Australia、5:Melbourne Genomics Health Alliance,
Melbourne, Australia
ABSTRACT
Purpose
To prospectively evaluate the diagnostic and clinical utility of singleton whole exome sequencing (WES) as a first-tier test in
infants with suspected monogenic disease.
Methods
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Singleton WES was performed as a first-tier sequencing test in infants recruited from a single pediatric tertiary center.
This occurred in parallel with standard investigations, including single-gene or multi-gene panel sequencing where clinically
indicated. The diagnosis rate, clinical utility and impact on management of singleton WES were evaluated.
Results
Of 80 enrolled infants, 47 received a molecular genetic diagnosis through singleton WES (58.8%) compared with eleven
(13.75%) using standard investigations in the same patient group. Clinical management changed following exome diagnosis
in 15 out of 47 diagnosed participants (32%). Twelve relatives received a genetic diagnosis following cascade testing, and 28
couples were identified as being at high risk of recurrence in future pregnancies.
Conclusions
This prospective study provides strong evidence for increased diagnostic and clinical utility of singleton WES as a first-tier
sequencing test in infants with a suspected monogenic disorder. Singleton WES outperformed standard care in terms of
diagnosis rate and the benefits of a diagnosis, namely impact on management of the child and clarification of reproductive
risks for the extended family in a timely manner.
Poster Session
Tue(3)-P-273
Resolving barriers to the use of genomic sequencing in clinical practice: evaluation of a whole-of-system
approach
Clara L. Gaff 1 ，Melissa R. Martyn 1,2 ，Emily K. Forbes 1 ，William J. Wilson 3 ，Louise A. Keogh 4 ，
Sylvia A. Metcalfe 2,4 ，Ivan Macciocca 1,5 ，Emma Creed 1,6 ，Gemma Brett 1,5 ，Ella Wilkins 1,6 ，Nessie Mupfeki 1 ，
The Melbourne Genomics Health Alliance
1:Melbourne Genomics Health Alliance, Australia、2:Murdoch Childrens Research Institute, Victoria, Australia、3:Commonwealth Scientific
and Industrial Research Organisation (CSIRO), NSW, Australia、4:University of Melbourne, Vic, Australia、5:Victorian Clinical Genetics
Services, Vic, Australia、6:Melbourne Health, Vic, Australia
Numerous and diverse barriers to the use of genomic medicine have been identified previously (Manolio et al 2015, 2013).
The Melbourne Genomics Health Alliance is taking a patient- and clinician-driven approach to overcoming barriers across
the health system as it implements genomics into practice. The Alliance comprises ten independent organisations, including
five tertiary hospitals spanning specialist practice across the lifecycle.
A demonstration project was undertaken to simultaneously identify barriers and enablers of the use of genomic sequencing
at the point of care and to foster change in clinical practice. The project entailed more than 30 clinicians from eight disci-
plines prospectively providing whole exome sequencing (WES) with targeted gene analysis to consenting patients (n = 315)
suspected of having one of five germline or somatic conditions. Testing was in parallel to standard investigations.
A process evaluation of the demonstration project has been conducted with data collected from multiple sources, including
patient surveys and interviews with 18 geneticists and 16 other specialty clinicians participating in the project.
Participant surveys (n > 160, 60% return rate) suggest participants understood the implications of WES and were appropri-
ately counselled prior to testing. Few had concerns about testing.
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ICHG2016 1116
Clinicians emphasised the value of a ‘learning by doing’ approach and multidisciplinary team work. They shared their
experiences of the processes involved, including patient selection, informed consent and return of results. They suggested
models for effective service delivery and efficient use of the workforce in clinical genetics and mainstream practice.
The results of this evaluation are the basis of state-wide implementation of genomic medicine and the development of robust
systems acceptable to stakeholders and appropriate for use in healthcare.
Tue(3)-P-274
Initiatives on Rare and Undiagnosed Diseases (IRUD) for adults: a national network deciphering rare
and undiagnosed diseases
Hidehiro Mizusawa 1 ，Yuji Takahashi 1 ，Kenjiro Kosaki 2 ，IRUD consortium
1:National Center Hospital, National Center of Neurology and Psychiatry, Japan、2:Center for Medical Genetics, Keio University School of
Medicine
[Introduction]
Recent advances of molecular genetics have revolutionalized molecular diagnosis and gene identification of rare disorders.
However, many rare diseases have yet remained undiagnosed and identification of causative genes is often difficult owing to
the rarity of multiple pedigrees. National projects such as Undiagnosed Disease Program (UDP) in USA have been launched
to address this issue. International collaborative networks are organized to expanding these pioneering projects, including
Poster Session
Initiatives on Rare and Undiagnosed Diseases (IRUD) project in pediatrics in Japan.
[Objects] To expand IRUD project to adult diseases.
[Subjects and Methods]
Enrollment criteria, the scheme for IRUD organization and IRUD diagnostic matrix facilitating patient access and encom-
passing all-round specialty are designed.
[Results]
The enrollment criteria are as follows: A) exclusion of diseases obviously caused by environmental factors or acquired con-
ditions and B) undiagnosed diseases lasting for more than 6 months and substantially impairing daily activities which fulfill
the following 1) or 2): 1) two or more organs are affected, representing objective findings which are not explained by single
organ dysfunction, 2) genetic causes are postulated in the diseases including positive familial history. The scheme for IRUD
organization include approximately 10 center hospitals with IRUD diagnostic committees which cover the whole areas of
Japan. IRUD speciality subcommittees deal with all the fields of subspecialties such as Neurology, orthopedics and Dentistry.
The 2 types committees form the IRUD matrix covering all the geographical and medical areas. The IRUD Stiring Committee
and the office run the IRUD organization including the Central Analysis Consortium and IRUD Data Center.
[Discussion and Conclusion]
IRUD is a nation-wide network to enhance the diagnostic accuracy and promote the genetic research of rare diseases leading
finally to overcome these diseases.
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ICHG2016 1117
Tue(3)-P-275
Family history taking in pediatrics: it’s much more than just a checklist
June C Carroll 1 ，Laure Tessier 2,3 ，Jamie C Brehaut 2 ，Beth K Potter 2 ，Pranesh Chakraborty 3 ，Brenda J Wilson 2 ，
CIHR Emerging Team in Genomics in Screening
1:Family and Community Medicine, Mount Sinai Hospital, University of Toronto, Canada、2:University of Ottawa、3:Childrens Hospital of
Eastern Ontario
Background: Family history (FH) is a risk factor for many conditions in pediatric practice. There is interest in supporting
systematic FH taking by identifying core conditions for enquiry and developing point of care tools. There is little published
about current practice to inform such changes.
Objective: To explore pediatricians’ attitudes, beliefs, and practices regarding FH taking in order to inform future interven-
tions
Methods: The Theoretical Domains Framework (TDF) was used to develop a comprehensive interview scheme. Semi-
structured interviews were conducted with pediatricians in Ottawa, Canada (n=11). Interviews were recorded and tran-
scribed. Analysis used the constant comparison method, with a thematic approach.
Findings: FH was found to be a firmly embedded, complex, important aspect of pediatric practice and part of regular holistic
care. FH and social history were linked and often appeared to be part of the same concept to participants. FH was reported
as used for a range of purposes. In addition to risk assessment, FH information helped clarify diagnosis and select medication,
Poster Session
tailor overall patient management based on family circumstance and provide psychosocial support for parents. Participants
expressed confidence in their FH skills and reported tailoring their approach with experience. Most were not concerned about
formal evidence for FH and would not change their practice except for“good reason”.
Conclusion: The use of the TDF helped ensure a comprehensive approach to FH taking in pediatric practice. The findings
suggest that FH taking in this setting is a complex activity, embedded in routine care. Recommendations for systematic FH
inquiry about specific conditions cannot be seen as a simple addition to current practice. Efforts to make FH taking more
systematic may founder if they fail to take into account pediatricians’ attitudes, perspectives, and practices. Further studies
are needed to confirm our observations.
Tue(3)-P-276
APPROACH TO PATIENTS WITH GENETIC DISEASES IN EMERGENCY SERVİCE
1,2
Tarik Ocak ，Arif Duran 1 ，Zeynep Ocak 3
1:Emergency Medicine, Kanuni Sultan Suleyman Research and Training Hospital, Turkey、2:Abant Izzet Baysal University Department of
Emergency Medicine、3:Kanuni Sultan Suleyman Research and Training Hospital, Department of Medical Genetics
Purpose: It is known that general prevalence of genetic disorders is %60 in society. Physicians generally don’t remember
too much about genetic diseases although they are taught as detailed during medicine education. It was aimed to investigate
Q00-Q99 diagnosis codes identified by specialist doctors while using ICD-10 as an international coding system.
Methods: Patients who applied to Abant İzzet Baysal University Hospital between 01/11/2014 and 01/11/2015 were included
to study. Electronic recordings of patients were analyzed retrospectively.
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Results: According to ICD-10 international coding system, 1630 patients with Q00-Q99 codes and 40 different diagnosis
codes were determined while analyzing patients who applied to Abant İzzet Baysal University Hospital between 01/11/2014-
01/11/2015. Age range of patients was 6,3184±11,71(min: 0 max: 91 median: 2) and 1474 patients were 17 years old or
younger. Most seen diagnoses regarding patients are stated respectively: Q65- Congenital Hip Deformity (653 patients; %40,1),
Q53-Undescended Testis (436 patients; %26,7), Q54-Hypospadias (141patients, %8,7), Q02-Microcephali (105 patients; %6,4),
Q07.0 Arnold-Chiari Syndrome (40 patients; %2.5), Q05-Spina Bifida (39 patients;%2.4), Q90-Down Syndrome (37 pa-
tients ; %2.3 ), Q35-Cleft Palate (24 patients,%1.5), Q66- Congenital Foot Deformity (22 patients;%1.3), Q36-Cleft Lip( 18
patients; %1.1). Most diagnosed disease for 0-1 age group is Q65-Congenital Hip Deformity (533 patients; %66),most di-
agnosed disease for 1-17 age group is Q53-Undescended Testis (309 patients; %47,8) and the one for 17-91 age group is
Q65-Congenital Hip Deformity (49 patients; %27,8).
Conclusion: In outpatient clinics, recognizability for patients with genetic diseases is unfortunately low. These patients usu-
ally expect for special attention. Education about genetic disorders should be considered for specialist doctors.
Tue(3)-P-277
INVESTİGATION TO PATIENTS WITH GENETIC DISEASES IN EMERGENCY SERVİCE
Arif Duran 1 ，Tarik Ocak 1,2
，Zeynep Ocak 3
Poster Session
1:Emergency Medicine, Abant Izzet Baysal University, Turkey、2:Kanuni Sultan Suleyman Training and Research Hospital, Department of
Emergency Medicine、3:Kanuni Sultan Suleyman Training and Research Hospital, Department of Genetics
Purpose: Emergency services are most crowded clinics in hospitals. General prevalence of genetic diseases in any society
is known as 600/1000. In emergency services, it is frequently encountered with genetic disorders like Marfan Syndrome
which can be associated with aorta aneurysm and Osteogenesis Imperfecta which is characterized with fragile bones. Clinical
findings and radiological assessment is important for differential diagnosis. Studies which can be performed on patients with
genetic disorders may help for determining underlying molecular mechanisms and development of target-specific treatment.
It is aimed to enhance recognition about genetic diseases for physicians working in emergency services with this study.
Methods: Patients, who applied to Abant İzzet Baysal Training and Research Hospital in last one year, were analyzed to
determine knowledge store of emergency medicine doctors about genetic disorders and ICD-10 coding system. Diagnoses
coded Q00-Q99 were investigated.
Results: It was determined that aforementioned code was entered for only 16 patients among 224779 ones who applied
to emergency service in last 1 year. Diagnosed congenital malformations are; Q67-Congenital Musculoskeletal Deformity of
Cranium, Face, Vertebra and Chest (7 patients), Q54-Hypospadias (4 patients), Q36-Cleft Lip (2 patients), Q81-Epidermolysis
Bullosa (1 patient), Q35-Cleft Palate (1 patient) and Q28-Congenital Malformations of Circulatory System (1 patient).
Conclusion: Recognisability for patients with genetic diseases is pretty low in emergency services. These individuals deserve
special attention and various treatment options. In this connection it must be considered to train emergency medicine doctors
about genetic diseases. Purposes of education should be explained.
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ICHG2016 1119
Tue(3)-P-278
Patients and their Families and Friends as Developers of Medical Treatments/Devices
Sofia A Oliveira 1 ，Pedro Oliveira 2
1:Instituto de Medicina Molecular, Portugal、2:Catolica-Lisbon School of Business and Economics
This study looks at the sources of health care innovations and finds that patients of chronic diseases and their non-professional
caregivers have developed a very significant number of non-drug medical innovations that have proven valuable in dealing
with their diseases, namely by improving their quality of life. Many of these innovations were also evaluated as novel by
expert medical evaluators. In some cases, patients even saved their own lives. These innovations usually occur behind closed
doors and might never be knowledge or used by anyone else. However, if successful solutions and knowledge were shared
with other patients with similar need, it could improve the lives of many others. One way to intervene is to reduce the
diffusion costs and develop a centralized inventory of patient developed solutions. With this in mind, Patient Innovation
- https://patient-innovation.com - was developed as a nonprofit international, multilingual and open platform, designed to
allow patients and caregivers to show and share the innovative solutions they developed to fight their diseases, as well as to
foster collaboration among patients, caregivers and others. This experimental platform is aimed at increasing both the rate
of patient innovations and its diffusion. Prestigious institutions and reputable individuals, including several Nobel Laureates,
distinguished scholars and patient associations from around the world have endorsed it. From February 2014 to September
2015 the Patient Innovation platform collected and curated about 400 innovative solutions developed by patients and caregivers
from 30 countries with the USA, Portugal, England, Australia and Brazil as the main contributors. In this poster we will
report the developments of the project and the implications for health-care innovation practice and policy.
Poster Session
Tue(3)-P-279
Gender Differences in Genetic Contribution to Longevity
1
Min Junxia
1:Zhejiang University, China
One of the enduring enigmas in human biology is why females have a higher life expectancy but more physical disabilities and
other adverse health outcomes than males, which is known as the "Male-female health-survival paradox". We used a genetic
approach to explore gender differences in longevity. We conducted a gender-specific genome-wide association study (GWAS)
of the largest cohort of Han Chinese 564/1614 male/female centenarians and 773/1,526 male/female middle-age controls.
In addition to traditional high-throughput SNP array-based genotyping and GWAS we performed pathway modeling and
other in silico analyses. We identified 24 male-only SNPs and 36 female-only SNPs significantly (p<10-5 ) associated with
longevity. These SNPs’associations with longevity were replicated in independent gender-stratified datasets with a P<10-5 in
its combined dataset, but NOT significant at all (P>0.05) in the opposite gender for the independent or combined analyses.
Further pathway and eQTL analyses revealed gender-biased signaling pathways related to longevity. Our gender-specific
pathway and eQTL analysis suggest that gender-differential metabolic and inflammatory pathways with multiple SNPs and
genes may play some important roles in the human aging process which partially contribute to the “Male-female health-
survival paradox”. Future studies aim to investigate the mechanisms through which gender-specific genes/pathways and
interaction with environmental factors modulate aging and health in both human and animal models.
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Tue(3)-P-280
Mainstreaming genomics - A theory-informed systematic review of clinicians’ genetic testing practices
Jean L Paul 1 ，Hanna Leslie 2 ，Alison H Trainer 3,4
，Clara L Gaff 4,5,6
1:Molecular Development, Murdoch Childrens Research Institute, Australia、2:Paediatric & Reproductive Unit, SA Clinical Genetics Service,
Adelaide, South Australia, Australia、3:Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, VIC Australia、4:Department
of Medicine, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Parkville VIC Australia、5:Department of
Paediatrics, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Parkville VIC Australia、6:Melbourne Genomics
Health Alliance, Parkville VIC Australia
Background: Advances in genomic tests have increased technical efficiency and sensitivity of variant detection. Ethical and
practical concerns surrounding the introduction of such tests have been widely discussed. Incorporating new tests into existing
practice involves a change in clinical practice and a lag has previously existed between the development of a genetic test and
its adoption into mainstream healthcare. Lessons from monogenetic testing may help us anticipate clinicians’ needs and
concerns towards offering genomic tests, facilitating the appropriate introduction of such tests into mainstream healthcare.
Objective: To identify factors affecting the appropriate use of genetic tests by non-genetic clinicians through a systematic
review grounded in behaviour change theory.
Methods: Studies which investigated non-genetic clinicians’ experience with offering genetic tests were identified from 5
electronic databases. These were critically appraised and using content analysis, were mapped to the behaviour change
Theoretical Domains Framework (TDF).
Poster Session
Results: Twenty-five studies met inclusion criteria. The majority were conducted in the USA, used quantitative design, and
investigated cancer genetic testing. Many had low response rates, and survey design lacked a theoretical basis. TDF factors
identified which may impact clinicians’ decisions to offer genetic tests included: knowledge, genetic test factors (uncertainty,
incidental results), patient factors, organisational factors, professional factors, and ethical, legal, social and systemic factors.
Conclusions: Using the TDF, we produced a detailed picture of factors influencing clinicians’ testing decisions, identifying
areas for possible change to support mainstreaming genomic testing. Findings demonstrate that more than education is
required to incorporate new tests into clinical practice, and further theory-based research is needed to inform the successful
introduction of genomic testing.
Tue(3)-P-281
MéXICO ´ S NATIONAL BIOBANKING SERVICE LABORATORY
1
Hugo A Barrera-Saldana
1:Laboratorio Nacional Biobanco, Facultad de Medicina y Hospital Universitario de la UANL, Mexico
A leading institution in patient care and clinical research needs to obtain the greatest profit from the clinical samples of the
patients it serves. Thus, it should shelter any surgical samples and, whenever possible, body fluids (blood, urine, cerebrospinal
fluid, liquid-base cytology, etc.) from deserving cases. When it does occur, it is not always performed in the right way, and
when it is, the samples are usually not used beyond immediate traditional analyses nor are properly preserved for future
studies (1).
The integration of a BioSpecimens Research Program into the clinical practice of said leading institutions, allows more and
better discoveries which can be of world impact (2).
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A Biobank collects, processes, stores, and distributes clinical samples and their information for research purposes. It can also
offer the possibility of recovering and analyzing their informative biomolecules, such as DNA and RNA.
It is only through a bioabank service that the study of diseases that are presently of greatest concern, such as obesity,
diabetes and cancer, can be addressed. These studies require many samples from a large number of analyzable patients taken
repeatedly over several years. To foster in Mexico more of this type of studies, this project aims in its first stage to raise the
rank of our Pilot Biobank (1) in NE México to a National Biobank Service. At the same time, to help establish the biobank
of the most prestigious National Institute of Medical Sciences (INCMNSZ) in central Mexico. In its second stage proposes to
do so in several other medical research centers/hospitals to build a national network of biobanks.
With this initiative the author and his collegues wish to further impacting medical research in México (3).
References.
1. Garza-Rodriguez, ML et al. (2014) Medicina Universitaria. 16:99-101
2. Ojesina, A et al. (2014). Nature. 506: 371-375
3. Barrera-Saldaña, HA (2015) Mexico Health Review. Toguna press. México, DF. p.154-5.
Poster Session
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Poster Session
Genetic Counseling
Tue(3)-P-282
The free software "f-tree" for drawing a pedigree in genetic counseling
Koji Kumagai 1 ，Masahiro Sakai 1 ，Takayoshi Maeda 1
1:Department of Gynecology, Osaka Railway Hospital, Japan
[Objective] Drawing a pedigree is an important method in genetic counseling. However, a novice in genetic counseling may
find it difficult to draw a pedigree. The free software “f-tree” released in 2015 (http://iwate-megabank.org/genetic/) can
help a novice to easily draw a pedigree. In this study, we examined the usefulness of the software “f-tree” for a novice in
drawing a pedigree.
[Methods] A novice in genetic counseling was asked to solve nine questions required to draw a pedigree using“f-tree.” These
questions were disclosed in a previous examination (2012-2014) for clinical geneticists in Japan. The cases that appeared in the
questions were 3 autosomal dominant disorders, 2 autosomal recessive disorders, 1 X-linked recessive disorder, 1 chromosomal
disorder, 1 still birth, and 1 bone disease. Four cases among these included 1 adopted child and 7 offspring of cousin marriages.
Poster Session
We then confirmed if the novice drew the correct pedigrees using the software “f-tree.”
[Results] The novice easily learned how to use the software“f-tree” in about 1 hour. The software correctly created common
pedigree symbols and lines in 56% of the cases (5/9). However, a square bracket, which indicates adoption, and a double line,
which indicates cousin marriage, were not covered in this software (44% of the cases; 4/9).
[Conclusion] These results indicate that the software“f-tree” is useful to help a novice draw a pedigree, because it is easily
handled and correctly creates common pedigree symbols and lines. The software can further be revised to cover adoption and
cousin marriage.
Tue(3)-P-283
Factors affecting the decision to undertake non-invasive prenatal testing
Masahiro Murakami 1 ，Kaori Mori 1 ，Akane Kondo 1 ，Tsuyako Iwai 1 ，Kazuhisa Maeda 1
1:Clinical Genetics, Shikoku Medical Center for Children and Adults, Japan
Aim: To investigate the current state of non-invasive prenatal testing (NIPT) at Shikoku Medical Center for Children and
Adults and the factors affecting the decision to undertake this test.
Background: NIPT is rapidly advancing in Japan and it can help diagnose three types of chromosomal abnormalities, including
Down syndrome, by testing the mother’s blood. All patients are counseled prior to the test to ensure that they have a clear
understanding of NIPT; however, some do not opt for NIPT even after counseling.
Material and Methods: In total, 150 patients received pre-test counseling in our hospital between April 1, 2014 and June 30,
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2015. Thereafter, we performed a survey, where these patients had to fill out a questionnaire.
Results: All patients in the assisted reproductive technology (ART) group (n = 33) underwent NIPT after counseling and
were able to conceive. Patients in the non-ART group also underwent NIPT (Group A; n = 99), while the remaining 18
patients did note choose NIPT after counseling (Group B). There was no difference in the mean maternal ages and the income
between Group A and Group B. Group B was examined by the only reason of the maternal advanced age. In addition to
advanced maternal age, 34 percent of Group A also listed family advice as a factor in the decision-making process.
Conclusion: Our findings indicate that the ART group was more actively examined than non-ART groups. The precise
technique costs around 200,000 yen; however, expense did not appear to be a deterrent. On the other hand, the advice of
relatives influenced the choice to undergo NIPT. Moreover, we think that counseling is effective for a patient who wished for
undergoing NIPT based on advanced maternal age.
Tue(3)-P-284
The examination about wish of prenatal testing and mental background factorof pregnant women by
assited reproductive technology
Miwa Sakamoto 1 ，Nahoko Shirato 1 ，Tatsuko Hirose 1 ，Keiko Miyagami 1 ，Akihiko Sekizawa 1
1:Obstetrics and Gynecology, Showa University, Japan
Poster Session
Objects Pregnant women through assisted reproductive technology (ART) are an increasing trend in recent years. They have
many choices for prenatal testings, and it is expected that psychosomatic stress of pregnant women is likely increasing. In
the present study, we examined the change of their psychological status, such as stressor, anxiety, and depression in the view
point of ART.
Methods We subjected 300 pregnant women who answered to the questionnaire between April and September 2015, and
sub-classified into two groups: one is spontaneous pregnancy (N group) and another is get pregnant through ART (ART
group). The questionnaire includes a psychosocial factor evaluation tag; Hospital Anxiety and Depression Scale(HADS) and
stress VAS. This study was approved by institutional Ethics Committee.
Results This questionnaires were asked to 290 of pregnant women, and were recovered from 20 cases in ARTgroup and 238
cases in Ngroup. The average age of pregnant women and their husband were 36.1 and 37.6 in Artgroup and 31.7 and 33.4
in N group, respectively. The percentages of wishing prenatal testing were 56 and 42% in Art and N group, respectively.
Psycho-social factors numbers in the groups were 20.1 and 18.4, HADS-A score were 5.6 and 5.5, HADS-D score were 6.1
and 6.4 and VAS score were 57.1 and 42.7, respectively. Stress VAS in ART group was significantly higher than in N group
(P=0.01), whereas we could not observe any significant difference in other foctors.
Conclusion We revealed that the ages of pregnant women and their husband were higher in ART group than in N group,
and that pregnant women in ART group have a tendency to choose prenatal testings, and the score of stress VAS was higher
in ART group. These findings indicate that genetic counseling, including psychological supports in ART group should be
provided to pregnant women who get pregnant through ART.
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Tue(3)-P-285
Effect of the mental background factor of after childbirth women who done prenatal testings
Nahoko Shirato 1 ，Miwa Sakamoto 1 ，Keiko Miyagami 1 ，Junko Yotsumoto 1 ，Atshko Saito 1 ，Tatuko Hirose 1 ，
Mikiko Izumi 1 ，Ryu Matsuoka 1 ，Kiyotake Ichizuka 1 ，Akihiko Sekizawa 1
1:Obstetrics and Gynecology, SHOWA University, Japan
(Purpose) To assess the effect of knowledge of prenatal testings on the mental stress of pregnant women and after childbirth
women, we examined about factors related with stress, anxiety and depression in after childbirth women who received genetic
counseling for prenatal testings. A questionnaire to evaluate stress factors, the anxiety and depression was performed in women
who did NIPT at 1 year after the testing. (Methods) We subjected 214 women who received NIPT and got negative results
between April and June 2014. After birth, we sent questionnaires, including a psychosocial factor evaluation tag and HADS
(Hospital Anxiety and Depression Scale). Statistical analysis was performed by using variance analysis. (Result) Although
the NIPT results were negative in all women, congenital diseases excluding chromosomal abnormalities were detected after
birth in 7 cases. For the evaluations of HADS-A and HADS-D, we classified into 3 groups: normal group (N-group) is less
than 7 points, doubted group (D group) is 8 to 10 points, and patient group (P-group) is more than 11 points. The numbers
of women of N, D, and P-group were 107, 21, and 23 (70.9, 13.9, 15.2%) in the HADS-A, and those were 94, 34, and 23
(62.3, 22.5, 15.2%) in the HADS-D, respectively. The VAS values of N, D, and P group were 31.8, 54.2, and 66.7 in HADS-A,
and 34.7, 48.5, and 54.4 in HADS-D, respectively. The VAS values were significantly higher in D and P group than that
in N group. Among the groups, 74.8-95.6% of women reported about factors of their own stress in HADS-A and HADS-D.
(Conclusion) In after birth women with high score of HADS, there was tendency to have anxiety and depression, and to have
high score of stress VAS. The psychosocial stress of these women was associated with their own factors. It is indicated that
Poster Session
careful genetic counseling including physical and mental supports is very much important for these women before the NIPT
and after the child birth.
Tue(3)-P-286
Genetic counseling in pregnant women whose fetus had Robertson translocation
Tatsuko Hirose 1 ，Keiko Miyagami 1 ，Nahoko Shirato 1 ，Mikiko Izumi 1 ，Shoko Hamada 1 ，Keiko Koide 1 ，
Tetsuro Kondo 1 ，Junko Yotsumoto 1 ，Ryu Matsuoka 1 ，Kiyotake Ichizuka 1 ，Akihiko Sekizawa 1
1:Obstetrics and Gynecology, Showa University School of Medicine, Japan
Background: We made an outpatient clinic for genetic counseling in the Hospital in June, 2009. Since then, we experienced 5
cases of Robertson translocation. In the cases, wide variety of explanations such as a carrier diagnosis, the prediction of the
phenotype, possibility of UPD (uniparental disomy), influence to the next generation, and the possibility of the miscarriage
were provided in the counseling. In the present study, we extracted the tasks that we have to work in the genetic counseling
of Robertson translocation.
Method: We retrospectively analyzed medical records of Robertson translocation cases in the perinatal genetic counseling
between June, 2009 and March, 2015. The contents of genetic counseling and genetic testings were assessed.
Result: Five cases were summarize in order of age, indication of testing, method of testing, karyotype; Case 1: 39y, hy-
drops fetalis, Amniocentesis, 46,XX,der(21;21)(q10;q10),+21, Case 2: 37y, Still birth (multiple abnormality, oligoamnios),
Products of Conception ( POC ), 45,XY,der(15;21)(q10;q10)[14]/46,XY[6], Case 3: 39y, advanced age, Amniocentesis,
45,XY,der(14;22)(q10;q10)[14]/46,XY[26], Case 4: 30y, Still birth (hydrops fetalis), POC, 46,XX,der(13;14)(q10;q10),+21,
Case 5: 39y, advanced age, Amniocentesis, 45,XX,der(13;14) (q10;q10). In 3 out of 5 cases, chromosomal karyotyping of the
parents were performed. In Case 5, analyses of UPD and microarray were performed.
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Conclusion: When we detect Robertson translocation in the fetus, we have to be responsible for the cases in the genetic
counseling. Furthermore, in spite of balance type Robertson translocation in karyotyping, some cases may have abnormal
phenotype such as Case 2. This indicated the insufficiency in G-banding, leading to the need of microarray or other genetic
testing. Since detailed genetic analysis may not resolve the association between the genotype and phenotype, enough genetic
counseling is very important.
Tue(3)-P-287
Role of Genetic Counseling in Pediatric Transplantation of Genetic Disorders: A Report from Children’s
Medical Center in Japan
1,3
Shiho Ito ，Tomu Kuchikata 2 ，Hiroshi Yoshihashi 2 ，Hironao Numabe 3
1:Department of Nursing, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan、2:Department of Medical Genetics, Tokyo Metropoli-
tan Children’s Medical Center, Tokyo, Japan、3:Department of Genetic Counseling, Graduate School of Human Genetics and Science,
Ochanomizu University, Tokyo, Japan
Backgrounds: Transplantations are effective treatment for various genetic diseases in pediatrics. In Japan, since the revised
Organ Transplantation Law came into effect on July 2010, brain-dead organ donor under age of 15 had been legalized. Despite
this legislation, scarcity of donor organs still persist, living-related donor transplantation take most of the role. Method: We
review the cases of genetic counseling between April, 2010-September, 2015. The cases regard the criteria, (1) single gene
disorders that require transplantation for the treatment in the future, (2) pathogenic mutation of causative gene detected
in proband (3) genetic risk of the other family members were informed and may lead to the living-related donor suitability.
Poster Session
Results: 15 cases meet the criteria and categorized in 7 single gene disorders, including Hunter syndrome, Alagille syndrome,
Citrin deficiency, primary hyperoxaluria, Schwachman-Diamond Syndrome, X-Linked adrenoleukodystrophy, and Ornithine
transcarbamylase deficiency. After the genetic counseling performed, 4 cases underwent transplantation. In one case, 5-years-
old sib of the proband had the carrier testing for the purpose of selecting the donor. Discussion: The genetic information may
reveal the suitability for a living-related donor. In contrast the family members may confront a dilemma and incidentally
find the genetic characteristics of themselves in the process of choosing a donor candidate. The future autonomy should
be also protected for the underage sibs of the recipient as much as possible. The transplantation using a graft from the
affected patient and carrier remains controversial questions of long-term prognosis in both donors and recipients. Conclusion:
There are points to remember for pediatric transplantation in Japan. Pediatric transplantation deeply requires collaboration
between the medical geneticist/genetic counselor and clinical specialists in consideration of different conditions.
Tue(3)-P-288
Uptake of gene test among family members with BRCA 1/2 mutation in Japanese population Uptake
of gene test among family members with BRCA 1/2 mutation in Japanese population
Megumi Okawa 1 ，Shiro Yokoyama 2 ，Chie Watanabe 2,3 ，Hisako Kanai 1 ，Mikiko Aoki 1 ，Junko Takei 1 ，
Atsushi Yoshida 1 ，Hideko Yamauchi 1 ，The registration committee of The Japanese HBOC consortium
1:St Luke’s International Hospital, Japan、2:Showa University, Breast Center、3:Sophia University, Faculty of Human Sciences, Department
of Nursing
Background:Hereditary Breast and Ovarian cancer syndrome (HBOC) is known as a syndrome that causes breast and ovarian
cancers at exceptionally high rate in patients who have genetic mutation in BRCA1 and BRCA2 . Penetration rate of BRCA1
and BRCA2 in Japanese population showed 30.7% as high as the Western population. The Japanese HBOC Consortium
was established in 2012 and registration trial has been provided by registration committee.Purpose:The purpose of this study
was to identify the uptake rate of gene test among family members with BRCA1/2 mutation and affected factors for the
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test.Materials & Methods:Eight hundred and forty-six families were registered up to August 2015, and 180 families were found
to have BRCA1/2 mutation. No other family members were tested except a proband in one hundred and five families (non-
test group). One hundred thirty one family members in 75 families underwent the test, and 68 family members were found
to have BRCA1/2 gene mutation (test group).Results:The uptake rate of gene test among family members was 42.7%.The
prevalence rate of family members who affected breast or ovarian cancer was 85.7%.The family members whose family member
had died by ovarian cancer underwent gene test proactively (p<0.05). In the test group, the age of proband which diagnosed
breast cancer was older than non-test group (average 44.1vs39.1, p<0.05), and most of family members who underwent the
gene test were categorized as s daughter. There were no significant differences in clinical features, pathological features, or
family history.Conclusion:Ovarian cancer death may affect for the uptake rate of BRCA1/2 gene test of family members. It
was important to educate for gynecologist to recognize for HBOC. In the test group, the age of proband which diagnosed
breast cancer may be affected by their daughter’s age.
Tue(3)-P-289
Charcot-Marie-Tooth disease (CMT) Patient Registry in Japan
Masanori Nakagawa 1 ，Kensuke Shiga 3 ，Yu-ichi Noto 2 ，Yukiko Tsuji 2 ，Toshiki Mizuno 2 ，
The research group of clinical evidence to improve Charcot-Marie-Tooth Disease patient care
1:Neurology, North Medical Center, Kyoto Prefectural University of Medicine, Japan、2:Department of Neurology, Kyoto Prefectural
University of Medicine、3:Department of Medical Education and Primary Care, Kyoto Prefectural University of Medicine
Background: More than 80 causative genes for CMT and related disorders have been identified so far. However, molecular
Poster Session
epidemiology and clinical evidence to improve CMT patient care has been poorly developed in Japan. Aim: In collaboration
with neurologists, orthopedists, rehabilitation specialists, pediatricians and the CMT patient group in Japan, we developed
the CMT Patient Registry (CMTPR) system to undertake a nationwide survey regarding genetic background and clinical
manifestation of CMT patients. Methods: We developed a patient-lead online registration system with Fujitsu IT Co.
Patients with CMT were recruited in clinics where either neurologists, foot surgery specialists, or rehabilitation specialists
see at least more than one patient with CMT or through the CMT patient group. The recruited patients are encouraged
to register patient identification data in CMTPR, in which they were prodded to fill in a questionnaire on their history,
physical or working status and genetic test results, if available, on the Internet. Results: As of November 1st, 2015, a total of
213 patients with CMT participated in the registration to the CMTPR. However, only 132 patients successfully entered the
clinical information in CMTPR. The information on the genetic test results on CMT genes were entered in only 77 patients:
PMP22 duplication 36, MPZ 7, GJB1 7, MFN2 6, GDAP1 2, PMP22 point mutation 2, BSCL2 1, LMNA 1, MTMR2 2,
NEFL 1, PMP22 deletion 1, PRX 1, SETX 1, and 10 patients were under examination. Discussion: First, only 62 percent
of patients who registered in the CMTPR filled in a questionnaire. The poor turnout might be due to the complexity of the
questionnaire which required a certain amount of time. Secondly, the CMTPR revealed that, out of the CMT patients who
filled in the questionnaire, approximately 30% didn’t have the genetic tests performed. It must be further underscored to
encourage CMT patients or clinicians about the importance on genetic testing.
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Tue(3)-P-290
Current Status of Social Issues for People with Down Syndrome in Japan: From Nationwide Survey
Hidehiko Miyake 1 ，Shigehito Yamada 1,2 ，Yosuke Fujii 3 ，Mariko Taniguchi-Ikeda 4 ，Mari Urano 5 ，Yuka Ozasa 6 ，
Makoto Kanai 7 ，Akimune Fukushima 8 ，Yoichi Matsubara 9 ，Kayoko Saito 5 ，Ikuo Konishi 2
1:Clinical Genetics Unit, Kyoto University, Japan、2:Department of Gynecology and Obstetrics, Kyoto University、3:Kyoto University
Hospital、4:Department of Pediatrics, Kobe University、5:Institute of Medical Genetics, Tokyo Women’s medical university、6:Nursing
Division, Tokyo Medical and Dental University、7:Department of Obstetrics and Gynecology, Shinshu University、8:Department of Clinical
Genetics, Iwate Medical University、9:National Research Institute for Child Health and Development
In Japan, the total fertility rate was 1.41, and the average age at which mothers gave birth to their first child was increased to
30.3 years old, in 2012. Owing to the increased risk of fetal aneuploidy with maternal age, prenatal testing and prenatal genetic
counseling draw increasing attention the past few years in Japan. Down syndrome (DS) is the most common chromosomal
aberration detected in prenatal testing. Recently, Life expectancy of people with DS extends into the 50s or 60s. To provide
well-balanced information about DS, clinical geneticists and genetic counselors should know long-term prognosis, including
employment, education and daily life. However, there is no current data about the life about young and adult people with
DS in Japan. The aim of this study is to explore current status of health and social issues, of people with DS.
We conducted a nationwide survey on the total membership of the Japan Down Syndrome Society (JDS). In October 2015, a
questionnaire was mailed to about 5,000 households on the mailing lists of the JDS. JDS was consulted during questionnaire
production to ensure that it was applicable and appropriate.The following items were included in the questionnaire: basic
information of the proband, educational status,employment status, public assistance, welfare service, delivering a diagnosis
for the person with DS, and daily life. This study was funded by Health Labor Sciences Research Grant (MHLW 2014-2015),
Poster Session
and was approved by the ethical committee of Kyoto University.
Present study could clarify the needs and the challenges in daily life of young and adult person with DS. Moreover, this large
data will contribute to not only genetic counseling but also welfare system.
Tue(3)-P-291
Genetic counseling for clinical sequencing using the next-generation sequencincer panel analysis
Tetsuya Okazaki 1,2 ，Megumi Murata 3 ，Masachika Kai 4 ，Kaori Adachi 3 ，Naoko Nakagawa 5 ，Noriko Kasagi 6 ，
Wataru Matsumura 1,2 ，Yoshihiro Maegaki 1 ，Eiji Nanba 2,3,5
1:Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Japan、2:Division of Clinical
Genetics, Tottori University Hospital,、3:Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori
University、4:Division of Technical Department, Tottori University、5:Center for Promoting Next-Generation Highly Advanced Medicine
Tottori University Hospital、6:Department of Fundamental Nursing, School of Health Science, Faculty of Medicine, Tottori University
Objective: Clinical sequencing using a next-generation sequencer (NGS) is rapidly becoming an attractive tool for diagnostic
testing in medical genetics. We report here what we should consider the genetic counseling of clinical diagnosis using next
generation sequencing.
Methods: 17 families and 20 patients submitted specimens to the clinical laboratory for targeted gene testing. All patients had
signed written consent in genetic counseling before collection of blood. Each patient was explained about incidental findings,
defined as conditions unrelated to the present symptom. We explained that in this clinical research, we only investigate the
indicated genes of patient’s present symptoms, not incidental findings. Targeted resequencing was performed using TruSight
One sequencing panel (Illumina, USA), which includes 4,813 genes.
Results: We detected causative mutations in 6/17 (35%) families. In 15/17 (88%) families, genetic counseling provided to
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each patient before the collection of blood was only once. In the genetic counseling after the clinical sequencing, most families
and patients seemed to be satisfied. However one family hesitates to know the result, we cannot report it. In undiagnostic
families, two families did not hope for further testing if a new analysis method become available in the future.
Conclusions: In clinical sequencing using NGS, the inheritance pattern cannot be understood until a causative gene is
identified. It is necessary to perform genetic counseling to provide clients with knowledge of inheritance patterns first, and to
assume their inheritance pattern based on their family history. Genetic counseling for pre-clinical sequencing using the NGS
should be necessary to spend more effort and time than conventional genetic counseling. Although, in this research, we did
not examine the incidental findings, we must think about how we handle the incidental findings.
Tue(3)-P-292
Characteristics of the Genetic Counseling in Kyoto University Hospital to Figure Out the Genetic Coun-
seling Needs in Japan
Manami Matsukawa 1 ，Hitomi Nishio 1 ，Yumie Hiraoka 1 ，Sayaka Honda 1 ，Akira Inaba 1 ，Eriko Takamine 1 ，
Ayumi Yonei 1 ，Masako Torishima 2 ，Hiromi Murakami 2 ，Shin-ichiro Kitajiri 2 ，Takahito Wada 1,2 ，Hidehiko Miyake 1,2
，
Shigehito Yamada 2 ，Toshio Heike 2 ，Shinji Kosugi 1,2
1:Genetic Counselor Course, School of Public Health, Kyoto University, Japan、2:Clinical Genetics Unit, Kyoto University Hospital, Japan
Poster Session
Background: The development of genetic testing technologies threw a new light in our future planning. Genetic Counseling
(GC) is a helpful way to make a suitable decision for ourselves and our families. However, there are some people who are not
familiar with GC in Japan. Kyoto University Hospital Clinical Genetics Unit (KUHCGU) has welcomed all the clients from
every field which relates to genetics and heredity. Our short term goal is to make the word GC and the practice of it much
more familiar to the public and medical professionals in order for them to utilize GC.
Objectives: Our objectives of this analysis were to get the ideas on how to spread the GC through out the public and medical
professionals from the past anonymized GC notes of KUHCGU.
Method: 1. Compiled following a)-d) of each GC retrospectively from the anonymized GC notes of the last seven years. a)
the number of clients and their categorized field in each year, b) the number of hours spent in GC, c) major complaints, d)
client components. 2. Analyzed the data from the major four fields (familial tumors, neuromuscular diseases, chromosomal
abnormalities, and hereditary deafness) ranked by the number of clients visited KUHCG.
Results: Familial tumor field clients came by themselves or with their parents, and asked about heredity and genetic testing.
Most of the neuromuscular-disease-field clients were at-risk subjects, and desired preclinical diagnosis test. Many chromosomal-
abnormality-field clients were at-risk subjects, and requested genetic testing to know the reason of the disease. Hereditary
deafness field clients came with their family to get tested from the genetic aspect.
Conclusion: Each GC content showed a tendency in each field, meaning that GC prevalence campaign should be performed
with a view of the needs and the timing to face genetic problems characterized in each field.
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Tue(3)-P-293
A case of osteogenesis imperfecta (OI) diagnosed during pregnancy whose mother’s feeling for fetus
changed from denial to acceptance and whose genetic diagnosis was planned after genetic counseling
Masahiro Shiba 1 ，Yasuhiro Matsumoto 1 ，Minako Shimizu 1 ，Takako Higa 1 ，Shigenari Namai 1 ，Hideo Kamata 1 ，
Koichi Umezawa 1 ，Akinori Taguchi 1 ，Yukifumi Sasamori 1 ，Koichiro Kido 1 ，Eiji Ryo 1 ，Takuya Ayabe 1
1:Obstetrics & Gynecology, Teikyo University, Japan
OI is a heterogeneous group of connective tissue disorders. About 85-90% of OI are caused by gene mutations in COL1A1
and COL1A2 which show autosomal dominant inheritance, coding for the chains of type I collagen.
A 37-year-old gravida 5, para 3 woman was referred to our perinatal center at 25 weeks of gestation for suspicion of fetal
anomaly. All fetal long bones shortened. Femur and tibia were curved. Cranial bones seemed thin. Thorax did not seem so
narrow. We thought this fetus non-lethal skeletal dysplasia (SD). There was no consanguinity, no family history of SD. At
first, she expressed disapproval of resuscitation of her newborn baby. She and her husband hoped to take a fetal CT scan as
an adjunct to the diagnosis and for mental preparedness. Fetal CT at 31 weeks of gestation shows slightly curved long bone of
bilateral lower limbs. Cranial bones seemed thin, but a little ossified. Thoracic volume seemed normal. There is no fracture
sign. These findings supported the fetus as OI type I or IV (mild form). At 34 weeks of gestation, obstetrician, pediatrician
and nursing staff talked with her and her husband, then they approved acute phase resuscitation. Cesarean section was
performed at 37 weeks of gestation for breech presentation and considering fetal bone fracture during vaginal delivery.
A male infant 1,870 g was delivered with Apgar scores of 7 and 9 at 1 and 5 minute(s), respectively. Respiratory status was
Poster Session
good. Roentgenogram showed mild curvature, deformity and remodeling of the extremital long bones, especially in the lower
limbs. Cranial bones were thin. Thoracic deformity was very mild. We diagnosed this baby as mild form of OI. Mother and
her husband’s acceptance was satisfactory. They hoped genetic diagnosis. After counseling was performed by the clinical
genetics specialist, we planned genetic analysis of COL1A1 and COL1A2 .
Tue(3)-P-294
Genetic counsering of 46,XY DSD for eight years -a case report-
Nobuko Nishioka 1 ，Tomohito Ishiguro 1 ，Shihori Nishizawa 1 ，Atsuko Yamada 1
1:Koshigaya Municipal Hospital, Japan
Disorders of sex development (DSD) are defined as congenital conditions when chromosome, gonadal development or anatomic
sex is atypical. When a patient is diagnosed as DSD, genetic counseling may have an important role for the patient and their
parent to help understanding about the disease, and to help for decision making of the treatment, and to avoid psychosocial
distress. We also need a long-term patient-centered care.
This is a case report of a 46,XY DSD with genetic counseling for 8 years.
A 16-year-old girl was referred to our hospital because of primary amenorrhea. Genetic analysis was performed after obtaining
informed consent, which revealed as 46,XY DSD with mutation of SRY. Genetic counseling was performed for several times
including emotional support. First when laparoscopic bilateral gonadectomy was necessary because of gonadal tumors.
Pathology of the gonad was seminoma or dysgerminoma. Counseling was done carefully to explane about gonadal tumors
and necessity of operation. Second when she was 19-year-old, she had a question for pregnancy. And the counseling was done
to tell about fertility. Third when she was 24-year-old, counseling was done to tell about medical histories, karyotype and
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diagnosis.
Telling the truth to the patient about medical histories, karyotype and diagnosis needs trusting relationship between doctor
and patient. It will be necessary when the patient are mature enough to understand, and able to make a decision themselves.
It will take time to make a good relationship between doctor and patient, therefore long-term patient-centered care is needed.
Tue(3)-P-295
Mental background of pregnant women in the view point of delivering facilties
Keiko Miyagami 1 ，Nahoko Shirato 1 ，Miwa Sakamoto 1 ，Junko Yotsumto 1 ，Atsuko Saito 1 ，Tatsuko Hirose 1 ，
Mikiko Izumi 1 ，Taro Morimoto 2 ，Shuichi Kitamura 3 ，Ryu Matsuoka 1 ，Akihiko Sekizawa 1
1:Showa University School of Medicine, Japan、2:Hatanodai Lady’s clinic、3:Dr Kitamura’s clinic
<The purpose>To assess the effect of knowledge of prenatal testings on the mental stress of pregnant women, we exam-
ined about factors related with stress, anxiety and depression in pregnant women in the view point of the delivering fa-
cilities.<Methods>Questionnaire, including a psychosocial factor evaluation tag and HADS (Hospital Anxiety and Depres-
sion Scale) was asked to pregnant women who did prenatal care in private clinic and would deliver in the faculties nearby
the parents’ home town between April and September, 2014. Statistical analysis was performed by using the Wilcoxon
tests.<Rsults>A total of 290 pregnant women answered to this questionnaire. We sub-classified into 4 groups depend on
their intended delivering facilities: 55 cases were perinatal center (C), 197 cases were hospital (H), 15 cases were midwifery
Poster Session
home (M), and 23 cases were not decided yet (U). As the background of the pregnant women, we compared among C, H, M,
and U groups and could not observe any significant difference. M was significantly lower than the other groups in average
stress VAS score. The percentages of women in M group who will not receive prenatal testings were lower than the other
group. On the other hands, percentages of women in M group who wish to receive the testings were higher than the other
groups. Depending on the results of HADS-A and HADS-D, pregnant women were sub-classified into 3 groups: normal case
(N-cases) was less than 7 points, doubted case (D cases) was 8-10 points, and patient case (P-cases) was more than 11 points.
In HADS-A, the rate of D cases was significantly higher than in C and M group. The rate of P cases was 15.4% and was
higher among the other cases.<Conclusion> It was found that M group who wish midwifery home had less mental stress,
and that C group has a high degree of interest for prenatal testings. Therefore it was suggested many people ware interested
in prenatal testings.
Tue(3)-P-296
Genetic diagnosis, counseling and management of androgen insensitivity syndrome : a case report
Mizue Teramoto 1 ，Akira Ishii 2 ，Masahito Mizuuchi 1 ，Tsuyoshi Baba 1 ，Shinichi Ishioka 1 ，Toshiaki Endo 1 ，
Tsuyoshi Saito 1
1:Department of Obstetrics and Gynecology, Sapporo Medical University, Japan、2:Department of Pediatrics, Iwamizawa Municipal Gemeral
Hospital
INTRODUCTION:Androgen insensitivity syndrome (AIS) is a disorders of sex development characterized by variable defects
in virilization of 46,XY individuals. This is due to loss-of -function mutations in the androgen receptor gene, which results in
resistance to the actions of androgens. The phenotype presentation of AIS is variable, and these individuals usually develop
as women.
CASE OUTLINE:A 15-year-old female patient was admitted at our hospital further evaluation and treatment of bilateral
inguinal mass. The patient had never menstruated. On physical examination, her breast development and pubic hair was
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normal, but her uterus and ovaries were absent. She had a short blind ending vagina, mild clitoromegaly and labial fusion.
Cytogenetic analysis showed a 46,XY,inv(9)(p12q13) karyotype. Her testosterone was 15.2ng/ml. The Magnetic resonance
imaging (MRI) showed the testicles were on both sides of the inguinal canals. Sequence analysis of the androgen receptor (AR)
gene revealed a mutation in exion 8 (c.2639A>T), as known as the pathogenetic mutation for partial androgen insensitivity
syndrome (PAIS).We provided a series of psychological and genetic counseling to her and her parents regarding the diagnosis,
reinforcement sexual identity, gonadectomy planning and hormone replacement therapy.Bilateral gonadectomy was performed
at 16 years old. Hormone replacement therapy was prescribed after gonadectomy. She is 18 years old now, and we advise
vaginal dilatation to avoid dyspareunia.
CONCLUSION:The diagnosis of AIS is based on clinical, hormonal analysis, karyotype and the molecular defect in the AR
gene. Bilateral gonadectomy is generally recommended after puberty to avoid the risk of testicular malignancy. Vaginal
length may be short and require dilatation to avoid dyspareunia.Proper genetic counseling play an important role in support
the patient and the family to reinforce their identity.
Tue(3)-P-297
Genetic Counseling for Patients and Family Members with Endocrine Disease: Experience of Specialized
Genetic Counselor
Hye In Kang 1 ，Jin Wook Yi 1 ，Hyungju Kwon 1 ，Young Jun Chai 1 ，Su-Jin Kim 1 ，Mun Woo Sung 2 ，Jung Hee Kim 3 ，
Hye Yoon Park 4 ，Kyu Eun Lee 1
1:Department of Surgery, Seoul National University Hospital, Korea, South、2:Department of Laboratory Medicine, Seoul National University
Poster Session
Hospital、3:Department of Endocrinology, Seoul National University Hospital、4:Department of Neuropsychiatry, Seoul National University
Hospital
Background: Recent advancement in genetic science has been applied to clinical fields, and there is growing needs of genetic
counseling for the patients and the family members with genetic disease. Among them, endocrine tumors such as medullary
thyroid carcinoma (MTC), pheochromocytoma (PHEO), and paraganglioma are good subjects for genetic counseling because
a great number of germ line mutations have been investigate. Herewith, we introduce a genetic counseling protocol of our
institution.
Methods: Since June 2011, thyroid cancer center of Seoul National University Cancer Hospital has started genetic counseling
for the patients with suspicious genetic endocrine disease by an experienced nurse. Firstly, patients were asked past medical
history, familial history, and family tree information at the outpatient clinic. And if genetic disease was suspicious by the
history taking, genetic mutation tests for MEN1, MEN2a, MEN2b, VHL, SDHD, SDHB, and NF1 were conducted with
patient’s peripheral blood after patient’s informed consent.
Result: We have found 34 patients with genetic mutations. There were 5 MEN1, 17 MEN2a, 1 MEN2b, 6 VHL, 4 SDHD,
and 1 NF1 patients. There was no patient with mutation at SDHB. Genetic mutations and presented diseases were as
follows; MEN1 - 5 parathyroid adenoma, MEN2a - 5 MTC, 3PHEO, 8 with MTC with PHEO, 1 with MTC with PHEO with
Hyperparathyroidism MEN2b - 1 MTC with PHEO, VHL - 5 PHEO, 1 renal cell carcinoma, SDHD - 4 PHEO, and NF1 - 1
PHEO. We regularly follow up the affected patients to screen the secondary tumor development, and continue to counsel the
34 mutation carrier family members.
Conclusion: We could find substantial amount of patients with genetic disease during the study period. Genetic counseling
can offer them a better understanding for their disease status and suggest proper genetic tests. Eventually it may play a role
to lead them to make a beneficial decision for their disease screening.
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Tue(3)-P-298
Families who were suspected to be HBOC families but didn’t show pathogenic mutations in both BRCA1
and BRCA2 in genetic testing
Nao Sugimoto 1 ，Keika Kaneko 1 ，Sachiko Kiyoto 1,2
，Mina Takahashi 1,2
，Kenjiro Aogi 1,2
，Shozo Ohsumi 1,2
1:Familial Tumor Counseling Service, NHO Shikoku Cancer Center, Japan、2:Department of Breast Oncology, NHO Shikoku Cancer Center
<Introduction> Approximately 5 ~ 10% of breast cancer patients are believed to have hereditary background in etiology.
Hereditary Breast and Ovarian Cancer (HBOC) is the commonest hereditary breast cancer syndrome and account for about
50% of hereditary breast cancer patients. On the other hand, frequently pathogenic mutations in BRCA 1 or 2 are not found
in families who are suspected to have HBOC.
We report HBOC suspected families without pathogenic mutations in both BRCA1 and BRCA2, and present our surveillance
policy for them.
<Patients> We performed genetic counseling and genetic testing (DNA sequencing and MLPA) for 31 patients from March
to June, 2015.
In this report, we present 22 patients who didn’t show pathogenic mutations in either BRCA1 or BRCA2 .
<Personal and Family histories> All the patients suffered breast cancer, and one had endometorial cancer as well.
Poster Session
Regarding family history of breast cancer within third degree relatives, 5 (22.7%) have three or more members, 9 (40.9%)
have two, 6 (27.3%) have one and 2 (9.1%) have none. In terms of family history of ovarian cancer, 5 (22.7%) have one
member and the others (77.3%) have none. Three patients (13.6%) have family history of both breast and ovarian cancers.
<Our Surveillance Policy> We believe that there is almost no possibility of HBOC for those 22 patients.
For patients with breast cancer familial history, close female relatives are recommended to have annual screening mammog-
raphy. Furthermore, we recommend annual breast MRI and/or breast ultrasound for close kindred females who have strong
breast cancer family history.
For those with ovarian cancer familial history, close kindred females have higher risk of ovarian cancer than general population.
We discuss biannual transvaginal ultrasound and serum CA-125.
<Discussion> Guidelines of surveillance for the families with strong breast and/or ovarian family history but without
pathogenic mutations of both BRCA1 and BRCA2 are necessary.
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Tue(3)-P-299
Factors influencing the decision not to choose prenatal aneuploidy screening in pregnant women receiving
genetic counseling for advanced maternal ages
Emiko Kise 1,2 ，Masumi Ishikawa 1 ，Kyoko Takano 1,3 ，Satoshi Ohira 1,4
，Ryoichi Asaka 4 ，Hidehiko Miyake 2 ，
Makoto Kanai 1,4,5 ，Yoshimitsu Fukushima 1,3 ，Tomoki Kosho 1,3
1:Division of Clinical and Molecular Genetics, Shinshu University Hospital, Japan、2:Department of Medical Ethics, Kyoto University
School of Public Health、3:Department of Medical Genetics, Shinshu University School of Medicine、4:Department of Obstetrics and
Gynecology, Shinshu University Hospital、5:Department of Family and Child Nursing, and Midwifery, Shinshu University School of Health
Sciences
In Japan, non-invasive prenatal testing (NIPT) has been available as a clinical research since the introduction in 2013. Shinshu
University Hospital does not participate in this clinical research, and offers careful genetic counseling solely for the decision
whether or not to have amniocentesis in cases of advanced maternal ages (AMA). Our prenatal genetic counseling (GC)
for AMA includes (1) pre-counseling by certified genetic counselors (CGC) for about 0.5 hours by phone or after prenatal
checkups, where reservations are made and family trees are described; (2) main GC by CGC for 1−1.5 hours, collecting
more information and following narratives, and by clinical geneticists specializing in chromosomal or genetic disorders for 1
hours, adding comprehensive medical and social information and discussing freely what the testing truly mean for the women
and their husbands; (3) post-counseling by CGC for 0,5 hours by phone or after prenatal checkups. In total, 69 pregnant
women received such GC from April 2013 to March 2015: 34 (49%) had testing (amniocentesis in most) and the rest 35 did
not. Among the two groups, mean ages and the percentages of having histories of infertility treatment and delivery were
not different. Factors influencing the decision to choose the testing included “hope of knowing fetal information as much
as possible”, and “hope of having relieves”. Factors influencing the decision not to choose the testing included “refusal
Poster Session
to terminate their fetuses” and “knowledge of any pregnant women having possibilities of being mothers of babies with
congenital disorders or handicaps and also of presence of medical and social support system”. These observations implicate
the fundamental value of prenatal GC, both for invasive testing and for NIPT, that appropriate information and fruitful
discussion could empower pregnant women to imagine which decision would fit them truly in their lifelong point of view.
Tue(3)-P-300
Genetic counseling of a woman with malignant pheochromocytoma caused by multiple endocrine neo-
plasia type 2A
Misaki Fukue 1 ，Masato Maekawa 1 ，Go Kuroda 2 ，Yutaka Oki 3
1:Clinical&Molecular Genetics Center, Hmamatsu University Hospital, Japan、2:Second Department of Internal Medicine, Hamamatsu
University School of Medicine、3:Family and Community Medicine, Hamamatsu University School of Medicine
A 55-year-old woman with malignant pheochromocytoma (PHEO) was admitted to our hospital. She also had a thyroid
nodule with coarse calcification, however she was not clearly diagnosed with medullary thyroid carcinoma (MTC). We firstly
supposed that she has any genetic factor causing PHEO, and talked with her mainly about hereditary pheochromocytoma/
paraganglioma syndromes in genetic counseling. With her consent, we underwent genetic testing in some genes associated
with PHEO: SDHx, MAX, RET, and VHL genes, and heterozygous germline mutation for C634R of RET gene was detected.
The genetic mutation was a common cause of Multiple endocrine neoplasia type 2A (MEN2A) and especially associates with
much higher risk of MTC. Bilateral PHEO is often found in patients with MEN2A, and carriers of the mutation at codon 634
have high penetrance of PHEO. PHEO usually occurs after MTC or concomitantly. However, in 13%-27% of individuals with
MEN2A, PHEO is the first symptom. Malignant transformation occurs in about 4% of patients with PHEO. We counseled
with clients about such medical information and management for MEN2A and PHEO, and supported their adaption process in
continued counseling. Her daughter also underwent the genetic testing for C634R of RET, and was revealed to be heterozygous
for the mutation. Because PHEO was the first symptoms of client, she and her sibs more worried about malignant PHEO
than benign PHEO and MTC. It was unacceptable fact that they have high risk of developing MTC. At genetic counseling
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of malignant PHEO like this case, we should provide accurate and objective information after understanding client’s risk
perception.
Tue(3)-P-301
The positive test result ｀ s effects on condition of health, ability to function and mental health as
evaluated by Finnish male BRCA1/2 mutation carriers
1,2,3 1,2 2,3,4 1,2,5
Outi Kajula ，Maria Kaariainen ，Jukka S. Moilanen ，Helvi Kyngas
1:Research Unit of Nursing Science and Health Management, University of Oulu, Finland、2:Medical Research Center, Oulu University
Hospital and University of Oulu, Oulu, Finland、3:Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland、4:PEDEGO
Research Unit (Research Unit for Pediatrics, Dermatology, Clinical Genetics, Obstetrics and Gynecology), University of Oulu, Oulu, Finland、
5:Northern Ostrobothnia Hospital District, Oulu, Finland
Despite the growth in genetic counseling for familial cancer syndromes, only little study has examined the high quality genetic
counseling practices. Being a carrier to BRCA1 or BRCA2 mutations can cause carriers e.g., fear of developing cancer. The
positive test result for BRCA1/2 mutation can also increase distress, which can be long-term in some cases.
This study is part of the study concerning developing the model of genetic counseling for hereditary breast and ovarian
cancer, particularly for BRCA1 and BRCA2 mutation carriers. The present study described how positive test result effects
on condition of health, ability to function and mental health in a sample of Finnish male BRCA1/2 mutation carriers (n=35).
The data was collected by modified questionnaire based on the quality of counseling model from the Departments of Clinical
Genetics at five university hospitals in Finland. Descriptive statistics and non-parametric statistical analysis, such as Kruskall-
Poster Session
Wallis test was used to analyze the data.
Positive BRCA1/2 test result could have effect on mental health. Being BRCA1/2 mutation carrier had decreased mental
health according to 29 % (10/35) of the men. Most men (97%, 34 /35) evaluated that ability to function has not changed and
9% (3/35) evaluated that condition of health had decreased after positive test result. The men, who evaluated decrease in
mental health, evaluated also decrease in health condition (p =0.019) compared to others. The men described that positive
test result caused e.g., fear and distress.
More evidence is needed to improve genetic counseling practices. Next part of the study is studying the subject by qualitative
methods by female and male BRCA1/2 mutation carriers. Understanding the experiences of being BRCA1/2 mutation carrier
has benefit to development of the patient-centered model of the genetic counseling for hereditary breast and ovarian cancer.
Tue(3)-P-302
Genetic counseling to couples having noninvasive prenatal genetic testing
Mai Sono 1 ，Akira Hata 1,2
，Misuzu Fujita 1 ，Emi Utsuno 2 ，Hisao Osada 2,3
1:Department of Public Health, Graduate School of Medicine, Chiba University, Japan、2:Department of Clinical Genetics, Chiba University
Hospital、3:Department of Maternal-fetal Medicine, Chiba University Hospital
Objective: Coincidence of informed choice between couple is prerequisite for having a noninvasive prenatal genetic testing
(NIPT) in Japan. In division of Clinical genetics of Chiba University Hospital, a team of a certified specialist in medical
genetics and a certified genetic counselors are in charge of Genetic Counselling (GC) for NIPT to promote their accurate
understanding for the topics such as NIPT, chromosomal and congenital disorders, prenatal test. The purpose of this study
was to ascertain the efficacy of GC on their understandings and intentions to have NIPT.
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Subjects and Methods: Subjects of the study were couples visited divisions of Clinical genetics of Chiba University Hospital
for having NIPT during the period from August to October, 2015. Brief questionnaire containing 16 questions related to their
degree of understanding, using a point scale of 0 (no understanding) to 5 (excellent understanding) for each individual before
and after the GC. Total number of points was used as an indicator of overall understanding.
Results: Responses were obtained from 68 individuals of 34 couples (response rate 97.1%). It was shown that there was no
difference in the degree of understanding between males and females prior to GC. Results showed the depth of understanding
after GC significantly increased for both gender with no significant difference. Couple’s coincident rates for intention to have
NIPT before, at, and after GC were 61.8%, 71.9%, was 81.3%, respectively.
Discussion: GC performed in our division has found to contribute increased depth of clients’ overall understanding with no
significant gender difference. This result may depend on significant amount of work of our limited staff, thus further studies
in other medical facilities would be expected.
Poster Session
Tue(3)-P-303
Genetic Counseling for Hereditary Breast and Ovarian Cancer Syndrome in our hospital
Hiroyuki Maeda 1 ，Takanori Goi 1 ，Akio Yamaguchi 1 ，Ikue Hata 2 ，Yuji Wada 2 ，Makoto Yoneda 2
1:First Dept.of Surgery, Faculty of Medicine, University of Fukui, Japan、2:Dept.of clinical Genetics Faculty of Medicine University of Fukui
Objective:The problem of genetic counseling for hereditary breast and ovarian cancer syndrome in our hospital were a few
breast cancer patients who had received BRCA genetic testing.
Method: In order to investigate the reason for refusing genetic testing, we asked the 24 breast cancer patients who were
performed genetic counseling from Februally 2011 to November 2015 in our hospital about the genetic testing.
Result: Among 24 patients, 5 patients underwent BRCA genetic testing. Main reasons for their refusal were expensive cost
and the bad influence to taking a policy on their relative life or marriage, so that they could not find out the benefit of
genetic testing. After starting precounseling by the nurses practitioner, one breast cancer patient with two relatives suffering
from recurrent breast cancer, really understood and had the genetic testing in order to know the risk, medical examination
and prevention of breast cancer, and ovarian cancer for herself or daughters. After induction of chemotherapy including
calboplatin and gemcitabine, four patients took genetic testing for the decision of operative methods and the adjuvant or
neoadjuvant chemotherapy.
Conclusion: The precounseling were very useful to hearing family history and to teaching HBOC syndrome. It was important
to explain the more benefit of genetic testing such as the induction of the effective chemotherapy or riskreduction surgery
than the screening of breast and ovarian cancer in the genetic counseling.
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Tue(3)-P-304
Eleven-year summary of genetic counseling in Kyoto Prefectural University of Medicine
Tomohiko Taki 1 ，Tomokatsu Yoshida 1 ，Yuuki Arai 1 ，Yoshifumi Fujita 1 ，Hirofumi Sakaguchi 1 ，Ikuko Mizuta 1 ，
Misako Hyogo 1 ，Masafumi Taniwaki 1 ，Masanori Nakagawa 1
1:Division of Genetic Counseling, Kyoto Prefectural University of Medicine, Japan
Our hospital opened the genetic counseling room in September, 2004. In this study, we summarized our experiences in genetic
counseling from September, 2004 to October 2015. In these 11 years, 229 new cases visited to our genetic counseling room
(totally 297 times). These included 142 (62.0%) single gene / mendelian disorders, 37 (16.2%) chromosomal disorders, 22
(9.6%) multifactorial disorder, and the remaining 28 cases (12.2%), based on the types of genetic background. On the other
hand, based on the related medical care regions, 20 (8.7%) inherited neoplasms, 80 (34.9%) congenital anomaly / pediatric
disorders, 20 (8.7%) reproduction/perinatal period disorders, 106 (46.3%) adult disorders, and the remaining 3 cases (1.3%)
were included. Thirty-four cases (14.8%) visited more than twice (up to 8 times). New cases have increased gradually (94
cases in the first 5 years and 115 in the last 5 years). Of these, the cases associated with neuromuscular disorders are the
most frequent (68 cases; 29.7%) and they also have gradually increased (22.3% of new cases in the first 5 years and 31.3% in
the last 5 years). Eight cases received genetic testing, including BRCA1/2 , RET , and spinocerebellar ataxia (SCA) genes,
and 3 received chromosome testing (parents who had patients with unbalanced chromosome or Robertsonian translocation).
Adequate and counselees-supporting genetic counseling is essential in the recent medical care.
Poster Session
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Poster Session
Genetics/Genomics Education
Tue(3)-P-305
Genetic Counselling in Practice: an international course for clinical geneticists and genetic counsellors
Aad Tibben 1 ，Francesca Forzano 2 ，Christine Patch 3 ，Domenico Coviello 4 ，Heather Skirton 5 ，Giovanni Romeo 6
1:Clinical Genetics, Leiden University Medical Centre, Netherlands、2:Clinical Genetics Unit, Galliera Hospital, Genova, Italy、3:Clinical
Genetics, Guys Hospital, London, UK、4:Laboratory of Human Genetics, Galliera Hospital, Genova, Italy、5:Faculty of Health and Human
Sciences, Plymouth University, Plymouth,UK、6:European School of Genetic Medicine, Bologna, Italy
The European School of Genetic Medicine (ESGM), founded in Italy by Giovanni Romeo and Victor McKusick in 1988, offers
courses with particular attention to applications in the field of clinical genetics. The 13th ‘Genetic Counselling in Practice’
course is planned for 2016. Each of the previous editions has attracted participants (a maximum of 35 students per course)
from Europe, Asia, Africa, and the Middle East. The most recent course (2015) tailored to local culture and legislation was
organized jointly by Sultan Qaboos University and ESGM in Muscat, Oman, in April 2015 and attracted 33 students from
countries of the Gulf region.
The Basic Section of the course, lasting 2.5 days, addresses topics including inheritance models, molecular genetics, cytoge-
Poster Session
netics, dysmorphology, cancer genetics and ethics. Students are supported to translate theory to practice through workshops
focussed on clinical work. In the Advanced part of the course, lasting 3.5 days, students are offered interactive lectures on
theory of counselling and communication but most of the time students develop their communication skills in a range of
exercises using clinical scenarios. First, they exercise basic skills such as asking open questions, paraphrasing and reflecting
feelings. Subsequently, students practice their communication skills in specific counselling situations such as exploring the
need for help and information, discussing results of risk assessment or predictive or prenatal testing, counselling about testing
children, and coping with patient scenarios that are challenging. Students are invited to present difficult cases from their own
clinical practice to be discussed in a plenary. Finally, to increase professional awareness, students are encouraged to reflect on
their personal professional qualities and pitfalls. Students receive intensive supervision from the teachers and feedback from
other students.
Tue(3)-P-306
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Tue(3)-P-307
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Tue(3)-P-308
Exploring education models of genomic medicine for general publics in informal learning settings
ShioJean Lin 1 ，Meeiren Wang 1
1:Genetic Counseling Center, Chi Mei Hospital, Taiwan
The goal of this project is to promote education on genomic medicine for general publics through informal science learning.
In this three years action research project, there are three objectives: 1. explore how people learn science in informal
environments; 2. establish contents of genetic education and teaching strategies suitable for informal learning settings; 3.
evaluate the effectiveness of education model on genomic medicine in informal learning settings. We will recruit three groups
of participants with various knowledge and motivation levels, such as women, clients who take health examine or participate
in health promoting activities, and senior citizens in rural communities. The education models will be tested in non-school
settings such as mothers’ clubs, health promoting/examination centers and community centers. The results of this project
Poster Session
will provide education models and recommendations for future research on fostering genetic health literacy among general
publics.
Tue(3)-P-309
Develop multimedia genetic instruction according to the cognitive theory of multimedia learning and
cognitive load theory
Ting-Kuang Yeh 1 ，Chi Yang 1 ，Chun-Hui Jen 1 ，Pei-Jung Lin 2 ，Chun-Yen Chang 1
1:National Taiwan Normal University, Taiwan、2:National Taiwan University
The current study aimed to examine the effectiveness of using animation and static to support high school students’ learning
of genetics. In the current study, we designed both animation and static-pictures based instructions, based on the cognitive
theory of multimedia learning and cognitive load theory. A total of 181, 7th grade students participated in this study. Students’
learning outcomes was evaluated by using a Genetics Concepts Test (GCT) and a self-rating, cognitive load questionnaire
(CLQ). The results indicated that: (1) Students in the animation group scored substantially and significantly better than
the static-pictures group on the open-ended questions. (2) Students in the static-pictures group scored better (with small
effect size) than the animation group on the multiple-choice questions. (3) Students in the animation group perceived lower
cognitive load than those of the static-pictures group. The findings of the present study may shape practical implications
that, compare to static picture, animation based instruction may provide more sufficient information for learning complex
conceptions.
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Tue(3)-P-310
Genetic Counseling Education at Kindai University
1,2 1,2 1,2 1,2 2
Junko M Tatsumi ，Kazuo Tamura ，Takeshi Minami ，Kazuma Saigoh ，Kazuo Fujikawa
1:Department of Life Science, Kindai University, Japan、2:Graduate School of Science and Engineering Research, Kindai University
In 2003, the training process for non-medical genetic counselor profession was launched with master’s programs at Shinshu
University Graduate School of Medicine and the Graduate School of Medical Science, Kitasato University, Japan. In 2005,
the following seven master programs of genetic counseling, Chiba Univ., Ochanomizu Univ., Kitasato Univ., Shinshu Univ.,
Kyoto Univ., Kindai Univ. and Kawasaki Univ. were accredited by Japanese Board of Genetic Counseling (JBGC) as the
first certified institutions. In Kindai University, the Genetic Counseling Program, a two-year course for Master’s Degree
of Science, in Graduate School of Science and Engineering Research has started in April 2005. The program is housed in
the Department of Life Science which consists of the following four fields; “Genetics and Molecular Biology”, “Structural
and Functional Biopolymer”, “Developmental Biology and Physiology” and “Environmental Science and Bioethics”. The
teaching staff of our program is composed of the member of the department, the faculty of medicine of our university as well
as other medical institutions. Every student in the program is expected to become a genetic counselor with the knowledge of
molecular genetics, quantitative genetics and principles of genetic risk assessment. They also experience more than 100 cases
in various clinical fields in two years. Our program has joint case conferences with the Graduate School of Medicine of Kyoto
University. In these conferences, participants discuss on actual cases, which are exhaustively examined from perspectives
including psychological and social aspects. In addition to the above requirement, the department graduate school requires
thesis work. Three to five students are entering our course every year. Finishing 28 students in 10 years of our program has
Poster Session
passed the qualifying examination for certification and are working as genetic counselors in all over Japan.
Tue(3)-P-311
Knowledge and attitudes of Gastroenterology fellows working in various hospitals of United States of
America, on genetic testing for disease specific biomarkers and knowledge of Precision Medicine
Shima Ghavimi 1 ，Hamed Azimi 2 ，Peter Sealy 1
1:Internal Medicine, Howard University Hospital, USA、2:Howard University, Cancer Center
Objectives: The aim of the study was to assess knowledge and attitudes of Gastroenterology fellows training in various
hospitals of United States of America, on genetic testing for gastrointestinal specific disease biomarkers and knowledge of
Precision Medicine.
Methods: We distributed self-administered questionnaire to the fellows either through email or by being in contact with them
with phone. Logistic regression models were used to evaluate the determinants of knowledge and attitudes towards their
knowledge of Genetics and Precision Medicine.
Results: 105 fellows answered the survey questions. 11% answered correctly the questions on regarding the genes involved
in developing colorectal cancer. Knowledge of Precision Medicine was highest among fellows which had prior genetic testing
during graduate training (14%) and inversely associated with female gender. As for cancer screening and specific biomarkers,
fellows were more knowledgeable if they attended courses on cancer genetic testing for biomarkers (11%) or postgraduate
training courses in epidemiology and evidence-based medicine (11%). More than 88% asked for the additional training on the
genetic testing and genetic testing for cancer during the specialization training.
Conclusion: The knowledge of Genetic testing for disease specific biomarkers and Precision Medicine among residents and
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fellows who answered the questionnaire appears to be insufficient. There is a need for additional training in this field. We
suggest AGA to incorporate at least one month of Genetic testing training for disease specific biomarkers and/or further
Continuing medical education on Genetic testing and Precision Medicine of colorectal cancer during the fellowship training.
Tue(3)-P-312
Analysis of the education guidelines and textbooks to investigate the feasibility of educating human
genetic in primary and secondary education system in Japan
Nana Akiyama 1 ，Masako Torishima 1 ，Takahito Wada 1 ，Shinji Kosugi 1
1:Department of Medical Ethics and Medical Genetics, Kyoto University Graduate School of Medicine, Japan
[Background] Now that the human genome has been sequenced, human genetics is likely to become even more closely
associated with our daily lives, highlighting the necessity of enhancing public knowledge of this field through basic education.
However, Japan’s current school education system rarely provides opportunities to learn it. There are two goals of human
genetics education: enhancing scientific understanding of genetics; and promoting moral and ethical understanding of human
diversity.
[Objective] With the aim of providing a basis for human genetics education while examining the textbooks and curriculum
guidelines to confirm the roles of human genetics-related items in the current school education system.
Poster Session
[Methods] The textbooks, supplementary readers, and curriculum guidelines currently used in Japan were examined, focusing
on the roles of human genetics-related items in each grade.
[Results] In the education materials for first to second-grade elementary school students, issues related to daily life activities
also covered disabilities. In those for third-grade junior high school students, science-related issues included basic genetics,
not explaining human traits, but outlining the human genome and cloning technology on some occasions.
[Discussion] Based on these results supporting the current school education system to develop a basic understanding of the
concept of genetics and diversity, it may be possible even for first-grade elementary school students to understand the basics
of human genetics. As future perspectives, it may be necessary to incorporate the following issues into learning programs for
each grade and link their contents: first and second grades in elementary school: pedigree charts; third and fourth: inheritance
of genes from parents to their children; fifth and sixth: lifestyle-related diseases; and junior high school: bioethics related to
human genetics.
Tue(3)-P-313
The Current Landscape of the After-Sales Services of Direct-To-Consumer (DTC) Genetic Testing in
Japan
Eriko Takamine 1 ，Hidehiko Miyake 1,2 ，Manami Matsukawa 1 ，Akira Inaba 1 ，Ayumi Yonei 1 ，Yumie Hiraoka 1 ，
Sayaka Honda 1 ，Hitomi Nishio 1 ，Takahito Wada 1,2 ，Shinji Kosugi 1,2
1:Genetic Counselor Course, Kyoto University, School of Public Health, Japan、2:Clinical Genetics Unit, Kyoto University Hospital
Background: In Japan, there are no specific laws which regulate Direct-To-Consumer (DTC) genetic testing. Professionals
have been working on establishing regulations, but currently, DTC genetic testing is self-regulated. Due to this fact, one of the
major concerns for genetic professionals has been how accurately consumers understand their results and whether after-sales
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services are provided by the DTC-genetic-testing companies.
Objectives: The objectives of this research are to figure out the current situation of DTC-genetic-testing after-sales services,
and to investigate the needs and interests of consumers through the after-sales services, which could provide ideas of ap-
proachable ways to educate the public.
Method: Twelve companies which conduct DTC genetic testing among the 29 which are the members of the Council for
Protection of Individual Genetic Information (CPIGI) were evaluated. The information was collected through their websites
which are open to the public.
Results: The total count of DTC-genetic-testing products turned out to be 28 since some companies have multiple genetic
testing products. Some products had a few different after-sales services. Fourteen products of the 28 came with diet advice
and five with exercise advice, and eight products had counseling services provided at the company’s office or an allied clinic.
Two products did not have any after-sales services, and four did not mention after-sales services.
Discussion: This research showed that most DTC-genetic-testing after-sales services focus on changeable factors such as diet
and exercise which are familiar to consumers. Considering situations where consumers receive testing and want after-sales
services, the changeable factors could be a first step to approach the public regarding education on genetics and to increase
the understanding of genetics.
Poster Session
Tue(3)-P-314
Education tools to teach children about genetics, variation, and evolution
Tomoko Kobayashi 1,2 ，Aizawa Yayoi 2 ，Sugawara Michiko 5 ，Sakurai Yageta Mika 1 ，Danjoh Inaho 3 ，
Yamaguchi Kabata Yumi 3 ，Kuriki Miho 4 ，Kuriyama Shinichi 5,6 ，Nagami Fuji 4 ，Yasuda Jun 3 ，Kawame Hiroshi 2 ，
Yamamoto Masayuki 3 ，Suzuki Yoichi 1,2
1:Department of Genomic Medicine Education, Tohoku Medical Megabank Organization (ToMMo), Tohoku University, Japan、2:Department
of Education and Training, ToMMo, Tohoku University、3:Department of Integrative Genomics, ToMMo, Tohoku University、4:Department
of Public Relations and Planning, ToMMo, Tohoku University、5:Osaki Community Support Center, ToMMo, Tohoku University、
6:Department of Preventive Medicine and Epidemiology, ToMMo, Tohoku University
Improving the genetic and genomic literacy of not only medical staff but also the general public is required to promote
personalized medicine and healthcare. Educating children is an important approach for improving genetic literacy in the
general public because if children become interested in genetics and genomics, their parents will do so as well. There are
few easy-to-use, efficient genetic education tools for children in Japan. Therefore, we have developed such education tools
for children. The themes of our education tools are genetics, variation, and evolution. Each of the three tools includes a
worksheet and instruction manual. The genetics worksheet is a spot-the-difference puzzle that consists of two illustrations
of the DNA double helix structure, one with the correct pairing of ATGC bases, and the other with incorrect. The manual
includes a series of illustrations ranging from macro to micro levels: cell → nucleus → chromosome → DNA. The variation
worksheet is also a spot-the-difference puzzle with two illustrations of the human face: one has a single-edged eyelid, and
the other has a double. The manual describes how eyelid shape is produced by a DNA code difference between individuals
and that all aspects of human habitus are determined not only by genetic diathesis but also by environmental factors. The
evolution worksheet is a puzzle that consists of five illustrations of animals and plants. Testers need to arrange them in order
of the number of genes and are expected to realize that bigger or complex organisms do not necessarily have larger number
of genes. The manual describes how an evolutionary tree is explored using gene analysis.To evaluate the degree of interest in
our education tools, we asked 39 children age 2 to 15 years to play with one of our tools. On a four-point interest scale, 88%
of the children age 5 to15 years gave it relatively high scores (3 or 4), suggesting that the tools were favorably accepted by
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most children.
Tue(3)-P-315
The survey of recognition of medical students about recent topics related to genetic medicine
Satomi Aihara 1 ，Tomoko Yamamoto 1 ，Keisuke Tsumura 1 ，Satoshi Nisiyama 1 ，Yoshifumi Nakao 1 ，
Masatoshi Yokoyama 1
1:Department of Obstetrics and Gynecology, Faculty of Medicine Saga University, Japan
[Background and Aims] Obstetrics and Gynecology is deeply related to genetic medicine; such as Hereditary Breast Ovarian
Cancer Syndrome (HBOC) and Noninvasive prenatal genetic testing (NIPT). In our university, 4th degree medical students
receive a lecture of Obstetrics and Gynecology. Genetic medicine has become more important in clinical medicine. There is a
need to teach the medical genetics in medical education. In order to know what important things to teach in medical genetics
lecture, we have investigated whether the medical students have the perception and knowledge of genetic testing.[Results]
Sixty (92%) and 30 (46%) students had at least heard about hereditary tumor and HBOC, respectively.They know about
HBOC from lectures and news. Fifty-two (80%) students answered there is needs of genetic testing in high risk individuals.
Thirty students don’t understand the need for Risk Reducing Surgery, and 21 students answered that hereditary cancer
could be prevented by surveillance. Fifty-three students (84%) had at least know about NIPT, only nine students (14%)
were able to answer about NIPT correctly. Twenty-one (32%) desired to receive NIPT, and 39 (61%) students didn’t decide
whether receive NIPT if they were pregnant. Ten students (16%) want to select abortion if result of NIPT would be positive .
Fifty-three (83%) and 48 (77%) students want to receive special lecture about HBOC and NIPT, respectively. [Conclusion]
Poster Session
Few students understand about current genetic topics correctly. There is needs of education of genetic medicine for medical
students. We are considering a small group lecture in the clinical practice of medical students.
Tue(3)-P-316
Developing genome science literacy at school: exploring opportunities in the Australian secondary school
science curriculum
1,2 2
Bronwyn N Terrill ，Stephen Keast
1:Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Australia、2:Monash University
The changing needs of citizens in the genomic era have prompted new thought about teaching and learning. There is increasing
need for accessible genomics education that enables students to become informed citizens and participate effectively in societal
discussions about genomics. According to literature and expert conversations, ’genomically-literate’ citizens and consumers of
genomic technologies would be expected to understand that their characteristics are a result of complex interactions between
their genes and environment; have skills to critically evaluate evidence and deal with risk information; and appreciate the
uncertainty of a rapidly changing science.
This study explored how genomics literacy could be most effectively incorporated into school science by analysing opportunities
at three levels in the school system: namely the national curriculum, the state syllabus, and the classroom. Data collection
combined qualitative content analysis of a document archive - including framework, curriculum and syllabus documents,
consultation reports and correspondence - with qualitative analysis of three semi-structured interviews with classroom teachers
of Year 10 science. Data sets and lesson outlines for genomic literacy-focused lessons to align with state syllabi were generated
as part of this project and used as prompts for discussion.
At the level of the national framework, the Australian Curriculum standards provide significant opportunity to develop
genomic literacy. However, individual member states and territories are responsible for implementing the national standards.
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State by state implemenation varies significantly in the approach, emphasis on, and interpretation of, scientific literacy.
Ultimately, teachers determine how a topic such as genomics is addressed in the classroom, but assessment requirements and
accessible resources have significant influence on the strategies employed.
Tue(3)-P-317
Genetics Objective Structured Clinical Exam (Genetics OSCE) A tool for assessing and improving medical
genetics communication skills and knowledge
Simon G Kupchik 1 ，Elizabeth Kachur 1 ，Lilian Torrey 1
1:Pediatrics, Maimonides Infants and Children’s Hospital of Brooklyn at Maimonides Medical Center, USA
The relevance of basic clinical genetics skills and knowledge for primary care physicians (PCPs) continues to expand with
increased availability of testing capabilities such as nextgen sequencing. PCPs are facing newer, complex and difficult chal-
lenges with regards to genetics testing and counseling. The Objective Structured Clinical Exam (OSCE) is a well established
methodology to assess, among others, cultural competence and communication skills. At the Maimonides Infants and Chil-
dren’s Hospital of Brooklyn at Maimonides Medical Center (MICH at MMC) we developed a Genetics OSCE as a tool to both
assess and improve on genetics knowledge and skills of physicians in training. Briefly, it consists on five different standardized
medical genetics patients encounters by third year pediatric residents followed by extensive feedback and debriefing We will
present on our over ten years successful experience administering and scoring our uniquely developed Genetics OSCE.
Poster Session
Tue(3)-P-318
Innovative approaches to workforce transformation: Preparing England’s National Health Service to
deliver a genomic medicine service
Michelle Bishop 1 ，Val Davison 1 ，Anneke Seller 1 ，Sue Hill 2 ，HEE’s Genomics Education Programme
1:Genomics Education Programme, Health Education England, UK、2:Chief Scientific Officer, NHS England
A key aim of England’s 100,000 Genomes Project is to create a new genomic medicine service for the National Health Service
(NHS). Health Education England is responsible for the education and training of NHS staff, and its Genomics Education
Programme (GEP) has been tasked to ensure NHS staff have the knowledge, skills and experience required to deliver a
world-leading personalised medicine service allowing patients to benefit from advances in genomics. The GEP is taking a
co-ordinated national approach with two aims: wide-scale transformation that will prepare the current workforce for the
integration of genomics; and ensuring the right training to deliver the future workforce. To support these aims, The GEP has
developed an innovative Master’s in Genomic Medicine, providing education in genomics applicable to both clinical practice
and medical research where individual modules that can be used alone for continuing personal and professional development.
A national network of leading universities is delivering this programme, with the GEP funding Masters and CPPD places.
Students will access data from the 100,000 Genomes Project for their research module, providing practical experience in
analysing genomic data and contributing to cutting edge research. Future workforce work is initially focusing on the scientific
and clinical expertise needed to integrate genomic technologies into clinical practice. The GEP has developed accredited
training pathways for emergent fields (eg bioinformatics) and re-shaped training pathways for established professions (eg
genetic counselling). The GEP has also funded new doctoral-level training posts in genomic science and bioinformatics to
ensure the leadership expertise needed to integrate genomics in the NHS. This work will pave the way for the inclusion
of genomics in all professional education and training, ensuring the legacy of the 100,000 Genomes Project to deliver a
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personalised medicine service for all patients.
Tue(3)-P-319
Developing a MANGA cartoon medium that can promote Family Health History and Human Genetics
to the public
Yumie Hiraoka 1 ，Masako Torishima 2 ，Nana Akiyama 1 ，Sayaka Honda 1 ，Hitomi Nishio 1 ，Takahito Wada 1 ，
Shinji Kosugi 1
1:Genetic Counselor Course, Kyoto University School of Public Health, Kyoto, Japan、2:Clinical Genetics Unit, Kyoto University Hospital,
Kyoto, Japan
[Background] Today genetic technology has been rapidly advancing and genetic testing is largely available in medical practice.
In Japan, we have little chance to learn human genetics at school, and we, genetic counselors and medical geneticists, should
play a vital role to promote human genetics literacy of the public for providing optimal genetics service. “Family Health
History (FHH)” (1) is an accessible tool that can captures genetics information, lifestyle and environmental factors, (2)
allows health care providers to diagnose conditions and to assess risks and (3) increases health and genetics knowledge for
the individual and the family. In this study, we developed a MANGA booklet, as a new educational implement of human
genetics and FHH. Japanese MANGA, or a book in cartoon fashion, has been a widely spreading subculture in the world
now, therefore, could be one of the useful ways in genetics education.
[Study] We developed a new type of tool, the MANGA booklet, which has basic information about (1) human genetics
Poster Session
including diversity of genes and environmental risks, and about (2) FHH, including instructions for gathering detailed medical
information for family members and creating a pedigree chart. These were assessed by certified specialists in medical genetics
and genetic counselors, and the undergraduates studying genetic counseling
[Discussion] FHH is“the first genetic test” in medical practice or genetic counseling. Our MANGA tool seems to be a
practical tool to interest the public in human genetics, and help them learn familial and own health status. We expect it to
be accessible, easy to comprehend human genetics and FHH. We are also planning to translate the MANGA textbook into
other languages to be available in many countries. We are now conducting to measure the effectiveness of the MANGA.
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Poster Session
Statistical Genetics and Genetic Epidemiology
Wed., April 06, 2016 13:45-14:45 Event Hall (1F)
Wed(4)-P-1
Effect sizes in genetic-epidemiological studies of complex diseases
Michael Nothnagel 1 ，Sabine Siegert 1 ，Andreas Wolf 2 ，David N Cooper 3 ，Michael Krawczak 2
1:Cologne Center for Genomics, University of Cologne, Germany、2:Institute of Medical Informatics and Statistics, Christian-Albrechts
University Kiel、3:Institute of Medical Genetics, Cardiff University
Research into the genetic basis of complex disease usually invariably assumes that causative mutations are over-represented
among patients as compared to controls. However, we show that this supposition is not true and that a mutation contributing
