Genotype–Phenotype Analysis of 4q Deletion
Syndrome: Proposal of a Critical Region
Eugen-Matthias Strehle,1Linbo Yu,2Jill A. Rosenfeld,3Sandra Donkervoort,2Yulin Zhou,2,4
Tian-Jian Chen,5Jose E. Martinez,5Yao-Shan Fan,6Deborah Barbouth,6Hongbo Zhu,6Alicia Vaglio,7
Rosemarie Smith,8Cathy A. Stevens,9Cynthia J. Curry,10Roger L. Ladda,11Zheng (Jane) Fan,12
Joyce E. Fox,13Judith A. Martin,14Hoda Z. Abdel-Hamid,15Elizabeth A. McCracken,16
Barbara C. McGillivray,17Diane Masser-Frye,18and Taosheng Huang2,19,20*
1Institute of Human Genetics, Newcastle upon Tyne, United Kingdom
2Department of Pediatrics, University of California, Irvine, California
3Signature Genomics Laboratories, Spokane, Washington
4The Prenatal Diagnostic Center, Xiamen Women and Children’s Hospital, Xiamen, China
5College of Medicine, University of South Alabama, Mobile, Alabama
6Department of Pediatrics, Miller School of Medicine, University of Miami, Miami, Florida
7Instituto de Gen? etica M? edica, Hospital Italiano, Montevideo, Uruguay
8Pediatric Specialty Care, Maine Medical Partners, Portland, Maine
9Department of Pediatrics, TC Thompson Children’s Hospital, Chattanooga, Tennessee
10Genetic Medicine Central California, Fresno, California
11Department of Pediatrics, Penn State Hershey Children’s Hospital, Hershey, Pennsylvania
12Department of Neurology, University of North Carolina at Chapel Hill, North Carolina
13Department of Pediatrics, Steven and Alexandra Cohen Children’s Medical Center of New York, New Hyde Park, New York
14Inland Northwest Genetics Clinic, Spokane, Washington
15Division of Child Neurology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania
16Department of Medical Genetics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania
17Department of Medical Genetics, The University of British Columbia, Vancouver, Canada
18Department of Genetics, Rady Children’s Hospital, San Diego, California
19Department of Pathology, University of California, Irvine, California
20Department of Developmental Biology, University of California, Irvine, California
Manuscript Received: 8 December 2010; Manuscript Accepted: 7 May 2012
Chromosome 4q deletion syndrome (4q- syndrome) is a rare
variable, the clinical spectrum commonly includes craniofacial,
developmental, digital, skeletal, and cardiac involvement. Data
on the genotype–phenotype correlation within the 4q arm are
limited. We present detailed clinical and genetic information
by array CGH on 20 patients with 4q deletions. We identified a
Taosheng Huang, M.D., Ph.D., Division of Genetics, Department of
Pediatrics, University of California, 314 Robert R. Sprague Hall, Irvine,
CA 92697. E-mail: email@example.com
Article first published online in Wiley Online Library
(wileyonlinelibrary.com): 27 July 2012
How to Cite this Article:
S, Zhou Y, Chen T-J, Martinez JE, Fan Y-S,
Barbouth D, Zhu H, Vaglio A, Smith R,
Fox JE, Martin JA, Abdel-Hamid HZ,
D, Huang T. 2012. Genotype–phenotype
analysis of 4q deletion syndrome: Proposal of
a critical region.
Am J Med Genet Part A 158A:2139–2151.
? 2012 Wiley Periodicals, Inc.
patient who has a ?465kb deletion (186,770,069–187,234,800,
hg18 coordinates) in 4q35.1 with all clinical features for 4q
deletion syndrome except for developmental delay, suggesting
that this is a critical region for this condition and a specific gene
responsible for orofacial clefts and congenital heart defects
resides in this region. Since the patients with terminal deletions
all had cleft palate, our results provide further evidence that a
gene associated with clefts is located on the terminal segment of
4q. By comparing and contrasting our patients’ genetic infor-
mation and clinical features, we found significant genotype–
phenotype correlations at a single gene level linking specific
phenotypes to individual genes. Based on these data, we con-
structed a hypothetical partial phenotype-genotype map for
chromosome 4q which includes BMP3, SEC31A, MAPK10,
SPARCL1, DMP1, IBSP, PKD2, GRID2, PITX2, NEUROG2,
ANK2, FGF2, HAND2, and DUX4 genes.
? 2012 Wiley Periodicals, Inc.
