CLINICAL REPORT

Two Further Patients with the 1q24 Deletion

Syndrome Expand the Phenotype: A Possible Role
For the miR199–214 Cluster in the Skeletal
Features of the Condition
Tazeen Ashraf,1* Morag N. Collinson,2 Joanna Fairhurst,3 Rubin Wang,4 Louise C. Wilson,4
and Nicola Foulds5
1
Guy’s Clinical Genetics Service, Guy’s Hospital, London, United Kingdom
2
Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, Wiltshire, United Kingdom
3
Radiology Department, University Hospital Southampton NHS Foundation Trust, Southampton, Hampshire, United Kingdom
4
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
5
Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, Hampshire, United Kingdom

Manuscript Received: 2 November 2014; Manuscript Accepted: 2 August 2015

Submicroscopic deletions within chromosome 1q24q25 are as-

sociated with a syndromic phenotype of short stature, brachy-
dactyly, learning difficulties, and facial dysmorphism. The
critical region for the deletion phenotype has previously been
narrowed to a 1.9 Mb segment containing 13 genes. We describe
two further patients with 1q24 microdeletions and the skeletal
phenotype, the first of whom has normal intellect, whereas the
second has only mild learning impairment. The deletion in the
first patient is very small and further narrows the critical interval
for the striking skeletal aspects of this condition to a region
containing only Dynamin 3 (DNM3) and two microRNAs that
are harbored within intron 14 of this gene: miR199 and miR214.
Mouse studies raise the possibility that these microRNAs may be
implicated in the short stature and skeletal abnormalities of this
microdeletion condition. The deletion in the second patient
spans the previously reported critical region and indicates
that the cognitive impairment may not always be as severe as
previous reports suggest. Ó 2015 Wiley Periodicals, Inc.
Key words: genetics; microdeletion; 1q24; dynamin-3; DNM3;
dysmorphology; syndrome; skeletal; phenotype; miR199
INTRODUCTION
Burkardt et al. [2011] reported nine patients with 1q24q25 dele-
tions defined by oligonucleotide-based array comparative genomic
hybridization (array-CGH). These patients had a consistent phe-
notype of prenatal onset growth deficiency with severe propor-
tionate short stature, microcephaly, facial dysmorphism, a
distinctive pattern of brachydactyly, and severe cognitive disability.
The phenotype is consistent with that previously reported in other
patients including those defined using traditional cytogenetic
How to Cite this Article:
Ashraf T, Collinson MN, Fairhurst J, Wang
R, Wilson LC, Foulds N. 2015. Two further
patients with the 1q24 deletion syndrome
expand the phenotype: A possible role for
the miR199–214 cluster in the skeletal
features of the condition.
Am J Med Genet Part A 167A:3153–3160.
techniques [Franco et al., 1991; Chaabouni et al., 2006; Callier
et al., 2007; Descartes et al., 2008; Nishimura et al., 2010].
By aligning the deletion and phenotypic data in their nine
patients, Burkardt et al. [2011] identified a critical deletion region
spanning 1.9Mb at 1q24.3q25.1 containing 13 genes. They pro-
posed that the growth deficiency and microcephaly might result
from deletion of the gene CENPL, encoding a centrosomal protein,
based on the involvement of centrosomal genes in other growth
deficiency syndromes. They also surmised that the cognitive dis-
ability in their patients might result from deletion of DNM3, which
is expressed in brain and has a role in synaptic function.
We report two further patients with small 1q24 microdeletions
who share the characteristic physical phenotype but not the severe
cognitive disability. One is an adult with normal intellect, whereas


Correspondence to:
Tazeen Ashraf, Guy’s Clinical Genetics Service, Guy’s Hospital, London
SE1 9RT, United Kingdom.
E-mail: Tazeen.Ashraf@gstt.nhs.uk
Article first published online in Wiley Online Library
(wileyonlinelibrary.com): 3 September 2015
DOI 10.1002/ajmg.a.37336