to the etiology of a complex disease can, under certain circumstances, be depleted among patients. We repeatedly simulated
populations with defined disease prevalence using a Wright-Fisher model, assuming various types of population history
and genotype-phenotype relationship and subsequently evaluating mutation-specific population frequencies and odds ratios
(ORs). While rare diseases (prevalence <1%) met the expectation of being consistently caused by rare mutations with ORs>1,
pandemic diseases (prevalence 10-20%) featured up to 20% of mutations with ORs<1 and in general a wide distribution of
ORs and population mutation frequency. This apparently paradoxical result is explicable in terms of mutual confounding
Poster Session
of the respective genotype-phenotype relationships due to a negative correlation between causal mutations induced by their
common gene genealogy. Extended simulations involving oligogenic models of up to 10 loci resulted in an attenuation of this
proportion of apparently protective, albeit deleterious mutations, but also predicted the presence of a substantial proportion of
such mutations even for polygenic models. Such ’protective’ mutations would normally tend to be excluded, albeit erroneously,
from further study. Consistent with our findings, a significant negative correlation became apparent in published genome-wide
association studies between the OR of genetic variants associated with a particular disease and the prevalence of that disease.
Wed(4)-P-3
Comparison of methods for meta-analysis of binary traits with linear mixed models
James P Cook 1 ，Andrew P Morris 1
1:Department of Biostatistics, University of Liverpool, UK
Linear mixed models (LMMs) are becoming increasingly popular for the analysis of genome-wide association studies (GWAS)
because they account for relatedness and population structure via a kinship matrix. However, these models assume that the
outcome of interest is quantitative, and their properties for binary traits have not been widely investigated, particularly in
the context of meta-analysis.
In this study, we performed detailed simulations to compare the power and type 1 error rate of binary trait analyses using
traditional logistic regression and LMMs. We assumed that meta-analysis of association summary statistics was performed
across ten studies, each of 2,000 individuals, comprising a total of 10,000 cases and 10,000 controls. Fixed-effects meta-analysis
was undertaken with inverse-variance weighting of effect sizes (implemented in GWAMA) and effective sample size weighting
of directed Z-scores (implemented in METAL). We simulated three scenarios for case-control imbalance: (i) no imbalance
(1:1 ratio across all studies); (ii) moderate imbalance (variable ratio of 3:1 to 1:3 across studies); and (iii) extreme imbalance
(variable ratio of 19:1 to 1:19 across studies). Within each set of simulations, comparisons were performed at effect allele
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frequencies (EAF) of 0.5, 0.2, 0.1, 0.05 and 0.01.
Results showed that all tests were well calibrated in terms of type 1 error rates, except for the case of rare variants
(EAF = 0.01), where the LMM was anti-conservative. For common variants (EAF>5%), the LMM is less powerful than
logistic regression in the presence of extreme case-control imbalance between studies and the inverse variance method is used
for meta-analysis. However, when all studies are balanced, or when there is only a moderate imbalance between studies, all
approaches had equivalent power.
Our study has important implications for the design and analysis of GWAS, and the utility of LMM approaches in large-scale
meta-analysis of complex binary traits.
Wed(4)-P-4
High-density Association Mapping and Interaction Analysis of PLA2R1 and HLA Regions with Idiopathic
Membranous Nephropathy in Japanese
Myo Thiri 1 ，Kenjiro Honda 2 ，Hodaka Suzuki 3 ，Tsuyoshi Watanabe 3 ，Eisei Noiri 2,4
，Katsushi Tokunaga 1
1:Department of Human Genetics, School of International Health, The University of Tokyo, Japan、2:Department of Nephrology and En-
docrinology, The University of Tokyo Hospital、3:Department of Nephrology, Hypertension, Diabetology, Endocrinology and Metabolism,
Fukushima Medical University School of Medicine、4:Department of Hemodialysis and Apheresis, The University of Tokyo Hospital
Idiopathic membranous nephropathy (IMN) is one of the major causes of adult nephrotic syndrome. Recent studies have
Poster Session
reported the association of the risk alleles of phospholipase A2 receptor 1 (PLA2R1) and HLA-DQA1 with IMN in the Euro-
pean populations, and the significant associations were replicated in Chinese, Taiwanese and Korean populations. However,
high-density association mapping covering the whole region of PLA2R1 and HLA regions for the association with IMN has
not been performed yet in the East Asian populations. In the first stage of the study, we performed genotyping of 15 SNPs
in PLA2R1 and HLA typing of HLA-A, B, C , DRB1 , DQB1 and DPB1 in patients with 53 Japanese biopsy-proven IMN
patients and 419 healthy controls. In the second stage, we performed replication study with 130 Japanese IMN cases and
392 healthy controls. We also analyzed the association in the combined data set including both first and second sample
sets. Moreover, interactive effects of HLA and PLA2R1 risk alleles were analyzed. In the first stage, single point analysis on
PLA2R1 identified 7 significant SNPs, and in the replication stage, 5 of which were confirmed (strongest association in the
combined data set: P=2.16 x 10-15 , OR=3.02). For HLA genes, strong associations were observed with HLA-DRB1*15:01
and HLA-DQB1*06:02 in the first stage, and both were successfully replicated in the second stage (P=3.94 x 10-13 , OR=3.09
and P=8.90 x 10-13 , OR=3.10, respectively, in the combined data set). In the interaction analysis, more than additive affect
was detected in the individuals carrying both risk alleles of HLA-DRB1 -DQB1 and PLA2R1 . The findings identified the
primary associations of HLA and PLA2R1 polymorphisms with IMN in the Japanese population. Furthermore, the increased
risk of IMN by combination of PLA2R1 and HLA risk alleles confirmed the importance of the interaction of these two genes
in the development of IMN.
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Wed(4)-P-5
Familial aggregation of Dupuytren’s disease
1,2
Laetitia Michou ，Valerie Chaudru 3 ，Daniel Cloutier 4 ，Elisabeth Petit-Teixeira 3
1:CHU de Quebec-Laval University, Canada、2:Division of Rheumatology, Department of Medicine, Laval University and CHU de Quebec Re-
search Centre, Quebec, QC, Canada、3:GenHotel-EA3886, Evry-Val d’Essonne University, France、4:Division of Plastic Surgery, Department
of Surgery, Laval University and CHU de Quebec research centre, Quebec, QC, Canada
Objective: This study aimed at investigating familial aggregation (up to the second degree of relatedness) of Dupuytren’s
disease, which is the most common hereditary connective tissue disorder in Caucasians, with prevalence of 13.6% in Canada.
Currently, 80 patients were recruited: 58 from Surgery department and 22 seen for another purpose in Rheumatology.
Methods: We conducted telephone interviews to obtain family history of Dupuytren’s up to the second degree in our 80
patients, as well as classical factors known to be associated with Dupuytren’s such as sex, hair and eye colors, scolarity
level, repeated finger flexion at work or during leisures, diabetes and its treatment, epilepsy and anti-epileptic, tobacco and
alcohol. Familial aggregation was calculated in siblings, at the first degree of relatedness (FDR), and was compared between
patients from Surgery versus Rheumatology. Classical risk factors of Dupuytren’s were also compared between patients from
each department and stratified for familial aggregation .
Results: Our preliminary results showed a highest familial aggregation among siblings (λsiblings=1.33) and FDR
(λFDR=1.11). Familial aggregation was increased in the Surgery group, in particular among siblings (λsiblings=1.61)
and FDR (λFDR=1.36), but not in Rheumatology participants. Probands from Rheumatology were less likely to have at
Poster Session
least one relative affected (43% in the Rheumatology versus 78% in Surgery, P=0.008), they were more likely to have light
hairs (64% in Rheumatology versus 31% in Surgery, P=0.02), and they were less likely to have an University level (23% in
Rheumatology versus 52% in Surgery, P=0.04). We did not find any association with classical risk factors of Dupuytren’s at
this stage of the study when we compared patients according to presence/absence of familial aggregation.
Conclusion: Familial aggregation was observed in Canadians with Dupuytren’s among siblings and FDR from Surgery group.
Wed(4)-P-6
Autosomal SNPs Genotyping for Identification of Missing Casualties
Jung-Hyun Park 1 ，Seung-Bum Hong 1
1:Division of DNA Analysis, Scientific Investigation Laboratory, Criminal Investigation Command, Ministry of National Defense, Korea,
South
To identify the remains of service members missing in the Korean War, a population-based and DNA-focused identification
system has been implemented since 2007 by the Ministry of National Defense Agency for Killed in Action Recovery and
Identification(MAKRI) in Korea. Since 2007, DNA Analysis of Korean War victims has been performed by the Ministry of
National Defense Criminal Investigation Command (MND CIC).
DNA profiles obtained from skeletal samples of Korean War victims are put into a database for random matching and kinship
analysis to confirm the relationship between missing casualties and their alleged relatives. It has been reported that the
problem of the possibility of erroneous match between unrelated people became significant especially with growth of the
number of genotypes in A-STR database. To solve the problem related with high false positive rates, higher kinship index
threshold is required. However, use of high kinship index threshold results in extremely high false negative rate. Therefore,
the use of increased number of autosomal markers with minimal kinship index threshold is recommended.
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Highly effective massively parallel SNP genotyping platforms using microarray technology were developed and have been used
in various human population studies. In this study, we adopted resequencing microarray platform to apply autosomal SNP
markers to inference of relatedness between missing casualties and their alleged relatives. Reseuencing microarray showed
reliable and robust results in sensitivity and degradation testing. Autosomal SNP markers analyzed using resequencing
microarray platform showed remarkably higher likelihood ratios than 23 autosomal STR markers in kinship analysis of first
to third degree of relatedness. Our results demonstrate that autosomal SNP markers hold great promise for identification of
missing casualties.
Wed(4)-P-7
Understanding gene expression changes in Systemic Lupus Erythematosus through a systems approach
Tingyou Wang 1 ，Yongfei Wang 1 ，Yan Zhang 1 ，Mengbiao Guo 1 ，Jing Yang 1 ，Wanling Yang 1
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with unclear pathogenesis. Even though the hypothesis-
free GWAS have provided valuable insights into the genetic basis of SLE, and identified more than 50 susceptibility variants,
the identified variants so far only explain approximately 20% of disease heritability for SLE. Gene expression represents
the intermediate phenotype that might be indicative of disease phenotypic variation, and provides insights regarding the
effects of genetic variation and epigenetic aberrations. Making use of public data from NCBI GEO, we have identified 419
differentially expressed genes (DEGs) in three different cell types through gene expression meta-analysis. Functional analysis
Poster Session
showed that upregulated genes were involved mainly in immune and inflammatory responses, type I interferon-mediated
signalling pathways and responses to viral infection. Integrative analysis of state-of-the-art, high-throughput biomedical data,
such as expression quantitative trait loci (eQTLs) and protein-protein interactions allowed us to bridge genetic findings and
gene expression changes, to link disease-associated genes (DAGs) to DEGs in a systems level. We found that some known
SLE susceptibility loci were eQTLs whose associated genes were DEGs, some potentially functional modules including both
DAGs and DEGs. In epigenetic level, DNA methylation analysis was employed to decipher gene expression changes. A high
correlation was observed between upregulated DEGs and DNA hypomethylation.
In conclusion, this study provided clear biological mechanistic interpretation for DEG in SLE by incorporating information
from eQTL, differential methylation, and genetic association.
Wed(4)-P-8
Identification of predisposing genes in severe neural tube defects by whole exome sequencing in multiplex
families
Philippe Lemay 1 ，Alexandre Dionne-Laporte 3 ，Dan Spiegelman 3 ，Edouard Henrion 3 ，Ousmane Diallo 3 ，
Patrizia De Marco 2 ，Elsa Merello 2 ，Guy A. Rouleau 3 ，Valeria Capra 2 ，Zoha Kibar 1
1:Universite de Montreal, Canada、2:Gaslini Hospital, Genova, Italy、3:Montreal Neurological Institute, McGill University, Montreal
Neural tube defects (NTD), including anencephaly and spina bifida, are among the most common and severe birth defects
affecting nearly 1 in 1000 births. They are caused by partial or complete failure of neural tube closure during embryogenesis.
The etiology of NTD is complex including genetic and environmental factors that remain largely unknown. While preconcep-
tional intake of folic acid protects against 50-70% of NTDs, they still affect thousands of families urging the need for novel
preventive and counseling strategies.
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Here we use whole exome sequencing (WES) in familial severe forms of NTDs to identify novel candidate pathways or genes
implicated in NTD etiology. In analyzing the WES data, we prioritize highly pathogenic variants in genes previously as-
sociated to NTDs and biological processes burdened by a high amount of rare coding mutations. Seven multiplex families
with at least 2 NTD affected individuals were recruited. Exome sequencing data obtained on 31 individuals was treated by
a bioinformatics pipeline. The output was filtered for rare (>5% in public databases) and high quality mutations resulting
in a list of 200 to 300 mutations per family. The list was then screened for enrichment of biological processes and highly
pathogenic mutations in genes previously associated to NTDs. Candidate processes or genes are then validated in a cohort of
87 control families. This approach resulted in the identification of biological processes significantly burdened with mutations
by DAVID 6.7 in two families. It also identified two highly deleterious variants in two folate related genes in the two affected
probands of one family suggesting a potential additive effect of those variants.
Our results suggest that WES combined to a hypothesis free gene enrichment approach and a candidate gene approach may
offer new insights into the complex etiology of NTDs. Identification of new genetic factors will lead to better counseling
strategies of affected families.
Wed(4)-P-9
Multivariate binary model for powerfull disease mapping
Susana Eyheramendy 1 ，Fernando Crespo 1
1:Statistics Department, Pontificia Universidad Catolica de Chile, Chile
Poster Session
Most genetic association studies perform association with a single phenotype at a time, despite the fact that usually there
are several other diseases or traits also available to the study. There are several statistical advantages to the joint modelling
of correlated diseases, such as, more powerfull test of association can be performed and also more accurate estimates of the
genetic effects on the phenotypes can be obtained. There are also biological advantages on the joint modelling of diseases, for
example, a pleiotropic effect can be assessed in this stype of models. In our study we introduce a multivariate binary model
to assess the association of a single SNP on several diseases simultaneously. We develop a robust algorithm to estimate the
genetic effects on each phenotype and obtain a more powerfull test to measure significance on the association tests. We show
via simulations the advantages of the multivariate model over single univariate models.
Wed(4)-P-10
A novel computational tool for genome-to-phenotype prediction using VaDE, a manually-curated
database of reproducible associations between various traits and genomic polymorphisms
Tadashi Imanishi 1 ，Yasuko Takahashi 1,2
，Miho Sera 1 ，Kentaro Mamiya 1 ，Takuya Habara 1
1:Department of Molecular Life Science, Tokai University School of Medicine, Japan、2:Institute for Genome Research, The University of
Tokushima
Genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms (SNPs) associated with
the development of common diseases. However, it is clear that genetic risk factors of common diseases are heterogeneous
among human populations. Therefore, we developed a database of genomic polymorphisms that are reproducibly associated
with disease susceptibilities, drug responses and other traits for each human population: ‘VarySysDB Disease Edition’
(VaDE; http://bmi-tokai.jp/VaDE/). SNP-trait association data were obtained from the National Human Genome Research
Institute GWAS (NHGRI GWAS) catalog and RAvariome, and we added detailed information of sample populations by
curating original papers. In addition, we collected and curated original papers, and registered the detailed information of
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SNP-trait associations in VaDE. Then, we evaluated reproducibility of associations in each population by counting the number
of significantly associated studies. Finally, we could obtain 2697 and 619 reproducible associations for 427 and 151 traits in
the European and East Asian populations, respectively. Furthermore, we developed a novel computational tool for genome-
to-phenotype prediction using the VaDE database. This can be applied to specify individuals with high disease risks based
on their genomic information, and will be a useful tool of human genetics studies.
Reference: Nagai, Takahashi and Imanishi (2014) Nucleic Acids Research, 43: D868-72.
Wed(4)-P-11
Comparison of different approaches to gene-based association analysis of complex traits
Nadezhda M. Belonogova 1 ，Gulnara R. Svishcheva 1 ，Anna A. Torgasheva 1 ，Pavel M. Borodin 1 ，
Tatiana I. Axenovich 1
1:Institute of Cytology & Genetics, Russia
Rapid progress in whole-exome and whole-genome sequencing technologies provides new opportunities for detecting rare
variants that control complex traits. In this context, region-based association analysis becomes more powerful tool for gene
mapping than testing of individual genetic variants. Several approaches to regional association analysis have been developed
recently. The first, simplest of them, employs burden tests based on collapsing rare variants within a region of interest. The
second approach uses kernel machine regression for regional association analysis. This method compares average similarity of
Poster Session
genetic variants in the analyzed region for each pair of individuals with pairwise phenotypic similarity. The third approach is
based on a functional data analysis (FDA), which smoothes the data through the standard basis functions.
We review the advantages and limitations of different approaches and estimate them using a wide set of simulated scenarios.
The collapsing approach assumes that the majority of rare variants are causal and that their effects are unidirectional. In
practice, these assumptions rarely hold, and this method is the low-power in majority of situations. Kernel-based methods are
more flexible to the opposite direction of causal variant effects and limited proportion of causal variants. The optimal unified
test combines burden-based and kernel-based approaches and shows a higher power than the kernel-based test when causal
variants are unidirectional. Smoothing technique reduces the noise and/or observation errors and utilizes information on both
linkage and linkage disequilibrium. However, we show that this approach cannot be effectively used on regions with small
number of genetic variants where it reduces to multiple linear regression. For several scenarios, multiple linear regression has
advantage even for regions with large number of variants. Nevertheless, FDA-based methods are the most powerful for large
proportion of scenarios.
Wed(4)-P-12
Smooth-threshold multivariate genetic prediction with unbiased model selection
Masao Ueki 1 ，Gen Tamiya 2
1:Biostatistics Center, Kurume Unviersity, Japan、2:Tohoku Medical Megabank Organization, Tohoku University
We develop a new genetic prediction method, smooth-threshold multivariate genetic prediction, using single nucleotide poly-
morphisms (SNPs) data in genome-wide association studies (GWASs). Our method consists of two stages. At the first stage,
unlike the usual discontinuous SNP screening as used in the gene score method, our method continuously screens SNPs based
on the output from standard univariate analysis for marginal association of each SNP. At the second stage, the predictive
model is built by a generalized ridge regression simultaneously using the screened SNPs with SNP weight determined by the
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strength of marginal association. Continuous SNP screening by the smooth-thresholding not only makes prediction stable but
also leads to a closed form expression of generalized degrees of freedom (GDF). The GDF leads to the Stein’s unbiased risk
estimation (SURE) which enables data-dependent choice of optimal SNP screening cutoff without using cross-validation. Our
method is very rapid because computationally expensive genome-wide scan is required only once in contrast to the penalized
regression methods including lasso and elastic net. Simulation studies which mimic real GWAS data with quantitative and
binary traits demonstrate that the proposed method outperforms the gene score method and genomic best linear unbiased
prediction (GBLUP), and also shows comparable or sometimes improved performance with the lasso and elastic net being
known to have good predictive ability but with heavy computational cost. Application to whole-genome sequencing (WGS)
data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) exhibits that the proposed method shows higher predic-
tive power than the gene score and GBLUP methods.
Wed(4)-P-13
Genetic Epidemiology of Breast Cancer in a Less Developed District Bahawalnagar, Pakistan
Shamsa Kanwal 1 ，Muhammad Aslamkhan 1
1:Human Genetics and Molecular Biology Department, University of Health Sciences, Pakistan
Poster Session
The incidence data of breast cancer is not available for Pakistan; though a number of hospital-based studies report a high
prevalence. Study was designed to determine the prevalence of breast cancer and to see its association with socio-economic,
demographic and reproductive factors in Bahawalnagar. A total of 1920 females were recruited for the study from all the 5
tehsils (118 union councils). Only one female (>15 years) from each household was recruited randomly who was examined
for lump/breast cancer.
Out of 1920 females, 1690 (88%) were married. The consanguinity in the parents of probands (n = 1920) were 84.6%; of
which 43.9% were 1st cousins, 8.5% were 2nd cousins and 32.2% were Bradari (brotherhood). In the probands (n = 1690)
consanguinity were found in 74.5%; of which 48.34% were 1st cousins, 3.7% were 2nd cousins and 22.5% were Bradari. Based
on monthly income analysis, 44.6% belonged to lower, 52.9% to middle and 2.4% to upper-socioeconomic class.
The mean age at menarche was 14.01 +1.224 years (n = 1920) and 94.5% had regular menstrual cycle. The mean age at
marriage was 20.31+3.630 years (n = 1690) with 1st live birth at 21.93+3.652 years. Age at menopause was 46.58+4.442
years (n = 270). About 88.2% women were physically active and performing household chores regularly. Majority (93.1%)
of women had not heard about cancer in their first degree relatives while 7% had a family history of cancer. Ovarian cancer
had been reported by 1.3% females in their families. Breast cancer was reported by 2.9% females in their families. Diagnosed
breast cancer was proven by biopsy in 0.2% cases. Only 39% women were aware of breast cancer and 1% knew about breast
self-examination. On physical examination, 47 (2.4%) women had lump(s) in their breast region. Only 3 (0.156%) women
were found with breast cancer, already diagnosed from hospital, giving the prevalence of 156 per 100,000.
It appears that Pakistani population is genetically more prone to breast cancer.
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Wed(4)-P-14
Detecting gene-gene interactions for survival phenotypes using a unified multifactor dimensionality re-
duction analysis
Taesung Park 1 ，Yongkang Kim 1 ，Wenbao Yu 2 ，Seungyeoun Lee 3
1:Statistics, Seoul National University, Korea, South、2:University of Pennsilvania、3:Sejong University
Gene-gene interaction is one of the most popular approaches for finding and explaining the missing heritability of common
complex traits in genome-wide association studies. The multifactor dimensionality reduction (MDR) method has been widely
studied for detecting interaction effects. However, there are several disadvantage of existing MDR based approaches, such as
lack of efficient way of evaluate significance of multi-locus models and high burden of computation. In this work, we propose
a two-step unified model-based MDR approach to survival phenotypes, in which, the significance of a multi-locus model, even
a high-order model, can be easily obtained through a Cox regression framework and a semiparametric correction procedure.
Comparing to the convention permutation approach, the proposed semiparametric correction avoids heavy computational cost
for achieving the significance of a multi-locus model. The proposed approach is flexible in the sense of its ability to incorporate
different types of trait and evaluate significances of existing MDR extensions. Simulation studies and an application to a real
example are provided to demonstrate the utility of the proposed method. The proposed method achieves the same power
as Cox-MDR for most scenarios, and it outperforms Cox-MDR, especially when there are some SNPs having only marginal
effects, which makes it difficult for the existing MDR approaches to detect the causal epistasis for survival phenotypes.
Poster Session
Wed(4)-P-15
Risk factors, Insulin-Like Growth Factor-1 gene polymorphism and Breast Cancer Risk among Omani
Women: A Case-Control Study
1,2 1,3
Kawthar Alajmi ，Mansour S Al-Moundhri ，Shyam S Ganguly 1 ，Adil Alajmi 1,3
，Zahid Al Mandhari 4
1:Family Medicine and Public Health, Sultan Qaboos University, UK、2:University of Manchester、3:Sultan Qaboos University Hospital、
4:Royal Hospital
Aim: Breast cancer (BC) is the most common cancer worldwide with a significant global burden. This study evaluated
lifestyle & reproductive risk factors and the role of IGF1 CA repeats gene polymorphism with the risk of BC among Omani
women.
Method: Case control study was conducted using 174 Omani BC patients and 149 controls without any history of any type
of cancer. Questionnaire was used to assess the risk factors and blood samples were collected to investigate the IGF1 CA
repeats polymorphism.
Results: Univariate and multivariate logistic regression found Age, Occupation, Family Income, Family History of breast
cancer, use of contraceptives and duration of contraceptives use appeared to be associated with the development of BC among
Omani women. BC among Omani is presented at advanced stage and at younger age as compared to western countries. In
case of IGF1 CA repeats, CA 19 was the most frequent genotype among both cases and controls followed with CA 18. The
overall distribution of CA genotypes was significantly different between cases and controls (P value = 0.022) and it appeared
among premenopausal women (P value = 0.003) while among postmenopausal the distribution was not significantly different
(P value = 0.429). Odds Ratios and 95% CI for IGF1 genotype groups showed that there is no significant association between
BC and CA 19 either among pre or postmenopausal women even after adjusting the strongest risk factors of breast cancer.
However, there was a significant association between BC and both progesterone receptor status and type of the cancer.
Conclusion: Even though the breast cancer incidence in Oman is low but it is increasing. More concern should be taken by
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increasing the BC awareness especially the most significant risk factors among Omani women.
Wed(4)-P-16
Detecting and simulating heritability due to large-scale, cumulative epistatic effects
Jacob B. Hall 1 ，Jeremy R. Fondran 1 ，William S. Bush 1
1:Department of Epidemiology and Biostatistics, Institute for Computational Biology, USA
The overall impact of epistasis on human traits and diseases remains unknown. Here we present methods to estimate
cumulative epistatic effects between genomic regions and to precisely simulate additive, dominant, and epistatic effects within
datasets given a user-specified level of heritability.
First, we calculate SNP allele and genotype frequencies for every SNP and SNP pair. Second, we use previously published
calculations for partitioning genetic variance to extend Genome-wide Complex Trait Analysis’s (GCTA) method of calculating
genetic relationship matrices (GRMs) to create additional GRMs representing variance components for dominant and epistatic
effects. Third, we demonstrate a method to simulate large-scale additive, dominant, and epistatic effects.
We simulated datasets of 10,000 individuals with two sets of 100 SNPs for heritability levels of 1, 5, 10, and 20% for additive,
dominant, and epistatic components and then estimated power and precision of detecting those effects. We see 80% power
to detect heritability as low as 0.4% for single SNP components and 4.0% for interaction components. Using GCTA, we
Poster Session
were able to accurately estimate the proportion of variance explained by each simulated component; for example, when we
simulated 5% heritability for the additive-additive interaction component we observed an average of 5.28% of trait variation
explained. Using Cordell-encoded regression we show enrichment in significance for causal SNPs and SNP pairs versus non-
causal, however the observation of only marginal enrichment for interaction components illustrates the usefulness of estimating
cumulative effects rather than relying on many individual SNP pair tests. The ability to simulate and model strict genetic
effects, including interaction effects, both provides a platform for method validation as well as a tool to benefit development
of future genetic analysis methods, where datasets with specific simulated genetic interaction effects are needed.
Wed(4)-P-17
A comprehensive evaluation of family-based association tests for qualitative traits; usability, type-I error
and power
1,2 1,2,3 1,4,5
Tero S Hiekkalinna ，Markus Perola ，Joseph D Terwilliger
1:Genomics and Biomarkers Unit, National Institute for Health and Welfare, Finland、2:Institute for Molecular Medicine Finland FIMM、
3:University of Tartu, Estonian Genome Center, Tartu, Estonia、4:Department of Psychiatry, Department of Genetics and Development,
Gertrude H. Sergievsky Center, Columbia University, New York, USA、5:Division of Medical Genetics, New York State Psychiatric Institute,
New York, USA
In this post-GWAs era, whole genome sequencing (WGS) techniques will be used to generating a vast amount of data, including
relatives, which will raise enormous computational challenges for human genetics researchers. Scientists are now returning
to family-based designs, noting that under every model considered, they provided higher power for gene mapping, with the
reason for the shift to studying unrelated individuals having been motivated almost exclusively by cost and convenience of
acquiring large samples. Furthermore, researchers has published several new methods for family-based association (FBA)
analysis on WGS data. However, these newly developed methods has not been compared to classical FBA methods, such as
PSEUDOMARKER.
To this end, we have evaluated usability and compared empirical type I error rates and power of several classical methods
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and recently published implementations of FBA tests using datasets composed of mixtures of singletons and families. We
compare the performance of these tests under three hypotheses:(a) No linkage and no association; (b) Complete linkage and
no association;(c) Complete linkage and association. The first two represent potential null hypotheses in (a) joint tests of
linkage and association; and (b) conditional tests of association given linkage. Power was estimated for all methods for both
joint tests and conditional tests, over a range of effect sizes for the functional locus, and a range of LD between the functional
locus and a marker.
The most notable results are that new methods are not always easy to use, documentation is insufficient, more alarmingly,
and some of them have enormous type I error rates. This can lead to an unacceptable rate of spurious conclusions about the
presence of association, leading to fruitless follow up studies. Power is also shown to be optimal for methods based on full
likelihood analysis of complete pedigree data. Results from a simulation-based study will be presented.
Wed(4)-P-18
Properties of Global and Local Ancestry Adjustments in Genetic Association Tests
Eden R. Martin 1 ，Ilker Tunc 2 ，Zhi Liu 1 ，Robert C. Obrien 1 ，Carlos D. Bustamante 3 ，Gary W. Beecham 1
1:Hussman Institute for Human Genomics, University of Miami, USA、2:National Heart, Lung, Blood Institute, NIH、3:Department of
Genetics, Stanford University
Population substructure can lead to confounding in genetic association tests and failure to adjust properly can result in
spurious findings. Genetic ancestry can be measured on a global level, e.g., with principal components, or on a local level
for regions across the genome. Recent reports have considered whether it is preferable to adjust for local or global ancestry,
Poster Session
but the conclusions depend highly on the model for population structure and trait/disease model. Here we formally address
the question of confounding by ancestry, express regression parameters in terms of population genetics parameters to clarify
hypotheses from adjusted and unadjusted models, and consider questions of relative power. We examine theoretical expec-
tations to show population substructure scenarios under which we might expect confounding, and to show the consequence
of ancestry adjustment to genetic association tests. Theoretical calculations were verified and generalized using simulations.
Finally, simulated phenotypes were combined with GWAS data from the GOAL study to illustrate examples in real data from
admixed samples. We show that in a single admixed population, testing the trait locus itself does not lead to confounding
by ancestry so it is not necessary to adjust, and in fact adjusting tends to decrease power. However, when testing a marker
locus, both global and local ancestry can be confounders. We show that the genetic parameter of adjusted and unadjusted
models provides different tests for linkage disequilibrium (LD): the unadjusted model tests for LD in the admixed population,
while the local-ancestry adjusted model tests for LD in the ancestral populations. As such, it is recommended that global
ancestry adjustment be used for initial screening and that local ancestry for fine-mapping. Similar conclusions hold in strati-
fied admixed populations. Examples from simulations and real data further support these conclusions and show how relative
power depends on the LD values.
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Wed(4)-P-19
Gene-Environment Interactions using time to event is more effective than using case-control approach:
VTE case study
Mariza Andrade 1 ，Sebastian M Armasu 1 ，Bryan M McCauley 1 ，Tanya M Petterson 1 ，John A Heit 2
1:Health Sciences Research, Mayo Clinic, USA、2:Cardiovascular Diseases, Mayo Clinic
VTE is a major public health problem with over 500,000 events per year in the U.S. The average age- and sex-adjusted
annual VTE incidence is 132 per 100,000 person-years; VTE incidence increased by ~ 5% per decade over the last 35 years.
We suspect this incidence increase is largely due to our limited understanding of which individuals should be targeted for
prophylaxis. While several exposures (hospitalization, pregnancy, etc.) are strongly associated with VTE, these exposures
have poor predictive value for the individual. We had showed that VTE is highly heritable and follows a complex polygenic
inheritance mode with environmental interaction. Here, we focus on pregnancy as the environmental exposure using data from
our Mayo VTE study that included 472 incident VTE events among 1,146 women. Treating these women as a historical cohort
and date of birth as time zero, we performed time-to-VTE analyses. Pregnancy was associated with an increased hazard
of VTE (HR=2.49; 95%CI: 1.84, 3.36; p=3.2e-9). Of these 1,146 women, 634 had genome-wide genotype data imputed
to 1000G, and 277 had pregnancy-related VTE. Pregnancy remained associated with VTE in this cohort subset (HR=3.3;
p=1.4e-8). The proportional hazards assumption held in both data sets (p=0.73). In a GWA study, 2 chr 7 SNPs, rs10215876
and chr7:44909852:D, at 5-6kb 3’ of PURB and 1 chr 9 SNP in LINGO2 were associated with reduced hazards of VTE
in pregnancy (HRs=0.40 [0.28-0.58, p=1.2e-8], 0.41[0.29-0.59, p=3.3e-8] and 0.63 [0.52-0.75, p=3.3e-7], respectively). PURB
encodes for a DNA-binding protein that preferentially binds the purine-rish element, PUR; deletion of this gene is associated
with myelodysplastic syndrome and acute myeloid leukemia, both of which are associated with VTE. LINGO2 , a leucine rich
Poster Session
repeat protein, that was also identified as to be associated with hormone replacement therapy in VTE females.
Wed(4)-P-20
Gene-gene interaction among genes on transforming growth factor-β signaling pathway for non-
syndromic cleft lip with or without cleft palate in Chinese populations
Zhuqing Wang 1 ，Tao Wu 1 ，Holger Schwender 2 ，Ingo Ruczinski 3 ，Jeffrey Murray 4 ，Mary Marazita 5 ，
Ronald Munger 6 ，Ping Wang 7 ，Richard Redett 3 ，Yah Huei Wu-Chou 8 ，Samuel Chong 9 ，Vincent Yeow 10
，
Hong Wang 1 ，Ethylin Jabs 3,11 ，Bing Shi 12 ，Sun Ha Jee 13 ，Alan Scott 3 ，Terri Beaty 3
1:Peking University, China、2:Heinrich Heine University Duesseldorf、3:Johns Hopkins University、4:University of Iowa、5:University of
Pittsburgh、6:Utah State University、7:Beijing center for disease prevention and control、8:Chang Gung Memorial Hospital、9:National
University of Singapore、10:KK Women and Children Hospital、11:Mount Sinai Medical Center、12:Sichuan University、13:Yonsei University
Background: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with a complex and
heterogeneous etiology involving both genetic and environmental risk factors. Previous association studies have shown that
the TGF-β signaling pathway may play a role in NSCL/P. We performed a pathway analysis considering gene-gene (G×G)
interaction in the pathway, and between these genes and other loci identified by previous GWAS to further explore the etiology
of NSCL/P.
Method: We used 806 Chinese Han NSCL/P case-parent trios from a GWAS, where trios were drawn from an international
consortium. From the cleaned set of GWAS SNPs, we extracted 343 markers belonging to the 10 genes in the TGF-β
signaling pathway, plus 1027 markers in 13 genes/regions identified as significantly associated with NSCL/P with P<10-8 in
five previous GWAS studies. The transmission disequilibrium test (TDT) was used to test for effects of 343 SNPs in TGF-β
signaling pathway. The SNP pairs were tested for two-way G×G interactions using conditional logistic regression proposed
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by Cordell as implemented in the "trio" R package. We used Bonferroni correction for multiple comparison which required a
significance level of P ≤5×10-8 for genome-wide significance.
Results: For TDT, although 19 SNPs showed nominal significant association with NSCL/P, no significant evidence of as-
sociation was seen for all SNPs in 806 NSCL/P trios after Bonferroni correction. The SNP pair composed of rs4847294
(in ARHGAP29 ) and rs1942159 (in SMAD2 ) was approaching GWAS significant level(P = 5.76×10-7 ). Another SNP of
rs4847294 in ARHGAP29 also showed some evidence of interacting with rs1942159 in SMAD2 (P=1.18×10-6 ).
Conclusion: Our results support possible interactions between ARHGAP29 and SMAD2 in Chinese populations. G×G in-
teractions may explain some of the "missing heritability" in the risk of NSCL/P. Additional studies of NSCL/P should be
done to clarify potential G×G interactions.
Wed(4)-P-21
Exploring Disease Co-inheritance Patterns in High Quality Pedigrees from Collection of Family Health
History Obtained in a Primary Care Setting
Lori A Orlando 1 ，Rachel A Myers 1 ，Adam H Buchanan 2 ，R Ryanne Wu 1 ，Geoffrey S Ginsburg 1 ，
Elizabeth R Hauser 1
1:Medicine, Duke University, USA、2:Geinsinger Health System
Studies to identify diseases in families are often performed by examining pedigrees of probands affected by a targeted condition,
Poster Session
such as a breast cancer or heart disease, without considering other conditions in the family. Much could be learned about
the co-inheritance of common chronic diseases as an indication of genetic pleiotropy by examining pedigrees of unselected
probands. In this abstract we perform a proof-of-principle study to evaluate estimates of recurrence risks as a prelude to
studies of co-inheritance of multiple conditions. Using MeTree, a web-based family health history program, we collected FHHs
containing assessments on over 50 conditions from unselected individuals attending U.S. primary care clinics. Our database
currently contains 2700 high quality three-five generation pedigrees. Here we describe the prevalence of the condition in the
proband and compare the risk in relatives of affected probands to risk in relatives of all probands in the first 1184 pedigrees.
Results for exemplary conditions are: Diabetes 6% vs 15% (OR=2.5), heart attack 9.2% vs 12.4% (OR=1.3), Alzheimers 3.4%
vs 8% (OR=2.3), ovarian cancer 1.5% vs 11.8% (OR=7.9), colon cancer 1.6% vs 6.3% (OR=3.9), asthma 3% vs 8% (OR=2.7),
hereditary cancers 0.1% vs 8.4% (OR=84), and breast cancer 5% vs 14.8% (OR=3). These are consistent with published
estimates of recurrence risk to relatives and show that diseases with strong hereditary components, such as ovarian cancer
and hereditary cancer syndromes are readily identified as such using family health history. Likewise, the genetic component of
common complex diseases is also detected in these pedigrees, suggesting that the data quality of these pedigrees is sufficient to
study co-inheritance of other conditions. These results demonstrate the value of collecting a standardized FHH and support
the need for more in depth co-inheritance analyses. At the meeting we will also report the results of these more detailed
analyses.
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Wed(4)-P-22
Evidence of Gene-Gene Interaction among Cell-Cell Adhesion Genes for Nonsyndromic Cleft Palate in
Chinese
Yuan Yuan 1 ，Holger Schwender 2 ，Ingo Ruczinski 3 ，Jeffrey C Murray 4 ，Mary L Marazita 5 ，Ronald G Munger 6 ，
Ping Wang 7 ，Richard J Redett 8 ，Yah Huei Wu-Chou 9 ，Samuel S Chong 10 ，Vincent Yeow 11 ，Hong Wang 1 ，
Ethylin W Jabs 8,12 ，Bing Shi 13 ，Sun Ha Jee 14 ，Tao Wu 1 ，Alan F Scott 8 ，Terri H Beaty 3
1:Department of Epidemiology and Bio-statistics, Peking University Health Science Center, Beijing, China、2:Mathematical Institute,
Heinrich Heine University Duesseldorf, Duesseldorf, Germany、3:Johns Hopkins University, School of Public Health, Baltimore, Maryland,
United States of America、4:University of Iowa, Children’s Hospital, Iowa City, Iowa, United States of America、5:Center for Craniofacial
and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America、6:Utah
State University, Logan, Utah, United States of America、7:Beijing Center for Disease Prevention and Control, Beijing, China、8:Johns
Hopkins University, School of Medicine, Baltimore, Maryland, United States of America、9:Chang Gung Memorial Hospital, Taoyuan,
Taiwan、10:National University of Singapore, Singapore, Singapore、11:KK Women’s & Children’s Hospital, Singapore, Singapore、12:Mount
Sinai Medical Center, New York, New York, United States of America、13:State Key Laboratory of Oral Disease, West China College of
Stomatology, Sichuan University, Chengdu, China、14:Yonsei University, School of Public Health, Seoul, Korea
Abstract
Background: Nonsyndromic Cleft Palate (NSCP) is one of the most common human birth defects with a complex and
heterogeneous etiology. During embryonic development, the cell adhesion molecules are highly expressed in the median edge
epithelium of the palate. Cell-cell adhesion genes may play a role in NSCP. This study investigate the association and
gene-gene (G × G) interactions between NSCP and Cell-cell adhesion genes, including CDH1 , CTNNB1 , PVRL1 , PVRL2 ,
PVRL3 , ACTN1 , VCL and LEF1 .
Method: We performed the transmission disequilibrium test (TDT) using 202 Chinese NSCP case-parent trios from a genome-
Poster Session
wide association study (GWAS) in an international consortium. The strategy proposed by Cordell was applied to search for
possible G × G interaction using conditional logistic regression based on the children affected by NSCP and their matched
pseudo-controls.
Result: For transmission disequilibrium test, no significant evidence of association was seen for all SNPs in 202 NSCP case-
parent trios after Bonferroni correction. Tests of G × G interactions using Cordell’s method yielded significant evidence
between single-nucleotide polymorphisms in ACTN1 and PVRL2 . The most significant interaction is between rs3784140
(ACTN1 ) and rs387976 (PVRL2 ) among 202 NSCP case-parent trios (P=9.53×10-6 ).
Conclusion: This study suggest ACTN1 and PVRL2 may influence the risk of NSCP through gene-gene interaction. These
results emphasize the need to consider G × G interactions when searching for genes influencing risk to NSCP.
Wed(4)-P-23
A workbench for family-based genetic analysis using next-generation DNA sequencing data
Sungyoung Lee 1 ，Sungkyoung Choi 1 ，Joon Yoon 1 ，Taesung Park 1,2
，Sungho Won 1,3
1:Interdisciplinary Program in Bioinformatics, Seoul National University, Korea, South、2:Department of Statistics, Seoul National Univer-
sity、3:Graduate School of Public Health, Seoul National University
Mendelian transmission produces phenotypic and genetic relatedness between family members, giving family-based analytical
methods an important role in genetic epidemiological studies—from heritability estimations to genetic association analyses.
With the advance in genotyping technologies, whole-genome sequence data can be utilized for genetic epidemiological studies,
and family-based samples may become more useful for detecting de novo mutations. However, genetic analyses employing
family-based samples usually suffer from the complexity of the computational/statistical algorithms, and certain types of
family designs, such as incorporating data from extended families, have rarely been used. In this report, we present a
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Workbench for Integrated Superfast Association studies for Related Data(WISARD) programmed in C/C++. WISARD
enables the fast and comprehensive analyses of SNP-chip and next-generation sequencing data on extended families, with
applications from designing genetic studies to summarizing analysis results. In addition, WISARD can automatically be
run in a fully multithreaded manner, and the integration of R software for visualization makes it more accessible to non-
experts. WISARD has been successfully utilized to analyze the large-scale massive sequencing project for type 2 diabetes and
schizophrenia, indicating its practical value.
Wed(4)-P-23A
Targeted sequencing of Late-Onset Alzheimer Disease Loci Identifies Genomic Regions with Potential
Functional Variants
Margaret Pericak-Vance 1 ，Brian W Kunkle 1 ，Regina M Carney 2 ，Martin A Kohli 1 ，Naj C Adam 1,3 ，
Hamilton L Kara 1 ，Whitehead L Patrice 1 ，Wang Liyong 1 ，Cuccaro L Michael 1 ，Vance M Jeffery 1 ，Byrd Goldie 4 ，
Beecham W Gary 1 ，Gilbert R John 1 ，Haines L Jonathan 5 ，Martin R Eden 1
1:John P. Hussman Institute for Human Genomics, University of Miami, USA、2:Department of Psychiatry & Behavioral Sciences, University
of Miami, Miami, FL、3:Department of Biostatistics & Epidemiology, University of Pennsylvania, Philadelphia, PA、4:Department of
Biology, North Carolina A & T State, Greensboro, NC、5:Department of Epidemiology and Biostatistics, Case Western Reserve University,
Cleveland, OH
BACKGROUND: Genome-wide association studies (GWAS) have identified multiple loci that confer late-onset Alzheimer’
s disease (LOAD) risk. Few causal variants and genes at these loci have been identified however. We conducted targeted
sequencing of nine of these loci (ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM ) in
Poster Session
291 Non-Hispanic White (NHW) LOAD cases and 103 normal controls in order to identify potential functional variants for
follow-up experiments. METHODS: We prioritized variants on three criteria: (a) functionality (missense, nonsense, or splice-
site variant), (b) damaging potential, and (c) overrepresentation in cases vs. controls. We also examined variants grouped
by gene and function using multilocus association testing. Follow-up genotyping of 1) rare, damaging variants prioritized by
filtering and 2) 10 recently associated variants in these loci, was conducted in 2468 NHW familial and sporadic cases and
controls and 892 African-American (AA) cases and controls. RESULTS: Follow-up genotyping of 95 functional, damaging
variants enriched or present only in cases identified a 3-UTR splice variant in ABCA7 (chr19:1054190) present only in affecteds
(N=5), including all 4 affected siblings of one family. Additionally, follow-up genotyping of previously reported rare variants
in known AD loci confirmed the association of an intronic SNP (rs78117248) in the ABCA7 gene in NHW Americans, a result
originally reported in a Belgian population (P=0.0002). No significant results were found in the AA cohort. Region-based
analysis of the sequencing results identified several clusters of variants associated with LOAD including seven near MS4A
(P=0.0049) and seven upstream of BIN1 (P=0.0067). CONCLUSIONS: Targeted sequencing of LOAD risk loci identified rare
and novel coding variants in LOAD susceptibility loci, suggesting that rare variants at these loci may contribute to LOAD
risk.
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Poster Session
Genome structure, variation and function
Wed(4)-P-24
The functional RAI1-interactome analysis: Implications for molecular pathogenesis of Smith-Magenis
syndrome
Shu-Ting Chen 1 ，Masashige Bando 1 ，Sarah H. Elsea 2 ，Ian D. Krantz 3 ，Katsuhiko Shirahige 1 ，Kosuke Izumi 1
1:Molecular and Cellular Biosciences, The University of Tokyo, Japan、2:Dept. of Molecular and Human Genetics, Baylor College of Medicine、
3:Div. of Human Genetics, The Childrens Hospital of Philadelphia
Smith-Magenis syndrome is a multisystem developmental disorder characterized by intellectual disability, multiple congenital
anomalies, neurobehavioral abnormalities, circadian rhythm disturbance and obesity. The majority of the symptoms observed
in SMS is explained by haploinsufficiency of retinoic acid-induced 1 (RAI1 ) gene due to a heterozygous 17p11.2 microdeletion
or mutation within RAI1 . RAI1 is a plant homeodomain (PHD) finger containing protein, which suggests the ability of RAI1
as epigenetic regulator. Although it is clear that RAI1 regulates multiple biological process transcriptional programs that are
essential to embryogenesis from SMS disease mouse models and human cell lines study. While, the molecular action of RAI1
remains poorly understood. To break through the current SMS pathogenesis research and clarify the function of RAI1 in
Poster Session
development transcriptional program orchestration, we embarked the RAI1 molecular and cellular functional analysis using
SMS disease as model. To decipher RAI1-interactome profile comprehensively, the RAI1-interacting proteins were identified
by antibody affinity purification followed by LC-MS/MS identification. As expect, many transcriptional regulators including
chromatin remodeling complexes such as NuRD complex and BAF complex as well as transcriptional elongation complex,
SEC are identified as RAI1-associtate proteins. Germline mutations of BAF complex and SEC genes cause developmental
syndromes with overlapping features that are seen in SMS. Hence, such phenotypic overlap among these developmental
syndromes may be explained by this functional interaction. This result raise the possibility that haploinsufficiency of RAI1
may disrupt this functional interaction, which contribute to alter the transcriptional output. This transcriptome alteration
can be reflected on the pathological phenotype that seen in SMS disorder.
Wed(4)-P-25
Whole-exome sequencing enables copy-number variation analysis in the lower kilobase range
Maria Schotik 1,2,3,4 ，Filippo Beleggia 1,3,4
，Ferda Percin 5 ，Janine Altmueller 1,6
，Holger Thiele 6 ，Peter Nuernberg 4,6
，
Bernd Wollnik 1,3,4,7
1:Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany、2:Cologne Graduate School of Ageing Research, Cologne,
Germany、3:Center for Molecular Medicine Cologne (CMMC), Cologne, Germany、4:Cologne Excellence Cluster on Cellular Stress Responses
in Aging-Associated Diseases (CECAD), Cologne, Germany、5:Department of Medical Genetics, Faculty of Medicine, Gazi University, Ankara,
Turkey、6:Cologne Center for Genomics, University of Cologne, Cologne, Germany、7:Institute of Human Genetics, University Medical Center
Goettingen, Goettingen, Germany
Identification of structural variations in the genome by whole-exome sequencing (WES) constitutes a major challenge. Here we
use three different software programs for copy-number variation (CNV) analysis to identify a two-exons duplication in INSR
in a patient with Donohue syndrome. Donohue syndrome (OMIM 246200) or Leprechaunism is a rare, autosomal, recessively
inherited congenital disorder. It is characterized by severe insulin resistance, pre- and postnatal growth retardation, and
typical physical features such as lack of adipose and muscular tissues and an enlarged abdomen. We studied a Turkish
girl affected by Donohue syndrome, born to consanguineous parents. After excluding point mutations in INSR by Sanger
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sequencing, we performed WES and CNV analysis. Using the programs CODEX, XHMM, and FishingCNV, we successfully
identified a homozygous duplication of two exons, with an approximate size of 2.5 kb spanning exons 10 and 11 of INSR
(NM_000208). This duplication was confirmed to be in the homozygous state in the patient and in the heterozygous state in
the parents by qPCR analysis. Moreover, using a nested-PCR approach, we could characterize the duplication as a tandem
event, thereby resolving the genetic organization of the mutation. Sequencing of fibroblast INSR mRNA from the parents
showed that the mutated allele is nearly absent and is thus likely to undergo nonsense-mediated decay, consistent with the
predicted generation of a premature stop codon. To our knowledge, tandem duplications have not been described in Donohue
syndrome, indicating that a comprehensive molecular diagnostic approach might be necessary to identify all mutations in
INSR. Additionally, our study provides evidence that WES can be successfully used to identify duplications in the lower
kilobase range, below the resolution of standard array-based technologies. Therefore, WES is a rational first choice as a
diagnostic tool to detect a wide range of different mutational mechanisms.
Wed(4)-P-26
Gene Expression Profiling of Motor Neuron in Motor Neuron-Specific 26S Proteasome Conditional
Knockout Mice
Tomonori Hoshino 1 ，Hirofumi Yamashita 1 ，Yoshitaka Tashiro 2 ，Hidemi Misawa 3 ，Okiru Komine 4 ，Koji Yamanaka 4 ，
Makoto Urushitani 1 ，Ryosuke Takahashi 1
1:Department of Neurology, Graduate School of Medicine, Kyoto University, Japan、2:SK Project, Medical Inovation Center, Kyoto Uni-
veristy、3:Department of Pharmacology, Faculty of Pharmacy, Keio University、4:Department of Neuroscience and Pathobiology, Research
Institute of Environmental Medicine, Nagoya University
Poster Session
Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by loss of motor neurons.
Although the extensive studies in familial ALS previously identified ALS-causing genes such as SOD1, TDP-43, FUS, and
OPTN, the exact pathogenic mechanism underlying motor neuron degeneration in ALS remains unclear. In motorn neurons
of ALS patients, mislocalization and accumulation of ubiquitinated inclusions containing ALS-linked gene products such as
TDP-43 and FUS is a common feature, indicating that a failure to eliminate detrimental proteins is linked to pathogenesis of
ALS.
Previously, we created motor neuron-specific 26S proteasome conditional knockout mice (Rpt3 CKO mice), and we reported
Rpt3 CKO mice showed ALS-like phenotype. Rpt3 CKO mice displayed mislocalization and accumulation of ALS-linked
proteins such as TDP-43 and FUS in motor neurons accompanied by progressive motor neuron loss and locomotor dysfunction.
These findings indicate that the ubiquitin-proteasome system (UPS) dysfunction has important roles in pathogenesis of ALS.
In this study, to assess the effects of UPS dysfunction, we compared microarray profiles of motor neurons between Rpt3 CKO
and control mice (respectively; n=3). As a result, we found that the mRNA expression of 219 genes was significantly changed
in Rpt3 CKO mice (fold change >7.5) and some of 219 genes showed the same tendency as those of motor neuron-like NSC-34
cell line with proteasome inhibition treatment. Furthermore, we conducted an unbiased DAVID analysis of microarray data
of motor neuron in Rpt3 CKO and control mice. Gene Ontology term analysis of up-regulated and down-regulated genes
(fold change >2) in motor neuron from Rpt3 CKO relative to control mice demonstrated enrichment of transcription-related
genes. It suggests that disruption transcription function caused by UPS dysfunction may accelerate neurodegeneration.
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Wed(4)-P-27
Signature microRNA expression patterns identified in Williams syndrome
Masatoshi Nakata 1 ，Ryo Kimura 1 ，Kiyotaka Tomiwa 2 ，Tomonari Awaya 3 ，Takeo Kato 3 ，Yasuko Funabiki 4 ，
Toshio Heike 3 ，Masatoshi Hagiwara 1
1:Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Japan、2:Todaiji Medical and Educational Center、
3:Pediatrics, Kyoto Graduate School of Medicine、4:Human Coexistence, Kyoto University Graduate School of Human and Environmental
Studies
MicroRNAs are a class of short non-coding RNAs that regulate regulate gene expression. Emerging evidence have revealed
that patients with neurodevelopmental disorders have altered microRNA expression profiles. Williams syndrome (WS) is a
rare neurodevelopmental disorder with multiple phenotypic manifestations due to a 1.5 Mb deletion at 7q11.23 which covers
25 genes. Although global alteration in gene expression in WS has presented, the mechanism of gene regulation remains
unclear. In this study, our aim is to uncover epigenomic regulation of microRNAs in WS. Global microRNAs were profiled in
a discovery sample (15 WS patients and 15 sex-and-age-matched controls), using TaqMan Array Human MicroRNA Cards.
The data were analyzed with the R/Bioconductor package HTqPCR. The selected microRNAs were then validated by qRT-
PCR assays in a replication sample (72 WS patients and 49 controls). Further we analyzed the predicted target mRNAs
with Target Scan. We also integrate microRNA profiles with messenger RNA (mRNA) profiles to identify mRNA-microRNA
interactions. Some microRNAs were differentially expressed in WS, compared with matched control subjects. The altered
expressed microRNAs targeted many of the differentially expressed mRNAs. The changes in the mRNA and microRNA
expression patterns appeared to be functionally connected due to negative correlations. Our findings suggest the importance
of epigenomic regulation through microRNA regulation in WS. Further analyses of microRNAs in WS might lead to a better
understanding of the pathogenesis of WS.
Poster Session
Wed(4)-P-28
Sex-specific eQTLs and Their Implications in Gene Expression Regulation and Disease
Jiangshan Shen 1 ，Wanling Yang 1
1:HKU, Hong Kong
Despite sex being an important epidemiological factor, not much is known about sex-specific regulation. In this study, we use
whole transcriptome LCL data from 463 samples across two populations, to detect sex-specific expression quantitative trait
loci (eQTLs). We found 2001 such eQTLs genome-wide. Two such eQTL is in LD with a GWAS SNP: rs2298585 which is
associated with vitamin levels in Chinese men and rs610932 for Alzeihmer’s disease, respectively. Relative to non sex-specific
eQTLs detected from the same sample, sex-specific eQTLs were particularly enriched in super enhancer sites, and genes that
were regulated by sex-specific eQTLs were found in neurogenesis, polycomb protein targets, stem cell related pathways and
autoimmune disease related genes. These sex specific eQTLs may have implication for differential gene regulation between
sexes, as well as differential disease prevalence and severity between sexes.
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Wed(4)-P-29
Effects of topical mupirocin on the composition and abundance of the nasal microbiome in healthy
carriers with Staphylococcus aureus
1,2
Su-Hsun Liu ，Yi-Ching Tang 2 ，Hsiang-Yuan Yeh 2 ，Yhu-Chering Huang 1,2
，Leslie Y Chen 2
1:Chang Gung University, Taiwan、2:Chang Gung Memorial Hospital
Background: Short-term antibiotic use has been shown to alter the microbial composition and diversity of the gut microbiota.
However, how topical mupirocin use influences the nasal microbiome remains unknown.
Methods: We included four healthy females and repeatedly collected nasal swabs before and after topical mupirocin use as
well as at week 2, 4, 8, and 12 afterwards. We sequenced bacterial 16S ribosomal DNA via the next-generation sequencing
techniques.
Results: Three study participants were positive for Staphylococcus aureus (S. aureus, 75%) at baseline; two women carried
S. aureus at week 2 (25%) and week 4 (50%) after treatment. Although women with or without culturable S. aureus at
baseline shared a common phylar membership, each group had distinct dominant members, with Firmicutes (54.1%) and
Actinobacteria (39.7%) in S. aureus carriers; Proteobacteria (75.8%) in the noncarrier.
In Staphylococcal carriers, the median number of operational taxonomy units (OTUs) at the genus level decreased > 25%
(median: -27.6%; IQR: -60.5%, -13.9%) immediately after treatment. At week 12, the observed OTUs were still 14.4%
lower than those before treatment (IQR: -53.8%, -6.9%). In the noncarrier, the observed OTUs increased up to 35% before
Poster Session
returning, between week 8 and 12, to the original community richness.
Temporal changes in the community diversity also differed by the baseline culture results. The nasal microbiome in culture-
positive women displayed a > 40% decrease in the Shannon index (median: -40.2%; IQR: -75.7%, 20.3%), followed by a close
return at week 4 whereas that in the culture-negative subject showed a reverse course of change.
Conclusions: We showed that pre-treatment S. aureus carriage status determined how the nasal microbiome responded to
antibiotics. In addition to suppressing S. aureus, a single-time mupirocin use could perturbed the nasal commensal with a
lasting influence on the community composition and abundance up to 12 weeks post-treatment.
Wed(4)-P-30
Inherited genes without SNP defects (that could predispose a person to diseases), is the single most key
to longevity among 95+ individuals
1
Girish J Kotwal
1:Medicine, UMass Medical School, USA
BACKGROUND: There have been claims of Longevity Islands in the human genome and good genes in a person’s genome
that contribute to long life. Our hypothesis is that normal gene alleles are key to longevity but other factors are important
too.
APPROACH: We have studied several potential disease gene alleles from a person in his 97th year that are influenced by
single nucleotide polymorphisms by submitting to 23 and Me, the saliva of a person in his 97th year living in India and we
have ourselves isolated DNA from the same person and amplified the apo E gene and sequenced it to verify the read out from
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the 23andMe.
RESULTS: Our research suggests that longevity is multi-factoral but that a person with normal repertoire of genes has a
chance at a long life assuming that the person will have a balanced diet, low risk lifestyle, optimal level of physical activity,
appropriate on demand medical care, positive thinking, good social interactions etc. We have received analysis of the genes of
a 96 year old person with sharp memory by submitting the person’s saliva to 23andMe. Not a single gene defect was observed
in a total of over 50 genes that could have potentially defective alleles predisposing the person to disease contributing to
death and in order to confirm that the analysis is accurate we isolated the DNA from the saliva of the person and sequenced
the apoE gene to try and determine the apoE allele of the person. This person had apo E3 allele consistent with the person
having normal memory and not predisposed to Alzheimer’s disease. We have also studied several persons public history of
health of persons living beyond 100 including the late Mrs Okawa of Osaka and are not aware of any genetic defect.
CONCLUSION: We conclude that normal alleles are most critical for longevity although several other factors will also
contribute to ensuring that a person with normal genes lives beyond the age of 95.
Wed(4)-P-31
Identification of OCTN2 variants and their association with phenotypes of Crohn’s disease
Eun Young Kwon 1 ，Hyo Jin Park 1 ，Ji Ha Choi 1
1:Department of Pharmacology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Korea, South
Poster Session
Crohn’s disease (CD) is a chronic inflammatory bowel disease with multifactorial causes including environmental and genetic
factors. A genetic variant in OCTN2 , g.-207G>C, is significantly associated with CD susceptibility. This study was aimed to
identify novel OCTN2 functional promoter variants and their roles in transcriptional regulation via various in vitro assays.
Additionally, through genetic analysis of DNA samples from 193 patients with CD and 289 healthy controls, we investigated
the association between OCTN2 genotypes and the susceptibility of CD or corresponding CD phenotypes. Among the three
major OCTN2 promoter haplotype identified in this study, H3, showed a significant decrease in promoter activity, and
two polymorphisms in H3 were associated with a significant reduction in promoter activity. In particular, we found that
the differences in the binding affinity of the activators, NF-E2 and YY1, were responsible for the reduced transcriptional
activities. Their effects on OCTN2 promoter were confirmed by in vitro experiments such as co-expression or knock-down of
the transcriptional activators. The results of the clinical association study indicated that the functional variants or haplotype
of the OCTN2 promoter did not affect CD susceptibility. However, we found that the H3 haplotype was associated with
clinical characteristics of CD such as the disease behavior and need for hospitalization or surgery. Our results also suggest that
a common promoter haplotype of OCTN2 regulates the transcriptional rate of OCTN2 and influences the CD phenotypes.
Wed(4)-P-32
Diagnostic Yield in Autism Spectrum Disorder using Illumina Dense SNP Array and Association of CNVs
in ASD/ID genes and ASD-subphenotyes
1,2
Sulman Basit ，Alia Albalawi 1 ，Muhammad Iqbal 3 ，Laila Al-Ayadhi 3
1:Taibah University Almadinah, Saudi Arabia、2:Quaid-i-Azam University Islamabad、3:King Saud University Riyadh
Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder diagnosed in approximately 1 of 88 children and
manifests as deficit in social behaviour and language development, as well as restricted or sterotyped interests.
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Copy number variations (CNVs) have been implicated as an underlying genetic cause in ASD, however, there is a limited
understanding of the impact of CNVs on the subphenotypes of ASD. The objective of this work is to evaluate association
between CNVs in genes previously implicated in ASD/intellectual disability (ASD/ID). The sample consists of 110 cases of
Saudi Arabian origin from the Autism Research and Treatment (ART) Center with a daignosis of an ASD. A total of 2.5
million SNPs were genotyped in all cases and 100 control individuals. SNP data analysis using Illumina Genome Studio
software revealed atleast one rare CNV impacting previously reported ASD/ID genes.
Classifiation analysis to define sets of phenotypic characterstics and there association with CNVs identified association between
ASD sub-phenotypes and CNVs in ASD/ID genes.
Wed(4)-P-33
The autism-associated long noncoding RNA MSNP1AS regulates a network of genes involved in neuronal
process stability
Jessica DeWitt 1 ，Nicole Grepo 1 ，Brent Wilkinson 1 ，Kevin Morris 2 ，James A Knowles 1 ，Daniel B Campbell 1
1:University of Southern California, USA、2:The Scripps Research Institute, La Jolla, CA USA
From genome-wide association studies (GWAS), a novel gene was discovered that has a highly significant association with
autism spectrum disorder (ASD). The gene is a long non-coding RNA (lncRNA) designated MSNP1AS (moesin pseudogene
1, antisense). Expression of MSNP1AS was increased in the cerebral cortex of individuals with ASD and individuals with
Poster Session
the ASD-associated genetic marker. Overexpression of MSNP1AS in human neuronal cells caused decreased expression of
moesin (MSN ) mRNA and moesin MSN protein, which is involved in neuronal process stability and immune response. These
data indicate one aspect of the potential contribution of increased MSNP1AS expression in ASD. However, there are likely
to be additional transcriptomic impacts of this lncRNA. To determine the effects of altered MSNP1AS expression on the
neuronal transcriptome, we transfected human neuronal progenitor cells with constructs that overexpressed MSNP1AS or
transcriptionally silenced MSNP1AS. RNA-Seq analysis indicated altered expression of multiple genes that contribute to
altered neuronal process stability and immune response, including MSN . However, our data indicate several genes that are
impacted by MSNP1AS dysregulation more significantly than MSN , suggesting a network of genes that contribute to ASD
risk. Ongoing experiments seek to define the role of the MSNP1AS gene network in neuronal process stability.
Wed(4)-P-34
Anti-dsDNA IgG antibodies down-regulated mesangial cells miR-10a expression and increased CREB1
gene expression inducing cell proliferation
Pattarin Tangtanatakul 1 ，Asada Leelahavanichakul 1 ，Alain Jacquet 1 ，Trairak Pisitkul 1 ，Rangsima Reantragoon 1 ，
Yingyos Avihingsanon 1 ，Nattiya Hirankarn 1
1:Chulalongkorn University, Thailand
Lupus nephritis is a severe complication in SLE patients. Anti-dsDNA antibodies mediated mesangial cells functions is one of
disease pathogenesis. In order to investigate miRNA expression in mesangial cells during anti-dsDNA antibodies stimulation,
primary human mesangial cells were incubated with anti-dsDNA IgG antibodies purified from LN patients (N=20) compared to
pool normal IgG control (N=20). The miRNA and mRNA expression profiles were studies using Next Generation Sequencing
and cDNA microarray, respectively. The result showed that 103 miRNAs were up-regulated (fold-change > 1.5), and 20
miRNAs were down-regulated (fold-change < 0.5) after anti-dsDNA IgG antibodies stimulation. Integrative analysis between
miRNA and mRNA data showed that gene expression in MAPK signaling, TGF-beta signaling and cell cycle pathways
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were elevated (p-value < 0.05). Candidate miRNAs expression including miR-181a, miR-411, miR-146a, miR-127, miR-
125b and miR-10a, were validated using Stem-loop RT-PCR. The RT-PCR result showed that anti-dsDNA IgG antibodies
down-regulated miR-10a expression significantly (p-value < 0.05). The miR-10a was previously reported as a kidney specific
miRNA and also important in cell proliferation and differentiation. To investigate the role of miR-10a in mesangial cells,
miR-10a anti-sense were transfected into the cells. The MTT assay demonstrated that down-regulated miR-10a increased
cells proliferation significantly (p-value < 0.05). The miR-10a was predicted to control CREB1, NFAT5, PIK3CA, MAP4K4
and SMAD2 mRNAs expression which, are mainly signaling molecules in cell cycle pathway. Using Real-time PCR, miR-10a
knock-down significantly up-regulated CREB1 gene expression (p-value < 0.05). In conclusion, anti-dsDNA antibodies down-
regulated miR-10a expression, while it up-regulated CREB1 expression in mesangial cells. This resulted in mesangial cells
proliferation which is a prominent feature of lupus nephritis histology.
Wed(4)-P-35
Plasma miRNA Expression Profiles in Rheumatoid Arthritis Associated Interstitial Lung Disease
Shomi Oka 1,2 ，Hiroshi Furukawa 1,2
，Kota Shimada 2,3
，Atsushi Hashimoto 2 ，Akiko Komiya 2 ，Naoyuki Tsuchiya 1 ，
Shigeto Tohma 2
1:Faculty of Medicine, University of Tsukuba, Japan、2:Sagamihara Hospital, National Hospital Organization、3:Department of Rheumatic
Diseases, Tokyo Metropolitan Tama Medical Center
Background: Interstitial lung disease (ILD) is frequently associated with rheumatoid arthritis (RA) and influences the prog-
nosis of the disease. Micro RNAs (miRNAs) are small noncoding RNAs with approximate 22 nucleotide length and miRNAs
Poster Session
in the circulation could be potential biomarkers for various diseases. In this study, the plasma micro RNA profiles were
investigated to explore markers for ILD in RA.
Methods: ILD was diagnosed from computed tomography findings. RNA was isolated from plasma samples and cDNA was
synthesized. Real-time RT-PCR analysis was performed to evaluate 752 miRNA expression profiles in plasma pools from
RA patients with or without ILD. Nineteen selected miRNA levels were analyzed in individual plasma samples from 64 RA
patients with or without ILD.
Results: Expression levels of hsa-miR-214-5p (P= 0.0156) and hsa-miR-7-5p (P= 0.0362) were higher in plasma samples
from RA patients with ILD than in those without. The levels of miRNA index (214, 7) generated from hsa-miR-214-5p and
hsa-miR-7-5p for ILD was significantly elevated in RA patients with ILD compared with those without (P= 0.0010). The
area under the curve (AUC) value of the receiver operating characteristic (ROC) curve for the miRNA index (214, 7) was
0.740.
Conclusion: To the best of our knowledge, this is the first report of plasma miRNA profiles of ILD in RA. These data suggest
that hsa-miR-214-5p and hsa-miR-7-5p in plasma could be potential biomarkers for ILD in RA.
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Wed(4)-P-36
Analysis of copy number alteration andclinicopathological features in breast cancer
1,2
Fumi Taira ，Kaoru Mogushi 3 ，Mitsue Saito 1 ，Yoshinori Murakami 2
1:Breast Surgery and Oncology, Juntendo University, Japan、2:Division of Molecular Pathology, The Institute of Medical Science, The Univ.
of Tokyo、3:Center for Genomic and Regenerative Medicine, Juntendo University
Background Copy number variation (CNV) is a novel polymorphism that can now be identified in the human genome by
employing DNA fragments larger than 1kb. CNVs are present in the genomes of healthy individuals as polymorphisms,
though some have been shown to be associated with susceptibilities to a variety of diseases.
Methods We investigated 20 primary invasive breast cancer cases who had undergone surgery at the Department of Breast
and Endocrine Surgery of Juntendo University, Tokyo during the period from 2006 through 2010. Somatic alterations at the
sites of CNV were examined as somatic copy number alterations (CNAs) using array CGH specifically designed to detect
changes at these sites. Tumor DNA was extracted from surgically resected fresh-frozen tissue samples, while control DNA
was extracted from peripheral blood lymphocytes of the same patient.
Results Somatic CN changes were detected in 39.9% of probes. A high CNA rate correlated significantly with high nuclear
grade. Alterations of fragments exceeding 10Mb caused by chromosomal instability correlated significantly with nuclear grade
and high Ki-67 status. Meanwhile, short fragments less than 10kb correlated significantly with ER positivity and low Ki-67
status. CNAs correlated significantly with clinicopathological features, and many of the genes located in these CNA regions
are known to have cancer-related functions.
Poster Session
Wed(4)-P-37
Identification of the genes regulated by ZFAT in T cells through ChIP-seq analysis
Keiko Doi 1,2 ，Toshiyuki Tsunoda 1,2 ，Midori Koyanagi 1,2
，Shuhei Ishikura 1,2
，Yoko Tanaka 1,2
，
Kazuhiko Nakabayashi 3 ，Senji Shirasawa 1,2
1:Department of Cell Biology, Faculty of Medicine, Fukuoka University, Japan、2:Central Research Institute for Advanced Molecular
Medicine, Fukuoka University、3:Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development
ZFAT (a zinc-finger gene in autoimmune thyroid disease susceptibility region) is originally identified as an immune-related
transcriptional regulator containing 18 C2H2-type zinc-finger domains and one AT-hook, and is highly conserved among
species. We previously established the Zfat-deficient mouse and found that Zfat-deficiency causes embryonic lethal phenotype
and Zfat is an essential transcriptional regulator in primitive hematopoiesis. Recently, analyzing the Cd4Cre- and LckCre-
conditional Zfat KO mice, we have demonstrated that Zfat is a critical molecule for peripheral T cell homeostasis through
the expression of IL-7Ra and IL-2Ra, and that Zfat is required for T cell development in the thymus through regulating the
activities of ERK and p38. However, the target genes directly regulated by Zfat in T cells remain unknown. To identify
the genes directly regulated by Zfat in thymocytes, we performed chromatin immunoprecipitation-sequencing (ChIP-seq)
experiments and gene expression arrays in mouse thymocytes. The ChIP experiments were optimized by ten ChIP-seq grade
antibodies for Zfat, and Zfat-binding regions were identified by ChIP-seq analysis through Avadis NGS software. ChIP-Seq
analysis in mouse thymocytes revealed approximately 90 Zfat-binding regions both with at least 6-fold enrichment and with
less than 1.0E-6 FDR (false discovery rate). Most Zfat-binding regions were mapped to within 5 kb of the transcription start
site. The comparison between gene expression profiling and ChIP-seq data in mouse thymocytes indicated that approximately
30% of genes up- or down-regulated by Zfat-deficiency (Fold change > 1.5) are closely associated with the genes identified by
ChIP-seq analysis. We are currently validating the candidate Zfat-target genes by biological and functional approaches.
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Wed(4)-P-38
The evaluating of methods for the inference of ecological interactions in bacterial communities using
horizontal gene transfer events
Ben-Yang Liao 1 ，Ting-Yan Chang 1
1:Intitute of Population Health Sciences, National Health Research Institutes, Taiwan
Among all human body parts, gut is a place housing complex microbial communities varied among individuals and is an arena
for important microbial-microbial and host-microbial interactions that can significantly impact our health. To understand
the ecological relationships might exist among gut microbes and the underlying reasons, various metrics have been used
previously to define the co-occurrence patterns of microbes and to guide the formation of hypotheses. These metrics included
Euclidean distance, Bray-Curtis distance, Kullback-Leibler distance, Pearson’s correlation coefficient, Spearman’s correlation
coefficient, and the index implemented in SparCC. Unfortunately, it was showed previously that the results produced from
different metrics are often inconsistent. Based on the assumption that horizontal gene transfer (HGT) events require the
spatial coexistence of the two species exchanging DNAs, we used HGT events identified from 484 bacterial fully sequenced
genomes to evaluate methods for co-occurrence relationship detection. The co-occurrence relationships at the species level
were calculated from oral or gut metagenomes sampled from individuals of diverse ethnic groups (154 Americans, 52 Hans,
103 Russians and 38 Hadza Africans). The results of the evaluations are presented. Furthermore, we confirmed that human
gut is the hotspot allowing HGT event to occur evolutionarily for bacterial species residing in human bodies.
Poster Session
Wed(4)-P-39
One cannot presume siblings with similar clinical findings result from the same underlying genetic cause!-
familial genome instability or leaky proof reading mechanism as a genetic predisposition?
1,2
Anne Chun-hui Tsai ，Kory Keller 2 ，Jassica Kushner 2 ，Karen Kovak 2 ，Stephen Moore 2
1:Pediatrics/Genetics and Metabolism, University of Colorado School of Medicine, USA、2:Division of Genetics and Metabolism, OHSU
When siblings present with similar clinical findings, it is not uncommon for a clinical geneticist to order testing on one child
presuming the same diagnosis. For a cytogenetic anomaly identified by microarray, the lab often suggests a FISH study for
at- risk individuals instead of a full microarray. We present three families with multiple children affected with similar features
but the underlying diagnoses among siblings within each family are different.
Family 1 is composed of a fraternal twin set: SGA with similar dysmorphism. A 180k oligo array showed a 1.94 Mb 5q35.2q35.3
dup(175,491,045-177,427,809) x3, including the entire NSD1 gene, which is deleted in Sotos syndrome in the female who has
the reverse-Sotos phenotype. The male twin’s array showed a single copy gain of 435.7 Kb (maximum size 458 Kb) in
5q35.2q35.3 (176,700,522-177,136,262) x3. His duplication resides in the sister’s duplication and is predicted to disrupt the
NSD1 gene and present with Sotos syndrome. Family 2 consists of a fraternal twin set, both with autism and small optic
nerves. Microarray revealed a 22q11.21 deletion (19,408,946-19,790,658)x1 in one and a 16p13.11 duplication (15126709-
16292235) x3 in the other. Family 3 consists of 2 maternal half siblings with dysmorphism and intellectual disability:the
brother has a 969.6 duplication at 1p13.3 and the sister has a 598 kb deletion at 16p11.2 and the1p13.3 dup.
Review of the literature found half siblings each had de novo HRAS and KRAS mutations; an autism multiplex family with
16p11.2p12.2 microduplication syndrome in MZ twins and distal 16p11.2 deletion in their brother. I hypothesize there is
a genetic contribution to handle the recombination errors and DNA repair threshold; therefore some family may be more
errors. In conclusion, one cannot presume siblings with similar clinical findings result from the same underlying genetic cause!
Appropriate genetic causes should be considered individually in siblings.
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Wed(4)-P-41
Association analysis between the clinical factors of primary open-angle glaucoma and the risk allele of
CDKN2B-AS1 variant
Yoko Ikeda 1 ，Kazuhiko Mori 1 ，Morio Ueno 1 ，Yuji Yamamoto 1 ，Kengo Yoshii 2 ，Kojiro Imai 1 ，Yuko Maruyama 1 ，
Ryuichi Sato 3 ，Fumiko SAto 3 ，Masakazu Nakano 3 ，Kei Tashiro 3 ，Shireru Kinoshita 4 ，Chie Sotozono 1
1:Ophthalmology, Kyoto Prefectural University of Medicine, Japan、2:Medical Statistics, Kyoto Prefectural University of Medicine、3:Genomic
Medical Sciences, Kyoto Prefectural University of Medicine、4:Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural
University of Medicine
Purpose: To investigate the association between the risk allele of CDKN2BAS-1 variant and the clinical factors of primary
open-angle glaucoma (POAG) patients and normal control (NC) subjects.Subjects and Methods: We used the genotype
data of Affymetrix SNP 6.0 1000K array previously obtained from 823 POAG and 974 NC subjects. We analyzed the
AA/AG/GG (risk allele: A) genotype of rs7865618 in regard to the association with the following clinical factors: patient
age at glaucoma diagnosis, baseline intraocular pressure (bIOP), max IOP (mIOP), optic disc area (DA), vertical cup-to-disc
ratio (VCDR), central corneal thickness (CCT), axial length (AL), and refractive error (RE) of the phakic eye. DA/VCDR,
CCT, and AL were measured by Heidelberg Retina Tomograph II, Pentacam, and IOL master, respectively. If the data of
both eyes was available, we applied the data showing the larger absolute value for the above-listed clinical factors. As for
the NC subjects, bIOP was regarded as mIOP. Statistical analysis was performed by means of regression analysis among the
POAG, NC, and POAG+NC groups. Results: In POAG patients, but not in the NC subjects, DA and VCDR showed a
significant association with the risk allele of CDKN2B-AS1 variant. In the POAG+NC group, mIOP, DA, and VCDR showed
a significant association with CDKN2B-AS1 variant (p<0.05).Conclusion: Some clinical factors in the POAG or POAG+NC
groups showed a significant association with the risk allele of CDKN2B-AS1 variant.
Poster Session
Wed(4)-P-42
The detection of transposon sequences in RNA sequence
1,2
Shiro Yamada ，Takahide Hayano 1 ，Hirohumi Nakaoka 1 ，Jumpei Ito 1 ，Kazuyoshi Hosomichi 3 ，Ryota Sugimoto 1 ，
Ituro Inoue 1
1:Department of Human Genetics, National Institute of Genetics, Japan、2:Children Clinic Sone, Takasaki, Japan、3:Department of Bioin-
formatics and Genomics, Graduate School of Medical Sciences, Kanazawa University
<<Introduction»Transposable Elements (TEs) are pervasive material of the genome. It consists about a half of the human
genome, but the functional significance of these elements are not elucidated yet. There could be two major effects of TEs on
the function of the genome. One is the Mobile Element Insertion (MEI) which destruct the gene or its regulatory elements, the
other could be the direct and indirect influence on tuning of the gene network system. TEs can be both cis-elements and/or
trans-elements. To know how TEs influence as trans-element, we studied how TEs are expressed. We developed a pipeline
to detect TEs sequences in RNA sequence data. <<Material and Methods» We got RNAseq data from iPS cells established
from normal human peripheral white blood cells. Using Human Repeat database (HumRep) as reference, RNAseq data was
screened for the existence of TEs sequences. The reads which have TEs sequences are pooled. By comparing both pair-end
sequences of one reads, each reads are grouped, (i) composed with TEs sequence only, (ii) the chimeric reads of TEs and uniq
mRNA sequence. The number of each TEs (i.e. Alu, LINE1, HERVs etc.) in both groups are calculated and normalized with
the number of total sequenced reads. In addition, the group (ii) is assessed whether it start with authentic Transcription
Start Sites (TSS) or not. <<Results» In almost cells, the expression of Alu, LINE1, and some subclass of HERVs are
highly expressed major components. The ratio of TEs are not largely different, but some kind of minor components differs
substantially. <<Discussion» It is reported that in the course of iPS reprogramming and differentiation, HERVH is highly
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expressed and returns to suppression. This dynamic change is necessary for the establishment of iPS cells. Besides this fact,
It would be important to know the dynamic change of TEs and its influence on gene expression for normal and disease cells.
Wed(4)-P-43
Microelectrode array captures seizure-like activity due to down-regulation of microRNA-128
1,2 1,3
K. Melodi McSweeney ，Ayal B Gussow ，Shelton Bradrick 4 ，Slave Petrovski 1 ，David Goldstein 1
1:Genetics; Institute for Genomic Medicine, Columbia University, USA、2:University Program in Genetics and Genomics; Duke University,
Durham NC 27708、3:Computational Biology and Bioinformatics; Duke University, NC 27708、4:Biochemistry and Molecular Biology,
University of Texas Medical Branch; Galveston, TX 77555
Microelectrode arrays (MEAs) are powerful tools for detecting spontaneous neuronal activity. MEAs have been used to
detect the response of primary dissociated neurons to neurotoxins and are emerging as reliable drug screening platforms.
Recent studies indicating the involvement of microRNAs in epilepsy phenotypes encouraged us to investigate the effect of
modulating microRNA-128, on neuronal activity. Mice deficient in microRNA-128 are prone to fatal seizures. Modulating
microRNA-128 in the MEA system allowed us to directly test whether MEAs are useful to screen other microRNAs that
influence risk of seizures. In particular, we sought to evaluate whether down-regulation of microRNA-128 results in clear
excitability phenotypes by MEA analysis. We used primary cortical neurons from wild-type post-natal day zero C57BL6
mice and a lentivirus delivered microRNA sponge to target the mature microRNA-128. Sponges are competitive microRNA
inhibitors which express tandem repeats that are partially complementary to the microRNA sequence. We recorded neuronal
activity on the MEA for 15 minutes each day to collect spike, burst, and network synchronicity data. Our data show that
Poster Session
down regulation of microRNA-128 by inhibition with a sponge results in significantly increased neuronal activity. These
features are consistent with the previous observations that microRNA-128 deficiency promotes neuronal excitability 1. These
experiments illustrate the utility of the MEA platform in evaluation of microRNAs in regulation of network phenotypes.
Wed(4)-P-44
Persistent and stability of circulating miRNAs in postmortem blood sample
Kornkiat Vongpaisarnsin 1 ，Pattarakorn Saengkaeotkakul 1 ，Kwin Rasameephaisarn 1
1:Forensic Medicine, Faculty of Medicine, Chulalongkorn University, Thailand
MicroRNAs (miRNAs) are small non-coding RNAs and play an important role at post-transcriptional level in the regulation
of gene expression, including translational repression, mRNA cleavage, and deadenylation. In addition to a highly tissue-
specific expression, miRNAs were used as tissue identification marker in forensic investigation. It is only recently that forensic
researchers have applied miRNAs to determine a cause of death using their expression profile. One of a great concern is a
postmortem phenomena that affects to a quality and quantity of miRNAs in blood. The objective of this research is to study
a persistent and stability of circulatory miRNAs in different postmortem periods.
Our preliminary study was tested in 4 blood samples using miRNA-499 and U6B gene (a reference control gene) with
postmortem interval during 12-18 hours after death. The results presented a persistent and stability of miRNA-499 in all
samples. Our analysis revealed that the circulatory miRNA is a stable biomarker which could be observed in early postmortem
stage to 18 hours after death.
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Wed(4)-P-45
Functional partitioning of local and distal gene expression regulation in human tissues
Xuanyao Liu 1 ，Hilary K Finucane 1,2 ，Alexander Gusev 1 ，Gaurav Bhatia 1 ，Brendan Bullik-Sullivan 3,4
，
Fred A Wright 5 ，Patrick F Sullivan 6 ，Benjamin M Neale 3,4 ，Alkes L Price 1,7
1:Harvard Chan School of Public Health, USA、2:Department of Mathematics, Massachusetts Institute of Technology, Cambridge,
Massachusetts, USA、3:Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston,
Massachusetts, USA、4:Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA、
5:Bioinformatics Research Center, North Carolina State University, North Carolina, USA.、6:Department of Genetics, University of North
Carolina at Chapel Hill, Chapel Hill, North Carolina, USA、7:Program in Medical and Population Genetics, Broad Institute of MIT and
Harvard, Cambridge, Massachusetts, USA
Large-scale eQTLs mapping studies have identified a large number of local eQTLs, but the molecular mechanism of how genetic
variants regulate expression is still unclear, particularly for distal eQTLs. In this study, we use a heritability partitioning
approach to dissect the functional architecture of gene expression. We utilize stratified LD score regression (Finucane et al.
2015 Nat Genet) that leverages on all variants to partition heritability by functional category.We estimate the proportion of
SNP-heritability explained by SNPs in each category and define enrichment as this proportion divided by the proportion of
SNPs in each category. Standard errors were computed by jackknifing on the regression SNPs. We first analyzed a large data
set of gene expression in peripheral blood (Wright et al. 2014 Nat Genet). Our results included local functional enrichment of
FANTOM5 enhancers(4.17x), 5’ UTR(4.17x) and TSS(4.0x), and distal functional enrichment of conserved elements(4.38x),
weak enhancer(4.37x), and broadly defined DHS(1.57x). All of these results were highly statistically significant (P < 10-12 );
the distal enrichments would not be detected only from the significant distal eQTLs. We next analyzed the gene expression in
adipose, skin and LCL(Grundberg et al. 2012 Nat Genet). Our results show that local functional enrichments are consistent
across tissues. The functional enrichments in gene expression were also compared to the enrichments in complex traits/diseases.
Poster Session
Except for a few functional categories(conserved regions, FANTOM5 enhancers etc.), functional enrichments in gene expression
are consistent with functional enrichments in complex traits/diseases, and demonstrate much higher statistical significance.
This suggests that gene expression could generally serve as a proxy for understanding the underlying molecular mechanism
of complex traits, though some functional categories such as conserved regions might affect traits through other mechanism.
Wed(4)-P-46
Correlation of the expression with FLT3 and RAC1 with the leukaemic fusion gene AML1-MTG8 in AML
M2
Adam Azlan 1 ，Saifulaman Said 1 ，Narazah Yusoff 2 ，Emmanuel J Moses 2 ，Nur Ainina Abdollah 2
1:Faculty Of Applied Sciences, Universiti Teknologi MARA, Malaysia、2:Universiti Sains Malaysia
The study was designed to elucidate the relationship between the expression of FLT3 and RAC1 on the AML1/MTG8
leukaemic fusion gene (AFG) which is highly diagnostic of Acute Myeloid Leukaemia (AML) M2 subtype via RNA interference.
The experiment was carried out by inhibiting the expression of FLT3 and RAC1 and quantifying the changes in the expression
of the genes by quantitative polymerase chain reaction (qPCR) and western blot analyses. A change in the cell proliferation
was measured using wst-dye bioreduction protocol (DOJINDO, Japan). Initial results showed that the inhibition of RAC1gene
expression does not affect the expression of AFG both at transcript and protein level ; however a 2-fold downregulation of
FLT3 was observed at transcript level. RAC1 gene expression inhibition also does not affect cell proliferation. On the other
hand, inhibition of FLT3 gene expression results in two-fold upregulation of the RAC1 gene ; however no changes were
observed in AFG expression at the transcript level. Overall, our results indicate a relationship between RAC1 and FLT3 at
transcript level and no correlation between AFG to RAC1 at the protein and transcript level.
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Wed(4)-P-47
Improving smear-negative tuberculosis diagnosis through gene expression signatures
Nusara Satproedprai 1 ，Sirilada Suphankong 1 ，Nuanjun Wichukchinda 1 ，Licht Toyo-oka 2 ，Tassawan Kuntima 3 ，
Hideki Yanai 4 ，Katsushi Tokunaga 2 ，Surakameth Mahasirimongkol 1
1:Department of Medical Sciences, Medical Life Science Institute, Thailand、2:Department of Human Genetics, Graduate School of
Medicine, the University of Tokyo、3:TB-HIV Research Foundation, Chiangrai, Thailand、4:Fukujuji Hospital, Japan Anti-Tuberculosis
Association
Tuberculosis (TB) is a major global health threat. Inadequate clinical and laboratory information leads to patients diagnosed
with smear-negative TB, leaving responsiveness to anti-tuberculosis treatment as the only applicable diagnostic strategy.
This leads to higher proportion of non-TB being misdiagnosed as smear-negative TB. Our previous GWAS study identified
a locus next to MAFB associated with young onset TB. Gene expression levels of 7 genes, including MAFB, discriminated
smear-positive TB from healthy individuals with high sensitivity and specificity. We aimed to determine the characteristics
of these gene expression levels in smear-negative TB.
Total RNA were isolated from blood of 80 smear-negative TB cases from Chiangrai, Thailand with 96% of subjects having
repeated smear-negative and 71% having negative culture. Expression levels of target genes were measured using multiplex
real-time PCR. Comparison between groups was analyzed using ANOVA.
Among 9 genes that were measured, gene expression levels of 7 genes were statistical different between a group of smear-
negative patients whom later were diagnosed as “not TB” and a group of smear-negative, culture positive patient as
follows; FCGR1A (p=0.00098), FCGR1B variant1 (p=0.014), FCGR1B variant2 (p=0.0084), APOL1 (p=0.014), GBP5
Poster Session
(p=0.000078), KCNJ15 (p=0.019) and STAT1 (p=0.027). On contrary, KAZN and MAFB shows no differences (p=0.138
and 0.754). Levels of those 7 genes were found to be statistically reduced in a group of patients with smear-negative, culture-
negative as compared to patients with smear-negative, culture-positive indicating difference in response to active TB between
these 2 groups of patients.
Our results demonstrated that gene expression assay could be used to identify smear-negative, culture positive TB from other
differential diagnosis in smear-negative TB. This blood-based RNA assay has potential for improving TB diagnosis while
preventing patients from unnecessary treatment.
Wed(4)-P-48
Characterization of HTRA1 regulatory element in Patients with Exudative Age-Related Macular Degen-
eration.
Daisuke Iejima 1 ，Mao Nakayama 1 ，Takeshi Iwata 1
1:National Institute of Sensory Organs, National Hospital Organizaiton Tokyo Medical Center, Japan
Background: Age-related macular degeneration (AMD) is a leading cause of vision loss and blindness in the elderly. The dry
form is more common and accounts for about 85 ~ 90% of AMD patients in US, while Japanese AMD patients predominantly
progress to wet-form or polypoidal choroidal vasculopathy (PCV). Recent studies have shown HTRA1 , a serine protease gene,
as major risk factor for wet form AMD. Furthermore, we reported that the Japanese typical wet form AMD patients showed
significant association with ARMS2-HTRA1 . The purpose of study is to elucidate the function of ARMS2-HTRA1 gene
regulatory element in wet-form AMD patients.
Methods: Human peripheral blood was obtained from patient with control (cataract patient: 228 case) and Wet-AMD (226
case). Genome DNA was extracted from peripheral blood samples using Magtration System 8Lx and DNA sequenced using
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ABI 3130 Genetic analyzer. ARMS2-HTRA1 regulatory element activity was measured by luciferase assay. More, we also
generated a transgenic (Tg) mouse, which overexpress mouse HtrA1 and human ARMS2 in the entire body and observed
the pathological change by fundus observation, fluorescein angiography, indocyanine green angiography and optical coherence
tomography over 12 month after birth.
Results: The regulatory element sequence experiment showed that a great number of AMD patients had specific indel
mutation in 3.8 Kb upstream of HtrA1 gene. 2 ~ 3-fold increase of regulatory element activity was observed in indel
HTRA1 regulatory element compared to control sequence. These results suggest that HTRA1 gene expression is influenced
by transcription factor specifically binding to this region. And more, using transgenic mice ubiquitously overexpressing mouse
HtrA1 using the chicken actin promoter, continuous induction of HtrA1 in vivo was shown to lead to CNV, similar to wet
AMD patients
Conclusion: Human HTRA1 expression is enhanced by AMD specific indel mutation in the regulatory element region of
HTRA1 gene.
Wed(4)-P-49
Genetic alteration in the Exon 3 of SEPTIN12 gene in infertile men referred to Royan Institute
1,3
Amir Parhizkar ，Parnaz Borjian Boroujeni 2 ，Maryam Shahhoseini 2 ，Marjan Sabbaghian 3 ，Parichehreh Yaghmaei 1
1:Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran、2:Department of Genetics, Reproductive
Poster Session
Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran、3:Department of Andrology, Repro-
ductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
It is estimated that 10-15% of couples are infertile and male infertility affects approximately 50% of all infertile couples,
but the etiologies of most cases are still unknown. The SEPTINS belongs to a highly conserved family of polymerizing
GTP-binding cytoskeletal proteins. SEPTINS perform cytoskeletal remodeling, cell polarity, mitosis, and vesicle’s trafficking
by interacting with various cytoskeletons. SEPTIN12 is a testis-specific gene critical for the terminal differentiation of male
germ cells. The chimeric mice with Septin12 +/+ /Septin12 +/- have multiple reproductive defects including the presence of
immature sperm in the semen, sperm with bent neck (defect of the annulus) and nuclear DNA damage. These facts make
SEPTIN12 a potential sterile gene in humans.
In this case-control study, the genetic alterations of exon 3 coding region of SEPTIN12 gene were analyzed in population of
72 infertile men (55 azoospermic, 17 asthenozoospermic men) and 32 fertile men who had normal spermogram as the control
group. After DNA extraction from blood samples of selected individuals, PCR method was done and ultimately sequencing
was used to determine genetic changes of the mentioned area.
Our results showed one missense SEPT12 mutation, c.225 G>A/ p.Trp75Stop, in 5 azoospermic patients. All of them were
heterozygote for this mutation. This mutation was not observed in the control group.
