Transmitted Deletions of Medial 5p and Learning
Difficulties; Does the Cadherin Cluster Only Become
Penetrant When Flanking Genes Are Deleted?
John C.K. Barber,1* Shuwen Huang,2Mark S. Bateman3and Amanda L. Collins4
1Human Genetics Division, Southampton University School of Medicine, Southampton General Hospital, Southampton, UK
2National Genetics Reference Laboratory (Wessex), Salisbury Foundation Hospital NHS Trust, Salisbury, Wiltshire, UK
3Wessex Regional Genetics Laboratory, Salisbury Foundation Hospital NHS Trust, Salisbury, Wiltshire, UK
4Wessex Clinical Genetics Service, Southampton University Hospitals NHS Trust, Southampton, Hants, UK
Received 3 March 2011; Accepted 10 July 2011
in that large, cytogenetically visible interstitial deletions segre-
5p13.3 to 5p14.3 co-segregated with learning and/or behavioral
difficulties in six family members. Facial dysmorphism was not
deletion was 12.23Mb in size (chr5:20,352,535–32,825,775) and
contained fifteen known protein coding genes. Five of these
(GOLPH3; MTMR12; ZFR; SUB1; and NPR3) and an ultra-
conserved microRNA (hsa-miR-579) were present in an 883kb
candidate gene region in 5p13.3 that was deleted in the present
family but not in previously reported overlapping benign dele-
tions. Members of the cadherin precursor gene cluster, with
brain specific expression, were deleted in both affected and
benign deletion families. The candidate genes in 5p13.3 may
besufficient toaccount fortheconsistent presence orabsence of
phenotype in medial 5p deletions. However, we consider the
possibility of position effects in which CDH6, and/or other
cadherin genes, become penetrant when adjacent genes, or
cadherin cluster, the cognitive phenotype in medial 5p deletion
syndrome and the greater severity of intellectual disability in
patients with cri-du-chat syndrome and deletions of 5p15 that
extend into the region deleted in the present family.
? 2011 Wiley Periodicals, Inc.
learning disability; intellectual disability; candidate genes; pene-
trance; cadherin genes; transmitted imbalance; DNA array
well-characterized classical cri-du-chatdeletion syndrome (CdCS)
which results from a terminal deletion in ?78% of cases, an
in ?5% [Cerruti Mainardi, 2006]. After analyzing 94 patients with
array comparative genomic hybridization (aCGH), Zhang et al.
which (IDI and II1) overlap the CdCS critical region and contain
candidate ID genes Semaphorin 5A in 5p13.1 (SEMA5A) and d-
catenin (CTNND2) in 5p15.2 [Cerruti Mainardi, 2006]. The third
larger region, IDIII, is proximal to the CdCS critical region and
paradox in that multiple family members with deletions of, and
ID associated with deletions of IDI and IDII is more severe when
IDIII is also deleted [Zhang et al., 2005]. As a result, the normal
Additional supporting information may be found in the online version of
Grant sponsor: Department of Health (UK) [to SH].
John C.K. Barber, Human Genetics Division, Southampton University
School of Medicine, Southampton General Hospital, Tremona Road,
Southampton SO16 6YD, UK. E-mail: email@example.com
Published online in Wiley Online Library
1Previously known as MRI and MRII.
How to Cite this Article:
Barber JCK, Huang S, Bateman MS, Collins
AL. 2011. Transmitted deletions of medial 5p
and learning difficulties; Does the cadherin
cluster only become penetrant when flanking
genes are deleted?
Am J Med Genet Part A 9999:1–9.
? 2011 Wiley Periodicals, Inc.
phenotype in families with IDIII deletions has been described as
fragile [Zhang et al., 2005].
Transmitted imbalances can be a useful guide to the phenotype
ascertainment bias, by comparison with de novo imbalances in
unrelated individuals, and the presence of the same imbalance in
multiple family members with a greater degree of common genetic
abnormalities havebeenreported in theshort armof chromosome
5 than any other chromosome arm [Barber, 2005] and these
include at least eleven terminal deletions, two unbalanced trans-
locations and eight interstitial deletions (Fig. 1) [Baccichetti et al.,
1988; Kushnick et al., 1984; Walker et al., 1984; Overhauser et al.,
et al., 2000; Hand et al., 2000; Zhang et al., 2005; Fang et al., 2008].