Ó 2015 Wiley Periodicals, Inc. 3153

3154
the other has been assessed as having only mild cognitive im-
pairment at 12 years of age. Comparison of the array-CGH results
in our patients with those previously reported allows the critical
region of overlap for the skeletal phenotype to be substantially
narrowed to a region that contains only the DNM3 gene and two
microRNA’s that are harbored within intron 14, miR199 and
miR214 (Fig. 5). Dynamin-3 is highly expressed in human adult
brain, but has little or no expression in the skeleton [Nagase et al.,
1998]. However it has been observed that in mice, downregulation
of miR199 and miR214 expression results in embryos that exhibit
several skeletal abnormalities including craniofacial hypoplasia,
defects of dorsal neural arches, and spinous processes of the
vertebrae and osteopenia [Watanabe et al., 2008]. More recently,
further work on the miR199–214 cluster has shown that it is on the
opposite strand of DNM3 in an arrangement that is highly con-
served across vertebrate species [Gradus and Hornstein, 2010; Scott
et al., 2012]. These authors show expression patterns for the two
microRNA’s predominantly in tissues surrounding developing
craniofacial skeletal elements and conclude that miR199 and
miR214 have a conserved role in vertebrate skeletogenesis. We,
therefore, suggest that the miR199–214 gene cluster within DNM3
is the most likely candidate to account for the striking skeletal
phenotype observed in the 1q24 deletion syndrome.
CLINICAL REPORT
Patient A
Patient A is one of monozygous twins. She was born at 38 weeks
gestation via forceps delivery weighing 1.84 kg (<0.4th centile).
The parents were non-consanguinous Caucasians and the family
history was unremarkable. There were no antenatal concerns and
no significant maternal illnesses during pregnancy. The patient was
FIG. 1. Photographs of Patient A. (a) Facial appearance: fullness of upper eyelids with mild bilateral ptosis, bulbous nasal trip. (b) Hands:
small hands, brachydactyly, proximally placed thumb, fifth finger clinodactyly, small nails. (c) Foot: wide foot, pes planus, broad great toe,
brahydactyly of all toes, small nails. [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/
journal/ajmga].
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
born in a good condition and admitted to the Special Care Baby
Unit (SCBU) for nasogastric tube feeding to maintain adequate
blood sugar levels. She was described as dysmorphic in the neonatal
period with small and deeply set eyes, apparently low-set ears and
an upturned nose. She had a small anterior fontanelle and large
posterior fontanelle. A skull X-ray confirmed partial coronal
craniosynostosis. Cranial ultrasound of the brain identified normal
structures. She had a negative congenital infection (TORCH)
screen and normal female karyotype. A diagnosis of Saethre–
Chotzen syndrome was suspected. Her twin sister had similar
features and skeletal findings, but did not seek further genetic
input. Both sisters required calvarial surgery for craniosynostosis at
6 months of age.
By the age of 3 years, the patient had undergone surgical
correction of a strabismus and had also had an umbilical hernia
repair. She was in good health but concerns were raised regarding
short stature. Provocation tests demonstrated normal growth
hormone (GH), insulin-like growth factor 1 (IGF-1), and binding
protein-3 levels (BP3). She was commenced on GH at 10 years of
age for 4 years when she measured 110.3cm (4.5 SD).
At age 14, she was seen again by clinical genetics. Examination
revealed a generalized brachydactyly with broad thumbs, clino-
dactyly of fifth fingers and broad feet with widened great toes. She
had bilateral ptosis, more marked on the left than the right (Fig. 1).
There were distinctive radiographical features noted on X-ray
(Fig. 2).
The patient was lost to follow-up until the age of 25 years when
she presented to genetics. Her final height was 142 cm (4 SD). She
had hypermetropia with a prescription of þ6.75 and þ5.75. She
had not required any additional support at school and was
employed in a skilled profession.
Due to the history of coronal craniosynostosis, sequencing of
exon 7 of FGFR1, exons IIIa and IIIc of FGFR2, exons 7 and 10 of
ASHRAF ET AL.
FIG. 2. Radiographs of Patient A. (a) Radiograph of right wrist aged 18 years 7 months: broad distal ulna, underdeveloped ulnar styloid, and