Based on the results, it is expected that c.225 G>A/ p.Trp75Stop variation in SEPTIN12 gene may be associated with
spermatogenesis failure, although This suggestion needs further studies.
Key words: Male infertility, Septin, SEPTIN12, Genetic mutation.
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Wed(4)-P-50
Global transcriptome profiling during acute anaphylactic reaction reveals involvement of complex net-
works of signaling, interactions and recruitment of distinct immune cell types
Matija Rijavec 1 ，Ales Maver 2 ，Keli Hocevar 2 ，Mira Silar 1 ，Mitja Kosnik 1 ，Borut Peterlin 2 ，Peter Korosec 1
1:University Clinic of Respiratory and Allergic Diseases Golnik, Slovenia、2:Clinical Institute of Medical Genetics, Division of Obstetrics
and Gynaecology, University Medical Centre, Ljubljana
Anaphylaxis is a severe, systemic, life-threatening allergic reaction that occurs with rapid onset affecting multiple organs, and
is difficult to predict, diagnose, and treat. It mainly involves the activation of mast cells and/or basophils, followed by the
release of mediators of anaphylaxis. To better characterize the mechanisms leading to potentially lethal events, analysis of
global transcriptional alterations in peripheral blood samples of patients during acute anaphylaxis was performed.
We performed RNAseq based characterization of human transcriptome on total RNA population in whole blood samples of
15 patients with acute allergic reaction. The sampling points were at the time of presentation to the emergency department
followed by sampling 7 days and 1 month after the anaphylactic episode. We performed extensive characterization of dif-
ferential gene expression, cell-specific transcriptional alterations, analysis of alternative splicing patterns in anaphylaxis and
functional characterization of detected alterations.
Whole transcriptome expression analysis revealed striking alterations of gene expression during acute anaphylaxis in com-
parison to 7 days and 1 month after the episode reflecting cellular and subcellular mechanisms taking place during acute
anaphylaxis, most notably in categories of cellular movement, cell-to-cell signaling, interaction and immune cell trafficking as
Poster Session
well as inflammatory response. Furthermore, when comparing the transcriptional differences during acute anaphylaxis with
expression signatures of peripheral immune cells, significant under-expression of basophil and/or mast cell signatures and
over-expression of eosinophil and neutrophil signatures were detected.
This finding improve our understanding of biological mechanisms underlying anaphylaxis, since our data suggests that com-
plex networks of signaling, interactions and recruitment of several different immune cells lead to the development of this
life-threatening allergic reaction.
Wed(4)-P-51
Expression profiling of long non-coding RNA ecCEBPA in cell lines and gastric cancer tissues
1,2 1,2 3,4 1,2,5
Mojdeh Nasrollahzadeh Khakiani ，Majdaddin Rezaei ，Modjtaba Emadi-Baygi ，Parvaneh Nikpour
1:genetics and molecular biology, Isfahan university of medical science, Iran、2:Applied Physiology Research Center, Isfahan University of
Medical Sciences, Isfahan, Iran、3:Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran、4:Research
Institute of Biotechnology, Shahrekord University, Shahrekord, Iran、5:Child Growth and Development Research Center, Research Institute
for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
Background: Gastric cancer as the second cause of cancer death terminates the lives of a plenty of people every year
worldwide, therefore inquiring molecular mechanisms involved in this cancer is pivotal. Unrestricted proliferation is one of the
characteristics of cancerous cells that is due to the deficiency in cell regulatory system. Long non-coding RNAs (lncRNAs)
have been emerged as critical regulators of the epigenome. This class of pervasive genes play a crucial role during cancer
progression. LncRNA extra coding CEBPA (ecCEBPA) which is encoded from CEBPA locus is involved in DNA methylation.
This lncRNA diminishes CEBPA methylation by interacting with DNA methyltransferase 1. Previous studies have revealed
its presence in Hl-60 and U937 cell lines. This study was designed to examine the expression of ecCEBPA gene in various
cultivated cells and gastric cancer tissues.
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Methods and Materials: The human cell lines HUVECs (human umbilical vein endothelial cells), SKBR3 (human breast
cancer cells), A542 (human pulmonary carcinoma cells), MCF7 (human breast cancer cells) and NT2 (the human embryonic
carcinoma cell line, NTERA2) were cultured. Total RNA extraction and cDNA synthesis were done for cell lines and forty
paired gastric cancer tissues. Quantitative real-time RT-PCR was performed with specific primers for lncRNA ecCEBPA
gene as well as GUSB gene (as an internal control).
Results: Our results showed that ecCEBPA is expressed in A542 and HUVEC cells but not in the other cell lines. The
presence data report that ecCEBPA did not show any expression in 26 pairs of tumoral or non-tumoral tissues (65%) whereas
in 14 paired tissues only tumor samples had ecCEBPA gene expression (35%).
Conclusion: Heterogeneous or undetected expression levels of ecCEBPA suggests that this lncRNA is not a critical regulatory
player in the tumorogenesis of gastric cancer. The presence of this ecCEBPA in various cell lines may indicate its tumor
specific function in different cancers.
Wed(4)-P-52
Regulation of human natural killer cells by genetically variable and conserved receptor systems - aden-
oviruses target a conserved receptor-ligand axis for immune escape
1,2 3,4,5 2,3,5
Makoto Yawata ，Jodhbir S Mehta ，Nobuyo Yawata
1:Pediatrics, National University of Singapore, Singapore、2:Singapore Institute for Clinical Sciences、3:Duke-NUS Graduate Medical School、
Poster Session
4:Singapore National Eye Center、5:Sinagpore Eye Research Institute
Anti-virus responses of innate lymphocytes differ substantially between human individuals. This is in part due to the diversity
in control of immune responses by multiple receptor types that are encoded by variable and conserved gene families. Some of
these receptors recognize members of HLA class I, one of the most polymorphic gene families in the human genome. The HLA
class I-related receptor-ligand interactions are crucial in programming the responses of natural killer (NK) cells, a process
termed licensing.
In an ongoing clinical study, we have investigated the mechanisms of NK cell responses against adenovirus infection and the
roles of class I human leukocyte antigens (HLA) / lymphocyte HLA receptors. We find that the adenovirus types causing
severe ocular surface inflammation escape from NK cell responses by causing immune suppression through a conserved HLA
class I receptor-ligand interaction, rather than targeting other receptor-ligand systems that are highly variable among humans.
Through the results of immunological co-culture assays, we find that expression of the oligomorphic HLA-E molecule is
significantly upregulated in epithelial cells when infected by various adenovirus types, while the highly polymorphic HLA-A,
B, C isoforms are downregulated. The observations infer that NK cell responses are dampened by engagement of HLA-E by
the NKG2A inhibitory receptor expressed as a major regulator of NK cells in human peripheral blood. We hypothesize that
adenoviruses have thus evolved to utilize this strategy to cancel out the effects of NK cell licensing as a means of immune
evasion.
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Wed(4)-P-53
Methyleugenol DNA-Adducts in Human Liver are Associated with SULT1A1 Copy Number Variations
1,2
Roman Tremmel ，Walter Meinl 3 ，Kristin Herrmann 3 ，Kathrin Klein 1,2
，Hansruedi Glatt 3 ，Ulrich M. Zanger 1,2
1:Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany、2:University Tuebingen, Tuebingen, Germany、
3:German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
Methyleugenol is a secondary metabolite in plants including fennel, basil and many other herbs, and is used as a flavor.
Following cytochrome P450 (CYP)-mediated hydroxylation and sulfotransferase (SULT)-mediated sulfation the electrophilic
metabolites can bind covalently to DNA and form adducts. In rodents, methyleugenol is a genotoxic carcinogen and DNA
adduct formation depends on functional SULT1A1 enzyme. Here we investigated whether SULT1A1 polymorphisms including
copy number variations (CNV) are associated with methyleugenol DNA adduct levels in human liver samples.
The level of DNA adducts was measured using mass spectrometry in surgical human liver tissue samples (n=121). We
identified CNVs using next generation sequencing and TaqMan assays. Genome wide SNP data was obtained from microchip
experiments. Additionally, we quantified SULT1A1 mRNA by microarray analysis and protein by Western blot analysis of
liver cytosols.
Methyleugenol DNA adduct levels were highly variable (coefficient of variation (CV)= 79%) significantly correlated to mRNA
levels of metabolizing enzymes, including CYP1A1 and CYP1A2, whereas the correlation with SULT1A1 was strongest
(rS =0.43). The detected CNVs, including deletions (f=3.3%) and duplications (f=36%) of SULT1A1 were significantly
associated with SULT1A1 mRNA (p=2.8e-6 ) and protein (p=5.1e-12 ) as well as methyleugenol DNA adduct levels (p= 0.03).
Poster Session
Carriers of multiple copies of SULT1A1 had 2.8-fold higher methyleugenol DNA adducts levels compared to carriers with
a single gene copy. These observations confirm a strong impact of SULT1A1 CNVs on SULT1A1 hepatic phenotype and
suggest a strong role in methyleugenol DNA adduct formation. Further studies are required to investigate cancer risk of
methyleugenol in relation to the uptake of the natural compound and SULT1A1 copy number status.
The study was supported by the Robert Bosch Foundation, Stuttgart, and the German Federal Institute for Risk Assessment,
Berlin, Germany
Wed(4)-P-54
Homozygous deletions of non-coding DNA sequences in Autism spectrum disorder
Klaus E Schmitz-Abe 1,2,3,4 ，Ryan Doan 1,2 ，Sean Hill 1,2 ，Guzman Sanchez-Schmitz 2,5 ，Eric M. Morrow 6 ，
Michael E. Greenberg 7 ，Timothy W. Yu 1,2 ，Christopher A. Walsh 1,2,8 ，Kyriacos Markianos 1,2
1:Division of Genetics and Genomics, Harvard Medical School and Children Hospital Boston, USA、2:Department of Pediatrics and
Neurology, Harvard Medical School, Boston, MA, USA、3:Manton Center for Orphan Disease Research、4:Broad Institute of Harvard
and MIT, Cambridge, MA, USA、5:Division of Infectious Diseases, Department of Medicine, Boston Childrens Hospital, Boston, MA、
6:Department of Molecular Biology, Cell Biology and Biochemistry and Department of Psychiatry and Human Behavior, Brown University,
Providence, RI, USA、7:Department of Neurobiology, Harvard Medical School, Boston, MA, USA、8:Howard Hughes Medical Institute,
Boston Children’s Hospital, Boston, MA, USA
Noncoding DNA comprises 99% of the genome but methods for identifying its contribution to disease have greatly lagged
our understanding of protein-coding mutations. Autism Spectrum Disorder (ASD), associated with defects in social and/or
cognitive function, has previously been linked to de novo Copy Number Variants (CNVs), de novo Single Nucleotide Variants
(SNVs) or inherited recessive biallelic SNVs; however, most cases remain unexplained. We analyzed CNVs in 187 families
with ASD enriched for consanguinity and compared CNV patterns with 1,767 families from two additional ASD cohorts.
In consanguineous families, individuals affected with ASD are significantly enriched for autosomal homozygous deletions
compared to unaffected siblings (17% versus 4%, p<0.001). Most homozygous deletions were small (<50 kb, 20/28) and only
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a few were predicted to result in protein inactivation through coding exon disruption. In contrast, affected individuals were
significantly enriched for homozygous deletions in DNA regulatory regions, with 23/28 regions disrupting ENCODE histone
peaks, a rate much higher than predicted by chance (p<0.004). Our data suggest an important new noncoding mechanism of
ASD, define a powerful approach to identifying essential noncoding regions in the human genome, and highlight the potential
importance of patterned gene activation and regulation in cognitive and social function.
Wed(4)-P-55
Genome-wide landscape of insersions/deletions with a functional impact on transcription factor binding
sites
Francesco Lescai 1,2,3 ，Esben Eickhardt 1,2,3
，Thomas Damm Als 1,2,3
，Manuel Mattheisen 1,2,3
，Jakob Grove 1,2,3,4
，
Anders Boerglum 1,2,3,5
1:Department of Biomedicine, Aarhus University, Denmark、2:iSEQ - Centre for Integrative Sequencing, Aarhus C, Denmark、3:iPSYCH
- Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark、4:BiRC - Bioinformatics Research Centre, Aarhus
University, Aarhus C, Denmark、5:Research Department P, Aarhus University Hospital Risskov, Denmark
Transcription factor (TF) binding is crucial for regulation of gene expression, and variants in TF binding sites (TFBSs) might
therefore have important regulatory effects. Position weight matrices (PWMs), derived from chromatin immuno-precipitation
sequencing, provide a way to predict the probability of a TF to bind any given sequence using an additive model. PWMs have
been shown to accurately predict TF binding in vitro, and therefore can be used as a bioinformatic tool to calculate a score
for any mutation in TFBSs. More recently, genotype calling on deoxyribonuclease I hypersensitive sites (DHS)-sequencing
data allowed to infer the impact of SNPs on TF binding, by assessing the depth of each allele in DHS reads. Due to the
Poster Session
nature of these data however, the influence of INDELs remains under-investigated, despite they are expected to introduce
more severe changes in the binding sequences.
In this investigation we address this gap, by developing a method, based on PWMs, to score all human variation sequenced
in 1000 Genome phase 3 (~ 85 million variants). Our TFBS-score ensures comparable results with SNPs on experimental
data, and also provides an unprecedented assessment of the influence of INDELs on TF binding.
TFBS-scores differ significantly between SNPs and INDELs (p = 2.2x10-16): insertions have the most distinct score profile,
and deletions the most severe consequences. In order to understand the pathological relevance of our scores, we divided
the variants in three categories, according to the overall distribution of the TFBS-scores. We tested each score category for
enrichment of variants classified as pathogenic and benign in ClinVar, and found the most negative scores to be significantly
enriched for pathogenic variants (p = 6.6x10-6). In this poster we describe in more detail our findings and we provide
a straightforward solution to infer the potential influence of INDELs in TF binding, as well as their relevance for human
diseases.
Wed(4)-P-56
Genetics of gut microbiome composition in healthy individuals
Alexandra Zhernakova 1 ，Marc Jan Bonder 1 ，Alexander Kurilshikov 1 ，Ettje Tigchelaar 1 ，Lude Franke 1 ，
Melanie Schirmer 2 ，Tommi Vatanen 2 ，Leo Joosten 3 ，Mihai Netea 3 ，Ramnik Xavier 2 ，Jingyuan Fu 1 ，
Cisca Wijmenga 1
1:Department of Genetics, University of Groningen, University Medical Center Groningen, Netherlands、2:The Broad Institute of MIT and
Harvard, Cambridge, MA, USA、3:Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
The human gut microbiome have been linked to many diseases and traits, including lipid metabolism, immune diseases and
cancer. Multiple factors, such as age, diet, medications and lifestyle influence gut microbiome. The role of genetic factors in
microbiome has been suggested by substantial heritability of selected bacteria in twin studies, however was not yet investigated
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in a big scale.
In this work we aimed to identify genetic variants that influence gut microbiome composition in healthy population. For
the discovery we used the population cohort of LifeLinesDEEP (LLD) that includes 1200 individuals from Groningen, the
Netherlands. Replication was done in 500 samples from the Functional Genomics project (500FG) from Nijmegen, the
Netherlands. For both cohorts extensive information on diet, diseases and lifestyle was available. In all samples genome-wide
genotyping was performed and missing SNPs and HLA alleles were imputed. Gut microbiome composition was analysed
by paired-end metagenomic shotgun sequencing on Illumina HiSeq2000 platform. The microbial reads were mapped using
MetaPhlAn2.2.
We performed the quantitative analysis of effects of SNPs and HLA alleles on abundance of gut bacteria. Overall, we
observed moderate effect of genetic variants on microbiome composition. However, correction for the other intrinsic and
environmental factors increases the power of genetic analysis for ±10%. The strongest effect was observed for SNPs in LCT
locus on Bifidobacteria. In particular, individuals homozygous for lactose-intolerant rs4988235 minor allele have increased
abundance of Bifidobacteria species (p=9x10-8 in LLD, p=0.06 in 500FG). Correlation of genotype with bacterial abundance
was dependent on consumption of milk and other dairy products.
Overall, our results indicate that genetic variants influence gut microbiome composition, and this effect is more pronounced
after correction for other intrinsic and environmental factors.
Poster Session
Wed(4)-P-57
Genetic control of ADCY3 and IRF4 expression is critical for the Mycobacterium leprae triggered immune
response
Jeremy Manry 1,2 ，Yohann Nedelec 3,4 ，Vinicius M Fava 1,2
，Aurelie Cobat 5 ，Guillaume Laval 6,7
，Marianna Orlova 1,2
，
Luis B Barreiro 3,4,8 ，Erwin Schurr 1,2
1:Human Genetics, Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health
Centre, Montreal, Quebec, Canada、2:McGill International TB Centre and Departments of Medicine and Human Genetics, McGill University,
Montreal, Quebec, Canada、3:Sainte-Justine Hospital Research Centre, Montreal, Quebec, Canada、4:Department of Biochemistry, Faculty of
Medicine, University of Montreal, Montreal, Quebec, Canada、5:Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut
National de la Sante et de la Recherche Medicale, Paris, France、6:Institut Pasteur, Unit of Human Evolutionary Genetics, Department of
Genomes and Genetics, Paris, France、7:Centre National de la Recherche Scientifique, Paris, France、8:Department of Pediatrics, Faculty of
Medicine, University of Montreal, Montreal, Quebec, Canada
Leprosy is a human infectious disease caused by Mycobacterium leprae. A strong host genetic contribution to leprosy suscepti-
bility is well established. However, the modulation of the transcriptional response to infection and the mechanism(s) of disease
control are poorly understood. To address this gap in knowledge of leprosy pathogenicity, we conducted a genome-wide search
for expression quantitative trait loci (eQTL) that are associated with transcript variation - before and after stimulation with
M. leprae sonicate in whole blood cells. Such stimulation is expected to trigger an immune response. Indeed, among the genes
upregulated by M. leprae antigen stimulation we observed a striking enrichment of immune related genes. We identified 36700
cis-eQTL for 818 genes, most of the “immune response” eQTL (>95%) were eQTL for genes in the HLA region. In addition,
we found 7814 eQTL as being specific to either stimulated or to non-stimulated cells but not under both conditions. Hence,
such eQTL show significant evidence for interaction with the stimulus and are termed response eQTL (r-eQTL). r-eQTL
correspond to regulatory variations that affect the interaction between human whole blood cells and M. leprae sonicate, and
thus likely between the human host and M. leprae themselves. Remarkably, ADCY3 - previously identified as a leprosy type-I
reaction signature gene - was strongly upregulated by M. leprae antigen and expression levels were significantly modulated by
a r-eQTL that exhibited signatures of positive selection in the Asian population. IRF4, a key inflammatory mediator gene,
was the only gene harbouring distinct r-eQTL before and after infection, and one of these r-eQTL also displayed a signature
of positive selection in the Asian population. Considering the evidence of natural selection on r-eQTL for the ADCY3 and
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IRF4 genes, both genes emerge as critical mediators of the protective anti-M. leprae immune response.
Wed(4)-P-58
Rare variant discovery by deep whole-genome sequencing of thousands Japanese individuals and bioin-
formatics
Masao Nagasaki 1,2,3 ，Yosuke Kawai 1,2 ，Kaname Kojima 1,2 ，Takahiro Mimori 1 ，Yumi Yamaguchi-Kabata 1,2 ，
Tomoko F Shibata 1,2 ，Kazuharu Misawa 1,2 ，Yukuto Sato 1,2 ，Inaho Danjoh 1,2 ，Sakae Saito 1,2 ，Shin Ito 1 ，
Nobuo Fuse 1,2 ，Kengo Kinoshita 1,3,4 ，Shigeo Kure 1,2 ，Nobuo Yaegashi 1,2 ，Fumiki Katsuoka 1,2 ，Jun Yasuda 1,2 ，
Masayuki Yamamoto 1,2 ，ToMMo Japanese Reference Panel Project
1:Tohoku Medical Megabank Organization, Tohoku University, Japan、2:Graduate School of Medicine, Tohoku University、3:Graduate
School of Information Sciences, Tohoku University、4:Institute of Development, Aging and Cancer, Tohoku University
The Tohoku Medical Megabank Organization reports the whole-genome sequences of 1,070 healthy Japanese individuals and
construction of a Japanese population reference panel (1KJPN). Here we identify through this high-coverage sequencing (32.4
× on average), 21.2 million, including 12 million novel, single-nucleotide variants (SNVs) at an estimated false discovery rate
of <1.0%. This detailed analysis detected signatures for purifying selection on regulatory elements as well as coding regions.
We also catalogue structural variants, including 3.4 million insertions and deletions, and 25,923 genic copy-number variants.
The 1KJPN was effective for imputing genotypes of the Japanese population genome wide. These data demonstrate the
value of high-coverage sequencing for constructing population-specific variant panels, which covers 99.0% SNVs of minor allele
frequency ≥0.1%, and its value for identifying causal rare variants of complex human disease phenotypes in genetic association
studies. This task also inform the progress of the thousands referene panel and related bioinformatics tools.
Poster Session
Wed(4)-P-59
Coordinated Regulation of DNMT3B, PTEN, and TET3 via a Competing Endogenous RNA (ceRNA)
Network
Kenneth Anthony R Roquid 1 ，Reynaldo L Garcia 1
Phosphatase and Tensin Homolog (PTEN) acts as a tumor suppressor by negatively regulating the PI3K-Akt survival pathway
and the MAPK cellular proliferation pathway. Loss of function mutations in and dysregulation of PTEN almost always lead to
cancer progression. More recently, PTEN derepression by a competing endogenous RNA network, which is able to sequester
shared miRNAs from PTEN, provided a miRNA-dependent and coding-independent mechanism for suppressing cancer. In
silico analysis shows that PTEN shares miRNA binding sites with DNMT3B and TET3, enzymes involved in methylation /
demethylation. This study reports on the cloning of their 3’UTRs downstream of a luciferase reporter in the target expression
vector pmirGLO and shows via luciferase assays that they may be subject to endogenous miRNA regulation in the context of
HCT116. Co-transfection of the 3’UTR target with a mir-4465 cloned in pmR-Zsgreen, followed by semi-qRT-PCR, shows that
mir-4465 may contribute to this endogenous regulation. This implicates mir-4465 as a shared miRNA regulating DNMT3B,
PTEN, and TET3. Overexpression of the 3’UTR region of one ceRNA transcript leads to the upregulation of its putative
endogenous competitor; assessed by semi-qRT-PCR and verified by gel quantification. Individual knockdown of DNMT3B,
PTEN, and TET3 was also done to further validate this ceRNA network. These findings were supplemented with Western
Blot analysis and functional assays which suggest that a ceRNA network does exist between DNMT3B, PTEN, and TET3.
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Wed(4)-P-60
High-throughput sequencing method of the KIR haplotype for integrated HLA-KIR genotyping approach
for clinical applications
Kazuyoshi Hosomichi 1 ，Toshio Yabe 3 ，Takashi Shiina 4 ，Atsushi Tajima 1 ，Ituro Inoue 2
1:Department of Bioinformatics and Genomics, Graduate School of Medical Sciences, Kanazawa University, Japan、2:Division of Human
Genetics, Department of Integrated Genetics, National Institute of Genetics、3:Japanese Red Cross Kanto-Koshinetsu Block Blood Center、
4:Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine
Killer-cell immunoglobulin-like receptors (KIRs) expressing on natural killer (NK) cells are ligands of human leukocyte antigen
(HLA) class I molecules. The KIR genes are located on the approximately 150 kb small genome region as being haplotype
of gene cluster, and are classified into two categories; inhibitory and activating receptors to regulate activity of the NK cells.
The number of KIR genes is different among KIR haplotypes, therefore each individual has a different number of inhibitory
and activating KIR genes. Disease associations with KIRs, HLA class I molecules and their combinations has been reported
for reproduction, infection, autoimmunity, cancer, and haematopoietic stem-cell transplantation. Here, we established high-
throughput sequencing method to identify the haplotype structure of KIR genes as allelic gene sequences. The DNA libraries
for KIR typing was prepared by sequence capture method with custom oligo probes, which was designed by recorded seventeen
KIR genes (KIR3DL3, 2DS2, 2DL2, 2DL3, 2DL5B, 2DS3, 2DP1, 2DL1, 3DP1, 2DL4, 3DL1, 3DS1, 2DL5A, 2DS5, 2DS1,
2DS4, and 3DL2 ) in Immuno Polymorphism Database (IPD-KIR). 96 DNA libraries were pooled and subsequently subjected
to hybridization reaction in one tube, and one MiSeq run (350 bp and 250 bp paired-end). Sequence reads from seventeen
KIR genes could be aligned. The alignment result of thirteen KIR genes (KIR2DS2, 2DL2, 2DL3, 2DL5B, 2DS3, 2DP1,
2DL1, 3DL1, 3DS1, 2DL5A, 2DS5, 2DS1, and 2DS4 ) has distinct depth indicating copy number variation (CNV). The other
Poster Session
four KIR genes (KIR3DL3, 3DP1, 2DL4, and 3DL2 ) were observed in all KIR haplotypes. The single nucleotide variants
(SNVs) were used to estimate haplotype in KIR gene region as KIR allele sequence. In addition, combination of CNV and
SNVs as KIR allele could be available to estimate KIR haplotype structure. Our new KIR typing strategy will be a useful
tool as integrated HLA-KIR genotyping approach for clinical applications.
Wed(4)-P-61
Preliminary Investigations on the Putative Role of the Antisense Transcripts DYT3 and INGX in X-linked
Dystonia Parkisonism
Jian Kenzo O. Leal 1 ，Reynaldo L. Garcia 1 ，Joshua Reginald P. Malapit 1 ，Kenneth Anthony R. Roquid 1
1:National Institute of Molecular Biology and Biotechnology, Philippines
X-linked Dystonia Parkinsonism (XDP: locally known as“lubag”) is a neurodegenerative disorder found exclusively in people
whose roots can be traced to the Panay Island, Philippines. The disease phenotype has been mapped to a multiple transcript
system (MTS) composed of the TATA-binding protein-associated factor 1 (TAF1) and DYT3, a putative non-coding RNA
(ncRNA). There has been no definitive proof that this MTS is causative of the disease, but XDP-specific changes (XDP-SCs)
have been found in it. INGX is another ncRNA found antisense to DYT3. It is a pseudogene belonging to the ING-family
of proteins, which is involved in cellular proliferation, cellular senescence, and apoptosis. We cloned both ncRNAs with a
view to investigating which of the two antisense transcripts is responsible for the disease phenotype. INGX and DYT3 were
cloned into the pTarget mammalian expression vector, and transfected heterogously into different cell lines for overexpression
studies. We also did site-directed mutagenesis to generate the observed XDP-SCs. Here, we provide, preliminary data on the
effects of the antisense transcripts on cellular proliferation, cellular senescence, and apoptosis. The assays performed include
the beta-galactosidase assay for cellular senescence, kits for monitoring apoptosis, and the cellular proliferation assay. Our
data suggest that INGX and DYT3 are indeed involved in regulating cellular proliferation, cellular senescence, and apoptosis.
Future directions include the generation of mutations in DYT3 and INGX to check its effect on said parameters.
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Wed(4)-P-62
The CRNDE lncRNA instigates distinct programs of stemness, chemoresistance, proliferative capacity
and invasiveness
Jose Lorenzo M. Ferrer 1 ，Tiffany T Ong 1 ，Robert Lorenz C Chua 1,2
，Reynaldo L Garcia 1
1:Disease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular Biology and Biotechnology, University of the
Philippines Diliman, Philippines、2:Georg-August-Universitat Gottingen International Max Planck Research School
Colorectal Neoplasia Differentially Expressed (CRNDE) is a long non-coding RNA that was first seen to be highly upregulated
in over 90% of colorectal cancers but has since been shown to have elevated levels across many different cancer types,
highlighting its potential use as an important cancer biomarker. However, not enough functional data on CRNDE has been
obtained. We hypothesize that CRNDE may instigate multiple cancer-associated programs. The functional sequelae of
both CRNDE overexpression and knockdown were observed in the following assays: Semi-quantitative/quantitative RT-PCR
was performed to assess the effect of CRNDE overexpression on chosen stemness and chemoresistance markers. A cellular
proliferation assay and a focus formation assay were performed to observe the effect of CRNDE overexpression on proliferation
while a scratch-wound assay and cytochemistry were used to determine if CRNDE overexpression affects metastatic potential.
Based on the data generated from these experiments, CRNDE indeed seems to instigate 4 distinct programs of stemness,
chemoresistance, proliferative capacity, and invasiveness. Thus, its potential use as a biomarker for cancer is validated,
especially because CRNDE has been described to be selectively packaged into exosomes, which are small membranous vesicles
containing biomolecules that function in cellular communication and are secreted from viable cells, including cancer cells.
These exosomes may be utilized to develop a less invasive diagnostic and/or prognostic method that is based on a signature
composed of CRNDE and other long non-coding RNAs. Preliminarily, we detected expression of CRNDE and other colorectal
Poster Session
cancer-associated lncRNAs including Carlo5, lncRNA 91H, lncRNA-ATB, and lncRNA-422, which are oncogenic, and GAS5,
which is a tumor suppressor, in HCT116. We are currently attempting to detect these lncRNAs from exosomes secreted by
the said cell line.
Wed(4)-P-63
S100PBP, TET3 and their shared microRNA response elements (MREs) suggest existence of a compet-
itive endogenous RNA (ceRNA) network
Lech Havel O. Tizon 1 ，Robert Lorenz C. Chua 1 ，Reynaldo L. Garcia 1
1:National Institute of Molecular Biology and Biotechnology, University of the Philippines - Diliman, Philippines
S100P is a Ca2+ binding protein that is widely considered as a potential tumor biomarker by its heightened expression in
various cancers, e.g. breast, colon, prostate, lung, and pancreatic adenocarcinomas. It can mediate Ca2+ dependent signal
transduction involved in the regulation of cell shape, motility, proliferation, differentiation, and survival. In colorectal cancer,
overexpression is due to hypomethylation but the mechanism leading to initiation of the demethylation process is unknown.
S100PBP, the antagonistic binding partner of S100P, and TET3, a dioxygenase that initiates the demethylation process show
shared miRNA binding sites, otherwise known as miRNA response elements (MREs), hinting at possible co-regulation and/or
competition for endogenous miRNA binding. By cloning the S100PBP and TET3 3’UTR downstream of a luciferase reporter
into the pmirGLO miRNA target expression vector, this study showed regulation of both genes by endogenous miRNAs. The
putatively shared miRNAs hsa-miR-19a and hsa-miR-23b have been cloned into the precursor miRNA expression vector pmR-
ZsGreen1 and the effects of their overexpression, separately or together, on the co-transfected cloned 3’UTR and endogenous
targets were observed. Reduced luciferase activity suggests that both miRNAs are able to bind to the 3’UTR, while current
endogenous targets seem to show stronger binding of hsa-miR-23b. This is also supported by bioinformatics prediction of
miRNA binding affinity that shows hsa-miR-23b has lower free energies of binding than hsa-miR-19a. Taken together, the
results seem to validate the hypothesized competitive endogenous RNA (ceRNA) network effect. In the long-term, the goal
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is to test if overexpression or the knockdown of one of the above mRNA targets would modulate the level of expression of the
other, with consequent physiological effects leading to oncogenesis.
Keywords: S100P, ceRNA, Methylation, Epigenetics, Cancer
Wed(4)-P-64
The effect of high copy number of salivary amylase gene on adiposity in Korean
Ho-Young Son 1 ，Jin Ho Park 2 ，Joohon Sung 3 ，Charles Lee 5,6
，BeLong Cho 2 ，Jong-Il Kim 1,4
1:Department of Biochemistry, Seoul National University college of medicine, Korea, South、2:Department of Family Medicine, Seoul National
University College of Medicine、3:Department of Epidemiology, School of Public Health, Seoul National University、4:Genomic Medicine
Institute, Medical Research Center, Seoul National University、5:Department of Life Sciences, Ewha Womans University、6:The Jackson
Laboratory for Genomic Medicine
The diversity of human copy number variation (CNV) and its functional impact was well known. It was found for the
extensive increase in copy number of AMY1 gene (2-17 copies) and populations with high-starch diet were found to be
significantly associated. The association between low copy number of salivary amylase gene and increased body mass index
(BMI) was reported. Recently, structure of human amylase locus, their haplotypes and relationship of nearby single nucleotide
polymorphisms (SNPs) were reported. However, in this report, AMY1 copy number and BMI was found not to have any
association. Here, our group conducted a study in association of AMY1 CNV with obesity indices and fat storage amount in
Poster Session
2,270 Koreans, known to be a homogenous and high starch diet population. We investigated whether AMY1 CNV has any
impact on fat storage level using three obesity indices; BMI, waist circumference (WC) and visceral adipose tissue (VAT).
We used computed tomography (CT) to measured central adiposity as an obesity index, which can test for more accurate
association between AMY1 CNV and fat storage amount. We identified several interesting but conflicting findings compared
to the previous reports. First, we tested the association between estimate AMY1 copy number and obesity indices. We didn’t
find any significant association, but the positive correlation (β > 0) was shown between the AMY1 copy number and obesity
indices. Second, we found that obese group defined by (VAT) showed significantly higher AMY1 copy number than that of
the non-obese group. Third, high AMY1 copy number group (≥8 copy) showed increased levels of all obesity parameters.
Conclusively, in Korean population, AMY1 copy number had weak but positive association with fat storage amount, contrary
to the previous result. These opposite findings may have resulted from different level of dependence on starch or different
genetic architecture among populations.
Wed(4)-P-65
Ribosomal RNA deplection from Single Cell RNA Sequencing
1
Colin A Baron
1:Qiagen, Germany
Recent advances in single-cell RNA sequencing technologies have revealed high heterogeneity of the gene expression profiles in
individual cells. However, most single cell RNA-seq methods use oligo-dT priming in the reverse transcription steps and detect
polyA-positive protein-coding transcripts, but miss important RNA species such as non-coding RNA. Random oligo-based
priming can be paired Multiple Displacement Amplification (MDA) to efficiently amplify scarce amounts of RNA to enable
transcriptional profiling.
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The potential drawback to reverse transcription using random oligos is that ribosomal RNA (rRNA) will often be detected
alongside non-coding RNA species. rRNA comprises more than 90% of the total RNA and should be depleted from the
RNA-seq library to ensure efficient usage of the sequencing capacity. Commonly used hybridization-based rRNA depletion
methods can preserve non-coding RNA in the standard RNA-seq library. However, such rRNA depletion methods require
high input amount of total RNA and do not work at the single cell level or with limited input DNA.
This poster describes a novel method for RNA-seq library construction from single cells or a minimal amount of RNA
using a thermostable duplex-specific nuclease to effectively remove ribosomal RNA sequences following whole-transcriptome
amplification and sequencing library construction.
Wed(4)-P-66
Functional characterization of long non-coding RNAs in FANTOM6
Michiel de Hoon 1 ，Jay Shin 1 ，Chung Chau Hon 1 ，Jordan Ramilowski 1 ，Masayoshi Itoh 1 ，Takeya Kasukawa 1 ，
Naoto Kondo 1 ，Harukazu Suzuki 1 ，Alistair Forrest 2 ，Piero Carninci 1
1:RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Japan、2:Harry Perkins Institute of Medical
Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Perth, Australia
FANTOM (Functional ANnoTation Of the Mammalian genome) is a worldwide research consortium aiming at a comprehensive
identification and annotation of the mammalian transcriptome. Previous FANTOM projects have demonstrated that most
transcripts in mammalian cells are non-coding, upending the previously held belief that the vast majority of cellular transcripts
Poster Session
code for proteins. In the recent FANTOM5 project, we observed strong enrichment of disease-associated SNPs at lncRNA
loci as well as at transcribed enhancers, providing evidence that non-coding RNAs are functional. In contrast to proteins,
for which an initial functional annotation can be generated based on the amino acid sequence, the function of non-coding
RNAs cannot be reliably predicted from the nucleotide sequence alone, and therefore is still unknown for 98% of non-coding
transcripts.
In the sixth edition of the FANTOM project (FANTOM6), we aim to systematically elucidate the function of long non-coding
RNAs (lncRNAs) in the human genome using high-throughput strategies to perturb hundreds of lncRNAs in multiple cell
types, followed by transcriptome profiling using CAGE to assess the molecular phenotype. These perturbation experiments
are complemented by genome-wide profiles to establish the basal state of the transcriptome and epigenome in each cell type.
The lncRNAs selected for perturbation include both published transcripts and novel transcripts that are being discovered as
part of FANTOM5. The FANTOM6 data generated so far show the distinct response of the human transcriptome to the
lncRNA perturbations, consistent with their functional role in cellular regulation.
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Poster Session
Molecular Basis of Mendelian Disorders 2
Wed(4)-P-67
ROCK inhibition is essential during in vitro neurogenesis and promotes phenotypic rescue of human
iPSCs-derived neurons with Oligophrenin-1 loss of function
Ginevra Zanni 1 ，Claudia Compagnucci 1 ，Sabina Barresi 1 ，Stefania Petrini 2 ，Enrico Bertini 1
1:Depatment of Neurosciences, OPBG, Italy、2:Department of Research Laboratories, OPBG
Rho-GTPases have relevant functions in various aspects of neuronal development such as differentiation, migration and
synaptogenesis. Loss of function of OPHN1 causes X-linked intellectual disability with cerebellar hypoplasia and leads to
hyperactivation of the RhoA/Rho-kinase (ROCK) pathway. ROCK mainly acts through phosphorylation of the Myosin
Phosphatase targeting subunit 1 (MYPT1) triggering actin-myosin contractility. We show that during in vitro neurogenesis
ROCK activity decreases from day 10 until terminal differentiation, whereas in OPHN1-deficient human induced pluripotent
stem cells (h-iPSCs), the levels of ROCK are elevated throughout differentiation. ROCK inhibition favors neuronal-like
appearance of h-iPSCs, in parallel with transcriptional up-regulation of nuclear receptor NR4A1 known to induce neurite
outgrowth. This study analyzes the morphological, biochemical and functional features of OPHN1-deficient h-iPSCs and their
Poster Session
rescue by treatment with ROCK inhibitor Fasudil, shedding light on the relevance of the ROCK pathway during neuronal
differentiation and providing a neuronal model for human OPHN1 syndrome and its treatment.
Wed(4)-P-68
Epidermodysplasia verruciformis lacking TMC6 and TMC8 mutations
Tokimasa Hida 1 ，Junji Kato 1 ，Masae Okura 1 ，Toshifumi Nomura 2 ，Toshinari Miyauchi 2 ，Toshiharu Yamashita 1
1:Department of Dermatology, Sapporo Medical University School of Medicine, Japan、2:Department of Dermatology, Hokkaido University
Epidermodysplasia verruciformis (EV) is a chronic skin disorder characterized by abnormal susceptibility to beta-human
papillomaviruses (HPVs) and development of multiple non-melanoma skin cancers. Although most patients have an autosomal
recessive inheritance, some display a pattern of autosomal dominant or X-linked recessive inheritance. Two EV susceptibility
loci, EV1 and EV2 , have been found on chromosomes 17 and 2, respectively. It is in the EV1 locus that two EV-responsible
genes, TMC6 and TMC8 , are located. Here, we present a case of EV that lacks pathogenic mutations in the TMC6 or TMC8
genes. The patient was a 70-year-old woman with squamous cell carcinoma (SCC) in the left shin and Bowen’s disease (SCC
in situ) in the left calf and the right index finger. She also had multiple seborrheic keratosis-like brown papules/macules on
sun-exposed areas of her skin. The patient’s family history was unremarkable and her parents were non-consanguineous.
By HPV DNA analysis using HPV consensus primers, HPV-14, -23 and -111 were detected in the seborrheic keratosis-like
benign lesions and the SCC tissue. The patient was clinically diagnosed with EV because of the existence of multiple skin
cancers and beta-HPV. Genetic analysis of the TMC6 and TMC8 genes did not detect any pathogenic mutations in the
coding regions or exon-intron boundaries. A rare homozygous variation was detected in the 3’-untranslated region of TMC8 .
TMC8 expression in the patient’s peripheral blood cells was examined but mRNA and protein levels were comparable to
those of healthy individuals. Consequently, the pathogenic mutation in the current patient could not be determined and was
surmised to lie in the non-coding regions of TMC6/8 genes or in other unidentified genetic loci. There have been previous
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reports of EV patients without TMC6/8 mutations. It is hoped that future comprehensive genomic analyses may elucidate
the mechanism of these patients.
Wed(4)-P-69
Clinical and Genetic Characteristics of Thai Patients with 46, XY Disorders of Sex Development
Chupong Ittiwut 1 ，Jaturong Pratuangdejkul 2 ，Vichit Supornsilchai 1 ，Sasipa Muensri 1 ，Yodporn Hiranras 1 ，
Taninee Sahakitrungruang 1 ，Suttipong Watcharasindhu 1 ，Kanya Suhapeetiporn 1 ，Vorasuk Shotelersuk 1
1:Pediatrics, Chulalongkorn University, Thailand、2:Microbiology, Mahidol University
Objective: To determine the clinical, hormonal and genetic characteristics of Thai patients with 46, XY DSD.
Design: Descriptive and analytic study.
Setting: Division of Endocrinology and Center of Excellence for Medical Genetics
Patients: Forty three patients with 46, XY DSD with normal testosterone production evaluated by hCG stimulation test.
Interventions: Basal and hCG-stimulated testosterone and dihydrotestosterone (DHT) levels were determined. PCR-
sequencing of the entire coding regions of the SRD5A2 and AR genes was performed. Molecular modeling analysis of AR
Poster Session
ligand binding domain (AR LBD) of a novel mutation was constructed.
Main Outcome Measures: Pathogenic mutations of the SRD5A2 and AR genes. Determination of protein structure in
mutated AR. Differences in clinical and hormonal characteristics among the 5 α-reductase deficiency, the partial androgen
insensitivity syndrome (PAIS) and the undefined group.
Results: Mutations were found in 7 patients (16.3%); 5 (11.6%) and 2 (4.7%) patients had mutations in SRD5A2 and
AR, respectively. Two novel mutations, SRD5A2 c.383A>G (p.Y128C) and AR c.2179C>T (p.R727C), were identified.
Dimentional structure of the novel mutated AR (p.R726C) affected the co-activator binding (BF-3), not the testosterone
binding site. Short phallus length was associated with 5 α-reductase deficiency. No clinical or hormonal features were
associated with PAIS.
Conclusion(s): Mutations of SRD5A2 and AR genes were identified in 16.3% of Thai patients with 46, XY DSD. Two novel
mutations were described, expanding mutational spectrum. The new mutated AR (p.R726C) was located at the co-activator
binding site. Phallus length was an association factor for 5 α-reductase deficiency.
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Wed(4)-P-70
Two cases with miscarriages caused by resistance to thyroid hormone
Katsuhiko Tsunekawa 1 ，Tomoyuki Aoki 1 ，Osamu Araki 1 ，Takao Kimura 1 ，Makoto Nara 1 ，Hiroyuki Sumino 1 ，
Masami Murakami 1
1:Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, Japan
No Abstract
Wed(4)-P-72
Phenotypic and Genetic Spectrum of Hereditary Sensory and Autonomic Neuropathy in Japan
Junhui Yuan 1 ，Yujiro Higuchi 1 ，Akihiro Hashiguchi 1 ，Akiko Yoshimura 1 ，Yuji Okamoto 1 ，Yusuke Sakiyama 1 ，
Tomonori Nakamura 1 ，Eiji Matsuura 1 ，Hiroshi Takashima 1
1:Kagoshima University, Japan
Objective To evaluate the frequency and distribution of mutations in Japanese patients with hereditary sensory and autonomic
neuropathy (HSAN), and to further investigate their phenotypic spectrum and genotype-phenotype interactions.
Poster Session
Methods We collected 37 index patients (27 males and 10 females) in our nationwide inherited neuropathy cohort who were
referred with a diagnosis of HSAN on the basis of clinical and electrophysiological assessment. Using a next-generation
sequencing system (Illumina, MiSeq), mutation screening of all coding exons and exon-intron junctions of 18 HSAN-related
genes was carried out. The suspected pathogenic variants and low-coverage domains (depth of less than 10) were validated
by Sanger sequencing, and segregation analysis was utilized to evaluate the pathogenicity if available.
Results Mean age of the patients was 50 years (range, 17 ~ 74 years), and the median onset age was 32.1 years, including
12 early-onset cases (32.4%; <12 years). 15 cases come from a consanguineous family or have at least one affected relative.
Among these patients, loss of pain and temperature sensation was recorded in 86.5% (32 cases), whereas only 54% patients
(20 cases) presented with autonomic nervous dysfunctions. Motor nervous system involvement was recognized in 10 cases
(27%). With respect of the accompanied symptoms, we identified cerebellar ataxia or atrophy (12 cases), hearing loss (8
cases), cognitive impairment (8 cases), pain (5 cases), and hyposmia (4 cases). Mutational analysis revealed 8 pathogenic
mutations and 2 likely pathogenic variants in four genes, DNMT1 (3 cases), SCN9A (3 cases), WNK1 (3 cases), and SPTLC2
(1 case).
Conclusions In our HSAN cohort, the mutation detection rate (27% within 18 genes) was higher than the previous studies,
and the highest mutation frequency shared by DNMT1 , SCN9A, and WNK1 genes, which is also different from the western
countries.
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Wed(4)-P-74
Novel homozygous MAGMAS/PAM16 mutation in a patient with radiological features of odontochon-
drodysplasia: first evidence for phenotypic overlap?
Shahida Moosa 1,2,4,5 ，Janine Altmueller 1,3
，Holger Thiele 3 ，Peter Nuernberg 3,4,5
，Virginia Fano 6 ，Gen Nishimura 7 ，
Bernd Wollnik 1,2,4,5
1:Institute of Human Genetics, University of Cologne, Germany、2:Institute of Human Genetics, University Medical Center Goettingen,
Goettingen, Germany、3:Cologne Center for Genomics (CCG), University of Cologne, Germany、4:Center for Molecular Medicine Cologne
(CMMC), University of Cologne, Cologne, Germany、5:Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases
(CECAD), University of Cologne, Cologne, Germany、6:Department of Paediatrics, Garrahan Pediatrics Hospital, Buenos Aires, Argentina、
7:Department of Pediatric Imaging, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan
Recently, a homozygous missense mutation (p.N76D) in PAM16 (MAGMAS; OMIM 614336) was shown to underlie the
Megarbane-Dagher-Melki type of spondylometaphyseal dysplasia (SMDMDM; OMIM 613320) in four patients from two
unrelated Lebanese families with a rare lethal spondylometaphyseal dysplasia. Here we report on a further patient with a
novel homozygous mutation in PAM16 . Our patient is the only child to distantly-related Argentinian parents of European
descent. He presented shortly after birth with an undiagnosed spondylometaphyseal dysplasia. Interestingly, his radiological
features most closely resembled those of odontochondrodysplasia. At the age of 2 years, he showed additional clinical features,
including severe developmental delay, severe hypotonia, bilateral hearing loss, atlantoaxial instability and dysmorphic facial
features, which have become coarser with age. Trio whole exome sequencing (WES) revealed the homozygous c.221A>C
mutation, which at the protein level leads to the substitution of a glutamine by proline at the amino acid position 74 (p.Q74P).
Both parents were confirmed heterozygous carriers of the mutation. We compare and contrast his clinical-radiological features
with the original SMDMDM patients, thereby expanding the PAM16 -associated phenotype. Importantly, we also highlight
for the first time the phenotypic overlap between patients with PAM16 mutations and those with odontochondrodysplasia.
Poster Session
Wed(4)-P-75
De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing
Hirotomo Saitsu 1 ，Tenpei Akita 2 ，Jun Tohyama 3 ，Hadassa Goldberg-Stern 4 ，Yu Kobayashi 3 ，Roni Cohen 4 ，
Mitsuhiro Kato 5 ，Chihiro Ohba 1 ，Satoko Miyatake 1 ，Yoshinori Tsurusaki 1 ，Mitsuko Nakashima 1 ，Noriko Miyake 1 ，
Atsuo Fukuda 2 ，Naomichi Matsumoto 1
1:Human Genetics, Yokohama City University, Japan、2:Neurophysiology, Hamamatsu University School of Medicine、3:Pediatrics, Epilepsy
Center, Nishi-Niigata Chuo National Hospital、4:Epilepsy Center, Schneider Children Medical Center、5:Pediatrics, Yamagata University
Faculty of Medicine
The voltage-gated Kv2.1 potassium channel encoded by KCNB1 produces the major delayed rectifier potassium current
in pyramidal neurons. Recently, de novo missense KCNB1 mutations have been identified in three patients with epileptic
encephalopathy and a patient with neurodevelopmental disorder. Here, we report two patients with novel de novo missense
KCNB1 mutations (p.R306C and p.G401R), both of whom show psychomotor developmental delay and severe infantile
generalized seizures with spike and wave EEG discharges. Expression of the Kv2.1 mutants in Neuro2a cells and primary
cortical neurons shows that the R306C mutation significantly disrupts sensitivity and movement of the Kv2.1 voltage sensor,
while the G401R mutation selectively abolishes endogenous Kv2 currents, indicating a dominant-negative effect on wild-type
channels. Both mutants exert loss-of-function effects on production of sufficiently deep interspike voltages, thereby inhibiting
repetitive action potential firing. Our findings suggest that de novo KCNB1 mutations are associated with psychomotor
developmental delay and infantile generalized seizures, highlighting the importance of Kv2.1 for brain development and
function in humans.
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Wed(4)-P-76
Advantage of next generation sequencing in molecular diagnosis in DMD -mutation screening with long
preserved dried umbilical cord and detection of mosaicism-
Ai Unzaki 1 ，Mariko Taniguchi-Ikeda 1,2 ，Yasuhiro Takeshima 3 ，Tomoko Lee 3 ，Hiroyuki Awano 1 ，
Mariko Yagi 4 ，Hiroki Kurahashi 5 ，Ichiro Morioka 1 ，Tatsushi Toda 2,6 ，Masafumi Matsuo 7 ，Kazumoto Iijima 1 ，
Mariko Taniguchi-Ikeda
1:Pediatrics, Kobe University Graduate School of Medicine, Japan、2:Division of Genetic Counseling, Kobe University Hospital、3:Depart-
ment of Pediatrics, Hyogo College of Medicine、4:Nikoniko-house Medical Welfare Center、5:Division of Molecular Genetics, Institute for
Comprehensive Medical Science, Fujita Health University、6:Department of Neurology/Molecular Brain Science, Kobe University Graduate
School of Medicine、7:Department of Medical Rehabilitation, Kobegakuin University
Introduction: Duchene muscular dystrophy (DMD) is an X-linked recessive disorder that affects approximately 1 in 3,500
live male newborns. DMD is a progressive muscle wasting disease, caused by mutations in the dystrophin (DMD) on the
X-chromosome. DMD located at Xp21.2, which is 2.4 Mb in size, and consists of 79 exons that form a 14 kb mRNA transcript.
One-third of patients are estimated to have de novo mutations. To provide in depth genetic counseling, the comprehensive
identification of mutations is mandatory. Using multiplex ligation-dependent probe amplification (MLPA), approximately
70% of DMD patients have been shown to have partial deletions or duplications. However, some of their mutational types
were difficult to identify due to the size and number of exons of DMD.
Case: Consultee is a 36-year-old woman, the sister of the proband. She visited our genetic counseling unit to have a carrier
genetic test for DMD. Proband was born 38 years previously, diagnosed with DMD because of clinical manifestations at 5
years of age. He passed away from cardiomyopathy at 14 years of age. Genetic diagnosis was not performed. To identify his
mutational type, we extracted genomic DNA from proband’s dried umbilical cord.
Poster Session
Results: His genomic DNA was severely degraded, MLPA analysis was performed but no gross mutations found. Sanger
sequencing was attempted but not conclusive. Next generation sequencing (NGS) was performed by controlling the tag-
mentation during library preparation. A nonsense mutation in DMD (p.Arg2095*) was clearly identified in the proband.
Consequently, the identical mutation was detected as an 11% mosaic mutation from his healthy mother. And the proband’
s sister was diagnosed as a non-carrier of the mutation.
Conclusion: We have identified a pathogenic DMD mutation from degraded DNA and low-level somatic mosaicism by NGS.
Thus, NGS enables deep resequencing of previously undetected low-grade mosaic mutations by Sanger sequencing.
Wed(4)-P-77
Homozygous ADCY5 mutation causes movement disorder with severe intellectual disability
Nobuhiko Okamoto 1 ，Fuyuki Miya 2,3 ，Tatsuhiko Tsunoda 2,3
，Mitsuhiro Kato 4 ，Shinji Saitoh 5 ，Mami Yamasaki 6 ，
Yonehiro Kanemura 7,8 ，Kenjiro Kosaki 9
1:Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Japan、2:Department of
Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University、3:Laboratory for Medical Science Mathe-
matics, Center for Integrative Medical Sciences, RIKEN、4:Department of Pediatrics, Showa University School of Medicine、5:Department of
Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences、6:Department of Pediatric Neurosurgery, Takat-
suki General Hospital、7:Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National Hospital
Organization、8:Department of Neurosurgery, Osaka National Hospital, National Hospital Organization、9:Center for Medical Genetics, Keio
INTRODUCTION:Familial dyskinesia with facial myokymia (OMIM #606703), is an autosomal dominant disorder that is
exacerbated by anxiety. Chen et al. (Arch Neurol. 2012) performed whole-exome sequencing and revealed Adenylate cyclase
5 (ADCY5 ) mutation (c.2176G>A, p.A726T). ADCY5 is 1 of 9 membrane-bound adenylyl cyclases that convert ATP to
pyrophosphate and cAMP, the second messenger in various cellular activities. They further identified a de novo mutation
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(c.1252C>T, p.R418W) in ADCY5 in 2 unrelated sporadic cases. Both mutant ADCY5 caused a significant increase in
cAMP in response to the stimulation. We report a girl with severe intellectual disability (ID) and movement disorder with
homozygous ADCY5 mutation.
CLINICAL REPORT:The 3-year-old female was the first child of healthy and non-consanguineous Japanese parents. Her
developmental milestones were delayed. At 3 years, she could not control her head and could not roll over. She showed axial
hypotonia and dystonic posturing. Deep tendon reflexes were exaggerated. She developed plantar flexed posture at both
ankles, dystonic posturing of upper limbs. Attempt to reach object was disturbed by dystonia. She suddenly moved her
extremities just like surprised. She showed severe ID. Her physical growth was also disturbed. Her head circumference was
47.0 cm (-2.2SD).
METHODS:With the approval of the institutional ethics committee, the samples were analyzed using WES. We planned a
proband-parent trio approach using WES.
RESULTS :Homozygous mutation in exon21of the ADCY5 (c.C3712T: p.R1238W) was identified. Her parents were heterozy-
gous for the mutation. This residue is highly conserved and the change is predicted to be damaging.
DISCUSSION :We identified a homozygous mutation in ADCY5 in a patient with severe ID, dystonic movement, and micro-
cephaly. Heterozygous carriers were free from clinical manifestations. We suggest that autosomal recessive type of ADCY5
mutations may cause a novel neurogenetic syndrome.
Poster Session
Wed(4)-P-78
A surgical case of chronic pancreatitis with SPINK1p.N34S mutation
Koji Tezuka 1 ，Wataru Kimura 1 ，Ichiro Hirai 1 ，shinji Okazaki 1 ，shuichiro Sugawara 1 ，Tsuyoshi Fukumoto 1 ，
Toshihiro Watanabe 1
1:First Department of Surgery (Department of Gastroenterological, Breast, Thyroid and General Surgery), Yamagata University Faculty of
Medicine, Japan
Mutations, especially the N34S mutation, in the SPINK1 gene, which encodes a pancreatic secretory trypsin inhibitor, are
associated with idiopathic and familial chronic pancreatitis (CP). We have experienced a suspected case of alcoholic CP in
which the N34S mutation was revealed by genetic testing several years after surgery.
A 50-year-old Japanese man was referred to our hospital because of acute exacerbation of CP. Computed tomography demon-
strated a number of calcifications in the head of the pancreas. Endoscopic retrograde cholangiopancreatography revealed
stenosis of the main pancreatic duct (MPD) in the head of the pancreas and dilation of the MPD distal to the stenosis. A
plastic pancreatic stent (7Fr, 5 cm) was inserted, and this stent was later removed when the patient was 55 years old. Three
months after stent removal, acute exacerbation of CP occurred again. As it was difficult to insert a guide wire into the distal
MPD due to stenosis, the patient underwent pancreatoduodenectomy at the age of 56 years. By the age of 49 years, his
average alcohol intake had been about 50 g/day. Genetic testing, performed 6 years after surgery, revealed a SPINK1p.N34S
heterozygous mutation.
Continuous alcohol intake of more than 80 g/day is a commonly employed diagnostic criterion for alcoholic CP. However, it
is necessary to be aware of the possible presence of SPINK1 mutation in patients with CP whose daily alcohol consumption
is less than this.
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Wed(4)-P-79
Next Generation Sequencing as a Clinical Diagnostic Tool for Hereditary Spinocerebellar Degeneration
Katsuya Nakamura 1 ，Kunihiro Yoshida 2 ，Tomoki Kosho 1 ，Kyoko Takano 3 ，Keiko Wakui 3 ，Shunichi Satoh 4 ，
Yoshiki Sekijima 5 ，Hideo Makishita 6 ，Shinji Ohara 7 ，Masumi Ishikawa 1 ，Shu-ichi Ikeda 5 ，Yoshimitsu Fukushima 1,3
1:Division of Clinical and Molecular genetics, Shinshu University School of Medecine, Japan、2:Department of Brain Disease Research,
Shinshu University School of Medicine、3:Department of Medical Genetics, Shinshu University School of Medicine、4:Departmet of
Neurology, Nagano Red Cross Hospital、5:Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine、
6:Department of Neurology, Hokushin General Hospital、7:Department of Neurogy, Matsumoto Medical Center
Spinocerebellar degeneration (SCD) is a group of related diseases as characterized by cerebellar ataxia with variable involve-
ment of the brainstem and spinal cord. Hereditary SCDs are consist of genetically and clinically heterogeneous single gene
mutations. To confirm a genetic diagnosis is important for having an appropriate genetic counseling and information about
disease prognosis. For most patients who had excluded common inherited dominant repeat expansion SCAs (SCA1-3, 6-8,
12, 17, 31, DRPLA), it is challenging to confirm a molecular diagnosis because of a high level of genetic heterogeneity and
involvement of large genes. Moreover, for some patients, ataxia may develop in conjunction with neuropathy, optic atrophy
and spastic paraplegia.
To offset these problems in the clinical diagnosis of cerebellar ataxia, we performed a panel based exome sequencing approach
in 25 affected individuals (24 families). Samples were processed with a Trusight™ One panel (Illumina) containing 4,811
genes in which mutations detectable by next generation sequencing (NGS) cause mendelian diseases. Exome sequencing was
performed on a MiSeq™ (Illumina) followed by bioinformatics analyses using our in-house pipeline. This analysis revealed
variants identified 1 patients (4%) with clearly pathogenic homozygous nonsense mutations in 1 genes (SYNE1 ). 5 patients
Poster Session
(20%) with probably pathogenic heterozygous mutations in 3 genes (ITPR1 , PDYN , KIF21A), and 5 patients (20%) with
possibly pathogenic heterozygous mutations in 6 genes (KIF1A, NEFL, SPTBN3 , ITPR1 , TGM6 , KCNC3 ). 2 patients (8%)
complicated neuropathy, 5 patients (21%) had sporadic onset of symptoms.
We have successfully applied panel based exome sequencing approach to our cohort of SCD cases and identified a pathogenic
nonsense mutation in 4% and novel sequence variants that may cause disease in an additional 40% of our cohort. Our approach
has important implications for genetic counselling and diagnostic service provision.
Wed(4)-P-80
Gender effects on the severity of spinal muscular atrophy (SMA) in 286 Japanese patients diagnosed in
1996-2015
Ai Shima 1 ，Mawaddah Ar Rochmah 1 ，Naoya Morisada 1,2 ，Shinichiro Yanagisawa 3 ，Nur Imma Fatimah Harahap 1 ，
Toshio Saito 4 ，Aiko Umeno 5 ，Kaori Kaneko 5 ，Kayoko Saito 5 ，Kazumoto Iijima 2 ，Hisahide Nishio 1,2
1:Department of Community Medicine and Social Healthcare Sciecnce, Kobe University Graduate School of Medicine, Japan、2:Department of
Pediatrics, Kobe University Graduate School of Medicine、3:Faculty of Pharmaceutical Sciences, Himeji Dokkyo University、4:Department of
Neurology, National Hospital Organization Toneyama National Hospital、5:Institute of Medical Genetics, Tokyo Women’s Medical University
Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by mutations in survival of motor neuron (SMN )
1 gene. SMA is characterized by degeneration of lower motor neurons leading to progressive muscle wasting and loss of
movement. It is clinically classified into three subtypes in accordance with the age of onset and the highest achieved motor
milestones; SMA type 1 (age of onset is 0-6 months old, unable to sit without aid), type 2 (age of onset is 7-18 months
old, able to sit alone but unable to stand or walk without aid) and type 3 (age of onset is >18 months old, able to stand
and walk without aid). While SMA shows wide range of severity, some disease-modifying factors have been reported such
as copy numbers of SMN2 gene and a deletion of neuronal apoptosis inhibitory protein (NAIP) gene. Multiple copies of
SMN2 can compensate to some degree for the lack of SMN1 since SMN2 , centromeric homolog of SMN1 , mainly encodes
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the exon7-skipped form of SMN, but also express the full-length SMN at much lower level. Although those two factors are
widely accepted as SMA-modifying factors, gender-related modifying factors or gender effects of SMA on its severity are still
controversial. Here, we analyzed 286 Japanese patients diagnosed as SMA in 1996-2015 by classifying them into two categories:
the non-walker group (SMA type 1 and 2) and the walker group (SMA type 3) and found a predominance of male patients
in the walker group. The further study analyzing 122 patients (60 females and 62 males) who carried homozygous deletion
of SMN1 exon 7 and exon 8 showed a significantly higher frequency of male patients (or a significantly lower frequency of
female patients) in the walker group with non-NAIP-deletion and high SMN2 copy numbers. Our study suggests that gender
might affect disease severity in SMA, especially patients’ locomotive ability.
Wed(4)-P-81
Association study between CAG repeats of PolyQ-related genes and SCA3/MJD
Hong Jiang 1,2,3 ，Zhao Chen 1 ，Caifa Zheng 1 ，Zhe Long 1 ，Beisha Tang 1,2,3 ，
Chinese Clinical Research Cooperative Group for Spinocerebellar Ataxias (CCRCG-SCA)
1:Department of Neurology, Xiangya Hospital, Central South University, China、2:Key Laboratory of Hunan Province in Neurodegenerative
Disorders, Central South University、3:State Key Laboratory of Medical Genetics, Central South University
Objective: To investigate other factors involved in the variability of age at onset (AO) for Chinese Han SCA3/MJD pa-
tients.Methods: A total of 802 SCA3/MJD patients from mainland China were recruited. All subjects had genetically
determined CAG repeat expansion in ATXN3 by PCR amplification and capillary electrophoresis. The participating subjects
were genotyped for 9 other polymorphic (CAG)n-containing genes (ATXN1, ATXN2, CACNA1A, ATXN7, TBP, ATN1,
Poster Session
IT15, KCNN3, RAI1 ). Analysis of the CAG repeats related to the AO of SCA3/MJD were performed using ANCOVA
and multiple regressive.Results: The longer allele of ATXN3 contributed to 56.9% variation of AO for SCA3/MJD. The
shorter allele of ATXN3 with CAG repeats <19 or ranging from 26 to 40, contributed to 1.3% and 1.9% variation of AO
respectively. Subjects with an intermediate ATXN2 allele (27-32), which contributed to 23.2% variation of AO, had an earlier
AO (about 2.48±1.58 years). The intermediate CACNA1A homozygous alleles(9-17) in SCA3/MJD patients contributed to
4.8% variation of AO. The shorter allele of ATXN7 with CAG repeats <10 or the longer allele(12-17) in SCA3/MJD patients
contributed to 2.5% and 1.6% variation of AO respectively. The longer allele of ATXN7 with CAG repeats ranging from 12
to 17 and the shorter allele (>10) in SCA3/MJD individuals contributed to 3.8% variation. The shorter RAI1 allele with
CAG repeats 12 or the longer allele (13-14)contributed to 0.7% and 5.2% variation of AO respectively. The longer allele
of RAI1 with CAG repeats ranging from 13 to 14 and the shorter allele (>11) in SCA3/MJD individuals contributed to
7.3% variation.Conclusion: In Chinese Han population the CAG repeats in the longer allele of ATXN3 contribute to 56.9%
variation of AO in SCA3/MJD. ATXN1 , ATXN2, KCNN3, CACNA1A, ATXN7 and RAI1 gene may modulate the AO of
SCA3/MJD.
Wed(4)-P-82
Genetic analysis in West syndrome and Ohtahara syndrome: a single center study
Jun Tohyama 1,2 ，Yu Kobayashi 1 ，Shinichi Magara 1 ，Kenichi Okazaki 1 ，Takao Komatsubara 1 ，Noriyuki Akasaka 1,3
，
Mitsuko Nakashima 4 ，Mitsuhiro Kato 5 ，Hirotomo Saitsu 4 ，Naomichi Matsumoto 4
1:Department of Child Neurology, Nishi-Niigata Chuo National Hospital, Japan、2:Niigata University Medical and Dental Hospital、3:Depart-
ment of Paediatrics, Hamagumi Prefectural Rehabilitation Centre、4:Department of Human Genetics, Yokohama City University Graduate
School of Medicine、5:Department of Paediatrics, Show UniversitySchool of Medicine
Introduction: West syndrome (WS) and Ohtahara syndrome (OS) are a continuum of early onset epileptic encephalopathy
(EOEEs), which is characterized by epileptic spasms, characteristic electroencephalographic findings such as hypsarrhythmia
(WS) or suppression-burst (OS), and severe developmental delay. These syndromes are associated with many underlying
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conditions, and the etiology in many cases remains unclear despite intensive biochemical and neuroradiological investigations.
Recent genetic studies have elucidated causative roles for genetic abnormalities in EOEEs. In this study, we investigated the
underlying genetic causes in patients with WS and OS.
Methods: Patients were recruited from Nishi-Niigata Chuo National hospital between 2004 and 2015. 28 patients (25 of
WS, and three of OS), who had unknown etiology, no chromosomal abnormality in G-band analysis and microarray analysis,
and no cortical malformation on MRI, were included in this study. All showed severe developmental delay. We performed
candidate gene analysis in eight patients for ARX , STXBP1 , SPTAN1 , or SCN2A by high-resolution melting analysis or PCR
direct sequence. In four patients, target capture and sequencing against 38 genes were performed. Whole exome sequence
was performed in 18 patients including three patients with negative results of target sequencing.
Results: We identified pathogenic mutation in 11 genes (ARX , CDLK5 , STXBP1 , SPTAN1 , GNAO1 , SCN2A, CASK ,
ALG13 , EEF1A2 , TBL1XR1 and SETD5 ) in 16 of 28 patients (57%). No mutations in known causative gene were found in
the remaining 12 patients.
Conclusion: We found pathogenic genetic alterations in 16 of 28 patients. Genetic backgrounds of EOEEs are heterogeneous.
Our results in a single center may reflect the current state of genetic background of EOEEs. Further accumulation of patients
with precise clinical evaluation will facilitate genotype-phenotype correlation in EOEEs.
Wed(4)-P-83
Poster Session
Genetic analysis of HPRT1 gene in five patients with HPRT deficiency
Atsuo Taniguchi 1 ，Miyuki Toyono 2 ，Ken Momosaki 3 ，Hiroaki Ueda 4 ，Masae Ono 5 ，Yasukazu Yamada 6 ，
Noriko Nomura 6 ，Hirotaka Kaneko 1 ，Chieko Sekita 1 ，Hikota Osawa 1 ，Mari Tochihara 1 ，Naomi Ichikawa 1 ，
Kayoko Saito 7 ，Hisashi Yamanaka 1
1:Institute of Rheumatology, Tokyo Women’s Medical University, Japan、2:Department of Pediatrics, Akita Prefectural Center on
Development and Disability、3:Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University、4:Department of
Pediatrics, Osaka City General Hospital、5:Department of Pediatrics, Tokyo Teishin Hospital、6:Department of Genetics, Institute of
Developmental Research, Aichi Human Service Center、7:Institute of Medical Genetics, Tokyo Women’s Medical University
The human hypoxanthine phosphoribosyltransferase (HPRT) deficiency is an inborn error of purine metabolism. HPRT1
localizes at Xp26 and mutations give rise to Lesch-Nyhan disease (LND), HGprt-related neurological dysfunction and HGprt-
related hyperuricemia (HRH). We present five mutations including three novel ones in patients with different clinical phe-
notypes. Case reports: The case 1 is a 3-year-old boy who is diagnosed as having LND based on severe neurological deficit
with self mutilation and hyperuricemia. The case 2 is a five-months-old boy with psychomotor retardation and hyperuricemia
and LND is suspected. The case 3 is a two-year-old boy with SUA 13.0 mg/dl and no neurologial deficit. The case 4 is a
44 year-old man with juvenile onset gout and urolithiasis. The case 5 is a 19-year-old man with tophaceous gout. HRH is
suspected in the latter three cases. Results: A novel 116kb deletion spanning intron 1 on HPRT1 to intron 2 on PLAC1 was
detected in the case 1. In the case 2, c.151 C>T, one of the two most common hot spots of LND, was detected. The case
3, 4 and 5 were revealed to have, c.393G>C, c.584A>G and c.100A>T, respectively. The c.584A>G has been reported to
be the cause of HRH in Japanese and the remaining two were novel. Discussion:The genotype and phenotype correlations of
HPRT deficiency are complex and the clinical diagnosis of new cases with novel mutations is sometimes difficult. New cases
with mutations already described have a high probability of developing a phenotype similar to the previous case (Fu R. Brain
2014; 137:1282). This study reconfirmed the importance of accumulation of individual mutations with phenotypes. Moreover,
a novel deletion in the case 1 involves locations of some genes between HPRT1 and PLAC1 . In LND, involvement of deletion
in genes other than HPRT1 has rarely been reported. The clinical phenotype of the case will provide additional information
of the function of those genes.
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Wed(4)-P-84
Whole-exome sequencing combined with homozygosity mapping reveals a novel TCAP gene mutation
in a consanguineous family with LGMD2G initially diagnosed as heredity inclusion body myopathy
Qiji Liu 1 ，Pengfei Lin 2 ，Fei Gao 1 ，Jiangxia Li 1 ，Xianli Bian 1 ，Yaoqin Gong 1 ，Chuanzhu Yan 2
1:Department of Medical Genetics, Shandong University, China、2:Laboratory of Neuromuscular Disorders and Department of Neurology,
Qilu Hospital, Shandong University, Jinan, Shandong, China;
LGMD2G, a rare autosomal recessive hereditary neuromuscular dystrophy, characterized by proximal and distal lower limb
weakness, calf hypertrophy and loss of ambulation. TCAP encoded telethonin is a 19 kDa protein, which plays an important
role in anchoring titin in Z disc of the sarcomere, is the exclusive known causative gene of LGMD2G. hIBM, a similar
autosomal recessive muscle disorder characterized by proximal and distal weakness, with sparing of quericeps femoris muscles,
is caused by mutation of GNE. We identified a consanguineous family which has two siblings with late onset neuromuscular
disorders, which was initially diagnosed as hIBM in terms of detailed clinical examination, but that diagnosis was excluded
after molecular genetic analysis on GNE gene. Genome-wide homozygosity mapping using Human Omni ZhongHua-8v1-1
chip suggested that disease gene is located on chr17:36474601-75158519 interval, subsequent whole exome sequencing identified
a homozygous c.165_166insG mutation in TCAP gene in this region. The mutation was confirmed by Sanger sequencing
and further excluded from the possibility as a rare polymorphism. Western blot analysis indicated this mutation leads to
a truncated protein. Therefore, we deduced that the homozygous c.165_166insG(p.Gln56AlafsX52) mutation in exon 2 of
TCAP gene is the causative change of the disease.
Poster Session
Wed(4)-P-85
Gender difference in effect of artificial ventilation in patients with myotonic dystrophy
Toshio Saito 1 ，Toshiaki Takahashi 2 ，Satoshi Kuru 3 ，Mikiya Suzuki 4 ，Tsuyoshi Matsumura 5 ，Harutoshi Fujimura 5 ，
Saburo Sakoda 5
1:Division of Child Neurology, Department of Neurology, National Hospital Organization Toneyama National Hospital, Japan、2:Department
of Neurology, National Hospital Organization National Sendai Nishitaga Hospital、3:Department of Neurology, National Hospital Organization
National Suzuka Hospital、4:Department of Neurology, National Hospital Organization Higashisaitama Hospital、5:Department of Neurology,
National Hospital Organization Toneyama National Hospital
Since 1999, Japanese muscular dystrophy research group have been developing a database of inpatients with muscular dys-
trophy and related disorder treated at 27 institutes specializing in muscular dystrophy treatment. The database includes
number of inpatients, age, diagnosis, respiratory condition, nutritional state of October 1, and cause of death of each year.
Patients with myotonic dystrophy (DM) occupy 15 % of inpatients in this database. Now, for treatment to respiratory failure
of muscular dystrophy, artificial ventilation such as non-invasive ventilation and tracheal intermittent ventilation is intro-
duced. Duchenne muscular dystrophy patients prolonged their life span dramatically in their 20s to 30s by this intervention.
However, the effect of artificial ventilation to DM patients is not clear. We recruited the genetically confirmed DM patients,
which include 260 male and 148 female patients, in the database. In male patients, artificial ventilation was introduced to
117 patients. One hundred forty three patients did not use artificial ventilation. In female patients, artificial ventilation was
introduced to 78 patients. Seventy patients did not use. We conducted the Kaplan-Meier analysis with death assigned to
endpoint in each gender. Mean survival age of male patients with artificial ventilation was 61.7 years (SE 0.9) and that of male
patients without artificial ventilation was 60.6 years (SE 0.8). There was no significant difference. On the other hand, mean
survival age of female patients with artificial ventilation was 65.4 years (SE 1.1) and that of female patients without artificial
ventilation was 62.3 years (SE 0.9). There was significant difference between two female groups (Log Rank (Mantel-Cox)).
Artificial ventilation is effective for treatment of DM patients. However, gender difference may affect the efficacy of artificial
ventilation in DM patients.
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Wed(4)-P-86
Identification of novel mutations in C21ORF2 from Japanese patients with early-onset retinitis pigmen-
tosa
Akiko Suga 1 ，Mitsuhiro Kato 2 ，Kazutoshi Yoshitake 3 ，Astushi Mizota 4 ，Kazuho Ikeo 5 ，Takeshi Iwata 1
1:Division of Molecular and Cellular Biology, National Institute of Sensory Organs, Tokyo Medical Center, Japan、2:Department of Pediatrics,
Showa University School of Medicine, Tokyo, Japan、3:Japan Software Management, Yokohama, Japan、4:Department of Ophthalmology,
Teikyo University School of Medicine, Tokyo, Japan、5:CIB-DDBJ, National Institute of Genetics, Mishima, Japan
Retinitis pigmentosa is one of the major hereditary eye diseases with loss of photoreceptor functions. To date, more than
55 causal genes with various functions have been identified for autosomal recessive retinitis pigmentosa, which half of them
have roles in ciliogenesis and ciliary transport. We found Japanese siblings affected by early-onset retinitis pigmentosa with
developmental skeletal defects. Whole exome sequencing from these two patients and their healthy parents limited compound
heterozygous mutations on a single gene, C21ORF2. The both candidate mutations located in the C-terminal cap domain
of the Leucine rich repeats (LRRCT) of C21ORF2 protein. In consistent with the role of LRRCT to maintain the stability
of Leucine rich repeat proteins, mutated C21ORF2 showed lower expression levels compared to the wild type. Considering
that C21ORF2 is required for ciliogenesis in vitro, our data suggested that the shortage of functional C21ORF2 caused
photoreceptor degeneration. C21ORF2 was recently reported as a causal gene for Jeune syndrome with cone-rod retinopathy
and retinal degeneration from Saudi Arabia and Europe. This is a report of novel mutations and the first case from Japanese
patients with retinitis pigmentosa.
Poster Session
Wed(4)-P-87
Parathyroid hyperplasia induced by uniparental disomy in a MEN1 patient with a frame-shift mutation
Hidenori Koyama 1 ，Akio Miyoshi 1 ，Yoshie Yoshikawa 2 ，Tomoko Hashimoto-Tamaoki 2 ，Yukie Enomoto 3 ，
Yasuo Miyoshi 3 ，Manabu Kadoya 1 ，Masafumi Kurajoh 1 ，Takuhito Shoji 1 ，Yuji Moriwaki 1 ，Tetsuya Yamamoto 1 ，
Mitsuyoshi Namba 1
1:Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Hyogo College of Medicine, Japan、2:Department
of Genetics, Hyogo College of Medicine、3:Division of Breast and Endocrine Surgery, Department of Surgery, Hyogo College of Medicine
Forty-three years-old female was referred to our department for hypercalcemia during pregnancy. Her adjusted serum calcium
level was 11.1 mg/dl, serum phosphate 2.5 mg/dl, and intact parathyroid hormone 203 pg/ml. Computed tomography,
ultrasonography and MIBI scintigraphy revealed bilaterally enlarged upper parathyroid glands. Magnet resonance imaging
identified microadenoma (5 mm diameter) in the pituitary. Her mother had histories of parathyroidectomy, ovariectomy, and
resection of skin tumor. Direct sequencing of leukocyte DNA from the patient and her mother revealed A>T heterozygous
mutation in the final codon (1049) of the exon 7. With a diagnosis of hyperparathyroidism caused by MEN1-related hyperplasia
of parathyroid glands, the subtotal parathyroidectomy was performed. Analysis of the DNA from the resected parathyroid
tumor exhibited homozygous 1049A>T mutation, without any apparent gene deletions by the MLPA method. Direct DNA
sequencing of the entire MEN1 genome identified homozygous changes of heterozygous 3 SNPs and a microsatellite repeat
polymorphism, suggesting uniparental disomy (UPD). Sequencing of tumor MEN1 mRNA revealed the 1048-1049GU deletion,
suggesting generation of truncated protein (p.Asp350LeufsX15). This is considered to be due to DNA mutation of the last
codon (1049A>T) in the exon 7 resulted in a misrecognition as the splicing donor site (1048-1049GA>GT). Western blotting
of the menin protein confirmed disappearance of the intact protein. Thus, homozygosity by UPD can be a mechanism of
parathyroid tumorigenesis in MEN1 patients.
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Wed(4)-P-88
Identification of DGUOK and MPV17 Mutations in Patients with Hepatocerebral Mitochondrial DNA
Depletion Syndrome
Minji Kang 1 ，Beom Hee Lee 1,2
，Kei Murayama 3 ，Sun Hee Heo 1 ，Gu-Hwan Kim 2 ，In Hee Choi 2 ，Han-Wook Yoo 1,2
1:Asan Institute for Life Sciences, Asan medical center, Korea, South、2:Medical Genetics Center, Asan Medical Center Childrens Hospi-
tal,University of Ulsan College of Medicine、3:Department of Metabolism, Chiba Childrens Hospital, Chiba, Japan
Mitochondrial DNA (mtDNA) depletion syndromes may affect either one or a combination of organs, including muscle,
liver, gastrointestinal tract, brain, and kidney. Hepatocerebral mtDNA depletion syndrome is characterized by early-onset
hepatopathy and neurological manifestations. The hepatopathy can be detected as elevated hepatic enzymes with neonatal
cholestasis, which progresses hepatic failure in some patients. Neurological manifestations include developmental delay,
hypotonic, motor and sensory polyneuropahty and leukoencephalopathy. mtDNA depletion syndrome can be diagnosed
by mtDNA copy number analysis and electron transport chain (ETC) activity. The prevalence of hepatocerebral mtDNA
depletion syndrome has been reported as very rare and here we report five children affected by this condition which was
confirmed by genetic testing.
All five patients presented with hypotonia, developmental delay and neonatal cholestasis in their neonatal periods. Recurrent
vomiting, diarrhea and nystagmus were also noted. Serum lactate and lactate/pyruvate ratio (18.4-142 mg/mg) was increased
in all patients. Liver biopsy showed diffuse fatty changes, cholestasis, and fibrosis. Electron microscopic examination revealed
increased numbers of mitochondria which were swollen and lost cristae. Quantification of mtDNA and ETC activity was
measured in one patient, both of which were markedly decreased. Genetic testing for POLG, DGUOK and MPV17 were
Poster Session
done in all patients and one patient had DGUOK mutations, whereas the other four had MPV17 mutations. The follow-up
evaluations were possible for four patients with MPV17 mutations but all of them died of sepsis or liver failure within 3
years of age. Our experience underlines the devastating clinical outcomes of patients with hepatocerebral mtDNA depletion
syndrome and genetic testing for suspicious cases is needed for rapid diagnosis and may help to manage and counsel the
patients and their families.
Wed(4)-P-89
Characterization of Japanese patients with FHL1 myopathy
Yukiko K. Hayashi 1 ，Ichizo Nishino 2
1:Pathophysiology, Tokyo Medical University, Japan、2:National Institute of Neuroscience, NCNP
Mutations in the four and a half domains 1 (FHL1 ) gene on chromosome Xq26.3 are known to cause variable types of
myopathies such as reducing body myopathy, scapuloperoneal myopathy, X-linked myopathy with postural muscle atrophy,
rigid spine syndrome, and Emery-Dreifuss muscular dystrophy (EDMD). Presence of reducing bodies in muscle fibers is a
characteristic pathological feature of FHL1 myophty.
In this study, we performed FHL1 mutation screening for the patients whose muscle specimens contain reducing bodies, and
also EDMD patients with unknown cause.
All 15 patients from 10 families with reducing bodies had a mutation in the second LIM domain of FHL1, all of which altered
the Cysteine residues in this domain. On the other hand, no mutation was found in FHL1 in the 22 EDMD patients.
Clinical symptoms of FHL1 myopathy were quite variable from early infantile severe form to adult onset milder form. Nine
of 15 (60%) patients showed asymmetrical muscle involvement and some had been diagnosed to have facioscapulohumeral
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muscular dystrophy. Pathological changes of muscles were also variable, and some showed nearly normal with a few reducing
bodies, but others had numerous atrophic fibers with abundant reducing bodies.
FHL1 myopathy can show quite variable clinical and pathological features, and identification of reducing bodies using MAG
stain without substrate is quite useful for the diagnosis.
Wed(4)-P-90
Novel SACS gene mutations in Japanese patients lacking spasticity
Mridulata Bohara 1 ，Yuji Okamoto 1 ，Akiko Yoshimura 1 ，Junhui Yuan 1 ，Yujiro Higuchi 1 ，Shiro Saito 1 ，
Akihiro Hashiguchi 1 ，Yuji Tashiro 1 ，Eisuke Dohi 3 ，Masayuki Honda 2 ，Taiji Sakamoto 1 ，Hiroshi Takashima 1
1:Neurology, Kagoshima University, Japan、2:Tokyo Metropolitan Neurological Hospital、3:Hiroshima University
Objective To investigate new disease-causing genes and molecular mechanisms of Japanese patients with hereditary neu-
ropathies. In particular, we would like to describe clinical features of patients harbouring SACS gene mutation.
Methods We carried out whole exome sequencing using Illumina Hiseq2000 among 399 patients with unknown CMT after our
initial genetic screening. After the comprehensive data analysis, the suspected variants were validated by Sanger sequencing,
Poster Session
and segregation analysis was applied to evaluate the pathogenicity if available.
Results The whole exome sequencing revealed novel compound heterozygous SACS gene mutations in two patients (c.468-
469delCT, p.L156fs26X; c.1315C>T, p.R4386X and c.12980-12981insA; c.10448delC) and a novel homozygous missense tran-
sition mutation (c.2402C>T, p.P801L) in another patient, thus, were genetically diagnosed of autosomal recessive spastic
ataxia of Charlevoix-Saguenay (ARSACS). The patients presented with pronounced early onset of ataxia (onset ages were 2,
3 and <10), retinal hypermyelination, however, spasticity which is considered to be another core clinical feature of (ARSACS)
was absent in all of them. The nerve conduction studies of all three patients revealed delayed MCV with slightly increased
CMAP amplitude and prolonged duration suggesting axonal degeneration with diffuse peripheral demyelination. The marked
atrophy of the superior cerebellar vermis was noted in two patients whereas the brain MRI of the rest appeared normal.
Conclusions We detected SACS gene mutations in 3 patients and all of them (3 genotypes) had never been described before.
The absence of spasticity is comparable to the previously reported Japanese patients but this variation may require further
research.
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Wed(4)-P-91
A case of osteogenesis imperfecta caused by PPIB mutation (First Japanese case)
Junko Kanno 1 ，Sayaka Kawashima 1 ，Chisumi Sogi 1 ，Miki Kamimura 1 ，Tetsuya Niihori 3 ，Yoko Aoki 3 ，Shigeo Kure 1 ，
Ikuma Fujiwara 2
1:Department of Pediatrics, Tohoku University school of Medicine, Japan、2:Department of Pediatric Endcrinology and Environmental
Medicine, Tohoku University School of Medicine、3:Department of Medical Genetics, Tohoku University School of Medicine
Background:Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue characterised by increased bone fragility,
low bone mass and bone deformity. The majority of patients with OI have a heterozygous mutation in either COL1A1 or
COL1A2 , the genes that encode type 1 collagen. Recently, mutations in the PPIB encoding cyclophilin B were identified as
causes of recessive OI. This protein forms a complex with P3H1and CRTAP that 3-hydroxylates a proline residue on the α 1
(I) chain and has cis/trans isomerase activity essential for proper collagen folding. Case presentation:The patient was born
at 39 wk of gestation after an uncomplicated pregnancy. She was the first child of non consanguineous Japanese parents. She
had a femur fracture without any specific triggers seven days after birth. She had suffered femur fracture five times until the
referral to our hospital at 6 years of age. At that time, her height was 108 cm, and she did not show any clear blue sclerae
or tooth hypoplasia. She could not walk alone without help. Lumber bone mineral density (BMD) by DXA was extremely
low (0.246 g/cm2 , -5.81SD). With a diagnosis of OI, we started pamidronate treatment. Her BMD gradually increased, and
she had not experienced any fractures afterwards. Now at 9 years of age, her height is 116.3 cm, and her BMD has been
improved to 0.497 g/cm2 (-1.4SD). By whole exome sequencing, we identified a homozygous mutation (c. 377A>G, p.E126G)
in the PPIB. Her parents were heterozygous carriers. OI caused by the absence of cyclophilin B is much milder than the
severe or lethal OI caused by a deficiency of P3H1 or CRTAP. The clinical penotype of our patient was similar to those
Poster Session
patients described in the previous reports. The parents of the case were not related, but they were from the same community.
Conclusions: We identified a homozygous PPIB mutation in an OI patient. To our knowledge, we present the first Japanese
family with recessive OI caused by PPIB mutation.
Wed(4)-P-92
Development of SMN protein analysis in human blood cells as a spinal muscular atrophy biomarker
Reiko Arakawa 1 ，Noriko Otsuki 1 ，Masayuki Arakawa 2 ，Kaori Kaneko 1,3
，Ryoko Aoki 1 ，Kayoko Saito 1,3
1:Institute of Medical Genetics, Tokyo Women’s Medical University, Japan、2:Institute of Microbial Chemistry, Microbial Chemistry Research
Foundation、3:Affiliated Field of Genetic Medicine, Division of Biomedical Engineering and Science, Graduate Course of Medicine, Graduate
School of Tokyo Women’s Medical University
Childhood spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by the degeneration of anterior horn
motor neurons in the spinal cord. It is one of the common severe hereditary diseases of infancy and childhood. Mutations of
the survival motor neuron (SMN1 ) gene lead to reduced survival motor neuron (SMN) protein expression and SMN complexes
in spinal motor neurons and other tissues in SMA cases. In humans, SMN1 is duplicated with a highly homologous copy
called SMN2 and both genes are transcribed. The SMN2 gene is present in all SMA patients but cannot compensate for the
SMN1 gene defects, resulting in low levels of the full-length SMN protein due to a single nucleotide difference in exon7 of the
SMN2 gene.
Recently, SMN protein has been used as a therapeutic biomarker in SMA clinical trials. We developed a novel methodology
which employs imaging flow cytometry (IFC) as a SMN protein analysis system. In our prior research, we showed that IFC
can identify different expression patterns and subcellular localizations of endogenous SMN protein, by using human dermal
fibroblasts from a healthy control and from SMA patients. In this study, we demonstrated that IFC can be successfully
applied to analyzing the SMN protein in human peripheral whole blood cells. In addition, EB virus-transformed-lymphoblasts
exhibited different SMN protein expression levels in SMA patients versus the control. We suggest that our analytical method
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ICHG2016 1197
for SMN protein has potential as an evaluation tool in SMA clinical trials.
Wed(4)-P-93
Detecting mutations in PRPH2 in 407 families with non-syndromic high myopia by exome sequencing
1
Bei Gao
1:Genetics Lab, Zhongshan ophthalmic center of Sun Yat-sen University, China
Purpose: High myopia is the common cause of irreversible visual impairment worldwide while the underlying molecular
mechanism of a large part of patients awaits to be uncovered. The gene Peripherin/RDS (PRPH2) encodes an integral
membrane glycoprotein expressed mainly in rod and cone outer segments. Mutations in PRPH2 had been demonstrated
to be associated with a variety of retinal diseases. However, in our study, we found more variations of PRPH2 by whole
exome sequencing in patients with high myopia phenotype other than retinal diseases. So here we aimed to investigate the
relationship between mutations in PRPH2 and the phenotype of high myopia in Chinese ethnic.
Methods: Whole Exome sequencing were used to analyze 407 families with high myopia previously. Variants in PRPH2 were
selected and analyzed by bioinformatics. Potential variants were testified by Sanger Sequencing and validated in available
family members and 192 normal controls. Available families were calling back for a double check. Clinical data were collected
and reviewed.
Poster Session
Results: Six heterozygous variants, including two reported (c.533A>G: p.Q178R, c.658C>T: p.R220W) and four novel
(c.38G>A: p.R13Q, c.346G>T: p.A116S, c.857T>C: p.L286P, c.863C>A: p.T288K), were identified in six families with high
myopia. All six variants are predicted to be damaging or probably damaging by SIFT or Polyphen. None of the six variants
were found in 192 normal controls. Two variants were co-segregate with high-myopia, and two out of these six families were
successfully calling back, they all have a high myopia fundus and just in one family the 40-year-old father was detected to
have the early sign of pattern dystrophy on the last visit by fundus auto-fluorescence imaging.
Conclusion: High myopia might be the earliest clinic feature of diseases caused by PRPH2 mutations. Other fundus damage
corresponding with typical PRPH2 phonotypes might occur later in patients’ life.
Wed(4)-P-94
Clinical and genetic characteristics of the Russian patients with Lynch syndrome
Alexei Tsukanov 1 ，Natalya Pospekhova 1 ，Vitaly Shubin 1 ，Igor Sachkov 1 ，Dmitriy Semenov 1 ，Sergei Achkasov 1 ，
Vladimir Kashnikov 1 ，Yuri Shelygin 1
Lynch syndrome caused by germline mutation in one of the mismatch repair genes is the most frequent of all hereditary
colorectal cancer syndromes. Patients with Lynch syndrome from different populations tend to have both genetic and clinical
characteristics. To this moment there have not been a study about clinical and genetic characteristics of the Russian patients;
the objective of this study is to close this gap.
Patients suspected of Lynch syndrome was carried out study of microsatellite instability in tumor samples by fragment analysis
and germline mutation in mismatch repair genes by Sanger sequencing and NGS. As study material we took clinical data of
25 patients (14 male and 11 female) with confirmed Lynch syndrome.
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ICHG2016 1198
Patients (n=25) with Lynch syndrome have mutation frequency in MLH1 gene of 52% (13/25), in MSH2 - 40% (10/25), and
in MSH6 - 8% (2/25). One mutation in the MLH1 (c.1852_1854del) was found in 3 unrelated patients, another one in the
MSH2 (c.942+3A>T) was found in 2 unrelated patients. Eleven of the first colorectal tumors were localized in the left side
of the colon, 8 - in the right side and 6 - in the rectum; the prevailing number of patients 84% (21/25) had a T1-4N0M0
disease stage. Metachronous colorectal cancer occurred in 16 patients. Third cancer developed in 3 patients. There were two
time periods for metachronous tumors occurrence: 1-8 and 18-28 years.
Genetic and clinical characteristics of the Russian patients with Lynch syndrome are: high frequency of MLH1 mutations,
predominantly left side of colorectal cancer and two time intervals for metachronous tumors.
Wed(4)-P-95
High prevalence of CDH23 mutations in patients with a common clinical characteristics of early childhood
hearing loss and the genotype-phenotype correlations
Tatsuo Matsunaga 1 ，Kunio Mizutari 1,2 ，Hideki Mutai 1 ，Kazunori Namba 1 ，Atsuko Nakano 3 ，Yukiko Arimoto 3 ，
Sawako Masuda 4 ，Noriko Morimoto 5 ，Hirokazu Sakamoto 6 ，Kimitaka Kaga 1
1:National Institute of Sensory Organs, National Tokyo Medical Center, Japan、2:Department of Otolaryngology-Head and Neck Surgery,
National Defense Medical College、3:Division of Otorhinolaryngology, Chiba Children’s Hospital、4:Department of Otorhinolaryngology, Na-
tional Mie Hospital、5:Division of Otolaryngology, National Center for Child Health and Development、6:Department of Otorhinolaryngology,
Poster Session
Hyogo Prefectural Kobe Children’s Hospital
Mutations in CDH23 gene are responsible for Usher syndrome 1D and autosomal recessive non-syndromic hearing loss
DFNB12. In this study, we sought to reveal the prevalence of CDH23 gene mutations in patients with hearing loss pre-
senting specific clinical characteristics and genotype-phenotype correlations.
After excluding patients with GJB2 mutations and mitochondrial m.1555A > G and m.3243A > G mutations, 72 subjects
were prospectively selected as the first group for CDH23 mutation analysis according to the following criteria: 1) Sporadic or
recessively inherited hearing loss 2) bilateral non-syndromic congenital hearing loss, 3) no cochlear malformation, 4) a poorer
hearing level at high frequencies than at low frequencies, and 5) severe or profound hearing loss at higher frequencies. As
the second group, we retrospectively selected 15 subjects who had obvious progressive hearing loss as determined by repeated
audiometry, profound hearing loss over 80 dB at frequencies above 2 kHz, as well as fulfilling the five aforementioned criteria
for the first group.
By Sanger sequencing the all CDH23 gene exons, we identified homozygous or compound heterozygous CDH23 mutations
in 13 of 72 subjects in the first group (18.1%) and 3 of 15 subjects in the second group (20.0%). In total, we identified 16
mutations, including five novel mutations. These results revealed that CDH23 mutations are highly prevalent in patients with
congenital high-frequency sporadic or recessively inherited hearing loss and that the mutation spectrum was diverse.
A high proportion of subjects homozygous for the p.P240L mutation had more severe low frequency hearing loss compared
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ICHG2016 1199
with subjects with non-p.P240L homozygous mutations, indicating a genotype-phenotype correlation. There were no signifi-
cant differences between the subjects with truncating mutations associated with missense mutations and those with biallelic
missense mutations.
Wed(4)-P-96
Novel missense and nonsense mutations in the LRP5 gene in patients with osteoporosis-pseudoglioma
syndrome
Minna Pekkinen 1 ，Giedre Grigelioniene 2 ，Leyla Akin 3 ，Shah Krati 4 ，Kadri Karaer 5 ，Selim Kurtoglu 3 ，
Alka V Ekbote 4 ，Elif Sagsak 6 ，Sumita Danda 4 ，Eva Astrom 2 ，Outi Makitie 1,2
1:Folkhalsan Institute of Genetics, Folkhalsan Research Center, Finland、2:Karolinska Institutet and Karolinska University Hospital,
Stockholm, Sweden、3:Erciyes University, Faculty of Medicine, Department of Pediatric Endocrinology, Turkey、4:Department of Clinical
Genetics, Christian Medical College and Hospital Vellore, India、5:Intergen, Genetic Diagnosis Research and Application Center, Ankara,
Turkey、6:Dr.Sami Ulus Children’s Hospital, Department of Pediatric Endocrinology, Ankara,Turkey
Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder with congenital or early-onset blindness
and severe osteoporosis. OPPG is caused by biallelic mutations in the low-density lipoprotein receptor-related protein 5
(LRP5) gene. We present six novel LRP5 mutations and the resulting phenotypes in five consanguineous Indian and Turkish
families. DNA was extracted from the blood samples of affected probands and their parents using standard procedures. The
LRP5 gene was analyzed by direct sequencing after PCR amplification. The observed sequence changes were compared with
reference database and 200 control samples.
Poster Session
Seven patients from five families were included in the study. All patients had severe osteoporosis with fractures, and congenital
or early-onset blindness. In addition, three patients had delayed mental development. DNA sequencing demonstrated in each
of the five probands homozygous LRP5 mutations. All mutations were novel and located in exons 1, 2, 3, 6 and 12 of the LRP5
gene. In one family, the affected child had homozygous sequence variations A3A, A4A, P5L and a deletion of the rs72555376
microsatellite; the healthy parents had none of these changes. In three families with altogether five affected children we found
homozygous missense mutations D116N, P197R, I882N and one nonsense mutation R462*; the parents were heterozygous for
the changes. Mutations in exon 3 and 12 were associated with mental retardation.
We report six novel LRP5 mutations in Turkish and Indian patients with OPPG. All mutations regardless of the location
resulted in similar ocular and skeletal phenotype. Mutations in exons 3 and 12 resulted also in developmental delay. The
deletion of rs72555376, in exon 1, has previously been described in heterozygous state by Chung et al. 2008; the disease
mechanism and origin of the homozygous deletion together with 3 other sequence changes in our patient remains to be
elucidated in further studies.
Wed(4)-P-97
No parent-of-origin effects detected in a large group of children with Williams syndrome
Elaine Tam 1 ，Ariel M Pani 2 ，Colleen A Morris 3 ，Lucy R Osborne 1 ，Carolyn B Mervis 4
1:Medicine, University of Toronto, Canada、2:University of North Carolina, Chapel Hill, NC, USA、3:University of Nevada School of Medicine,
Las Vegas, NV, USA、4:Psychological & Brain Sciences, University of Louisville, KY, USA
Williams syndrome (WS), a neurodevelopmental disorder caused by deletion of ~ 25 genes on chromosome 7q11.23, is
associated with an array of medical problems, characteristic facial features and a distinct cognitive and behavioral profile.
Although almost all individuals have the same genes deleted, there is considerable variation in the severity of each aspect of
the disorder including cognitive ability and behavior. One potential source of phenotypic variability is the parental origin of
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the deleted genes. The same gene can be expressed at different levels on maternally and paternally inherited chromosomes