Key words: 4q deletion syndrome; genotype–phenotype corre-
lation; molecular genetic analysis; comparative genomic hybrid-
ization; fluorescent in situ hybridization
The 4q deletion syndrome, also called 4q- syndrome, is a rare
of the long arm of chromosome 4, with an estimated incidence of
1 in 100,000 [Strehle et al., 2001; Strehle and Bantock, 2003]. The
majority of deletions are de novo but approximately 14% of cases
result from unbalanced segregation of parental reciprocal trans-
locations [Strehle and Bantock, 2003]. The male to female ratio is
approximately equal. 4q deletion syndrome is a distinct congenital
malformation syndrome associated with clinical findings affecting
multiple organs and systems including developmental delay, facial
and digital dysmorphology, Pierre Robin sequence, abnormalities
of the cardiovascular, musculoskeletal and gastrointestinal
systems. A review of 101 patients with 4q deletion syndrome
ally, a majority of the patients had digital anomalies, more than
half had skeletal anomalies, and almost half had congenital heart
disease (CHD) [Strehle and Bantock, 2003]. Autistic spectrum
disorder and attention deficit hyperactivity disorder are part of
the behavioral phenotype in 4q deletion syndrome [Strehle and
Middlemiss, 2007]. Figure 1 shows a female infant with typical
features of 4q deletion syndrome.
Interstitial deletions have been associated with short limbs
and small hands, Rieger syndrome and piebaldism [Strehle and
Bantock, 2003]. More distal deletions involving 4q34-q35 were
associated with a lesser degree of characteristic features and cog-
nitive impairment [Keeling et al., 2001; Kocks et al., 2002]. Satyr
mainly found in terminal deletions involving 4q34 [Vogt et al.,
2006]. Region 4q33 has been proposed as the critical region for 4q
deletion syndrome [Keeling et al., 2001; Giuffre ? et al., 2004],
containing genes responsible for development of the left ulnar
ray, central nervous system and cleft lip and palate.
The first review on 4q deletions including a clinical correlation
patients with 4q deletion syndrome have been reported in the
literature [Lin et al., 1988; Strehle, 2011]. Many of these patients
have been evaluated through traditional chromosome analysis
with standard or high resolution banding only. Traditional cyto-
genetic studies such as high resolution chromosome banding will
not detect a deletion less than 3–5 million base pairs, and exact
breakpoints cannot be defined. Therefore, it is difficult to establish
individual genotype–phenotype correlations. With the emergence
of microarray-based comparative genomic hybridization (array
CGH), the resolution for detecting deletions can reach the single-
Recently,array CGHhas beenused to characterizepatients with
4q deletions in an attempt to elucidate genotype–phenotype cor-
et al., 2008; Sensi et al., 2008; Hillhorst-Hofstee et al., 2009; Rossi
et al., 2009; Al-Owain et al., 2010; Bonnet et al., 2010; Chien et al.,
2010; Moreira et al., 2010]. Previously published reports are
limited to a small number of cases. For this study, we characterize
array CGH. Significant correlations were found between deletions
on the 4q arm and clinical signs and symptoms; they enabled us to
propose genotype–phenotype correlations for a larger group of
MATERIALS AND METHODS
All patients were recruited under the Institutional Review Board
(IRB) protocol approved by the human subjects committee of the
FIG. 1. Six-month-old girl with terminal deletion 4q33. The clinical
features include growth deficiency, cleft palate, cardiovascular
malformations (ASD, VSD). Dysmorphic features include
microcephaly, rounded facies, small eyes, broad nasal bridge,
Pierre-Robin sequence. She also has developmental delay and
2140AMERICAN JOURNAL OF MEDICAL GENETICS PART A
the 4q region diagnosed by array CGH as described previously
[Quadrelli et al., 2007a] were eligible to enroll. One group of
patients was seen by our group at the University of California
Irvine Medical Center (UCIMC). After consent was obtained, the
or geneticists. Medical records were obtained and reviewed.
on patients with a 105K-feature whole-genome microarray
(SignatureChip Oligo Solution?, custom-designed by Signature
Genomics Laboratories, made by Agilent Technologies, Santa
Clara, CA). Microarray analysis was performed as previously
described [Quadrelli et al., 2007a,b].
microarrayanalysis was performed
Fluorescence In Situ Hybridization (FISH)
All deletions determined to be abnormal by array CGH were
with metaphase FISH.
The clinical and molecular data for 20 patients were analyzed and
summarized in Table I. The patients were numbered from 1 to 20
based on the location of the deletion, with number 1 closest to the
centromere and number 20 closest to the telomere. Fourteen
females and six males were enrolled in the study ranging from
age 3 days to 33 years.
The most common features seen in over half the patients were
hypotonia and digital involvement. Less than half of the patients
had cardiac involvement. Less common but distinctive features
include developmental delay and behavioral problems (Table II).
The frequency and characteristics of clinical symptoms in our
cohort were similar as previously reported [Strehle and Bantock,
2003] as illustrated in Table II, with a few new observations. Our
cohort had a lower incidence of hearing and respiratory tract
abnormalities. A higher incidence of dentition abnormalities was
reported. Parental chromosomes were available on nine patients
13 abnormal parental chromosomes in a cohort of 90 (Table II)
[Strehle and Bantock, 2003].