Here, we present a family in which learning difficulties co-
segregated with an interstitial deletion of medial chromosome 5
from p13.3 to p14.3 in six family members. Comparison of the
behavioral difficulties in a 5p medial deletion syndrome that can
some deletion carriers [Walker et al., 1984; Keppen et al., 1992;
Johnson et al., 2000]. However, deletion of cadherin genes in both
affected and unaffected families raises the possibility that variable
penetrance of the cadherin cluster might account for the cognitive
phenotype in this and other affected families as well as the addi-
tional severity of ID in distal cri-du-chat deletions that extend into
the IDIII region [Zhang et al., 2005].
CLINICAL FAMILY REPORT
of family concerns about her speech and language development.
Her chromosomes were analyzed because of the family history of
learning difficulties (Fig. 2). She wasborn at term weighing3.31kg
eighteen months of life with normal motor development. When
assessed at the age of two years, her verbal skills were at the twelve-
month level. Eyesight and hearing were normal. Her length was
46.6cm (10th–25th centile). Byage 6years9months,herOFC was
49.5cm (3rd–10th centile). The proband’s younger sister (III.5,
mother (II.2, del 5p) was working as a kitchen assistant in a
residential home. She had initially attended mainstream schools
Her OFC as an adult was 53.2cm (?10th centile). Her three
brothers had also all attended special schools.
Her eldest brother (II.3, del 5p) had attended a special boarding
school, primarily for behavioral problems. As an adult he has had
numerous short-term jobs. He suffered with psoriasis and nasal
obstruction due to polyps. On examination his height was 180cm
was not dysmorphic and had four daughters. His eldest daughter
(III.6, normal chromosomes) had no health, developmental or
behavioral problems. At 7 years 1 month, her height was 125cm
(?75th centile) and her OFC 55cm (>97th centile). His second
daughter (III.7, del 5p) was slow to walk (18 months) and be toilet
requiring myringotomy tubes on three occasions, and was far-
sighted. She may have had nasal obstruction developing and also
(?25th centile). As a young child she had behavioral problems,
had apnea in infancy, which stopped by 10 months of age. Her
speech may have been slightly delayed but her development was
otherwise normal. She had eczema and asthma and pulled hair out
from the top of her head. She did not have pre-auricular pits or
normal chromosomes) died after attempted repair of her total
anomalous pulmonary venous return congenital heart defect.
The mother’s second oldest brother (II.5) had declined chro-
mosome analysis. He had two children who were reported not to
have any learning difficulties. His siblings considered him the
brightest of them and he had successfully managed a fast food
FIG. 1. Twenty-two directly transmitted imbalances of the short
arm of chromosome 5 are illustrated. As in the Chromosome
Anomaly Collection, the bar to the left indicates the extent of the
duplication and bars to the right the extent of the deletions of
5p with a ‘‘4’’ above the similar deletions found in four separate
families, the ‘‘t’’ above the two unbalanced translocations and an
hatched bars indicate families with affected children and normal
parents; solid bars indicate families with affected parents and
children (and those with clear centers families reported in
abstract only). The letters O, Z, H, J, B, K, W, and M are below the
deletions reported by Overhauser et al. , Zhang et al.
, Hand et al. , Johnson et al. , Barber et al.
[this issue], Keppen et al. , Walker et al. , and
Martinez et al. .
2AMERICAN JOURNAL OF MEDICAL GENETICS PART A
outlet. The mother’syoungest brother(II.7, del 5p) had attended a
different special boarding school for learning difficulties. He was
write. He had no children.
MATERIALS AND METHODS
Giemsa-banded chromosomes were prepared using standard
methods. The D5S23 cri-du-chat syndrome cosmid was obtained
from ONCOR (Qbiogene, Cambridge, UK) and the whole chromo-
some 5 paint from Cambio (Cambridge, UK). Yeast Artificial
Chromosome (YAC) 921-f-07 was provided by the Max-Planck
Institute (Berlin, Germany) and amplified for fluorescence in situ
hybridization (FISH) by DOP-PCR. Cosmid H748 (TUPLE1) was
provided by Dr Peter Scambler of the Institute of Child Health,
London. A FISH assay was carried out according to the man-
ufacturer’s instructions or using in-house methods (available upon
to measure the number of repeats at the fragile X loci (FRAXA and
Wessex Constitutional Array CGH V1 design No. 015543, Agilent
Technologies, Santa Clara, CA) as described [Barber et al., 2008].
gave normal results, and whole chromosome painting for chro-
mosome 5 provided no evidence of the deleted material elsewhere
been mapped to 5p13.3–5p14.1, confirmed the deletion of this
region of 5p (data not shown). Normal results were found at the
fragile X loci with alleles of 20 and 29 repeats at FRAXA and
homozygosity for the commonest allele of 15 repeats at FRAXE.