shortened fifth metacarpal and mildly shortened fourth metacarpal. (b) Trauma radiograph of left foot aged 23 years: short and broad proximal
phalanges of second, fifth and great toe, shortened second to fourth middle phalanges, and shortened distal phalanges in all toes.
FGFR3, and exon 1 of TWIST1 was undertaken together with
MLPA for TWIST1, RUNX2, ALX1, ALX3, ALX4, MSX2, EFNB1.
No pathogenic mutations, deletions or duplications were identified
excluding Muenke syndrome and as far as possible excluding
Saethre–Chotzen, Crouzon, and Pfeiffer syndromes. Biochemical
testing for pseudohypoparathyroidism was also normal.
Array-CGH was undertaken which identified a deletion involv-
ing the region 1q24.2 to 1q24.3 with a minimum size of 2.4 Mb
(arr[hg18] 1q24.2q24.3(168,007,914–170,448,198) x1) and a max-
imum size of 2.6 Mb (arr[hg18] 1q24.2q24.3(167,916,942–
170,502,632) x1). Fluorescence in situ hybridization (FISH) with
the probes RP11-33H27 and RP11-277C14 confirmed the deletion
in this patient and showed that it was de novo.
This chromosomal deletion is smaller than those in previously
reported cases. It contains 17 genes: C1orf112, METTL18, SCYL3,
KIFAP3, METTL11B, GORAB, PRRX1, MROH9, FMO3, FMO2,
FMO1, FMO4, PRRC2C, MYOC, VAMP4, METTL13, and DNM3.
MYOC lies just centromeric of DNM3 and although missense and
nonsense mutations have been associated with autosomal-domi-
nant primary open angle glaucoma, there is no current evidence
that haploinsufficiency increases the risk [Kwon et al., 2009].
However, as a precaution the patient is being followed by ophthal-
mology services because of the deletion of MYOC.
Patient B
Patient B is a 12-year-old girl, the second child of non-consan-
guinous Caucasian parents. She was noted to have short femurs on
an ultrasound scan at 20 weeks gestation but otherwise her
antenatal course was unremarkable. She was born at 39 weeks
gestation weighing 2.64 kg (2–9th centile). At 10 days of age, she
had a length of 44 cm (<0.4th centile). She had a patent ductus
arteriosus diagnosed at 5 weeks of age, which required catheter
closure, but was otherwise well.
There were concerns about short stature and motor delay from
around 18 months of age when Griffiths assessment showed she was
3155
functioning around the 10-month level for locomotor skills and at a
14–15-month level in all other areas. She walked independently just
after 2 years of age. Speech milestones were within normal limits.
Reassessment at 3 years 9 months showed she was functioning
around the 2.5 to 3-year level. Behavior and social interactions have
been normal throughout. The patient attends mainstream school.
She has required additional support for her fine motor skills,
hearing, and phonics but assessment at 12 years of age showed
that her literacy is above average, while her reasoning and numer-
acy are below average but within normal limits. She has not had any
special educational needs to date.
At 2 years 9 months, when she presented to clinical genetics, she
had a height of 74.5 cm (5 SD) weight 9.64 kg (2.5 SD), and
OFC of 44.5 cm (2.5 SD). GH commenced at 5 years of age with
good response, with an initial growth velocity of 9 cm/year. She
continues to respond with her most recent growth velocity being
6.3 cm/year at 11.4 years of age.
Her medical history has also included recurrent episodes of otitis
media with effusion for which she has had four sets of grommets.
She developed a conductive hearing loss and wears hearing aids
bilaterally. She developed amblyopia secondary to mild hyperme-
tropia of the right eye, which responded to patching. She was noted
incidentally to have myelinated nerve fibers at the optic disc. She
developed headaches associated with snoring and sleep studies
confirmed obstructive sleep apnea which has improved consider-
ably following adenotonsillectomy at 10 years of age.
On examination, she had characteristic features described pre-
viously in this condition (Fig. 3). Additionally, she had delayed
dentition, generalized joint laxity, and an everted umbilicus. When
last reviewed at 10 years of age, after 5 years of GH treatment, she
had a height of 116 cm (3.5 SD), weight 24.35 kg (2nd centile),
and OFC of 49.1 cm.
Her radiographs at 2 years 9 months, 4 years, and 9 years 11
months are illustrated. The salient abnormalities are disharmoni-
ous skeletal maturation with delays in carpal ossification to a
greater degree than epiphyseal ossification, only 11 pairs of ribs,
3156 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