due to epigenetic regulation, e.g. imprinting. It has been hypothesized that in the context of a chromosome microdeletion
such skewing of gene expression on the intact chromosome could impact the phenotype. Previous studies have reported
parent-of-origin (PoO) effects on growth, head circumference and gene expression in WS, but none has considered cognitive
and behavioral measures and all have studied small samples.
We determined PoO in a large group of children with WS aged 4 - 17 years and tested for association with cognitive
and behavioral measures using ANOVA. We measured full scale IQ (DAS-II, n=191), vocabulary (PPVT-4, n=192; EVT-2,
n=195), adaptive behavior (SIB-R parent interview, n=235), language and social communication (CCC-2 parent questionnaire,
n=161), executive function (BRIEF school age parent questionnaire, n=188) and anxiety disorders (ADIS parent interview,
n=184). Approximately half the children were male and half were female.
We found no significant association of PoO of the WS deletion with any cognitive or behavioral measure (all ps > 0.01).
These results, from the largest group of children with WS studied to date, suggest that PoO has little or no primary effect
on the phenotypic outcome of cognition and behavior and that variability in the WS cognitive and behavioral profile is not
due to the parental origin of the deletion itself.
Wed(4)-P-98
Panel-based next generation sequencing identifies novel compound heterozygous variants of BMP1 un-
derlying osteogenesis imperfecta
Poster Session
Agnieszka Gach 1 ，Iwona Pinkier 1 ，Aleksander Jamsheer 2 ，Dominik Salachna 1 ，Karolina Antosik 3 ，
Lucjusz Jakubowski 1
1:Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland、2:Department of Medical Genetics, Poznan
University of Medical Sciences, Poznan, Poland、3:Department of Clinical Genetics, Medical University of Lodz, Lodz, Poland
Whereas approximately 90% of individuals with osteogenesis imperfecta (OI) are heterozygous for mutations in the COL1A1
and COL1A2 genes with dominant pattern of inheritance or sporadic mutations, 11 genes crucial for type I procollagen
biosynthesis have been associated with rare recessive OI forms. Because of the highly genetically heterogeneous nature of
the disorder, we employed panel-based next generation sequencing (NGS) as a cost-effective molecular diagnostic tool for
mutation identification in patients with OI phenotype.
Here we report a 25-year old patient with moderate form of OI characterised by over 20 fractures, deformity of the limbs
and mild scoliosis, in whom we identified novel compound heterozygous mutations in a BMP1 gene. The gene encodes for
alternatively spliced bone morphogenetic protein-1 (BMP1) and mammalian tolloid, both of which cleave the C-propeptides
of type I procollagen during the synthesis of collagen fibrils.
The patient is of Caucasian origin, the only child of nonconsanguineous Polish parents. He presented his first fracture by the
age of 3. By the age of 25 he had sustained over 20 fractures upon minimal trauma. He is of normal height and is able to
walk unaided. Sequencing revealed c.1043G>T transition in exon 8 and c. 1148G>A transition in exon 9, leading to missense
alterations: p.(C348F) and p.(R383Q), respectively. Both mutations affect highly conserved residues across distant species
localised in CUB1 domain. Mutations are predicted to be likely pathogenic according to PolyPhen-2 and SIFT.
Thus far, mutations in BMP1 gene have been identified within metalloprotease, CUB2 and CUB3 domains, signal peptide, 3’
UTR sequence but not in CUB1 domain. Together with protease and CUB2 domains, CUB1 has been shown to be necessary
for BMP1 activity. Interestingly, our patient presents a milder phenotype than previously reported OI cases with BMP1
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mutations. Our study broadens insights into genotype-phenotype correlation in OI.
Wed(4)-P-99
SNCA p.Ala53Glu mutation in Parkinson’s disease
Petra Pasanen 1 ，Liisa Myllykangas 2 ，Minna Poyhonen 3,4 ，Maija Siitonen 1 ，Anna Raunio 2 ，Seppo Kaakkola 5 ，
Jukka Lyytinen 5 ，Pentti J. Tienari 5,6 ，Juha O. Rinne 7,8 ，Anders Paetau 2
1:Department of Medical Biochemistry and Genetics, University of Turku, Finland、2:Department of Pathology, University of Helsinki and
HUSLAB, Helsinki, Finland、3:Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland、4:Department
of Medical Genetics, University of Helsinki, Helsinki, Finland、5:Department of Neurology, University of Helsinki and University Central
Hospital, Helsinki, Finland、6:Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland、
7:Turku PET Centre, Turku University Hospital and University of Turku, Turku, Finland、8:Division of Clinical Neurosciences, Turku
University Hospital and University of Turku, Turku, Finland
We have previously reported a novel alpha-synuclein mutation, p.Ala53Glu, in three affected members of a Finnish family. The
index patient was clinically diagnosed with atypical Parkinson’s disease with age of onset at 36 years. In the neuropathological
analysis performed at the age of 60, highly abundant SNCA pathology was observed throughout the brain and spinal cord
showing features of multiple system atrophy and Parkinson’s disease. Neuronal and glial (including oligodendroglial) SNCA
inclusions and neurites were found to be particularly prominent in the putamen, caudatus, amygdala, temporal and insular
cortices, gyrus cinguli and hippocampus CA2-3 region. These areas as well as the substantia nigra and locus coerulaeus
showed neuronal loss and gliosis. TDP-43 positive, but mostly SNCA negative perinuclear inclusions were also detected in
the dentate fascia of the hippocampus. MLPA analysis of the index patient’s DNA excluded triplication or duplication of the
SNCA gene. Sequencing of the coding region of SNCA revealed a heterozygous NM_000345.3: c.158C>A mutation. This
Poster Session
mutation was found in all three affected patients of the family.
These results prompted us to screen a cohort of approximately 150 PD patients from Southwest Finland for this mutation.
DNAs from the affected patients have been extracted from either EDTA blood or deep frozen brain tissue samples using
standard protocols. The p.Ala53Glu mutation is screened with Sanger sequencing. Our preliminary analyses show that the
SNCA p.Ala53Glu mutation is rare, since no carriers of this mutation have been identified in the post mortem cohort of 104
patients.
Wed(4)-P-100
Genetic heterogeneity of muscular dystrophy in Mali
Guida Landoure 1,2 ，Christopher Grunseich 2 ，Salimata Diallo 3 ，Nouhoum Bocoum 2 ，Katherine G Meilleur 4 ，
Seybou H Diallo 3 ，Kelian Chen 2 ，Simona Dimitriu 5 ，Thomas Coulibaly 1 ，Salimata Diarra 1 ，Koumba Bagayoko 1 ，
Dramane Coulibaly 6 ，Hamidou O Ba 6 ，Youssoufa Maiga 3 ，Cheick O Guinto 1 ，Moussa Traore 1 ，Carsten Bonneman 2 ，
Kenneth H Fischbeck 2 ，H3Africa
1:Service de Neurologie, Centre Hospitalier Universitaire du Point G, Mali、2:Neurogenetics Branch, NINDS, NIH, Bethesda, MD、3:Service
de Neurologie, CHU de Gabriel Touré, Bamako, Mali、4:Tissue Injury Branch, NINR, NIH, Bethesda, MD、5:Centre for Nephrology, UCL,
London, UK、6:Service de Medecine, Hopital Mere-Enfant le Luxembourg, Bamako, Mali
Muscular dystrophies are characterized by proximal weakness and progressive disability but are rarely reported in sub-Saharan
Africa.
In this study, we evaluated 90 families with hereditary neurological conditions, and eighteen of them presented with diverse
features of muscular dystrophy; making it the second most prevalent in our cohort. Three families with four affected boys
had Duchenne muscular dystrophy, and their genetic testing revealed two novel mutations (c.3784delG [Glu1262fsX1282]
and c.1423G>T [Glu475X]) and a previously reported exon deletion (del46-51) in the dystrophin gene. Fifteen families had
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features consistent with limb girdle muscular dystrophy (LGMD). In one family with no history of consanguinity, genetic
analysis revealed two novel heterozygous mutations in DYSF (c.2643+1G>A and c.4018G>C [Gly1340Arg]). While one
consanguineous family with three affected siblings had a homozygous nonsense mutation in SGCA (c.574C>T, Arg192X)
recently reported in a family with European decent, another with five affected individuals was negative for all known muscular
disease genes, suggesting that this family may have mutation in a new gene. In addition, testing of clinically relevant muscular
dystrophy genes including CAPN3 , DYSF , SGCA, SGCB, SGCG in several other families was negative.
Our study has identified four novel sequence variants in muscular dystrophy genes and at least one family with a possible
novel disease gene. This suggests that muscular dystrophy is not uncommon in this region of Africa, and that better
clinical characterization and genetic analysis may lead to new disease-causing genes that could then be investigated in other
populations. Further analyses are underway to uncover the genetic basis of the diseases in these families.
Wed(4)-P-101
Mutational analysis of TBK1 in Taiwanese patients with amyotrophic lateral sclerosis
1,2 1,2
Yi-Chung Lee ，Pei-Chien Tsai
1:Neurology, Taipei Veterans General Hospital, Taiwan、2:Department of Neurology, National Yang-Ming University, Taipei, Taiwan
Mutations in the TBK1 gene were just recently identified to cause amyotrophic lateral sclerosis (ALS), and their role in ALS
in various populations remains unclear. The aim of this study was to determine the frequency and spectrum of mutations
Poster Session
in TBK1 in a Taiwanese ALS cohort of Han Chinese origin. Mutational analyses of TBK1 were carried out by direct
nucleotide sequencing in a cohort of 207 unrelated patients with ALS. Among them, the genetic diagnoses of 168 patients
remained elusive after mutations in SOD1, C9ORF72, TARDBP, FUS, ATXN2, OPTN, VCP, UBQLN2, SQSTM1, PFN1,
HNRNPA1, HNRNPA2B1, MATR3, CHCHD10 and TUBA4A had been excluded. We identified one nonsense mutation,
p.R444X (c.1330C>T), in one patient with apparently sporadic ALS-frontotemporal dementia (FTD). In vitro functional
study demonstrated the p.R444X mutation resulting in a truncated TBK1 protein product, low protein expression, and loss
of kinase function and interaction with optineurin. The frequency of TBK1 mutations in ALS patients in Taiwan is, therefore,
approximately 0.5% (1/207). This study reports a novel TBK1 mutation and stresses on the importance to consider TBK1
mutation as a possible etiology of ALS.
Wed(4)-P-102
Differentiated genetic landscape of familial and sporadic amyotrophic lateral sclerosis
Qing Liu 1,2 ，Fang Liu 2,3 ，Bo Cui 1,2 ，Xianan Guo 2,3
，Rongrong Wang 2,3
，Chaoxia Lu 2,3
，Mingsheng Liu 1,2
，
Xiaoguang Li 1,2 ，Liying Cui 1,2 ，Xue Zhang 1,2,3
1:Department of Neurology and Laboratory of Clinical Genetics, Peking Union Medical College Hospital, China、2:Neuroscience Center,
Chinese Academy of Medical Sciences & Peking Union Medical College、3:McKusick-Zhang Center for Genetic Medicine, Chinese Academy
of Medical Sciences & Peking Union Medical College
Background and purpose: More than twenty genes had been associated with amyotrophic lateral sclerosis and a number of
patients were reported to carry potentially pathogenic variants in more than one ALS genes. We intended to evaluate burden
influence on ALS phenotype and to compare mutation spectrum in familial and sporadic ALS.
Methods: Targeted next-generation sequencing was applied to identify variants in 24 known ALS-associated genes in 254
Chinese patients. Expansion sizes of C9ORF72 and ATXN2 were also analyzed.
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Results: Rare coding variants or an expanded repeat in C9ORF72 or ATXN2 were detected in 40.0% of familial and 23.5%
of sporadic subjects. 5.5% (14/254) patients were carrying potentially pathogenic variants in more than one ALS genes.
When burden influence was estimated, no statistical significance was observed as for disease age of onset, region of onset or
survival. Twenty-three disease-causing mutations were identified in SOD1 , FUS, TARDBP, OPTN , UBQLN2 and C9ORF72 .
Among them, 35% FALS carried well-established mutations with a mutant frequency varied from 30.6% in SOD1 to 5% in
UBQLN2 . Only 5.6% SALS carried mutations in these genes, accounting for 21.3% of total rare variants in SALS. None of
these mutations were identified in dbSNP Database unless as pathogenic. ALS-associated variants were detected in SETX ,
DAO, ATXN2 , AR, DCTN1 , FIG4 , GRN , NEFH , TAF15 , and TF G. These variants dispersed mainly in SALS cases and
23.1% (12/52) were recorded in dbSNP Database. Variations in TARDBP, ANG, VCP, CHMP2B, PFN1 and PRPH , as
well as homozygous ALS2 and SIGMAR1 variants, were not detected in the current cohort. A previously reported mutation
(p.P56S) in VAPB failed to show linkage disequilibrium in a large ALS family by segregation analysis.
Conclusions: Holding variants in multiple ALS-associated genes might not evidently influence ALS phenotypes. FALS and
SALS differed in genetic landscape, and most rare variants in SALS are still of unknown significance.
Wed(4)-P-103
Ribosomal Dysfunction Leads to Erythropoiesis Failure in a Zebrafish Model of Diamond-Blackfan Ane-
mia
Naoya Kenmochi 1 ，Tamayo Uechi 1 ，Yukari Nakajima 1 ，Maki Yoshihama 1 ，Yutaka Suzuki 2 ，Sumio Sugano 2
Poster Session
1:Frontier Science Research Center, University of Miyazaki, Japan、2:The University of Tokyo
Mutations in genes involved in ribosome biogenesis have been identified in patients with specific disease conditions, called
ribosomopathies. Diamond-Blackfan anemia (DBA) is one of such disorders, characterized by diminished numbers of erythroid
progenitors and associated physical deformities. To date, heterozygous mutations in 13 ribosomal protein (RP) genes have
been identified in more than 50% of the DBA patients. However, it remains unknown how mutations in such ubiquitously
expressed genes specifically affect erythropoiesis.
To investigate the molecular pathogenesis of DBA, we developed a zebrafish model of DBA by knocking down the zebrafish
ortholog (rps19 ) of the human RPS19 that is the most frequently mutated gene in the patients. The knockdown embryos
(morphants) displayed a drastic reduction of red blood cells, whereas differentiation of other myeloid cells seemed to be
normal. The anemia phenotype was almost completely rescued by injecting wild-type rps19 mRNAs, but not by mRNAs
with patient-type mutations. Although previous studies suggested a critical role of Tp53 in DBA, simultaneous inhibition of
tp53 and rps19 in zebrafish did not alleviate the erythroid aplasia. Interestingly, we found that the treatment with particular
amino acids, such as L-Leucine or L-Arginine that augment mRNA translation via mTOR pathway, recovered the anemia
phenotype. To evaluate the impact of RP deficiency on translation, we carried out RNA-seq analysis of the polysomal mRNAs
from RPS19-deficient and control embryos, and deduced the changes of translational rate of respective mRNAs. We found
that the translational rate of several hematopoietic genes was repressed by more than 50% in the morphants. These genes
may paly an important role in DBA pathogenesis.
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Wed(4)-P-104
Molecular genetic and clinical characterization of male Rett syndrome
Hyun-Joo Lee 1 ，Yoon-Hee Ko 1 ，Cheol-Ho Lee 1 ，Joon-Soo Lee 1 ，Heung-Dong Kim 1 ，Jin-Sung Lee 1
1:Pediatrics, Yonsei University College of Medicine, Korea, South
Rett syndrome is a typical epigenetic disorder that is caused by mutations within MECP2 gene and characterized by neu-
rodevelopmental regression that severely affects motor, cognitive, and communications skills. After it was first reported in
1965, it became one of the most important disease that has to be screened first when female children show developmental
regression with unknown origin. Recently, there are some clinical variants of Rett syndrome identified and male patients with
MECP2 mutations have been reported.
In this report, we present the results of molecular analysis and clinical findings of 3 male patients who were verified as male
Rett syndrome. Two of them were identified by whole exome sequencing and another patient was identified by microdeletion
test using MLPA technique. Even Rett syndrome is known as a disease lethal to male, it may be needed to screen for MECP2
mutations or duplication for males who show similar symptoms or neurologic symptoms of unknown origin.
Wed(4)-P-105
Molecular genetic study of 80 patients with ATR-X syndrome in Japan
Hiroko Shimbo 1 ，Kenji Kurosawa 2 ，Nobuhiko Okamoto 3 ，Takahito Wada 4
Poster Session
1:Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama, Japan、2:Department of Medical Genetics, Kanagawa Chil-
dren’s Medical Center, Yokohama、3:Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka、4:Department of
Medical Ethics and Medical Genetics, Kyoto University Graduate School of Medicine, Kyoto
[Introduction] X-linked a-thalassemia mental retardation syndrome (ATR-X syndrome; MIM#603040) is characterized by
severe intellectual disability, dysmorphic facies, hypotonia, genital and skeletal abnormalities and down-regulation of the
a-globin genes (a-thalassemia). More than 80 patients have been molecularly diagnosed in Japan and more than 200 patients
worldwide. Most of their mutations are clustered in two functionally important regions: the ADD (ATRX-DNMT3-DNMT3L)
and helicase domains domain (Chromatin remodeling domain). In order to delineate molecular and clinical characteristics,
Here, we review identified mutations in the ATRX (MIM*300032) of 80 patients from 65 families in Japan and report one
rare case with two different pathogenic mutations, ERCC6 (MIM*609413) and ATRX. [Methods&Results] Genomic DNA
and total RNA was extracted from blood leucocytes. Most of their mutations are clustered in two functionally important
regions: 37 out of 80 mutations (46.2%) reside in ADD (ATRX-DNMT3-DNMT3L), 29 (36.3%) in helicase domains and other
14 (17.5%) mutations outside of these domains. The type of mutations are as follows; 59 missense mutations, 2 nonsense
mutations, 10 splicing mutations and frame shifts, 3 intragenic deletions, 2 nucleotide exchanges in introns, 1 large insertion
in a intron, 2 nucleotide exchange in 5’- and 3’-UTR, and 1 large deletion. [Discussion] Although we did not find a
clear correlation between genotype and phenotype, patients with missense mutations in ADD domains seem to present with
more severe symptoms, as previously reported. A boy was diagnosed with Cockayne syndrome with compound heterozygous
mutations in ERCC6 , and a splice site mutation in ATRX subsequently found in the whole genome sequencing. N-terminal
splice site mutation produces in premature stop codon and protein truncation, results in lacking the functionally important
domains, but interestingly he has presented with mild phenotype of ATR-X syndrome.
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Wed(4)-P-106
Clinicogenetic features of PLOSL (polycystic lipomembranous osteodysplasia with sclerosing leukoen-
cephalopathy)
Takao Kiriyama 1 ，Ryogo Shobatake 1 ，Nobuyuki Eura 1 ，Kazuma Sugie 1 ，Jun-ichi Satoh 2 ，Satoshi Ueno 1
1:Department of Neurology, Nara Medical University、2:Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical
University
We report the clinical, genetic, and neuroradiological features of Nasu-Hakola (NHD) disease, also known as polycystic
lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). PLOSL is a rare autosomal recessive disorder
characterized by progressive presenile dementia and systemic multiple cystic bone lesions resulting in pathological fractures.
PLOSL was first independently reported in Japan and Finland in the 1960s. So far about 200 cases have been identified
in the world, mostly in Japan (over 100) and Finland, but there is a global distribution. PLOSL is caused by a structural
defect in one of the two genes encoding different subunits of the same receptor signaling complex, TREM2 (triggering receptor
expressed on myeloid cells 2) and DAP12 (DNAX-activating protein of 12 kDa). We present a 43-year-old Japanese woman
for clinical course and findings of neuroimaging including MRI, CT scan and ECD-SPECT. The genetic analysis of our patient
confirmed a mutation of DAP12 gene (a homozygous single-base deletion of 141G in exon 3). We compare our case with 6
reported cases. The clinical features include progressive dementia with frontal syndrome, pyramidal signs, extrapyramidal
signs, aphasic symptoms, and epilepsy. The CT scan shows calcification of bilateral basal ganglia and cerebral atrophy
particularly in the frontal and temporal lobes. The brain MRI reveals low signal intensity of bilateral basal ganglia and
diffuse confluent white matter abnormalities on T2WI. In our case the pathological fracture is not outstanding. Moreover,
recently it was reported that heterozygous rare variants in TREM2 linked to increased risk of Alzheimer’s disease. We here
Poster Session
discuss phenotype-genotype correlation of TREM2 and DAP12.
Wed(4)-P-107
SMN1 , SMN2 and hybrid SMN gene analysis in spinal muscular atrophy using long-range PCR followed
by sequencing
1,2,3
Yuji Kubo ，Kayoko Saito 1 ，Hisahide Nishio 4,5
1:Institute of Medical Genetics, Tokyo Women’s Medical University, Japan、2:Toppan Printing Co., Ltd.、3:Riken Genesis Co., Ltd.、4:De-
partment of Community Medicine and Social Health Care, Kobe University Graduate School of Medicine, Kobe, Japan、5:Department of
Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of anterior
horn cells in the spinal cord, leading to progressive proximal muscle weakness and atrophy. Approximately 95% of SMA
patients have homozygous disruptions of survival motor neuron gene 1 (SMN1 ) owing to deletion or conversion of SMN1
to SMN2 , while 5% harbor compound heterozygous mutations such as an SMN1 deletion allele and an intragenic mutation
in the other SMN1 allele. It is difficult to detect intragenic mutations in SMN1 because of the high degree of homology
between SMN1 and SMN2 . We have developed a novel approach, which is more efficient and broadly applicable than older
methods, using long-range PCR to detect intragenic mutations in SMN1 , SMN2 and hybrid SMN genes. We analyzed 30
unrelated SMA patients using the SMN deletion test, SMN copy number analysis, and the long-range PCR method followed
by sequencing. We thus confirmed a novel mutation in SMN1 exon 1 in a patient with SMA type III and in exon 6 in one
with SMA type I, who also had an SMN1 deletion allele. Moreover, we identified three hybrid SMN gene types resulting
from a gene conversion of SMN1 to SMN2 in patients with homozygous deletions of SMN1 exon 7. Three hybrid SMN gene
types were documented: large conversion regions, small conversion regions and complex conversion. We speculate that milder
symptoms may correspond to small conversion regions. We herein report distinct variants in SMN1 , SMN2 and hybrid SMN
genes that we have identified using the long-range PCR method.
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Wed(4)-P-108
Spectrum and frequency of STK11 mutations of Russian patients with Peutz-Jeghers syndrome
Vitaly Shubin 1 ，Yury Shelygin 1 ，Alexey Tsukanov 1 ，Igor Sachkov 1 ，Sergey Frolov 1 ，Vladimir Kashnikov 1 ，
Olga Maynovskaya 1 ，Natalia Pospekhova 1
Peutz-Jeghers syndrome (PJS) is a rare hereditary syndrome associated with STK11 mutation. Clinical implications of pa-
tient PJS is presence of mucocutaneous pigmentation and hamartomatous polyps of intestinal tract. Patients with PJS have
high-risk different cancers: breast cancer, colorectal cancer, pancreatic cancer, stomach cancer, ovarian cancer and other.
Often patients with PJS do not have family history.
Material for study was blood of 9 patients from 7 families with Peutz-Jeghers syndrome in accordance with clinical data.
Eight female and one men were investigated. Mean age was 29-63 years. Detection of STK11 mutations were performed by
Sanger sequencing.
At results 5 families with STK11 mutation were found. Mutations in STK11 i.e. c.598-1G>A, c.933_936delGAAA
(p.Lys311AsnfsX24), c.1009_1010delGT (p.Val337GlyfsX22), c.200T/C (p.L67P), c.803_810dup8 (p.Ser271GlyfsX19) were
discovered. Four mutation (c.598-1G>A, c.933_936delGAAA, c.1009_1010delGT and c.803_810dup8) we found for first
time. Hamartomatous polyps located in stomach and large intenstine were detected for 8 patients and 5 patients, respec-
tively. Breast cancer, cancer of the cecum, ovarian cancer, cervical cancer were detected in four patients.
Poster Session
The frequency of STK11 germline mutations for Russian patients was 71.4% (5/7). Due to high risk of cancer development
careful diagnostic examination beginning from young age are require for patients with PJS.
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Poster Session
Therapy for Genetic Disorders
Wed(4)-P-109
Dendrosomal Curcumin Nanoformulation is Inducing Apoptosis and Up-Regulates Long Non-Coding
RNA CCAT2 in Human Breast Cancer MCF-7 And T47D Cell Lines
Aref Sobhkhizy 1 ，Esmail Babaei 1 ，Mohammad Ali Hoseinpour Feizi 1,2
，Neda Jafari 1 ，
Reyhaneh Ravanbakhsh Gavgani 1
1:Natural Science faculty, University of Tabriz, Iran、2:East Azarbaijan Technology and Science Park
Recently many various Lnc-RNAs have identified as biomarker for detection of different types of Cancers but their role in
cancer treatment has neglected. Lnc-RNA CCAT2 was discovered in human Colorectal Cancer with higher expression in
tumor tissues in compare to its adjacent normal tissues, but its role in cancer treatment is remained anonymous. There is
various types of anti-cancer agents inducing apoptosis in cancer cell lines but have strong side effects, Curcumin is a recently
taken into consideration apoptosis inducing reagent with no side effect on human normal cells. Because of hydrophobic nature
of Curcumin which causes low intestine and cellular uptakes, we have evaluated new form of curcumin called Dendrosomal
Nano Curcumin (DNC) with improved cellular uptakes and effective apoptosis induction. Here we have evaluated the effect
Poster Session
of DNC on regulation of expression of Lnc-RNA CCAT2 and apoptosis induction in human breast cancer MCF-7 and T47D
cell lines.
Results:
Annexin V/FITC assay confirms apoptosis processes in both T47d and MCF-7 cell lines in the manner of time and doses.
But despite to earlier studies on expression level of Lnc-RNA CCAT2 in T47D cells which says this gene is not expressing in
T47D cells, for the first time, we report high expression of Lnc-RNA CCAT2 in human T47D cell line. Also despite to the
fact that this gene is overexpressed in several cancers tissues and is an oncogene, treatment of Breast cancer cell lines using
DNC demonstrated that DNC is upregulating Lnc-RNA CCAT2 expression in the manner of dose and time in both apoptosis
induced T47D and MCF-7 Cells.
Discussion: Here we have proved that DNC is upregulating Lnc-RNA CCAT2 and causes to c-Myc upregulation in apoptotic
cells and c-Myc as direct target of CCAT2, induces TP53 independent apoptosis pathway in T47D cells which is mutated in
P53.
Note: Still we’re working on the reasons of upregulation of an oncogene in apoptosis induced cells.
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Wed(4)-P-110
CHO-intermediated Chromosome Engineering (CHOiCE) technique using CRIPSR/Cas9
1,2
Narumi Uno ，Katsuhiro Uno 2 ，Shinya Komoto 2 ，Yasuhiro Kazuki 1,2,3
，Mitsuo Oshimura 1
1:Chromosome Engineering Research Center, Tottori University, Japan、2:Department of Biomedical Science, Institute of Regenerative
Medicine and Biofunction, Graduate School of Medical Science, Tottori University、3:Department of Molecular and Cellular Biology, Faculty
of Medicine, Tottori University
Chromosome engineering techniques including microcell-mediated chromosome transfer (MMCT) using Chinese hamster ovary
(CHO) cells and chromosome modification techniques using homologous recombination-proficient chicken pre-B cells, DT40,
are attractive techniques in order to generate humanized animal models, and correct genetic disorders via construction of
human artificial chromosome (HAC) and mouse artificial chromosome (MAC). However, these techniques require two cell
lines; DT40 cell is for chromosome modification, and CHO cells is for transfer to targeted cells. Our data showed that
chromosome engineering could be performed via CRISPR/Cas9 system in CHO cells without using conventional strategy via
DT40 cells. An EGFP and a selectable marker (BSr ) were inserted to a human chromosome 21 via homologous recombination
(HR) mediated by CRIPSR/Cas9 systems targeting two sites. Seventeen of thirty seven clones showed positive for the
correct HR. Another chromosome 21 was also truncated on a pericentromeric region by telomere seeding at a specific site.
Eight of thirty eight clones showed positive for the desired homologous recombination. The modified chromosomes were
transferred from the CHO cells to mouse embryonic stem cells by MMCT. Thus, a combination of CHO cell-intermediated
chromosome engineering (CHOiCE) technique involving CRISPR/Cas9 system and MMCT could shorten the required period
of the process, suggesting that the technology will facilitate for the generation of humanized animal models and the correction
of cells with genetic disorders.
Poster Session
Wed(4)-P-111
Hematopoietic stem cell transplantation for adolescent and adult onset cerebral X-linked adrenoleukodys-
trophy
Takashi Matsukawa 1 ，Tomotaka Yamamoto 1 ，Takashi Toya 2 ，Akihito Shinohara 2 ，Yasuhito Nanya 2 ，Sachiko Seo 2 ，
Keiki Kumano 2 ，Motoshi Ichikawa 2 ，Yuji Takahashi 1 ，Hiroyuki Ishiura 1 ，Jun Mitsui 1 ，Masaki Tanaka 1 ，Jun Goto 1 ，
Mineo Kurokawa 2 ，Shoji Tsuji 1
1:Department of Neurology, The University of Tokyo, Japan、2:Department of Hematology and Oncology, The University of Tokyo
Background & Purpose: There have been accumulating evidences supporting the efficacy of the hematopoietic stem cell
transplantation (HSCT) for childhood-onset cerebral X-linked adrenoleukodystrophy (ALD) when performed at an early
stage of the disease. To date, there have been only two reported cases of adult-onset cerebral ALD (ACALD) treated with
HSCT and the clinical efficacy remains to be established. The purpose of this study is to evaluate the clinical efficacy of HSCT
for patients with adolescent/adult-onset cerebral ALD. Methods: To determine the optimum timing for HSCT at an early
stage of adolescent/adult-onset cerebral ALD, we have been following 31 ALD patients [1 adolescent cerebral ALD, 1 ACALD,
9 AMN with later development of cerebral ALD (AMN-Cer), 3 cerebello-brainstem ALD (OPC), 2 OPC-Cer, 12 AMN, 2
Addison only, and 1 presymptomatic male]. The average observation period was 5.5 years. The patient has been observed
at the interval of 3-6 months to detect appearance of the early cerebral symptoms. The indications for HSCT include an
early stage of the disease and the presence of Gadolinium-enhancing white matter lesions on brain MRI. Conditioning regime
included intravenous busulphan and cyclophosphamide, or fludarabine and melphalane. Result: We performed HSCT for 4
patients who developed cerebral form at an early stage. 3 patients received HSCT from 8/8 HLA-matched unrelated donor,
and 1 patient from one HLA-DR-mismatched unrelated donor. Observation periods after HSCT for each patient are 7, 3, 1.5
and 1 years with stable clinical course. Enhancement on brain MRI remains disappeared after HSCT with no enlargement
of white matter lesions. Surprisingly, the white matter lesions reduced after HSCT in 3 patients. Conclusion: The present
study suggests the efficacy of HSCT for adolescent/adult-onset cerebral ALD. It will be important to determine the optimum
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timing of HSCT for adolescent/adult-onset cerebral ALD to accomplish a good outcome from HSCT.
Wed(4)-P-112
The analysis of suppressive effects of citrus peel ingredient on the abnormal protein accumulation-related
phenomena induced by mutant proteins of glaucoma and amyotrophic lateral sclerosis causative genes
(OPTN and TARDBP)
Masafumi Ohtsubo 1 ，Yoshihiro Hotta 2 ，Shinsei Minoshima 1
1:Department of Photomedical Genomics, Hamamatsu University School of Medicine, Japan、2:Department of Ophthalmology, Hamamatsu
Background: Optineurin (OPTN) has been reported as a causative gene for not only glaucoma but also amyotrophic lateral
sclerosis (ALS). Other ALS causative genes have been also known (especially, SOD1 for familial ALS, TAR DNA-binding
protein-43 (TDP-43) gene (TARDBP) for sporadic cases). For both diseases, various in vivo (I) (see below) and in vitro
(II) phenomena relating to the abnormal protein accumulation have been reported: (I) the inclusion bodies which contain
OPTN, SOD1, or TDP-43 are detected in nerve cells of ALS patients; (II-1) the "cytoplasmic inclusion" (inclusion) is found
in TARDBP-transfected cells; (II-2) the "OPTN granules" (foci) are formed in the cells transfected with OPTN which has a
glaucomatous mutation E50K; and (II-3) a specific OPTN-interacting protein SLC4A2 induces a generation of the "vacuole-
like abnormal structure" (vacuole) when it is coexpressed with OPTN. Here, we examined the suppressive effect of "Sitraren
(STR)" (a provisional name) on such in vitro phenomena, which is a polymethoxylated flavone from the citrus peel.
Poster Session
Methods: To evaluate the autophagy induction effect with STR or the mTOR inhibitor, the proteins were extracted, and
then the antibody specific to LC3 (an autophagy marker protein) was used for western blotting (WB). The activation state
of mTOR and related proteins in HeLaS3 cells was assayed by WB using antibodies specific to phosphorylated form of each
mTOR pathway protein.
Results: TDP-43-related "inclusion" and OPTN E50K-related "foci" and "vacuole" were suppressed by STR through the
induction of autophagy. An mTOR inhibitor also showed the similar effect. However, the STR action did not depend on
mTOR inhibition.
Conclusion: We found that STR has a suppressive effect on a certain type of the abnormal protein accumulation-related
phenomena. Therefore, this type of chemicals may be effective as drugs for the treatment of ALS or glaucoma patients caused
by TARDBP or OPTN, respectively.
Wed(4)-P-113
Targeting Heat Shock Protein 90 with Ganetespib for the Treatment of Lymphoma
Hanqing Liu 1 ，Yongjin Lu 1 ，Dongsheng Shang 2 ，Xiaofeng Shi 3 ，Peishan Zhang 1 ，Jingjing Zhao 1 ，Lingling Ruan 1 ，
Yanfang Wu 2 ，Zhigang Tu 2
1:School of Pharmacy, Jiangsu University, China、2:Institute of Life Sciences, Jiangsu University、3:Affiliated Hospital of Jiangsu University
Effective treatments for lymphoma remain a serious unmet medical need: the incidence of lymphoma continues to rise, and
lyphoma tumors can relapse in patients who initially respond to treatment. Heat shock protein 90 (HSP90) has become an
attractive therapeutic target in treating many cancers including blood cancers. In our study, we show that ganetespib, a
clinically promising and actively investigated second-generation HSP90 inhibitor, dramatically reduced growth of a couple
of different kinds of lymphoma, such as mantle cell lymphoma and Burkitt’s lymphoma in a dose-dependent manner.
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It induced G2/M cell-cycle arrest and apoptosis in all studied cell lines, such as Ramos, Jeko-1, Granta-519, Raji, etc.
Ganetespib significantly inhibited growth of xenograft tumors in vivo and results of H&E staining, TUNEL assays, and
immunohistochemistry staining of Ki-67 and other proteins revealed significant differences in ganetespib-treated tumors. A
panel of signaling network proteins with a hub of HSP90 were screened for the effects of ganetespib and these pathways were
studied mechanistically. In addition, lymphoma cells from patients’ samples from peripheral blood and other resources are
currently cultured and tested with ganetespib. In summary, our data suggest that ganetespib can be potentially used for the
molecularly targeted therapy of lyphoma patients.
Acknowledgments
This work was supported by the Jiangsu Specially-Appointed Professor Program (to H. Liu); Jiangsu Recruitment Program
of Leading Creative and Entrepreneurial Talents (to H. Liu and Z. Tu); National Natural Science Foundation 81402145 (to H.
Liu) and 31471294 (to Z. Tu); Natural Science Foundation of Jiangsu Province BK20140572 (to H. Liu); Start-up Scientific
Research Fund for the Returned Oversea Scholars from Chinese Ministry of Education (to Z. Tu); Senior Talent Start-up
Funds of Jiangsu University 14JDG050 (to H. Liu) and 14JDG011 (to Z. Tu).
Poster Session
Wed(4)-P-114
Role of Fmr1 (Fragile X Mental Retardation gene 1) mRNA level during neurodevelopment: implication
in the pathophysiology of FXTAS (Fragile X-Associated Tremor/Ataxia Syndrome)
Bardoni Bardoni 1 ，Olfa Khalfallah 1 ，Samantha Zongaro 1
1:CNRS UMR7275, France
Fragile X syndrome is the most common form of inherited intellectual disability and is caused by an expansion of a CGG repeat
located in the 5’UTR of the mRNA of the FMR1 gene. The full mutation (> 230 CGGs) is abnormally methylated resulting
in the inactivation of FMR1 , while moderate unmethylated expansions (60/200 CGGs) are called premutations. Premutated
individuals have normal intellectual abilities, but they can be affected by attention deficit hyperactivity disorder, anxiety and
autism spectrum disorders and may be affected by a neurodegenerative disorder, the Fragile X associated Tremor/Ataxia
syndrome (FXTAS). FXTAS is characterized by an elevated expression of FMR1 mRNA and the presence of intranuclear
inclusions in neurons and astroglias.
Increasing evidence pointed out the importance of the elevated level of Fmr1 mRNA in some early FXTAS phenotypes linked
to neurodevelopment and not related to the presence of nuclear inclusion and neurodegeneration. For this raison, we decided
to study the morphology of cultured cortical and hippocampal neurons obtained from wild type and FXTAS mice. While
the analysis of spine morphology is still in progress, we found that in FXTAS cultured cortical neurons (without nuclear
inclusions) the length of the axon and the complexity of the arborization of dendrites are reduced. We used lentiviruses
expressing two shRNAs specifically targeting Fmr1 mRNA to reduce its expression in cultured cortical and hippocampal
neurons obtained by FXTAS mice without affecting the expression level of FMRP protein. Remarkably, in these conditions,
we observed the rescue of some phenotypes of FXTAS neuron.
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Our data highlight the importance of Fmr1 mRNA expression level during neurodevelopment. For this reason, experiments
are in progress to rescue some learning-memory phenotypes of FXTAS mice by normalizing the mRNA level of Fmr1 in
different brain regions.
Wed(4)-P-115
Methionyl-tRNA Synthetase Promotes Reactive Oxygen Species Accumulation by Producing Homocys-
teine Thiolactone that Induces Lysine Homocysteinylation
Wei Xu 1 ，Shimin Zhao 1,2
，Yan Lin 1
1:Institutes of Biomedical Sciences, Fudan University, China、2:School of Life Sciences, Fudan University
Hyperhomocysteinemia is an established independent risk factor for neural tube defects (NTDs), coronary artery disease,
thrombosis, tumors and other diseases. Folic acid supplementation is the world-wide used approach to lower circulating
homocysteine (Hcy) albeit folic acid resistant patients persist. The development of anti- folic acid resistant approaches is
prevented by the incomplete understanding of the pathologies of hyperhomocysteinemia. Here, we report that lysine ho-
mocysteinylation underlies pathology of hyperhomocysteinemia. High Hcy promotes production of homocysteine thiolactone
(HTL) through noncanonical catalytic activity of methionyl-tRNA synthetase (MARS) that converts homocysteine (Hcy) to
HTL, a reactive compound that spontaneously modifies the ε-amine of lysine to form lysine homocysteinylation (N-Hcy) in
proteins, including the ROS scavengers superoxide dismutase 1 and 2 (SOD1/2), in cells. N-Hcy inactivates SOD1/2 and
results in elevated cellular ROS levels that abnormally activate Wnt/b-catenin signaling. Inhibiting MARS production of HTL
Poster Session
with Hcy analogs N-acetylcystine (NAC) or acetyl homocysteine thioether (AHT) reversed hyperhomocysteinemia effects and
decreased the onset of NTDs in a folic acid-responsive all-trans retinoic acid (ATRA) rat model. Thus, we revealed a novel
pathologic mechanism of hyperhomocysteinemia and identified MARS as an intervening target for hyperhomocysteinemia
associated diseases.
Wed(4)-P-116
Generation of a non-cytotoxic herpes simplex based vector for neural transduction
1,2
Yoshitaka Miyagawa ，Gianluca Verlengia 3 ，Michele Simonato 3 ，Justus B. Cohen 2 ，Joseph C. Glorioso 2
1:Department of Biochemistry and Molecular Biology, NIPPON MEDICAL SCHOOL, Japan、2:Department of Microbiology and Molecular
Genetics, University of Pittsburgh, USA、3:Department of Medical Sciences, University of Ferrara, Italy
We recently reported the development of a high-capacity, non-toxic HSV vector system capable of expressing large therapeutic
transgenes. The vector, termed J∆NI5, is deleted for all immediate-early (IE) gene expression and is consequently non-toxic
for most cell types but also transcriptionally silent. However, foreign gene expression cassettes introduced into the latency-
associated transcript (LAT) region are transcriptionally active in the absence of IE gene products in a variety of cell types.
Here we demonstrate that additional deletion of the gene (vhs) encoding the viral host shut off protein further improves
the utility of the vector for transduction of neural cells and tissue. Vhs-deleted J∆NI5, termed J∆NI8, showed increased
transgene expression from both the LAT locus and a terminal repeat (TR) site compared to the parental J∆NI5 in explanted
rat dorsal root ganglions (rDRGs) but not in human fibroblasts. Furthermore, we found that J∆NI8 provides abundant
transgene expression in rat brain at a similar level as ICP0-rescued J∆NI5, well above the level seen with (ICP0-deficient)
J∆NI5. We observed significant cytotoxicity and evidence of immunogenicity with attendant decline in transgene expression
in brains injected with ICP0-rescued J∆NI5 whereas no cytotoxicity or immune activity were detected in J∆NI8-injected
brain, and robust transgene expression persisted for an extended period of time. These results suggest that vhs negatively
influences transgene expression from an IE gene-depleted, non-toxic HSV vector in neural cells, although not in non-neural
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cells, and thus that vhs deletion may be a critical component of non-toxic HSV vector designs for efficient neural transduction.
Wed(4)-P-117
MOLECULAR MEASURING OF BCR-ABL1 TRANSCRIPTS ON INTERNATIONAL REPORTING
SCALE IN CHRONIC MYELOID LEUKEMIA PATIENTS
Shariq Ahmed 1 ，Muhammad Nadeem 1 ，Gul Sufaida 1 ，Kousar Naseem 1 ，Danish Zahid 1 ，Saba Faraz 1 ，
Tasneem Farzana 1 ，Uzma Zaidi 1 ，Mehwish Taj 1 ，Munira Borhany 1 ，Sidra Maqsood 1 ，Saad Ahmed 1 ，
Tahir Sultan Shamsi 1
1:Genomics, National Institute of Blood Diseases & Bone Marrow Transplantation, Pakistan
INTRODUCTION: Since the start of targeted therapy in Chronic Myeloid Leukemia (CML) with Tyrosine Kinase Inhibitors
(TKIs), the monitoring of response by cytogenetic analysis for Philadelphia Chromosome and BCR-ABL1 transcript levels
by qPCR have become a mandatory procedures in the follow up of these patients. The standardization of BCR-ABL1 tran-
script levels on international scale have removed the earlier discrepancies in reporting from different centers. Now molecular
monitoring is done as early as three months of start of therapy to predict the major molecular response at 12 and 18 months.
STUDY DESIGN: Retrospective study design.
PLACE AND DURATION: The study was conducted in National Institute of Blood Disease & BMT (NIBD) with duration
from June 2012 to September 2015.
Poster Session
PATIENT AND METHOD: Traditional Real-time quantitative PCR method was used for measuring BCR-ABL1 mRNA
transcript levels in peripheral blood of CML patients. Transcripts quantification was done by using Nanogen advance diag-
nositic, ipsogen qiagen kits from June 2012 to December 2014 and later on Xpert BCR-ABL monitor™ Assay from January
2015 to present. GeneXpert Dx System (Cepheid) is fully automated system and results are reported as a percentage of
BCR-ABL1/BCR on MMR-International scale (IS-Scale).
RESULTS: Total 432 samples of 331 patients were analyzed, females were 163(49%) and males were 168(51%). Median age
was 40(8-86) years. Mean baseline bcr/abl transcripts was 67.3 ± 65.3. Baseline analysis was done in 178(41%) and remaining
254(59%) were on follow ups. Major molecular response occurred in 237(93%) patient at median 6 months of therapy with
TKIs. On subsequent follow-up loss of molecular response was seen in 27(11%) patients.
CONCLUSION: We conclude that the quantitative measurement of BCR/ABL1 transcripts by qPCR should be done for
monitoring minimal residual disease for the early detection of relapse and as an assessment of treatment response in all the
patients of CML on TKIs
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Wed(4)-P-118
rFSH monotherapy prior to hCG-rFSH combination therapy is an effective new treatment to achieving
future fertility in adolescent patients with congenital male hypogonadotropic hypogonadism
1,2
Naoko Sato ，Akiko Hosokawa 3 ，Sachiko Kitanaka 1 ，Toshiaki Tanaka 2
1:Department of Pediatrics, Tokyo University, Japan、2:Tanaka Growth Clinic、3:Hikari Clinic
[Background] Congenital male hypogonadotropic hypogonadism (CMHH), a disorder associated with infertility, is treated
with hCG-rFSH combination therapy (hCG-rFSH) to achieve fertility. However, approximately 60% of CMHH could not
achieve sufficient spermatogenesis with the current hCG-rFSH (Sato et al.). Dywer et al. reported on the effectiveness of
rFSH mono-therapy followed by hCG-rFSH to improve spermatogenesis in adult patients with CMHH with small testis. But
there is no report of this treatment in adolescent patients with CMHH (ADCMHH).
[Objective] With the aim of improving spermatogenesis of ADCMHH, new methods are to be proposed and effectiveness for
spermatogenesis is discussed.
[Proposal for new treatment] After rFSH (75IU) for two months, hCG-rFSH is administered in appropriate therapeutic dose
according to age.
[Cases of treatment] Case 1: 18-year-old male: He was diagnosed as Kallmann syndrome (KS) because of micropenis and
hyposmia in infancy and identified with KAL1 mutation. From the age of 12 years, low dose testosterone was administered.
At the age of 16, treatment was changed to rFSH mono-therapy for 4 months. From the age of 17 to the present, hCG-rFSH
Poster Session
has been continued. After two months of switching to rFSH-hCG, testosterone reached adult level and testicular volume was
increased to double. Sperm count was confirmed by semen test at the age of 18. Case 2: 21-year-old male: At the age of 18,
He was diagnosed as KS because of cryptorchidism, delayed puberty and hyposmia. rFSH mono-therapy was administered
daily for 60 days, then switched to hCG-rFSH. Testis volume was less than 1 ml when treatment began and increased to 5
ml in two years. Testosterone reached adult level. Nocturnal emission was confirmed.
[Conclusion] rFSH mono-therapy prior to hCG-rFSH was used to treat ADCMHH with small testis. Enlargement of testis
and spermatogenesis were recognized. This result suggests the effectiveness of this new method to achieve future fertility in
ADCMHH.
Wed(4)-P-119
Therapeutic effects of recombinant adeno-associated virus-mediated muscle transduction to express
bone-targeted alkaline phosphatase of lethal hypophosphatasia model mice
Aki Nakamura-Takahashi 1 ，Koichi Miyake 1 ，Atsushi Watanabe 1,2 ，Yukihiko Hirai 1 ，Osamu Iijima 1 ，Noriko Miyake 1 ，
Kumi Adachi 1 ，Yuko Nitahara-Kasahara 1 ，Hideaki Kinoshita 3 ，Taku Noguchi 4 ，Shinichi Abe 4 ，Takashi Shimada 1 ，
Takashi Okada 1
1:Department of Biochemistry and Molecular Biology, Nippon Medical School, Japan、2:Division of Clinical Genetics, Nippon Medical School
Hospital, Tokyo, Japan、3:Department of Dental Materials Science, Tokyo Dental College, Tokyo, Japan、4:Department of Anatomy, Tokyo
Dental College, Tokyo, Japan
[BACKGROUND]
Hypophosphatasia (HPP) is a systemic skeletal disease, caused by deficiency of tissue-nonspecific alkaline phosphatase
(TNALP). Although considerable amount of attention has been focused on the enzyme replacement therapy as a“Break-
through therapy”, repeated injection of large amounts of recombinant TNALP is required to achieve clinical benefits. As an
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alternative approach, we recently showed that TNALP knockout (Akp2 -/- ) mice can be treated by a single intravenous injec-
tion of recombinant adeno-associated virus (rAAV) expressing bone-targeted TNALP with deca-aspartates at the C terminus
(TNALP-D10) by the tissue non-specific CAG promoter at the neonatal period. However, the safety of a systemic injection of
the rAAV into the neonates has not yet been established because of transduction of non-target tissue. In this study, to exploit
a safe and clinically applicable protocol, we constructed a new self-complementary type 8 AAV (scAAV8) vector harboring
the muscle creatine kinase (MCK) promoter to express TNALP-D10 and examined the feasibility of muscle transduction for
HPP gene therapy.
[METHODS]
The scAAV8-MCK-TNALP-D10 was intravenously injected into the newborn Akp2 -/- mice (n=10) at 2.5×1012 v.g./body.
Clinical phenotypes, plasma ALP activity, X-ray images, micro CT and pathology of the treated mice were analyzed.
[RESULTS and DISCUSSION]
The plasma ALP activity was elevated and sustained at therapeutic level (>1.0 unit/ml) for at least 3 months in the scAAV8-
MCK-TNALP-D10-treated mice. The treated Akp2 -/- mice grew well and survived over 3 months with healthy appearance
(9/10), while untreated Akp2 -/- mice died within 3 weeks (n=10; p<0.001 ). Improved mineralization of the knee joints
Poster Session
was demonstrated by X-ray images and micro CT analysis. These results suggest that rAAV-mediated muscle TNALP-D10
transduction strategy would be promising to treat the severe infantile form of HPP.
Wed(4)-P-120
Dual-vector suicide gene therapy using retroviral replicating vectors derived from amphotropic murine
leukemia virus and gibbon ape leukemia virus
Shuji Kubo 1 ，Yuki Mawatari-Furukawa 1 ，Misato Takagi-Kimura 1 ，Christopher R Logg 2 ，Noriyuki Kasahara 2,3,4
1:Genetics, Hyogo College of Medicine, Japan、2:Medicine, David Geffen School of Medicine, University of California, Los Angeles、3:Medical
& Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles、4:Cell Biology and Pathology, Miller
School of Medicine, University of Miami
Retroviral replicating vectors (RRVs) have been shown to achieve efficient tumor transduction and enhanced therapeutic
benefit in a wide variety of cancer models. Here we evaluated two different RRVs derived from amphotropic murine leukemia
virus (AMLV) and gibbon ape leukemia virus (GALV), encoding two different suicide genes, the yeast cytosine deaminase
(CD) and HSV thymidine kinase (TK) in Hep3B human hepatocellular carcinoma cells.
Both RRVs expressing GFP gene (AMLV-GFP and GALV-GFP) efficiently replicated in Hep3B cells and spread in culture.
Additionally, AMLV-GFP can spread in GALV-mCherry pretransduced Hep3B cells but not in AMLV-mCherry pretransduced
cells. Similarly, GALV-GFP can spread in AMLV-mCherry pretransduced cells but not in GALV-mCherry pretransduced cells.
Notably, however, replication and spread of either RRV in culture was not affected by pretransduction with the counterpart
RRV encoated with the other envelope.
In order to investigate the effect of combined prodrug-dependent cell killing vs. multiple vector copy transduction in vitro,
Hep3B cells were transduced with the AMLV-CD, GALV-CD, AMLV-TK, GALV-TK, respectively or in combination. The
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resultant cells were used to evaluate the cytotoxic effect of RRV-mediated suicide gene therapy with CD and TK in the
presence of their respective prodrugs, 5-fluorocytosine and Ganciclovir. In vitro cytocidal effects obtained by combining
different suicide genes were significantly greater than when the same suicide genes were delivered with two different vectors.
These data indicate the potential utility of dual-vector suicide gene therapy using two different RRVs carrying different suicide
genes.
Wed(4)-P-121
ER-Golgi transport may serve as a novel drug target for Pelizaeus-Merzbacher disease caused by PLP1
amino acid substitutions
Ken Inoue 1 ，Heng Li 1 ，Priyanthi R Mangalika 1 ，Ayako Nishizawa 1 ，Yurika Numata 1 ，Shoko Nakamura 1 ，
Toshifumi Morimura 1 ，Hideyuki Saya 2 ，Yu-ichi Goto 1
1:Dept. of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry,
Japan、2:Div Gene Regulation, Inst Advanced Medical Research, Keio Univ, Tokyo, Japan
Pelizaeus-Merzbacher disease (PMD) is the most common, but incurable inherited hypomyelinating leukodystrophy caused by
various mutations in the PLP1 gene, which encodes a major myelin membrane lipidprotein. PLP1 amino acid substitutions
often cause severe form of PMD. It has been proposed that activation of the apoptotic pathway of unfolded protein response
(UPR) triggered by an accumulation of the mutant PLP1 in endoplasmic reticulum (ER) is the major cellular mechanism
for oligodendrocyte cell death. However, attenuation of this pathway doesn’t rescue the cellular phenotypes, suggesting
an involvement of other disease mechanisms. We recently identified that mutant PLP1 carrying A243V alteration reduces
Poster Session
the intracellular transport of both secretary and membrane proteins from ER to Golgi apparatus, leading to accumulation
of these proteins in ER. These findings has led us to hypothesize that the mutant PLP1-induced dysfunction of ER-Golgi
transport possibly affects the cellular homeositasis and the ER-Golgi transport may serve as novel cellular pathological
mechanism for PMD. We also hypothesized that the drug-based correction of the deficient ER-Golgi transport may rescue
the cellular phenotype caused by mutant PLP1. To identify such drugs, we have screened a library of 1400 existing medicine,
so that our findings are immediately applicable to the clinical study, using a screening system with HeLa cells transiently
co-expressing mutant PLP1 and secretable renilla luciferase reporter. We selected 20 compounds that can also rescue the
abnormal intracellular localization of KDEL receptor that is normally present in Golgi apparatus but is mislocalized in ER
when co-expressed with mutant PLP1. Altogether, ER-Golgi transport may serve as a novel drug target for PMD and these
compounds may serve as candidate drugs.
Wed(4)-P-122
Improved transduction of canine X-linked muscular dystrophy with rAAV9-microdystrophin by MSCs
pre-treatment
Hiromi Hayashita-Kinoh 1,2 ，Yuko Nitahara-Kasahara 1,2 ，Hironori Okada 1,2
，Kiwamu Imagawa 3 ，
Katsuhiko Tachibana 3 ，Shin’ichi Takeda 2 ，Takashi Okada 1
1:Department of Biochemistry and Molecular Biology, Nippon Medical School, Japan、2:Department of Molecular Therapy, National
Institute of Neuroscience, NCNP、3:JCR Pharmaceuticals Co., Ltd.,
Background: Duchenne muscular dystrophy (DMD) is a congenital disease causing progressive deterioration of skeletal and
cardiac muscular dystrophy because of mutations in the dystrophin gene. Supplementation of dystrophin using rAAV is
effective to improve pathogenesis of animal models of DMD. However, we previously reported that local injection of rAAV2 or
rAAV8 into canine skeletal muscles resulted in insufficient transgene expression with potent immune responses. Mesenchymal
stem cells (MSCs) regulate various inflammatory diseases including GVHD by virtue of their immunosuppressive effects.
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Methods: Bone marrow-derived MSCs and rAAV9-Luciferase or rAAV9-µDys were intravenously injected into the normal
or CXMDJ dog at 8 weeks old. Seven days after injection, MSCs were systemically injected again. At 8 days after 1st
injection, rAAV9-Luciferase or rAAV9-µDys was intramuscularly or intravenously injected into the same dog. To examine the
immune response against rAAV, purified canine peripheral leukocytes were exposed to rAAV9, and then IFN γ expression
was analyzed using qRT-PCR. Skeletal muscles of the rAAV injected animals were sampled by biopsy for expression analysis
at 4 weeks after injection.
Results: Administration of rAAV following MSCs treatment resulted in higher expression of transgene at the injected muscle,
compared to the rAAV transduction alone. Expression of IFN γ in the purified peripheral blood leukocytes after the rAAV
exposure were not enhanced in the rAAV with MSCs, suggesting the immune suppressive effects of the MSCs.
Conclusion: Our results demonstrate that rAAV injection with MSCs pre-treatment improved expression of rAAV- derived
transgene in dogs. This strategy would be effective approach to analyze the expression and function of transgene in vivo.
These findings also support the future feasibilities of rAAV mediated protein supplementation strategies.
Wed(4)-P-123
Development of a safeguard system for an ideal gene- and cell- therapy vector
Shinya Komoto 1 ，Narumi Uno 2,3 ，Katsuhiro Uno 3 ，Teruhiko Suzuki 4 ，Masaharu Hiratuka 1 ，Mituhiko Osaki 5 ，
Yasuhiro Kazuki 1,2,3 ，Mituo Oshimura 2
Poster Session
1:Molecular and Cellular Biology, Tottori University, Japan、2:Chromosome Engineering Research Center, Tottori University、3:Department
of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University、4:Stem
Cell Project, Tokyo Metropolitan Institute of Medical Science、5:Division of Pathological Biochemistry, Faculty of Medicine, Tottori
University
Human artificial chromosome (HAC) vector and mouse artificial chromosomes (MAC) vector exhibit several useful charac-
teristics, e.g.; stable and independent maintenance from chromosomes in host cells, and the insertion of large genome region
including its regulatory region. Thus, HAC/MAC is expected as an ideal gene delivery vector for gene- and cell-therapy. On
the other hand, for cell therapy, there is a risk of malignant tumor formation derived from transplanted cells. Therefore, a
safeguard system is required for the suppression of such malignant tumor formation towards the ideal regenerative medicine.
However, the conventional safeguard systems require the viral or plasmid transduction disrupting the host chromosomes, and
the prodrugs for the suicide genes. In this study, for the proof-of-concept to show a safeguard system without genomic disrup-
tion and automatically tumor suppression without prodrug, we used a MAC vector harboring a safeguard system (TS-MAC).
The TS-MAC contained an MHC H2-K(d) expression cassette promoted by the hTERT promoter for the specific expression
in tumor cells. The TS-MAC was transferred to C57BL/6-derived melanoma (B16F10) cells with MHC H2-K(b). In order
to evaluate the function of the TS-MAC, subcutaneous implantations were performed using B16F10 cells with/without the
TS-MAC and with empty MAC vector. B16F10 cells without the TS-MAC and with the empty MAC showed a high tumori-
genicity. When B16F10 cells with the TS-MAC transplanted into C57BL/6, the tumor volume was relatively decreased. In
order to enhance the anti-tumor activity, the acquired immunity against MHC H2-K(d) was been activated via immuniza-
tion. Then, the tumor volume of transplanted B16F10 cells with the TS-MAC was significantly reduced comparing to the
no-immunized condition.
These results proved that the safeguard system can suppress the tumor formation of the transplanted cells by the immunity
without disruption of host chromosomes and using prodrug.
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Wed(4)-P-124
CORRELATION LEVELS OF ACTIVITIES OF DAILY LIVING AND DISACCHARIDE CONCENTRA-
TIONS IN MUCOPOLYSACCHARIDOSES
1,5
Adriana M Montano ，Katherine E. Foerster 1 ，Qi Gan 1 ，Mary Campbell 2 ，Shunji Tomatsu 3 ，Tadao Orii 4 ，
Yasuyuki Suzuki 4
1:Pediatrics, Saint Louis University, USA、2:CWHM, Saint Louis University、3:Alfred I Dupont Children Hospital、4:Gifu University、
5:Biochemistry and Molecular Biology, Saint Louis University
Mucopolysaccharidoses (MPS) are inherited lysosomal storage disorders. Patients are deficient in lysosomal enzymes that
degrade glycosaminoglycans (GAGs) including chondroitin sulfate (CS), heparan sulfate (HS), keratan sulfate (KS), dermatan
sulfate (DS), and hyaluronan. Accumulation of GAGs in lysosomes leads to cell, tissue, and organ dysfunction. Therapeutic
options, including Enzyme Replacement Therapy (ERT) and Hematopoietic Stem Cell Transplant (HSCT), are available.
Symptoms may be evaluated based on how they impact Activities of Daily Living (ADLs), self-care activities that are
completed daily and measure quality of life. Here we describe an analysis of ADL scores, treatment, and disaccharide levels
for 62 MPS patients. ADL scores were categorized into domains of Movement, Movement+Cognitive Performance, and
Cognitive Performance and were determined by a 12-item questionnaire completed by patients or guardians. Dried blood
spots of 62 de-identified MPS patients were digested with chondroitinase B, heparitinase and keratanase II, and analyzed
using a LC-MS/MS at Saint Louis University. Concentrations of HS subtypes and KS were determined for each patient.
Student’s t-test was used to compare mean ADL scores and mean disaccharide concentrations among age-divided treatment
groups. Linear regression analysis was used to compare ADL scores to disaccharide concentrations among age groups. We
found that ERT-treated patients had higher ADL scores than untreated patients. HSCT-treated patients had higher ADL
Poster Session
scores than untreated patients in certain ADL categories and age groups. ERT-treated and HSCT-treated patients had lower
disaccharide concentrations than untreated patients. Although limited by the small number of MPS patients, relationships are
seen between treatment type and ADL score, treatment type and disaccharide concentration, and ADL score and disaccharide
concentration.
Wed(4)-P-125
Exacerbation in the IL-10 deficient dystrophic mice and an anti-inflammatory strategy with mesenchymal
stromal cells
Yuko N Kasahara 1,2 ，Hiromi H Kinoh 1,2
，Nana Tsumita 2 ，Chiaki Masuda 1 ，Hironori Okada 1,2
，Shin’ichi Takeda 2 ，
Takashi Okada 1,2
1:Biochemistry and Molecular Biology, Nippon Medical School, Japan、2:Molecular Therapy, National Institute of Neuroscience, NCNP
Duchenne muscular dystrophy (DMD) is a severe X-linked muscle disease in which mutations in the gene encoding the
cytoskeletal protein, dystrophin. Inflammation is a key pathological characteristic of dystrophic muscle lesion formation,
although its role and regulation in the disease time course has not yet been examined. In the present study, we generated
IL-10 -/- /mdx mice lacking both dystrophin and the anti-inflammatory cytokine, interleukin-10 (IL-10) and characterized
the mice as a dystrophic model with chronic inflammation and severe cardiorespiratory dysfunction. Our result suggests
that a predisposition to inflammation is an important indicator of DMD disease progression. Therefore, we focused on cell
therapeutic approach using multipotent mesenchymal stromal cells (MSCs) because of their ability to differentiate into various
cell types with immunosuppressive properties. We also revealed that increased IL-10 production in MSCs improved the limited
survival of the transplanted MSCs. IL-10 transduction of sMSCs might enhance the immunosuppressive function of MSCs.
The development of anti-inflammatory strategies to use IL-10-producing MSCs would retard the disease progression of DMD.
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Wed(4)-P-126
Lentiviral Vector and Zinc Finger Nucrease System mediated Gene Therapy for Krabbe disease
Hiroshi Kobayashi 1,4 ，Yohta Shimada 1 ，Takashi Higuchi 1 ，Sayoko Izuka 1 ，Takeo Iwamoto 2 ，Takahiro Fukuda 3 ，
Masamichi Ariga 1,4 ，Yoshikatsu Eto 1,4,5 ，Hiroyuki Ida 1,4 ，Toya Ohashi 1,4
1:Research Center for Medical Sciences, The Jikei University School of Medicine, Japan、2:Division of Biochemistry, Research Core Facilities,
The Jikei University School of Medicine、3:Department of Neuropathol., Dept. of Neurosci., Res.Ctr.Med.Sci., The Jikei University School
of Medicine、4:Department of Pediatrics, The Jikei University School of Medicine、5:Advanced Clinical Research Center, Institute of
Neurological Disorders
Krabbe disease is classified in Lysosomal Storage diseases, characterized by rapid progressive neurodegeneration due to
genetic deficiency of b-galactocerebrosidase (GALC), results in the degeneration of myelin-forming cells (oligodendrocytes
and Schwann cells) caused by an accumulation of galactosylsphingosine (psychosine), toxic for central and peripheral nervous
system.
We constructed the recombinant lentivirus vector to transduce the cells with the normal GALC cDNA, using a minimal HIV-
1 backbone with the addition of minimal RRE sequence, and tried gene therapy for newborn model mouse by intravenous
injection (in vivo). We detected efficient reduction of psycosine accumulation in the brain (p=0.009), improvement of sciatic
nerve pathology, and delay of the onset (p=0.0193) in the gene therapy group comparing to the disease control group. And
in combination with L-cycloserine, reductase of the production of brain cerebrosides as the substrate, we have succeeded in
efficient improvement of life span (p=0.013).
And for the trial of safer gene therapy using homologous recombination, we tried the experiment model of gene editing
Poster Session
mediated by Zinc Finger Nucrease (ZFN) system for Krabbe disease. We designed the homology arm of the donor plasmid
including the sequence of point mutation. After co-transfection of ZFN, the donor plasmid, and Schwann cell line origin from
model mouse by electroporation, we detected the efficient GALC expression in the cell line (p=0.021). The result suggests
gene editing method as ZFN system should be applicable for the ‘safe and site specific’ exo vivo gene therapy for Lysosomal
Storage Diseases as Krabbe disease.
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Wed(4)-P-127
J-RARE: patient registry for the better life of rare and intractable diseases’ patients
Soichi Ogishima 1,2 ，Kunihiro Nishimura 2,3
，Masatoshi Iwasaki 2 ，Shun Emoto 2,4
，Yukiko Nishimura 2,4
，
J-RARE patient organizations
1:Tohoku Medical Megabank Organization, Tohoku University, Japan、2:ASrid、3:Graduate School of Information Science and Technology,
University of Tokyo、4:Japan Patients Association
J-RARE is a patient registry and personal health record service for rare and intractable diseases’ patients, which has been
started in September 2013. J-RARE has been developed and maintained by patient groups in cooperation with JPA (Japan
Patients Association) and ASrid. It has been financially supported by Health and Labor Sciences Research Grant funded by
MHLW (Ministry of Health, Labor and Welfare of Japan). Aim of J-RARE is both patients-centered management of their own
PHRs to clarify their natural history, and coordination of stakeholders who participate in studies both to reveal mechanism of
pathogenesis and to develop drug for rare and intractable diseases. Target diseases of J-RARE are distal myopathy, replacing
polychondritis, Russell-Silver syndrome, and Marfan syndrome. Type of Inputted data is (1) daily life data, (2) questionnaire
data, (3) hospital record data transcribed by patients, and (4) patient history data. By using J-RARE, patients, of course,
physicians compare their own data, and could know common (in some cases, unknown) symptoms and natural histories.
Pharma and university could efficiently start their clinical trials with enough number of patients with physicians. Japanese
government plans to develop and maintain national database (registry) of rare and intractable (called “NANBYO”) patients,
and J-RARE plans to work together with national database (registry) .
Poster Session
Wed(4)-P-128
Androgens & Antioxidants Management Facing Controversy &/or Unavailability of Hematopoietic Stem
Cell Transplantation: Clinical & Hematologic Response in Fanconi Anemia Egyptian Patients
Aya Tarek 1 ，Ghada Yousef El-Kamah 1 ，Maha Eid 1
Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome characterized by hypersensitivity to
clastogenic agents particularly diepoxybutane (DEB) and cancer predisposition. Oxidative stress plays a major role in
the pathogenesis of leukemia-prone diseases such as FA. Recently there is controversy concerning hematopoietic stem cell
transplantation (HSCT) in abolishing the threat of malignancies, which with progressive bone marrow failure are the cause of
mortality in FA. Aim: Evaluating clinical & hematological response to androgens and antioxidant therapy as an alternative
when HSCT is not available. Subjects and Methods: 45 cases descending from unrelated consanguineous pedigrees were
included in the study and confirmed through DEB hypersensitivity. DNA micronuclear damage, among other parameters,
were measured as an indicator to FA patients’ stress condition. Patients were kept on androgens, prednisone and Vitamins
A, E, and C according to the recommended daily allowance. Clinical and hematological follow-up were conducted for all
patients over a period of one & half year with 3 monthly reevaluation schemes. Results: The median age at onset was 7 years
(4m-10.5 years). Average Hb (7.6 g/dl), RBC (2.6x1012 /L), WBC (3.7 x109 /L) and platelet count (53x103 /uL). 20% had low
birth weight, 90% café au lait spots, 38% radial reduction, renal disease in 4 cases & other skeletal affection in 78%. DEB
showed wide range of break/cell (3.4-12.5), with mean 6.0. Elevated levels of oxidative stress and DNA damage were detected.
Hematological parameters improved in response to androgen therapy, mostly WBCs by 40%, followed by hemoglobin (9%)
and lastly platelets by only 5%. Oxidative stress parameters and DNA damage improved after antioxidant administration.
Conclusion: Androgen therapy improved the hematological condition of patients. Early administration of antioxidants in FA
slows disease course, ameliorate symptoms and improve general health.
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Wed(4)-P-129
AAV8-mediated Expression of N-acetylglucosamine-1-phosphate Transferase Attenuates Bone Loss in a
Mouse Model of Mucolipidosis II
Young Bae Sohn 1 ，Ah-Ra Ko 2 ，Su Jin Kim 3 ，Sung Won Park 4 ，Malgorzata Przybylska 5 ，Nelson S. Yew 5 ，
Seng H. Cheng 5 ，Jung-Sun Kim 6 ，Sung Yoon Cho 7 ，Dong-Kyu Jin 7
1:Medical Genetics, Ajou University Hospital, Korea, South、2:Clinical Research Center, Samsung Biomedical Research Center、3:De-
partment of Pediatrics, Myongji Hospital、4:Cheil General Hospital and Woman’s Health Care Center、5:Genzyme, a Sanofi Company、
6:Department of Pathology, Samsung Medical Center、7:Department of Pediatrics, Samsung Medical Center
Mucolipidoses II and III (ML II and ML III) are lysosomal disorders in which the mannose 6-phosphate recognition marker is
absent from lysosomal hydrolases and other glycoproteins due to mutations in GNPTAB, which encodes two of three subunits
of the heterohexameric enzyme, N -acetylglucosamine-1-phosphotransferase. Both disorders are caused by the same gene,
but ML II represents the more severe phenotype. Bone manifestations of ML II include hip dysplasia, scoliosis, rickets and
osteogenesis imperfecta.
In this study, we seeked to determine whether a recombinant adeno-associated viral vector (AAV2/8-GNPTAB) could confer
high and prolonged gene expression of GNPTAB and thereby influence the pathology in the cartilage and bone tissue of a
GNPTAB KO mouse model. The results demonstrated significant increases in bone mineral density and content in AAV2/8-
GNPTAB-treated as compared to non-treated KO mice. We also showed that IL-6 expression in articular cartilage was
reduced in AAV2/8-GNPTAB treated ML II mice. Together, these data suggest that AAV-mediated expression of GNPTAB
in ML II mice can attenuate bone loss via inhibition of IL-6 production. This study emphasizes the value of the MLII KO
mouse to recapitulate the clinical manifestations of the disease and highlights their amenability to therapy.
Poster Session
Wed(4)-P-130
Clinical features, molecular analysis and outcome of ERT in Korean patients with Mucopolysaccharidosis
type VI
Eun Kyung Cho 1 ，Khunton Wichajarn 2 ，A Ram Yang 1 ，Jinsup Kim 1 ，Young Bae Sohn 3 ，Su Jin Kim 4 ，
Sung Won Park 5 ，Sung Yoon Cho 1 ，Beom Hee Lee 6 ，Jin-Ho Choi 6 ，Han-Wook Yoo 6 ，Dong Hwan Lee 7 ，
Dong-Kyu Jin 1
1:Department of Pediatrics, Samsung Medical Center, Korea, South、2:Division of Medical Genetics, Department of Pediatrics, Faculty
of Medicine, Khon Kaen University、3:Department of Medical Genetics, Ajou University School of Medicine、4:Department of Pediatrics,
Myongji Hospital, Seonam University College of Medicine、5:Department of Pediatrics, Jeil Hospital, Dankook University College of
Medicine、6:Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine、7:Department of
Pediatrics, College of Medicine, Soonchunhyang University
Mucopolysaccharidosis type VI (MPS VI) is a rare disease caused by the mutation of ARSB with prevalence range from
1/5,000 in northeast Brazil to 1/2,057,529 births in Czech Republic. In Asia, there is only one published data in Taiwan
about 1/833,000 births. The exact prevalence in Korean population is unknown but we estimated the incidence of MPS VI
is about 0.03/100,000 live births. Enzyme replacement therapy (ERT) with recombinant human Arylsulfatase B (rhASB) is
a modality for treatment of MPS VI that increase excretion of urine glycosaminoglycan (GAG) and improve joint motion,
pulmonary function and endurance.
We presented clinical features, molecular analysis and outcome of ERT in 3 Korean MPS VI patients. All patients had the
typical characteristic clinical features of MPS IV. Short stature, dysostosis multiplex, corneal opacity and valvular heart
diseases was found at first presentation, while restrictive lung disease and carpal tunnel syndrome developed later in all pa-
tients. Molecular analysis demonstrated novel missense and nonsense mutation in Korean including, p.Ile67Ser, p.Gly328Arg,
p.Arg191*, p.Asp352Asn and p.Gly17Asp. After ERT, urine GAG was decrease in all patients. Skeletal involvement, corneal
opacity, heart valve abnormalities and pulmonary function were not improved with ERT but it had better outcome on joint
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ICHG2016 1221
motion and endurance. One patient had allogenic bone marrow transplantation (BMT) prior ERT but clinical response was
not quite improved after BMT. This study would demonstrate clinical phenotypes and molecular analysis of severe form MPS
VI Korean patients.
Poster Session
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Poster Session
Psychiatric Genetics, Neurogenetics and Neurodegeneration
Wed(4)-P-131
Polygenic Risk Score, Parental Socioeconomic Status, Family History of Psychiatric Disorders, and the
Risk for Schizophrenia
Esben Agerbo 1,4,6 ，Patrick F Sullivan 2 ，Bjarni J Vilhalmsson 3 ，Carsten B Pedersen 1,4,6 ，Ole Mors 5 ，
Anders D Børglum 7 ，David Hougaard 8 ，Mads V Hollegaard 8 ，Sandra Meier 4,6 ，Manuel Mattheisen 7 ，
Stephan Ripke 9,10 ，Naomi Wray 11 ，Preben B Mortensen 1,4,6
1:Aarhus University, Centre for Integrated Register-Based Research and National Centre for Register-Based Research, Denmark、
2:Department of Genetics, University of North Carolina at Chapel Hill, NC, USA、3:BIRC-Bioinformatic Research Centre, Aarhus
University, Aarhus, Denmark、4:Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark、5:Department P,
Aarhus University Hospital, Risskov, Denmark、6:National Centre for Register-Based Research, Aarhus University, Denmark、7:Department
of Biomedicine and Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark、8:Danish Center for Neonatal Screening,
Statens Serum Institut, Copenhagen, Denmark、9:Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston,
MA, USA、10:Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA、11:The Queensland
Brain Institute, The University of Queensland, St Lucia, Australia
OBJECTIVE
To estimate (1) how strongly the risk for schizophrenia relates to the effects of the polygenic risk score, parental socioeconomic
Poster Session
status, and family history of psychiatric disorders; (2) the fraction of cases that could be prevented if no one was exposed;
(3) whether family background interacts with the genetic liability so that subgroups are particularly risk prone; and (4) to
what extent a proband’s genetic makeup mediates the risk associated with familial background.
METHODS
We conducted a population-based case-control study consisting of 866 patients with schizophrenia between January 1, 1994,
and December 31, 2006, and 871 matched controls. Genome-wide data and family psychiatric and socioeconomic background
information were obtained from neonatal biobanks and national registers. Results from a separate meta-analysis (34600 cases
and 45968 control) were applied to calculate polygenic risk scores. Polygenic risk scores, parental socioeconomic status, and
family psychiatric history. Odds ratios (OR), attributable risks, liability R2 values, and proportions mediated were estimated
RESULTS
Schizophrenia was associated with the polygenic risk score (OR, 8.01; 95%CI, 4.53-14.16), socioeconomic status (8.10 (3.24-
20.3)), and history of psychoses (4.18 (2.57-6.79)). The R2 values were 3.4%(2.1-4.6) for the polygenic risk score, 3.1%(1.9-4.3)
for parental socioeconomic status, and 3.4%(2.1-4.6) for family history. Socioeconomic status and psychiatric history accounted
for 45.8% (36.1-55.5) and 25.8% (21.2-30.5) of cases. There was an interaction between the polygenic score and family history
(P = .03). A total of 17.4%(9.1-26.6) of the effect associated with family history was mediated through the polygenic risk
score.
CONCLUSIONS
Schizophrenia was associated with the polygenic score, family psychiatric history, and socioeconomic status. Our study
demonstrated that family history of psychoses is partly mediated through the individual’s genetic liability
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ICHG2016 1223
Wed(4)-P-132
Clinical phenotype-genotype correlation of Alexander disease with GFAP mutation: Analysis of 34
Japanese cases
Tomokatsu Yoshida 1 ，Ikuko Mizuta 1 ，Rei Yasuda 1 ，Kozo Saito 1 ，Mao Mukai 1 ，Masanori Nakagawa 2 ，
Toshiki Mizuno 1
1:Neurology, Kyoto Prefectural University of Medicine, Japan、2:Neurology, North Medical Center, Kyoto Prefectural University of Medicine
Alexander disease (AxD) is a rare neurodegenerative disorder, exhibiting the pathological characteristics of the formation of
cytoplasmic inclusions in astrocytes called Rosenthal fibers and white matter degeneration. The genetic mutation of glial
fibrillary acidic protein (GFAP) is observed in approximately 97% of cases. Here, we describe the clinical phenotype-genotype
correlations of 34 cases of AxD with GFAP mutation, including 3 cases of cerebral AxD (type 1), 20 of bulbo-spinal AxD
(type 2), and 11 of the intermediate form (type 3). The patients with type 1 had an infantile onset with the presence of
one or more seizures, psychomotor developmental retardation, and macrocephaly, and showed abnormalities in the superior
frontal cerebral white matter observed on brain MRI. The patients with type 2 had an adult onset with the presence of one
or more of muscle weakness, hyperreflexia, and bulbar symptoms, and showed signal abnormalities and/or atrophy observed
on MRI of the medulla oblongata and upper cervical spinal cord. The patients with type 3 had the characteristics of both
types 1 and 2. Twenty-one kinds of point mutation and two kinds of insertion of one or two amino acids were identified in the
GFAP-coding region. Six kinds of GFAP mutation were detected in two or more patients, including two cases of R88C, two
of M74T, three of R79H, two of Y242N, five of N386S, and three of R416W. Although the age at disease onset of all patients
with N386S was over 50, four of them showed type 2 and one showed type 3. It was the same as R79H, which showed two of
type 3 and one of type 2, and Y242N, which showed one of type 2 and one of type 3. The phenotypes of R88C and R416W
Poster Session
were types 1 and 3, respectively. However, different types have been reported in each of the genotypes. While there is no
doubt that GFAP mutation is a cause of AxD, modifying factors may exist that regulate disease onset and severity.
Wed(4)-P-133
Detection of CYP2D6 polymorphism using Luminex xTAG technology in Autism spectrum disorder:
CYP2D6 activity score and its association with risperidone levels
Natchaya Vanwong 1 ，Apichaya Puangpetch 1,2 ，Yaowaluck Hongkaew 1,2 ，Chonlaphat Sukasem 1,2 ，
Montri Chamnanphon 1,2 ，Nopadol Nuntamool 1,2,4 ，Nattawat Ngamsamut 3 ，Ananya Sinrachatanan 3 ，
Penkhae Limsila 3
1:Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol
University, Bangkok, Thailand, Mahidol University, Thailand、2:Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical
Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand、3:Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital,
Department of Mental Health Services, Ministry of Public Health, Thailand、4:Molecular Medicine, Faculty of Science, Mahidol University,
Bangkok, Thailand
The objective of this study was to apply the Luminex xTAG technology to detect significant CYP2D6 polymorphisms and copy
number variation, including assessment the relationship of CYP2D6 polymorphisms and risperidone plasma concentration
in autism spectrum disorder children (ASD) treated with risperidone. All 84 ASD patients included in this study had been
receiving risperidone at least for 1 month. The CYP2D6 genotypes were determined by luminex assay. Plasma concentrations
of risperidone and 9-hydroxyrisperidone were measured using LC/MS/MS. Among the 84 patients, the most common genotype
was CYP2D6*1/*10 (26.19%). The most common allele was CYP2D6*10 (51.79%) and the second most allele was CYP2D6*1
(27.98%). There were 46 (55.42%) classified as EM, 33 (39.76%) as IM, and 4(4.82%) as UM. The plasma concentration of
risperidone and risperidone/9-OH-risperidone ratio in the patients with were significant differences among the CYP2D6
predicted phenotype group (P=0.001 and P<0.0001 respectively). Moreover, the plasma concentration of risperidone and
risperidone/9-OH-risperidone ratio in the patients with CYP2D6 activity score 0.5 were significantly higher than those with
the CYP2D6 activity score 2.0 (P=0.004 and P=0.002 respectively). In conclusion, the present study suggest that it would
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ICHG2016 1224
be ideal to identify the CYP2D6 genotype of patients before prescribing and administering risperidone. It is a possibility
that the use of Luminex xTAG technology for detection of CYP2D6 polymorphisms could help us more accurately identify
an individual’s phenotype than Taqman assay. Furthermore, the use of CYP2D6 gene scoring system to determine an
individual’s metabolic capacity may become an essential tool for a more rational and safer drug administration. It could
help clinicians to provide better treatment for every Thai child with ASD and reduce adverse reactions or therapeutic failure.
Wed(4)-P-134
A polymorphism in CRAT is associated with HLA-DQB1*06:02 negative essential hypersomnia
Taku Miyagawa 1,2 ，Seik Soon Khor 2 ，Hiromi Toyoda 2 ，Hiroto Kojima 3 ，Takaomi Futagami 3 ，Maria Yamasaki 2 ，
Hiroh Saji 3 ，Kazuo Mishima 4 ，Yutaka Honda 5 ，Makoto Honda 1,5 ，Katsushi Tokunaga 2
1:Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Japan、
2:Department of Human Genetics, Graduate School of Medicine, The University of Tokyo、3:HLA Foundation Laboratory、4:Department
of Psychophysiology, National Institute of Mental Health, National Center of Neurology and Psychiatry、5:Japan Somnology Center,
Neuropsychiatric Research Institute
Essential hypersomnia (EHS) is a lifelong sleep disorder characterized by excessive daytime sleepiness but no cataplexy,
can be divided into two broad classes based on the presence or absence of HLA (human leukocyte antigen)-DQB1*06:02 .
HLA-DQB1*06:02 positive EHS and narcolepsy with cataplexy are associated with the same susceptibility genes. However,
there are fewer studies of HLA-DQB1*06:02 negative EHS. We hypothesized that HLA-DQB1*06:02 negative EHS has a
different etiological pathway from that of narcolepsy with cataplexy and HLA-DQB1*06:02 positive EHS. Therefore, in order
to identify susceptibility genes associated with HLA-DQB1*06:02 negative EHS, we performed a genome-wide association
Poster Session
study of 476,446 SNPs in 119 Japanese patients with HLA-DQB1*06:02 negative EHS and 1,582 Japanese healthy individuals.
A replication study was also conducted on 191 Japanese patients with HLA-DQB1*06:02 negative EHS and 433 Japanese
healthy individuals. SNP rs10988217 located in CRAT (carnitine acetyltransferase) was found to be significantly associated
with HLA-DQB1*06:02 negative EHS (P < 5×10-8 , odds ratio = 2.8). An eQTL analysis showed that SNP rs10988217
was significantly correlated with expression levels of CRAT in various tissue or cell types, including brain tissue (P < 0.05).
CRAT gene encodes the carnitine acetyltransferase protein, which is a key enzyme for metabolic pathways involved with the
control of the acyl-CoA/CoA ratio in mitochondria, peroxisomes and endoplasmic reticulum. In addition, The Metabolomics
GWAS Server (Shin SY et al., Nat Genet. doi: 10.1038/ng.2982.) showed that SNP rs10988217 affected succinylcarnitine
levels in blood (P < 10-17 ). The results suggest that HLA-DQB1*06:02 negative EHS may have an underlying dysfunction
in fatty acid oxidation pathway.
Wed(4)-P-135
Copy number variations in pediatric obsessive-compulsive disorder: First high-resolution chromosomal
microarray analysis
Beatrice Oneda 1 ，Edna Gruenblatt 2,3,4 ，Juliane Ball 2 ，Julia Geissler 6 ，Regina Reissmann 1 ，Marcel Romanos 6 ，
Anita Rauch Rauch 1 ，Susanne Walitza 2,3,5
1:Institute of Medical Genetics, University of Zurich, Switzerland、2:University Clinic of Child and Adolescent Psychiatry, University of
Zurich、3:Neuroscience Center Zurich, University of Zurich and ETH Zurich、4:Department of Psychiatry, Psychosomatic and Psychotherapy,
University Hospital of Würzburg, Würzburg, Germany、5:Zurich Center for Integrative Human Physiology, University of Zurich、6:Center
of Mental Health, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg
Large (>500 kb) copy number variations (CNVs) have recently been reported in obsessive-compulsive disorder (OCD), with
a particularly higher burden of large deletions, which have been associated with other neurodevelopmental disorders, too.
Nevertheless, recent findings pointed to the importance of rare CNVs of smaller size in the ethiopathology of OCD. We
performed the first high-resolution chromosomal microarray analysis in 121 pediatric early onset OCD (EO-OCD) patients
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ICHG2016 1225
and in 124 random controls, focusing on rare and small (<500 kb) CNVs. Although the frequencies of rare CNVs in EO-OCD
patients did not differ significantly from the controls, a focused analysis of the CNVs encompassing brain related genes revealed
a significantly higher frequency of deletions in patients with EO-OCD (p=0.040, OR=3.303 overall. p=0.025, OR=3.733 in
the comorbid tics subgroup). Pathway analysis of the genes present in those CNVs showed specific gene-clusters involved in
synaptic/brain related functional pathways. No such clusters were found in the control group.
In 26 patients (89.7%), the CNV was inherited. E.g. two boys had a maternally inherited hemizygous deletion on the
X chromosome affecting the genes UBE2NL and MTMR8 , previously reported to be associated with X-linked neurological
disorders. In two additional patients with comorbid tics we detected de novo CNVs encompassing genes (NRXN1, ANKS1B,
UHRF1BP1 ) associated with different neurodevelopmental disorders. The frequency of de novo aberrations observed is higher
than what has previously been reported for large CNVs in OCD (1.44%). In summary, our results underline the role of rare
small CNVs, particularly deletions, as susceptibility factors for EO-OCD.
Wed(4)-P-136
A selective detection of lysophosphatidylcholine in dried blood spot for diagnosis of adrenoleukodystrophy
by LC-MS/MS
Ryuichi Mashima 1 ，Misa Tanaka 1 ，Eri Sakai 1 ，Tadayuki Kumagai 1 ，Motomichi Kosuga 2 ，Torayuki Okuyama 1
1:Department of Clinical Laboratory Medicine, National Center for Child Health and Development, Japan、2:Division of Medical Genetics,
National Center for Child Health and Development
Poster Session
Adrenoleukodystrophy (ALD) is a common metabolic disorder characterized by an impaired beta-oxidation of very long-chain
fatty acids (VLCFAs) in peroxisomes. Thus, it is widely observed the accumulation of them, particularly hexacosanoate
(C26:0), in the blood as well as all tissues. Earlier studies reported the accumulation of total C26:0 in the extracts of lipids as
a measure of ALD, however, the level of total C26:0 could also be affected by other factors such as dietary intake, suggesting
that a more selective biomarker for ALD needs to be explored. Recent studies have suggested that 1-hexacosanoyl-2-hydroxy-
sn-glycero-3-phosphocholine (Lyso-PC 26:0) could be such a promising candidate for this disease. Thus, we investigated a
diagnostic procedure to determine Lyso-PC 26:0 in DBS. We found that Lyso-PC 26:0 can be detectable at quantitative levels
in the lipids extracted from DBS from healthy human subjects using liquid chromatography with tandem mass spectrometry
(LC-MS/MS). Within examined, we observed an approximately 10-fold increase in Lyso-PC 26:0 in the DBS from ALD
patients compared with those from healthy subjects with a statistically significant difference. Furthermore, consistent with
previous observation, the ratios of Lyso-PC 26:0 to other molecular species of Lyso-PC were also increased in ALD patients.
Conclusively, our method using LC-MS/MS can be applicable for diagnostic use and second tier analysis of newborn screening
for ALD.
Wed(4)-P-137
CHCHD2 is down-regulated in neuronal cells differentiated from iPS cells derived from patients with
lissencephaly
Keiko Shimojima 1,2 ，Akihisa Okumura 3,4
，Masaharu Hayashi 5 ，Takayuki Kondo 6,7
，Haruhisa Inoue 6,7
，
Toshiyuki Yamamoto 1
1:Institute for Integrated Medical Sciences, Tokyo Women’s Medical University, Japan、2:Precursory Research for Embryonic Science and
Technology (PRESTO), Japan Science and Technology Agency (JST), Kawaguchi, Japan、3:Department of Pediatrics, Juntendo University,
Tokyo, Japan、4:Department of Pediatrics, Aichi Medical University, Nagakute, Japan、5:Department of Brain Development and Neural
Regeneration, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan、6:Center for iPS Cell Research and Application (CiRA),
Kyoto University, Kyoto, Japan、7:Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency
(JST), Saitama, Japan
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The human cerebral cortex is peculiar for a six-layered cellular-sheet structure with convolution, which is a consequence of
neuronal migration. Dysfunctions of the pathways contributing to this mechanism typically lead to lissencephaly manifesting
smooth brain surfaces. To investigate the unknown mechanism underlying neuronal migration disorders, we generated induced
pluripotent stem (iPS) cells from two patients with lissencephaly. Whole gene expression study for iPS cells derived from
a patient with a LIS1 deletion showed reduced expression of the coiled-coil-helix-coiled-coil-helix domain containing 2 gene
(CHCHD2 ), which was also confirmed in iPS cells derived from a patient with a TUBA1A mutation. CHCHD2 expression
was detected in neuronal cells differentiated from normal iPS cells in a time-dependent manner, as well as in the brain
of a fetus at 26-28 weeks gestational age, suggesting development-dependent expression. Migrating neuronal cells showed
CHCHD2 expression, suggesting its functional relevance to neuronal migration. This study was performed under permission
from ethical committee in the institution. Patients’ samples were accumulated after obtaining written informed consents.
Wed(4)-P-139
A Rare Clinical Condition Apert Syndrome Associated with Autistic Spectrum Disorder
Yeliz Cengiz 1 ，Mahmut C Ergoren 2
1:Child and Adolescent Psychiatry, Near East University, Medical Faculty Hospital, Cyprus、2:Department of Medical Genetics, Medical
Faculty, Near East University
There is an agreement in the literature that genetic factors play an important role in the aetiology of autism and that some
congenital medical conditions have an increased prevalence rate of autism when compared to the general population. Apert
Poster Session
syndrome is the most frequent form of the acrocephalosyndactyly syndromes (AS). It has an estimated incidence of one in
65000 to 88000 newborns.
A three year old child with the karyotype of 46,XY and diagnosed with Apert Syndrome was directed to our clinic for
delay in speech acquisition. This child is the first case of Apert Syndrome in the Island of Cyprus. Due to the mutation in
fibroblast growth factor receptor 2 (FGRF2) gene, he was born with the typical phenotype of Apert Syndrome patients such
as craniosynostosis and type II syndactyly, bulging and etc.
During clinical assessment, the child was distracted and showed increased psychomotor activity; also he was avoiding making
eye and social contacts, absence of verbal and non-verbal communication skills and not using any gestures. He preferred to
play alone and was not responding to his name.
Ankara Developmental Screening Inventory (ADSI) has been applied and the outcome of ADSI showed that the child might
have been between 13-15 months of developmental age with more than 30% of growth retardation. As far as we present the
second case of 46,XY child who was diagnosed with AS and show strong association with autistic spectrum disorders (ASDs).
We wrote this case report with the hope that it will raise awareness of a possible association between acrocephalosyndactyly
syndromes and ASDs. In the future, researchers should be to try to screen a sample of acrocephalosyndactyly cases for ASDs
to try to clarify whether there is an association. If that association proved positive then further study of such cases could
help clarify the aetiology of ASDs.
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Wed(4)-P-140
Genome-wide association study identifies SESTD1 as a novel risk gene for lithium responsive bipolar
disorder
Jie Song 1 ，Sarah E. Bergen 1,2 ，Arianna Di Florio 3 ，Robert Karlsson 1 ，Alexander Charney 4 ，
Douglas M. Ruderfer 4 ，Eli A. Stahl 4 ，Kimberly D. Chambert 2 ，Jennifer L. Moran 2 ，Katherine Gordon-Smith 5 ，
Liz Forty 3 ，Elaine K. Green 6 ，Ian Jones 3 ，Lisa Jones 5 ，Edward M. Scolnick 2 ，Pamela Sklar 4,7,8 ，
Jordan W. Smoller 9 ，Paul Lichtenstein 1 ，Christina Hultman 1 ，Nicholas Craddock 3 ，Mikael Landén 1,10 ，
The International Cohort Collection for Bipolar Disorder (ICCBD)
1:Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden、2:Stanley Center for Psychiatric Research, The
Broad Institute of MIT and Harvard, Cambridge, MA, USA、3:National Centre for Mental Health, MRC Centre for Neuropsychiatric
Genetics and Genomics, Cardiff University, Cardiff, UK、4:Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of
Medicine at Mount Sinai, New York, NY, USA、5:Department of Psychiatry, School of Clinical and Experimental Medicine, University
of Birmingham, Birmingham, UK、6:School of Biomedical and Healthcare Sciences, Plymouth University Peninsula Schools of Medicine
and Dentistry, Plymouth, UK、7:Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA、
8:Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.、9:Psychiatric and Neurodevelopmental
Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA、10:Institute of Neuroscience and Physiology,
The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden
Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across
individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this
genetically and phenotypically diverse disorder. Here we performed genome-wide association studies (GWAS) to identify
(i) specific genetic variations influencing lithium response, (ii) genetic variants associated with risk for lithium-responsive
BD. Patients with BD and controls were recruited from Sweden and the UK. GWAS were performed on 2698 patients with
subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium
response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and
8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant
Poster Session
associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with
controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory
genotyping (rs116323614, P=2.74×10-8 ). It is an intronic SNP on chromosome 2q31.2 in the gene SEC14 and spectrin domains
1 (SESTD1) which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated
as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by
common variants (“SNP-heritability”) as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a
genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology
could be furthered by focusing on this subtype of BD.
Wed(4)-P-141
Genetic Variants in N-Methyl-D-Aspartate Glutamate Receptor influence Emotion Performance in Ado-
lescents
Pei-Jung Lin 1 ，Ting-Kuang Yeh 2 ，Li-Ching Lee 2 ，Chun-Yen Chang 2
1:National Taiwan University, Taiwan、2:National Taiwan Normal University
Considerable evidence has suggested that the epigenetic regulation of N-methyl-D-aspartate (NMDA) glutamate receptors
plays a crucial role in neuropsychiatric disorders. Previous exploratory studies have been primarily based on evidence from
patients and have rarely sampled the general population. This exploratory study examined the relationship of single-nucleotide
polymorphism (SNP) variations in the genes encoding the NMDA receptor (i.e., GRIN1, GRIN2A, GRIN2B, GRIN2C, and
GRIN2D) with emotion and social behavior in adolescents. For this study, 832 tenth-grade Taiwanese volunteers were
recruited, and their scores from the Beck Youth Inventories were used to evaluate their emotional and social impairments.
Based on these scores, GRIN1 (rs4880213) was significantly associated with depression and disruptive behavior. In addition,
GRIN2B (rs7301328) was significantly associated with disruptive behavior. Because emotional and social impairment greatly
influence learning ability, the findings of this study provide important information for clinical treatment and the development
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of promising prevention and treatment strategies, especially in the area of psychological adjustment.
Wed(4)-P-142
Frequency and complexity of de novo structural mutation in autism
William M Brandler 1 ，Danny Antaki 1 ，Madhusudan Gujral 1 ，Jonathan Sebat 1
1:Psychiatry, University of California, San Diego, USA
Genetic studies of Autism Spectrum Disorder (ASD) have established that de novo duplications and deletions contribute to
risk. However, ascertainment of structural variation (SV) has been restricted by the coarse resolution of current approaches.
By applying a custom pipeline for SV discovery, genotyping and de novo assembly to genome sequencing of 235 subjects, 71
cases, 26 sibling controls and their parents, we present an atlas of 1.2 million SVs (5,213/genome), comprising 11 different
classes. We demonstrate a high diversity of de novo mutations, a majority of which were undetectable by previous methods.
In addition, we observe complex mutation clusters where combinations of de novo SVs, nucleotide substitutions and indels
occurred as single events over tens of kilobases. We estimate a high rate of structural mutation in humans (20%). Genetic
risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs but not an elevated rate of genome
rearrangement.
Wed(4)-P-143
Poster Session
Aging and Alzheimer’s disease connections derived from dysregulation and comorbidity networks suggest
new counteractions and treatments
Yi-Shian Peng 1 ，Chia-Wei Tang 1 ，Po-Jen Chang 1 ，Hung Chang 1 ，Yi-Yun Peng 1 ，Li-Ching Wu 1 ，Shu-Lin Kuo 2 ，
Hoong-Chien Lee 1,3,4
1:Department of Biomedical Sciences and Engineering, National Central University, Taiwan、2:Cathay Medical Research Institute, Cathay
General Hospital, Taipei, Taiwan、3:Department of Physics, Chung Yuan Christian University, Zhongli, Taiwan、4:Center for Dynamical
Biomarkers and Translational Medicine, National Central University, Zhongli, Taiwan
Alzheimer’s disease (AD) is the most prominent of aging disorders (AG) and one of the most challenging social problems
of the 21st century. It is characterized by the progressive impairment of cognition and other mental functions typical of
neurodegenerative disorders. The regulation of major culprits such as amyloid-β protein precursor (A β PP) in AD and AG
is still unclear. Recent reports showed type 2 diabetes (T2D) patients have an increased risk of AD and dementia. Here,
in order to gain insight in the pathology and symptoms of AG, AD, and T2D, we constructed for the three disorders, a
dysregulation gene network using public gene expression microarray data, and a comorbid disease network using hospital
clinical records of patients.
The results revealed AD to be caused by multi-functional gene abnormalities; in most cases, loss of function is much more
severe in AD than AG. New candidate genetic signatures, including KCNA6 for AG and MRPL12 for AD, were discovered.
Currently, For AD, five highly co-expressed gene pairs involving A β PP (ex: APP-CLCN7) in the hippocampus region
were identified. Significantly expressed genes in T2D and in AD were observed to exhibit a statistically significant inverse
correlation. Our comorbid network revealed that while AD and T2D may separately be comorbid with another disorder
(e.g., essential hypertension, unspecified, (ICD-9-401.9)) in early stage, these comorbidities are mostly disjoint. These results
provide new insights useful for the early detection of AG, AD and T2D.
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Wed(4)-P-144
Aicardi-Goutieres and Singleton-Merten overlapping phenotype due to IFIH1 mutation
Yuji Sugawara 1,2 ，Ayako Kashimada 2 ，Kengo Moriayam 2 ，Shinpei Baba 2 ，Kohsuke Imai 2 ，Ryuta Nishikomori 3 ，
Mizuho Motegi 4 ，Yasuo Takeuci 5 ，Tomohiro Morio 2
1:Pediatrics, Soka Munincipal Hospital, Japan、2:Pediatrics, Tokyo Medical and Dental University、3:Pediatrics, Graduate School of
Medicine, Kyoto University、4:Pediatric Dentistry, Tokyo Medical and Dental Univesity、5:Periodontology, Tokyo Medical and Dental
University
<Introduction> Aicardi-Goutieres syndrome (AGS) is an early-onset genetic encephalopathy characterized by microcephaly

