1

3q29 microdeletion syndrome associated with developmental delay and pulmonary

stenosis: a case report

ABSTRACT

Introduction. 3q29 microdeletion syndrome (OMIM # 609425), first described in 2005, is a

rare copy number variation (CNV), accompanied by various neurodevelopmental and

psychiatric problems. Phenotypic features of the syndrome have not been fully characterized

due to the new definition and rarity. Facial dysmorphology, musculoskeletal anomalies,

cardiovascular abnormalities, gastrointestinal abnormalities, and dental abnormalities can be

seen.

Case report. A 28-month-old male patient was brought to the child and adolescent psychiatry

clinic with a complaint of speech delay. He had mild dysmorphic symptoms. He was also

sensitive to voice and often covered his ears. Balloon valvuloplasty was performed on the

postnatal 28th day due to severe pulmonary stenosis. While karyotype was found to be normal,

in array-Comparative Genomic Hybridization (aCGH), a copy loss was detected in the long

arm of chromosome 3 (arr [hg19] 3q29 [196209689-197601344] x1), which contains

approximately 1.4 Mb of 30 genes. Genetic counseling was given to the family of the patient

who was diagnosed with 3q29 microdeletion syndrome.

Conclusion. Performing genetic analysis in patients with developmental delay for which the

cause cannot be explained will prevent these rare diseases from being overlooked, and the

characteristics of the disease will be better characterized with the reported cases.

Keywords: 3q29 microdeletion syndrome, aCGH, developmental delay, child, cardiac defects
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Introduction

3q29 microdeletion syndrome (OMIM # 609425), first described in 2005, is a rare copy

number variation (CNV), accompanied by various neurodevelopmental and psychiatric

problems.1 The deletion is usually caused by de novo mutations and is rarely inherited. 2

Phenotypic features of the syndrome have not been fully characterized due to the new

definition and rarity. The neuropsychiatric aspects of 3q29 microdeletion syndrome have been

emphasized in the literature. Facial dysmorphology, musculoskeletal anomalies, recurrent ear

infections, ocular abnormalities, cardiovascular abnormalities, gastrointestinal abnormalities,

and dental abnormalities can be seen. Frequently reported clinical features are given in Table

I.3,4

----------------------------------------------Table I is here-------------------------------------------------

In this article, a 28-month-old male patient who presented with speech delay and was

diagnosed with 3q29 microdeletion syndrome is presented, and the importance of genetic

evaluation in cases of unexplained global developmental delay (GDD) is emphasized. This

may also contribute to the genotype–phenotype relationship of 3q29 microdeletion syndrome.

Case

A 28-month-old male patient was brought to the child and adolescent psychiatry clinic with a

complaint of speech delay. The case had 5–6 words and could not make sentences. He was

also sensitive to voice and often covered his ears. When he was evaluated in the playroom

with his parents, it was observed that he made eye contact, looked when his name was called,

performed commands, established joint attention, and played imaginary games. The patient

had no seizure history, and his neurological examination was normal.

On physical examination, he had mild dysmorphic symptoms such as broad nasal type and

broad bridge, short philtrum, wide forehead, small chin, and widely spaced teeth. There was a
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café au lait spot on his right leg. His height was 100 cm (90 th percentile), weight was 15 kg

(86th percentile), and head circumference was 49.5 cm (57th percentile).

Since the risk was detected in the triple screening test, it was learned that Noninvasive

prenatal testing (NIPT) was performed in the prenatal period and the NIPT results showed

low risk. He was born at 3.350 kg (50th percentile), with head circumference 36 cm (89 th

percentile), height 50 cm (52nd percentile), and at full-term (40th gestational week) via a

caesarean delivery. Balloon valvuloplasty was performed on the postnatal 28 th day due to

severe pulmonary stenosis. While there was no delay in holding his head and walking, he

spoke his first words at age two. There was no toilet training. There was no problem in his

visual or hearing examinations. Ek olarak konuşma gecikmesi nedeniyle dış merkezde işitme

testi yapıldığı ve sonucunun normal çıktığı öğrenildi.

The case has a healthy 32-year-old mother and father who have no consanguineous

relationship. This case was the first child in the family. The patient's maternal uncle had died

on the after second day of his birth. The cause was unknown.