Figure 2 shows the region of the deletion for all 20 patients. The
smallest deletion detected was 160kb (3 OMIM genes) and the
largest deletion was 25.7MB (45 OMIM genes) covering a region
from 4q32.3 to 4q35. The clinical features shared by Patient 1 and
Patient 2 include short stature, brachydactyly, hypotonia, move-
ment disorder, developmental delay, absence of speech and incon-
dysplasia. Patient 5wasfoundtohaveamicropenis while Patient 7
deletion in Patient 6 is relatively small and has no overlap with any
other patients. The phenotypeof Patient 6 includes developmental
delay and speech delay, behavior problems, staring spells, a large
tongue, a large head, asthma and possible overgrowth syndrome.
The deletions in Patients 17–20 overlap with the deletions in
Patients 13–16. Patients 18, 19, and 20 all have abnormal teeth and
finger/toe anomalies. Patients 17, 18, and 20 have a large tongue
and congenital heart defects. Patients 17, 18, and 19 have devel-
opmental delay and speech delay. In addition, Patients 17 and 20
both have cleft palate, upturned nose, hypotonia and gastroeso-
and 20 both have frontal bossing, hypertelorism, and cleft lip.
The size of the deletion is largest in Patients 13–16 and is
progressively smaller in Patients 17, 18, 19, and 20 with each
preceding patient covering the same deletion the later ones have.
Therefore one might expect that the severity of the phenotypic
progressively less severe in Patients 17, 18, 19, and 20 and that
phenotype that the later one has. However, such correlations were
not seen in our data.
Most interestingly, Patient 20, who has only two genes deleted,
PDLIM3 (PDZ and Lim Domain Protein 3) and TLR3 (Toll-Like
Receptor 3), shows a variety of abnormal features that are difficult
to explain by the two genes deleted. The only phenotype that
presents inallotherpatientsbutnotinPatient 20isdevelopmental
and speech delay. However, since the patient was young (3 years
old) at the time of evaluation and had multiple congenital anoma-
lies including ventriculomegaly, it is very likely that she will have
developmental delay later in life. It is also interesting to see that
Patients 13, 15, 17, and 20 all have cleft palate. Although a specific
gene, which could be responsible for clefts or influence palate
development, could not be located, it is most likely to reside in
In this study, we recruited 20 individuals with 4q deletion charac-
terized by array CGH. Clinical phenotypes were also intensively
evaluated. The clinical characteristics of our patients are compa-
malformation, developmental delay, and digital, skeletal, and con-
genital heart defects. Array CGH is an emerging technology for
characterizing patients with 4q deletion syndrome in an attempt
to elucidate genotype–phenotype correlations [Quadrelli et al.,
2007b]. Recently, Li’s group reported two patients with 4q dele-
tions. In one of their cases, they found a 2.5Mb duplication and a
12.6Mb deletion in 4q34.1. In the other case, a patient presented
with history of Pierre-Robin sequence, cardiac malformation, and
4q34.1 to 4q35.2 [Rossi et al., 2009]. The authors suggested that a
4Mb region on chromosome 4q is harboring a candidate gene for
Molecular genetic information for patients with chromosome 4
STREHLE ET AL.
TABLE I. Array CGH Results and Phenotypic Characteristics of 20 Patients With 4q Deletion Syndrome
Central nervous system
Widely spaced teeth
Small hands and feet,
short fingers and toes
Severe global DD, no
speech, can sit but not
crawl or walk, fully
dependent on caregiver,
Aggressive behavior, on
Large head, hypoplastic supraorbital
ridges, low-set posteriorly rotated
ears, short nose, philtrum and
neck, short palpebral fissures,
Brachydactyly, club feet
DD, no speech, short
Autism, severe LD
Microcephaly, right ear has simple
helix and is protuberant, nasal
septum extends below the nares,strabismus
Clinodactyly of left 5th
VM and white matter
changes on MRI,
decreased volume in the
gyri of both frontal lobes
on CT, HIE
DD,speech delay, growth
deficiency (wt. <3%)
vomiting, left multicystic
dysplastic kidney, VUR,
6 months of age
Microcephaly, arched eyebrows, blue
sclerae, up slanting palpebral fis-sures, anteverted notched nares,
long philtrum, thin upper lip
Hypotonia, hypoplasia of
Global DD, little speech,
Feeding problems, GER,
Severe DD, no speech
Caf? e-au-lait macules
Large head, macroglossia
DD, speech delay, weight
and height >98%
Low IQ, behavior
problems, anxiety, ADHD,
covering one arm
3 days, F
Glaucoma, low-set ears, thick ear
helices, short nose with bulbous
tip, natal tooth
Single transverse palmar
Excess umbilical skin
4q deletion: 112,026,190
X deletion: 9,441,237–9,757,010