with basal ganglia calcification and severe developmental delay. Affected individuals also present variable neurological symp-
toms such as dystonia, a hallmark of basal ganglia involvement. Serological examinations often show autoimmune features,
and seven genes regarding innate immunity have been confirmed causative, including IFIH1 (interferon induced with helicase
C domain 1). Recently, a specific IFIH1 mutation (p.Arg822Gln) was reported to cause Singleton-Merten syndrome (SMS), a
genetic disorder characterized by aortic calcification, osteoporosis and dental abnormalities (periodontitis with severe alveolar
bone resorption). AGS and SMS are clinically distinct, and no individual case has been reported to share both of the pheno-
types of these two syndromes. <Case Report> 5-year old female patient who showed severe developmental delay, dystonia,
hypotonia, seizure, and microcephaly with basal ganglia calcification. She also presented periodic fever and immunological
abnormalities, such as positive autoantibodies. Whole-exome sequencing disclosed de novo IFIH1 p.Arg779His mutation, a
previously reported gain-of-function mutation that results in type-1 interferon overproduction. Surprisingly she also exhibited
generalized periodontitis with severe alveolar bone resorption, characteristic of SMS. However, major periodontopathic bac-
teria were not detected from periodontally diseased sites. Subsequent examinations revealed neither aortic calcifications nor
systemic osteoporosis. <Discussion> Gain-of-function IFIH1 mutation can cause a spectrum of phenotypes encompassing
Poster Session
AGS and SMS. Periodontitis holds a unique position in this spectrum, and excessive immune response of the host may play
an important role in the pathogensis.
Wed(4)-P-145
Milder progressive cerebellar atrophy caused by biallelic SEPSECS mutations
Kazuhiro Iwama 1,2 ，Masayuki Sasaki 3 ，Shinichi Hirabayashi 4 ，Chihiro Ohba 5 ，Emi Iwabuchi 3 ，Satoko Miyatake 1 ，
Mitsuko Nakashima 1 ，Noriko Miyake 1 ，Shuichi Ito 2 ，Hirotomo Saitsu 1 ，Naomichi Matsumoto 1
1:Human Genetics, Yokohama City University, Japan、2:Pediatrics, Yokohama City University、3:Child Neurology, National Center of
Neurology and Psychiatry、4:Neurology, Nagano Children’s Hospital、5:Clinical Neurology and Stroke Medicine, Yokohama City University
Cerebellar atrophy is recognized in various types of childhood neurological disorders with clinical and genetic heterogeneity.
Genetic analyses such as whole-exome sequencing (WES) are quite useful for elucidating genetic basis of these conditions.
Pathological recessive mutations in SEPSECS have been reported in a total of 11 patients showing pontocerebellar hypoplasia
type 2, progressive cerebellocerebral atrophy or progressive encephalopathy, but detailed clinical features were limited only to
four patients. Although five missense, one nonsense, one splice site change and a gross deletion were reported in SEPSECS,
it has been suggested that genotypes did not clearly indicate phenotypic difference and severity. We newly found two
families showing progressive cerebellar atrophy with biallelic SEPSECS mutations by WES: c.356A>G (p.Asn119Ser) and
c.77delG (p.Arg26Profs*42) in family 1 and c.356A>G (p.Asn119Ser) and c.467G>A (p.Arg156Gln) in family 2. They showed
similar clinical courses in which disease progression is obviously slower than previously reported cases. During their infancy,
their development was slightly delayed, and initial brain MRI showed normal findings. Ataxia and motor disability slowly
progressed. Cerebellar atrophy was first recognized by MRI at age of 9 years and 18 years, respectively, and the degree
of atrophy was mild. Considering the common mutation [c.356A>G (p.Asn119Ser)] in our two individuals, it was possible
to estimate that c.77delG (p.Arg26Profs*42) (individual 1) had more deleterious effects on SEPSECS function compared
with that of c.467G>A (p.Arg156Gln) (individual 2), supporting the fact that individual 2 showed much milder phenotype
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than individual 1. In conclusion, we identified two families with cerebellar atrophy arising from biallelic novel SEPSECS
mutations. Late-onset and milder phenotypes were recognized, indicating that SEPSECS mutant phenotypes showed wide
range of clinical phenotypes.
Wed(4)-P-146
Familial aggregation of patients with early-and adult-onset schizophrenia and their nonpsychotic relatives
using neurological soft signs
I-Ning Tsai 1 ，Jin-Jia Lin 2 ，Ming-Kun Lu 3 ，Sheng-Hsiang Lin 1
1:National Cheng Kung University, Taiwan、2:Chimei Medical Center、3:Jianan Mental Hospital
Neurological soft signs (NSSs) have been considered potential endophenotypes for schizophrenia, and it is commonly accepted
that NSSs are more prevalent in schizophrenia patients than healthy controls. Moreover, the onset age of schizophrenia
is related to the severity of the subsequent symptoms, and thus it may be possible to estimate the predictive abilities of
NSSs from early- and adult-onset schizophrenia. This study included 177 schizophrenia patients, 143 unaffected first-degree
relatives of schizophrenia patients, and 228 healthy controls. We estimated the predictive abilities of NSSs between early-
onset schizophrenia (EOS) (onset age < 20) and adult-onset schizophrenia (AOS) (onset age ≥ 20) using three data mining
methods. We further assessed the magnitude of the familial aggregation of NSSs in EOS and AOS families using recurrence
risk ratios. The results of artificial neural networks were significantly more accurate than those of two other methods. The
accuracies of EOS and AOS were 85% and 78%, respectively. There are significant differences between EOS and AOS for
Poster Session
familial aggregation in two NSSs subscales. In the Sensory Integration subscale, the results showed that highest risk ratios
were 6.74 (95%CI: 1.84-24.60) in EOS families, and 3.82 (95%CI: 0.82-17.69) in AOS families. In the Motor Coordination
subscale, the results showed that highest risk ratios were 24.54 (95%CI: 7.81-77.05) in EOS families, and 19.91 (95%CI: 6.49-
61.10) in AOS families. These findings provide support for the potential of NSSs as a vulnerability indicator to schizophrenia,
and Sensory Integration and Motor Coordination subscale within NSSs could distinguish EOS from AOS. Furthermore, the
study suggests that early-onset families might have higher familial aggregation than adult-onset ones.
Wed(4)-P-147
Nano-interventions for Alzheimer’s disease. Role of Dendrimers
1
Jerzy W. Leszek
1:Psychiatry, Wroclaw Medical University, Poland
Dementia of Alzheimer’s type(AD) affects memory, thinking and behavior. The need to diagnose and treat the devastating
disease at an early stage is critical to manage and treat AD. Unfortunately, the lack of valided biomarkers limits the possibility
of the earlier stages of AD. The avance of nanotechnology could offer huge opportunities in early-stage diagnosis and well-
treatment of AD. This presentation discusses the challenges of current treatment and diagnosis of AD and the development
on biocompatible nanoparticles like Dendrimers and provide the rational and potentials of using this kind of nanoparticles for
both drug carrier and imaging contrast agent for diagnosis and treatment of AD. Biocompatible nanoparticles with diameter
in the range 1-100 nm(like Dendrimers) could be used as targetes delivery system for drugs(e.g Rivastigmine) to overcome
the blood-brain barrier(BBB), and to minimize the side effects caused by over-dosage. In addition anti-inflammatory and
anti-B-amyloid properties of dendrimers, decribed by us and other authors, have led to development of a variety applications
of these macromolecules, including new way for treatment of AD.
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Wed(4)-P-148
Familial spinocerebellar ataxia with sensory neuropathy associated with compound heterozygous inter-
mediate CAG expansions in MJD locus
Masahiro Kanai 1 ，Yuji Takahashi 1 ，Tomoya Taminato 1 ，Shoko Watanabe 1 ，Masafumi Ogawa 2 ，Miho Murata 1
1:Department of Neurology, National Center of Neurology and Psychiatry, Japan、2:Department of Neurology, Nagahama City Hospital
[Background]Full penetrance alleles of affected individuals presenting with the classic Machado-Joseph disease (MJD) pheno-
type range from 60 to 87 CAG expansion repeats, whereas normal alleles from 12 to 44 repeats. The clinical implication of
intermediate alleles, ranged from 45 to 60 repeats, remains elusive.
[Objective]To elucidate the clinical implication of compound heterozygous intermediate alleles in MJD locus.
[Subjects and Methods] A pedigree with five siblings consisting of three affected and two unaffected individuals participated
in this study. No symptoms suggestive of spinocerebellar ataxia were reported in their parents who were deceased over age
80. Detailed neurological examinations were performed and DNA samples were obtained with informed consent for all the
individuals except for an unaffected elder brother. PCR-based fragment analysis, repeat-primed PCR and direct nucleotide
sequencing method were employed to determine the CAG repeat numbers in MJD locus.
[Results] The index patient was a 67 years-old male presenting with slowly-progressive cerebellar ataxia with sensory neu-
ropathy with the age of onset at 56 years old. Neurological examinations revealed that his younger sister, 62 years old,
presented with similar phenotype as the index patient and his younger brother with very mild gait ataxia complicated with
Poster Session
long-standing alcohol intoxication, whereas his elder sister, 69 years old, with no symptoms and signs. The CAG repeat
numbers of the index patient, the affected sister, the affected brother and the unaffected sister were 55/49, 55/49, 57/21 and
50/7, respectively.
[Discussions and Conclusions]This study demonstrated that the compound heterozygous intermediate CAG expansions in
MJD locus were associated with spinocerebellar ataxia with sensory neuropathy. Of note, the intermediate alleles are as-
sumed to have an additive effect, considering that each intermediate allele is unlikely to be a full penetrance allele for MJD
by itself.
Wed(4)-P-149
Methadone Use in a Male With the FMRI Premutation and FXTAS
Zukhrofi Muzar 1,2 ，Reymundo Lozano 2 ，Andrea Schneider 2 ，Patrick E Adams 2 ，Sultana MH Faradz 3 ，
Flora Tassone 2 ，Randi J Hagerman 2
1:Histology, Muhammadiyah University of North Sumatera, Faculty of Medicine, Indonesia、2:University of California Davis MIND Institute,
USA、3:Diponegoro University, Indonesia
Background
The fragile X-associated tremor ataxia syndrome (FXTAS) is caused by the premutation in FMR1 gene. Recent reports of
environmental toxins appear to worsen the progression of FXTAS.
Methods
We present a case of male adult with FXTAS and a long history of methadone use. CGG repeat size and methylation status
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(Activation Ratio, AR) were measured by Southern Blot and PCR analysis. Two different structural Brain MRI protocols
were used for the radiological evaluations of the subject (1.5 Tesla at baseline and 3 Tesla at follow up)
Results
The patient had 127 CGG repeats. He was placed on methadone maintenance, started at 20 years of age and left on it for
many years. At age 60, he was started on a higher dose of methadone of 180 mg per day and his ataxia and falling became
much worse. At age 64, he started to taper the methadone maintenance dosage to approximately 24
mg per day. As he was tapered down from the methadone, his falling decreased. His MRI abnormalities at age 64 were
somewhat increased from his visit at age 59 and showed severe increased T2 signal intensity in both the truncus and the
splenium of the corpus callosum, in the deep white matter of the cerebrum, and in the pons.
Conclusions
The patient shows a faster progression in both symptoms of disease and MRI changes compared to what is typically seen in
FXTAS. We hypothesize that in this case, methadone may have contributed to a faster progression of FXTAS.
Wed(4)-P-150
Genome-wide association study in a Japanese sample identified candidate loci for HLA-DRB1*13:02 -
Poster Session
negative panic disorder
Mihoko Shimada 1 ，Takeshi Otowa 2 ，Taku Miyagawa 1,3 ，Seik-Soon Khor 1 ，Yosuke Omae 1 ，Licht Toyo-oka 1 ，
Nagisa Sugaya 4 ，Yoshiya Kawamura 5 ，Tadashi Umekage 6 ，Akinori Miyashita 7 ，Ryozo Kuwano 7 ，Hisanobu Kaiya 8 ，
Kiyoto Kasai 9 ，Hisashi Tanii 10 ，Yuji Okazaki 11 ，Katsushi Tokunaga 1 ，Tsukasa Sasaki 12
1:Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan、2:Graduate School of Clinical
Psychology, Teikyo Heisei University Major of Professional Clinical Psychology, Tokyo, Japan、3:Department of Psychiatry and Behavioral
Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan、4:Department of Epidemiology and Public Health, Graduate
School of Medicine, Yokohama City University, Kanagawa, Japan、5:Department of Psychiatry, Shonan Kamakura General Hospital,
Kanagawa, Japan、6:Division for Environment, Health and Safety, The University of Tokyo, Tokyo, Japan、7:Department of Molecular
Genetics, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan、8:Panic Disorder Research Center,
Warakukai Med. Corp., Tokyo, Japan、9:Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo,
Japan、10:Department of Psychiatry, Institute of Medical Life Science, Graduate School of Medicine, Mie University, Mie, Japan、11:Tokyo
Metropolitan Matsuzawa Hospital, Tokyo, Japan、12:Department of Physical and Health Education, Graduate School of Education, The
University of Tokyo, Tokyo, Japan
Panic disorder (PD) is an anxiety disorder characterized by panic attacks and anticipatory anxiety. Not only environmental
factors but also genetic factors have been proved to be involved in PD pathogenesis, although these mechanisms are remained
to be clarified. To date, SNPs in TMEM132D and COMT , are only a few genetic factors of PD that were replicated in
several studies in the European population, albeit not in the Japanese population. We previously reported that a frequency of
HLA-DRB1*13:02 , was significantly higher in PD patients than in control (case positivity: 18.1%, control positivity: 11.5%,
P = 2.62 × 10-5 , odds ratio (OR) = 1.70) (Shimada-Sugimoto M, Brain Behav Immun. 2015).
Previous studies have reported that genetic factors and clinical features of several HLA associated diseases are different
between the associated HLA allele-positive and -negative patients. Hence, there is a possibility that the genetic backgrounds
of PD subjects with or without HLA-DRB1*13:02 might differ. In this study, we performed a sub-group analysis of GWAS
to take the effects of HLA-DRB1*13:02 into account. The SNP genotype data were subdivided into two datasets: those of
HLA-DRB1*13:02-positive subjects (cases: N = 103; controls: N = 198) and those of HLA-DRB1*13:02-negative subjects
(cases: N = 438; controls: N = 1,341). As a result, one SNP located at 8p23 was found to be significantly associated
with PD in subjects without HLA-DRB1*13:02 (P = 4.23×10-8 , OR = 1.61). SNPs in the TMEM132D region showed
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suggestive associations with PD in subjects without HLA-DRB1*13:02 (P = 3.88×10-6 , OR = 1.51). Meanwhile, these HLA-
DRB1*13:02 -negative PD associated SNPs were found not to be associated with PD in subjects with HLA-DRB1*13:02 ,
indicating that the genetic backgrounds of PD subjects with or without HLA-DRB1*13:02 might differ. Further studies are
needed to confirm these results and clarify the underlying mechanisms causing PD.
Wed(4)-P-151
Mutational analysis of causative genes for autosomal recessive spinocerebellar degeneration (SCD) to
delineate molecular epidemiology of early-onset SCD
Yuka Hama 1 ，Yuji Takahashi 1 ，Masahiro Kanai 1 ，Shoko Watanabe 1 ，Miho Murata 1
1:Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Japan
Background:
Spinocerebellar degeneration (SCD) is a group of disorders characterized by progressive ataxia caused by dysfunction and
atrophy of cerebellum or its afferent or efferent projections. Hereditary SCD is genetically heterogeneous, composed of
autosomal dominant (AD), autosomal recessive (AR) or X-linked SCD with more than 50 causative genes. To establish
efficient diagnostic algorithms for early-onset SCD excluding AD-SCD, it is imperative to elucidate the molecular epidemiology
in these disorders.
Poster Session
Purpose:
To elucidate the molecular epidemiology of early onset SCD excluding AD-SCD by the mutational analysis of causative genes
for AR-SCD.
Methods:
Subjects with the age of onset under age 40 who were diagnosed as SCD excluding SCA1, SCA2, SCA3/MJD, SCA6, SCA8,
SCA12, SCA17, SCA31, DRPLA, ataxia oculomotor apraxia type 2 (AOA2) or ataxia with vitamin E deficiency (AVED)
were enrolled in this study. DNA samples obtained with informed consent were subjected to the mutational analysis of the
whole exons of APTX , SACS and SPG7 employing direct nucleotide sequencing method. This study was approved by the
Institutional Review Board of National Center of Neurology and Psychiatry.
Results:
Among 139 patients with the diagnosis of SCD registered in our cohort, 30 patients consisting of 19 males and 11 females
were fulfilled the enrollment criteria. The mean age of onset was 17.2 years old (ranges: 0 - 39). Seven patients had positive
family-history including four patients with affected pedigree members in multiple generations and three with affected siblings.
No homozygous or compound heterozygous pathogenic mutations were identified in APTX , SACS or SPG7 .
Conclusion:
This study revealed that AOA1, AR-SACS, or SPG7 is not a frequent cause in the early-onset SCD in the Japanese population.
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Considering the considerable genetic heterogeneity of AR-SCD, exome-first approach would be efficient for genetic diagnosis
of early-onset SCD.
Wed(4)-P-152
Mapping of novel homozygous loci for cognitive dysfunction in consanguineous families
1,2
Muhammad Y Zahoor ，Shaheen N Khan 2 ，Sheikh Riazuddin 3
1:Molecular Biology & Forensic Sciences Laboratory, Institute of Biochemistry & Biotechnology, Faculty of Biosciences, University of
Veterinary & Animal Sciences, Pakistan、2:National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore Pakistan、
3:Allama Iqbal Medical College, University of Health Sciences, Lahore Pakistan
Elucidation of the molecular determinants contributing to cognitive dysfunction or intellectual disability at present is one of
the biggest challenges. The majority of genetic components are still undiscovered for this heterogeneous disorder specially
role of recessive monogenic defects. The identification of recessive mutations has been hampered by the lack of families
with multiple affected siblings. However, the prevalence of such families is significantly larger in countries with a high
rate of consanguineous unions that increases the risk for homozygosity for rare alleles to give rise disease condition. The
DNA of consanguineous affected Pakistani families with their consents was screened through genotyping for already reported
autosomal recessive nonsyndromic CD loci/genes. The four unlinked families having multi-affecteds, were subjected to
genome-wide linkage analysis through microsatellite markers. The ABI PRISM Linkage Mapping Set of markers was used,
Version 2.5, consisting of 370 fluorescent dye-labeled microsatellite markers, organized in 27 panels in configurations at a ~
10cM resolution human index map. These markers had been selected from the 1996 Genethon Human genetic map based on
Poster Session
chromosomal location and heterozygosity. Genome-wide scan revealed three novel linkage intervals/loci for nonsyndromic CD
mapped on three families with significant statistical values i.e. LOD score. The novel homozygous loci have been mapped
at chromosome 11q14.1, chromosome 5q14.1-14.3 and at chromosome 22q12.1-12.3. These newly mapped loci will help to
identify the causative variants involved for this disorder and molecular pathway involved in process of learning and memory.
It will also help in providing carrier status and genetic counseling services.
Wed(4)-P-153
Retinitis pigmentosa is a common phenotype in affected females with mutations in PRPS1
Prasit Phowthongkum 1 ，Michael Weiss 2 ，Robin Bennett 1 ，Michael Dorschner 3 ，Suman Jayadev 1,2
1:Medical Genetics, University of Washington, USA、2:Neurology, University of Washington、3:Pathology, University of Washington
To date, sequence variants in PRPS1 have been associated with four different phenotypes PRPS1 superactivity, Arts syndrome,
Charcot-Marie-Tooth 5 and non-syndromic sensorineural deafness. These are X-linked recessively inherited and manifest with
varying severity in male patients. Recently, variability in phenotype was demonstrated in female PRSP1 mutation carriers in
one affected family, retinitis pigmentosa (RP) was manifest in all female cases. Whole exome sequencing (WES) was applied to
a 38 year old woman with RP, progressive ataxia, psychomotor retardation, and peripheral neuropathy and hearing loss with
no family history of neurological disease. WES was performed at University of Washington, Center for Precision Diagnostic.
Variants are assessed for pathogenicity using available information from the mutation databases, published literature, clinical
correlation, and predicted functional or splicing impact using evolutionary conservation analysis and computational tools. A
novel missense variant (c.287G>T, p.Arg96Leu) was identified in PRPS1 in the proband. This variant was not identified in
EXAC database. The Arg96 residue is located within the ATP-binding domain of PRPS1 and predicted to directly interact
with incoming ATP. It is conserved across multiple species. Conversion of the polar Arg to a non-polar Leu at this residue
likely disrupts the interaction of ATP, which would impair PRSP1 enzyme activity. Our patient has neurological symptoms,
including ataxia, hypotonia, delayed motor development, intellectual disability and hearing loss consistent with Arts syndrome
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and also developed retinitis pigmentosa as previously reported in affected females in a Spanish family. A complex neurological
phenotype in an affected adult with no family history is associated with predicted loss-of-function mutation in PRSP1. This
case underscores that RP is a common phenotype across the spectrum of PRPS1 deficiency syndromes in affected females
with PRSP1 mutation.
Wed(4)-P-154
Combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway asso-
ciated megalencephaly syndromes
Yutaka Negishi 1 ，Fuyuki Miya 2,3 ，Ayako Hattori 1 ，Naoki Ando 1 ，Ikumi Hori 1 ，Takao Togawa 1 ，Kohei Aoyama 1 ，
Kei Ohashi 1 ，Shinobu Fukumura 4 ，Seiji Mizuno 5 ，Ayako Umemura 6 ，Yoko Kishimoto 7 ，Nobuhiko Okamoto 8 ，
Mitsuhiro Kato 9 ，Tatsuhiko Tsunoda 2,3 ，Mami Yamasaki 10 ，Yonehiro Kanemura 11,12 ，Kenjiro Kosaki 13 ，
Shinji Saitoh 1
1:Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Japan、2:Department of
Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan、3:Laboratory for Medical
Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan、4:Department of Pediatrics, Sapporo Medical
University School of Medicine, Sapporo, Japan、5:Department of Pediatrics, Central Hospital, Aichi Human Service Center, Aichi, Japan、
6:Department of Pediatric Neurology, Central Hospital, Aichi Human Service Center, Aichi, Japan、7:Department of Pediatrics, Shimada
Ryoiku Center Hachiouji, Tokyo, Japan、8:Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal
and Child Health, Osaka, Japan、9:Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan、10:Department of
Neurosurgery, Takatsuki General Hospital, Osaka, Japan、11:Division of Regenerative Medicine, Institute for Clinical Research, Osaka
National Hospital, National Hospital Organization, Osaka, Japan、12:Department of Neurosurgery, Osaka National Hospital, National
Hospital Organization, Osaka, Japan、13:Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
Objectives PI3K-AKT-mTOR pathway has been demonstrated to be involved in megalencephaly syndromes whilst com-
prehensive molecular-genetic analyses only uncover pathogenetic mutations in limited number of patients. We applied the
Poster Session
biochemical method in combination with genetic analysis to reveal the constitutional activation of PI3K-AKT-mTOR pathway
in patients with megalencephaly syndromes. Study design Ten patients with an increased head circumference and neurolog-
ical symptoms were enrolled. We performed whole-exome sequencing or multiplex targeted sequencing including 15 genes
involved in the PI3K-AKT-mTOR pathway. Furthermore, we analyzed the expression level of phosphorylated S6 ribosomal
(phospho-S6) protein in lymphoblastoid cells from all patients by Western blotting. Results We identified pathogenetic mu-
tations in 5 (AKT3 , 1 patient; PIK3R2 , 2 patients; PTEN , 2 patients) of 10 patients. Developmental delay, dysmorphic
facial features were observed in almost all patients. Syndactyly/polydactyly or capillary malformations were not observed
even in patients with AKT3 or PIK3R2 mutations. We were able to demonstrate the increased expression of phospho-S6
protein in all mutation-positive patients. Moreover, increased expression was also observed in three mutation-negative pa-
tients. There were no common phenotypes or MRI findings among these patients. Conclusions We identified involvement of
the PI3K-AKT-mTOR pathway in 8 of 10 patients (80%) with megalencephaly syndromes, indicating that combination of
genetic and biochemical analyses would be a feasible and practical diagnostic approach for the PI3K-AKT-mTOR pathway
associated megalencephaly syndromes. Our study also disclosed the surprisingly broad clinical spectrum of the PI3K-AKT-
mTOR pathway associated megalencephaly syndromes, and these should be suspected on patients with megalencephaly even
when syndactyly/polydactyly, capillary malformations or cortical malformations in MRI are absent.
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Wed(4)-P-155
Novel PLA2G6 mutations associated with an exonic deletion due to non-allelic homologous recombina-
tion in a patient with infantile neuroaxonal dystrophy
Toshiyuki Yamamoto 1 ，Keiko Shimojima 1 ，Takashi Shibata 2 ，Mari Akiyama 2 ，Makio Oka 2 ，Tomoyuki Akiyama 2 ，
Harumi Yoshinaga 2 ，Katsuhiro Kobayashi 2
1:Tokyo Women’s Medical University Institute for Integrated Medical Sciences, Japan、2:Department of Child Neurology, Okayama University
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital
Infantile neuroaxonal dystrophy (INAD) (MIM #256600) is a rare autosomal-recessive neurodegenerative disorder involving
both the central and peripheral nervous system. This disorder is typically occurs because of mutations in the phospholipase
A2 group VI gene (PLA2G6 ) located on the 22q13.1 region. Currently, broad clinical features due to PLA2G6 mutations
are recognized as a phenotypic spectrum of PLA2G6 -associated neurodegeneration (PLAN). Recently, we encountered a
Japanese female patient with INAD at 2 years and 8 months old who showed progressive tetraplegia beginning at 9 months.
An electroencephalogram showed a diffuse increase in fast waves, and brain magnetic resonance imaging showed progressive
brain atrophy and T2 hypointensity in the globus pallidus. This study was performed under the permission obtained from the
ethics committee of the institution. After obtaining the written informed consent, next generation sequencing was performed
and a novel PLA2G6 mutation, p.Asp283Asn, was identified. The mutation in the homologous allele was unclear. Then,
mRNA was evaluated and an exonic deletion was identified. The genomic deletion was further analyzed and the breakpoint
sequence showed a 12-bp homologous sequence, indicating a unique intragenic deletion of exons 4 and 5 due to non-allelic
homologous recombination. The similar genomic sequences existed in this region suggest predisposition of the genomic
rearrangements in this region.
Poster Session
Wed(4)-P-156
Single nucleotide variations in CLCN6 identified in patients with benign partial epilepsies in infancy
and/or febrile seizures
Toshiyuki Yamamoto 1 ，Keiko Shimojima 1 ，Yuta Komiike 2 ，Atsushi Ishii 3 ，Shinpei Abe 4 ，Shintaro Yamashita 5 ，
Katsumi Imai 6 ，Tetsuo Kubota 7 ，Tatsuya Furkasawa 7 ，Tohru Okanishi 8 ，Hideo Enoki 8 ，Takuya Tanabe 9 ，
Akira Saito 10 ，Toru Furukawa 1 ，Toshiaki Shimizu 4 ，Carol J Milliagan 11 ，Steven Perou 11 ，Sarah E Heron 12 ，
Leanne M Dibbens 12 ，Shinichi Hirose 3 ，Akihisa Okumura 4
1:Institute for Integrated Medical Sciences, Tokyo Women’s Medical University, Japan、2:Department of Hygiene and Public Health 1,
Tokyo Women’s Medical University, Tokyo, Japan、3:Department of Pediatrics, Fukuoka University Faculty of Medicine, Fukuoka, Japan、
4:Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan、5:Department of Pediatrics, Juntendo Nerima Hospital,
Tokyo, Japan、6:National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan、7:Department of
Pediatrics, Anjo Kosei Hospital, Anjo, Japan、8:Department of Child Neurology, Seirei Hamamatsu General Hospital, Hamamatsu, Japan、
9:Tanabe Monbayashi Child Clinic, Hirakata, Japan、10:StaGen Co., Ltd., Tokyo, Japan、11:Florey Neuroscience Institute, Melbourne
Brain Centre, The University of Melbourne, Melbourne, Victoria, Australia、12:Epilepsy Research Program, School of Pharmacy and
Medical Sciences, University of South Australia, Adelaide, South Australia, Australia
Nucleotide alterations in the gene encoding proline-rich transmembrane protein 2 (PRRT2 ) have been identified in most
patients with benign partial epilepsies in infancy (BPEI)/benign familial infantile epilepsy (BFIE). However, not all patients
harbor these PRRT2 mutations, indicating the involvement of genes other than PRRT2 . In this study, we performed whole
exome sequencing analysis for a large family affected with PRRT2 -unrelated BPEI. We identified a non-synonymous single
nucleotide variation (SNV) in the voltage-sensitive chloride channel 6 gene (CLCN6 ). A cohort study of 48 BPEI patients
without PRRT2 mutations revealed a different CLCN6 SNV in a patient, his sibling and his father who had a history of
febrile seizures (FS) but not BPEI. Another study of 48 patients with FS identified an additional SNV in CLCN6 . Chloride
channels (CLCs) are involved in a multitude of physiologic processes and some members of the CLC family have been linked
to inherited diseases. However, a phenotypic correlation has not been confirmed for CLCN6 . Although we could not detect
significant biological effects linked to the identified CLCN6 SNVs, further studies should investigate potential CLCN6 variants
that may underlie the genetic susceptibility to convulsive disorders. This study was performed under permission of the ethical
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committee in the institution. Informed consent was obtained from all participants.
Wed(4)-P-157
Withdrawn