FIG. 3. Photographs of Patient B. (a) Facial appearance at 2.75 years: Metopic narrowing with overlaying capillary stain, mild bilateral partial,
micrognathia, bulbous nasal tip. (b) Ear: small, posteriorly rotated with thickened helices. (c) Hand aged 10 years: small hand with
generalized brachydactyly, fifth finger clinodactyly, short nail beds. (d) Foot aged 10 years: short broad foot and hallux, generally short toes
with broad nail beds. [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmga].

mild coxa valga, and brachydactyly which initially predominantly
involved the second and fifth middle phalanges associated with
cone epiphyses and progressed to involve the lateral metacarpals
and distal phalanges (Fig. 4).
Investigations included a normal female karyotype and nor-
mal ADAMTSL2 sequencing undertaken because of the possi-
bility of acromicric dysplasia. Further detailed chromosome
testing by array-CGH revealed a submicroscopic 1q24.2q25.2
deletion with a minimum size of 9.2 Mb (arr[hg19] 1q24.2q25.2
(170,042,861–179,275,314) x1) and a maximum size of 9.4 Mb
(arr[hg19] 1q24.2q25.2 (169,995,664–179,420208) x1). Proband
and parental FISH studies using probe RP11-64I24 confirmed
the deletion in this patient was de novo. The deletion spans the
critical region reported by Burkardt et al. [2011] (Fig. 5). It
includes the anti-thrombin 3 (SERPINC1) gene, deletion of
which is associated with increased thrombophilia risk due to
a 50% reduction in antithrombin III activity. The patient has
had detailed hematology investigations which have confirmed,
as expected, that she has type 1 antithrombin deficiency for
which advice has been given. The deletion also includes MYOC,
for which she attends an annual eye check at her high street
optician.

FIG. 4. Radiographs of Patient B. (a) Radiograph of left hand aged 2 years 9 months: delayed bone age approximating 2 years in epiphyses
and 1.5 years in carpals. Shortened distal phalanges, shortened and broad fifth metacarpal, cone epiphyses in thumb distal phalanx. Short
proximal phalanges 2–5 with distal pointing giving a bullet-shaped configuration. The proximal epiphyses were significantly thickened. All of
the middle phalanges were short and broad, but this was most marked in the index and little fingers. The distal phalanges were slightly
shortened and moderately broad, again with thickened epiphyses. Mild metaphyseal flaring of the distal radius and ulna. (b) Radiograph of
the left foot (4 years): shortened and broad proximal phalanges with cone epiphyses, shortened distal phalanx of the hallux. Skeletal Survey
aged 9 years 11 months: (c) Radiographic of left hand/wrist: delayed bone age, disharmonious carpal maturation. (d) Radiographic of pelvis:
mild flattening of the femoral head, mild coxa valga, prominant broad-based greater trochanters. (e) Radiograph of the ankle: flattened,
irregular, and sloping talar dome with associated thinnings of distal tibial epiphysis. (f) Skull radiograph: shallow anterior cranial fossa with
very shallow markedly sloping floor.
ASHRAF ET AL. 3157

FIG. 5. Schematic demonstrating chromosome deletions in previously reported patients, patients A and B and magnification onto the common
region of overlap containing DNM3, miR199, and miR214. [Color figure can be seen in the online version of this article, available at http://
wileyonlinelibrary.com/journal/ajmga].