Glaucoma, hypertelorism, down
slanting eyes, epicanthus,sluggishpupils,low-setsmallears,
cleft palate, small chin, long nose
with high nasal root and down
pointing tip, short webbed neck
Single transverse palmar
crease, overlapping toes
and hypoplastictoe nails
DD, LD, speech delay,
Upturned nose, small mouth
DD, speech delay
dolichocephaly, flat supraorbital
ridges, right divergent squint,
asymmetrical pupils, low-set
posteriorly rotated ears,prominent philtrum, double
Mother: 46, XX, inv(9)
Hypotelorism, epicanthic folds,
pattern,smallears,shortnoseandphiltrum, retrognathia, facial
Hypoplastic 5th finger
nails, small toe nails
Delayed motor and
mild LD, growth
Graves’ disease, multiple
nevi, scoliosis, valgus
TABLE I. (Continued)
Central nervous system
4q deletion: 145,016,967
–147,149,231 (2.13Mb); 4q
Mother: 46, XX, del(4)
(q31.21 q31.22); del(X)
Macrocephaly, frontal bossing,
maxillary hypoplasia, shortsaddle
Speech delay, learning
difficulties, poor weight
gain, short stature
(harlequin type) on
forehead, arms and legs,
family history of
Facial asymmetry, glabellar
hemangioma, prominent nasal
root with hypoplastic alae, short
nose with anteverted nares,
overfolded ear helices, flat
philtrum, cleft soft palate, dental
Absent left 3rd, 4th, and
DD, speech delay, severe
learning difficulties and
delay in adaptive
behavior, short stature
Recurrent UTI, left
Absent left ulna, short
curved left radius
(25.7Mb) [Quadrelli et al., 2007b]
Hypoplastic supraorbital ridges, large
fontanelles, upslanting and short
palpebral fissures, hypertelorism,
glabellar hemangioma, overfoldedear helix, microstomia and
clinodactyly of 5th
fingers, hypoplastic 5th
toe overlaps 4th toe
COA, PDA, VSD
DD, growth deficiency
abnormal labia minora,
(24.6Mb); duplication: 7,051,757
Father and sister have
Increased fetal nuchal translucency,
microcephaly, broad nasal bridge,
full cheeks, absent lower incisors,
cleft palate, micrognathia (Pierre
Bilateral pes planus,
malpositioned 4th toes
Tetralogy of Fallot
DD, speech delay, low
birth weight and poor
hearing loss, genu valga
Epicanthic folds, upturned nose,
Hypoplastic 5th finger,
DD, weight and height
High forehead, facial asymmetry,
almond-shaped eyes, coloboma,
upturned nose, low-set ears, cleft
soft palate, macroglossia
DD, growth hormone
growth on hormone
4q deletion: 180,707,438
–190,490,075 (9.78Mb); 4q
Glabellar nevus flammeus, eyelid
abnormality, thin lips,
macroglossia, delayed tooth
Small hands and feet,
joints, brittle finger and
toe nails, overlapping
LD, speech delay, wt and
Feeding difficulties in
4q deletion: 186,766,425
4p deletion (Wolf–Hirschhorn
‘‘Greek warrior helmet’’
appearance, prominent glabella,
frontal bossing, hypertelorism,
broad beaked nose, upslantingpalpebral fissures, bilateral
epicanthic folds, short philtrum,
small protruding ears
palmar creases, right
clinodactyly of the 5th
fingers, syndactyly of
2nd and 3rd fingers
DD, LD, severe speech
delay, growth deficiency,
neck and face,
overfolded ear helix, frontal
bossing, large fontanelles, broad
nasal bridge, upturned nose, cleft
lip, submucous cleft palate,
macroglossia, missing teeth,midline cleft of tongue, tongue
hamartomas, multiple frenulae
clinodactyly of 2nd and
5th fingers, small hands
PVS, PDA, ASD, VSD
hips; CHD, congenital heart defect; PVS, pulmonary valve stenosis; ASD, atrial septal defect; —, not present.
the emergence of high-density oligonucleotide array CGH allowed
in twenty patients with 4q deletion syndrome. Our genotype–
phenotype analyses noted the following observations classified
by interstitial and terminal deletions.
Among the genes deleted in Patients 1 and 2, Bone Morphogenetic
Protein 3 (BMP3) gene is a member of the transforming growth
TABLE II. Comparison of the Clinical Characteristics Found in This Study With Those of the 101 Patients Reviewed by
Strehle and Bantock 
Abnormal parental chromosomes
Central nervous system defects
Skeletal and extremity defects
Respiratory tract anomaly
Gastrointestinal tract anomaly
Renal and urinary anomalies
Our study (%?CI)
aParental chromosomes available on 9 cases.
bDevelopmental history applicable on 19 cases.
cGrowth history applicable on 19 cases.
dParental chromosomes available on 90 cases.
eDevelopmental history applicable on 82 cases.
fGrowth history applicable on 94 cases.
gHearing evaluation available on 43 cases.
FIG. 2. Ideogram of the long arm of chromosome 4 depicting the position and size of each of the 20 deletions described in this report.
2144 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
be associated with short stature and the skeletal anomalies shared
thecoat protein complexII(COPII)dependentcollagen secretion.