Wed(4)-P-158
The immunogenetic basis of auditory hallucinations in schizophrenia: Role for HLA-G
Ashwini Rajasekaran 1,2 ，Manjula Subbanna 1,2 ，Venkataram Shivakumar 2 ，Sunil V Kalmady 2 ，Deepthi Venugopal 1,2 ，
Anekal C Amaresha 3 ，Sri Mahavir Agarwal 2 ，Janardhanan C Narayanaswamy 2 ，Ganesan Venkatasubramanian 2 ，
Monojit Debnath 1
1:Human Genetics, National Institute of Mental Health and Neurosciences, India、2:Translational Psychiatry Lab, Dept. of Psychiatry,
National Institute of Mental Health and Neurosciences、3:Dept. of Psychiatric Social Work, National Institute of Mental Health and
Neurosciences
BACKGROUND & AIM: Schizophrenia (SCZ) is a complex neuropsychiatric disorder, characterized by wide range of symp-
Poster Session
toms. Auditory hallucinations (AH), the most salient positive symptom are seen in 70% of SCZ patients. Studies have shown
that genetic variations are likely to play a role in the development of AH. HLA-G, a vital immunomodulatory molecule has
recently been implicated in psychiatric disorders including SCZ. However, the precise role of HLA-G and its impact on clinical
phenotypes of SCZ is yet to be ascertained. Given the importance of HLA-G in immunoinflammation, its involvement in
conferring susceptibility to AH in SCZ seems likely.
The current study aimed at investigating the possible role of three functional polymorphisms [14bp Insertion/Deletion (IN-
DEL), +3142G>C and +3187A>G] at HLA-G locus in SCZ.
SUBJECTS & METHODS: A total of 154 (M:F=84:70) SCZ patients and 150 (M:F=87:63) healthy controls were examined
in this study. Genotyping of 14bp INDEL was determined by PCR and direct sequencing, +3142G>C by PCR-RFLP and
+3187A>G by TaqMan allelic discrimination assay.
RESULTS: There were no significant difference in the allele and genotype frequencies between patients and healthy controls at
any of the three polymorphic sites (14bp INDEL: χ2 = 2.86, p=0.23; +3142G>C: χ2 =2.17, p=0.33; +3187A>G: χ2 =3.67,
p=0.15). Correlation analysis revealed a significant association between HLA-G 14bp insertion genotype and lifetime presence
of third person AH (ρ=0.20; p=0.04). Further, on exploring gender based effects we observed that this influence was more
pronounced in male patients (ρ=0.34; p=0.01). The other two variants did not show any association.
CONCLUSION: HLA-G 14bp INDEL polymorphism that influences HLA-G expression may confer vulnerability to AH in
SCZ. This understanding might help in delineating the possible link between HLA-G mediated inflammation and AH in SCZ.
Keywords: Schizophrenia, HLA-G, Auditory hallucinations
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Wed(4)-P-159
Progression and sex difference of multiple sclerosis is associated with chondroitin sulfate β-1,4-N-
acetylgalactosaminyltransferase-1 polymorphism
Kazumasa Saigoh 1,2 ，Satoshi Yoshimura 3 ，Tomomi Izumikawa 4 ，Toshiyasu Koike 4 ，Yasuharu Tabara 5,6 ，
Tetsuro Miki 5 ，Katuichi Miyamoto 2 ，Makito Hirano 2 ，Hiroshi Kitagawa 4 ，Jun-Ichi Kira 3 ，Susumu Kusunoki 2
1:Department of Life Science, Kinki University Faculty of Science and Engineering, Japan、2:Department of Neurology, Kinki University
Faculty of Medicine、3:Department of Neurology, Kyushu University Graduate School of Medicine、4:Department of Biochemistry, Kobe
Pharmaceutical University、5:Department of Geriatric Medicine, Ehime University Graduate School of Medicine、6:Center for Genomic
Medicine, Kyoto University Graduate School of Medicine
Objective
We hypothesized that the clinical course of multiple sclerosis (MS) is influenced by the level of expression of the ChGn-1
(chondroitin sulfate β-1,4-N-acetylgalactosaminyltransferase-1) gene.
Results
Chondroitin sulfate proteoglycans (CSPGs) is a constituent of the matrix of the central nervous system (CNS), likely par-
ticipating as regulatory molecules in the process of demyelination, remyelination, axonal degeneration and regeneration in
the CNS. ChGn-1 is a key enzyme for production of CSPGs and knock-out mice of this gene showed better recovery from
spinal cord injury. We hypothesized that the clinical course of multiple sclerosis (MS) is influenced by the level of expression
of ChGn-1 gene. We recruited 147 patients with MS and 181 healthy control subjects and analyzed single nucleotide poly-
Poster Session
morphisms (SNPs) of this gene. We found the coding SNP (cSNP: rs140161612) in approximately 10 % of patients with MS
as well as normal controls. The cSNP is changed from serine to leucine at position 126 (p.S126L). The expressed ChGn-1
mutant proteins exhibited no enzyme activities in COS-1 cells. In men, patients who had MS with S126L had a slower disease
progression.
Conclusion
This SNP may possibly be associated with the sex differences in clinical course of multiple sclerosis (MS).
Wed(4)-P-160
Regional Heritability Analysis Indicates NETRIN1 Signaling Pathway is Associated with Major Depressive
Disorder
Yanni Zeng 1 ，Pau Navarro 2 ，Ana Maria Fernandez-Pujals 1 ，Lynsey Hall 1 ，Toni Kim Clarke 1 ，Pippa Thomson 3,4
，
Blair Smith 5,6 ，Lynne Hocking 6,7 ，Sandosh Padmanabhan 6,8 ，Caroline Hayward 6,9 ，Donald MacIntyre 1 ，
Naomi Wray 10 ，Ian Deary 3,11,13 ，David Porteous 3,4,12 ，Chris Haley 2,13 ，Andrew McIntosh 1,3,12 ，
Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium
1:Division of Psychiatry, University of Edinburgh, UK、2:MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine,
University of Edinburgh, Edinburgh, UK、3:Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh,
United Kingdom、4:Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular
Medicine, University of Edinburgh, Edinburgh、5:Division of Population Health Sciences, University of Dundee, Dundee, UK、6:Centre for
Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK、7:Division
of Applied Health Sciences, University of Aberdeen, Aberdeen, UK、8:Institute of Cardiovascular and Medical Sciences, University of
Glasgow, Glasgow, UK、9:MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh,
UK、10:Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia、11:Department of Psychology, University
of Edinburgh, UK、12:Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine,
University of Edinburgh, Edinburgh, UK、13:The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh,
UK
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Background: genome-wide association studies of Major Depressive Disorder have identified very few associations of genome-
wide significance. Analyses testing the aggregation of genetic variants in particular biological pathways may be more successful.
Regional heritability analysis can be utilized to detect local genomic regions contributing to disease risk.
Methods: we integrated pathway analysis and multi-level regional heritability analyses in a pipeline designed for identifying
MDD-associated pathways, and applied it to two independent GWAS studies (GS:SFHS, N=6,455) and PGC:MDD (release
1, N=18,755)). A polygenic risk score (PRS) composed of SNPs from the pathway most consistently associated with MDD
was created and tested for predictive accuracy for MDD using logistic regression and linear mixed modeling(LMM).
Results: In GS:SFHS, four pathways were significantly associated with MDD in pathway analysis. Pathway-level regional
heritability was significant in two of them. In PGC:MDD, one pathways was significantly associated with MDD in pathway
analysis. Significant pathway-level regional heritability was detected in this pathway in one subset of PGC:MDD. In both
samples the regional heritability were further localized to gene and sub-region level. NETRIN1 signaling pathway showed the
most consistent association with MDD across the two samples. The predictive accuracy of the NETRIN1 signaling pathway
PRSs surpassed that of the whole-genome PRSs in logistic regression and using LMM.
Conclusions: these post-GWAS analyses highlight the value of combining multiple methods on multiple GWAS type data in
the identification of risk pathways for MDD. The NETRIN1 signaling pathway is identified as a candidate pathway for MDD,
and should be explored in further large population studies.
Poster Session
Wed(4)-P-161
Mutational and functional studies on HNRNPA1 mutations in familial amyotrophic lateral sclerosis in
the Japanese population
Hiroya Naruse 1 ，Hiroyuki Ishiura 1 ，Jun Mitsui 1 ，Hidetoshi Date 1 ，Yuji Takahashi 2 ，Akiko Ishii 3 ，Akira Tamaoka 3 ，
Koichiro Doi 4 ，Jun Yoshimura 4 ，Shinichi Morishita 4 ，Jun Goto 5 ，Shoji Tsuji 1
1:Department of Neurology, Graduate School of Medicine, The University of Tokyo, Japan、2:Department of Neurology, National Center
of Neurology and Psychiatry、3:Department of Neurology, Faculty of Medicine, University of Tsukuba、4:Department of Computational
Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan、5:Department of Neurology,
International University of Health and Welfare Mita Hospital
Objective: To describe molecular epidemiology and clinical presentations of familial amyotrophic lateral sclerosis (FALS)
with HNRNPA1 mutations in the Japanese population, and to elucidate biological features associated with the HNRNPA1
mutations. Background: HNRNPA1, the gene encoding heterogeneous nuclear ribonucleoprotein A1, has been reported as the
causative gene for inclusion body myopathy with frontotemporal dementia, Paget’s disease of bone and ALS. The disease-
causing mutations have been shown to result in excess recruitment of hnRNPs (including TDP-43, FUS and hnRNPA1)
into stress granules (SGs). We investigated mutational and functional studies on HNRNPA1 mutations in FALS in the
Japanese series. Methods: Whole exome-sequence analysis was performed for a series of 37 FALS pedigrees. Mutations
in HNRNPA1 were confirmed by direct nucleotide sequence analysis. To elucidate biological features associated with the
HNRNPA1 mutations, we analyzed intracellular localizations of FLAG-tagged wild-type and mutant hnRNPA1 in HeLa
cells. Results: We identified a novel heterozygous p.P288A mutation in HNRNPA1 in a Japanese FALS pedigree. The
clinical presentations of the family were characterized by slowly-progressive muscle weakness and atrophy with mild upper
motor neuron signs without obvious cognitive impairment. This mutation (p.P288A) is located in the nuclear localization
signal (NLS) of HNRNPA1 . When mutant hnRNPA1 (P288A) is expressed in HeLa cells, there was significantly greater
incorporation of the mutant hnRNPA1 into constitutive SGs than that of the wild-type hnRNPA1. Conclusions: A novel
p.P288A mutation in HNRNPA1 in a Japanese FALS family was identified. This mutation, located in the NLS of hnRNPA1,
enhances the recruitment of the mutant hnRNPA1 into SGs, confirming the importance of SGs and NLS of hnRNPA1 in ALS
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pathogenesis. This study also indicated that mutations in HNRNPA1 are not the frequent cause for FALS in the Japanese
population.
Wed(4)-P-162
Transcriptome responses to lithium in microglia and peripheral blood monocyte
1,2 1,3
Yuta Takahashi ，Zhiqian Yu ，Mai Sakai 1 ，Hiroshi Komatsu 4 ，Fumiaki Ito 2 ，Hiroo Matsuoka 2 ，Hiroaki Tomita 1,3
1:Department of Disaster Psychiatry, International Research Institute of Disaster Science, Tohoku University, Japan、2:Department of
Psychiatry, Tohoku University Hospital、3:Tohoku Medical Megabank Organization、4:Miyagi Psychiatric Center
Lithium (Li) is a common mood stabilizer for bipolar disorder (BD). Although microglia may be involved in the pathophys-
iology of BD, there is a technical restriction in direct assessment of microglia in vivo. Monocytes share the same origin
with microglia, so phenomena observed in monocytes may reflect phenomena observed in microglia. We hypothesize that
there may be peripheral biomarkers in monocytes which reflect the functional changes of brain microglia after Li treatment
because of the similarity between monocytes and microglia. To screen potential biomarkers, we conducted microarray-based
gene expression analyses on Li-treated mouse monocytes and microglia to identify similar changes in their gene expression
profiles, and compare the data with Li response in human monocyte gene expression profiles. Sixty male mice were divided
into two groups, one of which were given Li-containing water. CD11b-positive microglia and Mac-1-positive monocytes were
isolated from dissociated brains and bloods, respectively, with MicroBeads and a magnetic cell separator, and subjected to
microarray experiments. The number of genes upregulated >1.2-fold by Li in monocytes, microglia, and in both of the cell
types, were 747, 601, and 127, respectively. In contrast, the number of genes downregulated <0.83-fold by Li in monocytes,
Poster Session
microglia, and in both of the cell types, were 1744, 1123, and 326, respectively. There were 4 genes upregulated >2-fold in
two cell types by Li, and one of the genes was significantly induced in Li responders among the patients with BD in previous
findings. In gene set enrichment analysis, genes categorized to “inflammatory response” were significantly overrepresented
among genes commonly increased in two cell types. Genes categorized to “autophagy” were overrepresented among genes
commonly decreased in two cell types, however the overrepresentation did not reach the statistical significance after adjusting
for multiple comparisons.
Wed(4)-P-163
Involvement of lncRNAs in CNV deletions in schizophrenia risk
Qingtuan Meng 1 ，Kangli Wang 1 ，Chao Chen 1 ，Chunyu Liu 1,2
1:The State Key Lab of Medical Genetics, Central South University, Changsha, China、2:Department of Psychiatry, University of Illinois at
Chicago, IL, USA
Schizophrenia (SZ) is a complex psychiatric disorder with high heritability. Studies demonstrated that rare copy number
variations (CNVs) contribute to the risk of SZ. In this study, we explored the potential roles of long non-coding RNAs
(lncRNAs) inside CNV deletions in SZ risk.
We collected the CNV (1q21.1, 3q29, 15q11.2, 15q13.3, 17p12, 17q12, 22q11.2) deletions that were repeatedly identified to be
associated with SZ by large case-control studies. CNV deletion may reduce expression of the lncRNAs transcribed from the
CNV regions and further perturb expression of the lncRNA target genes. We retrieved the 118 annotated lncRNAs mapped
to these CNV regions and all 20,011 expressed protein-coding RNA using the RNA-seq data from the Human Body Map 2.0
project. By testing their pairwise correlations, we found that 97 of the 118 lncRNAs co-expressed with 4937 protein-coding
genes (Pearson’s r>0.9 and P<0.05). These protein-coding genes were significantly enriched in spermatogenesis, and multiple
neuronal system functions. These genes were also enriched at parts of synapse and neurons, and several kinds of ion channel
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activities. Pathway analysis showed that these genes were enriched in nicotine addiction and neuronal system.
We further found that 46 of the 4937 genes were mapped to the SZ gene network, which is a protein-protein interaction
network consisting of top SZ susceptibility genes based on the latest genome-wide association study and their corresponding
interactive genes. Interestingly, these 46 genes were significantly enriched in nucleosome assembly which is consistent with
the findings in a previous publication by Luo et al.
In summary, our study suggests that CNV deletions may contribute to the risk for SZ through lncRNA regulation cascades.
A set of lncRNAs, their co-expressed genes, and related protein interaction networks may be involved in development of SZ.
Wed(4)-P-164
Variants in the PARL gene confer genetic susceptibility to Alzheimer’s disease in Han Chinese
Rui Bi 1 ，Qun Xiang 1 ，Li-Li Kong 1 ，Yong-Gang Yao 1
1:Kunming Institute of Zoology, Chinese Academy of Sciences, China
Background: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease leading to severe memory loss in
elderly population. The presenilin associated, rhomboid-like (PARL) protein is an evolutionarily conserved protease residing
in mitochondrial inner membrane. PARL was found to interact with the COOH-terminus of presenilin, which is the catalytic
core of γ-secretase and was proved to be a pathogenic gene for familial AD. It is of note that the pathways PARL involved
Poster Session
in were all important in AD pathology, but there is still no report concerning the role of PARL in AD so far.
Methods: We conducted a two-stage case-control study in a total of 2045 Han Chinese subjects to investigate the association
between the PARL gene and AD. The role of PARL in AD related pathways was further characterized at the cellular
level. Data-mining and integrating analysis of clinical information, genetic association data, eQTL data, biomarker data and
neuroimaging data were performed to define the genotype-phenotype association in AD progression.
Results: SNPs in the PARL gene were significantly associated with AD risk in several independent case-control cohorts. Data
mining of the ADNI database and neuroimaging analysis revealed that the AD associated SNPs rs7653061 and rs3749446 were
significantly related to altered brain structures and cognitive ability, and also linked to significantly changed AD biomarkers
in cerebrospinal fluid. eQTL data revealed that the risk genotype of rs3749446 was related to significantly decreased PARL
mRNA level in brain. The association between PARL and AD was further verified by functional experiments in U251 cells.
Conclusions: PARL could confer genetic susceptibility to AD in Han Chinese, probably through affecting AD biomarker levels
and brain structure. Independent validating studies and essential functional assays are necessary to further characterize the
putative role of PARL in AD.
Wed(4)-P-165
C2822T in ARHGAP4 gene, a candidate disease mutation in a family with mental retardation
Hui Guo 1 ，Fuhua Liu 2 ，Minglin Ou 2 ，Linhua Lin 1 ，Jinghui Ren 1 ，Yong Dai 1
1:ShenZhen People’s Hospital, China、2:GuiLin 181 Hospital
Objective: To explore the candidate disease gene in a mental retardation family. Method: The proband’s chromosome
karyotype was analysed, whole-exome sequencing was detected to screen the candidate gene, and Sanger sequencing was
used to check the result of whole-exome sequencing and to investigate the genotypes in the patient’s family. Result: The
proband’s karyotype was normal(46, XY) in G-banding level. Using whole-exome sequencing method, 1455 SNPs and 187
Indels were identified in the proband. Combined with the family information and the result of sanger sequencing, ARHGAP4
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gene with C2822T mutation in X chromosome was filtrated from the data to be the candidate disease-causing gene in this
family. Conclusion: C2822T in ARHGAP4 gene might be the candidate mutation causing mental retardation in this family.
Wed(4)-P-166
Mutation analysis of the myocyte enhancer factor 2C gene (MEF2C ) in Japanese patients with febrile
seizures
Junko Nakayama 1 ，Nobuaki Iwasaki 1 ，Kenzo Hamano 2 ，Tadao Arinami 3 ，Emiko Noguchi 3
1:Pediatrics, Ibaraki Prefectural University of Health Sciences, Japan、2:Pediatrics, Kitaibaraki Municipal General Hospital、3:Medical
Genetics, University of Tsukuba
Febrile seizures (FS) represent the most common form of childhood seizures: they affect 2%-5% of Caucasian infants and are
more common among Japanese infants (6%-9%). Susceptibility to FS has a significant genetic component: extensive genetic
studies have shown that at least 11 loci are responsible for FS. Microdeletions within chromosomal bands 5q14.3q15 were
recently identified to underlie several neurological features including epilepsy. This chromosomal region overlaps with FEB4 ,
which we have previously reported significant evidence of linkage to FS. The myocyte enhancer factor 2C gene (MEF2C ) is
considered a phenotypic candidate gene for the 5q14.3q15 microdeletion syndrome.
To investigate whether MEF2C is a susceptibility gene for FS, we performed a systematic search for mutations in 48 unrelated
Japanese patients with FS. Informed consent was obtained from their parents, and this study was approved by the Ethics
Committee of the University of Tsukuba, Japan. All coding exons of MEF2C with exon-intron boundaries were amplified by
Poster Session
PCR and sequenced using the BigDye Terminator v.1.1 Cycle Sequencing and ABI 3130xl Genetic Analyzer (Life Technologies,
Foster City, CA). Multiplex ligation-dependent probe amplification (MLPA) was performed using the SALSA MLPA probemix
P395-A1 (MRC-Holland, Amsterdam, The Netherlands). Copy number values were calculated by the Coffalyser software
(MRC-Holland) using values from four healthy controls.
We detected a synonymous mutation (c.1302C>T) and four intronic variants (IVS3+155T>G, IVS4-211A>G, IVS4-139A>G,
IVS5-95G>T). No non-synonymous mutation was detected. According to the dbSNP database, all detected variants were
considered polymorphisms. By MLPA, a duplication involving exon 1 of MEF2C was observed in one patient, which was
reported as a CNV on the DGV database. Our results indicate that genomic variations in MEF2C are not likely to be
substantially involved in the etiology of FS in a Japanese population.
Wed(4)-P-167
Search for a novel causative gene of hereditary spastic paraplegia
Miho Kawabe 1 ，Hiroyuki Ishiura 1 ，Jun Mitsui 1 ，Atsushi Iwata 1 ，Jun Yoshimura 2 ，Koichiro Doi 2 ，
Shinichi Morishita 2 ，Jun Goto 3 ，Shoji Tsuji 1
1:Department of Neurology, Graduate School of Medicine, the University of Tokyo, Japan、2:Department of Computational Biology,
Graduate School of Medicine, the University of Tokyo、3:Department of Neurology, International University of Health and Welfare
Introduction
Hereditary spastic paraplegias (HSP) are inherited neurodegenerative disorders characterized by slowly progressive spasticity
and weakness of lower limbs. As many as 61 spastic paraplegia genes (SPGs) have been identified. However, 33% of cases
suspected of autosomal dominant HSP remain undiagnosed in our department.
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In this study, we performed genetic analysis of a pedigree with hereditary spastic paraplegia and aimed to identify a novel
causative gene of HSP.
Method
The proband is a sixty-three years old man. He developed gait disturbance from the age of thirty-eight years followed by
appearance of dysesthesia of bilateral legs. On neurological examination, he had spasticity and weakness of his legs and
dysesthesia in the distal legs. Mildly slurred speech and pathological reflexes were also observed. Since his cousin had similar
symptoms and neurological findings, we assumed that spastic paraplegia was inherited as an autosomal dominant trait in
this pedigree. We performed exome sequencing using SureSelect V5+UTRs and array CGH analysis. The parametric linkage
analysis employing SNP HiTLink and allegro was carried out based on the analysis of four individuals of this pedigree.
Result
There were no mutations in the known causative 61 genes for HSP identified by exome sequencing or array CGH analysis.
Linkage analysis revealed a maximum LOD score of 0.76. In the candidate regions of 508Mb, SPG19 and SPG36 loci were
included. The two affected patients shared twelve rare variants (MAF <0.5%) in the candidate regions.
Poster Session
Discussion
The exome analysis revealed twelve potential mutations. Further intensive search for causative mutations in other undiagnosed
patients with autosomal dominant HSP will be needed to determine the causative gene.
Wed(4)-P-168
New results from the largest GWAS of Autism to date
Jakob Grove 1 ，the iPSYCH-SSI-Broad/MGH collaboration and Psychiatric Genomics Consortium Autism Working Group
1:Biomedicine, Aarhus University, Denmark
Autism Spectrum Disorder (ASD) is a psychiatric disorder characterized by impairments in social interaction, communication
and repetitive stereotypic behavior. The prevalence is about 1% and the etiology largely unknown, but ASD is highly heritable
and common variation is estimated to explain half of the genetic risk. iPSYCH, Statens Serum Institut and Broad/MGH
have conducted the largest GWAS of ASD so far, and meta-analysed with the ASD GWAS from the Psychiatric Genomics
Consortium (PGC) in an analysis of 44k subjects.
The iPSYCH sample is a population sample with cases from the Danish Psychiatric Central Research Register and a random
sample from the same birth cohorts as control group. All subjects were subsequently identified in the Danish Neonatal
Screening Biobank, their DNA extracted, whole-genome amplified and genotyped on the PsychChip. Most analyses are
conducted in the Ricopili pipeline of PGC with heritability and genetic correlations estimated using LDSC and GCTA.
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We report on the latest freeze with 13k cases and 24k controls. Preliminary analyses of the Europeans show a robust genome-
wide significant locus on chr 20. This is maintained in the meta-analysis with the PGC sample of 11k, where altogether
six genome-wide significant loci are found. Association test on chr X will follow. Polygenic risk show a 23% overlap with
schizophrenia (SCZ), and more frequent than expected same-direction-of-effect among the 128 SCZ loci from PGC, p < 5e-8.
There is a sizable positive genetic correlation with educational attainment and childhood intelligence. When partitioning
heritability, the tissues that show significant enrichment are certain brain tissues and neuronal stem cells.
With a total sample of 44k we are under-powered for truly dissecting the genetic architecture behind ASD. However, results
indicate that we may be on a discovery path similar to what has been seen for SCZ, and we start to see the contours of
interesting shared genetics with other phenotypes.
Wed(4)-P-169
Investigating functional deficits of the intellectual disability gene, IQSEC2 on dendritic spine morpho-
genesis
1,2
Cheryl Shoubridge ，Shervi Lie 1 ，Lachlan Jolly 1 ，Susan J Hinze 1
1:Pediatrics, University of Adelaide, Australia、2:Robinson Research Institute, University of Adelaide, Australia
There is considerable genetic and phenotypic heterogeneity associated with intellectual disability (ID), ADHD, autism and
epilepsy. Our laboratory has been involved in identifying genetic causes of ID, focusing on genes of the X-chromosome including
Poster Session
the IQ motif and SEC7 domain containing protein 2 (IQSEC2 ) gene. The disease spectrum due to mutations in IQSEC2
continues to expand with mutations contributing to non-syndromic ID though to early onset seizure phenotypes in affected
males, and in some cases, female patients. The pathogenesis underpinning these mutations is not known. Here, we outline
our investigations on the role of IQSEC2 on the plasticity of dendritic spines. A lentiviral shRNA approach achieved a 57%
ablation of Iqsec2 expression in primary hippocampal cell cultures from mice, modeling partial loss-of-function mutations.
Investigating gross morphological parameters after eight days of in vitro culture (8DIV) identified a ~ 32% reduction in
primary axon length, and 27% increase in the number and 31% increase in complexity of dendrites protruding from the cell
body. Focusing on the development of dendritic spine structures at 15DIV there was an increase of 34% in the number of
protrusions per dendritic segment compared to control with the proportion of immature filopodia to mature spines similar
across all treatments. By 21DIV the number of dendritic spines had normalised between the controls and ablation groups
but showed a reduction in the number of immature spines with Iqsec2 ablation. In contrast to this increased complexity
and spread of dendritic neurons with ablation of Iqsec2, overexpression of IQSEC2 WT leads to neurons with shorter axons
that are more compact and display simpler dendritic branching. These observations provide evidence of dosage sensitivity for
this gene that normally escapes X-inactivation in females and links these disturbances in expression with alterations in the
morphology of developing neurons.
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Wed(4)-P-170
Rare variants in histone methyl transferase genes involved in H3K9 methylation in Autism Spectrum
Disorders
Shabeesh Balan 1 ，Yoshimi Iwayama 1 ，Motoko Maekawa 1 ，Tomoko Toyota 1 ，Shu Takagai 2 ，Tomoyasu Wakuda 3 ，
Yosuke Kameno 3 ，Daisuke Kurita 3 ，Kohei Yamada 2 ，Katsuaki Suzuki 3 ，Masatsugu Tsujii 2,4 ，Norio Mori 2,3 ，
Yoichi Shinkai 5,6 ，Takeo Yoshikawa 1
1:Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Japan、2:Research Center for Child Mental Development,
Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan、3:Department of Psychiatry, Hamamatsu University School of
Medicine, Hamamatsu, Japan、4:Faculty of Sociology, Chukyo University, Chukyo, Aichi, Japan、5:CREST (Core Research for Evolutionary
Science and Technology), Japan Science and Technology Agency, Kawaguchi, Saitama, Japan、6:Cellular Memory Laboratory, RIKEN,
Wako, Saitama, Japan
Histone H3 methylation at lysine 9 (H3K9) is a conserved epigenetic signal, mediating heterochromatin formation by trimethy-
lation, and transcriptional silencing by dimethylation. Histone lysine methyltransferases (HMTs), EHMT1, EHMT2, WIZ,
SETDB1, SUV39H1 and SUV39H2, mainly contribute to this di- and trimethylation. Defective HMTs involved in mono and
dimethylation of H3K9 confer autistic phenotypes and behavioral abnormalities in animal models. Further loss of function
mutations in HMTs has been observed in patients with intellectual disability, developmental delays and psychiatric disorders.
We examined the role of HMTs in the etiology of autism spectrum disorders (ASD) and suggest that rare functional variants
in these genes that regulate H3K9 methylation may be associated with ASD. We sequenced the protein-coding regions and
exon/intron boundaries of EHMT1, EHMT2, WIZ, SETDB1, SUV39H1 and SUV39H2 in Japanese ASD subjects. The
detected variants were prioritized based on novelty and functionality. Expression of these genes was also tested in blood cells
and postmortem brain samples from ASD and controls. Novel and rare missense variants in EHMT1, EHMT2, SETDB1 and
SUV39H2 genes were identified exclusively in ASD patients; but they showed no statistically significant association with ASD.
Poster Session
The rare variant Ala211Ser identified in SUV39H2, located in the Pre-SET domain was predicted to affect the structural
stability of the methyltransferase domain. The EHMT2 and SETDB1 transcript expression was significantly elevated in the
peripheral blood cells of ASD when compared with control samples. However, the expression of SUV39H1 and SUV39H2
were found to be downregulated in Brodmann area 21 and dorsal raphe nucleus respectively in ASD subjects. To summarize,
we identified novel rare missense variants in HMT genes in ASD patients. The elevated expression of EHMT2 and SETDB1
in peripheral blood cells from ASD patients may support a restrictive chromatin state in ASD.
Wed(4)-P-171
Correlation between brain atrophy and clinical severity in patients with xeroderma pigmentosum group
A harboring the founder mutation in Japan
Takehiro Ueda 1 ，Fumio Kanda 1 ，Chikako Nishigori 2 ，Tatsushi Toda 1
1:Division of Neurology, Kobe University Graduate School of Medicine, Japan、2:Division of Dermatology, Kobe University Graduate School
of Medicine
Background: Xeroderma pigmentosum (XP) is an inherited congenital disease presenting with dermatological and neurological
manifestations. In Japan, XP group A (XPA) is most frequently observed in eight complementation groups, and patients with
XPA harboring the founder mutation suffer from severe manifestations including progressive brain atrophy during childhood.
In this study, we aimed to elucidate the start and the progression of neurological deficits by quantitative analysis.
Subjects and Methods: Twelve Japanese patients with XPA harboring the founder mutation and three disease controls were
included. Brain MRI was performed for each patient once or more. Three-dimensional T1 weighted images were segmented to
gray matter, white matter, and cerebrospinal fluid, and each volume was calculated. To assess clinical severity, an established
neurologist examined patients using our original scale, namely XP rating scale (XPRS).
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Results: Conventional MRI demonstrated progressive whole brain atrophy in patients with XPA. Moreover, volumetric
analysis showed that reductions of total gray matter volumes (GMV) and total brain volumes (TBV) started around the age
of five. The slope of reduction was similar in all cases. GMV and TBV values in disease controls were higher than those in
XPA cases. Meanwhile, XPRS also showed the clinical worsening of neurological manifestations and activity of daily living
after the age of five.
Conclusions: Progression of brain atrophy and clinical severity were correlated from early childhood in patients with XPA
harboring the founder mutation in Japan.
Wed(4)-P-172
Copy number variation analysis using whole-exome sequencing data for the diagnosis of neurodegener-
ative diseases
Masaki Tanaka 1 ，Hiroyuki Ishiura 1 ，Jun Mitsui 1 ，Jun Yoshimura 2 ，Koichiro Doi 2 ，Shinichi Morishita 2 ，Kishin Koh 3 ，
Yuta Ichinose 3 ，Yoshihisa Takiyama 3 ，Yujiro Higuchi 4 ，Akihiro Hashiguchi 4 ，Hiroshi Takashima 4 ，Shoji Tsuji 1
1:Department of Neurology, University of Tokyo, Graduate School of Medicine, Japan、2:Department of Computational Biology, Gradu-
ate School of Frontier Sciences, The University of Tokyo、3:Department of Neurology, Interdisciplinary Graduate School of Medicine and
Engineering, University of Yamanashi、4:Department of Neurology and Geriatrics, Kagoshima University
Backgrounds: There are a number of genes that cause neurodegenerative diseases by copy number variation (CNV), such as
PMP22 (Charcot-Marie-Tooth disease type 1A or hereditary neuropathy with liability to pressure palsies), SNCA (Parkinson’
s disease), APP (Alzheimer’s disease) and SMN1 (spinal muscular atrophy). Usual whole-exome sequencing (WES) analysis,
Poster Session
however, cannot detect this type of mutations.
Purposes: To evaluate usefulness of CNV detection using whole-exome sequencing data as a diagnostic tool for neurodegen-
erative diseases.
Materials: We analyzed 1468 patients with neurodegenerative diseases, including spastic paraplegia (492 cases), amyotrophic
lateral sclerosis (392), hereditary neuropathy (335), spinocerebellar degeneration (160), muscular dystrophy/myopathy (35),
leukodystrophy (34), and Parkinson’s disease (20).
Methods: We used read-depth based algorithm (CoNIFER) to call CNVs from WES data. For well-known diseases-causing
CNVs, the read-depth data was directly checked to avoid false negative results. To detect homozygous SMN1 deletions, which
were missed by CoNIFER, we used a custom-made program focusing on single nucleotide variants in SMN . Detected CNVs
consistent with the clinical diagnosis and mode of inheritance were further validated by the comparative genomic hybridization
array analysis.
Results: After validation, we identified 35 pathogenic CNVs in 10 genes: SPAST (11 cases), PMP22 (12), OPTN (3), SACS
(2), SMN1 (2), FA2H (1), KIF5A (1), SLC25A46 (1), SPG11 (1) and ZFYVE26 (1). In three patients, previous genetic
diagnosis of“homozygous mutation” was corrected to “compound heterozygous mutations (one deletion and one single
nucleotide variant)”.
Conclusions: Our data revealed that CNV analysis using WES data is useful for the diagnosis of neurodegenerative diseases.
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Wed(4)-P-173
Japan Consortium of Ataxias (J-CAT): a Cloud -based national registry for ataxias integrating genetic
diagnosis networks and prospective natural history researches
Yuji Takahashi 1 ，Kinya Ishikawa 2 ，Jun-ichi Kira 3 ，Satoshi Kuwabara 4 ，Ichiro Miyai 5 ，Kenji Nakashima 6 ，
Masatoyo Nishizawa 7 ，Hidenao Sasaki 8 ，Makoto Sasaki 9 ，Gen Sobue 10 ，Hiroshi Takashima 11 ，Atsushi Takeda 12
，
Yoshihisa Takiyama 13 ，Shoji Tsuji 14 ，Yoshikazu Ugawa 15 ，Kunihiro Yoshida 16 ，Koichi Wakabayashi 17 ，
Hidehiro Mizusawa 1
1:Department of Neurology, National Center of Neurology and Psychiatry, Japan、2:Department of Neurology and Neurological Science,
and Predictive and Preventive Medicine, Tokyo Medical and Dental University、3:Department of Neurology, Neurological Institute,
Graduate School of Medical Sciences, Kyushu University、4:Department of Neurology, Graduate School of Medicine, Chiba University、
5:Neurorehabilitation Research Institute, Morinomiya Hospital、6:Division of Neurology, Department of Brain and Neurosciences, Faculty
of Medicine, Tottori University、7:Department of Neurology, Brain Research Institute, Niigata University、8:Department of Neurology,
Hokkaido University Graduate School of Medicine、9:Division of Ultra-High Field MRI, Institute for Biomedical Sciences, Iwate Medical
University、10:Department of Neurology, Nagoya University Graduate School of Medicine、11:Department of Neurology and Geriatrics,
Kagoshima University, Graduate School of Medical and Dental Sciences、12:Department of Neurology, Sendai Nishitaga National Hospital、
13:Department of Neurology, University of Yamanashi、14:Department of Neurology, Graduate School of Medicine, The University of
Tokyo、15:Department of Neurology, School of Medicine, Fukushima Medical University、16:Division of Neurogenetics, Department of Brain
Disease Research, Shinshu University School of Medicine、17:Department of Neuropathology, Institute of Brain Science, Hirosaki University
[Background]
Ataxias are heterogeneous groups of disorders caused by dysfunction and degeneration of cerebellum or its afferent or efferent
projections. Neurodegenerative ataxias comprise hereditary and sporadic ataxias: the majority of hereditary ataxias are
autosomal-dominant spinocerebellar degeneration (AD-SCD) and the remaining are autosomal-recessive SCD (AR-SCD) or
X-linked SCD.
Poster Session
[Objective]
To develop a national registry for ataxias, thereby to elucidate genetic epidemiology, prospective natural history and genetic
causes of SCD.
[Subjects and Methods]
We adopted the Cloud database server system originally developed for Remudy, a national registry of Duchenne and Becker
muscular dystrophies, which implemented a searchable encryption technology to ensure the security. A multi-institutional
network for genetic diagnosis was constructed for comprehensive mutational analysis. A data acquisition framework for
disease-specific prospective natural history was designed.
[Results]
This system, named as J-CAT, allows patients themselves to register with informed consent and input clinical data with
the assistance of physicians online. The information acquired upon registry includes clinical and biochemical data, imaging
studies, neurophysiological workups as well as SARA and UMSARS clinical scores. The registered patients are routinely
subjected to comprehensive mutational analysis including massively parallel sequencing, which is conducted by the genetic
diagnosis network within the consortium. A data acquisition framework with periodic telephone interviews by clinical research
coordinators is implemented in the system to establish disease-specific prospective natural history.
[Discussion and Conclusion]
J-CAT has been launched to elucidate molecular epidemiology, disease-specific natural history and genetic causes of SCD.
This system would provide infrastructure to facilitate clinical trials of ataxias by efficiently recruiting suitable candidates.
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Wed(4)-P-174
Functional Analysis of COQ2 V393A Variant Associated with Multiple System Atrophy Based on Mea-
surement of Oxygen Consumption Rate of Transformed Yeasts Carrying human COQ2 cDNAs
Tsutomu Yasuda 1 ，Takashi Matsukawa 1 ，Jun Mitsui 1 ，Shoji Tsuji 1
1:Neurology, The University of Tokyo, Japan
Background & Purpose: Several association studies in East Asia indicated that V393A in COQ2 confer susceptibility to
developing sporadic multiple-system atrophy (MSA). COQ2 encodes parahydroxybenzoate-polyprenyl transeferase which is
essential for the biosynthesis of coenzyme Q10. To determine the functional effect of V393A on the mitochondrial aerobic
energy production in which coenzyme Q10 plays an essential role in the electron transfer, we measured oxygen consumption
rate (OCR) in the yeast coq2-null strain transformed with wild type or V393A mutated human COQ2 cDNA.
Methods: OCR was measured using an extracellular flux analyzer (XFe 24, Seahorse Bioscience). A COQ2 -null strain of
BY4741 was transformed with human wild type or V393A COQ2 cDNA. The yeasts were grown for a day in a non-fermentable
glycerol medium to log phase at 30 °C. 1 x 105 cells/well were seeded on XF24 Cell Culture Microplates precoated with Poly-D
Lysine (50 µg/mL) and centrifuged at 50 xg for 1 minute. The Seahorse sensor cartridge was rehydrated at 30 °C for 24
hours. The extracellular flux analyzer was set at 30 °C. After 1 minute of mixing and 1 minute of wait time, measurement of
OCR was conducted for 2 minutes. Three consecutive measurements were taken and the means were compared using t-test.
Result: The OCR in the yeast COQ2 -null strain transformed with V393A mutated human COQ2 cDNA was approximately
60% compared with the wild type which was statistically significant.
Conclusion: Measurement of OCR in the yeast COQ2 -null strain transformed with mutated human COQ2 cDNA can directly
Poster Session
determine the functional effect of mutant COQ2 , which enables us to further investigate association of COQ2 variants
conferring susceptibility to MSA.
Wed(4)-P-175
Common inversion polymorphisms under selection are susceptibility factors for autism and schizophrenia
Luis A Perez-Jurado 1,2,3 ，Armand Gutierrez-Arumi 1,2,3
，Alejandro Caceres 4,5
，Marcos Lopez-Sanchez 1,2,4
，
Ivon Cusco 1,2,3 ，Juan R Gonzalez 4,5
1:Universitat Pompeu Fabra, Spain、2:Hospital del Mar Research Institute (IMIM)、3:Centro de Investigacion Biomedica en Red de
Enfermedades Raras (CIBERER)、4:Centre de Recerca en Epidemiologia Ambiental (CREAL)、5:Centro de Investigacion Biomedica en
Red de Epidemiologia y Salud Publica (CIBERESP)
Despite a major genetic contribution of common inherited variants to the etiology of autism and schizophrenia spectrum
disorders (ASD and SSD) based on twin studies and epidemiological data, a significant proportion of their heritability is still
missing. We hypothesized that part of this heritability could be hidden in poorly explored and functionally relevant genomic
variants, such as submicroscopic chromosomal inversions. We have then genotyped the haplotypic signatures generated by
suppressed recombination of four common candidate ancestral chromosomal inversions (inv17q21.31, inv8p23.1, inv15q24.2 and
inv16q11.2; size range 0.45-4.5Mb), using available data from several genome-wide association studies. Two of these inversions
were associated with neuropsychiatric phenotypes. The H2-allele at the 0.9Mb inv17q21.31 was found over-transmitted to
ASD probands of the Autism Genome Project (11%, p=3.2e-04), mainly from fathers, in high functioning and verbal ASD
and in multiplex families. In contrast, the same H2-haplotype was nominally associated with protection for SSD (OR=0.86,
CI=0.78-0.96, p=0.028) in data of the Genetic Association Information Network. Over-transmission of the inversion allele at
the 4.5Mb inv8p23.1 was also observed in three independent ASD datasets (4165 trios, 7.1% over-transmission, p=2.5e-05).
Both inversions display a remarkably uneven distribution among human populations. The combined population attributable
risk of ASD for both inversion alleles was 11.08% in Europeans. We also found a strong correlation of inversion alleles at both
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loci with differential expression of several regional genes in specific brain areas, providing candidate genes and mechanisms
for the associated phenotypes. Therefore, two common chromosomal inversions at 8p23.1 and 17q21.31, unevenly distributed
among human populations, underlie part of the hidden genetic susceptibility to ASD and SSD, most likely through modulating
the expression of regional genes.
Wed(4)-P-176
Manic State-Related Biomarkers Using Co-Expressed Transcriptome Analyses
Ya-Chin Lee 1 ，Ming-Chyi Huang 2,3
，Wen-Ying Chen 2 ，Yu-Lin Chao 4,5
，Ming-Hsien Hsieh 6 ，Po-Hsiu Kuo 1,7
1:College of Public Health, National Taiwan University, Institue of Epidemiology and Preventive Medicine, Taiwan、2:Department of Psychi-
atry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan、3:Department of Psychiatry, School of Medicine, Taipei Medical
University, Taipei, Taiwan、4:Insititute of Medical Science, Tzu Chi University, Hualien, Taiwan、5:Department of Psychiatry, Buddhist
Tzu Chi General Hospital, Hualien, Taiwan、6:Department of Psychiatry, National Taiwan University Hosipital, Taipei, Taiwan、7:Research
Center for Genes, Environment and Human Health, National Taiwan University, Taipei, Taiwan
Bipolar disorder (BPD) is a highly heritable psychiatric disorder with recurrent episodes of depression and mania. Previous
genomic studies of BPD are often restricted to diagnosis per se without considering its episodic feature in nature. The current
study focused on a special feature of bipolar illness, the manic episode. We investigated the gene/transcript expression
patterns of manic episode at a genome-wide level to identify its potential molecular targets. We enrolled 11 BPD patients
with collected biological samples and clinical data at two time points, the acute manic episode and remission status. Six BPD
patients were exploratory samples and the other 5 BPD patients were replicate samples. First, we used the Affymetrix HTA-
array on exploratory samples to detect the state-related transcriptomes and their modules with weighed gene co-expression
Poster Session
network analysis (WGCNA). In the exploratory samples, most of the transcripts were down-regulated in manic state comparing
with remission. The top significant differentially expressed transcripts were DLC1, NFASC, and CLMN. These transcripts
patterns were validated by qRT-PCR with the same direction of HTA-array. With WGCNA, 3 different modules associated
with manic-state were found. We then applied RNA-sequencing in the replicate samples. Comparing the results between
HTA-array and RNA-sequencing, we found highly consistent expressed pattern. We then performed intra-module pathway
analysis to identify possible pathways that are regulated by the genes in the modules. The top significant pathways of the
3 top modules were Neurotransmitter release, Focal adhesion and Arginine and proline metabolism. With comprehensive
transcriptome data obtained by different high-throughput technologies, we were able to find potential transcripts that are
related to manic status in BPD patients. These findings would assist to conduct therapeutic studies and to explore possible
pathologic mechanisms underlying BPD in the future.
Wed(4)-P-177
Genetic determinants of multiple sclerosis susceptibility in populations with non-European ancestry
Jacob L. McCauley 1,2 ，Ashley H. Beecham 1,2 ，Noriko Isobe 3 ，Clara P. Manrique 1 ，Brett T. Lund 4 ，Alex Levy 4 ，
David V. Conti 5 ，Gary W. Beecham 1,2 ，Philip L. De Jager 6 ，Silvia R. Delgado 7 ，Jorge R. Oksenberg 3 ，
Lilyana Amezcua 4
1:John P. Hussman Institute for Human Genomics, University of Miami, USA、2:Dr. John T. Macdonald Department of Human Genetics,
Miller School of Medicine, University of Miami, Miami FL, USA、3:Department of Neurology, University of California at San Francisco,
San Francisco CA, USA、4:Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles CA, USA、
5:Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles CA, USA、6:Program in
Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham & Women’s
Hospital, Boston MA, USA、7:Multiple Sclerosis Division, Department of Neurology, Miller School of Medicine, University of Miami, Miami
FL, USA
Multiple Sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system which exhibits variable
prevalence across populations, with European populations having a higher prevalence than Hispanic, African or Asian pop-
ulations. Genetic association studies in individuals of European descent have identified 110 established MS risk variants in
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103 discrete loci outside of the Major Histocompatibility Complex. We sought to determine whether these 110 variants also
confer risk for MS in genetically admixed samples from Hispanic and African American populations. Targeted genotyping
was performed using a custom Illumina ExomeChip+ BeadChip. In the Hispanic (1056 cases and 1232 controls) and African
American (1319 cases and 1173 controls) samples, logistic regression was used to test for association of the additive genetic
effect of each variant on MS risk after controlling for ancestry. Ancestry proportions of European, African, and Asian admix-
ture were computed by ADMIXTURE. Additionally, a genetic risk score for the 110 variants was calculated using odds ratios
previously published in studies of European populations, and an association between MS and the risk score was assessed. The
genetic risk score was significantly higher in MS cases than controls in both samples (one-sided p=2.08E-30 in Hispanics and
p=2.93E-14 in African Americans). In Hispanic and African American cases respectively, 94 (40 demonstrating one-sided p
< 5.0E-02) and 78 (20 demonstrating one-sided p < 5.0E-02) of the risk variants had over-representation of the same allele as
seen in European cases. This increased proportion of over-representation in Hispanics could be due in part to the increased
European admixture at these loci in Hispanics as compared to African Americans. A more in depth look at the local ancestry
at these loci will provide further insight into the ancestral origin of these risk alleles.
Wed(4)-P-178
Improving Autism Spectrum Disorder (ASD) specific diagnosis with Copy Number Variant (CNV) pro-
filing: results in a cohort of children with neurodevelopmental problems under age five
Astrid M Vicente 1,2,3 ，Katarzyna Kwiatkowska 1 ，Ines Conceicao 1,2,3 ，Catarina Rodrigues 1 ，Isabel Picanco 1 ，
Isabel Marques 4 ，Joana Melo 4 ，Susana Ferreira 4 ，Catia Cafe 5 ，Joana Almeida 5 ，Susana Mouga 5,6 ，
Guiomar Oliveira 5,6,7,8
Poster Session
1:Dep Health Promorion and Non Communicable Disease Prevention, Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal、
2:Biosytems and Integrative Sciences Institute、3:Instituto Gulbenkian de Ciencia、4:Laboratorio de Citogenetica e Genomica, Faculdade
de Medicina da Universidade de Coimbra、5:Unidade Neurodesenvolvimento e Autismo, Centro de Desenvolvimento, Hospital Pediatrico
(HP), Centro Hospitalar e Universitario de Coimbra (CHUC)、6:Instituto Biomedico de Investigacao em Luz e Imagem, Faculdade de
Medicina da Universidade de Coimbra、7:Faculdade de Medicina da Universidade de Coimbra、8:Centro de Investigacao e Formacao Clinica
do HP-CHUC
The present study examined if CNV profiling can improve the discrimination between ASD and other neurodevelopmental
disorders (NDDs), including language impairment, psychomotor developmental delay and other behavioral problems with no
ASD phenotype. This discrimination is often difficult at early ages, when it is crucial for specific intervention and improved
prognosis. The study assessed 211 consecutive subjects referred to the clinic with developmental problems (mean age 3.93, M:F
ratio of 8:1). CNV analysis was performed by aCGH. Clinical significance of CNVs was assigned according to gene content,
frequency in controls and current knowledge from literature/databases. 116 subjects presented with 85 genetic loci previously
implicated in NDDs. Overall, CNV profiling improved diagnostic yield relative to clinical diagnosis (80.5% to 89.1%) and
sensitivity/specificity (from 0.787/ 0.813 to 0.885/0.893, ∆AUC=0.093). According to DSM-V criteria, 63 children were
diagnosed with ASD, 34 with other NDD and 19 had unclear diagnosis. Molecular diagnosis yield was 51.6% and 70.8% for
ASD and other NDDs, respectively. CNV profiling for ASD vs other NDDs had low sensitivity and specificity (0.5164/0.2917),
and was a poor predictor of ASD status vs other NDDs. Improvements in specificity/sensitivity to discriminate ASD or other
NDD subjects without Intelectual Disability (ID) vs all subjects with ID (ASD, NDD or unclear) suggest that molecular
profiling may be a better discriminative factor for ID among all NDDs. Analysis of CNV gene contents by diagnostic category
provided lists of genetic loci specific for ASD (N=96) and other NDDs (N=30), allowing further categorisation of most patients
with unclear diagnosis. The overall results indicate that molecular profiling can improve the discriminative power of diagnosis,
and is useful for earlier, specific diagnosis of ASD. Loci lists will also contribute to the definition molecular pathways specific
for ASD and other NDDs.
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Wed(4)-P-179
Expression profile of candidate genes in children and adolescents with major depressive disorder
Vanessa K Ota 1,2,3,4 ，Leticia M Spindola 1,2,3,4 ，Pedro M Pan 1,3,4 ，Patricia N Moretti 1,2,3,4 ，Hugo Cogo-Moreira 1,3,4
，
Marcos L Santoro 2,3,4 ，Carolina M Carvalho 1,2,3,4 ，Ary Gadelha 1,3,4 ，Rodrigo B Mansur 1,3,4 ，
Mateus Levandowski 4,6,7 ，Giovanni Salum 4,8 ，Gisele G Manfro 4,8 ，Jair J Mari 2,3,4 ，Helena Brentani 4,5 ，
Rodrigo Grassi-Oliveira 4,6,7 ，Elisa Brietzke 1,3,4 ，Euripedes C Miguel 4,5 ，Luis A Rohde 4,8 ，João R Sato 4,9 ，
Rodrigo A Bressan 1,3,4 ，Sintia I Belangero 1,2,3,4
1:Psychiatry, Universidade Federal de Sao Paulo, Brazil、2:Genetics Division, Universidade Federal de Sao Paulo、3:Interdisciplinary
Laboratory of Clinical Neurosciences, Universidade Federal de Sao Paulo、4:National Institute of Developmental Psychiatry for Children
and Adolescents (INPD)、5:Department & Institute of Psychiatry, University of Sao Paulo Medical School、6:Post-Graduation Program
in Psychology, Pontifical Catholic University of Rio Grande do Sul、7:Developmental Cognitive Neuroscience Research Group (GNCD),
Pontifical Catholic University of Rio Grande do Sul、8:Department of Psychiatry, Federal University of Rio Grande do Sul、9:Center of
Mathematics, Computation and Cognition, Universidade Federal do ABC
Major Depressive Disorder (MDD) is a heterogeneous and complex disorder. Studies investigating MDD in childhood and
adolescence, a more homogenous subgroup of MDD, are relevant to understand the underlying mechanisms of this disorder,
with less influence of environmental and treatment factors. Our aim was to investigate the expression of candidate genes
in childhood MDD. We tested whole blood mRNA expression levels of 12 genes playing a role in glucocorticoid receptor
function, inflammation, neurotransmission and neurodevelopment in 23 children and adolescents with MDD diagnosis (MDD
group), 49 subjects without MDD diagnosis but with high levels of depressive symptoms (SYMPTOMS group) and 61 healthy
controls (HC group). For the differentially expressed genes, we used a mediation model to verify if childhood maltreatment,
an environmental trait that influences MDD risk, could affect MDD diagnosis via gene expression. We also evaluated the
correlation between gene expression and global psychopathology assessed by the Child Behavior Checklist (CBCL). Gene
expression analysis was performed using Taqman Low Density Array (TLDA) and δ Crt values were used in the statistical
Poster Session
analyses. We found that NR3C1 , TNF , TNFR1 and IL1B expression levels were decreased in MDD group compared to
SYMPTOMS and HC groups. We also found that childhood maltreatment impacts expression of these four genes that in
turn influences the MDD diagnosis. In contrast, we have not observed correlation between δ Crt values and CBCL scores
and we have not found any difference of mRNA levels between SYMPTOMS and HC groups. To our knowledge, this is the
first study investigating the gene expression in blood of children with MDD. We could demonstrate that the expression of
NR3C1 , TNF , TNFR1 and IL1B may be a peripheral marker for childhood MDD, supporting a role of glucocorticoids and
inflammation on this disorder. These changes may also be mediating the effect of childhood maltreatment on MDD.
Wed(4)-P-181
Oligogenic model in Amyotrophic Lateral Sclerosis?
Claire S Leblond 1,2 ，Kevin Mouzat 3 ，Patrick Vourc’h 4 ，Sandra B Laurent 2,7 ，Dan Spiegelman 2,7
，Serge Lumbroso 3 ，
Philippe Corcia 4,5 ，William Camu 6 ，Patrick A Dion 2,7 ，Guy A Rouleau 2,7
1:Human Genetics Department, McGill University, Canada、2:Montreal Neurological Institute and Hospital, Mc Gill University, Montreal Qc
Canada、3:Department of Genetics, CHU Nimes, Nimes, France、4:UMR INSERM U930, Université François-Rabelais, Tours, France、5:Centre
SLA, CHRU of Tours, Tours, France、6:ALS Center, CHU Gui de Chauliac and INSERM U1051, Université Montpellier 1, Montpellier,
France、7:Department of Neurology and Neurosurgery, Mc Gill University, Montreal Qc Canada
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease characterized by the degeneration of upper and
lower motor neurons. The majority of ALS cases are sporadic (SALS) and only 5-10% have a family history (FALS). Genetic
research identified more than 110 genetic factors related to ALS including genes associated with high-risk of ALS (causative
genes) and genes associated with low-risk of ALS (susceptibility factors). Among the high-risk ALS genes, SOD1 (Cu/Zn
superoxide dismutase 1), FUS (fused in sarcoma), TARDBP (TAR DNA-binding protein 43), and C9ORF72 (chromosome 9
open reading frame 72) are the most penetrant and frequently mutated in ALS. Furthermore, several studies have described
a number of patients carrying potentially pathogenic variants in more than one ALS associated genes suggesting that ALS
could be explained by an oligogenic model.
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Considering that the role played by some genes in the pathology of ALS is still unclear, and that the contribution of specific
mutations in well-established ALS genes is still questionable, we are attempting to evaluate the mutation frequency and the
co-occurrence of 28 ALS associated genes in 383 independent individuals including 41 FALS, 198 SALS and 144 controls.
Among the cases with ALS, 41 familial and 78 sporadic cases are carriers of the C9ORF72 repeat expansion. The mutation
frequency of ALS associated genes in our cohort will be investigated using Molecular Inversion Probe (MIP) sequencing, a
method of targeted deep sequencing. 988 MIP were designed to cover 28 ALS associated genes and the high-throughput
sequencing is performed using Illumina HiSeq.
To conclude, the results of MIP sequencing will bring more light on the genetic model underlying the inheritance of ALS. If
the oligogenic hypothesis is proven to be true in ALS, it will have profound implications about the re-sequencing of individuals
with known mutations that are commonly excluded in whole-exome/genome sequencing studies.
Wed(4)-P-182
Novel compound heterozygous mutations of SPG11 gene in sporadic spastic paraplegia with thin corpus
callosum
Haruo Shimazaki 1 ，Tohru Matsuura 1
1:Neurology, Jichi Medical University, Japan
[Background] Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders that show pro-
Poster Session
gressive spasticity in the lower extremities with variable additional symptoms. To date, more than 70 genetic loci (SPG) have
been assigned in HSPs. HSP with thin corpus callosum (TCC) is a feature associated with SPG1, SPG11, SPG15, SPG18,
SPG21, SPG44-47, SPG49, SPG54, SPG56, SPG63, SPG67, SPG71, and so forth. We encountered a sporadic case of spastic
paraplegia with thin corpus callosum. We tried to identify the causative gene mutation of this case.
[Methods] A non-consanguineous family including one patient with TCC was examined. We performed whole-exome sequenc-
ing (WES) of the patient’s DNA and searched deleterious mutations of HSP genes in the WES result. Mutations were
confirmed by Sanger sequencing and co-segregation study in this family.
[Result] The patient noticed his gait difficulty at age 13. His gait disturbance was gradually worsened and wheel-chair bound
at age 23. He had mental impairment. His brain MRI showed marked thin corpus callosum. We could identify a novel
nonsense mutation in exon 6 and a missense mutation in exon 14 of SPG11 gene. We confirmed that these mutations were
co-segregated within this family.
[Discussion] SPG11 is the most common type of autosomal recessive (AR) HSP-TCC. SPG11 shows early-onset spastic para-
plegia with thin corpus callosum and mental impairment. The symptoms of this patient were identical with those of SPG11.
We identified novel nonsense mutation of SPG11 gene. This study showed that WES is one of the useful methods for search
the causative gene mutations even in the sporadic cases with spastic paraplegia with TCC.
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Wed(4)-P-183
The association between GWAS peak on 6p21.3-22.1 and cognitive impairment in trio-families with
schizophrenia
Wan-Jung Lui 1 ，Po-Chang Hsiao 1 ，Ling-Ling Yeh 2 ，Chih-Min Liu 3 ，Chen-Chung Liu 3 ，Tzung-Jeng Hwang 3 ，
Ming H. Hsieh 3 ，Yi-Ling Chien 3 ，Yi-Ting Lin 3 ，Sharon D. Chandler 4 ，Stephen J. Glatt 5 ，Nan Laird 6 ，
Stephen V. Faraone 5 ，Ming T. Tsuang 4 ，Hai-Gwo Hwu 1,3,7 ，Wei J. Chen 1,7,8,9 ，PsychChip Working Group
1:Epidemiology, Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taiwan、
2:Department of Healthcare Administration, College of Health Science, Asia University, Taichung, Taiwan、3:Department of Psychiatry,
College of Medicine and National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan、4:Center for Behavioral
Genomics, Department of Psychiatry, University of California San Diego, La Jolla, California, USA、5:Departments of Psychiatry and
Behavioral Sciences and Neuroscience and Physiology, Medical Genetics Research Center, SUNY Upstate Medical University, Syracuse,
New York, USA、6:Department of Biostatistics, Harvard University, Boston, Massachusetts, USA、7:Institute of Brain and Mind Sciences,
College of Medicine, National Taiwan University, Taipei, Taiwan、8:Department of Public Health, College of Public Health, National
Taiwan University, Taipei, Taiwan、9:Genetic Epidemiology Core Laboratory, Division of Genomic Medicine, Research Center for Medical
Excellence, National Taiwan University, Taipei, Taiwan
Schizophrenia, a severe, chronic and disabling brain disorder, has a prevalence of 1% worldwide. The disease symptoms
contain positive symptoms, negative symptoms and cognitive deficits.
In 2014, a meta-analysis from Psychiatric Genomics Consortium (PGC) has shown that the most significant result of genome-
wide association study was on the major histocompatibility complex (MHC) region, located on 6p21.3-22.1. It has been
discussed that this region included lots of immune-related genes; however, the relationship between this region and neu-
rocognition was still controversial. As an intermediate phenotype, some studies have indicated that the MHC variants were
associated with decreased brain volume in schizophrenia, at the region associated with memory and learning, though the odds
ratios were small. But the relationship between MHC variants and cognitive impairment in schizophrenia was less discussed.
Poster Session
Hence, my study aim is to find the genetic variants at MHC region and cognitive impairment in schizophrenia.
Approximately 600 Taiwanese trio-families with schizophrenia were recruited from the Schizophrenia Trio Genomic Research
of Taiwan (STOGET). The genotype data was from PsychChip, which designed by PGC. In this genotype data, total 333074
SNPs passed the quality control and 3249 SNPs were in the MHC region.
The association of single SNPs in family samples will be analyzed by logistic regression using PLINK. In addition, polygenic
risk score analysis will be conducted between the SNPs and cognitive test: continuous performance test and the Wisconsin
card sorting test in patients, seeking that if there some SNPs associated with worse cognitive performance.
Wed(4)-P-184
Clinical Utility of Next Generation Sequencing for Undiagnosed Genetic Disorders
Younhee Ko 1 ，Hyun-Joo Lee 1 ，Heung-Dong Kim 2 ，Joon-Soo Lee 2 ，Cheolho Lee 1 ，JinSung Lee 1
1:Department of Clinical Genetics, Department of Pediatrics, Yonsei University, College of Medicine, Korea, South、2:Department of Pedi-
atrics, Division of Pediatric Neurology, Pediatric Epilepsy Clinics, Yonsei University, College of Medicine
Many neurodegenerative genetic disorders are complicated with variety of clinical signs and multiple causes, which preventing
an accurate diagnosis and the understanding of genetic basis. Next generation sequencing (NGS) leads to the identification
of genetic variants that could be associated with disease susceptibility. Here, we investigated the utility of NGS in diagnosis
of 128 patients with unknown genetic origin and molecular characterization. Intractable epilepsy or seizure like phenotype
(64 patients) is the most prevalent type in our cohort. Patients having delayed development disorder or metabolic disorder
are 55, 31 respectively.
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Our pipeline for the analysis of disease-associated variants, could successfully identified the definite genetic causes as well as
likely pathogenic variants. In this study, we utilized the Trusight One sequencing panel providing comprehensive coverage
of < 4,800 clinically known disease-associated genes. Among of total 128 patients with undiagnosed genetic disorders, we
successfully identified the definite genetic causes of 65 patients (51%). All mutations have been confirmed by conventional
Sanger sequencing and validated by parent testing. Many pathogenic variants including known SCN8A (p.Glu710Lys) and
SCN2A (p.Thr435Pro) genes are identified as genetic origin for the epilepsy. However, novel pathogenic variants associated
with GRIN2A, STXBP1, and CDKL5 were also identified. In this study, we showed that targeted NGS has been successfully
applied as a diagnostic tool for patients with undiagnosed genetic disorders. We conclude that NGS are likely to be a very
useful in a diagnostic setting.
Wed(4)-P-185
Novel rare variations of oxytocin receptor (OXTR) gene in autism spectrum disorder individuals Novel
rare variations of oxytocin receptor (OXTR) gene in autism spectrum disorder individuals
Xiaoxi Liu 1 ，Katshushi Tokunaga 1 ，Tsukasa Sasaki 2
1:Department of Human Genetics, University of Tokyo, Japan、2:Department of Physical and Health Education, Graduate School of Edu-
cation, The University of Tokyo
The oxytocin receptor (OXTR) gene has been implicated as a risk gene for autism spectrum disorder (ASD) — a neurode-
velopmental disorder with essential features of impairments in social communication and reciprocal interaction. The genetic
associations between common variations in OXTR and ASD have been reported in multiple ethnic populations. However,
Poster Session
little is known about the distribution of rare variations within OXTR in ASD patients. In this study, we performed resequenc-
ing of the full length of OXTR in 105 ASD individuals, by using an approach which combined the power of next-generation
sequencing (NGS) technology, long-range PCR (LR-PCR) and DNA pooling. We demonstrated that rare variants with minor
allele frequency as low as 0.05% could be reliable detected by our method. We identified 28 novel variants including potential
functional variants in the intron region and one rare missense variant (R150S). We subsequently performed Sanger Sequenc-
ing and validated 5 novel variants that are located in previously suggested candidate region in ASD individuals. Further
sequencing on 312 healthy subjects shows that the burden of rare variants is significantly higher in ASDs compared with
healthy individuals. Currently we are working on the functioanal study to evaluate the effects of rare variants in OXTR.
Wed(4)-P-186
The effects of tooth loss and APOE ε 4 allele on mild memory impairment in the Fujiwara-kyo study
of Japan
Nozomi Okamoto 1 ，Masayuki Morikawa 2,3
，Shin Takasawa 4 ，Norio Kurumatani 1
1:Community Health and Epidemiology, Nara Medical University, Japan、2:Mie Prefectural Mental Care Center、3:Psychiatry, Nara Medical
University、4:Department of Biochemistry, Nara Medical University
Background: Several studies have suggested that periodontal disease contributes to exacerbate pro-inflammatory status of
brain. Tooth loss is one of alternative evaluation indexes of periodontal disease. Apolipoprotein E ε 4 allele (APOE ε 4
allele) is a risk factor of Alzheimer’s disease. There are few data on the effects of tooth loss on memory decline, according
to presence or absence of APOE ε 4 allele.
Objective: To determine if the tooth loss is associated with mild memory impairment (MMI) and if this relation is modified
by the presence of APOE ε 4 allele.
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Design and Setting: A 5-year prospective cohort study was conducted from 2007 to 2012 in Nara prefecture, Japan.
Participants: Nine hundred eighty four Japanese elders aged 65 years over with cognitive intact at baseline in 2007.
Main Outcome Measures: MMI at follow-up in 2012.
Results: During follow-up, 190 subjects experienced MMI. After adjustment for demographics, vascular risk factors, and
APOE ε 4 allele, multivariate adjusted odd ratio of 8 or less teeth was 1.87 (95% confidence interval [CI], 1.13-3.08,
P=0.014), compared to 25-32 teeth. The adjusted odd ratio of per 1 fewer number of teeth were 1.02 (95%CI, 1.01-1.04,
P=0.011). Participants with both presence of at least 1 APOE ε 4 allele and 8 or less teeth had a higher risk of MMI,
compared with those with neither (odds ratio, 2.65; 95%CI, 1.23-5.71, P=0.013). Those with either risk factor alone did not
have a higher risk of MMI.
Conclusion: Elders with both the fewer number of teeth and APOE ε 4 allele may have an increased risk of developing mild
memory impairment.
Wed(4)-P-187
Polygenic risk for schizophrenia and neurocognitive performance in patients with schizophrenia
Shi-Heng Wang 1 ，Po-Chang Hsiao 1 ，Ling-Ling Yeh 2 ，Chih-Min Liu 3 ，Chen-Chung Liu 3 ，Tzung-Jeng Hwang 3 ，
Poster Session
Ming H. Hsieh 3 ，Yi-Ling Chien 3 ，Yi-Ting Lin 3 ，Sharon D. Chandler 4 ，Stephen V. Faraone 5 ，Nan Laird 6 ，
Stephen J. Glatt 5 ，Ming T. Tsuang 4 ，Hai-Gwo Hwu 3 ，Wei J. Chen 1
1:Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taiwan、2:Department of
Healthcare Administration, College of Health Science, Asia University、3:Department of Psychiatry, College of Medicine and National
Taiwan University Hospital, National Taiwan University、4:Center for Behavioral Genomics, Department of Psychiatry & Institute for
Genomic Medicine, University of California San Diego、5:Departments of Psychiatry and Behavioral Sciences and Neuroscience and
Physiology, Medical Genetics Research Center, SUNY Upstate Medical University、6:Department of Biostatistics, Harvard University
Schizophrenia is a severe mental disorder characterized by impairments in cognitive function. Both neurocognitive deficits
and schizophrenia are highly heritable. Family and twin studies indicated that the correlation between the two phenotypes
is substantial, and the covariance between the two is mostly explained by common genetic variants. The genetic overlap
between neurocognitive deficits and schizophrenia has been observed in the general population, but this needs to be further
explored in the clinical population. This study aimed to examine if neurocognitive performance can be attributed to the
polygenic architecture of schizophrenia in patients with schizophrenia. Schizophrenia polygenic risk scores were calculated
using information from the Psychiatric Genomics Consortium (PGC) on schizophrenia. Sets of variants with a p-value below
different cut-offs for association test with schizophrenia were defined. Summary results from PGC data were used to calculate
individual polygenic risk scores in our independent sample of 1130 schizophrenia patients and 2260 healthy parents, who
were recruited from the Schizophrenia Families in Taiwan (S-TOGET) project, & genotyped using the PsychChip array.
The dimensions of neurocognitive performance in this study included sustained attention deficit as measured on Continuous
Performance Test (CPT) and executive function as measured on Wisconsin Card Sorting Test (WCST). We applied a structural
equation model in order to construct latent variables estimated from multiple measured indices in CPT and WCST, and then
tested the association between the polygenic risk score and the latent variables inferred to neurocognitive performance.
The results indicated that higher polygenic risk of schizophrenia was associated with poor neurocognitive performance in
patients with schizophrenia under different cut-offs. Neurocognitive performance can be attributed to polygenic architecture
of schizophrenia in the clinical population.
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Wed(4)-P-188
Effect of CX3CR1 polymorphisms on the structure and function in the human brain
Mai Sakai 1 ，Hikaru Takeuchi 3 ，Yoshie Kikuchi 2 ，Chiaki Ono 2 ，Zhiqian Yu 1,2,5
，Yasuyuki Taki 4,5
，Hiroaki Tomita 1,2,5
1:Disaster Psychiatry, Graduate School of Medicine, Tohoku University, Japan、2:Disaster Psychiatry, International Research Institute
of Disaster Science, Tohoku University、3:Developmental Cognitive Neuroscience, Institute of Development, Aging and Cancer, Tohoku
University、4:Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer, Tohoku University、5:Tohoku Medical Megabank
Organization,Tohoku University
CX3CR1, a 7-transmembrane domain G-protein-coupled receptor, is involved in various inflammatory processes. CX3CR1 is
expressed on the surface of various peripheral cells, such as T lymphocyte, macrophage, neutrophil, monocyte, NK cell, CD4
positive cell, while microglia is the only CX3CR1-expressing cell in the brain. Several studies have reported that CX3CR1
plays important roles in pruning of synapses, memories and neurogenesis. It was also reported that decreases of the CX3CR1
expression was associated with the number of synapses in the brain of patients with schizophrenia. Thus, evidence suggests
involvement of CX3CR1 into brain function and the pathophysiology of psychiatric diseases. On the other hand, a non-
synonymous single nucleotide polymorphism (SNP) of CX3CR1 , T280M (rs3732378), is related to difference in leukocyte
functions including adhesion, signaling, and chemotaxis. This polymorphism is associated with various peripheral diseases,
the polymorphism may affect brain function as well as susceptibility to psychiatric disorders, and however the associations
between this SNP and phenotypes in the brain have not been investigated. To investigate effect of genetic variations in
CX3CR1 on the structure and function of the human brain, we evaluated association between the SNP and MRI findings,
including volume of gray and white matters, diffusion tensor imaging (DTI)-based white matter integrity and mean cerebral
blood flow (CBF) during rest using arterial spin labeling (ASL), among 1,301 healthy Japanese people. The G allele of the
SNP was significantly associated with increased arterial blood volume around the precuneus. There was no major difference
Poster Session
between brain structural indicators in any brain areas among genotypes. This finding suggests that CX3CR1-T280M may
affect brain artery structures via interaction between microglia and vascular endothelial cells, and underlie relevant brain
functions and susceptibilities to brain diseases.
Wed(4)-P-189
Withdrawn