According to the Denver II Development Screening Test, while gross motor skills were at the

level of peers, personal–social (18–19 month), lingual (16–17 month), and fine motor (14–15

month) skills were behind their peers. The Childhood Autism Rating Scale (CARS) score for

the child was 21 (indicates no autism), and the Autism Behavior Checklist (ABC) score was

20 (indicates no autism).

Array-Comparative Genomic Hybridization (aCGH) and chromosome analysis from

peripheral blood were performed using the CytoScan® Optima Assay platform on the patient,

who was referred to the Medical Genetics department due to his dysmorphic characteristics.

Karyotype was found to be normal. In aCGH analysis, a copy loss was detected in the long

arm of chromosome 3 (arr [hg19] 3q29 [196209689-197601344] x1), which contains

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approximately 1.4 Mb of 30 genes (Figure I). Genetic counseling was given to the family of

the patient who was diagnosed with 3q29 microdeletion syndrome. He was referred to therapy

for his developmental delay and was followed up for possible risks.

Written informed consent was obtained from the patient's family.

------------------------------------------------Figure I is here----------------------------------------------

Discussion

3q29 microdeletion syndrome yüksek nöropsikiyatrik ve nörogelişimsel fenotip yükü

taşımakla birlikte; kardiyak belirtiler bu sendromun en ciddi belirtilerindendir (Russo). Bu

makalede moleküler stogenetik teknik kullanılarak 3q29 (chr3: 196209689-197601344, hg19)

bölgesinde 1.4 Mb delesyon saptanan ve dismorfik özellikler ve nörogelişimsel sorunlara ek

olarak ciddi pulmoner stenozu bulunan bir olgu sunduk. Bildiğimiz kadarıyla literatürde az

sayıda benzer vaka tanımlanmıştır (Glassford MR,).

3q29 microdeletion syndrome was first described in 2005 in six patients with GDD or

intellectual disability (ID) ranging from mild to moderate in all cases. 1 Daha sonra yapılan

araştırmalarda reported that 3q29 deletion is the highest genetic risk factor (40-fold increased

risk) for schizophrenia6 ve the risk of autism increases 34 times in girls and 16 times in boys.

3q29 delesyon sendromlu 17 katılımcıyla yapılan MRI çalışmasında serebellar korteks hacmi

ile psikoz eğilimi arasında bir ilişki olduğu saptanmıştır (Sefik, E.,).

Despite the strong relationship of 3q29 deletion syndrome with neurodevelopmental

disorders, it is unclear how and which genes affect the phenotype and the impaired cellular

mechanisms associated with these genes. 3q29 mikrodelesyon sendromu kompleks

nöropsikiyatrik hastalıklarla ilişkili genleri araştırmak için önemli bir fırsat sunar. However,

in this case, PAK2, DLG1, BDH1, ZDHHC19, and FBXO45 genes in the deletion region
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have been shown to have an important role in nervous system development and neurosynaptic

maturation.7

DLG1, AMPA ve NMDA reseptörleri ile etkileşime giren ve synaptic plasticity and dendritic

spine formation’da rol alan synaptic scaffold proteini üretir (Hinze). PAK2, family of

serine/threonine kinases’dır ve cytoskeletal remodeling and dynamics’in önemli bir

regülatuarıdır (Wang, Y., 2018). FBXO45 ise ubiquitin ligase’I kodlar ve presinaptik

veziküllerin hazırlanması için gerekli bir protein olan Munc13 ‐1'in degradasyonuna aracılık

ederek glutamat salınımını düzenler [Tada et al., 2010].

Araştırmalarda özellikle bu üç gen (DLG1, PAK2, FBXO45), sinaptik iletimde kanıtlanmış

merkezi rolleriyle öne çıkmaktadır ve ID/GDD, autism ve Sch patogeneziyle

1, 8, 9 Xing, J
ilişkilendirilmiştir . Bununla birlikte benzer moleküler etilenime ragmen bazı 3q29

mikrodelesyon sendromlarında bu olguda olduğu gibi otizm gelişmezken bazılarında otizmin

görülmesinin nedeni hala bililnmemektedir. Bu durum genomdaki ek varyantlar veya çevresel

faktörlerle ilişkili olabilir (Quintero‐Rivera F 2010).. Ayrıca bu olgudaki psikiyatrik

semptomlar delesyon alanındaki genlerin bireysel etkisinden ziyade sinerjik etkileşiminden

kaynaklanıyor olabilir (Grice SJ 2015, Quintero‐Rivera F 2010).