It has previously been shown to be important for normal cranio-
facial development [Stagg et al., 2008], therefore this gene may be
associated with the abnormal craniofacial development shared by
these two patients. In contrast with Patient 2, Patient 1 also has
abnormal teeth. This suggests that Galactokinase 2 (GK2) specif-
ically deleted in Patient 1 may be associated with abnormal teeth
and other specific phenotypes. Similarly, the genes deleted specif-
ically in Patient 2 may be responsible for his specific phenotypes,
including macrocephaly and hypoplastic suborbital region,
short palpebral fissures, and other craniofacial features. With
this approach, we found:
tant role in neuronal apoptosis. Disruption of this gene in a de
novo balanced translocation has been reported, associated with a
patient with pharmacologically resistant epileptic encephalopathy
[Shoichet et al., 2006]. Therefore, the deletion of MAPK10 may be
associated with the finding of epilepsy in Patients 2 and 3.
Polycystin-2 (PKD2) encodes the membrane protein polycystin
2. This protein affects renal tubule development, morphology, and
function. It is able to modulate intracellular calcium and other
signal transduction pathways [Wu et al., 2002]. The protein inter-
kidney disease [Mochizuki et al., 1996; Harris and Torres, 2009].
Patient 3 has unilateral polycystic dysplasia indicating that hap-
loinsufficiency of PKD2 may be responsible for the cystic renal
Dentin matrix acidic phosphoprotein 1 (DMP1) is an extra-
with autosomal recessive hypophosphatemia, a disease that
manifests as rickets and osteomalacia [Feng et al., 2006]. Deletion
of DMP1 in mice results in decreased bone matrix development.
disease. Therefore, whether deletions of DMP1 in Patients 3 and 4
Integrin-binding sialoprotein (IBSP) is also a bone matrix
protein. Deletion of the IBSP gene could also play an important
role in the differentiation of the osteoblast and development of the
bone matrix [Ogata, 2008]. Therefore, deletion of IBSP may be
associated with the growth deficiency in these two patients.
Tachykinin receptor 3 (TACR3) is deleted in Patient 5 but not in
puberty failure [Topaloglu et al., 2009]. Therefore, a deletion of
TACR3 may be associated with the micropenis and small testes in
The 160kb deletion in Patient 6 has no overlap with any
other patients and covers a total of three genes listed in the
OMIM database: 30-phosphoadenosine 50-phosphosulfate synthase
1 (PAPSS1), Sphingomyelin synthase 2 (SGMS2), and Cytochrome
P450, family 2, subfamily U, Polypeptide 1 (CYP2U). Haploinsuffi-
in this patient.
PAPSS 1 is the sulfate donor co-substrate for sulfotransferase
(SULT) enzymes [Xu et al., 2000]. SULTs catalyze the sulfate
conjugation of many endogenous and exogenous compounds,
including drugs and other xenobiotics. In humans, PAPS is syn-
thesized by two isoforms, PAPSS1 and PAPSS2. In brain and skin,
PAPSS1 is the major expressed isoform [Venkatachalam, 2003].
PAPSS1 is implicated to be a candidate hepatocellular carcinoma-
susceptibility gene in hepatitis B carriers [Shih et al., 2009]. The
enzyme that catalyzes sphingomyelin (SM) biosynthesis. SM is a
major component of cell and Golgi membranes. Experiments by
[Ding et al., 2008] indicated that SGMS2 is a key factor in the
control of SM and diacylglycerol levels within the cell and thus
influences lipopolysaccharide-mediated apoptosis. The effect of
hemizygosity for SGMS2 on this patient’s phenotype is unclear.
Lastly, Cytochrome P450, Family 2, Subfamily U, Polypeptide 2
(CYP2U1) encodes a member of the cytochrome P450 superfamily
of enzymes. This enzyme is a hydroxylase that metabolizes arach-
Long chain fatty acids have recently emerged as critical signaling
et al.  postulate that CYP2U1 plays an important physio-
logical role in fatty acid signaling processes in both cerebellum and
thymus, and therefore it may play a role in brain and immune
The deleted regions in Patients 7–10 overlap and have many
genes in common. The genes that are deleted in these four patients
are Traf-interacting protein with Forkhead-associated domain
(TIFA), Alpha-kinase 1 (ALPK1), Neurogenin-2 (NEUROG2), La
(ANK2). There are no obvious clinical features shared by these
patients except for developmental delay. Among the deleted genes,
NEUROG2 is of particular interest. NEUROG2 is a member of the
genes that play an important role in neurogenesis from migratory
which controls neurogenesis in the embryonic cortex, directly
induces the expression of the small GTP-binding protein Rnd2
in newly generated mouse cortical neurons before they initiate
migration. Thus, deletion of this gene may be associated with
neurological findings in some of these patients.
ANK2 encodes a member of the ankyrin family of proteins that
link the integral membrane proteins to the underlying spectrin–
actin cytoskeleton. Ankyrins play key roles in activities such as cell
motility,activation, proliferation, contact, and the maintenance of
specialized membrane domains. The protein encoded by this gene
is required for targeting and stability of Na/Ca exchanger 1 in
cardiomyocytes. A loss-of-function (E1425G) mutation in ANK2
causes dominantly inherited type4 long-QT cardiac arrhythmia in
humans [Mohler et al., 2003], suggesting that the patients with
deletion of ANK2 should be examined for arrhythmia.