METHOD
Chromosome analysis was carried out on cultured peripheral
blood lymphocytes following routine G-banding analysis proce-
dures. Oligonucleotide array comparative genomic hybridization
(array-CGH) was performed using the Oxford Gene Technology’s
(OGT, Oxford, UK) International Standard Cytogenomic Array
Consortium (ISCA) custom 8  60 K array, manufactured by
Agilent Technologies (Agilent Technologies, Santa Clara, CA),
on patient A according to manufacturer’s instructions. Promega
pooled control DNA was used as a reference. The results were
analyzed using OGT CytoSure Interpret Software version 3.4.8.
Array-CGH was performed on patient B using the NimbleGen
135 k CGH microarray in accordance with manufacturer’s instruc-
tions (NimbleGen Arrays User’s Guide: CGH and CGH/LOH
Arrays v9.1, Roche NimbleGen, Madison, WI). The microarray
was washed and then scanned on an Axon GenePix 4400A Scanner
using GenePix Pro 7 software (Molecular Devices, Sunnyvale, CA).
Raw data were normalized, LOESS correction applied, and the data
ratios calculated using DEVA v1.01 Software (Roche NimbleGen).
The normalized data were processed using Infoquant Fusion v6.0
software (Infoquant, London, UK). Fluorescence in situ hybrid-
ization (FISH) was carried out on Patient A and both parents using
standard methods. The Ensembl 30 K cloneset bacterial artificial
chromosomes (BACs) RP11-332H7 and RP11-277C14 were used
to confirm the deletion and showed that it was de novo.
DISCUSSION
Several cases of 1q24q25 microdeletions have been described in the
literature associated with a recognizable phenotype comprising
facial dysmorphism, small hands and feet with fifth finger clino-
brachydactyly, severe proportionate short stature with microceph-
aly, and severe cognitive disability. The facial dysmorphism
includes partial ptosis, mild micrognathia, and small ears with
3158
attached lobes in a number of patients, including our Patient B
(Fig. 3b). Our patient A adds craniosynostosis to the list of clinical
features that have occurred with this microdeletion and it is of
interest that Patient B has metopic narrowing but without a
clinically significant degree of trigonocephaly. However, additional
in-utero factors associated with twinning could also have contrib-
uted to the craniosynostosis in patient A. The short stature is
typically prenatal in onset, proportionate, and is not associated
with any demonstrable endocrine abnormality. Many reported
patients have failed to respond to growth hormone treatment
[Burkardt et al., 2011]. Patient A achieved a final adult height of
4 SD despite 4 years of treatment with growth hormone. Al-
though Patient B is felt to be responding, her height remains at
3.5 SD despite 5 years of treatment.
The skeletal features seen in our patients resemble those previ-
ously reported with 1q24 deletion, namely the delayed and dishar-
monious carpal ossification, metacarpal and phalangeal
shortening, soft tissue syndactyly in the toes, and occasional
cone epiphyses. Coxa valga and 11 pairs of ribs have also previously
been described in this condition. Novel findings in our cases
include the modelling deformity of the distal ulna, the sloping
talar dome, the broad and large lesser trochanters, and the marked-
ly shallow anterior cranial fossa.
The pattern of brachydactyly associated with this microdele-
tion is distinct from the widely recognized Types A–E but appears
to evolve consistently according to the reports where it is
adequately documented. Initially it predominantly involves the
second and fifth middle phalanges and later the lateral meta-
carpals and distal phalanges, although more generalized phalan-
geal shortening may occur. The bony shortening may be
associated with cone epiphyses and similar changes are observed
in the feet. All patients reported to date have had both short
stature and brachydactyly raising the possibility that both result
from haploinsufficiency of the same gene. Patients who have
short stature and brachydactyly with normal intellect may escape
detailed chromosome testing by array-CGH but recognition of
this pattern of brachydactyly in the future may help identify
patients with smaller deletions or even intragenic mutations of a
candidate gene in the region.
Our patient A has the smallest deletion reported to date.
Burkardt et al. [2011] suggested CENPL as a candidate gene for
growth failure, but since the chromosome deletion in Patient A
did not contain CENPL which lies telomeric to the distal deletion
breakpoint, it is unlikely that CENPL is solely responsible for
short stature in these patients. Comparison of the deleted
intervals (Fig. 5) shows that Patient A’s findings narrow the
critical region for the short stature and brachydactyly substan-
tially, essentially to DNM3 together with the miR199–214
cluster. In support of this locus as the candidate for the skeletal
features of 1q24 is the case report by Della Monica et al. [2007],
whose patient is reported to have significant learning disability
and autism but not short stature or brachydactyly and whose
deletion does not include DNM3 or the miR199–214 cluster.
Genome-wide association studies (GWAS) have also shown a
significant correlation between DNM3 sequence variants and
final adult height [Gudbjartsson et al., 2008; Lango et al., 2010;
Berndt et al., 2013].
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
DNM3 comprises 18 exons and is predicted to encode a 702
amino acid protein called Dynamin-3. It appears to be highly