RNF168 is associated with DNA damage repair and is involved in the etiology of

immunodeficiency.10 Its pathological variants cause RIDDLE syndrome, characterized by

immunodeficiency and ID. However, in this case, no findings suggested immunodeficiency.

Kardiyak sorunlar sendroma sık eşlik etmektedir (Russo) ve bu olgudaki gibi sendromun ilk

klinik yansıması olabilir. 3q29 mikrodelesyon sendromunda şimdiye ASD, VSD, aort

stenozu, PDA gibi çeşitli malformasyonlar bildirilmişken (Kaynaklar…) pulmoner stenoz

literatürde az sayıda vakada (yaklaşık % 5) tanımlanmıştır (Glassford MR,). Bu yönüyle

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yazarlar bu çocukların teşhis anında EKO ile doğuştan kalp hastalıkları açısından taranması

gerektiğini belirtmiştir (Russo).

Genetik anormallikler, KKH'li hastaların% 30'unda mevcuttur ve çeşitli genetik sendromlar olarak

tezahür edebilirler. (Pediatric Cardiac Genomics Consortium) Bu nedenle, KKH'li yenidoğanlarda

genetik anormalliklerin yokluğunu veya varlığını doğrulamak önemlidir. KKH hastalarında genetik

kusurların tarama testleri yoluyla erken doğrulanması, nörolojik sorunları ve kalp dışı

malformasyonları erken tahmin etmemizi sağlayabilir, böylece uygun erken müdahaleyi

kolaylaştırarak ve hastanın ailesine uygun tavsiyelerde bulunarak geri dönüşü olmayan hasarı

önlemeye yardımcı olabilir (Pierpont, M. E., Basson, 2007)

Literatürde kardiyak sorunlardan yola çıkılarak yapılan ileri genetik analizler sonucunda tanı

konulan vakalar da vardır. Örneğin yakın zamanda yayınlanan bir olgu sunumunda

intrauterine VSD saptanan fetüse 3q29 delesyon teşhisi konulmuş ve çift genetic danışmanlık

sonucunda gebeliği sonlandırmayı seçmiştir Yue, F., Çin’de konjenital kalp hastalığı olan 200

fetüsle yapılan diğer bir araştırmada prenatal chromosome microarray analysis (CMA) ve

CMA’sı negatiflere de whole exome sequencing (WES)' uygulanmış; olguların yarısında

3q29 mikrodelesyon send.’u da dahil çeşitli kromozom anomalileri tespit edilmiştir. (Lu,

Fengying and Xue 2021).

The aCGH method is used as a first-line clinical diagnostic genetic test for further

investigation in unexplained GDD/ID cases despite detailed evaluations of history, hearing–

vision, and EEG recordings (in suspicious cases). Through aCGH, it has become easier to

identify many new microdeletion/microduplication syndromes in individuals with idiopathic

ID/GDD or congenital anomalies. In conclusion, we present 3q29 microdeletion syndrome

with GDD, dysmorphic face, voice hypersensitivity, and severe pulmonary stenosis.

Performing genetic analysis in patients with developmental delay for which the cause cannot
 7

be explained will prevent these rare diseases from being overlooked, and the characteristics of

the disease will be better characterized with the reported cases.

The aCGH method is used as a first-line clinical diagnostic genetic test for further

investigation in unexplained GDD/ID cases despite detailed evaluations of history, hearing–

vision, and EEG recordings (in suspicious cases). Pollak et al. also emphasized that these

children should be screened from an early age, especially neuropsychiatric and cognitive

screening, and followed throughout their development.

Bulgular, GDD/ID patogenezinde sinaptik disfonksiyonun yer aldığı hipotezini destekler

niteliktedir. Delesyon ve resiprokal duplikasyonun rollerini öğrenebilmek için CNV

bölgesindeki bireysel genlerin ve gen varyantlarının katkılarını anlamak artık büyük önem

taşımaktadır. Verilerin verifikasyonu ve aynı bölgeye ait, gen anlatım ve proteomiks

çalışmaları hastalığın patogenez mekanizması ve tedavi stratejileri açısından önemli ipuçları

sağlayabilir.

Hastalığa neden olan kritik delesyon bölgesinin ve klinik özelliklerle ilgili spesifik genlerin

belirlenebilmesi ve daha net bir genotipfenotip ilişkisinin kurulabilmesi için daha fazla

hastada, daha ayrıntılı moleküler analizlerin yapılması gerekmektedir.