Several genes of interest are found in the deletions carried by
STREHLE ET AL.
of the neurotrypsin family of serine proteases. Mutations in neuro-
trypsin 12 are associated with autosomal recessive intellectual
disability [Molinari et al., 2002]. Studies in Drosophila suggest
associated with learning and memory [Didelot et al., 2006].There-
fore, deletion of PRSS12 may affect learning in these patients.
Phosphodiesterase 5A (PDE5A) encodes for a phosphodiesterase
that specifically hydrolyzes cGMP to 50-GMP. It is involved in the
regulation of intracellular concentrations of cyclic nucleotides and
is important for smooth muscle relaxation in the cardiovascular
system [Sebkhi et al., 2003]. The effect of hemizygosity for PDE5A
on these patient phenotypes is not clear, but it is possible that
the deletion is relevant for the cardiovascular findings in these
growth factor (FGF) family. FGF2 is a wide-spectrum mitogenic,
tumor growth. The study of Ortega et al.  showed that FGF2
homozygous knockout mice had abnormalities in the cytoarchi-
tecture of the neocortex, most pronounced in the frontal motor-
participates in controlling fates, migration, and differentiation
of neuronal cells, whereas it is not essential for their proliferation.
The homozygous knockout mouse model by Montero etal. 
revealed that FGF2 helps determine bone mass as well as bone
formation. Using FGF2-deficient and wild type cardiomyocyte
precursor cells from neonatal mouse hearts, Rosenblatt-Velin
et al.  proposed that cardiogenic differentiation depends
8, and 10.
8–10) include Axenfeld–Rieger syndrome, hearing loss/impair-
ment, short nose, and ventricular septal defect. Among the genes
deleted in Patient 7 but not in Patients 8–10 is Paired-Like
Homeodomain Transcription Factor 2 (PITX2) which encodes a
member of the RIEG/PITX homeobox family. This protein is
involved in the development of the eye, teeth, and abdominal
organs and acts as a transcriptional regulator involved in basal
and hormone-regulated activity of prolactin. Mutations in this
gene are associated with the Axenfeld–Rieger syndrome, iridogo-
niodysgenesis syndrome, and sporadic cases of Peter’s anomaly.
in approximately 50% of affected individuals [Fitch and Kaback,
1978]. Deletion of PITX2 explains the glaucoma and Axenfeld
–Rieger syndrome present in Patient 7.
In contrast to Patient 10, Patient 11 has a deletion of PCDH10,
which belongs to the protocadherin gene family, asubfamily of the
cadherin superfamily. The gene encodes a cadherin-related neuro-
of specific cell-cell connections in the brain [Kim et al., 2007].
the deletion of PCDH10 and PCDH18 may be associated with the
neurological findings in Patient 11.
The deletion in Patient 12 has no overlap with any of the other
patients. The phenotype of patient 12 includes large head, frontal
polydactyly, clinodactyly of toes, short stature, poor weight gain,
speech delay, learning difficulties, hyperactivity, oppositional
behavior, cryptorchidism, seizures, and severe ichthyosis. The
2.13Mb deletion on chromosome 4q includes eight OMIM genes.
Among them, HHIP (hedgehog interacting protein) encodes a
protein similar to the mouse hedgehog-interacting protein, a
regulatory component of the hedgehog signaling pathway. Mem-
bers of the hedgehog family are evolutionarily conserved proteins,
which are involved in many fundamental processes in embryonic
development, including anteroposterior patterns of limbs and
regulation of left-right asymmetry. It has been reported that
heterozygous mutations in Indian hedgehog (IHH) result in bra-
chydactyly type 1 [Gao et al., 2009]. Thus, the deletion of HHIP
could potentially be associated with the digital anomalies in this
Another gene of interest in Patient 12 is SMAD1. SMAD1
mediates the signals of the bone morphogenetic proteins
(BMPs), which are involved in a range of biological activities
including cell growth, apoptosis, morphogenesis, development
and immune responses [Tsuchida et al., 2008]. This protein can
be phosphorylated and activated by the BMP receptor kinase. The
which is important for its function in the transcription regulation.
The clinical significance of heterozygosity for SMAD1 has not
been reported. A literature review of the other deleted genes on
chromosome 4q did not reveal any likely association between
those genes and the specific phenotype in Patient 12. This patient
also has a partial deletion of the X chromosome. Among the
genes deleted on chromosome X, the deletion of STS (Steroid
sulfatase) is known to cause X-linked ichthyosis (XLI). This
explains the presence of severe ichthyosis in this patient.
Patient 15 has a terminal 4q deletion and an additional chromo-
some abnormality; the 7MB duplication on chromosome 20p
includes a total of 55 OMIM genes. Among them, one gene of
interest is TMC2. The specific function of this gene is unknown;
however, expression in the inner ear suggests that it may be crucial
for normal auditory function. It has been reported to be associated
with autosomal recessive nonsyndromic hearing impairment
[Tlili et al., 2008]. The effect of duplication for TMC2 on this
patient’s phenotype is not clear, but it is possible that the dupli-
cation is relevant for the conductive hearing loss in Patient 15.