expressed in adult brain and spinal cord and at intermediate levels
in adult heart, lung, kidney, testis and ovary, and in fetal liver and
brain [Nagase et al., 1998]. In neurons, Dynamin-3 appears to have
a role in endocytosis of clathrin-coated vesicles [Lu et al., 2007].
Although expression studies have not supported a role for DNM3
in skeletal development to date, more recently intron 14 of DNM3
was found to harbour a 7.9 kb antisense transcript that codes for
two microRNAs, miR199 and miR214 [Watanabe et al., 2008]. This
7.9 Kb antisense transcript is expressed in mouse embryos in the
nasal process, pharyngeal arches, limb buds, and somites in a stage-
dependent manner during development. In later embryos, it is
expressed in perichondrial cells and periarticular chondrocytes,
tracheal cartilage and bronchi, all striated muscle and smooth
muscle of the great arteries, the dermis, upper and lower jaw,
and the cardiac cushions and valves. Knockout mice heterozygous
for the miR199–214 cluster were not reported to show any discern-
ible phenotype. Homozygous miR199–214 knockout mice, which
had apparently normal expression of dynamin-3, had feeding
difficulties, growth retardation, craniofacial hypoplasia, defects
in the dorsal neural arches, and spinous processes of the vertebrae
and osteopenia. Most died within 1 month of birth [Watanabe
et al., 2008]. Further work on DNM3 and its two guest miR’s has
supported the notion that the expression profile for this host gene
and its guests are different, and that miR199 and miR214 are
expressed strongly in mesenchyme and perichondrium around
the developing craniofacial skeletal elements [Desvignes et al.,
2014]. Further functional studies have also supported a role for
miR199 and miR214 in skeletogenesis including work that has
shown that TWIST1 regulates expression in the mouse [Lee et al.,
2009]. This observation is particularly interesting in relation to the
skeletal phenotype of the 1q24 deletion because Saethre–Chotzen
syndrome, which results from haploinsufficiency of TWIST1, has
significant phenotypic overlap. Of particular note, coronal cranio-
synostosis is often a prominent part of Saethre–Chotzen syndrome
and this occurred in patient A. Additionally, the cutaneous syn-
dactylies observed in a few patients in the 1q24 cohort and in
patient A, together with the ptosis, broad thumbs, and halluces that
were seen in patient A and B are all features of Saethre–Chotzen
syndrome. It is also of note that in early medical notes for patient A,
a working diagnosis of Saethre–Chotzen syndrome was proposed,
despite a failure to find any changes in this gene at the time.
Functional studies have also shown that miR199 expression
responds to BMP2 induction in human cell lines and inhibits
chondrogenesis by downregulating SMAD1, which is known to be
a regulator of bone and cartilage formation [Lin et al., 2009].
Additional work in human cell lines has shown that miR214
inhibits bone formation by targeting ATF4 (encoding a transcrip-
tion factor required for osteoblast function) and SP7 (an osteoblast
specific transcription factor) [Shi et al., 2013]. The data that are
emerging on several species suggest a conserved role for miR199
and miR214 in vertebrate skeletogenesis. Intron 14 of DNM3 (and
its guest miR’s) are deleted in both of our patients A and B and is
clearly within the critical region for the 1q24 deletion syndrome
and we suggest that this is the most likely candidate for the striking
skeletal phenotype of this condition.
ASHRAF ET AL.
DNM3 was proposed by Burkardt et al. [2011] to be responsible
for cognitive disability in patients with a 1q24 microdeletion
because it is highly expressed in brain. However, the region deleted
in our patient A included the majority of the DNM3 gene. Patient A
is of normal intelligence and now works in a skilled profession
indicating that haploinsufficiency for DNM3 is unlikely to be the
sole cause for cognitive impairment in this microdeletion syn-
drome. Furthermore, her deletion included C1orf112, METTL18,
SCYL3, KIFAP3, METTL11B, GORAB, PRRX1, MROH9, FMO3,
FMO2, FMO1, FMO4, PRRC2C, MYOC, VAMP4, and METTL13
making those unlikely candidates in patients whose deletions
extend more centromeric to the critical region outlined by Bur-
kardt et al. Our patient B has a deletion that is similar in extent to
several previously reported deletions and spans the critical region
of overlap identified by Burkardt et al. (Fig. 5). It is of interest that
our patient’s cognitive impairment is relatively mild and it is
anticipated that she will achieve independence as an adult. Of
note, she does not have associated autism or behavioral problems
which may have accentuated speech delay and learning disability in
other patients. There are several possible explanations for her mild
cognitive phenotype which include the possibilities that the cog-
nitive impairment results from cumulative haploinsufficiency for
more than one gene in the region, from sequence variations in the
non-deleted alleles within the region, or that haploinsufficiency for
genes within the deleted region may be compensated to varying
degrees by other genes across the genome. Delineation of further
patients and the results of ongoing whole exome and genome
sequencing studies in individuals with learning disability may help
clarify the contribution of genes within the deleted interval to
intellectual disability.
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