Wed(4)-P-190
Identification of SPG11/KIAA1840 mutations in patients with an autosomal recessive form of Charcot-
Marie-Tooth disease type 2
Celeste Montecchiani 1 ，Lucia Pedace 1 ，Temistocle Lo Giudice 1 ，Antonella Casella 1 ，Marzia Mearini 1 ，
Fabrizio Gaudiello 1 ，Josè L Pedroso 3 ，Chiara Terracciano 2 ，Carlo Caltagirone 2,4 ，Roberto Massa 2 ，
Peter H St George-Hyslop 5,6,7 ，Orlando GP Barsottini 3 ，Toshitaka Kawarai 8 ，Antonio Orlacchio 1,2
1:Laboratorio di Neurogenetica, IRCCS Santa Lucia, Rome, Italy、2:Dipartimento di Medicina dei Sistemi, Università di Roma Tor
Vergata, Rome, Italy、3:Department of Neurology, Universidade Federal de São Paulo, Brazil、4:Laboratorio di Neurologia Clinica e
Comportamentale, IRCCS Santa Lucia, Rome, Italy、5:Centre for Research in Neurodegenerative Diseases, University of Toronto, Ontario,
Canada、6:Department of Medicine, University of Toronto, Ontario, Canada、7:Department of Clinical Neurosciences, University of
Cambridge, Cambridge, United Kingdom、8:Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University
Graduate School, Tokushima, Japan
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ICHG2016 1257
Objective: This study focused on the SPG11/KIAA1840 screening in 28 unrelated pedigrees with autosomal recessive form
of Charcot-Marie-Tooth disease type 2, recruited in Italy, Brazil, Canada, England, Iran, and Japan.
Background: Mutations in the SPG11/KIAA1840 gene are common cause of autosomal recessive form of hereditary spastic
paraplegia with thin corpus callosum. Studies of genotype-phenotype correlations demonstrate a broad clinical spectrum,
including juvenile amyotrophic lateral sclerosis. We extended the genetic analyses of SPG11/KIAA1840 to Charcot-Marie-
Tooth disease, especially axonal form.
Design/Methods: The diagnosis was based on clinical findings and familiar history. Clinical and instrumental functional
analyses consist of neurological assessment, neuroimaging, electroneurographic assay, and sural nerve biopsy. Molecular
studies include linkage analysis, Sanger sequencing, RFLP analysis and bioinformatics.
Results: All known axonal Charcot-Marie-Tooth autosomal recessive loci, genes causing autosomal recessive hereditary spastic
paraplegia with thin corpus callosum and axonal peripheral neuropathy, as well as the causative gene of peripheral neuropathy
with or without agenesis of the corpus callosum were screened out. Linkage study of all families showed homozygous haplotypes
and produced positive logarithm of odds score in all affected subjects. Sanger sequencing identified 15 SPG11/KIAA1840
mutations in 12 families. All mutations were absent in controls. Two sequence changes were never reported before and in
silico analysis predicted their pathogenetic effect. Co-segregation of each mutation with disease was confirmed.
Conclusions: Our results indicate that SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features,
including autosomal recessive form of Charcot-Marie-Tooth disease type 2.
Poster Session
Wed(4)-P-191
A clinico-genetic study in a large cohort of patients with herediatry spastic paraplegia type 4 (SPG4)
Lucia Pedace 1 ，Marzia Mearini 1 ，Antonella Casella 1 ，Celeste Montecchiani 1 ，Fabrizio Gaudiello 1 ，Marialuisa Miele 1 ，
Roberto Massa 2 ，Carlo Caltagirone 2,3 ，Renato P Munhoz 4 ，Josè L Pedroso 5 ，Orlando GP Barsottini 5 ，
Toshitaka Kawarai 6 ，Antonio Orlacchio 1,2
1:Laboratorio di Neurogenetica, IRCCS Santa Lucia, Rome, Italy、2:Dipartimento di Medicina dei Sistemi, Università di Roma Tor Vergata,
Rome, Italy、3:Laboratorio di Neurologia Clinica e Comportamentale, IRCCS Santa Lucia, Rome, Italy、4:Movement Disorders Centre,
Toronto Western Hospital, University of Toronto, ON, Canada、5:Department of Neurology, Universidade Federal de São Paulo, Brazil、
6:Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
Objective: This study includes the mutational screening of the SPG4/SPAST gene and the evaluation of a comprehensive
spectrum of neurological features of patients with hereditary spastic paraplegia (HSP).
Background: HSP includes a heterogeneous group of neurodegenerative disorders with the characteristics of slowly progressive
spasticity and weakness of the lower limbs. Mutations in SPG4/SPAST represent the most frequent molecular etiology but
the worldwide incidence is unknown.
Design/Methods: A cohort of 726 patients, 98 sporadic and 628 subjects belonging to 215 families were recruited from Italian,
Brazilian, and Japanese populations in a period from 2008 to 2015. Clinical and instrumental functional analyses consist
of neurological assessment and neuroimaging. Mutational screening was carried out by direct sequencing and MLPA. Novel
variants were confirmed and pathogenetic effect was determined by co-segregation with the disease, population studies, and
in silico analysis. Haplotype studies were performed on three recurrent variants.
Results: Our study highlights clinical and epidemiological differences among the populations, showing unique genotype-
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phenotype correlations. The analysis revealed a great portion of private mutations worldwide and confirmed the founder
effect for one recurrent variant in the Italian population. Interestingly, mutations were detected in 21% of sporadic cases as
well as in a range from 16% to 100% of families, depending on the number of affected in the family.
Conclusions: This study represents the first worldwide SPG4/SPAST genetic screening on HSP patients. Epidemiological and
clinical results broaden the spectrum of the clinical presentations associated with mutations in SPG4/SPAST . Finally, our
findings provide evidence that the chance to detect SPG4/SPAST mutations varies proportionally to the number of affected
in the family.
Wed(4)-P-192
Analysis of retrotranposition in neurodegenerative disorders
Giovanni Pascarella 1 ，A. Busch 1 ，G. Gustincich 2 ，P. Carninci 1
1:RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Life Science Accelerator Technology Group, Transcriptome
Technology Team, Yokohama, Japan、2:Area of Neuroscience, International School for Advanced Studies, Trieste, Italy
Nearly 50% of the human genome is composed by Transposable Elements (TEs), discrete units of DNA capable of moving
within the genomic environment. DNA transposons duplicate though a cut-and-paste mechanism and have been inactivated
during evolution, while retrotransposons duplicate through RNA intermediates that are reverse-transcribed by a self-encoded
variant of RT and then inserted at new genomic locations. The human genome harbors at least three families of retrotrans-
posons that are currently capable of transposition: LINE-1 (L1), Alu and SVA elements, all belonging to the subclass of
Poster Session
non-LTR retrotransposons and accounting for approximately one-third of the human genome. Recent published data shows
that the impact of active retrotransposons on the shape and the integrity of the human genome is far deeper than previously
considered. With an estimated rate of one new insertion every 10-100 live births, active retrotransposons are able to influence
genetic diversity and to cause diseases, as supported by several cases of de novo insertions involved in the outbreak of cancers
and other genetic disorders. Yet, clinical studies of insertions involved in human diseases are usually focused on a very small
and local genomic scale. Somatic retrotransposition has been shown to occur in the normal human brain at higher rates
compared to other tissues, and de novo insertions can happen at different frequencies in different brain regions. We have
developed an oligonucleotide based liquid-phase capture protocol in order to specifically capture and sequence young, active
LINE-1 and AluY retrotransposons in the human genome. We have used this approach to study the brain retrotransposome
in samples obtained from donors affected by idiopathic Alzheimer’s disease (AD) and Parkinson’s disease (PD). Our pre-
liminary results show a significative differential content of somatic retrotransposition in several brain regions of AD and PD
patients versus controls.
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Poster Session
Pharmacogenetics
Wed(4)-P-193
A TALE OF GENETIC VARIATION IN THE HUMAN SLC22A1 GENE ENCODING OCT1 AMONG
TYPE 2 DIABETES MELLITUS POPULATION GROUPS OF WEST BENGAL, INDIA
1
Dipanshu Sur
1:Dept. of Zoology, University of Calcutta, India
The organic cation transporter 1, OCT 1 (also called SLC22A1-Solute Carrier Family 22 member 1), appears to play a role in
the efficacy and disposition of variety of organic cation including drugs. Genetic polymorphisms in the drug transporter have
been increasingly recognized as a possible source of variation in drug disposition and response. Genetic variants in OCT1 have
been identified largely in European, Asian (Japanese, Chinese and Korean) populations. Interestingly, eight genetic variations
were found in the human SLC22A1 gene, which encodes OCT 1, from 50 type 2 diabetes mellitus individuals (T2DM), in
West Bengal population. The purpose of this study was to investigate genetic variants of OCT1 in West Bengal populations.
We detected the three previously reported non-synonymous variations, 480 G>C (L160F); 1022 C>T (P341L); 1222 A>G
(M408V) and one synonymous variations 156 T>C (S52S) at a minor allele frequencies (MAF) of 0.63, 0.20, 0.43 and 0.27
Poster Session
respectively. We also found four previously reported intronic variations: IVS1-43(T>G), IVS2 -99(C>T), IVS5 -61(G>A),
IVS9 +43(C>T) with minor allele frequencies of 0.20, 0.17, 0.18, and 0.37 respectively. In conclusions, we identified eight
genetic variants including four exonic ones in SLC22A1 in 50 type 2 diabetes mellitus patients of West Bengal. This is the
first report of SLC22A1 variations among Indian, especially West Bengal’s type 2 diabetes mellitus patients. The present
results would be useful for haplotype analysis and pharmacogenetic studies on OCT1.
Wed(4)-P-194
Correlation of UGT1A1*28 and *6 polymorphisms with irinotecan-induced neutropenia in Thai colorectal
cancer patients
Chalirmporn Atasilp 1,2 ，Pichai Chansriwong 3 ，Ekapob Sirachainan 3 ，Thanyanan Reungwetwattana 3 ，
Montri Chamnanphon 1,2 ，Apichaya Puangpetch 1,2 ，Sansanee Wongwaisayawan 4 ，Chonlaphat Sukasem 1,2
1:Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol
University, Thailand、2:Laboratory for Pharmacogenomics, Clinical Pathology, Somdetch Phra Debharatana Medical Centre, Ramathibodi
Hospital、3:Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University、
4:Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University
UDP-glucuronosyltransferase1A1 (UGT1A1 ) polymorphisms have been related with irinotecan toxicity. The purpose of
this study was to determine the associations between UGT1A1*28 and *6 polymorphisms and irinotecan toxicity in Thai
patients with metastatic colorectal cancer. 44 metastatic colorectal cancer patients recievied irinotecan-based chemotherapy.
Hematologic toxicities were determined at first and second cycle of treatment. The genotypes of UGT1A1*28 and *6 were
analyzed by pyrosequencing technique. The frequencies of genetic testing for UGT1A1*28 and *6 polymorphism were
22.8% (TA6/TA7; 20.5%, TA7/TA7; 2.3%) and 15.9% (GA), respectively. No patient who had the homozygous UGT1A1*6
(AA). Either UGT1A1*28 or UGT1A1*6 polymorphisms were no significantly associated with severe hematologic toxicities.
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ICHG2016 1260
However, the combination of UGT1A1*28 and *6 analysis, these polymorphisms were associated with severe neutropenia at
first and second cycle (P=0.044, P=0.017, respectively). Both UGT1A1*28 and *6 polymorphisms may have an increase
risk of irinotecan-induced neutropenia in Thai colorectal cancer patients.
Keywords: UGT1A1*28 , UGT1A1*6, Neutropenia, Irinotecan, Colorectal cancer
Wed(4)-P-195
Impact of serotonin receptor 1A haplotypes on risperidone-induced weight gain in schizophrenia patients
Ying-Tzu Chang 1 ，Chih-Yu Chen 1 ，Yu-Ning Teng 1 ，Ying-Chieh Chen 1 ，Jia-Lian Yang 1 ，Wei-Chieh Liao 1 ，
Chin-Chuan Hung 1,2 ，Hsien-Yuan Lane 3,4
1:Department of Pharmacy, College of Pharmacy, China Medical University, Taiwan、2:Department of Pharmacy, China Medical University
Hospital、3:Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan、4:Institute of Clinical Medical Science, College
of Medicine, China Medical University, Taichung, Taiwan
Objectives
Risperidone is one of the most widely used atypical antipsychotics, with potent serotonin 5-HT2A and dopamine D2 receptor
blocking effects. A common side effect of atypical antipsychotics is weight gain, which leads patient non-compliance to
medication. The aim of this research was to investigate the association between serotonin receptor genetic polymorphisms
and risperidone-induced weight gain in Han Chinese schizophrenia patients.
Poster Session
Methods
A total of 114 schizophrenia patients treated with risperidone monotherapy were enrolled and all subjects have signed written
informed consent before the study began. Genomic DNA was extracted from peripheral blood and genotyping was performed
using real-time PCR. The tagging procedure was performed with the Haploview software and aggressive tagging was selected.
The r2 threshold was set at 0.8 and the minor allele frequency was set at 5% in Han Chinese. The significantly Antipsychotics-
induce weight gain was BMI ≥7% which according to FDA definition. The statistical analyses of associations between single
nucleotide polymorphisms (SNPs) and Risperidone-induced weight-gain were examined by SAS 9.1.3.
Results
Tagging SNPs in HTR1A were genotyped and both of them followed Hardy-Weinberg equilibrium. In the single locus analyses,
none of the included polymorphisms showed significant effect. Further haplotype analyses demonstrated that the HTR1A
haplotypes composed of rs10042486 A>G and rs878567C>T were significantly associated with risperidone-induced weight
gain (p<0.05).
Conclusions
These results suggested that risperidone-induced weight gain is related to HTR1A haplotypes in Han Chinese schizophrenia
patients.
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Wed(4)-P-196
Effects of Hyptis suaveolens and Boerhavia diffusa herbal extracts on recombinant human CYP enzyme
activity and cell cycle regulation
Nicholas E Thomford 1 ，Kevin Dzobo 1 ，Ambroise Wonkam 1 ，Collet Dandara 1
1:Pathology, Division of Human Genetics, University of Cape Town, Ghana
Introduction: Medicinal plants are commonly used in resource-constrained countries to support health care systems. Not much
has been done in evaluating the effects of commonly used medicinal plants. In this project, we focus on Hyptis suaveolens and
Boerhavia diffusa because of their predominant use among African populations for the treatment of several conditions including
cancer, malaria, hypercholesterolemia, ulcer, liver-related conditions and infections. Aim: This study was to investigate the
effects of Hyptis suaveolens and Boerhavia diffusa on the activities of some of the common drug metabolising enzymes as well
as their effects on the expression of some genes that play an important role in cell cycle regulation. Method: Recombinant
human CYPs were used to evaluate reversible and time-dependent inhibition (TDI) allowing for assessment of herb-drug
interactions (HDI). The potential of Hyptis suaveolens and Boerhavia diffusa to cause HDI was predicted accordingly and
TDI classification performed using the IC50 curve shift. qRT-PCR was used to evaluate the gene expression levels cell cycle
genes using WHC01 oesophageal cancer cells. DNA cell cycle analysis was performed using flow cytometry Results: Hyptis
suaveolens and Boerhavia diffusa exhibited reversible inhibition of activities of CYP2B6, CYP1A2, CYP2D6, CYP2C19,
CYP2C9 and CYP3A4. Differential -regulation of expression was observed for apoptotic and cell cycle associated genes and
DNA cell cycle analysis showed an arrest of cell cycle in the G0 /G1 phase Conclusion: Hyptis suaveolens and Boerhavia
diffusa are likely to cause an herb-drug interactions, thus, should be taken with caution. The differential expression of cell
cycle genes in the presence of herbal medicines calls for more studies to understand effects of drug-herb co-use.
Poster Session
Wed(4)-P-197
The associations between DRD2 and ANKK1 genetic polymorphisms and response to risperidone in
patients with schizophrenia
Ying-Chieh Chen 1 ，Chih-Yu Chen 1 ，Yu-Ning Teng 1 ，Ying-Tzu Chang 1 ，Jia-Lian Yang 1 ，Wei-Chieh Liao 1 ，
1:Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan、2:Department of Pharmacy, China Medical
University Hospital, Taichung, Taiwan、3:Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan、4:Institute of
Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan
Objectives
Risperidone is widely prescribed atypical antipsychotics for schizophrenia treatment. Despite of clinical benefit, large in-
terindividual variability of risperidone treatment response in schizophrenia patients has been reported and genetic factors
may be one of the contributors. The aim of this research was to evaluate the impact of DRD2 and ANKK1 genetic polymor-
phisms on the treatment responses of risperidone in Han Chinese schizophrenia patients.
Methods
Schizophrenia patients with risperidone monotherapy were enrolled from China Medical University Hospital. DNA was ex-
tracted from peripheral blood after all subjects provided written informed. Real-time PCR was used to perform genotyping.
The aggressive tagging procedure was selected in the Haploview software. The r2 threshold was set at 0.8 and the minor
allele frequency was set at 5% in Han Chinese. The treatment response of risperidone was evaluated by experienced psychia-
trists using the PANSS scores. The statistical analyses of associations between single nucleotide polymorphisms (SNPs) and
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ICHG2016 1262
risperidone treatment responses were examined by SAS 9.1.3.
Results
Tagging SNPs in DRD2 were genotyped and all of them followed Hardy-Weinberg equilibrium. In the single locus analyses,
none of the included polymorphisms showed significant effect. The DRD2 (rs1076560 and rs6275) and ANKK1 (rs1800497
known as Taq1A) showed strong linkage disequilibrium. Further haplotype analyses demonstrated that the haplotype and the
haplotype combination composed of DRD2 rs1076560 G>T, rs6275 T>C and the ANKK1 rs1800497 G>A were significantly
associated with improvement of PANSS scores under risperidone treatment (p<0.05).
Conclusions
Our results showed that DRD2 and ANKK1 genetic polymorphisms may influence the treatment response of risperidone in
schizophrenia patients
Wed(4)-P-198
Impact of HTR2A genetic polymorphisms on treatment outcomes of risperidone in patients with
schizophrenia
Jia Lian Yang 1 ，Chih-Yu Chen 1 ，Yu-Ning Teng 1 ，Ying-Tzu Chang 1 ，Ying-Chieh Chen 1 ，Wei-Chieh Liao 1 ，
Poster Session
1:Department of Pharmacy, College of Pharmacy, China Medical University, Taiwan、2:Department of Pharmacy, China Medical University
Hospital、3:Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan、4:Institute of Clinical Medical Science, College
of Medicine, China Medical University, Taichung, Taiwan
Objectives
Risperidone is one of the most widely prescribed atypical antipsychotics for schizophrenia treatment. Large interindividual
variability was observed in the responses of patients treated with risperidone. The purpose of the present study is to evaluate
the impact of HTR2A genetic polymorphisms on the treatment responses of risperidone in Han Chinese schizophrenia patients.
Methods
We recruited the total of 114 schizophrenia patients receiving risperidone monotherapy and all subjects provided written
informed consent before the study began. Genomic DNA came from peripheral blood and performed the genotyping using
real-time PCR. The procedure of tagging was performed with the Haploview software and selected aggressive tagging . The
r2 threshold was set at 0.8 and the minor allele frequency was set at 5% in Han Chinese. The experienced psychiatrists used
NOISE scores to assess the response of treatment. The associations between single nucleotide polymorphisms (SNPs) and
responses of risperidone treatment were statistically analyzed with SAS 9.1.3.
Results
Tagging SNPs in HTR2A were genotyped and all of them followed Hardy-Weinberg equilibrium. In the single locus analyses,
none of the included polymorphisms showed significant effect. In further haplotype analyses demonstrated that the HTR2A
haplotypes composed of rs3125 G>C and rs1923884 G>A were significantly associated with improvement of NOISE scores
under risperidone treatment (p<0.05).
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ICHG2016 1263
Conclusions
Our results indicated that HTR2A genetic polymorphisms may influence the response of risperidone treatment in Han Chinese
schizophrenia patients.
Wed(4)-P-199
Frequency of CYP2D6 poor metabolizers in a sample of Cuban patients with schizophrenia
Hilda Roblejo-Balbuena 1 ，Fernando de Andres 2 ，Beatriz Marcheco 1 ，Giselle Monzon 1 ，Teresa Collazo 1 ，
Adrian Llerena 2
1:National Center of Medical Genetics, Medical University of Havana, Cuba、2:CICAB Clinical Research Centre, Extremadura University
Hospital and Medical School, Badajoz, Spain
Background : CYP2D6 is central for the elimination of neuroleptic drugs. This enzyme has also been involved in the
metabolism of tyramine to dopamine and in the regeneration of serotonin from 5-methoxytryptamine, supporting the hypoth-
esis of a potential role of CYP2D6 in the vulnerability to schizophrenia. Some studies of association between the cytochrome
CYP2D6 and schizophrenia have shown a lower proportion of patients who are poor metabolizers, when compared with re-
ported frequencies in the source populations. Therefore, the purpose of this study was to investigate the frequency of CYP2D6
poor metabolizers in a sample of Cuban patients with schizophrenia.
Methods: CYP2D6 *3, *4, *5, *6 alleles were analysed in 212 unselected schizophrenia inpatients and 326 unrelated Cuban
Poster Session
healthy volunteers. Diagnosis of cases was established using DSM-IV. They were inpatients at Havana Psychiatric Hospital
(Havana, Cuba). Written informed consent and whole blood samples were obtained from each subject. The control group
were mostly Medical and Nursing school students and staff from the Faculty of Medicine ‘Calixto García’, and blood donors.
Results : The frequencies of CYP2D6 alleles that code for none activity was similar between patients with schizophrenia and
healthy volunteers. We also did not observe an under-representation of predicted PMs in our schizophrenic patients (1.88 vs
1.84 in healthy subjects). All the polymorphisms analyzed were in Hardy-Weinberg equilibrium in the cases and the controls.
Discussion : In this study, CYP2D6-predicted PM genotype might not be a determining factor of schizophrenia susceptibility
in Cubans. According to published data, 4.6% of a sample of individuals of the Cuban population were phenotypically poor
metabolisers for the enzyme CYP2D6. Even though the genotype does not always correlate with the drug hydroxylation
phenotype, is striking the low frequency of poor metabolizers found in both: the cases and controls.
Wed(4)-P-200
Trans-ethnic Study of N-acetyltransferase 2 diplotypes in anti-tuberculosis drug-induced liver injury
across Thai, Japanese, and Indonesian patients
Supharat Suvichapanich 1 ，Rika Yuliwulandari 2 ，Taisei Mushiroda 3 ，Hideki Yanai 4 ，Sukanya Wattanapokayakit 5 ，
Surakameth Mahasirimongkol 5 ，Katsushi Tokunaga 1
1:Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan、2:The University of Yarsi,
Jakarta, Indonesia、3:Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan、4:Fukujuji
Hospital, Japan Anti-Tuberculosis Association, Kiyose, Japan、5:Medical Genetics Center, Medical Life Sciences Institute, Department of
Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand
Tuberculosis (TB) remains important global infectious disease problem. The standard anti-TB regimen consisting of isoniazid,
rifampicin, and pyrazinamide, is well known for its hepatotoxicity. Polymorphisms of N-acetyltransferase 2 (NAT2) gene were
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ICHG2016 1264
reported to affect metabolic activity of isoniazid in liver and risk of anti-tuberculosis drug-induced liver injury (AT-DILI) in
several populations. In the present study, to assess the contribution of each NAT2 allele, individual NAT2 genotyping data
were obtained from case-control association studies in Thailand, Japan, and Indonesia. AT-DILI cases were defined according
to WHO toxicity classification standard. Tolerant controls were TB patients who completed standard treatment without
liver injury. Our trans-ethnic study was performed with Mantel-Haenzel test with fixed effect model. NAT2*6A/*6A and
NAT2*6A/*7B demonstrated remarkable associations with AT-DILI in three populations: NAT2*6A/*6A, 15 of 53 cases,
5 of 85 controls in Thais, 6 of 73 cases, 4 of 293 controls in Japanese, 12 of 50 cases, 18 of 191 controls in Indonesians
(meta-analysis OR 4.36; 95%CI 2.44 - 7.79, p-value = 6.1 x 10-8 ); NAT2*6A/*7A, 15of 53 cases, 2 of 85 controls in Thais, 4 of
73 cases, 5 of 293 controls in Japanese, 10 of 50 cases, 22 of 191 controls in Indonesians (meta-analysis OR 3.16, 95%CI 1.67
- 5.99, p-value = 0.0004). In contrast, NAT2*5B/*5B, *5B/*6A, *5B/*7B, and *7B/*7B were not significantly associated
with the risk of AT-DILI. Recently, the concept of ultra-slow acetylator, consisting of NAT2*6A and NAT2*7B haplotypes,
was proposed. Interestingly, our study provides evidence that only NAT2*6A/*6A and NAT2*6A/*7B, ultra-slow acetylator
diplotypes, but not all NAT2 slow acetylators are responsible for AT-DILI in Thais, Japanese and Indonesians. In summary,
our trans-ethnic study supported that NAT2*6A/*6A and NAT2*6A/*7A are the strong genomic biomarkers for predicting
risk of AT-DILI in Thais, Japanese, and Indonesians.
Wed(4)-P-201
Methadone Maintenance Treatment Combine use of Amphetamine is Associated with APBB2 Genetic
Variants
Poster Session
Chia-Chen Liu 1 ，Chiu-Ping Fang 1 ，Sheng-Wen Liu 1 ，Hsiang-Wei Kuo 1 ，Sheng-Chang Wang 1 ，Ing-Kang Ho 2,3
，
Yu-Li Liu 1
1:Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan、2:Center for Drug Abuse and Addiction, China
Medical University Hospital, Taichung, Taiwan、3:Graduate Institute of Clinical Medical Science, China Medical University, Taichung,
Taiwan
APBB2 (amyloid beta (A4) precursor protein-binding, family B, member 2) is associated with opioid dependence. In this
study, we analyzed the genetic variants on APBB2 in association with the methadone maintenance treatment (MMT) re-
sponses.
344 heroin-dependent patients undergoing MMT were recruited and assessed for urine amphetamine and morphine tests,
withdrawal severity, and side effects. The DNAs were genomewide genotyped for all patients. The single nucleotide poly-
morphisms (SNPs) on APBB2 genetic region were selected for methadone treatment responses association analyses. The
APBB2 genetic expression levels were measured by real-time polymerase chain reaction (PCR) in EBV-transformed patients’
lymphoblastoids.
Patients with urine amphetamine test positive also had significantly higher percentage of urine morphine test positive
(P=0.005), and insomnia (P=0.018) than amphetamine test negative patients. In single locus association analyses, both
genotypes and allele types of SNPs rs3935357, rs13126487 and rs4861075 at APBB2 intron 6 were significantly associated
with urine amphetamine test MMT patients (general linear model (GLM), P=0.0003, 0.001, and 0.0002 for genotype, and
0.0003, 0.002, 0.002 for allele type, respectively). The T allele type carriers of these three SNPs showed higher percentage of
urine amphetamine tests positive than the C allele type carriers. The TT genotype carriers on rs4861075 had significantly
higher total (P=0.02) and long-form (P=0.037) APBB2 genetic expressions than the CC genotype carriers.
MMT patients who had combined use of amphetamine had higher percentage in urine morphine test positive. The genetic
variants on intron 6 of APBB2 could be indicators for MMT patients combined use of amphetamine.
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ICHG2016 1265
Wed(4)-P-202
Systemic analyses of a methadone maintenance population reveal plasma N-cadherin network to treat-
ment outcome
1,2
Yu-Li Liu ，Hsiang-Wei Kuo 1 ，Jieh-Hen Tsung 1 ，Sheng-Wen Liu 1 ，Sheng-Chang Wang 1 ，Chia-Lung Shih 1
1:Center for Neuropsychiatric Research, National Health Research Institutes, Taiwan、2:Graduate Institute of Clinical Medical Science,
China Medical University
Background/Objective
Methadone maintenance treatment (MMT) is a standard prescription for heroin dependent patients. The treatment outcome
is usually judging by the urine opiate/morphine test results, but factors influence the outcome is not clear.
Method
A total of 344 MMT patients were recruited with genomewide genotyped and quality checked. The plasma cadherin 2, type 1,
N -cadherin (CDH2 ), cytokine IL-7 and metalloproteinase ADAM metallopeptidase domain 10 (ADAM10) were measured by
Enzyme-linked immunosorbent assay (ELISA). The single nucleotide polymorphisms (SNPs) locating at CDH2 were analyzed
by general linear model for statistical association analyses with blood pressure and plasma CDH2 concentration.
Result
Poster Session
Two SNPs locating at intron 2 of the cell adhesion molecule CDH2 showed significant associations with blood pressure and
plasma CDH2 concentration. In systemic correlation analyses, plasma CDH2 concentration showed correlations with cytokine
IL-7, HIV infection status, and urine morphine test result. The HIV infected MMT patients had lower plasma CDH2 and IL-7
concentrations than the non-infected patients. The urine morphine test negative patients had higher plasma CDH2 levels.
Plasma IL-7 was correlated with corrected current electrocardiogram (QTc) and gooseflesh skin withdrawal symptom score.
As plasma CDH2 were released from the biotransformation of metalloproteinase ADAM10, plasma ADAM10 was analyzed
and showed correlation with plasma vitamin D metabolite, nicotine metabolite, and R-methadone concentration.
Conclusion
This study suggested using systemic correlation analyses of plasma CDH2 might lead to the discovery of networks involving
with methadone treatment outcome.
Wed(4)-P-203
The frequencies of pharmacogenomically relevant rare variants in the Lithuanian population
Vaidutis Kucinskas 1 ，Aidas Pranculis 1 ，Tautvydas Rancelis 1 ，Laima Ambrozaityte 1 ，Ingrida Uktveryte 1 ，
Ingrida Domarkiene 1 ，Zita Ausrele Kucinskiene 1
1:Department of Human and Medical Genetics, Vilnius University, Lithuania
Cardiovascular disease (CVD) is one of the leading causes of death among Europeans and around the world. Major factors
that are considered relevant for the efficacy or adverse drug reactions (ADRs) caused by drugs used for CVD treatment have
been identified through GWAS studies mostly using low density common variant genotyping arrays.
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ICHG2016 1266
In this study whole exome sequencing was carried out with the Applied Biosystems 5500 SOLiD ™ Sequencer to identify rare
genomic variants relevant for CVD treatment. Sufficient coverage of over 20x was achieved to evaluate the prevalence and the
frequencies of possibly pharmacogenomically relevant SNVs and small indels in the exomes of the Lithuanian population. The
study group included 98 (49 males and 49 females) self-reported healthy unrelated individuals from the Lithuanian population
with at least 3 generations living in Lithuania. Genetic loci of 58 genes that were reported as relevant to the efficacy or ADRs
caused by drugs used for CVD treatment were analyzed using LifeScope™ and ANNOVAR software.
The analysis of small indels in the selected regions revealed no variants that have been shown to affect the efficacy or cause
ADRs in patients treated for CVDs. Over 400 potentially relevant SNVs in varying frequencies were found in the genes
reported to be important for CVD treatment. The strength of evidence analysis identified 14 SNVs most likely to be relevant
for CVD treatment. The frequency distribution of several variant alleles that have been shown to be highly important
for CVD treatment in the KCNJ11 (rs5219), CYP2D6 (rs16947) and ADRB1 (rs1801253) genes were determined to be
significantly (p<0.05) different from other Caucasian populations showing the potential benefit of pharmacogenomic testing
prior to treatment in the Lithuanian population.
This study is part of the LITGEN Project (VP1-3.1-MM-07-K-01-013) funded by the European Social Fund under the Global
Grant Measure.
Wed(4)-P-204
Poster Session
Genetic risk factors for phenobarbital and phenytoin-induced cutaneous adverse drug reactions in
Japanese population
Takeshi Ozeki 1 ，Taisei Mushiroda 1 ，Atsushi Takahashi 2 ，Michiaki Kubo 3
1:Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Japan、2:Laboratory for Stastical Analysis, RIKEN
Center for Integrative Medical Sciences、3:RIKEN Center for Integrative Medical Sciences
Anticonvulsants phenobarbital (PB) and phenytoin (PHT) are known to show incidences of cutaneous adverse drug reactions
(cADRs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity
syndrome (DIHS). To identify a gene(s) susceptible to PHT and PB-induced cADRs, we conducted a genome-wide association
study (GWAS) and subsequent HLA typing in 22 cases of PB and PHT-induced cADRs (consist of 10 PB, 10 PHT and 2
PB/PHT treated patients) and 882 subjects of a general population in Japanese. Among the SNPs analyzed in the GWAS
followed by imputation, 5 SNPs showed significant association with PB and PHT-induced cADRs, and rs34341880 showed
the smallest P-value for association with CBZ-induced cADRs (additive model, P = 3.70 x 10-11 ; dominant model, P = 4.84
x 10-10 ). These SNPs were located in the HLA-B loci. Thus, we genotyped the individual HLA-B alleles and found that
HLA-B*13:01 was present in 31.8% (7/22) of the cADR cases, but in 1.7% (15/880) of the general population controls (odds
ratio (OR) = 28.8, 95% confidence interval (CI) = 10.2-81.7, P = 2.47 x 10-7 ). By the conditional analysis for the amino-
acid sequences, HLA-B with 145Leu-158Ala (corresponding to HLA-B*13:01 and B*13:02) or HLA-B with 145Arg-158Thr
(HLA-B*38:01, B*38:02, B*39:01, B*39:02, B*39:04 and B*67:01) were associated with PB and PHT-induced cADRs. These
8 HLA-Bs were present in 68.2% (15/22) of the cADR cases, but in 10.3% (91/880) of the general population controls (odds
ratio (OR) = 18.6, 95% confidence interval (CI) = 7.4-46.8, P = 3.76 x 10-10 ). Comparison of genotypes of the HLA-B and
the marker SNP rs34341880 in all subjects revealed that the 8 HLA-B alleles was in strong LD with the T allele of rs34341880
(r2 = 0.95, D’ = 1.00).
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Wed(4)-P-205
Opportunities and Obstacles to International Implementation of Genetic Screening for Stevens Johnson
Syndrome/Toxic Epidermal Necrolysis: The Global Genomic Medicine Collaborative (G2MC)
Teri A. Manolio 1 ，Mark Avigan 2 ，Wasun Chantratita 3 ，Wen-Hung Chung 4 ，Ricardo Cibotti 5 ，Robert L Davis 6 ，
Joshua C Denny 7 ，Carolyn M Hutter 1 ，Lois LaGrenade 2 ，Surakameth Mahasirimongkol 8 ，Munir Pirmohamed 9 ，
Neil H Shear 10 ，Jeffery Struewing 1 ，Cynthia Sung 11 ，Ronald van Schaik 12 ，Robyn Ward 13 ，Lisa M Wheatley 14,15 ，
Geoffrey S Ginsburg 15
1:Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda MD, USA、2:Center
for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring MD、3:Medical Genomic Center, Ramathibodi
Hospital, Mahidol University, Bangkok, Thailand、4:Department of Dermatology, Drug Hypersensitivity Clinical and Research Center,
Chang Gung Memorial Hospitals, Taipei, Linkou, and Keelung, and College of Medicine, Chang Gung University, Taiwan、5:Division of
Skin and Rheumatic Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda MD、6:Center for Biomedical
Informatics, University of Tennessee Health Science Center, Memphis TN、7:Departments of Biomedical Informatics and Medicine,
Vanderbilt University, Nashville TN、8:Medical Genetics Center, Medical Life Sciences Institute, Department of Medical Sciences, Ministry
of Public Health, Nonthaburi, Thailand、9:Institute of Translational Medicine, University of Liverpool, Liverpool UK、10:Department of
Medicine (Dermatology and Clinical Pharmacology and Toxicology), University of Toronto, Toronto Canada、11:Duke-National University
of Singapore Graduate Medical School, Singapore、12:Department of Clinical Chemistry at the Erasmus University Medical Center,
Rotterdam, The Netherlands、13:Level 3 Brian Wilson Chancellery, University of Queensland, Brisbane, Queensland, Australia、14:Division
of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, Bethesda MD、15:Center for Applied
Genomics and Precision Medicine, Duke University, Durham NC
Genetic screening for risk of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) has reduced incidence of
carbamazepine-induced SJS/TEN in a cost-effective manner in several Southeast Asian countries where risk allele frequencies
are high, but the effectiveness of such approaches outside this region remains to be explored. The Global Genomic Medicine
Collaborative (G2MC), a multi-national coalition of genomic and policy experts from over 20 countries working to implement
genomics in clinical care, has identified genetic screening for SJS/TEN as a key opportunity and potential paradigm for
reducing morbidity and mortality through genomic medicine implementation.
Poster Session
G2MC also recognizes numerous obstacles to implementation of SJS/TEN screening and needs for addressing them. Basic
research is needed to clarify mechanisms of genetic risk and discover additional risk alleles in other ancestry groups. Rapid,
low-cost genotyping is needed for persons likely to receive high-risk drugs, along with improved population-specific reference
databases for accurate imputation, particularly in the HLA-B region where so many risk alleles lie. Reliable reporting of risk
status to patients and their clinicians and pharmacists will need to involve electronic health records and cloud-based queries
prior to prescribing and dispensing. Electronic clinical decision support models need to be collected and made available for
adaptation to other settings. Policy frameworks for consent, confidentiality, and appropriate access to clinical information
are needed and may vary regionally based on cultural norms and local practices.
Several countries have implemented such systems including the Netherlands, Singapore, Taiwan, and Thailand. G2MC seeks
to gather these models, evaluate their generalizability, disseminate them, and address key obstacles to implementing this
outstanding opportunity for reducing or eliminating SJS/TEN, one of the most devastating of all adverse drug reactions.
Wed(4)-P-206
NUCLEOTIDE VARIANTS IN THE PROMOTER REGION OF THE THYMYDILATE SYNTHASE
GENE PREDICT FOR TOXICITY TO FLUOROPYRIMIDINES IN COLORECTAL CANCER PATIENTS
Augusto Rojas-Martinez 1,2 ，Carlos Castro-Rojas 1,2,3 ，Irma S. Garcia-Gonzalez 4 ，Sergio Buenaventura-Cisneros 4,5
，
Oralia Barboza-Quintana 5 ，Hector Maldonado-Garza 5 ，Juan F. Gonzalez-Guerrero 5 ，Rocio Ortiz-Lopez 1,2
1:Centro de Investigacion y Desarrollo en Ciencias de la Salud, Universidad Autonoma de Nuevo Leon, Mexico、2:School of Medicine,
Universidad Autonoma de Nuevo Leon (Monterrey, Mexico)、3:School of Medicine, Universidad El Bosque (Bogota, Colombia)、4:Centro
Medico Nacional del Noreste UMAE 25, IMSS (Monterrey, Mexico)、5:University Hospital - Universidad Autonoma de Nuevo Leon
(Monterrey, Mexico)
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Fluoropyrimidines are the backbone of the fisrt-line chemotherapy for metastatic colorectal cancer (mCRC). Although about
17% of the patients treated with fluoropyrimidines develop severe toxicity, there are no biological markers for toxicity prediction
in the clinical setting (1,2). Thymidylate synthase (codified by the TYMS gene) is the molecular target of fluoropyrimidines
and its expression is influenced by the variants rs45445694, rs183205964 and rs2853542 located in the putative promoter
region of the gene. Such variants could be divided in those of Low (Lo) and High (Hi) expression, based in their effect on the
expression of the enzyme and could be potential biomarkers for toxicity with fluoropyrimidines (3-5). An association study
based on the genotypification of these three variants was conducted in 99 CRC Mexican patients treated with fluoropyrimidines
and 99 healthy matched individuals. Genotype frequencies for rs45445694 (2R/2R 18%, 2R/3R 48%) were in agreement with
the Hardy-Weinberg law. 42% of the patients developed toxicity, 24% of which were severe (3-4, CTCAE v4.1). Patients
were divided in Lo and Hi groups based in their genotypes (3). Lo genotypes were associated with severe toxicity (P=0.021 ,
OR=4.0, 95% IC=1.6-10.1). This result suggests that the rs45445694, rs183205964 and rs2853542 variants of TYMS are
potential biomarkers for toxicity to fluoropyrimidines.
References. 1. Cassidy, J., et al. Ann Oncol. 2002. 13(4):566-75 2. Schwab, M. et al. J Clin Oncol. 2008. 26(13):2131-2138.
3. Kawakami, K., Watanabe, G. Cancer Res. 2003. 63:6004-4007. 4. Gusella, M., Bolzonella, C., Crepaldi, G., Ferrazzi,
E., Padrini, R. Pharmacogenomics J.2006. 6(6):421-424. 5. Lincz, L. F., Scorgie, F. E., Garg, M. B., Ackland, S. P. Int J
Cancer.2007. 120(9):1930-1940.
Wed(4)-P-207
Performance of Novel Direct NAT2 haplotyping in Thai populations
Poster Session
Nuanjun Wichukchinda 1 ，Wimala Inunchot 1 ，Jirapha Pakdee 1 ，Punna Kunhapan 1 ，Supharat Suvichapanich 1 ，
Phongpan Muakmued 1 ，Sukanya Wattanapokayakit 1 ，Nusara Satpoedprai 1 ，Licht Toyo-oka 2 ，Katsushi Tokunaga 2 ，
Surakameth Mahasirimongkol 1
1:Department of Medical Sciences, Medical Life Sciences Institute, Thailand、2:Department of Human Genetics, Graduate School of
Medicine, The University of Tokyo, Japan
Introduction N-acetyltransferase 2 (NAT2), the major enzyme that acetylates isoniazid (INH), has high genetic diversity and
can be classified into rapid, intermediate and slow acetylator. NAT2 slow acetylator has strong risk for INH induced hepatitis.
However, the conventional method for NAT2 haplotyping by statistical inference from SNP genotyping is prone to errors and
difficult for non-statisticians. We aimed to develop the simplified low-cost NAT2 haplotyping to eliminate the haplotype
inference step that can be used in low and middle income countries.
Method We developed allele specific PCR-based method (AS-PCR) for NAT2 diplotyping which composed of 6 reaction tubes
with specific primers for NAT2*4, *5B, *6A, *7B, *12A, and *13A. A primer pair for TIMP1 amplification was utilized as
an internal control in each reaction. The haplotypes were directly determined by specific sizes of PCR product in agarose gel.
This method was validated in 520 DNA samples with inferred NAT2 diplotype from combining NAT2-exon2 sequencing and
computational PHASE analysis.
Results Concordance rate of diplotyping between the novel AS-PCR and the conventional method were 99.04%. The discordant
results (5/520 samples) were due to rare NAT2 haplotypes of *5C (n=3), *7C (n=1) and *11A (n=1), which were determined
by AS-PCR as *5B, 7B*, and *4, respectively.
Discussion This AS-PCR for NAT2 diplotyping provide perfect concordance of acetylator status (89 rapid, 229 intermediate,
and 202 slow) compared with standard method. The discordant haplotypes of *5C (slow), *7C (slow) and *11A (rapid) were
in the same acetylator status with their corresponding AS-PCR based haplotyping as *5B (slow), *7B (slow), and *4 (rapid).
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This method is direct NAT2 diplotyping, has no risk of errors from statistical haplotype inference, and can be implemented
in simple molecular laboratory. The novel AS-PCR is the first step to enable the routine use of NAT2 acetylator status in
clinical practice.
Wed(4)-P-208
The Evaluation of AmpliChip ™ CYP450 Test and Luminex xTAG  platforms for detection of polymor-
phisms in genes encoding CYP2D6 drug metabolizing enzyme in Thai subjects
1
Monpat Chamnanphon
1:Pathology, Division of Pharmacogenomics and Personalized Medicine, Faculty of Medicine, Mahidol University, Thailand
Introduction: The CYP2D6 enzymes is one of the most phase I drug metabolizing enzymes involved in a large number of
widely prescribed medications in clinical use. The analysis of CYP2D6 genotyping had affected the selection of appropriated
drug dose and treatment. However, current technology is not provided the perfect accuracy of CYP2D6 genotyping. There-
fore, the main objective was to evaluate the performance of CYP2D6 genotyping assay between AmpliChip ™ CYP450 Test
and allele-specific primer extension assay (ASPE, Luminex xTAG  v3) platforms.
Methods: We included 114 Thai subject samples who had completely investigated genotyping of CYP2D6 by using Am-
pliChip ™ CYP450 Test, which separated into 2 parts (83 called and 31 no-call genotypes) and compared to Luminex xTAG 
CYP2D6 v3 assay in existing clinical routine laboratory.
Poster Session
Results: The re-investigated results were almost entirely concordant except, especially 20.48% (17 of 83) including 4 gene
duplications, 3 discordant and 10 no-call genotypes of which Luminex assay was detected. The first part of CYP2D6 geno-
typing called by AmpliChip assay comprised 79.52% (66 of 83) of concordant rate with Luminex, with a highly successful
call rate of 87.95% (73 of 83), and total no-call rate of CYP2D6 by using Luminex was 12.05 % (10 of 83) and the results of
second part exhibited 74.19% (23 of 31) of successful call rate; moreover, the remaining results also revealed 25.81% (8 of 31)
of indeterminate genotypes by using Luminex.
Conclusion: Both platforms displayed the high frequency of discrepant, indeterminate genotyping results including SNP pat-
terns, gene duplication and indeterminate genotype; however, these results need to be confirmed and clarified by further
studies by using many tools for explicit all structures and functional consequence of CYP2D6 in a large Thai population.
Key words: CYP2D6 gene, Drug metabolizing enzyme, Genetic polymorphism, AmpliChip ™ CYP450 Test, Luminex xTAG 
CYP2D6 v3
Wed(4)-P-209
Development of a method for targeted resequencing of 100 pharmacogenes
Koya Fukunaga 1 ，Yukihide Momozawa 2 ，Michiaki Kubo 3 ，Taisei Mushiroda 1
1:Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Japan、2:Laboratory for Genotyping Development,
RIKEN Center for Integrative Medical Sciences、3:RIKEN Center for Integrative Medical Sciences
Pharmacogenes play a role in the absorption, distribution, metabolism and excretion of drugs and influence the pharmacokinet-
ics of drugs. Several pharmacogenes have been used for pharmacogenomic biomarker testing to predict adverse drug reactions
(ADRs) and/or drug efficacy. Although many genetic variations associated with drug concentration dependent ADRs and
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drug efficacy were reported in the pharamacogenes, there is a possibility that unknown common and rare variations, which
have large effects on drug responses, might exist in coding regions of the pharmacogenes. Therefore, we intended to develop
a method for the targeted resequencing of coding regions of 100 pharmacogenes using a next generation sequencer. As the
100 pharmacogenes to be examined, 37 transporters, 30 CYPs, 10 UGTs, 5 FMOs, 4 GSTs, 4 SULTs and 10 other genes were
selected. Specific primers were designed to amplify 1,138 coding regions. Targeted resequencing of the 100 pharmacogenes at a
20× minimum depth in a Japanese individual derived from the International HapMap Consortium was carried out. Coverage
of all coding regions was more than 99%. After visual confirmation in the Integrative Genomics Viewer, 158 single nucleotide
variations (SNVs), 4 insertions and 6 deletions were identified. When comparing the present results with those of the same
subject previously genotyped by whole exome sequencing of the 1000 genomes project, 140 and 18 SNVs were concordant and
discordant with our results, respectively. Based on comparison with all SNVs observed by Sanger sequencing, false positive
and false negative rates were 0% and 0.6%, respectively. In conclusion, we developed a high throughput and high accurate
method to find novel variations of 100 pharmacogenes by targeted resequencing.
Wed(4)-P-210
Risking Cardiac Failure to Cure Cancer: Identifying the Risk Factors for Adverse Drug Events
Horacia Naidoo 1 ，Rajkumar S Ramesar 1 ，Hannah Simonds 2
1:Pathology - Human Genetics, University of Cape Town, South Africa、2:Radiation Oncology, Tygerberg Hospital, University of Stellenbosch
INTRODUCTION: Breast cancer occurs in 25% of all cancer diagnoses. Early diagnoses and treatment advances have
Poster Session
significantly decreased mortality. Anthracycline-based chemotherapy specifically has increased survival from 30% - >80%.
However, efficacy is marred by the risk of anthracycline-induced cardiotoxicity (ACT) - estimated at 10-26%. Currently in SA,
there is no information on ACT in breast cancer patients. Our recruitment sites in Cape Town - Groote Schuur Hospital (GSH)
and Tygerberg Hospital (TBH) routinely treat patients with anthracyclines.OBJECTIVES: To provide insight into the clinical
management of breast cancer patients on anthracyclines focusing on ACT. To provide an index of genetic susceptibility to
ACT. METHODOLOGY: Retrospective patient analysis, from 2011-2015, found it difficult to clinically stratify those at high
risk of ACT. Recurring variability in individual response indicated a genetic predisposition to ACT which has been confirmed
by several studies. Compelling findings prompted the design of a prospective laboratory based study. Recruited patients’
blood samples are analysed for genetic variants, expression and cardiac injury utilising a biomarker. Demographics, clinical risk
factors, left ventricular ejection fraction (LVEF %) as a surrogate measure of cardiac function and chemotherapeutic regimen
data are also assessed. PRELIMINARY RESULTS: Retrospective findings indicated a significant trend for diminished cardiac
function due to anthracycline-based chemotherapy. Trends indicate specific genetic variants associated with an increased risk
of ACT and an increased likelihood of cardiotoxicity in the Indigenous African population. NEXT STEPS: There will be
comprehensive patient follow-up and exomic sequencing for “extreme phenotype” patients. Genetic data derived from the
study will contribute to a better understanding of ACT in a South African population and potentially allow for a personalized
treatment approach.
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Wed(4)-P-211
Determinants of plasma concentrations of rosuvastatin and its metabolite in Chinese patients with
hypercholesterolaemia by genome-wide analysis
Miao Hu 1 ，Rui Sun 2 ，Maggie Wang 2 ，Claudia Tam 1 ，Ronald Ma 1 ，Juliana Chan 1 ，Brian Tomlinson 1
1:Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong、2:JC School of Public Health and Primary
Care, The Chinese University of Hong Kong
Aim: This study examined associations between single-nucleotide polymorphisms (SNPs) and plasma concentrations of rosu-
vastatin and N-desmethyl rosuvastatin in Chinese patients with hypercholesterolaemia
Methods: A total of 369 patients who were treated with rosuvastatin 10 mg daily for at least 4 weeks were genotyped using
the Illumina Human Omni ZhongHua-8 v1.1 BeadChip. After quality control, 791,715 SNPs were analysed for association
with plasma concentrations of rosuvastatin and N-desmethyl rosuvastatin which were measured approximately 12 hour after
dose using liquid chromatography tandem mass spectrometry.
Results: In 291 patients with plasma concentrations of rosuvastatin available (mean(±SD) age: 56.0±11.7 years, 141 males), 8
linked SNPs on chromosome 4 were significantly associated with the plasma concentration of rosuvastatin (P<5×10-8 ). These
SNPs were near or within the gene ABCG2 which codes for the efflux transporter that plays an important role in the dispo-
sition of rosuvastatin. In addition, a SNP in chromosome 3 (rs117638523) which is located in TM4SF4 (transmembrane 4 L
six family member 4) was associated with the plasma concentration of rosuvastatin at genome-wide significance (p< 6×10-8 ).
A total of 22 SNPs on chromosomes 2, 4, 5, 6, 7, 8, 12, 15, 18 and 21 showed strong association with the ratio of plasma
Poster Session
concentrations of N-desmethyl rosuvastatin to rosuvastatin (P<6×10-8 ). The strongest statistical association signals were
observed with 3 SNPs (β-coefficient of 0.44, P<1×10-19 ) located at the intergenic region between E2F7 and LOC100507484
on chromosome 12, suggesting that this region may be related to the metabolism of rosuvastatin to N-desmethyl rosuvastatin.
Conclusions: The preliminary analysis of this genome-wide association study confirmed the association between ABCG2
and the pharmacokinetics of rosuvastatin and revealed some new loci which may be relevant to drug metabolism. Further
replication will be conducted.
Wed(4)-P-212
Genome-wide analysis for determinants of plasma concentrations of simvastatin and simvastatin acid in
Chinese patients with hypercholesterolaemia
Tomlinson Brian 1 ，Miao Hu 1 ，Rui Sun 2 ，Maggie Wang 2 ，Claudia Tam 1 ，Ronald Ma 1 ，Juliana Chan 1
1:Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong、2:JC School of Public Health and Primary
Care, The Chinese University of Hong Kong
Aim: Chinese patients have an increased risk of simvastatin-induced myopathy, which may be related to an increased systemic
exposure. This study examined associations between single-nucleotide polymorphisms (SNPs) and plasma concentrations of
simvastatin and simvastatin acid in Chinese patients with hypercholesterolaemia.
Methods: A total of 278 patients with hypercholesterolaemia who were treated with simvastatin 40 mg daily for at least 4
weeks were genotyped using the Illumina Human Omni ZhongHua-8 v1.1 BeadChip. After quality control, 791,715 SNPs
were analysed for association with plasma concentrations of simvastatin and simvastatin acid which were measured in samples
taken approximately 12 hour after dose using liquid chromatography tandem mass spectrometry.
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Results: In 242 patients with plasma concentrations of simvastatin available (mean(±SD) age: 55.5±11.0 years, 98 males), 6
SNPs on chromosome 2, 4 and 6 were significantly associated with the plasma concentration of simvastatin lactone (P<6×10-8 ).
The top 2 SNPs (β-coefficient of 3.34, P<5×10-9 ) were located at 6q14.1, near to the HTR1B (Serotonin Receptor 1B), which
functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive
substances. For simvastatin acid, 8 SNPs on chromosomes 2, 4, 5, 8, 11, 19 and 20 showed strong association (P<6×10-8 )
with a SNP in CRTC1 (CREB regulated transcription coactivator 1) located at 19p13.11 being the strongest signal (β
-coefficient of 8.40, P<5×10-10 ). Two SNPs in the efflux transporter ABCB11 were significantly associated with both plasma
concentrations of simvastatin and simvastatin acid.
Conclusions: This genome-wide association study identified several new loci which may be relevant to the disposition of
simvastatin. The findings of this study need to be replicated.
Wed(4)-P-213
Targeted resequencing of 340 ADME genes in human liver
Kathrin Klein 1,2 ，Roman Tremmel 1,2 ，Sarah Fehr 3 ，Stefan Winter 1,2
，Elke Schaeffeler 1,2
，Matthias Schwab 1,2
，
Saskia Biskup 3 ，Ulrich M Zanger 1,2
1:Pharmacogenetics, Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Germany、2:University Tuebingen、3:CEGAT GmbH
Tuebingen
We developed a panel-based targeted Next-Generation Sequencing (NGS) pipeline for exon sequence analysis of 340 genes
Poster Session
involved in absorption, distribution, metabolism and excretion (ADME) of xenobiotics and endogenous substances including
phase I/II enzymes, drug transporters and modifiers (nuclear receptors and other transcription factors). We focus here on cis
and trans associations of single nucleotide (SNV) and copy number variants (CNV) in modifiers with ADME gene expression
in human liver. A set of 150 extensively characterized Caucasian liver samples was sequenced in all exonic, exon/intron
boundaries, 5’ and 3’UTRs regions using a specifically designed NGS setup (1.17 Mbases total target size). Validation
was performed using Illumina HumanHAP300 SNP arrays and other genotyping methods. Functional effects of coding or
UTR SNVs were predicted using available online tools. The impact of SNVs/CNVs on gene expression (Illumina Human
WG6v2) was assessed. In total, 31,880 SNVs and INDELs meeting quality criteria were detected including about 1,000
SNVs/INDELs in target regions of 48 modifier genes of which 32% were not yet listed in dbSNP. 189 variants were located in
coding regions, 50 in splice regions and 380 in 5’/3’ UTRs. Of 145 missense variants 46 were predicted to be deleterious by
both PROVEAN and SIFT algorithms. Furthermore, several of the 3’UTR variants were predicted to interfere with miRNA
binding. Associations with gene expression in ADME gene families will be presented.
Our targeted NGS approach on an ADME gene panel provides high coverage to detect known and novel variations. Although
novel rare polymorphisms contribute to pharmacogenetic variability, the major challenge will be to predict and analyze their
functional impact on protein expression and activity.
The study was supported by the Robert Bosch Foundation, Stuttgart, Germany
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Poster Session
Cytogenetics
Wed(4)-P-214
Two novel constitutional incidental findings discovered during cancer workout may explain patient ex-
cessive clinical feature
1,2
Jacqueline R Batanian ，Mark Fesler 3 ，Leonard Grosso 4 ，Sagun Goyal 3 ，Cuevas Daniel 4
1:Pediatrics, Saint Louis University, USA、2:Cardinal Glennon Children’s SSM Medical Center、3:Hematology, Saint Louis University、
4:DePaul Health Center SSM Medical Center
Cytogenomics analysis was performed on two patient bone marrows to rule lymphoma. Following conventional cytogenetic
(CCA) and fluorescence-in situ hybridization (FISH) analyses, chromosome microarray analysis (CMA), the two patient
bone marrows were found to carry two submicroscopic deletions disrupting novel constitutional copy number variant (cCNV)
that may explain their excessive clinical feature. Both patients A and B were referred for NHL workout. CCA of the bone
marrow of patient A who also had an excessive dermatopathic lymphyadenopathy revealed an apparent balanced translocation
t(4;12)(q31;q24.3). FISH of T-cell lymphoma panel was negative. CCA of the bone marrow of patient B who also had severe
hemolytic anemia revealed normal chromosome and FISH MDS and NHL panels. CMA of patient A bone marrow and
blood revealed the translocation to harbor a submicroscopic deletion (173.26 kb) within 4q31 region involving LRBA gene
Poster Session
(Lipopolysaccharide-reponsive, beige-like anchor protein, OMIM# 606453) from intron 9 to intron 17 including exons 10
to 17. CMA of patient B bone marrow and blood revealed a 128 kb submicroscopic deletion at 7q31.31 involving KCND2
(potassium voltage-gated channel, shl-related subfamily, member 2) . Both aberrations were found in different tissues of the
patient indicating constitutional in origin.
LRBA gene if found homozygote deleted, is associated with the disorder common variable immunodeficiency, common variable,
8-T-cell regulatory with autoimmunity. This raises the question whether one copy deletion of the gene could have played a
role in patient excessive dermatitis at adult onset. Potassium gated channel genes like KCNE2 and not KCND2 as found here
is known to be associated with iron-deficient anemia. This raises the question whether the deletion in KCND2 in patient B
is playing a role in his severe anemia.These two CNVs appear to play a role in adult onset disesase. However, more cases are
needed to confirm this correlation.
Wed(4)-P-215
Interstitial Structural Variations associated with Congenital Anomalies
1,2
Mariluce Riegel ，Rafaella Mergener 2 ，Rafael FM Rosa 3
1:Service of Medical Genetics,Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil、2:Postgraduate Program in Genetics and
Molecular Biology, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil、3:Clinical Genetics, Universidade Federal de Ciências
da Saude de Porto Alegre (UFCSPA) and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), RS, Brazil
The elucidation of many genomic disorders associated with chromosomal rearrangements began with molecular technologies
that enabled detection of genomic changes which were smaller than those resolved by traditional cytogenetics (less than
5 Mb). Methods such fluorescent in situ hybridization (FISH) can resolve such changes but are limited to locus-specific
studies. The study of chromosome-disease disorders has rapidly advanced with the development of array-based techniques.
These enabled examination of the entire human genome at a higher level of resolution, allowing the elucidation of the basis
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of many disease-causing chromosomes rearrangements, originated by mechanisms that result in genomic changes leading to
copy number variation (CNV). The aim of our study was the cytogenomic evaluation of complex chromosomal rearrange-
ments present in five individuals with multiple congenital anomalies and also the understanding of the origin of interstitial
chromosome abnormalities. We delineated the structural and architectural features of three chromosome interstitial deletions
(del3q11.2q13.31, del6p24.3p22.3 and del 18q21.2q23) and two interstitial duplications (dup 18p11.32p11.21 and 8q24.13q24)
involving random genomic segments. The structural and architectural features of these segments, which can potentially result
in genomic instability, showed distinct mechanisms of origin leading to chromosome de novo and inherited deletions and dupli-
cations disease-and non-disease causing rearrangements. In the postgenomic era, our understanding of different mechanisms
leading to chromosome abnormalities has advanced very rapidly as the level of technical resolution has become higher. This
leads to a greater understanding of the effects of chromosome rearrangements present both in healthy subjects and individuals
with clinically relevant phenotypes and the understanding of the characteristics, features, and plasticity of our genome.
Wed(4)-P-216
Genomic imbalances associated with conotruncal heart defects
Mariluce Riegel 1 ，Karen R.S. de Souza 2 ，Nathalia Ortigara 1 ，Lucia Pellanda 3
1:Service of Medical Genetics, Hospital de Clinicas de Porto Alegre, RS, Brazil、2:Postgraduate Program in Genetics and Molecular Biology,
Universidade Federal do Rio Grande do Sul (UFRGS),RS, Brazil、3:Institute of Cardiology, University Foundation of Cardiology, RS, Brazil
Despite considerable advances in the detection of genomic abnormalities in congenital heart disease (CHD), the etiology of
CHD remains largely unknown. CHD is the most common birth defect and is a major cause of infant morbidity and mortality,
Poster Session
and conotruncal defects constitute 20% of all CHD cases. We used array comparative genomic hybridization (array-CGH) to
retrospectively study 60 subjects with conotruncal defects and identify genomic imbalances. The DNA copy number variations
(CNVs) detected were matched with data from genomic databases, and their clinical significance was evaluated. We found
that 38.3% (23/60) of CHD cases possessed genomic imbalances. In 8.3% (5/60) of these cases, the imbalances were causal
or potentially causal CNVs; in 8.3% (5/60), unclassified CNVs were identified; and in 21.6% (13/60), common variants were
detected. Although the interpretation of the results must be refined and there is not yet a consensus regarding the types of
CHD cases in which array-CGH should be used as a first-line test, the identification of these CNVs can assist in the evaluation
and management of CHD.The results of such studies emphasize the growing importance of the use of genome-wide assays in
subjects with CHD to increase the number of genomic data sets associated with this condition.
Wed(4)-P-217
Consanguinity and its genetic consequences: a detailed analysis of a cohort with multiple disabilities
using SNP array
Frenny J Sheth 1 ，George Mampilly 2 ，Tomy Mampilly 2 ，Stuti Tewari 1 ，Boris Keren 3 ，Neeradha Chandramohan 2 ，
Vijayalakshmy Janaki 2 ，Jayesh Sheth 1
1:Cytogenetics and Molecular Cytogenetics, FRIGE’s Institute of Human Genetics, India、2:Department of Physical Medicine & Rehabil-
itation, National Institute for Empowerment of Persons with Multiple Disabilities, Tamil Nadu, India、3:Assistance publique Hôpitaux de
Paris, France
Consanguinity has been associated with increased risk of congenital malformations, intellectual disability and recessively
inherited diseases in progeny. The inheritance of defective autosomal recessive genes in the progeny from parents is in the
order of 25% in each pregnancy. The aim of the study is to delineate possible risk of genetic abnormality in the disabled children
born to consanguineous parents and determine the inheritance of defective genes, if any. The study design employed SNP
array in 10 children to look for quantitative genomic imbalance in the form of deletions, duplications or Loss of Heterozygosity
(LOH). Parents and normal siblings were also tested and acted as controls. CNV was detected in 8 of 10 children. LOH
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spanning several base pairs on a number of chromosomes were noted in all cases. In 5 of the 8 children, autosomal recessive
genes of these LOH regions correlated to the phenotype of the patient. We also noted that normal siblings did not inherit
the defective gene and had lesser content of LOH regions. The results of this study throw light not just on the various
implications of consanguineous unions but also the genomic imbalances/changes resulting in phenotypic manifestations. In
such population, the formulation of a public health program with multi-level approach or a legislation mandating education
about the anticipated genetic consequences in consanguineous marriages and genetic counseling is a necessity.
Wed(4)-P-218
Molecular cytogenetic characterization of an analphoid marker chromosome derived from 12 pter in
Pallister Killian diagnosis: First case report in Canada and review of the reported cases
Faezeh Vasheghani Farahani 1 ，Marry Ann Thomas 2 ，Bob Argiropoulos 2 ，Judy Chernos 2
1:Human Genetics, McGill university, Canada、2:Alberta Children Hospital, Calgary, AB, Canada
Background: Pallister Killian Syndrome (PKS) is a rare sporadic genetic disorder which is caused by tissue limited mosaicim
of an extra copy on a derivative chromosome or an intrachromosomal duplication of the short arm (p) of the chromosome 12.
Results: In the present study, we describe the first PKS Canadian case which had different structural abnormality pattern.
First cytogenetic analysis showed partial tetrasomy mosaicim of 12p caused by an i(12p) marker chromosome in buccal swab
Poster Session
interphase FISH. The presence of marker chromosome was confirmed by CGH array. However, array results did not show
duplication in the centromeric region in chromosome 12. Thus, our hypothesis based on the presence of neocentromere in
this marker chromosome, was investigated by different molecular cytogenetics approaches. First, to validate our array results
we used the whole chromosome 12 painting probe and all human centromere probe (pans) in metaphase FISH. Our results
proved that although the arms of marker chromosome come from chromosome 12, the centromere of i(12p) not only does
not belong to chromosome 12, but also does not fit in to any other chromosomes. We determined the presence of analphoid
centromere i(12p) by having the negative results of C-banding, devoid of alpha-satellite DNA, analysis.
Conclusion: Our case is the first Canadian report, of a de novo analphoid marker chromosome originating from the short arm
of chromosome 12, and the fourth worldwide report of a neocentromere formation at 12p in PKS.
Keywords: Pallister Killian, mosaicim, CGH array, analphoid centromere
Wed(4)-P-219
Visualization of Cytogenetic Testing in Clinical Genetics
Mamoru Ozaki 1 ，Yo Niida 1,2
，Etsuko Takase 2 ，Yoritsune Ito 2,3
，Hitoshi Sato 2,3
，Toshiro Ikeda 4
1:Medical Research Institute, Kanazawa Medical University, Japan、2:Center of Genetic Counseling, Kanazawa Medical University Hospital、
3:Pediatrics, Kanazawa Medical University Hospital、4:Genetic Counseling Unit, Kagoshima University Hospital
Object
We make video contents about several technologies and the manual of cytogenetic testing and hand a record of an arrival
point of several technology until present to posterity.
Method
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This subject is a plan to be accomplished in three years of April 2015-March 2017.
In the first year, we started video production with the photographing equip- ments on our hands. We have already begun to
produce video contents of method of preparation for chromosome specimen, method of FISH for uncalutured amniocyte, and
method of preparation for chromosome specimen from abortion chorionic villus. After the 2nd year, we plan for acquisition
of the outside research fund of the science research grant and do more high-definition video production
We will complete video contents which net several technology of cytogenetic testing related to prenatal diagnosis.
Result
The 1st edition video about the method of preparation for chromosome specimen can be seen through home page
(http://www.g-band.com that is managed jointly with Dr. Toshiro Ikeda, Kagoshima University). In method of FISH for
uncalutured amniocyte, We had a vignetting trouble on phase contrast microscope image of prepared slide after pepsin
treatment.
Conclusion
New chromosome specimen preparation condition was found in production of this video content. A good result is maintained.
We are planning to introduce the new method of preparation for chromosome specimen by next version video content.It’s
possible to settle an enumerated problem by photography machinery and materials. We are aiming at acquisition of the
Poster Session
outside research fund (the science research grant) for it. As soon as other video contents are also getting ready and production
is ended, it’s expected to upload it in a home page at any time. Also we are planning to produce English version, upload it
in YouTube and send for the world.
Wed(4)-P-220
The importance of root cause analysis following an external quality assessment (EQA) to improve the
quality of a diagnostic service
Rosalind J Hastings 1 ，Nicola Foot 2 ，Cheryl Guiver 1 ，Sheila O’Connor 3 ，Bettina Quellhorst-Pawley 1 ，
Eva van den Berg de Ruiter 4
1:CEQAS, Oxford University Hospitals NHS Foundation Trust, UK、2:Viapath Genetic Labs, Guys & St Thomas’s NHS Foundation
Trust、3:Haematological Malignancy Diagnostic Service, Leeds Teaching Hospitals NHS Trust, Leeds、4:Dept. of Genetics, University of
Groningen, The Netherlands
External Quality Assessment (EQA) is essential to externally verify the quality and accuracy of the diagnostic service. When
new technologies emerge, EQAs need to be developed to verify the laboratory diagnostic validation process and enable bench-
marking of their performance. As an EQ A provider, CEQAS (Cytogenetic External Quality Assessment Service) provides
a range of EQAs for genetics including Constitutional and Acquired Cytogenetics, Molecular Pathology, Pre-Implantation
Genetic Diagnosis and Genetic Counselling.
EQA is intended to be educational so if a laboratory receives a poor performance, they are asked to review their results and
perform an audit so they can identify the root cause of the error. If required, repeat EQA samples are made available to
exclude the rare instances of a problem with a manufacturer’s kit.
Recent root cause analysis by laboratories has identified flaws in the internal quality management systems including sample
switches, incorrect probes applied, equipment service etc. A thorough root cause analysis by one participating laboratory
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identified a potential problem with one manufacturer’s probe. An independent verification by CEQAS using multiple FISH
probes and arrays confirmed a 967kb deletion of 13q14.2q14.3. There is a discordant result between the microarray and FISH
probes for one of the deletion breakpoints. As a consequence the manufacturer immediately withdrew the probe and replaced
it with a new product to eliminate the likelihood of future false negative results. Another laboratory identified a problem
with one of the fluorescent microscope filters resulting in an incorrect FISH result, once this filter was replaced a review of
all diagnostic cases from the previous 12 months had to be undertaken.
EQA benefits laboratories and regular participation is recommended. We will present data from different EQAs where internal
quality or training issues have been identified through EQA.
Wed(4)-P-221
MODIFYING INFLUENCE OF OCCUPATIONAL INFLAMMATORY DISEASES ON THE LEVEL OF
CHROMOSOME ABERRATIONS IN COAL MINERS
Maxim Yu. Sinitsky 1,2 ，Valentin P. Volobaev 1 ，Yury E. Kulemin 2 ，Aleksey V. Larionov 1 ，Varvara I. Minina 1,2
，
Alina V. Meyer 1 ，Marina V. Ulyanova 1
1:Biology Faculty, Department of Genetics, Kemerovo State University, Russia、2:Laboratory of Cytogenetics, Institute of Human Ecology
of SB RAS
Coal is one of the most abundant minerals in nature and the largest fossil fuel source used for the generation of energy.
Coal-mining is characterized by long-term contact with harmful occupational agents. The influence of such agents leads not
Poster Session
only to an increase in the risk of initiation of various chronic diseases but also to genotoxic risk. DNA damage resulting
from exposure to genotoxic agents can be registered using methods of assessing chromosomal aberrations (CAs) in human
lymphocytes.
Blood samples were obtained from 90 coal miners working in the mines of Kemerovo Region (Russia) and undergoing medical
examination. The study group included patients with occupational inflammatory pulmonary diseases. Blood samples obtained
from 124 healthy unexposed men were included in control 1, and samples from 42 healthy coal miners were included in control
2. Cytogenetic investigation was performed using the routine test for the assessment of CAs. Counting of the aberrations was
performed using light microscopy without karyotyping. The selection of metaphases included in the analysis and the criteria
for cytogenetic abnormalities conformed to the generally accepted recommendations.
The results of this work showed that coal miners are significantly characterized by increases in the total number of CAs (5.72
± 2.55% vs. 1.13 ± 1.00% in control 1) and in the frequency of several types of aberrations. The study of the contribution
of various lung diseases of inflammatory origin to overall genotoxicity showed a significant increase in chromosomee type
exchanges (0.39 ± 0.60% vs. 0.21 ± 0.35%) and chromosome type aberrations (1.79 ± 1.02% vs. 1.26 ± 0.88%) in occupational
inflammatory disease patients compared with control 2. There was no modifying effect of smoking on a level of chromosome
damage, and no correlation was found between age or work experience in hazardous conditions and the level of cytogenetic
damage.
This work was supported by State task No. 2015/2162.
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Wed(4)-P-223
Paternal Uniparental Disomy (UPD) Chromosome 14-like syndrome due to a rare case of partial deletion
of the imprinting region at 14q32.1-32.2.
Susan G. Brown 1 ，Lesley K McGregor 2 ，Alison H Attwood 1 ，Sarah M Smith 1 ，Sui Yu 1
1:Genetics and Molecular Pathology, SA Pathology, Australia、2:SA Clinical Genetics Service, Australia
A 4 day old boy with hypotonia, small chest and dysmorphic features was referred for CGH microarray testing. The baby
was large for gestational age weighing 4020g at term with polyhydramnios. He was hirsuit with marked truncal hypotonia.
Dysmorphic features include frontal bossing, a prominent philtrum, a small chin, dysplastic ears and a short neck. In addition,
he had long fingers and toes, fasciculations of the tongue, and a bell-shaped chest on X-ray.
Array CGH (BlueGnome 60K) identified an interstitial deletion of 217kb at 14q32.1-q32.2 [101,309,237-101,526,453(hg19)].
This deletion involved 20 OMIM genes, including three imprinted genes: MEG3, MEG8 and RTL1. SNP array analysis of
the proband and parents showed that the 14q32.1-q32.2 deletion was de novo and occurred on the maternal allele.
The imprinted gene cluster on chromosome 14q32 carries several paternally expressed genes (PEGs) DLK1, RTL1 and ma-
ternally expressed genes (MEGs) MEG3 and MEG8. Expression of these PEGs and MEGs is regulated by two differentially
methylated regions (DMR: Ig-DMR and MEG3-DMR). Deletions of the maternal copy of this imprinted region have been
reported in at least 10 patients with paternal UPD14-like syndrome. Most of these deletions included one or both of the
DMR regions which are considered critical to cause paternal UPD14-like syndrome.
Poster Session
The 14q32 deletion in our patient does not involve the Ig-DMR or MEG3-DMR. Three other patients with a smaller deletion
(122kb-160kb) not involving the DMRs have recently been reported in the literature (Corsello G, et al, 2015, Am j Med Genet
Part A9999A:1-9). The phenotypes of these four patients are reviewed and compared. The clinical features include prenatal
polyhydramnios (4/4), bell-shaped thorax (4/4), dysmorphic features (4/4) and hypotonia (3/4) and are consistent with a
paternal UPD(14)-like phenotype.
Wed(4)-P-224
Duplication/Deletion in chromosome 13 arising from a maternal paracentric inversion: A U-Type Re-
combination Event
Ben A Lundie 1 ，Jasen Anderson 1 ，Ross Brookwell 1 ，Michael Gattas 1 ，James Harraway 1 ，Mana Mahrjouy 2 ，
Niels Tommerup 2
1:Sullivan Nicolaides Pathology, Australia、2:Willhelm Johannsen Centre For Functional Genome Research, University of Copenhagen,
Denmark
We present a case of a 4 year old male with developmental delay. Initial investigation based on dysmorphic features and poor
feeding at birth by conventional cytogenetics revealed what appeared to be a paracentric inversion of 13q21.2-q22. Parental
chromosome studies were requested, and the presumed inversion was also found to be present in the proband’s mother.
More recently, based on the suspicion that a small duplication, deletion or gene disruption at the breakpoints may have
caused the proband’s phenotype, an array CGH study was requested. This study surprisingly revealed a 15.7mb deletion
at 13q21.31-q31.1 and a 15.7mb duplication at 13q31.1-q32.1. Microarray investigation of the proband’s mother showed no
genetic imbalance.
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Using mate-pair sequencing we have been able to exclude the possibility of a cryptic insertion, confirming the maternal
rearrangement as a paracentric inversion. In addition, the mate-pair sequencing establishes the orientation of the proband’
s rearrangement as a deletion and a tandem inverted duplication.
We propose that the imbalance observed in the proband appears to be the result of a rare U-type recombination event of the
maternal paracentric inversion during meiosis, resulting in the formation of a viable monocentric unbalanced recombinant.
Wed(4)-P-225
Chromosomal aberrations detected in Idiopathic mental retardation and multiple congenital abnormalities
(MCA): Validation of molecular cytogenetic techniques High resolution banding (HRB) and Fluorescent
in Situ Hybridization (FISH)
Venkatesh Huskur Narayana Rao 1 ，Jeru Manoj Manuel 1 ，Chetan G K 1
1:Human Genetics, NIMHANS, India
Mental retardation (MR) is defined as significantly decreased general intellectual functioning resulting in or associated with
concurrent impairments in adaptive behavior and manifested during the developmental stage (DSM-IV). Causes include either
genetic or environmental risk factors or by interplay of both. Chromosomal aberrations, single gene mutations and multiple
genes acting together account for the genetic causes of mental retardation. Chromosomal anomalies and simple Mendelian
traits account for 20% of the mental retardation and polygenic heredity for 10%, atleast 5% of the mental retardation is
Poster Session
solely due to environmental factors and etiology of the remaining 65% is either controversial or unknown i.e., Idiopathic.
Current study was aimed at exploring association of unknown genetic causative factors that could contribute to etiology of
idiopathic MR and thereby establish phenotype-genotype correlation. Conventional karyotyping followed by HRB and FISH
analysis was done on chromosome preparations of peripheral blood lymphocytes from 100 patients diagnosed with Idiopathic
MR and MCA. Intellectual and phenotypically normal healthy age-matched 50 individuals were chosen as control subjects.
Subtle chromosomal aberrations were observed in 12% (8: males, 4: females) of patients, such as two translocations, four
deletions, four inversions, and two ring chromosome formations using HRB and FISH (conventional karyotype did not show
abnormality). Familial analysis revealed one family with first degree consanguinity (two siblings affected with the same
chromosome anomaly in their karyotype), the rest showing no consanguineous union. Correlations of phenotypic-genotypic
status in subjects with Idiopathic MR have a clear cut association with chromosomal aberrations (12% in present study), but
molecular cytogenetic techniques need to be used. Genetic and psychological counseling becomes a necessity for parents of
the affected subjects for proper management.
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Wed(4)-P-226
Clinical and Molecular Delineation of Duplication 19p13.2 encompassing NFIX
Carlos Venegas 1,2 ，Mariano Guardado 3 ，Consuelo Cantu 4 ，Luis Zepeda 4 ，Rony Kersenovich 5 ，Jaime Berumen 2,3
，
Gildardo Zafra 5
1:Servicio de Genetica, Hospital General de Mexico, Mexico、2:Facultad de Medicina UNAM、3:Servicio de Medicina Genomica. Hospital
General de Mexico、4:GENOMI-K, Monterrey NL、5:Genomica. Hospital Espanol
Background: Haploinsufficiency of NFX1 due to 19p13.2 microdeletions, small intragenic deletions, and point mutations are
cause of Sotos syndrome-like features (Sotos syndrome 2) or Malan syndrome, characterized by development delay/intellectual
disability, macrocephaly, overgrowth, and distinctive facial findings. Duplications of 19p13.12-p13.2 encompassing NFIX have
been published in only two patients and interestingly, microcephaly is described. Methods and Results: Here, we reported a 35
years-old female patient with facial dysmorphic features, intellectual disability, microcephaly, and short stature. Chromosomal
microarray analyses identified a 19p13.2 microduplication of about 3.58 Mb (hg19:10,041,093-13,622,352). We recognized 7
additional cases with 19p13.12-p13.2 pure microduplications including NFIX annotated in DECIPHER database. The clinical
findings of all 10 individuals were reviewed, and the core phenotype consists of developmental delay/intellectual disability,
microcephaly, and short stature. Conclusions: Based in our case and literature review, we suggested that microduplications
containing NFIX on 19p13.2, could be associated with a contrasting phenotype of the Malan syndrome microdeletion, and
that a gene dosage effect of the NFIX gene is the likely cause.
Wed(4)-P-227
Poster Session
SCREENING OF MARKER CHROMOSOMES AND METHYL CpG BINDING PROTEIN-2 (MeCP2)
POLYMORPHISM IN SCHIZOPHRENIA PATIENTS IN COIMBATORE - A PILOT STUDY
Gomathi Mohan 1 ，Mahalaxmi Iyer 1 ，Balachandar Vellingiri 1 ，Sasikala Keshavrao 1 ，Human Molecular Genetics and Stem Cell Lab
Schizophrenia is a chronic, severe, disabling brain disorder with lifelong disability, characterized by perturbation in cognition,
hallucination and delusion. To observe the chromosomal alterations and MeCP2 mutation in patients with Schizophrenia
in Coimbatore population. Our study consists of 30 samples including 15 individuals of schizophrenia and equal number
of age matched controls. The schizophrenic and control subjects were categorized into three groups using DSM-V such as
Schizophrenics with positive symptoms (group I) n=5, Negative symptoms (group II) n=5 and Cognitive symptoms Group
(III) n=5.
Chromosome abnormalities were found in group I schizophrenia subjects were: 46,XY,t(5;15); 46,XX,del(6)(p21);
46,XY,del(7)(q32); 46,XY,del(22)(q13); group II: 46,XY,dup(7)(p15p21); 46,XY,t(5;15); 46,XX,del(6)(p21); 46,XY,inv(9)(p11q13);
XY,del(22)(q11) and group III : 46,XX,15ps+; 46,XY,inv(9)(p11q13); XY,del(22)(q11). The mean plasma dopamine (31.53
± 4.49) and cortisol (8.48 ± 0.05) levels were higher in group I than other groups. TSH is higher in group I (1.74 ±
0.67) and group III (1.35 ± 0.58) of schizophrenia, whereas lower level in group II (0.71 ± 0.37) of schizophrenia. The
genotypic frequency for the MeCP2 polymorphism was 61% for A/A genotype, 35% for the A/G genotype and 8% for the
G/G genotype. The controls showed 46%, 24% and 30% of A/A, A/G and G/G respectively. There was no significant
difference in the distribution of genotypes and allele frequency between schizophrenia and control subjects (p = 0.021;
p = 0.021) respectivelyIdentification of these chromosomal abnormalities associated with schizophrenia might provide
important implications for further research for the chromosomal location of major genes in this disease. Our findings suggest
that these regions are of interest in that they may harbor important genes for schizophrenia.
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Wed(4)-P-228
Turner Syndrome Caused by Rare Complicated X Chromosomal Structural Abnormalities
1,3
Niu Li ，Juan Li 2 ，Tingting Yu 1,3
，Xiumin Wang 2,3
，Yiping Shen 3 ，Jian Wang 1,3
1:Institute of Pediatric Translational Medicine, Shanghai Children Medical Center, Shanghai Jiaotong University School of Medicine, China、
2:Department of Endocrinology and Metabolism, Shanghai Children Medical Center, Shanghai Jiaotong University School of Medicine、
3:Department of Medical Genetics, Shanghai Children Medical Center, Shanghai Jiaotong University School of Medicine
Turner syndrome (TS) is a heterogenous genetic disorder caused by X-chromosomal structural abnormalities that affects
in about 1 of 2500 females. The affected individuals may develop diverse clinical features, including short stature, ovarian
dysgenesis, skeletal dysplasia, facial abnormalities and other disorders. Karyotype of 45, X accounts for nearly 50% in Turner
patients, other X-chromosomal structural abnormalities, containing deletions, duplications, rings, isodicentric chromosomes,
inversions, and translocations have been reported, successively. Here, we present chromosome microarray analysis (CMA)
in two Chinese female Turner patients with idiosyncratic karyotype, the first patient had a karyotype of 46, X, +mar, and
CMA results demonstrated the unknown chromosome was an abnormal X-chromosome composing of three deletions (Xp21.3-
p11.23, Xp11.1-q13.1, and Xq21.31-q28) as well as three duplications (Xp22.33-p21.3, Xp11.23-p11.1, and Xq13.1-q21.31).
The karyotype of the second patient was 46, X, der(X) t (X;?) (q22.1;?), inv(11)(q13.5q21), CMA revealed an Xq21.2-q27.1
duplication and an Xq27.2-q28 deletion. In addition, the genotype-phenotype correlation study results in the two cases
indicate that the SHOX gene isn’t the only causing gene responsible for the short stature in Turner patients.
Wed(4)-P-229
Poster Session
array CGH analysis of first and second trimester euploid miscarriages
Alihossein Saberi 1 ，Golamreza Shariati 1,2
，Hamid Galehdari 2,3
，Mohammad Hamid 2,4
，Nehzat Abdorasouli 2
1:Medical Genetics, Ahvaz Jundishapour University of Medical Sciences, Iran、2:Narge Genetics and PND Laboratory、3:Department of
Genetic, Shahid Chamran University、4:Department of Biotechnology, Pasteur Insistute, Tehran, Iran
Spontaneous abortions are common, with 10% to 15% of all clinically recognized pregnancy ending in early pregnancy loss.
Routine analysis of miscarriage samples has been performed by karyotyping of methaphase spreads after tissue culture. How-
ever, due to failure of culture growth, maternal contamination and poor chromosome morphology associated with conventional
karyotyping often no result or erroneous result is obtained. We analyzed 102 fetal tissue samples derived by first and second
trimester with a normal karyotype. Illumina 4x44k and 4x180k CGH array cytochips were utilized to detect genome wide
copy number variants (CNVs) in our samples. All identified CNVs were analyzed with references from Data Base of genome
Variants (DGV), database of DECIPHER, ISCA and OMIM, as well as comprehensive literature review to determine whether
the identified CNVs were pathogenic. Nine non polymorphic copy number variants (CNVs), ranging in size between 300kb
and 28.8Mb and their gene content were identified in 7 sample (7%) (4 gains, 5 losses). Clinically significant and pathogenic
CNVs were detected in 5 (~ 5%) of the samples. This study shows that by applying array CGH in prenatal diagnosis in
conjunction with chromosomal analysis, 3% additional clinically significant genomic imbalances can be detected when the
karyotype is normal.
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Wed(4)-P-230
VRK2 : A Novel Gene Causing Isolated Autosomal Dominant Bilateral Congenital Optic Nerve Hypopla-
sia
Eva Pipiras 1 ，Suzanne Kuzbari 2 ，Jonathan Levy 3 ，Camille Leroy 3 ，Celine Dupont 3 ，Marine Durand 1 ，
Anne-Claude Tabet 3 ，Brigitte Benzacken 1 ，Pierre Bitoun 4
1:Service d’histologie embryologie et cytogenetique, Hopital Jean Verdier, France、2:Departement de Genetique, Genetique moleculaire,
Hopital Robert Debre、3:Departement de Genetique, Cytogenetique, Hopital Robert Debre、4:Service de Pediatrie, Hopital Jean Verdier
Purpose :
Optic nerve hypoplasia (ONH) is a rare congenital ocular malformation causing severe visual handicap.Children are often
blind at birth or usually progress to severe visual incapacity in the first 2 years. ONH is often syndromic (septo-optic dysplasia
or de Morsier syndrome), and is associated with MRI anomalies of the pituitary region with endocrine hormonal deficiencies.
The genetic origin of isolated ONH is unknown; our purpose was to identify possible genetic causes of isolated ONH.
Methods :
5 probands with isolated ONH were tested using Illumina SNP array after informed consent.
Results :
Poster Session
A single subject was found to show a 410,4kb deletion of the arr2p16.1(58,012,833-58,423,312)x1 region encompassing the
VRK2 gene and the promoter and first exons of the FANCL gene. The501L9 (Blue-FISH) was used to confirm deletion of
the 2p26.1 region.Two other duplications were also detected:the first of 3.12 Mb (inherited from mother) in 16p13.11-p12.3
including 27 genes of which 3 OMIM are disease-associated (NDE1, MYH11, ABCC6), and a 106 kb 22q12.3 duplication
including 4 genes containing 2 OMIM disease-associated genes (APOL1 and MYH9).
VRK2 (Vaccinia Related Kinase-2) has previously been associated by GWAS with several neuro-psychiatric illnesses such as
schizophrenia, epilepsy or glaucoma. This kinase may thus play a role during the embryologic formation of the optic nerve.
We compare our findings with cases previously reported in the literature, and discuss the phenotype-genotype correlations.
We propose the 2p15-p16.1 microdeletion contiguous gene syndrome with novel minimal critical sub-region for isolated oph-
thalmologic impairment.
Conclusion :
We identified VRK2 as a putative autosomal dominant gene candidate involved in isolated optic nerve hypoplasia. This gene
is deleted in a proband as detected by SNP microarray in one of 5 families studied with ONH.
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Wed(4)-P-231
FREQUENCY OF CHROMOSOMAL BREAKS IN SUSPECTED CASES OF FANCONI’S ANAEMIA-
A SINGLE CENTER EXPERIENCE
Saira Shan 1 ，Muhammad Nadeem 2 ，Sheeba Shehzad 3 ，Saqib Ansari 4 ，Mehwish Taj 4 ，Munira Borhany 4 ，
Tasneem Farzana 4 ，Tahir S Shamsi 4
1:Clinical & Molecular Cytogenetics, National Institute of Blood Disease & Bone Marrow Transplantation Karachi, Pakistan、2:National
Institute of Blood Disease & Bone Marrow Transplantation、3:Karachi Institute of Biotechnology & Genetics Eng (KIBGE), University of
Karachi、4:National Institute of Blood Disease & Bone Marrow Transplantation
Introduction: Fanconi’s (FA) anemia is the most frequently reported rare inherited bone marrow failure syndromes. FA
accounts for about 25% cases of Aplastic Anaemia (AA). Screening of all patients undergoing bone marrow transplantation
especially those suffering from AA should be done due to therapeutic implications and selection of donor.
Objective: To determine the frequency of chromosomal breaks in patients referred to Cytogenetics Department on the
suspicion of FA/AA.
Location & Study Design: Retrospective study carried out from May 2010 - October 2015 in National Institute of Blood
Disease & Bone Marrow Transplantation Karachi, Pakistan.
Material & Method: Chromosomal Breakages analyses were performed on patients diagnosed as AA or with suspicion of
FA using stimulated 72 hrs cultures treated with Mitomycin C & without Mitomycin C employing solid Giemsa staining
technique.
Poster Session
Results: Peripheral Blood samples of 259 patients were analyzed for chromosomal breaks including 169 (65%) males and 90
(35%) females with median age of 12 years (range 03 months-64 years). Out Of total, 69 (27%) patients showed chromosomal
breaks ranges in 05% to 100% metaphases. Most of the patients, 31 (45%) exhibiting chromosomal breaks were suffering from
AA. Chromosmal breaks also seen in 03 (04%) donors of transplant patients, in siblings of FA patients 18 (26%) and patients
with phenotypic features suggestive of FA 17 (25%).
Conclusion: Fanconi’s Anaemia is diagnosed with increased frequency in centers managing haematological disorders. Most of
the patients are diagnosed when they develop bone marrow aplasia. All patients of Aplastic Anaemia/Hypocellular Marrow
and siblings of such patients are recommended to be screened for FA by Chromosomal Breakages Analysis.
Key Words: Aplastic Anaemia, Chromosomal Breakages, Fanconi’s Anaemia, Mitomycin C
Wed(4)-P-232
Computer simulation analysis of the three-dimensional relative positioning of chromosome 21 territories
in the human 21 trisomy cell nuclei
Koichi Sekizawa 1 ，Tomohisa Kato 1 ，Hideyuki Tanabe 2
1:Faculty of Health Sciences, Kyorin University, Japan、2:Department of Evolutionary Studies of Biosystems, School of Advanced Studies,
SOKENDAI (The Graduate University for Advanced Studies)
The spatial positioning of chromosome territories (CTs) in the case of numerical chromosome aberrations has much unknown
nature. Previously, we have examined the 3D relative positioning of 21 CTs in the human 21 trisomy cell nuclei by 3D-FISH
technique and have revealed that there was a tendency for which two 21 CTs were arranged mutually in the neighborhood
among three 21 CTs.
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Here, we investigated whether this phenomenon occurred in an active process or in a passive process, which was exposed
to a certain probability, by comparing the values from a 3D computer simulation with the measured values from the image
stack data of two cell lines, MR50 and MR74, using 3D-FISH technique. Both MR50 and MR74 are lymphoblastoid cell lines
showing a standard type of 21 trisomy.
Two indices were used for this analysis to express the distribution of the triangular "Shape" formed with numerically three
CTs. One is the Maxθ of the maximum interior angle, and the other is the R/r of the ratio to radius (R) of the circumcircle and
the inscribed circle radius (r). Statistical analysis of the computer simulation was carried out using Wilcoxon’s signed-rank
test and the actual measurement values of the two cell lines.
From the statistical analysis, we found that it can be classified into two types of spatial positioning with this simulation. One
was a“whole spatial type" located in the entire nucleus, and the other was a “boundary spatial type" that localized CTs near
the peripheral region around the nuclear membrane. Our data suggested that two cell lines, MR50 and MR74, were divided
into these two types, respectively. This might be due to different origin of the parental genomic backgrounds, even in the
standard type of 21 trisomy. It is very interesting that the relationships between the results of the computer simulation and
the clinical conditions, then we hope computer simulation would be contribute to the clinical applications in the future.
Wed(4)-P-233
Prenatal diagnosis of the unbalanced translocation between chromosome 15 and Y-chromosome in a
Poster Session
female fetus
HeeJu Park 1 ，RaJin Kwon 1 ，SooMin Lee 1 ，SangHee Go 1 ，SoHyun Park 1 ，SuKyung Jo 1 ，DongSuk Lee 1 ，
KiChul Kim 1 ，DoYeong Hwang 1
1:Hamchoon Women’s Clinic, Korea, South
Objectives : We analyzed conventional karyotyping combined with FISH and molecular genetics techniques of Yq/15p translo-
cation in order to provide genetic counseling for prenatal diagnosis.
Methods : Amniotic fluid and peripheral blood of family members were analyzed with G banding and molecular cytogenetics
analysis like this quantitative fluorescence PCR (QF-PCR), fluorescence in situ hybridization (FISH).
Results : Cytogenetic analysis of cultured amniocytes showed 46,XX,add(15). FISH result showed that there were two chro-
mosomes X and one derived chromosome 15 contained Yq12. The sex-determining region Y (SRY) gene was confirmed not
to be present by QF-PCR and FISH methods. Cytogenetic studies were carried out on the parents, paternal mother, pa-
ternal brother. The karyotype of the father using G-band technique was confirmed the unbalanced translocation between
chromosome Y and 15 : 46,XY,der(15)t(Y;15). The der (15) has been inherited from the paternal mother. Her karyotype was
46,XX,der(15)t(Y;15), and SRY gene was negative. Paternal brother’s karyotype was 46,XY,der(15)t(Y;15)mat. Our final
report on the karyotype : 46,XX,der(15)t(Y;15)(q12;q10)pat.
Conclusions : The main factor influencing sex determination of fetus is the sex-determining region Y (SRY) gene. It can
be confirmed by molecular genetic analysis with cytogenetic analysis. In addition, family history is necessary for genetic
counseling.
Keywords : Prenatal diagnosis, Quantitative fluorescence PCR (QF-PCR), Conventional cytogenetics
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Wed(4)-P-234
A novel Four-way Philadelphia translocation t(9;22;3;1)(q34;q11.2;q26;q32) along with unusual t(8;17)
in a chronic myeloid leukemia patient in chronic phase
Sonika Sharma 1 ，Vandana Lal 1 ，Saurabh K Bhattacharya 1
1:Cytogenetics, Dr Lal Path Labs, New Delhi, India
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease which originates in bone marrow stem cells. More than
90% of CML patients exhibit Philadelphia (Ph) chromosome produced as a result of reciprocal translocation between the q
arm of chromosome 9 (q34) and 22(q11.2). Approximately, 5-10% of these patients show complex translocations involving a
third chromosome in addition to chromosome 9 and 22. In this study, we present a unique variant Ph translocation involving
four chromosomes in a 29 year female who was diagnosed as CML in chronic phase. Chromosome analysis using GTG-banding
was performed according to standard procedures. A total of 20 metaphases derived from the unstimulated bone marrow of the
patient were analyzed. Karyotype was described according to the International System for human Cytogenetic Nomenclature
(2013). FISH using a LSI BCR/ABL and PML/RARA dual colour dual fusion translocation probe AbbottMolecular/Vysis,
USA) was applied according to the manufacturer’s instructions. Chromosome analysis revealed two cell lines with complex
karyotype. The first cell line had four way translocation t(9;22;3;1)(q34;q11.2;q26;q32). The second cell line in addition to
four way translocation had t(8;17)(q11.2q11.20). A dual-colour FISH using a probe specific for BCR and ABL revealed that
a typical Ph chromosome with a BCR/ABL fusion gene was present. However, the section of chromosome 22 was present on
chromosome 3 instead of chromosome 9 as determined by GTG banding. Dual-colour FISH using a probe specific for PML
and RARA was negative for fusion suggesting that typical PML/RARA breakpoints are not involved in this translocation.
Upto our knowledge, we report here a unique case of CML in chronic phase with a variant Ph involving four chromosomes
Poster Session
9q32, 22q11.2, 3q26,1q32 along with clonal evolution with t(8;17) as a secondary abnormality.
Wed(4)-P-235
The role of ROS in the context of the arecoline-induced mitotic chromosome fragmentation and non-
apoptotic cell death
1
Yueh-Chun Li
1:Biomedical Sciences, Chung-Shan Medical University, Taiwan
It was known that the oxidative stress from the elevated ROS impairs cellular functions involving in cytotoxicity, cell cycle
arrest, and DNA damage, etc. The arecoline-induced ROS was also identified in several cell lines. In this study, we identified
the role of ROS in the context of the arecoline-induced the mitotic chromosome fragmentation.
We used the cytogenetic examination and g-H2AX staining to evaluate the extent of mitotic chromosome fragmentation. The
ROS was quantitated using DCFH-DA detector. The oxidative DNA was detected using 8-OHdG antibody.
In this study, we found that arecoline induced cellular ROS in CHO-K1 cell, but undetectable ROS in S-G cell. The result
of 8-OHdG immunofluorescence showed this induced ROS cause the oxidative DNA damage. Furthermore, co-treated with
arecoline and GSH (a ROS scavenger), the ROS and 8-OHdG signal induced by arecoline in CHO-K1 cells can be scavenged.
The result of DNA content in PI-staining cells showed that the most cells were arrested in G2/M phase after ROS was induced
by arecoline. Mitotic chromosome fragmentation was found in ROS-producing CHO-K1 cell, but not in ROS-nonproducing
S-G cells. The frequency of mitotic chromosome fragmentation increased with the increasing ROS induced by arecoline and
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ICHG2016 1286
decreased after co-treated with GSH. This mitotic chromosome fragmentation appeared intensive g-H2AX staining and neg-
ative TUNEL staining. Therefore, we suggested that the ROS would associated with the mitotic chromosome fragmentation
and further cause a mitotic cell death. Chromosome fragmentation is different from the apoptotic DNA fragmentation.
The chromosome fragmentation caused genomic instability and then mitotic cell death usually. If this process was compro-
mised, the genomic complexity would increase predictably, that is common seen in cancer progression. Although it still remain
unclear about the mechanisms of chromosome fragmentation, this mitotic cell death needs to be detected in cancer.
Wed(4)-P-236
Mechanisms of Interchromosomal Insertional Translocation
Takema Kato 1 ，Yuya Ouchi 2 ，Hidehito Inagaki 1,2
，Yoshio Makita 3 ，Seiji Mizuno 4 ，Hiroki Kurahashi 1,2
1:Division of Molecular Genetics, Fujita Health University, Japan、2:Genome and Transcriptome Analysis Center, Fujita Health University、
3:Education Center, Asahikawa Medical University、4:Department of Pediatrics, Central Hospital, Aichi Human Service Center
Interchromosomal insertional translocation is relatively rare chromosomal structural aberration, since they require at least
three breaks. Although several mechanisms such as double-strand- repairs via non-allelic homologous recombination or
non-homologous end joining, and replication-based pathway have been implicated as mechanisms of chromosomal structural
aberrations, the mechanisms of the insertional translocation is still unknown. In this study, we analyzed breakpoints and
rearranged fragments in three insertions by means of FISH, SNP array and next generation sequencing, to gain insight into their
mechanisms of formation. To characterize the breakpoint diversity and insertion site complexities, we applied whole genome
Poster Session
sequencing and mate-pair sequencing using next generation sequencer. All insertion cases are not simple structural aberration
mediated by three breakages and three repairs. Inserted fragments are consisted of multiple pieces of genomic fragments.
These fragments are shuffled and joined in non-inverted or inverted orientation in association with copy number alternation.
All of the junctions have short microhomology or short insertional nucleotides. Polymorphism analysis revealed that insertion
site sequences are of the same parental origin with normal counterpart homologous chromosome. One case showed that an
insertion event is intermingled, i.e. maternal insertion site is inserted into another paternal chromosome. These data imply
that the interchromosomal insertional translocation results from a meiotic nondisjunction event followed by a trisomic rescue
at early post-zygotic stage with anaphase lag. Micronucleus that is formed from anaphase lagging chromosomes might undergo
chromothripsis-like rearrangements. Pulverized chromosomes might be then inserted into another chromosome. It is likely
that insertional translocation might be formed by several independent processes across pre- and post-zygotic events.
Wed(4)-P-237
Chromosomal instability and genomic diversity of neurons in aging brain and in neurodegeneration
1
Kazimierz Gasiorowski
1:Department of Basic Medical Sciences, Wroclaw Medical University, Poland
Neurons live for decades in a postmitotic state and their genomes are consistently exposed to DNA damage which lead to
cumulation of somatic mutations. Neuronal genomes exhibit surprisingly high rate of diversity, both chromosomal (aneuploidy)
and subchromosomal (retrotranspositions, DNA copy number variations, somatic single-nucleotide variants). It should be
perceived that each human cortical neuron contains a profoundly distinctive genome, harboring ontogenetically acquired
genetic distinctness. Genomic variety of neurons may contribute to functional diversity in the human brain and presumably
determines personal predisposition to accelerated brain aging and to neurodegeneration.
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Chromosomal instability the gain or loss of whole chromosomes is consistently described in 4-10% neurons of adult human brain
suggesting, that mosaic aneuploidies are compatible with normal brain function. However, as people age, the accumulation
of aneuploid cells in the brain result in functional decline, contribute to impairment of cellular homeostasis and, finally, lead
to neurodegeneration. Additionally, neurons in vulnerable regions of the AD brain (the hippocampus, the basal nucleus of
Meynert) have undergone aberrant reactivation of cell cycle with full or partial DNA replication which lead to significant
proportion (about 4%) of tetraploid or near-tetraploid neurons. Chromosomal instability of neurons seems to be a major
cause of distinct individual predisposition to neurodegeneration and also could significantly influence the disease progression.
Modern scientific technologies, as advanced FISH method, single-cell DNA quantification and single-cell DNA sequencing, can
markedly improve our understanding of functional diversity in the human brain and also amplify the search for mechanisms
of neurodegeneration.
Wed(4)-P-238
Xq DISOMY IN A MALE PATIENT WITH AN UNBALANCED t (X;15)(p11.1;p13) TRANSLOCATION
AND A RARE X-INACTIVATION PATTERN
Gianna Carvalheira 1 ，Luiza Sisdelli 1 ，Angela Vidi 2,3 ，Mariana Moyses-Oliveira 1 ，Danilo Moretti-Ferreira 4 ，
Magnus R Dias da Silva 2,3 ，Maria Isabel Melaragno 1 ，Adriana Di Battista 1
1:Morphology and Genetics, UNIFESP, Brazil、2:Biochemistry, UNIFESP、3:Medicine, UNIFESP、4:Genetics, UNESP
Patients with rearrangements involving X-chromosome may present clinical alterations, which are determined mainly by
Poster Session
the breakpoints and the X inactivation pattern. In these patients, X inactivation is usually not random, and depends
on whether the X rearrangement is balanced or not. We present a male patient with an unbalanced translocation and a
46,XY,dic(X;15)(p11.1;p13)mat karyotype, in which the Xq arm is attached to the short arm of chromosome 15, resulting
in a dicentric derivative chromosome and Xq disomy. He presents a severe intellectual deficiency, epilepsy, facial alterations
and sociable behavior with frequent smiling. The patient’s mother, phenotypically normal, presents this translocation in
the balanced form. Inactivation pattern was determined by Human Androgen Receptor Assay (HUMARA) and 5-ethynyl-2’-
deoxyuridine (EdU) incorporation assay. As BrdU, EdU is a thymidine analog which is incorporated during DNA synthesis.
Through the EdU assay, it is possible to identify which X-chromosome is preferentially inactivated in patients with X alter-
ations, normal X or derivative one. HUMARA revealed an extremely skewed inactivation in both patient and his mother with
98:2 and 0:100 ratios, respectively, showing different inactive X-chromosomes. On the other hand, EdU incorporation revealed
normal X late replication in patient’s mother’s metaphases, and late replication in Xq, from the dic(X;15) in patient’s
metaphases. In addition, apart from the inactivation of Xq segment in this dicentric chromosome, the late replication was
also observed in the 15q segment, varying from the proximal, interstitial and terminal regions, or occurring in these regions
simultaneously, suggesting a variable and discontinuous spreading of X-inactivation into the 15q portion. The patient’s severe
phenotype could be attributed to the presence of Xq disomy and to the spreading of the X-inactivation to 15q. Financial
support: FAPESP
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ICHG2016 1288
Wed(4)-P-239
A 3-way balanced interstitial translocation between chromosome 3, 4, 1 leads to male infertility
Arda Cetinkaya 1 ，Ali Karaman 1 ，M. Burak Mutlu 1
1:Medical Genetics, Zeynep Kamil Women and Children’s Hospital, Turkey
Balanced translocations are among the infrequent but important causes of infertility. A balanced translocation in ei-
ther of the parents may lead to unbalanced karyotypes in the offsprings, leading to fertility issues. Here, we report a
couple with primary infertility caused by a 3-way interstitial translocation between chromosomes 3, 4, and 1, leading to
46,XY,ins(1;4;3)(p32;q31.1q35.1;q25q23) karyotype. This translocation is inherited from the mother of the index case. The
index case has two siblings, one of which has a normal karyotype. However, the other sibling has inherited an unbalanced
form of this translocation leading to duplication of 3q23-3q25. This individual suffers from glaucoma, but is otherwise healthy.
To our knowledge, a similar translocation has not been reported in infertile couples. The specificity of the infertility to male
individual, but not to his mother, may be a gender specific effect of this translocation. However, it is also possible that the
couple may not have conceived an embryo with a balanced karyotype, and may conceive such a viable embryo in the future.
In addtion, here we associate glaucoma with duplication of 3q23-3q25 region, which has been reported previously as a finding
in more complex chromosomal rearrangement with more severe phenotypic features. Examination of more individuals with
similar karyotypic abnormalities may help delineate the consequences of 3q duplication in the future.
Wed(4)-P-240
Poster Session
Genetic analyses of Korean patients with unexplained mental retardation and developmental delay us-
ing the multiple ligation-dependent probe amplification (MLPA) and array-based comparative genomic
hybridization (array CGH)
Se Ra Sung 1 ，Ji Eun Park 1 ，Kyung Min Kang 1 ，Dong Hyun Cha 1,2
，Min Young Kim 3 ，Sang Woo Lyu 2 ，
Youl Hee Cho 4 ，Sung Han Shim 1
1:Genetics Laboratory of Fertility Center, CHA University School of Medicine, Korea, South、2:Department of Obstetrics and Gynecology,
CHA Gangnam Medical Center, CHA University、3:Department of Rehabilitation Medicine, CHA Bundang Medical Center, CHA
University、4:Department of Medical Genetics, Hanyang University
Submicroscopic chromosomal rearrangements cause serious consequences such as multiple congenital anomalies, severe mental
retardation and abnormal growth. Many studies have reported that approximately 5% of patients with unexplained mental
retardation and/or developmental delay (MR/DD) had these abnormalities. This study aimed to elucidate the prevalence
of the submicroscopic rearrangements in Korean patients with MR/DD and characterize the genomic imbalances using the
MLPA and array CGH technique. A total of 621 pediatric patients with unexplained MR/DD recruited from July 2011
to September 2015. The samples were initially analyzed using karyotype analysis and MLPA. 37 out of 621 patients were
selected based on MLPA results, clinical features, and family history and analysed using Affymetrix CytoScan™ HD array.
The subtelomeric aberrations were identified in 53 out of 621 cases (8.5%) using MLPA P070 probemix. 21 patients (3.5%)
had partial deletion, 22 (3.4%) had partial duplications and 8 (1.3%) were complex rearrangements. Subtelomeric deletions
in 13 different chromosomes and duplications in 10 different chromosomes were detected. We analyzed 24 predigrees of
the patients with an abnormal MLPA result. Eight cases were de novo, not confirmed in both parents. Whereas, the
abnormalities identified in 16 cases were inherited from one of parents. Although they were probably considered as a normal
copy number variation (CNV), further studies might be necessary. We analyzed CytoScan™ HD array in the 37 patients with
normal karyotype and normal MLPA result. Among the 37 patients analyzed, 16(43.2%) were detected cryptic chromosomal
imbalances: 8 patients with duplications, 4 patients with deletions and 4 patients with both deletions and duplications.In
conclusion, genome analyses using the MLPA and array-based CGH are very useful methods for identifying a causative genetic
abnormality in patients with unexplained mental retardation and developmental delay.
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Wed(4)-P-241
Postnatal diagnosis for DiGeorge syndrome in National Hospital of Pediatrics, Viet Nam by using FISH
technique
Le T. Lieu 1 ，Dinh T.H. Nhung 1 ，Ngo D. Ngoc 1
1:Human Genetic Department, National Hospital of Pediatrics, Vietnam
Background: DiGeorge syndrome (DGS) is one of the most common microdeletion syndrome. About 90% of the cases of DGS
are caused deletion occurs on the q arm of chromosome 22 at 22q11.2. DGS is estimated to affect at least one in 4.000 live
births. The features of DGS vary widely between individuals but commonly include congenital heart disease, characteristic
facial features, hypocalcemia, and immune deficiency. Many children with DGS have development delays including learning
difficulties, low levels of growth. Although the majority of deletion of DGS are de nove, the deletion can be transmitted as
an autosomal dominant. About 93% of cases have a de novo deletion and 7% have inherited the deletion from a parent. DGS
is a microdeletion syndrome that were too small to be seen under the microscope. Diagnostic testing for the deletion 22q11.2
of DGS is possible using fluorescence in situ hybridization (FISH) as well as miccoarrays. Objective: To detect the deletion
at 22q11.2 by FISH technique. Material and Method: 154 patients were suspected DGS in National Hospital of Pediatric
from January 2008 to July 2015. Apply FISH technique with D22S75 (N25) special probe to detect deletion at 22q11.2.
Result: 46/154 (29.8%) patients have deletion at 22q11.2 to diagnose DGS. Among 46 deletion patients, 60.8% patients have
congenital heart disease, 26.08% patients have brochopneumonia, 54.43% patients have characteristic facial features include:
cleft palate, ptosis, hooding of the upper lids,..43.4% patients have hypocalcemia, 4.3% patients have immune deficiency.
Conclusion: Using FISH technique to detect the deletion 22q11.2 is useful for diagnosis DGS. FISH technique is accurate,
fast method to diagnose DGS.
Poster Session
Wed(4)-P-242
Cytogenetic characterization of Sri Lankan patients with de novo Myelodysplastic Syndromes
1,2
W. M. Manoj S Bandara ，Hemali W W Goonasekera 1 ，Vajira H W Dissanayake 1
1:Hunam Genetics Unit, Faculty of Medicine, University of Colombo, Sri Lanka、2:Department of Pre-Clinical Sciences Faculty of Medicine,
General Sir John Kotelawala Defence University
Cytogenetic analysis has become a compulsory part of the diagnosis and prognostication of Myelodysplastic syndromes (MDS).
Differences in the cytogenetic profiles between Asian and Western MDS populations have been reported. Cytogenetics studies
of MDS in South Asian populations are limited. We performed a cytogenetic analysis of bone marrow (BM) of 20 Sri Lankan
patients with primary MDS and this is the first study reporting cytogenetics of MDS in Sri Lanka. The patients were
diagnosed according to WHO classification and patients who had secondary MDS were excluded from the study. Cytogenetic
analysis was conducted at the time of diagnosis using GTG-banding and Fluorescence in situ hybridization (FISH) was
performed to confirm the presence of del 5q. The patient population consisted of 11 RCUD, 5 RCMD, 3 RAEB and one
del 5q patients including 7 males (35%) and 13 females (65%) with median age of 64.5 years. Of the 20 patients, 7 patients
(35%) showed clonal chromosomal abnormalities. The abnormalities found were: del(5q) - 5%(1/20), del(11q) - 5%(1/20),
del(12p) - 5%(1/20), +19 - 5%(1/20) hypodiploidy - 5%(1/20) and random loss of chromosomes - 10%(2/20). Chromosomal
abnormalities were seen in 36% (4/11) of RCUD and 29% (2/5) of RCMD patients. In contrast to the Western studies where
del 5q is reported as the most common cytogenetic abnormality in MDS, we detected del 5q only in one patient (5%). The
findings of this study provide an overview of the cytogenetic profile of MDS patients in Sri Lanka.
Key words cytogenetic abnormality, MDS, BM, FISH
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Wed(4)-P-243
A case of Langer-Giedion syndrome with a deletion on chromosome 8q and a balanced reciprocal translo-
cation between chromosomes 2 and 4
Emre Kirat 1 ，Asuman Koparir 1 ，Hatip Aydin 2 ，Mehmet Seven 1 ，Hakan Ulucan 1
1:Cerrahpasa Medical School of Istanbul University, Turkey、2:Department of Medical Genetics Namik Kemal University
Langer-Giedion syndrome (LGS, MIM #150230) is a contiguous gene syndrome that is characterized by multiple exostoses
and peculiar facies with bulbous nasal tip, thickened alar cartilage, upturned nares, prominent philtrum and large protruding
ears. The phenotype is associated with loss of functional copies of the TRPS1 gene at 8q23.3 and the EXT1 gene at 8q24.11.
A case was 17-year-old Turkish boy of unrelated parents with multiple exostoses located on long tubuler bones, men-
tal retardation, scoliosis and facial dysmorphic features such as bulbous nasal tip, thickened alar cartilage, broad nasal
bridge, heavy eyebrows, large laterally protruding ear and prognathism. G-banding chromosome analysis revealed karyotype
46,XY,t(2;4)(q24;p15). Array comparative genomic hybridization (aCGH) revealed a submicroscopic deletion on chromosome
7 MB 8q consistent with the phenotype. No loss of genetic material was detected on broken arms of chromosomes 2 and 4 with
no imbalances. Here we present a rare co-occurrence of Langer-Giedion syndrome and balanced chromosomal translocation.
Wed(4)-P-244
A rare case of long term survival in a girl with Patau syndrome
Poster Session
Mehmet B Duz 1 ，Mehmet Seven 1 ，Hakan Ulucan 1
1:Medical Genetics, Istanbul University, Cerrahpasa Medical School, Turkey
Patau syndrome is a severe genetic disorder that was defined in 1960 by Patau as a trisomy of chromosome 13. Common
physical characteristics include cleft lip and/or palate, microphthalmia, microcephaly, and postaxial polydactyly. These clin-
ical findings can be accompanied by several cardiovascular malformations and respiratory difficulties including patent ductus
arteriosus or ventricular septal defect, central apnea and upper airway problems. It is known that trisomy 13 is the third
most common autosomal trisomy in newborns after Down syndrome (Trisomy 21) and Edward’s Syndrome (Trisomy 18).
Incidence of this rare syndrome is estimated at 1:5000 births or 1:20000 live births. National Health Service presented data
about survey of full trisomy 13 in 2013 and 142 (82%) of live births with trisomy 13 born in England and Wales. In addition,
the 3-month survival was 18% while 1-year survival was 8%.
Here, we report on an 11-year-old female with intellectual disability and persistent seizures. She was delivered by spon-
taneous normal vaginal delivery at 30th week of gestation. There was no information other than a severe omphalocele at
birth. At her 3rd year, she had neurodevelopmental delay, facial dysmorphism and bicuspid aorta. Her karyotype was 46,
XX,+13,rob(13;13)(q10;q10). Less than only ten cases passing 10 years of survival have been previously reported. We suggest
that, though its rarity among other chromosome abnormalities in those older than a-year-old, trisomy 13 should be taken
under consideration.
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ICHG2016 1291
Poster Session
Prenatal, Perinatal and Reproductive Genetics
Wed(4)-P-245
The regulatory micro-RNAs of EG-VEGF and their effects on trophoblastic cell function
Meitsz Su 1 ，Yichi Chen 1
1:National Cheng Kung University, Taiwan
MicroRNAs (miRNAs) are noncoding small RNAs emerging as posttranscriptional regulators in various biological processes.
They can regulate expression of their target genes by destabilizing the transcripts or by translational repression. Several
miRNAs are expressed in human gestational tissue and play some role in embryo implantation and placental development.
Some miRNAs are identified to be associated with placenta dysfunction and abnormal pregnancy status, such as intrauterine
fetal restriction, preeclampsia, ectopic pregnancy and recurrent miscarriages (RM), but the underlying mechanism is not
clear. Recently, EG-VEGF was regarded as a critical factor for embryo implantation and placental development; however, no
EG-VEGF related micro-RNAs have been published yet. In the past year, we aimed on the effect of two microRNAs (miR-346
and miR586-3p), which were picked based on the results of prediction program, on EG-VEGF. The two mircoRNAs (miR-346
and miR586-3p) were showed to regulate EG-VEGF expression through targeting seed sequence of 3’UTR, and further
Poster Session
alter intracellular calcium influx and suppress cell invasion ability in more than one cell lines. In conclusion, miR-346 and
miR586-3p could regulate the expression of EG-VEGF and may therefore influence several EG-VEGF related pathophysiology
of human pregnancy.
Wed(4)-P-246
False positive cases from non-invasive prenatal testing at a single tertiary hospital
Takol Chareonsirisuthigul 1 ，Wasun Chantratita 1 ，Ekawat Pasomsub 1 ，Budsaba Rerkamnuaychoke 1 ，
Somsri Pitukkijronnakorn 2 ，Panyu Panburana 2
1:Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand、2:Department of Obstetrics and
Gynecology, Faculty of Medicine Ramathibodi Hospital, Mahidol University
Non-invasive prenatal testing (NIPT) is a new option in the prenatal screening that utilizes bioinformatic algorithms and next-
generation sequencing of fragmented cell-free fetal DNA in maternal serum to determine the probability of certain chromosome
conditions in a pregnancy. Abnormal results indicate an increased risk for the specified condition. However, an abnormal
result is not diagnostic and confirmatory testing is recommended. An abnormal result may indicate an affected fetus, but
can also represent a false positive result in a normal pregnancy, confined placental mosaicism, placental and fetal mosaicism,
a vanishing twin, an unrecognized maternal condition or other unknown biological occurrence. In this study, we report four
cases of women who underwent amniocentesis to confirm the results from Thai-NIPT study at Ramathibodi Hospital during
January to June 2015. The NIPT results demonstrated high risk of one Trisomy 18, one Turner syndromes and two Triple
X. Using conventional cytogenetic analysis, the karyotype of all 4 fetuses were found to be normal. In conclusion, NIPT is a
screening test, meaning that it should not be used to diagnosis. Therefore, abnormal results from NIPT must be followed up
by invasive diagnostic testing.
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Wed(4)-P-247
Maternal mental stress and background of pregnant women who underwent NIPT at Nagoya City Uni-
versity Hospital
Kyoko Kumagai 1 ，Nobuhiro Suzumori 1 ，Eri Takeda 1 ，Kumiko Oseto 1 ，Yuki Obayashi 1 ，Yousuke Matsumoto 1 ，
Mayumi Sugiura 1
1:Obstetrics and Gynecology, Clinical Genetics, Nagoya City University, Japan
[Objectives]Prevalence of depression in Japan is about 6-15%, it occurs higher in women than in men. In this study, we
investigated mental stress and background of women who underwent NIPT by questionnaire in our hospital. [Methods]We
performed questionnaire for patients who visited our hospital for genetic counseling of prenatal genetic testing between October
2013 to October 2014. We investigated maternal and husband’s age, indications, gestational weeks at NIPT testing, mental
stress K6 score at early pregnancy and one month after delivery. [Results]During the period, 1,388 pregnant women visited
our Hospital for prenatal genetic counseling and underwent NIPT and we collected 1,156 valid questionnaires. Maternal mean
age at NIPT was 38.1±2.6 y.o. As for indications of NIPT, 97.5% were just for advanced maternal age of pregnancy. From
the questionnaires, mental stress K6 score was high (10 and above) in 113 women (8.1%) who suspected that their mental
stress was high. There were no significant differences of K6 score between primipara and multipara group. Ratio of high K6
score was higher in the group of maternal age under 35 y.o. than elder group. Within the 696 questionnaires, 387 included
postpartum K6 score. The K6 score were reduced in the group of high K6 score in 1st trimester. However, in the patients of
low K6 score in 1st trimester, K6 score were increased in 13 patients in the average of 6 points and became high K6 score after
delivery. [Conclusion]Support for maternal mental stress during peripartum period is very important. We need to consider
that there are patients who were low K6 score group in 1st trimester, but become high K6 score group after delivery. Our
Poster Session
data suggest that these women were required enough and continuous mental care.
Wed(4)-P-248
Clinical study of pregnant women with myotonic dystrophy and their new born babies
1,2
Yoshika Akizawa ，Mari Urano 2 ，Yuko Sato 2 ，Masaki Ogawa 1 ，Eiji Nanba 3 ，Hideo Matsui 1 ，Kayoko Saito 2
1:Obstetrics and Gynecology, Tokyo Women’s Medical University, Japan、2:Institute of Medical Genetics, Tokyo Women’s Medical University、
3:Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University
In this retrospective study on mothers with myotonic dystrophy (DM1) and their children, 34 cases in which genetic counselling
had been provided in our facility within the period between April 2004 and August 2015 for 25 pregnant females with DM1
were examined, focusing on their backgrounds and findings on their newborns. A diagnosis of DM1 was established before
and after pregnancy in 5/25 and 19/25 females, respectively. In the remaining 1 case, this could not be confirmed. The child
was also diagnosed with the disease in 28 cases; it was congenital (CDM) in 20 cases, and led to death during infancy in 6
cases . Prenatal diagnosis was performed for 10 pregnant females in 11 fetuses, and the results were positive in 8 fetuses.
Decisions after the diagnosis varied among cases. Children with the disease showed a longer CTG repeat compared with their
mothers. In many cases, the females were diagnosed with DM1 after pregnancy. Also, among their children with CDM, the
spectrum of clinical symptoms, such as requiring/not requiring respiratory management, varied. Based on these results, it
may be necessary to consider the possible presence of DM1 whenever idiopathic polyhydramnios and decreased distal muscle
strength of the extremities are observed during pregnancy. The importance of starting the provision of genetic counselling
services for females with DM1 desiring delivery and their partners before pregnancy was also suggested in this study.
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ICHG2016 1293
Wed(4)-P-249
Survey of University Student Attitude Toward Pre-conception Carrier Screening in Japan
Akane Kondo 1,2 ，Michiko Sone 1 ，Shizue Nambara 1 ，Kaori Mori 1 ，Tomoko Iba 1 ，Daichi Nakaoku 1 ，
Masahiro Murakami 1 ，Mikio Morine 1 ，Kenji Hinokio 1 ，Shunichiro Izumi 2 ，Kazuhisa Maeda 1
1:Clinical Genetics, OBGYN, Shikoku Medical Center for Children and Adults, Japan、2:Clinical Genetics, Toaki University School of
Medicine
[Background] Identifying carriers of autosomal recessive or X-linked disorders before pregnancy is known to have the potential
to benefit couples. Genetic information can be used for considering options such as prenatal diagnosis, preimplantation genetic
diagnosis, and donor gametes. Some couples might seek adoption or refrain from having children based on test results. In
some countries, governments offer preconception carrier screening (PCS) as a preventive measure to avoid specific diseases.
Overall, PCS is currently not done in Japan. However, some commercial companies have started offering PCS directly to
consumers. This study focuses on the opinion of Japanese university students toward PCS.
[Materials and Methods] A total of 25 students at a university of health sciences responded to a questionnaire based on the
semantic differential scale method. Average student age was 20.5 years old, and the female/male ratio was 2.13.
[Results] As health science students, all respondents claimed to be familiar with genetics at some level, and all felt that genetics
is a difficult issue. Almost all students except one tended to feel having PCS. 76% students feel to know their partner’s PCS
result and 16% did not. According to their comments, they would prefer thinking about this matter with their partner. Some
students expressed concern about the possibility of discrimination due to test results.
[Conclusion] The general opinion of Japanese university students toward PCS is not negative. This tendency suggests that
they might be influenced by recent scientific and media reports regarding genetic therapy and disease prevention. Most
Poster Session
students, although somewhat apprehensive, are willing to undergo PCS. Some students commented on concerns and issues
surrounding the future of PCS. It is important for this issue to be discussed not only amongst specialists but also with young
Japanese people before any future introduction of PCS is implemented in Japan.
Wed(4)-P-250
Evaluation of non-invasive prenatal testing of aneuploidy from maternal plasma in our hospital
Yuko Matsubara 1 ，Keiichi Matsubara 1 ，Yuka Uchikura 1 ，Kazuko Takagi 1 ，Takashi Sugiyama 1
1:Obstet and Gynecology, Ehime University Graduate School of Medicine, Japan
Objective
For clinical study of non-invasive prenatal testing of aneuploidy from maternal plasma, we established NIPT counseling
Outpatient Department on April, 2013 in our hospital. We evaluated the current state of the NIPT.
Methods
Under the permission by IRB, candidate is 288 pregnant women who visited NIPT counseling Department from April 2013
through August 2015. The test was conducted to detect aneuploidy in high-risk pregnant women following appropriate genetic
counseling. The clinical data, test results, and pregnancy outcomes were evaluated.
Results
Of 238 (82.6%) women tested, 3 (1.0%) had positive results, Among them,3 women who tested positive (trisomy 18), 1 cases
refused to undergo the invasive procedure so that resulted in intrauterine fetal death, and two positive cases confirmed on
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karyotyping, one was a normal karyotype, another was trisomy 18. 2 cases of 3 were detected abnormal ultrasound finding.
50 women didn’t receive. NIPT after genetic counseling. Twenty eight (56.0%) women underwent the invasive procedure.
Conclusion
After genetic counseling, women receiving the tests are increasing every year. The present study suggests that understanding
for pregnant women’s NIPT is gradually common. We should re-recognize the importance of pre- and post-test genetic
counseling.
Wed(4)-P-251
Prenatal diagnosis of the Premature chromosome separation/ mosaic variegated aneuploidy (PCS/MVA)
syndrome in fetus with microcephalus
Masanao Ohashi 1 ，Masatoshi Yamaguchi 1,2 ，Makiko Ishii 2 ，Tomoko Yamaguchi 1 ，Keiko Akeno 1 ，Midori Fijisaki 1 ，
Chikako Sumiyoshi 1 ，Hiroshi Sameshima 1 ，Mamoru Ozaki 3 ，Takema Kato 4 ，Hideto Inagaki 4 ，Hiroki Kurahashi 4
1:Obstetrics and Gynecology, University of Miyazaki, Japan、2:Division of Clinical Genetics, University of Miyazaki Hospital、3:Division of
Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University、4:Division of Molecular
Genetics, Institute for Comprehensive Medical Science, Fujita Health University
Premature chromosome separation/ mosaic variegated aneuploidy (PCS/MVA) syndrome is a rare genetic disorders. We
experienced a case of prenatal diagnosis of PCS/MVA syndrome.
Poster Session
Twenty four years old women was referred to our out clinic due to fetal growth restriction with extreme microcephalus
(-5.0SD). Initially, since toxoplasma IgM was positive, she was supposed to be toxoplasmosis. However, PCR test of the
amniotic fluid was negative in toxoplasma. Therefore, we excluded the possibility of toxoplasmosis.
In the same time, we ordered chromosomal analysis in order to exclude chromosomal abnormality. Few days later, laboratory
mailed to us they observed PCS phenomenon in the 80% of the cells. Therefore, we tested chromosomal analysis of the
parents. We observed 9% and 11% of PCS positive cell in the parent’s peripheral white blood cells, suggested father and
mother is a carrier of the PCS/MVA syndrome. We started genetic analysis of fetus and parents. PCS/MVA syndrome is
well known disease of very high incidence of various malignancy in childhood. Therefore, prenatal diagnosis may important
for postnatal care.
Wed(4)-P-252
The importance of pre-screening counseling - parents need more and precise information about fetal
anomaly and aneuploidy screening scan
Masahito Mizuuchi 1 ，Mizue Teramoto 1 ，Tsuyoshi Baba 1 ，Shinichi Ishioka 1 ，Toshiaki Endo 1 ，Tsuyoshi Saito 1
1:Dept. of Obstetrics, Sapporo Medical University, Japan
[Background and Objective] Fetal ultrasound has two aspects, one is testing for well being of the fetus and the other is
“genetic” sonogram. A clinical practice guideline in Japan currently does not recommend that all pregnant women be
offered prenatal screening for aneuploidy or malformation. We often experience the patients who are noticed the possibility
of fetal aneuploidy or malformation for the first time at 2nd or 3rd trimester without any informed consent about checking
the possibility of aneuploidy or fetal malformation. So in this presentation we discuss difficulties about the counseling issues
arise when anomalies are detected that are not discussed during the informed consent process.
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[Cases] Recently we experienced five aneuploidy cases with different backgrounds. All cases referred to our territory centre
after 22 weeks of gestation. None of the case was obtained informed consent about fetal anomaly scan at 1st trimester. In all
cases we need several counseling whether to have invasive testing. In two cases, parents declined having amniocentesis. Most
of parents complained that they did not have enough information about prenatal screening, and were embarrassed when they
underwent a screening test for aneuploidy or fetal malformation without consent.
[Discussion and Conclusions] In Japan, 1st trimester genetic screening is not offered to every pregnant but the pregnant
who wants to have it can access hospitals which offer first trimester screening including NIPT and genetic fetal scan. We
felt the difficulties about genetic counseling and noticed the importance of pre-screening counseling about fetal anomaly or
aneuploidy. Obstetricians should recognize the problem without informed consent about the fetal conditions including severe
anomaly or aneuploidy before routine scan. We should know the importance of pre-screening counseling and should give
enough information about prenatal screening.
Wed(4)-P-253
Can we construct a genetic prediction model for gestational diabetes mellitus in a Japanese population?
1,2
Yoshifumi Kasuga ，Kei Miyakoshi 1 ，Naoko Arata 3 ，Atsushi Tajima 4 ，Mamoru Tanaka 1 ，Kenichiro Hata 2
1:Department of Obstetrics and Gynecology, Keio University, School of Medicine, Japan、2:Department of Maternal-Fetal Biology, National
Research Institute for Child Health and Development、3:Department of Women’s Health, National Center for Child Health and Development、
4:Department of Bioinformatics and Genomics, Graduate School of Medical Sciences, Kanazawa University
Poster Session
Introduction: Gestational diabetes mellitus (GDM) is one of the most common perinatal complication and a multifactorial
disease such as type 2 diabetes mellitus (T2DM). Prediction of GDM is one of the most important objectives in not only
perinatal care but also maternal and children’s health care. The aim of this study is to investigate whether the prediction
model for GDM can be constructed using genetic variants for T2DM.
Methods: A total of 299 Japanese women (GDM: n=171, Normal OGTT: n=128) with singleton pregnancy who underwent
perinatal care between Jan. 2011 and Dec. 2014 at Keio University and National Center for Child Health and Development
were reviewed. Each received the diagnostic 75g oral glucose tolerance test (OGTT) at 2nd trimester. The T2DM risk gene
variants previously reported (45 single nucleotide polymorphisms [SNPs] from 36 candidate genes) were genotyped using
DNAs from maternal peripheral blood samples. We used genetic score weighted by odds ratio to assess genetic factors of
GDM using several SNPs.
Results: Three variants had nominal associations with Japanese GDM. With these three variants, women with five or more
risk alleles showed a 10.3-fold increased risk of GDM (p=0.0013, 95% confidence interval [CI]: 4.57-8.20), compared with those
having no more than one risk allele. Applying receiver-operating characteristics showed area under curve of 0.638 (95%CI:
0.57-0.71). Genetic score cut-off value of >5.164 had sensitivity of 66.9% and specificity of 58.0% in diagnosing GDM.
Conclusion: In our study, genetic variants were not able to predict GDM. However, T2DM risk genetic variants had cumulative
effects on the development of GDM.
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Wed(4)-P-254
Background of couples undergoing non-invasive prenatal testing (NIPT) in Japan
Eri Takeda 1,2 ，Nobuhiro Suzumori 1 ，Kyoko Kumagai 1 ，Kumiko Oseto 1 ，Takeshi Ebara 1 ，Junko Yotsumoto 2 ，
Hironao Numabe 2 ，Mayumi Sugiura-Ogasawara 1
1:Nagoya City University Hospital, Japan、2:Ochanomizu University
Aim: Our purpose was to assess the background of couples who undergoing noninvasive prenatal testing (NIPT) in Japan.
Methods: The characteristics of 2,486 women who had visited Nagoya City University Hospital for NIPT were compared with
those of women who did not receive NIPT to Japanese Demographic Trends (JDT) as controls. The questionnaire included
items regarding the maternal and paternal age, maternal age at marriage, age at first live birth, and conception mode.
Results: Compared with the controls, the percentage of women who 4 or more years older than their partner was larger in
the NIPT group (11.8% vs 6.3%). The maternal age at marriage, age first live birth, and the duration between marriage
and first birth tended to be greater in the NIPT group (32.6 years vs 29.3 years, 36.9 years vs 30.4 years, and 3.6 years vs
2.4 years, respectively), and the percentage of women who underwent assisted reproductive technology (ART) tended to be
higher in the NIPT group (35-39 years: 21.2% vs 7.5%, 40-45 years: 36.2% vs 12.6%), compared with the controls.
Conclusion: Knowing the specific backgrounds of couples who have undergone NIPT may be important for improving the
quality of genetic counseling for NIPT.
Poster Session
Wed(4)-P-255
Abnormally high levels of serum α-klotho result in a poor outcome for clinical pregnancy-A prospective
cohort study
Miyako Funabiki 1 ，Sagiri Taguchi 1 ，Yoshitaka Nakamura 1
1:Oak Clinic, Japan
Background: The klotho protein has been extensively studied. However, there are no studies examining the association
between serum α-klotho levels and the clinical outcome of post-clinical pregnancy.
Methods: We conducted a prospective cohort study in 42 patients (median age 37.4 years) to evaluate the association between
serum α-klotho levels during the follicular phase of preimplantation and the clinical outcome data of post-clinical pregnancy.
The patients provided informed consent at our clinic. The serum α-klotho levels were evaluated using a human soluble α
-klotho assay kit. The fetal chromosomal abnormalities were investigated by chorionic villus sampling at our clinic. We also
assessed the clinical outcomes of post-clinical pregnancies. The statistical analyses were performed using Welch’s t-test and
a multiple logistic regression analysis. The statistical significance was defined as p<0.05.
Results: The serum α-klotho level during the follicular phase of preimplantation for non-pregnant women was 544.31 pg/ml
(mean). The clinical pregnancy rate was 38.1%. There were chromosomal abnormalities observed in four unborn children
(9.5%; Down syndrome, etc).The serum α-klotho levels during the follicular phase of preimplantation in the chromosomal
abnormalities group were higher than in the group without chromosomal abnormalities (P=0.029, abnormalities group 659.26
pg/ml [mean] versus control 530.23 pg/ml [mean]). A multiple logistic regression analysis showed the chromosomal abnormali-
ties rates in unborn children were positively influenced by serum α-klotho levels during the follicular phase of preimplantation
(p=0.0008) and the patient’s age (p=0.008).
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Conclusion: Previous studies have demonstrated that increased α-klotho levels in human serum are positively correlated with
health. However, abnormally high levels of serum α-klotho during the follicular phase of preimplantation may predict a poor
outcome for clinical pregnancy.
Wed(4)-P-256
Fetal Pallister-Killian syndrome with congenital diaphragmatic hernia, umbilical hernia and hydrops: a
case report of prenatal genetic counseling and grief care
Susumu Miyashita 1 ，Hiroshi Suzumura 1 ，Yoshiyuki Watabe 1 ，Kazumi Tada 1 ，Hiroshi Watanabe 1 ，Ichio Fukasawa 1
1:Perinatal Medical Center, Dokkyo Medical University, Japan
A 34-year-old female patient, gravida 1, para 1, was referred to our institute at 14 weeks’gestation because of fetal generalized
edema. There was no familial hisory of hereditary disease or remarkable obstetric history. Chromosome analysis with G-band
of amniotic fluid at 16 weeks revealed 47,XX,+mar. The marker chromosome was thought to be extra isochromosome of
the short arm of the twelfth (12p) or long arm of the twenty-first chromosome (21q), but could not be distinguished. Fetal
ultrasound examinations at 18 weeks showed umbilical hernia and severe left diaphragmatic hernia. The large portion of the
liver was prolapsed and the lung-to-head ratio was less than 1.0, that suggested severe respiratory disturbance after birth.
Serial genetic counseling was provided and the parents shared the fetal lethal condition. They decided not to terminate
the pregnancy and to try to hold the natural course. The patient needed serial amniotic fluid reduction due to excessive
polyhydramnios after 25 weeks. Fetal bilateral pleural effusion and ascites were also developed after 30 weeks. The parents
Poster Session
offered their baby to be taken only supportive care without tracheal intubation, mechanical ventilation or intravenous infusion.
A preterm rupture of membrane was observed at 34 weeks and 5 days of gestation just before the labor pain onset. A female
infant weighting 2084 g was delivered transvaginally with Apgar Score of 4, 2 and 2 at 1, 5, and 10 minute after birth,
respectively. There was not placental morphological anomaly. She had severe respiratory disturbance with consequent early
demise after one hour life. FISH analysis of lymphocytes showed mosaic tetrasomy 12p. The fetal diagnosis of severe
condition in early pregnancy can be devastating. But serial genetic counseling could play a crucial role for supporting the
parents through the fetal evaluation, accepting process, conduct a postdelivery care and provide support to the grieving in
this case.
Wed(4)-P-257
Variants in maternal effect genes NLRP7 and C6orf221 are not a common risk factor for molar pregnancy
manifesting as sporadic or familiar cases
Iwona Pinkier 1 ，Lucjusz Jakubowski 1 ，Aleksander Jamsheer 2 ，Urszula Wysocka 1 ，Magda Rybak 3 ，Agnieszka Gach 1
1:Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland、2:Department of Medical Genetics, Poznan
University of Medical Sciences, Poznan, Poland、3:Department of Obstetrics and Perinatology, University Hospital in Krakow, Poland
Recently recognized genetic aspects of molar pregnancy have indicated the condition as an extreme example of a human
disorder caused by aberrant genomic imprinting. While in clinical practice the majority of hydatidiform moles (HM) are
sporadic, causative genes NLRP7 and C6orf221 were first discovered in the familiar form of disorder.
We have investigated the association between molar pregnancy and genetic variation of NLRP7 and C6orf221 in Polish
population in order to improve genetic counseling for couples with reproductive failure.
A subgroup of 15 women with a history of molar pregnancy was recruited from a group of about 700 women referred to our
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clinic due to recurrent miscarriages. Majority of HM cases were sporadic, one case was familiar with mother and daughter
experiencing molar pregnancy. Coding exons and intron/exon boundaries of NLRP7 and C6orf221 genes were bidirectionally
sequenced.
We identified 10 variants in NLRP7 gene and 2 variants in C6orf221 gene. Based on SIFT and PolyPhen prediction, all
missense variants were assigned as not pathogenic. Frequencies of the variants in the tested group were comparable to those
reported for general population in reference databases (UCSC, dbSNP). Interestingly, screening of the patient with a family
history of HM and recurrent molar pregnancy revealed presence of 4 missense variants in NLRP7 and 2 in C6orf221 gene.
This finding supports previously published observations showing higher frequency of nonsynonymous variants in patients with
a female family member experiencing reproduction failure compared to women with no relevant family history.
Our study suggests that NLRP7 and C6orf221 variants are not a common cause of HM in Polish population, thus routine
genetic testing in molar pregnancy does not seem to be justified. Nevertheless, HM seems to be a promising model to explore
consequences of genetic variation of other maternal effect genes.
This study was supported by NSC Grant no. 2012/07/D/NZ5/00664
Wed(4)-P-258
Superimposed preeclampsia complicated with multiple endocrine neoplasia type 1
Poster Session
Yoshinori Moriyama 1 ，Tomomi Kotani 1 ，Satoko Osuka 1 ，Yumiko Ito 1 ，Maki Goto 1 ，Fumi Utsumi 1 ，
Fumitaka Kikkawa 1
1:Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Japan
[Introduction] Multiple endocrine neoplasia type 1 (MEN1) is a rare disease with autosomal dominant inheritance, possibly
fatal when the neoplasm turns malignant or hormonal instability goes beyond control. There have been only limited informa-
tion on pregnant women with MEN1. This is the first report of the case complicated with severe superimposed preeclampsia.
[Case] A 37-year-old nulliparous woman got pregnant by IVF. When she had myomas at the age of 31, systemic examination
revealed multiple endocrine tumors and hormonal abnormalities, and genetic analysis showed a germline mutation in the
MEN1 gene. She was diagnosed as MEN1 and received surgery. Her father was also diagnosed genetically. Her sister had
died from pituitary apoplexy and her uncle had a history of pancreatic and adrenal surgery. She was referred to us because
of pregnancy with severe hypertension (HT) in the 10th week of gestation. Even with maximal dose of antihypertensives
her HT was uncontrollable. In the 27th week she was hospitalized to be administered MgSO4 and then nicardipine for the
management of HT and FGR. Proteinuria appeared, reaching 3.5 g/day in a week. Her fetus began to show abnormal flow
pattern of cord vessels. The situation had no sign for improving and her pregnancy was terminated in the 29th week. Her
daughter was born weighing 975 g and admitted into NICU. She went home on POD 10 and her daughter is now under
nutritional care in NICU. She had been worrying about what would happen to her daughter in the future, and she will have
genetic counseling and long-term clinical follow-up for her daughter.
[Discussion] MEN1 is rare and its phenotype varies widely. During pregnancy, hormonal dysfunction, especially extreme HT,
could be a severe problem for both the patient and her fetus. Strict and careful management is required for pregnancy with
MEN1. Therefore, it is important to inform the patient of the possible risk during pregnancy as well as to provide genetic
counseling.
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Wed(4)-P-259
The Usefulness of Interphase Fluorescence In Situ Hybridization (iFISH) for Prenatal Diagnosis
Hiroaki Nakamura 1,2 ，Nobuyoshi Tamagawa 1 ，Masaru Kato 1 ，Akiko Murakami 1 ，Takane Aoyama 1 ，
Sachiyo Nishimoto 2 ，Koji Kajitani 2 ，Kazuharu Tanaka 2 ，Osamu Nakamoto 2 ，Michiko Watanabe 1 ，Toru Yorifuji 1
1:Genetic Medicine, Osaka City General Hospital, Japan、2:Obstetrics, Osaka City General Hospital
Objective: From 2013, Non-Invasive Prenatal Testing (NIPT) for high risk pregnant women was started as the nationwide
demonstration project in Japan. This project requires the NIPT positive result cases should be confirmed karyotyping by
amniocentesis to exclude false-positive results. Also, we receive many maternal transport cases with fetal growth restriction
(FGR) or fetal structural abnormalities as the perinatal medical center. In these cases, rapid examination of fetal aneuploidies
is very important. So we started interphase fluorescence in situ hybridization (iFISH) on site testing. We report the usefulness
of iFISH for prenatal diagnosis.
Materials and Methods: From Sept. 2014 to Oct. 2015, 11 cases were tested by iFISH and G-band karyotyping using
amniocentesis. 6 cases were NIPT positive results and 5 cases were FGR with structural abnormalities. After amniocentesis,
uncultured amniotic fluid cells were examined using AneuVysion TM Assay Kit.
Results: 1. All iFISH results were consistent with G-band karyotyping results. 2. Of the 9 cases were aneuploidy, trisomy
21 for 5 cases, trisomy 18 for 3 cases and trisomy 13 for 1 case. 3. All iFISH results were reported within two days after
amniocentesis. On the other hand, conventional cultured FISH and G-band karyotyping were reported about five and twelve
days, respectively.
Poster Session
Conclusion: Using iFISH for extremely high risk pregnant women is useful for reducing patient anxiety and determining the
quick treatment policy.
Wed(4)-P-260
Prenatal diagnosis of microdeletion/microduplication syndrome using MLPA (Multiple Ligation -
dependent Probe Amplification) in Korean
Sohyun Na 1 ，Sanghee Go 1 ，Surim Park 1 ，Dongsuk Lee 1 ，Kunwoo Kim 1 ，Soonha Yang 1 ，Ki Chul Kim 1 ，
Doyeong Hwang 1
1:Hamchoon Institute of Fertility & Genetics, Korea, South
PURPOSE To present the application of multiplex ligation-dependent probe amplification (MLPA) based screening for the
simultaneous targeted detection of microdeletion syndrome in 5018 Korean pregnant women with the various indications.
MATERIAL AND METHODS Following amniocentesis or chorionic villus sampling, samples were processed for routine kary-
otype analysis while DNA was extracted in parallel for MLPA analysis. A total of 5018 prenatal samples were analysed by
commercial MLPA kits (SALSA P245, MRC-Holland, Netherland), by traditional cytogenetics methods.
RESUIT Among the 5018 samples, we identified fourteen cases of microdeletion syndrome (Digeorge syndrome, Wolf-
hirschhorn syndrome, Prader-Willi/Angelman syndrome, Sotos syndrome, Cri du chat syndrome), six cases of subtelomeric
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imbalanses (9p16.3 deletion and 13q34 duplication, 2q23.1 deletion, 4p16.3 deletion, 22q13 deletion) and forty six cases of
microduplication syndromes (4p, 3q, 5q, 7q, 8q, 10p, 15q, 16q, 17q, 22q).
CONCLUSION We present the largest prenatal screening for microdeletion. The additional MLPA screening of fetuses in a
routine prenatal diagnosis is likely to provide more accurate information in cases of various indications. Especially it is more
helpful in case of increased nuchal translucency.
KEYWORDS Prenatal diagnosis, Multiplex ligation-dependent probe amplification (MLPA), Microdeletion, Microduplica-
tion, Indication, Nuchal translucency(NT)
Wed(4)-P-261
Current condition and issues of prenatal testing at a tertiary center for maternal-fetal and neonatal
medicine
Hironobu Hyodo 1 ，Norihiko Nakazato 1 ，Naoko Fukuda 1 ，Etsuko Saito 1 ，Yukiko Fuse 1 ，Kanami Higashiue 1 ，
Chikako Hikosaka 1 ，Midori Funakura 1 ，Takayuki Seiki 1 ，Sorahiro Sunagawa 1 ，Satoshi Okada 1 ，
Takahiro Kasamatsu 1 ，Koji Kugu 1
Poster Session
1:Department of Obstetrics and Gynecology, Tokyo Metropolitan Bokutoh Hospital, Japan
Pregnant women are getting to have more interest about prenatal fetus year by year. Prenatal testing such as maternal
serum marker or amniocentesis are provided in many institutes at many situation. Although our institute, a tertiary center
for maternal-fetal and neonatal medicine, provides only amniocentesis, current condition and issues of prenatal testing were
considered with reviewing the results.
Twenty-five pregnant women received amniocentesis and fetal chromosomal analysis for twenty-six fetuses (one woman had
dichorionic twins) since April, 2013. All women were given information and instruction in regular check-up for the pregnancy.
Three were conducted after 22nd week as a part of diagnosis for fetal abnormalities. The remainder twenty-two women
received the test for a motivation to get to know whether the fetus would have chromosomal abnormality. Among these
twenty-two women, age distribution was 27 to 43, six were under 35, and eleven were nulliparas. Two had ever given birth
with chromosomal abnormality, one was referred to us because of positive result of maternal serum marker. The test was
conducted in 15+3 to 17+5 weeks. All were resulted in normal karyotype. One terminated the pregnancy in 21st week because
of Potter syndrome and another was diagnosed congenital heart anomaly.
Although our institute is a tertiary center for maternal-fetal and neonatal medicine, there seemed to be a demand for prenatal
testing because some women were referred to us in the first trimester or before. And the demand is not confined to only
women of advanced maternal age. It is required that the clients should be given genetic counselling and thorough information
to enable them to understand and to make a choice including“not doing tests”. But, to make it possible, it is necessary to
provide special clinic with specialized doctor and counselor.
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Wed(4)-P-262
Outcomes of 31 cases of trisomy 13 diagnosed in utero: A single center experience
Ken Takahashi 1 ，Aiko Sasaki 1 ，Miyuki Nishiyama 1,2 ，Chizuko Fujimura 4 ，Rika Sugibayashi 2 ，Katsusuke Ozawa 2 ，
Yuka Wada 3 ，Seiji Wada 2 ，Rika Kosaki 4 ，Yushi Ito 3 ，Haruhiko Sago 1,2,3
1:Division of Obstetrics, Center for Maternal-Fetal, Neonatal and Reproductive Medicine National Center for Child Health and Development,
Japan、2:Division of Fetal Medicine, Center for Maternal-Fetal, Neonatal and Reproductive Medicine National Center for Child Health and
Development、3:Division of Neonatology, Center for Maternal-Fetal, Neonatal and Reproductive Medicine National Center for Child Health
and Development、4:Division of Medical Genetics, Department of Medical Subspecialties National Center for Child Health and Development
The aim of this study was to clarify the prenatal and postnatal outcomes of trisomy 13 fetuses diagnosed prenatally at the
National Center for Child Health and Development between 2003 and 2015. The data were retrospectively reviewed from
medical records. Of the 31 cases, 12 patients were diagnosed before 22 weeks of gestation and 19 were diagnosed after 22
weeks of gestation. Nine families opted for early termination, 14 patients died, and 8 patients were born alive. Intensive
treatment was requested in two of the live birth cases, of which one patient achieved a long-term survival (7 years) and the
other died during infancy (on day 61). One of the patients for whom palliative treatment was requested achieved a long-term
survival (2 years). The patients who achieved a long-term survival tended to show mild abnormal ultrasonographic findings.
Fetal death and early neonatal death were common, however, there were few cases that could achieve a long-term survival
with intensive medical care. It is therefore important to provide comprehensive information to couples and their families who
have trisomy 13 fetuses during genetic counseling.
Wed(4)-P-263
Poster Session
Clinical Significance of Introduction of Y Chromosome Microdeletion Screening in Assisted Reproductive
Technology Clinics
Sumihide Okamoto 1 ，Rinko Fukushima 1 ，Yasuko Ueda 1 ，Jiro Eguchi 2 ，Hiroshi Yokoyama 3 ，Toshiaki Akiyoshi 1
1:ART Okamoto Women’s Clinic, Japan、2:Sasebo Mutual Hosipital、3:Yokoyama Hospital
Introduction: We examined the significance of a Y chromosome microdeletion screening test prior to testicular sperm collection
in ART.
Patients and Methods: We examined transitions of our ICSI and testicular sperm collection (MESA, RESA, and TESE) in
17 years from 1999 to 2015, as well as our Y chromosome AZF microdeletion screening, introduced in 2012. The screening
kit used was Promega Y Chromosome AZF Analysis System version 2.0 for multiplex PCR including partial deletions in the
AZFa, AZFb, and AZFc regions.
Results: We started RESA and TESE in 1999, and obtained RESA-ICSI pregnancy and childbirth in the same year. By
2009, 20 of 57 cases led to pregnancy including 5 cases of RESA, 24 of MESA and TESE, and 28 of only TESE. We started
treatment for Y chromosome infertility in 2010. The 31 cases out of the total 97 cases since 1999 led to pregnancy, and 23
live-borns were obtained in 21 cases. In 2011 and 2014, 2 XX male patients were detected. Klinefelter syndrome (XXY) was
detected in 2005 (1 case), 2008 (2), 2012 (2) and 2013 (1). Among them, 3 patients underwent sperm collection, 1 case led
to TESE-ICSI pregnancy that however ended with miscarriage. We introduced Y chromosome AZF microdeletion screening
in 2012, which was applied for a total of 13 patients. Three microdeletions were found. Case 1: A male, 32, carrying Y
chromosome microdeletions detected at the loci DYS223, DYS224, DYF51S1, DYS236, DAZ, and DYS240 in the AZFbAZFc
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regions, 46, X+r1[25]/46, X and +r2[3]/45, X[2]; Case 2: A male, 39, carrying deletions detected at the loci DYS148 and
DYS273 in the AZFa region; and Case 3: A male, 42, with a Ym-12 gr/gr deletion in the AZFc region. Treatment for Case 1
and 2 was discontinued. As Case 3 is a severe oligozoospermia, we have already started the ICSI program.
Conclusion: The Y chromosome microdeletion screening test not only avoids unnecessary TESE, but also allows us to expect
possible choice of ART for deletions in the AZFc region.
Wed(4)-P-264
Genetic counseling for recurrent miscarriage patients with abnormalities of chromosome structure who
have already had live children with duplication or deletion of the involved chromosomal region
Toshiaki Endo 1,3 ，Tsuyoshi Baba 1 ，Masahito Mizuuchi 1 ，Mizue Teramoto 1 ，Shinichi Ishioka 1 ，Aki Ishikawa 2 ，
Akihiro Sakurai 2 ，Tamotsu Kiya 3 ，Akira Nishikawa 4 ，Osamu Moriwaka 5 ，Hiroshi Hata 6 ，Takema Kato 7 ，
Hiroki Kurahashi 7 ，Yuko Takasu 1 ，Tsuyoshi Saito 1
1:Obstetrics and Gynecology, Sapporo Medical University, Japan、2:Medical Genetics, Sapporo Medical University、3:Ena Ladies’ Clinic、
4:NTT East Japan Hospital, Sapporo、5:Kamiya Ladies’ Clinic、6:Oyachi Ladies’ Clinic、7:Molecular Genetics, Fujita Health University
Poster Session
Abnormalities of chromosome structure can cause recurrent miscarriages. Although preimplantation genetic diagnosis (PGD)
is a unique treatment for couples having abnormal chromosomes that cause recurrent miscarriages, it is not considered
significant by everyone.
We usually explain in genetic counseling that, for such patients, there may be a possibility of having a healthy baby without
any treatment. Thus, some genetic counselors do not recommend PGD for these patients, and the significance of PGD for
patients with recurrent miscarriages is still controversial in Japan.
However, the situation for some recurrent miscarriage patients with abnormal ities of chromosome structure who have already
had live children with chromosomal abnormalities such as duplication or deletion of the involved chromosomal region is
different from that of other couples. Of course, such cases are very rare as only 2.9% of such patients have live children with
chromosomal abnormalities.
Unusually, we are currently taking care of 4 couples who have already had such children. The chromosomal types of one of the
partners are 46,XX,t(5;14)(p15.1;q13), 46,XY,t(15;21)(q12;q22.1), 46,XX,inv(8)(p12q21.2) and 46,XX,t(10;18)(p12.2;q21.3).
They very much want to have healthy children and are very afraid of having another miscarriage and also of having another
live child with abnormal chromosomes.
It is very easy to predict that they will be in a very difficult situation if they have 2 children with chromosomal abnormalities.
Thus, we think that PGD may be an appropriate method for such couples. Although PGD is not always ideal for couples with
abnormalities of chromosome structure who have recurrent miscarriages, it is recommended for couples with such abnormalities
who have already live children with abnormal chromosomes. Therefore, we provide information about the significance of PGD
to such couples in genetic counseling.
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Wed(4)-P-265
A pilot study: function-based analysis of cell free RNA using amniotic fluid supernatant in small-for-
gestational-age group
1,2
Dong Hyun Cha ，Yeon Kyung Cho 1 ，Yun-Jeong Shin 2 ，Ji Eun Park 2 ，Sung Han Shim 2,3
，Yong Wook Jung 1
1:Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, Korea, South、2:Genetics Laboratory,
CHA Gangnam Medical Center, CHA University, Seoul, Korea、3:Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul,
Korea
Objective: The purpose of this study was to identify differentially expressed genes and to investigate the important biological
pathway using cell-free fetal RNA of AFS in pregnancy with SGA fetus compared to normal pregnancy at second trimester..
Method: The amniotic fluids were collected from pregnant women (16-18 weeks). 9 samples of SGA and 13 samples of
control were selected and matched gestational age and fetal gender. Cell-free fetal RNA was isolated from each supernatant
of amniotic fluid for microarray. Gene expression profiles were identified and analyzed. Significant differential gene expression
for Affymetrix data were defined by t-test. Next, selected gene lists were satisfied the significance threshold criteria of p-values
defined by multiple testing corrections. For functional analysis, significant genes were analyzed by DAVID and IPA tools.
Results: In this study, 448 genes were differentially expressed in the compared groups. Of these DEGs, 204 genes were
up-regulated, while 244 genes were down regulated in SGA group. In terms of GO, up-regulated genes were highly related
to protein synthesis, while down-regulated genes were related to transcriptional regulation. In terms of tissue, almost genes
were involved in brain. In terms of function, most of the up-regulated genes are ribosomal protein genes involved ribosomal
pathways, whereas down-regulated genes are representative signaling factors involved diverse pathway. Conclusion: This
study identified differentially expressed genes in AFS from SGA fetuses and these genes had shown different tissue-specific and
biological aspect from those of AGA fetuses. This result demonstrated that important brain-related genes are predominantly
Poster Session
expressed in fetuses with SGA during the second trimester of pregnancy. Differentially up-regulated genes were involved in
protein synthesis-related pathway, while differentially down-regulated genes were involved in cell signaling-mediated pathway.
Wed(4)-P-266
Provided information and psychosocial support for decision-making process of pregnant women with
incidental diagnosis of fetal abnormalities in Japan - Online based survey
Sayaka Honda 1 ，Hidehiko Miyake 2 ，Yumie Hiraoka 1 ，Hitomi Nishio 1 ，Akira Inaba 1 ，Manami Matsukawa 1 ，
Eriko Takamine 1 ，Ayumi Yonei 1 ，Shinji Kosugi 1,2
1:Genetic Counselor Course, Kyoto University School of Public Health, Kyoto, Japan、2:Clinical Genetics Unit, Kyoto University Hospital
Background: In Japan, ultrasound examination is routinely used for fetal checkup in prenatal management. This enables not
only a form of noninvasive monitoring of the fetus, but also incidental detection of fetal abnormalities. However, some reports
have pointed that this potential implications of such monitoring are often unrecognized by pregnant women. Discussion has
been scarce about the decision-making processes of women with incidental diagnosis of fetal abnormalities, and the potential
role of the genetic counseling in such cases.
Objective: This study aimed to examine the experience of pregnant women and their families as they make decisions regarding
continuing or terminating pregnancy, the determinants involved, consequences of the pregnancy, and involvement of genetic
counseling.
Method: We conducted a web-based anonymous survey on the membership of Japanese self-help groups for women and their
partners who have experienced fetal/baby loss. The questionnaire consisted of both fixed-choice and open-ended questions.
Results: Most respondents experienced anxiety at the sudden unexpected diagnosis about their fetus. The amount of the
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information given by the primary doctors widely varied. Some respondents especially wanted to know about the precise
prognosis and fetal therapies to decide whether they should continue the pregnancy or not. Many women felt difficulties in
decision-making because of the absence of healthcare practitioners that are specialized in explaining the fetal health, psycho-
logical support and assistance in decision-making process.
Conclusion: Sufficient, relevant information for decision-making and appropriate psychosocial support from healthcare prac-
titioners varied among individuals reflecting their background. For improved quality of decision-making, the participation of
healthcare professionals such as genetic counselors, can be beneficial, although the precise role in such situation has to be
clarified in further studies.
Wed(4)-P-267
Investigation of False Positive Rates Newborn Screening Using Tandem Mass Spectrometry Technology
in Korea, Single Center Study
Sung Won Park 1 ，Su Jin Kim 2
1:Pediatrics, Cheil General Hospital & Wonmen’s Health Care Center, Korea, South、2:Pediatrics, Myunggy Hospital
Purpose:
Newborn screening leads to improved treatment and disease outcomes, but false-positive newborn screening results may impact
Poster Session
include parental stress and anxiety, perception of child as unhealthy, parent-child relationship dysfunction, and increased infant
hospitalizations. The purpose of this study was to investigate of the false positive rates and the causative factors of false
positive results in TMS in single center.
Methods
Records were reviewed for all 18,892 subjects who were born in Cheill General Hospital, during January 1st, 2012 to December
31th, 2014. 17,312 neonates(91.64%) were tested for tandem mass screening in 2-5th day of life .
Newborn babies whose first results were abnormal had been tested repeatedly by same methods in 7-14 day. If the results
were abnormal again, further evaluation was performed.
TMS analysis included data for the 43 disorders screened for using MS/MS broken down into three categories: fatty acid
oxidation disorders, organic acidurias, aminoacidopathies..
The impact of several factors on increased false positive rates was analyzed using a multivariate analysis:time from birth to
sample collection, birth weight, birth height, BMI, gender, gestational age, delivery type.
Resutlts
Flase positive rate of TMS was 1.30%, each rate were 0.61% in fatty acid oxidation disorders, 0.25% in organic acidurias,
0.45% in aminoacidopathies.
5 of all 7 analyzed factors have an influence on increased false positive rates in TMS, dependent on disorder group. Day of
test has an especially strong effect on abnormal results for unknown reasons.
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Conclusion
False positive rate of TMS was 1.30% in Cheil General Hospital. Gender, gestational age, birth weight,birth heifght, age at
sample collection were impact increased false positive rates.
Better understanding of factors that influence the reporting of screening tests, and the ability to modify these important
factors, may improve the screening process and reduce the need for retesting.
Wed(4)-P-268
Association analyses between copy numbers of genes in the azoospermia factor c (AZFc) region on the
Y chromosome and male infertility
Soushi Imani 1 ，Youichi Sato 1 ，Tatsuya Shimozawa 1 ，Teruaki Iwamoto 2 ，Aiko Yamauchi 1
1:Pharmaceutical information Science, Biochemical Science, Tokushima University Graduate School, Japan、2:Center for Infertility and IVF,
International University of Health and Welfare Hospital
Approximately 10% of couples find it difficult to have their own children, and about 40%-50% of these problems are due to
male infertility. The main causes of male infertility are spermatogenic failures such as azoospermia, oligozoospermia, and
asthenozoospermia. However, the genetic determinants of male infertility are still unclear. Deletions in the azoospermia
Poster Session
factor (AZF) regions (termed AZFa, b, and c) on the long arm of the Y chromosome, which are prevalent in 10%-15% of male
infertility patients, result in spermatogenic failure. The AZFc region has a palindromic structure, which contains multiple
copies of genes such as deleted in azoospermia (DAZ ), basic charge Y-linked 2 (BPY2 ), chromodomain protein Y-linked 1
(CDY1 ), testis-specific transcript Y-linked 4 (TTTY4 ), and golgin A2 pseudogene 2 Y-linked (GOLGA2P2Y ). In this study,
we investigated the relationship between the copy numbers of the genes in the AZFc region and male infertility. Patients
with azoospermia (n=73), oligozoospermia (n=46) and asthenozoospermia (n=24) were diagnosed based on semen analysis
according to the guidelines of the World Health Organization (WHO; 1999). We excluded patients with known causes of
infertility such as obstructive azoospermia, karyotype abnormalities, and complete deletion of AZF regions. As controls, we
recruited 740 partners of pregnant women. The copy number of the genes were determined by analyzing single nucleotide
variants (SNV) and sequence tagged sites (STS) using restriction fragment length polymorphism PCR (RFLP-PCR). Odds
ratios and their 95% confidence intervals were calculated using logistic regression analysis or Fisher’s exact test. We found that
reductions of the copy numbers of DAZ , BPY2 , TTTY4 , and GOLGA2P2Y were significantly associated with azoospermia,
suggesting that copy numbers of the genes within the AZFc region can have significant effects on spermatogenesis.
Wed(4)-P-269
A short-term non-verbal psychotherapeutic intervention on patients in perinatal period with high anxiety
1,2 1,2
Kaori T Mori ，Kazuhisa Maeda ，Akane Kondo 2 ，Masahiro Murakami 2 ，Tsuyako Iwai 2 ，Yoshihiro Nakadoi 1 ，
1
Ichiro Yokota
1:Clinical Research Department, NHO: Shikoku Medical Center for Children and Adults, Japan、2:Clinical Genetics Center, NHO: Shikoku
Medical Center for Children and Adults
After the consolidation of National Children’s Hospital and National Adult Hospital, National Hospital Organization: Shikoku
Medical Center for Children and Adults (Zentsuji City, Japan) was first established in May 2013 and soon after we launched
our Clinical Genetics Center. We have been concentrating on perinatal care and a facility has been running FISH and
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Chromosome analysis in the Center since 1976. In September 2013, we first introduced NIPT (Non-Invasive Prenatal Testing)
and the number of patients in perinatal period was increased. We have a number of 370 patients coming for the genetic
counseling since September 2013 to November 2015.
At the genetic counseling, we currently use ‘the Profile of Mood States-Brief Form Japanese Version’ to measure patients’
mental state. The Profile of Mood States (POMS) is a psychological rating scale and this short version of the POMS consists
of 30 adjectives on a 5-point scale: 0=not at all; 1=a little; 2=moderately; 3=quite a bit; 4=extremely. Patient have an
Administration Time of 5 minutes to fill the form and the time frame of how patient have been feeling during the past week,
including today. POMS-Brief consists of 6 subscales include: tension-anxiety (5 items); depression (5 items); anger-hostility
(5 items); vigor-activity (5 items); fatigue (5 items); confusion-bewilderment (5 items).
We questioned how much we could reduce patient’s anxiety within a genetic counseling. We then concentrated on psychological
intervention and when we found a patient with high score in POMS and when patient wish to meet a psychotherapist, we
decided to offer a short-term Art Psychotherapy. Art Psychotherapy usually offers a long-term therapy however, considering
that we need to deal with patient’s anxiety in a short-term period, Non-Verbal approach of Psychotherapy might be an
effective option for patient to explore their emotion visually by Art Psychotherapy.
Wed(4)-P-270
The effect that chromosome aneuploidy screening using the ultrasound testing gives for the decision
making of the pregnant woman
Poster Session
1
Ryuhei Nagai
1:Obstetrics, Kochi Health Sciences Center, Japan
Objective:We consider whether the aneuploidy screening using the ultrasound testing carried out in developed countries is
useful in Japan.
Method:We evaluate retrospectively about 351 singleton pregnant women who hoped for a prenatal diagnosis and consulted
our Hospital fetuses ultrasound testing outpatient between October 2009 and October 2014. We counseled it before testing
and conducted the intention confirmation of the pregnant woman, and FMF qualification carriers performed fetal sonography
for an applicant and they calculated a risk and explained results.
Results:255 of 351 patients (64.7%) were elderly pregnant women 35 years or older. 192 patients (54.7%) hoped for aneuploidy
screening, but it was only 33 cases (17.2%) to have conducted an invasive chromosome testing (amniocentesis) after ultrasound
testing as aneuploidy screening. When a risk of 21trisomy supposed more than 1/200 to be screening-positive, 65 patients
(14.9%) of 351 patients were positive and those five cases were aneuploidy. The aneuploidy case was not included in a screening-
negative case (100% of sensitivity, specificity 82.7%, positive-predictive value 8.2%, negative-predictive value 100%). 37 of 65
screening-positive cases (56.9%) did not finally choose an examination of decision by the hope of a pregnant woman and the
family.
Conclusion:The sorting of the screened group may have a problem in this study, but from this results the ultrasound testing
could extract aneuploidy high risk group and decreased the number of the invasive chromosome test enforcement of the
pregnant woman in consideration of a chromosome test. This is greatly different from a choice rate of the invasive testing
after the screening by NIPT shown generally. The pregnant woman in hope of a prenatal diagnosis did not necessarily demand
an invasive diagnosis, and the possibility that ultrasound testing played an important role in decision making was suggested.
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Wed(4)-P-271
A present situation of prenatal diagnosis in our hospital after non invasive prenatal genetic testing has
started
Takayo Shoji 1 ，Norio Miharu 1 ，Kenjiro Nakago 1 ，Akira Sasaki 1 ，Nobuko Yokoyama 2
1:Obstetrics and Gynecology, Chuden Hospital, Japan、2:Pediatrics, Chuden Hospital
Objective: In our hospital, we started to provide noninvasive prenatal genetic testing (NIPT) from September 2014.We
consider the present situation of NIPT and influence to other prenatal diagnosis after starting NIPT.
Method: This is the retrospective study of the prenatal diagnosis in our hospital during 1 year from September 2014 to August
2015.
Result: We did the first trimester genetic counseling for 537 pregnant women and her partners in this period. Among these
clients, 221 (43.7%) women chose NIPT. Amniocentesis had done for 196 (36.5%) patients, and 61 (11.4%) women chose
maternal serum screening test (Quad screening). 59 (11.0%) clients decided not to use prenatal diagnosis. First 6 months,
we provided NIPT for 87 patients, and next 6 months, provided for 134. Namely, the numbers of NIPT has increased. On
the other hand, after starting NIPT, amniocentesis has decreased. But maternal serum screening test has increased. In the
patients who chose NIPT, 134 (60.6%) were <40 years, and 87 (39.4%) were ≥40 years. 39-year-old was the most. The result
of the test, 217 (98.2%) were negative, and 4 (1.8%) cases were positive, including trisomy 21 (n=3), trisomy 13 (n=1). No
patients had result that was not reportable. In all of the positive cases, amniocentesis was performed. About three cases of
trisomy 21, the results demonstrated that the karyotype was 47,XY,+21 respectively. In a trisomy 13 case, it was reviled
Poster Session
that the karyotype was normal. One case of trisomy 21 decided to continue the pregnancy after several times of counseling.
Conclusions: By the start of NIPT, there has been growing interest in prenatal diagnosis of the general public. The main
prenatal diagnosis is being converted to NIPT from amniocentesis. We consider that it is essential more extensive counseling
for prenatal diagnosis.
Wed(4)-P-272
Prenatal testing for genetic disease at NCCHD in Japan
Aiko Sasaki 1 ，Seiji Wada 1 ，Kastusuke Ozawa 1 ，Rika Sugibayasghi 1 ，Chieko Fujimura 1 ，Miyuki Nishiyama 1 ，
Honryon Li 1 ，Ohsuke Migita 2 ，Yasuyuki Fukuhara 1 ，Motomichi Kosuga 1 ，Rika Kosaki 1 ，Torayuki Okuyama 1 ，
Haruhiko Sago 1
1:National Center for Child Health and Development (NCCHD), Japan、2:St.Mariannna University School of Medicine
Compared to chromosomal analysis, testing for genetic disease is limited in prenatal setting. In Japan, prenatal testing is
acceptable for genetic diseases which are lethal or severe in early-onset. There was few report about prenatal testing for
genetic diseases in Japan. The aim of this study is to report the current status of prenatal testing of genetic disease at
National Center for Child Health and Development between March 2002 and March 2015.
Prenatal testing included genetic testing(sequencing, capillary, linkage analysis, etc) and biochemical testing (enzyme activity
and analysis of organic acids). The data were retrospectively reviewed from medical records.
226 tests were performed in 176 couples, of which 193 samples were taken by chronic villous sampling (CVS) and 33 samples
by amniocentesis (AC). 93 cases of DNA sample were analyzed in our center, and 46 cases were analyzed at laboratories
in domestic medical facilities. In 83 cases, genetic counseling and analysis were performed in the other hospital and only
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sampling procedure was conducted in our center.
143 cases included 67 autosomal recessive, 62 X-linked recessive, 10 autosomal dominant, 2 mitochondrial and 2 microdeletion.
The common single gene disease diagnosed prenatally were 21-hydroxylase deficiency (16 cases), mucopolysaccharidosis type2
(Hunter syndrome)(13cases), ornithine transcarbamylase defficiency (OTCD)(12 cases), carbamoyl phosphate synthetase I
defficiency (9 cases) and adrenoleukodystrophy (ALD) (9 cases).
Our center is one of the biggest prenatal testing center in our country, therefore our data is likely to represent the actual
status of prenatal diagnosis for genetic disease in Japan.
Wed(4)-P-273
Prediction of pregnancy with hypertensive disorders using epigenetic and biochemical markers
JinWoo Kim 1 ，Shin Young Kim 1 ，Hyun Jin Kim 1 ，Yoo Jung Han 2 ，So Yeon Park 1 ，Hyun Mee Ryu 1,2
1:Laboratory of Medical Genetics, Cheil General Hospital and Women’s Healthcare Center, Korea, South、2:Department of Obstetrics and
The aim of this study was to investigate the maternal plasma levels of cell-free fetal DNA (cffDNA) and cell-free total DNA
(cfDNA) throughout pregnancy using tissue-specific epigenetic markers in pregnancies with hypertensive disorders. We also
evaluated the predictive value of separate and combination test based on maternal characteristics, cffDNA, cfDNA, and
prenatal screening biochemical markers for the early detection of hypertension disorders in pregnancy.
Poster Session
A nested case-control study was conducted with 280 singleton pregnancy plasma samples including 29 gestational hypertension
(GH), 62 preeclampsia (PE) and 189 controls. We performed a real-time quantitative PCR to measure levels of DSCR3 and
RASSF1A as cffDNA markers and HYP2 as a cfDNA marker during pregnancy. We estimated the area under the ROC curve
to compare predictive values of maternal characteristics, epigenetic and biochemical markers singularly, and in combinations
for predicting hypertensive disorders in pregnancy.
The median of log10 HYP2 was significantly elevated in both PE and EO-PE compared with controls from 6-14 weeks. At
15-23 weeks, log10 HYP2 was a significantly different between PE and controls, EO-PE and controls, EO-PE and GH as well
as EO-PE and LO-PE. At 24-32 weeks, log10 HYP2 was significantly higher in EO-PE than in controls. At 33-41 weeks, the
medians of log10 DSCR3, log10 RASSF1A and log10 HYP2 were significantly elevated in PE, EO-PE and LO-PE compared
with controls. Furthermore, these markers were significant differences among patient groups. Of the biochemical markers,
the first-trimester PAPP-A MoM level was significantly lower in PE groups than in controls. The combination of the first-
trimester log10 DSCR3 and log10 HYP2 with PAPP-A MoM and maternal characteristics had the highest predictive value for
PE.
This is the first study to demonstrate potential use of combined maternal characteristics, DSCR3 , HYP2 and PAPP-A for
the early prediction of PE.
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Wed(4)-P-274
Integrative analysis of DNA methylation and gene expression in trisomy 21 placenta
1,2
Hyun Mee Ryu ，Ji Hyae Lim 1 ，Shin Young Kim 1 ，Jin Woo Kim 1 ，Jung Yeol Han 2 ，Moon Young Kim 2 ，
So Yeon Park 1
1:Laboratoy of Medical Genetics, Cheil General Hospital and Women’s Healthcare Center, Korea, South、2:Department of Obstetrics and
Introduction: Trisomy21 is the most common aneuploidy affecting humans and is caused by an extra copy of all or part of
chromosome 21 (chr21). DNA methylation is an epigenetic event that plays an important role in human diseases via regulation
of gene expression. However, the integrative association between DNA methylation and gene expression in trisomy21 fetal
placentas has yet to be determined.
Methods: We profiled expression of 207 genes on chr21 and their DNA methylation patterns in placenta samples from normal
and DS fetuses and predicted the functions of differentially expressed genes using bioinformatics tools.
Results: We found 47 genes with significantly increased expression in the trisomy21 placenta compared to the normal placenta.
Hypomethylation of the 47 genes was observed in the trisomy21 placenta. Most of hypomethylated DNA positions were
intragenic regions, i.e. regions inside a gene. Moreover, the level of gene expression and the number of hypomethylated DNA
position showed significantly positive associations. By analyzing the properties of the gene-disease network, we found that
increased genes in the trisomy21 placenta were significantly associated with trisomy21 and trisomy21 related complications
such as mental retardation, neurobehavioral manifestations, and congenital abnormalities.
Discussion: To our knowledge, this is the first study to comprehensively survey the association between gene expression and
DNA methylation in chr21 of trisomy21 fetal placentas. Our findings provide a broad overview of the relationships between
Poster Session
gene expression and DNA methylation in the placentas of fetuses with trisomy21 and could contribute to future research
efforts concerning genes involvement in disease pathogenesis.
Wed(4)-P-275
Nuchal Translucency (NT) doubled the detection rate of Down syndrome and other chromosome abnor-
malities in our experience of 1441 case of amniocenthesis
Kenji Ida 1 ，Kiichi Shimizu 1 ，Kenzo Ida 1 ，Ryoko Imbe 1 ，Shin-ichi Sonta 2 ，Kaoru Suzumori 2 ，Hiraku Takebe 1
1:IDA clinic, Japan、2:Fetal Life Science Center
1441 cases of amniocenthesis was performed and analyzed. Thirty five cases of Down syndrome, 12 cases of 18trisomy, 10 cases
of Turner syndrome, 4 cases of Klinefelter syndrome and other chromosomal abnormality was detected. Amniocenthesis was
performed by a single physician free handed under real-time ultrasound guidance with 21 to 23 gause needles. We experienced
5 cases of pregnancy loss (0.35%) and 8 cases of recognized amniotic fluid leakage all of which are recovered after bed rest.
Nuchal Translucency (NT) indication was first appeared in our program in 1905. Amniocenthesis cases of 376 were performed
before 1905(1993-1904) in two big general hospitals. Cases of 1065 were performed thereafter in private clinic subspecialized
in genetic counselling (2005-2015) which include 184 cases (12%) of NT cases. In former 376 cases (which include no NT
cases) detection rate of chromosome abnormality was 3.5% comparing to 6.8% of the latter 1035 cases, almost doubling the
rate.
Furthermore, detection rate of chromosome abnormality in NT cases alone was found to be 14.7% (27/184) comparing to the
rest of case 4.1% (36/881), showing about four times higher.
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Wed(4)-P-276
Spermatogenic failure by impaired meiotic sex chromosome inactivation in a mouse with reciprocal
translocation
Makiko Tsutsumi 1 ，Takema Kato 1 ，Hidehito Inagaki 1 ，Tamae Ohye 1 ，Hiroki Kurahashi 1
1:ICMS, Fujita Health Univ., Japan
Balanced reciprocal translocation carriers are healthy but often have reproduction problems. They undergo recurrent miscar-
riages or give birth to offspring with congenital anomalies due to unbalanced translocation. Although these are seen in both
male and female carriers, a subset of the males are sterile due to azoospermia or oligozoospermia. Among male carriers with
the same translocation breakpoint, some undergo multiple miscarriages but others are sterile. The sexual dimorphism in the
gametogenesis process is considered as a main contributing factor of the sex differences. Particularly, it is suggested that the
association between the heterologous sex chromosomes in males and the behavior of the translocation chromosomes during
meiosis might be involved in it. However, it has not been fully elucidated yet.
In this study, we have analyzed the male meiosis of a reciprocal translocation mouse model. The homozygous T6 strain
carrying an autosomal reciprocal translocation was used. Balanced reciprocal translocation model was produced by mating
T6 strain with several different inbred mouse strains having the wild-karyotype. Male model mice exhibited the different
fertilities, semifertile or almost sterile, with reduced testis weights depending on the inbred strain used for the mating part-
ner. Apoptotic cells were detected both at the pachytene and the metaphase stages. Spermatocyte spreads showed that the
derivative chromosomes were defective in synapsis and often co-localized with the XY body. The immunofluorescence signal
for RNA polII, which is usually absent in the XY body, was positive in the model mice, indicating meiotic sex chromosome
Poster Session
inactivation (MSCI) failed in these cells leading to spermatogenic arrest. Severity of the male-specific reproduction pheno-
types was found to depend on the extent of MSCI failure. We propose a mechanism to cause MSCI failure that the XY
body-associated translocation chromosomes would switch on the inactivated sex chromosomes.
Wed(4)-P-277
A case of Antley-Bixler syndrome with hypospadias: prenatal course and key images for prenatal diagnosis
Aya Harada 1 ，Maiko Wagata 1,2
，Jin Muromoto 1,2
，Nobuo Yaegashi 3 ，Gen Nishimura 4 ，Jun Murotsuki 1,2
1:Department of Maternal and Fetal Medicine, Miyagi Children’s Hospital, Japan、2:Department of Advanced Developmental Medicine,
Tohoku University Graduate School of Medicine、3:Department of Obstetrics and Gynecology, Tohoku University School of Medicine、
4:Department of Radiology, Tokyo Metropolitan Cildren’s Medical Center
[Background] Antley-Bixler syndrome (ABS) is exceptionally rare craniosynostosis characterized by radiohumeral synostosis.
Other findings are midfacial hypoplasia, choanal stenosis, multiple joint contractures and ambiguous genitalia. POR (P450
oxidoreductase) mutation causes ABS with disordered steroidgenesis. Although the prognosis is poor due to airway compro-
mise, fetal life in ABS has been rarely elucidated.
[Case] 27-year-old woman was referred for the investigation of fetal microcephaly at 26 weeks gestation. Fetal ultrasound
showed multiple abnormalities including clover leaf skull, irregular curve of supine and abnormal external genitalia. Fetal
biparietal diameter (BPD) was -3.4SD and the shape of lateral ventricles was irregular and partially fused. Craniosynosto-
sis was suspected. Fetal MRI at 30 weeks revealed occipital encephalocele. As pregnancy advances, ventriculomegaly and
thinning of brain parenchyma progressed. Polyhydroamnios starting from 32 weeks required amnioreduction. Rapture of
membrane occurred on 35 week and 5 days, subsequently, 3251g male baby was born by c-section. Apgar score was 1/2.
Right eyeball was completely dislocated and hypospadias was confirmed. Joint contracture including neck made intubation
difficult. He died within 2 hours in spite of full resuscitation. Post-mortem imaging revealed fusion of cervical vertebrae from
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C1 to C7, multiple fusions of thoracic spine, bilateral radioulnahumeral synostosis and digital markings on skull which suggest
hydrocephalus with increased intracranial pressure.
[Discussion] POR dependent cholesterol synthesis is essential during skeletal development. Although ABS is systemic disease,
abnormalities in head and brain were the most prominent in our case. Symptoms associated with craniosynostosis have
progressively worsened during fetal life, especially, during third trimester. Prenatal diagnosis may be possible if fetal CT was
performed.
Wed(4)-P-278
Comparison of FISH and array CGH in the practice of PGD
Risa Mori 1 ，Ryota Kobayashi 1 ，Ayumi Yamamoto 1 ，Aisaku Fukuda 1 ，Michiko Anmae 2 ，Yoshiharu Nakaoka 2 ，
Tomoko Ioue 3 ，Yoshiharu Morimoto 3
1:IVF OSAKA Clinic, Japan、2:IVF Namba Cilinic、3:Horac Grand Front Osaka Clinic
Objective:Preimplantation genetic diagnosis (PGD) has been applied on recurrent miscarriage patients due to chromosomal
translocation following the guideline of Japan society of Obstetrics and Gynecology (JSOG) from 2008 at our facility. PGD
was initially performed by FISH. However, we applied aCGH from 2012 after approval of using this technology by JSOG
because of more accuracy. Therefore, the present study was conducted to compare the accuracy of diagnosis, subsequent
pregnancy rate and miscarriage rate between FISH and aCGH.
Poster Session
Method:Retrospective analyses were performed on 35 PGD cases (66 IVF cycles) due to reciprocal translocation from March,
2008 to April, 2015. Twenty eight cycles of FISH group (204 embryos) and 38 cycles of aCGH group (180 embryos) were
compared by the rates of normal embryo, clinical pregnancy and miscarriage. Although biopsy was performed on either
cleaved embryo or blastocyst, no comparison was done between the embryo stages.
Results:The determination of unbalanced translocation on embryos was diagnosed with significantly higher (P<0.001) in
FISH group (84.8%:173/204) compared to aCGH group (54.4%:98/180), but no difference on diagnosed normal chromosome
between FISH (15.2%:31/204) and aCGH (17.2%:31/180) groups. There were no difference in pregnancy and miscarriage
rates after transfer of the embryos diagnosed normal between FISH (33.3%:6/18 and 33.3%:2/6) and aCGH (42.9%:9/21 and
11.1%:1/9) groups.
Conclusion:Although FISH determined higher ratio of embryos with chromosomal abnormality than aCGH, subsequent preg-
nancy and miscarriage rates are similar in both group. Therefore, there must be more misdiagnosis or over diagnosis by
FISH compared to aCGH. We can’t conclude which is better FISH or aCGH due to small number of samples. FISH will be
replaced by aCGH or even next generation sequencing (NGS) soon or later, not only due to accuracy but also less cost and
labor.
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Wed(4)-P-279
Cytogenetic analysis of products of conception during 10 years
Nobuaki Ozawa 1 ，Mari Mitsui 1 ，Aiko Sasaki 1 ，Seiji Wada 1 ，Haruhiko Sago 1
1:Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Japan
Background
Spontaneous miscarriage occurs in 10-15% of all clinical pregnancies. Fetal chromosome abnormality is the most common
cause of miscarriage, but its incidence is quite different among previous reports; range 30-60%. We analyzed the cytogenetic
results of products of conception (POC) during past 10 years in association with clinical background.
Methods
345 spontaneous miscarriages (< 22 weeks) and 74 stillbirth were included in this study. Cytogenetic analysis was performed
by standard G-banding technique. Clinical information such as maternal age, previous reproductive history and gestational
age was reviewed from medical records. Miscarriage cases were divided into three groups by the ultrasonographic finding:
Group A (CRL<10mm), Group B (CRL=10 ~ 19mm) and Group C (CRL≥20mm).
Results
Poster Session
The success rate of cytogenetic analysis was 92.5% in miscarriages, 95.9% in stillbirth. Chromosomal abnormalities were
found in 82.1% in miscarriages (mean maternal age: 37.9y/o), 38.0% in stillbirth (36.6y/o). The frequency of chromosomal
abnormalities in miscarriages increased with maternal age, whereas it decreased with gestational age or the number of previous
miscarriages. In Group A, polyploidy and plural trisomy were observed more frequently and various kinds of trisomy were
detected (except 1, 11, 19 trisomy), but X monosomy not detected. On the other hand, most of trisomy were 21 trisomy and
X monosomy was detected in 10% of miscarriages in Group C.
Conclusions
The frequency of chromosomal abnormalities in POC was considerably higher in this study compared to previous reports.
High maternal age and high success rate of cytogenetic analysis explain the results. The gestational age at miscarriage greatly
influenced the type/frequency of abnormal karyotype of POC. More attention should be paid for clinical background and
analysis efficiency when considering chromosomal abnormalities of POC.
Wed(4)-P-280
Factors influencing the uptake of noninvasive prenatal testing among women of advanced maternal age
Shusaku Hayashi 1 ，Yoko Okamoto 1 ，Keiko Matsuda 2 ，Shiyo Ota 1 ，Haruka Muto 1 ，Asako Kanai 1 ，
Takeshi Kanagawa 1 ，Keisuke Ishii 1 ，Nobuaki Mitsuda 1
1:Maternal-Fetal Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Japan、2:Medical Genetics, Osaka
Medical Center and Research Institute for Maternal and Child Health
Aim
To determine the factors influencing the uptake of noninvasive prenatal testing (NIPT) among women of advanced maternal
age.
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ICHG2016 1313
Methods
A retrospective cohort study at a tertiary care hospital. Study participants were women of 35 years of age or older at delivery
managed from the first trimester onward at our hospital from February 2014 through June 2015. Multiple pregnancies and
recipients of donated oocytes were excluded. In our hospital, all pregnant women were informed of screening tests for fetal
aneuploidy in a non promotional manner at first prenatal visit. A screening option of NIPT was offered to women of 35 years
of age or older. Maternal ages of women conceived after frozen-thawed embryo-transfer were adjusted by the ages at ovum
pickup. The cost of NIPT was fixed during the study period. The following variables were selected as potential determinants
for the uptake of NIPT : maternal age (35-37, 38-40, 41-43, 44 or older) ; nulliparity; assisted reproductive technology (ART)
conception; previous obstetric history of trisomy 13, 18, or 21; date of delivery (divided into three terms). These factors were
analyzed with a multivariable logistic regression model.
Results
Of 454 women of 35 years of age or older at delivery, 48 (11%) had NIPT. The significant factors for the uptake of NIPT were
maternal age (adjusted odds ratio [aOR]: 1.58; 95% confidence interval [CI]: 1.01-2.28; P=0.014); nulliparity (aOR: 2.06; 95%
CI: 1.07-3.98; P=0.031); previous obstetric history of trisomy 13, 18, or 21 (aOR: 5.10; 95% CI: 1.15-22.7; P=0.032); date of
delivery (aOR: 1.90; 95% CI: 1.33-2.72; P<0.001).
Conclusions
Poster Session
The factors influencing the uptake of NIPT among women of advanced maternal age were determined. ART conception was
not associated with women’s preference for NIPT in our study population.
Wed(4)-P-281
Decision-making after prenatal genetic screening testing for fetal trisomies
Rina Akaishi 1 ，Aiko Sasaki 1 ，Miyuki Nishiyama 1 ，Kohei Ogawa 1 ，Rika Sugibayashi 1 ，Katsusuke Ozawa 1 ，
Masaki Sekiguchi 1 ，Nagayoshi Umehara 1 ，Mariko Uehara 1 ，Norihiko Kikuchi 1 ，shinji Tanigaki 1 ，Seiji Wada 1 ，
Nobuaki Ozawa 1 ，Haruhiko Sago 1
1:Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Japan
Objective
NIPT (noninvasive prenatal genetic testing) was started in Japan from April 2013. Since then, more women request prenatal
genetic testing due to anxieties about fetal diseases. NIPT has been reported to reduce the frequency of invasive genetic
testing because NIPT has a high sensitivity and specificity. Also, other non-invasive genetic testing such as the quad test has
decreased. This study tries to clarify the maternal decision making process after prenatal genetic screening testing.
Methods
All singleton pregnant women who received the prenatal genetic screening tests (combined test, quad test, NIPT) at our
hospital between April 2013 and September 2015 were included. They received genetic counseling before and after undergoing
prenatal tests. We reviewed the decisions for the result of the tests.
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ICHG2016 1314
Results
Among 3286 women, 230, 355 and 2701 underwent the combined test, quad test and NIPT as a first-line test, respectively.
There were 37 (16.1%), 58 (16.3%) and 47 (1.7%) positive cases, respectively. In those positive for the combined test, 6 cases
(16.2%) chose invasive testing, 19 cases (51.4%) opted for NIPT as a second-line test and 12 cases (32.4%) took no other tests
during pregnancy. Whereas, in those positive for the quad test, 32(55.2%), 5 (8.6%) and 21 (36.2%) chose invasive testing,
NIPT and continuation of pregnancy, respectively. Excluding 9 cases of fetal demise, 37 cases (97.4%) positive for NIPT
chose invasive testing.
Conclusions
The rates for choosing invasive testing in positive cases were significantly lower for the combined test than for NIPT. NIPT
thus acted as a second-line test for the combined test, thereby helping women to avoid unnecessary invasive testing. One
third of the positive cases for the combined test and quad test did not undergo any other tests while continuing pregnancy.
The estimated risk, background risk (maternal age and prior history of trisomy) and gestational weeks at testing all affected
the final maternal decisions.
Wed(4)-P-282
Increased levels of soluble corin in patients with pre-eclampsia and fetal growth restriction
Poster Session
Jun Miyazaki 1,2 ，Haruki Nishizawa 1 ，Asuka Kambayashi 1 ，Mayuko Ito 1,2 ，Yoshiteru Noda 1,2
，Sumire Terasawa 1,2
，
Takema Kato 2 ，Hironori Miyamura 1 ，Takao Sekiya 1 ，Hiroki Kurahashi 2 ，Takuma Fujii 1
1:Obstetrics and Gynecology, Fujita Health University, Japan、2:Division of Molecular Genetics, Institute for Comprehensive Medical Science,
Fujita Health University
Objectives
Corin is a cardiac hormone important in regulating blood pressure. Recently, it was reported that a subset of pre-eclampsia
(PE) patients carried loss-of-function mutations in the CORIN gene. In this study, we compared the expression of corin at the
RNA levels in women with normal (uncomplicated) pregnancies, severe PE and fetal growth restriction (FGR). To evaluate a
potential application of serum corin as a biomarker, we analyzed expression of placental and maternal blood corin in patients
with PE and FGR.
Method
Informed consent was obtained from each patient, and the study protocol was approved by the Ethical Review Board for
clinical researches at the our institute. Placental biopsy and maternal blood samples were obtained during caesarean sections
from each control (uncomplicated) pregnancies (n = 33), severe PE (n =36) and FGR (n = 20). To quantify the expression
levels in placentas, we performed quantitative RT-PCR and immunostaining. Serum concentrations were measured by ELISA.
Results
We found elevated serum corin levels in women with PE compared to those in uncomplicated pregnancy (p<0.01). Interest-
ingly, the serum corin levels were also elevated in pregnancy complicated with PE-related disorder, unexplained FGR without
hypertension, suggesting that the high corin activity is not simply due to the response to the maternal hypertension. CORIN
mRNA levels were not high either in placentas from PIH or FGR. Likewise, anti-corin antibodies showed similar signals in
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ICHG2016 1315
placental syncytiotrophoblast cells by immunostaining. In contrast, corin signals were stronger in maternal decidua cells from
PE and unexplained FGR.
Conclusion
These data suggest that corin may be upregulated in maternal decidua and serum in response to activation of pathway
common in PE and FGR, such as response to anti-angiogenic factors.
Wed(4)-P-283
Three cases of fetal cerebral ventriculomegaries suggesting inherited hydrocephalus
Satoko Osuka 1 ，Maki Goto 1 ，Tomomi Kotani 1 ，Yoshinori Moriyama 1 ，Yumiko Ito 1 ，Fumi Utsumi 1 ，
Yukako Muramatsu 2 ，Yonehiro Kanemura 3,4 ，Fumitaka Kikkawa 1
1:Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan、2:Department of Pediatrics,
Nagoya University Graduate School of Medicine, Nagoya, Japan、3:Division of Regenerative Medicine, Institute for Clinical Research,
Osaka National Hospital, National Hospital Organization, Osaka, Japan、4:Department of Neurosurgery, Osaka National Hospital, National
Hospital Organization, Osaka, Japan
Fetal cerebral ventriculomegaly is a relatively common finding on fetal ultrasound examination. Inherited hydrocephalus is
one of the cause of fetal cerebral ventriculomegaly. Ob-gyn doctors should conceive inherited hydrocephalus when they find
fetal ventriculomegaly without other anomalies or the patient has family history. X-linked hydrocephalus (XLH) is one of
the common form of inherited hydrocephalus. Mutations in the gene encoding neural cell adhesion molecule L1 (L1CAM)
Poster Session
are involved in XLH. We review three cases of women who were pregnant male fetus with overt isolated hydrocephalus and
suggested inherited hydrocephalus. First case is 21-year-old primigravid women with no remarkable family history. Her first
son’s ventriculomegaly was pointed out at 22 weeks of gestation. After the delivery, the neonatal care doctor recommended
genetic testing for him and genetic counseling. L1CAM gene testing, approved by Ethics Committee of the institutes, is held
and he was diagnosed XLH with one missense mutation in L1CAM gene. Second case is 38-year-old primigravid woman. She
has two older brothers, they both were suffered congenital hydrocephalus but haven’t had genetic testing. Her first son’s
ventriculomegaly was detected at 24 weeks of gestation. She had genetic counseling after the delivery and is considering about
L1CAM gene testing of the baby at present. The third case is 22-year-old women whose uncle has died in his twenties. Her
first and second son’s ventriculomegaly were detected at both 20 weeks of gestation. She terminated these two pregnancies.
After the second one, she was informed about inherited hydrocephalus and she had genetic counseling. She desired to perform
genetic testing of aborted fetuses and is planning to have L1CAM gene testing. Not a few findings from fetal ultrasonography
could be related to inherited diseases. We need to be aware of diagnostic characters of inherited diseases and importance of
genetic counseling.
Wed(4)-P-284
Fetal trisomy 3 and trisomy 18 mosaicism case detected by non-invasive prenatal screening (NIPS)
Chia-Cheng Hung 1 ，Tzu-Hung Lin 1,2
，Yi-Ning Su 1,2
1:Sofiva Genomics Co., Ltd., Taiwan、2:Dianthus Maternal Fetal Medicine Clinic
Background: Non-invasive prenatal screening (NIPS) has been proven to be a powerful method for the routinely detection
of trisomies 13, 18 and 21. Few cases have been reported about other rare aneuploidies. Here we describe a rare complex
chromosomal mosaicism case involving the trisomies of chromosome 3 (T3) and chromosome 18 (T18) detected by NIPS.
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ICHG2016 1316
Methods: A 21-year old women went for NIPS screening at 22 3/7 weeks of gestation because she had three miscarriages in
a row. We sequenced cell free DNA isolated from maternal plasma and the sequenced data were mapped to human genome
sequence (hg19). Z-socre were calculated for all the 23 pairs of chromosomes.
Results: Z-score increasing significantly of chromosome 3 was observed in this case and the Z-score value was 21.15. After
informaing the elevated risk for fetal trisomy, the pregnant women concluded to have amniocentesis. Amniotic fluid cells
were used for chromosome analysis by GTG-banding and oligo array comparative genomic hybridization (aCGH). The results
showed mos 47,XX,+18[16]/47,XX,+3[7] karyotype and arr[hg19] 3p26.3q29(93,979-197,837,020)x2 ~ 3, 18p11.32q23(148,993-
78,012,800)x2 ~ 3, (X)x2, (Y)x0 genotype.
Conclusion: In the current case report, we describe a case of mosaic karyotype 47,XX,+3/47,XX,+18 observed in NIPS. This
study show NIPS can provide information on other rare chromosomal abnormalities.
Keywords:
noninvasive prenatal screening; trisomy; mosaicism
Poster Session
Wed(4)-P-285
Withdrawn