Ayrıca bu olguda olduğu gibi kardiyak sorunlara ek dismorfik belirtiler, nöropsikiyatrik veya

nörogelişimsel sorunlar, gastrointestinal ya da kas iskelet anomalilerin eşlik ettiği durumlarda

CNV’ler akla getirilmeli ileri genetic analizler açısından değerlendirilmelidir.

Sonuç olarak, KKH'li yenidoğanların, herhangi bir ekstra-kardiyak semptomla birlikte olduğunda a-CGH

kullanılarak genetik anormallikler açısından taranmasını öneriyoruz. Bununla birlikte, bazı genetik anormallikler

a-CGH ile tanımlanamadığından, FISH veya tüm ekzom dizilimi, a-CGH'den negatif sonuç aldığımızda da dikkate

alınmalıdır. Erken teşhisin olumsuz etkilerini önlemek için, ebeveyn danışmanlığına yönelik tekniklerin daha

fazla geliştirilmesi gerekli olacaktır (Choi, B. G., Hwang).

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Conflict of Interest: The authors declare no conflict of interest.

References

1. Willatt L, Cox J, Barber J, et al. 3q29 microdeletion syndrome: clinical and molecular

characterization of a new syndrome. Am J Hum Genet 2005; 77: 154–160.

2. Digilio MC, Bernardini L, Mingarelli R, et al. 3q29 Microdeletion: A mental retardation

disorder unassociated with a recognizable phenotype in two mother ‐daughter pairs. Am J

Med Genet A 2009; 149A: 1777–1781.

3. Chirita Emandi A, Dobrescu AI, Doros G, et al. A Novel 3q29 Deletion in Association

with Developmental Delay and Heart Malformation Case Report with Literature Review.

Front Pediatr 2019; 7: 270.

4. Harner MK, Lichtenstein M, Farrell M, et al. Treatment-resistant psychotic symptoms and

early-onset dementia: A case report of the 3q29 deletion syndrome. Schizophr Res 2020;

224: 195-197.

5. Pollak RM, Murphy MM, Epstein MP, et al. Neuropsychiatric phenotypes and a distinct

constellation of ASD features in 3q29 deletion syndrome: Results from the 3q29 registry.

Molecular Autism 2019; 10(1): 30.

6. Mulle JG. "The 3q29 deletion confers >40-fold increase in risk for schizophrenia".

Molecular psychiatry 2015; 20(9): 1028-1029.

7. Chung FZ, Sahasrabuddhe AA, Ma K, et al. Fbxo45 inhibits calcium-sensitive proteolysis

of N-cadherin and promotes neuronal differentiation. J Biol Chem 2014; 289(41): 28448-

59.

8. Fernández‐Jaén A, Castellanos MDC, Fernández‐Perrone AL, et al. Cerebral palsy,

epilepsy, and severe intellectual disability in a patient with 3q29 microduplication

syndrome. American Journal of Medical Genetics Part A 2014; 164(8): 2043-2047.

 9

9. Shimanoe C, Hachiya T, Hara M, et al. A genome-wide association study of coping

behaviors suggests FBXO45 is associated with emotional expression. Genes Brain Behav

2019; 18(2): e12481.

10. Streata I, Riza AL, Sosoi S, Burada F, Ioana M. Phenotype Heterogeneity in 3q29

Microduplication Syndrome. Current health sciences journal 2020; 46(2): 193–197.

11. Russo, R. S., Gambello, M. J., Murphy, M. M., Aberizk, K., Black, E., Burrell, T. L., ... &

Mulle, J. G. (2021). Deep phenotyping in 3q29 deletion syndrome: recommendations for

clinical care. Genetics in Medicine, 1-9.

12. Glassford MR, Rosenfeld JA, Freedman AA, Zwick ME, Mulle JG; Unique Rare

Chromosome Disorder Support Group. Novel features of 3q29 deletion syndrome: Results

from the 3q29 registry. Am J Med Genet A. 2016;170A(4):999-1006.

doi:10.1002/ajmg.a.37537

13. Yue, F., Deng, S., Xi, Q., Jiang, Y., He, J., Zhang, H., & Liu, R. (2021). Prenatal detection

of a 3q29 microdeletion in a fetus with ventricular septum defect: A case report and

literature review. Medicine, 100(1), e24224.

https://doi.org/10.1097/MD.0000000000024224

14. Sefik, E., Aberizk, K., Espana, R., Guest, R., Goines, K., Novacek, D., ... & Mulle, J.

(2021). Structural Cerebellar Correlates of Psychotic and Sub-Threshold Psychotic

Symptoms in the 3q29 Deletion Syndrome. Biological Psychiatry, 89(9), S225-S226.