Literature review of the other duplicated genes does not reveal any
Patient 15 and Patient 18.
The deleted regions in Patients 13–16 have many genes in com-
mon. Patients 13–16 all have congenital cardiac defects, finger/toe
anomaly, developmental delay, and speech delay. Among the genes
that are deleted in Patients 13–16 is HAND2. The protein is a basic
helix-loop-helix family of transcription factor and expressed in the
2146AMERICAN JOURNAL OF MEDICAL GENETICS PART A
TABLE III. Deleted Genes and Their Functions in Patients With 4q Deletion Syndrome
1and 2 BoneMorphogenetic Protein3
Belongs to the transforming growth factor-beta
superfamily of regulatory molecules
Regulates cartilage cell proliferation [Gamer et al.,
Short stature and skeletal
1and 2 Sec31a
Component of the coat protein complex II (COPII)
dependent collagen secretion
Important for normal craniofacial development
[Stagg et al., 2008]
2and 3 Mitogen-Activated Protein
Kinase 10 (MAPK10)
Important role in neuronal apoptosis
Disruption in a de novo balanced translocation was
seen in a patient with pharmacologically resistant
epileptic encephalopathy [Shoichet et al., 2006]
Renal tubule development, morphology and
function. Encodes membrane polycystin protein
which interacts with polycistine 1
Modulates intracellular calcium and other signal
transduction pathways [Wu et al., 2002].
Heterozygous mutations in PKD1 and PKD2 are
associated with AD polycystic disease kidney
[Mochizuki et al., 1996; Harris and Torres, 2009]
Unilateral polycystic renal
3and 4 Dentin Matrix Acidic
Phosphorprotein 1 (DMP1)
Extracellular matrix protein
Mutations in DMP1 are associated with AR
hypophosphatemia characterized by rickets and
deletion show decreased bone matrixdevelopment. Carriers do not show evidence ofdisease
3and 4 Integrin-Binding Sialoprotein
Bone matrix protein
Involved in differentiation of osteoblasts and bone
matrix development [Ogata, 2008]
Tachykininreceptor3(TACR3) Encodes a receptor for tachykinin neurokinin 3
Homozygous mutations are associated with
congenital gonadotrophin deficiency and puberty
failure [Topaloglu et al., 2009]
Neurogenin 2 (NEUROG2)
Member of neurogenin subfamily of basic
important role in neurogenesis from migratory
neural crest cells
Controls neurogenesis in the embryonic cortex and
induces expression of GTP-binding protein Rnd2 in
newly generated mouse cortical neurons prior to
migration [Heng et al., 2008]
dystonia, delayed motor development)
Ankyrin 2 (ANK2)
spectrin–actin cytoskeleton. Plays key role in cell
motility, activation, proliferation, contact and themaintenance of specialized membrane domains.
Protein is required for targeting and stability of
Naþ/Ca2þexchanger in cardiomyocytes
dominantly inherited type 4 long-QT cardiac
arrhythmia in humans [Mohler et al., 2003]
Arrhythmia (screening of
7, 8,10 Protease Serine, 12 (PRSS12) Member of the neurotrypsin family of serine
PRSS12 mutations are associated with AR mental
retardation [Molinari et al., 2002]. Drosophila
studies suggest involvement in structural
reorganizations associated with learning and
memory [Didelot et al., 2006]
Learning disability and
STREHLE ET AL.
TABLE III. (Continued)
7, 8,10 Phosphodiesterase 5A
Hydrolyzes cGMP to 50-GMP
Regulation of intracellular concentrations of cyclic
nucleotides, important for smooth muscle
relaxation in the cardiovascular system [Sebkhi
et al., 2003]
Congenital heart defects
7, 8,10 Fibroblast Growth Factor 2
A mitogenic, angiogenic, and neurotrophic factor
expressed at low levels in many tissues and cell
types; it reaches high concentrations in brain and
pituitary gland. Implicated in diverse biological processes such as limb and nervous system development, wound healing, and tumor growth
Participates in controlling fate, migration, and dif-
ferentiation of neuronal cells [Dono et al., 1998].