Wed(4)-P-287
Cytogenetic confirmation of a positive NIPT result: chorionic villus sampling or amniocentesis?
Diane Van Opstal 1 ，Malgorzata Srebniak 1
1:Clinical Genetics, Erasmus MC, Netherlands
Non-invasive prenatal testing (NIPT) for fetal trisomy detection already revealed that there is a small chance of a false positive
and false negative result. This is partly due to the fact that the fetal DNA present in the cell free maternal plasma fraction is
derived from the cytotrophoblast of chorionic villi (CV). From cytogenetic studies in CV we know that the cytotrophoblast is
not always representative for the fetus due to chromosomal mosaicism. Therefore, a positive NIPT should always be confirmed
with invasive testing in order to investigate the fetal karyotype.
It is generally assumed that abnormal NIPT results should best be confirmed with amniocentesis. However, since this invasive
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ICHG2016 1317
test can only be safely performed after 15,5 weeks of gestation while NIPT can be done f

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MyAbstract

Main Hall (1F)

[PrCS] Pre-Congress Symposium

Garden and Banquet Hall Swan (1F)

Main Hall (1F)

[PL1] Plenary Lecture 1 10:30-12:00

[LS1] Luncheon Seminar 1

[CIS1] Concurrent Invited Session 1

[CIS2] Concurrent Invited Session 2

[O1] Cancer Genetics 1 18:00-19:30

[LS2] Luncheon Seminar 2

[CIS3] Concurrent Invited Session 3

Mon(2)-CIS3-1 Assessing the value of genomics ································································································ 159

[CIS4] Concurrent Invited Session 4

[O2] Genetics/Genomics Education 18:00-19:30

[LS20] Luncheon Seminar 20

Precision Oncology with IBM Watson ································································································ 493

[CIS5] Concurrent Invited Session 5

Mon(2)-CIS5-1 Genomic Profiling of a T-cell Leukemia ······················································································ 174

[CIS6] Concurrent Invited Session 6

[O3] Prenatal, Perinatal and Reproductive Genetics 1 18:00-19:30

[LS3] Luncheon Seminar 3

MaterniT™ GENOME” ·················································································································· 494

[CIS7] Concurrent Invited Session 7

[CIS8] Concurrent Invited Session 8

[O4] Bioinformatics and Genomic Technology 1 18:00-19:30

Room B-1 (2F)

[LS4] Luncheon Seminar 4

[CIS9] Concurrent Invited Session 9

Mon(2)-CIS9-1 Prenatal Presentation of Genetic Disorders ················································································· 195

[CIS10] Concurrent Invited Session 10

[O5] Clinical Genetics and Dysmorphology 1 18:00-19:30

Room B-2 (2F)

[O6] Complex Traits and Polygenic Disorders 1 18:00-19:30

Room C-1 (1F)

[O7] Molecular Basis of Mendelian Disorders 1 18:00-19:30

Room C-2 (1F)

[O8] Metabolic Disorders 1 18:00-19:30

[LS5] Luncheon Seminar 5

Addressing Unmet Medical Needs in Rare Hematological Diseases ························································· 496

[ED1] Educational Program 1

Mon(2)-ED1-1 How to Write a Scientific Paper ································································································· 452

[ED2] Educational Program 2

[O9] Psychiatric Genetics, Neurogenetics and Neurodegeneration 1 18:00-19:30

[O10] Development 18:00-19:30

[O11] Cytogenetics 18:00-19:30

[O12] Statistical Genetics and Genetic Epidemiology 1 18:00-19:30

Event Hall (1F)

[CIS11] Concurrent Invited Session 11

[CIS12] Concurrent Invited Session 12

Tue(3)-CIS12-1 Somatic mosaicism - How much of de novo is mitotic? ······························································ 209

[YIA1] Young Investigator Awards Session 1 13:50-15:20

[YIA2] Young Investigator Awards Session 2 15:40-17:10

Tue(3)-YIA2-1 LAT2 transporter is involved in age-related hearing loss ······························································· 485

[CIS13] Concurrent Invited Session 13

[CIS14] Concurrent Invited Session 14

[LS6] Luncheon Seminar 6

Asian Genome Project ····················································································································· 497

[O13] Cancer Genetics 2 13:50-15:20

[O14] Cancer Genetics 3 15:40-17:10

[CIS15] Concurrent Invited Session 15

[CIS16] Concurrent Invited Session 16

[LS7] Luncheon Seminar 7

[O15] Prenatal, Perinatal and Reproductive Genetics 2 15:40-17:10