15. Lu, Fengying and Xue, Peng and Zhang, Bin and Wang, Jing and Liu, Jianbin and Yu,

Bin, Estimate the Frequency of Causal Genetic Variants in Fetuses with Congenital Heart

Defect: A Chinese Cohort Study. Preprints with The Lancet 2021; published online Feb

22. http://dx.doi.org/10.2139/ssrn.3783780

16. Malt, E. A., Juhasz, K., Frengen, A., Wangensteen, T., Emilsen, N. M., Hansen, B., ... &

Nilsen, H. L. (2019). Neuropsychiatric phenotype in relation to gene variants in the

 10

hemizygous allele in 3q29 deletion carriers: A case series. Molecular genetics & genomic

medicine, 7(9), e889.

17. Hinze, S. J., Jackson, M. R., Lie, S., Jolly, L., Field, M., Barry, S. C., ... & Shoubridge, C.

(2017). Incorrect dosage of IQSEC2, a known intellectual disability and epilepsy gene,

disrupts dendritic spine morphogenesis. Translational psychiatry, 7(5), e1110-e1110.

18. Wang, Y., Zeng, C., Li, J., Zhou, Z., Ju, X., Xia, S., ... & Sun, Z. S. (2018). PAK2

haploinsufficiency results in synaptic cytoskeleton impairment and autism-related

behavior. Cell reports, 24(8), 2029-2041.

19. Grice SJ, Liu JL, Webber C. Synergistic interactions between Drosophila orthologues of

genes spanned by de novo human CNVs support multiple-hit models of autism. PLoS

Genet 2015; 11(3):e1004998.

20. Tada H, Okano HJ, Takagi H, Shibata S, Yao I, Matsumoto M, Saiga T, Nakayama

KI, Kashima H, Takahashi T, Setou M, Okano H. 2010. Fbxo45, a novel ubiquitin ligase,

regulates synaptic activity. J Biol Chem 285: 3840– 3849.

21. Xing, J., Kimura, H., Wang, C., Ishizuka, K., Kushima, I., Arioka, Y., Yoshimi, A.,

Nakamura, Y., Shiino, T., Oya-Ito, T., Takasaki, Y., Uno, Y., Okada, T., Iidaka, T.,

Aleksic, B., Mori, D., & Ozaki, N. (2016). Resequencing and Association Analysis of Six

PSD-95-Related Genes as Possible Susceptibility Genes for Schizophrenia and Autism

Spectrum Disorders. Scientific reports, 6, 27491. https://doi.org/10.1038/srep27491

22. Quintero‐Rivera F, Sharifi‐Hannauer P, Martinez‐Agosto JA. 2010. Autistic and

psychiatric findings associated with the 3q29 microdeletion syndrome: Case report and
review. Am J Med Genet Part A 152:2459–2467.
23. Choi, B. G., Hwang, S. K., Kwon, J. E., & Kim, Y. H. (2018). Array Comparative Genomic
Hybridization as the First-line Investigation for Neonates with Congenital Heart Disease:

Experience in a Single Tertiary Center. Korean circulation journal, 48(3), 209–216.

https://doi.org/10.4070/kcj.2017.0166

24. Pediatric Cardiac Genomics Consortium, Writing Committee:, Gelb, B., Brueckner, M., Chung, W.,
Goldmuntz, E., ... & Wong, H. (2013). The congenital heart disease genetic network study:
rationale, design, and early results. Circulation research, 112(4), 698-706.
 11

25. Pierpont, M. E., Basson, C. T., Benson Jr, D. W., Gelb, B. D., Giglia, T. M., Goldmuntz, E., ... &
Webb, C. L. (2007). Genetic basis for congenital heart defects: current knowledge: a scientific
statement from the American Heart Association Congenital Cardiac Defects Committee, Council
on Cardiovascular Disease in the Young: endorsed by the American Academy of
Pediatrics. Circulation, 115(23), 3015-3038.