Homozygous knockout mice had abnormalities in
cytoarchitecture of the neocortex, most
pronounced in the frontal motor-sensory area
mass as well as bone formation [Montero et al.,
2000]. Controls cardiogenic differentiation
[Rosenblatt-Velin et al., 2005]
May have an impact on CNS,
limb and cardiovascular
Protocadherin 10 and 18
Encodes a cadherin-related neuronal receptor
Establishment and function of specific cell–cell
connections in the brain [Kim et al., 2007]
Hedgehog Interacting Protein
Regulatory component of the hedgehog signaling
pathway. Evolutionarily conserved protein,
involved in many fundamental processes in
patterns of limbs and regulation of left-right
Heterozygous mutations result in brachydactyly
type 1 [Gao et al., 2009]
Digital anomalies (bilateral
polydactyly, clinidactyly of
Steroid Sulfatase (STS) (X
Membrane-bound microsomal enzyme, hydrolyzes
precursors for estrogens, androgens, and
Causes X-linked ichthyosis
7MB duplication on
AR nonsyndromic hearing impairment [Tlili et al.,
13–16 Heart And Neural Crest
Derivatives expressed 2
Basic helix-loop-helix family of transcription
factors Expressed in the developing ventricular
Essential role in cardiac morphogenesis; implicated
as mediators of congenital heart disease
[Morikawa and Cserjesi, 2008]. May play a role in
limb and branchial arch development [Liu et al.,
coarctation of aorta,cardiomegaly, Tetralogy of
Vascular Endothelial Growth
Factor C (VEGFC)
Platelet-derived growth factor/vascular endothelial
growth factor; active in angiogenesis andendothelial cell growth. Osmosensitive,
hypertonicity-driven gene; intimately involved in
of extracellular volume and blood pressure
homeostasis [Machnik et al., 2009]
Sorbin and SH3 domain containing 2 protein present
in epithelial and cardiac muscle cells
Adapter protein to assemble signaling complexes
linking ABL kinases and actin cytoskeleton [Hand
and Eiden, 2005]
Clefts and congenital heart
AD, autosomal dominant; AR, autosomal recessive; CNS, central nervous system; VSD, ventricular septal defect.
2148AMERICAN JOURNAL OF MEDICAL GENETICS PART A
morphogenesis, implicating them as mediators of CHD [Morikawa
2009]. The deletion of HAND2 may explain why Patients 13–16 all
have congenital cardiac defects.
Vascular Endothelial Growth Factor C (VEGFC) encodes a
platelet-derived growth factor/vascular endothelial growth factor,
of VEGFC may be associated with development of the glabellar
hemangioma in Patients 13 and 14.
SORBS2 which is partially deleted in Patient 20 encodes a protein
containing N-terminal sorbin and a C-terminal SH3 domain. The
proteins [Hand and Eiden, 2005]. High expression level in cardiac
tissue suggests that this gene may play an important role in heart
development and may potentially contribute to CHD in patients
with 4q deletion syndrome. Molecular tests in patients with
congenital heart defects for mutations in the SORBS2 gene are in
Methodological limitations of our study include small sample size,
limitations in the number of patients with deletions at any specific
Some of our patients have other chromosomal rearrangements that
complicate the analysis of a genotype–phenotype correlation. In
future, we plan to recruit additional patients with 4q deletion
syndrome and build a fine map of deletions, through which, using
phenotypes observed in 4q deletion syndrome. This information
should prove useful for developing a more specific management
and treatment plan for an individual with 4q deletion syndrome,
based on the location and gene contact of the deletion.
Our findings as summarized in Table III and Figure 3 suggest that
haploinsufficiency of the genes in 4q deletion syndrome is asso-
BMP3 on 4q21.21 may be associated with short stature and other
skeletal anomalies. The loss of SEC31A on 4q21.22 may affect
normal craniofacial development. The deletion of MAPK10 on
4q21.3 may be an explanation for the neurological findings and
epileptic activities in some 4q deletion patients. On 4q22.1,
SPARCL1 may be associated with central nervous system develop-
renal phenotypes. GRID2 may be associated with neurological
findings and wide-based gait. On 4q25, deletion of PITX2 is
an important role in neurogenesis in the embryonic cortex. The
deletion of ANK2 may be associated with cardiac arrhythmia, and
in cardiac morphogenesis, and the deletion of this gene may result
in congenital cardiac defects. Although none of our patients was
reported to exhibit features of FSHD, DUX4 located on 4q35.2 is
the patients with 4q deletions do not show the typical clinical
phenotype of this muscular dystrophy, suggesting that haploinsuf-
ficiency of DUX4 is not the causative mechanism in FSHD.
Recently, it was shown that specific single nucleotide polymor-
phisms (SNPs) in the chromosomal region distal to the last D4Z4
repeat play an important role in this condition [Lemmers et al.,
2010]. Finally,since four of our patientswith terminal deletionsall
had cleft palate, it is likely that a gene associated with clefts resides
on the 4q terminal region.
clinical findings with gene deletions by array CGH, with haploin-
sufficiency being the proposed underlying mechanism. In partic-
ular, the chromosome band 4q35.1 appears to harbor essential
genes that contribute to this condition, if they are missing or
mutated. However, considering the example of developmental
delay, which is universally present in 4q deletion syndrome, and
indeed in most chromosome imbalances, other causative mecha-
nisms such as epigenetic factors and gene dosage effects should be
FIG. 3. Schematic representation of chromosome 4 with arrows
the phenotype in patients with 4q deletion syndrome.
STREHLE ET AL.
We thank all patients for participating in our study and the
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reviewers for their comments. This research is partially supported
by the Howard Hughes Biomedical Science Program, the Helen &
Larry Hoag Foundation. After this manuscript was reviewed, we
became aware of the publication of Xu et al. , reporting a
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