Oligonucleotide aCGH with DNA from the proband showed
that the deletion was a minimum of 12.23Mb in size between base
pairs 20,352,535 in 5p14.3 and 32,825,775 in 5p13.3 (Fig. eS1, see
Supporting Information).This deletion is in a gene-poor region of
and nine hypothetical genes giving a gene density of ?2 genes per
Mb compared with the genome average of nine (Table I). The
46,XX or XY,del(5)(p13.3p14.3).ish del(5)(D5S23þ, 921f07?,
An apparently identical deletion was found in the proband’s
mother, in two of her three maternal uncles and in two of her
cousins (Fig. 2). The third uncle and the maternal grandmother
in all the other family members tested (Fig. 2) and there was no
evidence of a deletion of the 22q11 region in the deceased cousin
with a heart defect (TAPVD) (III.9) using the H748 (TUPLE1)
proximal DiGeorge critical region cosmid (data not shown).
We report on six members of a family with a 12.23Mb
interstitial deletion of 5p13.3 to 5p14.3 in the medial short arm
FIG. 2. Pedigreeofthepresentfamily:lefthandshadingindicatesspecialschooling(ormainstreamschoolingwithremedialhelp(II.1))andrighthand
shading a deletion carrier. The plus sign denotes congenital heart disease (III.9) and the letter N a family member with a normal karyotype.
FIG. 3. Partial karyotype of the proband with the normal
chromosome 5 on the left, the deleted chromosome on the right
and the approximate extent of the deletion indicated by the solid
bar to the left of the short arm of the normal chromosome 5.
BARBER ET AL.
TABLE I. Known Genes Within the Deleted Interval (Excluding C5orf17 and C5orf23)
Type II classical
Brain (especially fetal
hormone like-1 protein
Fetal newborn and
PR-domain zinc finger
Type II classical
putatively involved in
axon outgrowth andguidance
pituitary), fetal and
Type II classical
Type II classical
PDZ domain containing
Golgi phosphoprotein 3
Possible regulatory role
in Golgi trafficking
activation of class IIgenes, core promoterelement transcription
prominent in brain,heart, kidney, placenta, and lung
Zinc finger RNA
pancreas, placenta,brain and kidney
4AMERICAN JOURNAL OF MEDICAL GENETICS PART A
of chromosome 5. All six have had special schooling, either for
learning or behavioral difficulties. This is the only consistent
feature, but two members had preauricular pits, lacrimal fistulae,
or problems with nasal polyps.
To our knowledge, there are six families with transmitted
and seven other family members were all phenotypically normal
[Overhauser et al., 1986; Zhang et al., 2005]; in a further two, the
probands had phenotypes inconsistent [Hand et al., 2000] or
the features of the medial 5p deletion syndrome summarized in
Table II. In the first of these two affected families, a deletion of
5p13–5p15.1 (Fig. 4) was ascertained at prenatal diagnosis for
ID and had attended special schools [Walker et al., 1984]; in the
second affected family, a deletion of 5p13.3–5p14.3 (Fig. 4) was
ascertained in a small for dates neonate with microcephaly and
1992]. Some members of both of these families also had micro-
cephaly and/or mild dysmorphic features and one member of each
the affected proband with a normal father and a deletion within
5p14 [Johnson et al., 2000] (Fig. 4) is most likely to reflect bias of
ascertainment [Barber, 2005].
Candidate Genes in 5p13.3
Because of the normal phenotype in all six members of the family
with a deletion of 5p14 described by Overhauser et al. ,
then, Zhang et al.  used the molecular definition of the 5p14
deletion in patient 51, from a three generation asymptomatic
family, to define the IDIII region (Figs. 1 and 4) which included
10, 9, and 6) as well as the PMCHL1, PRDM9, and RNASEN genes
and an interruption of the PDZ domain containing protein 3 gene
(PDZK3). Comparison of IDIII with the deletion in the present
the Golgi phosphoprotein gene 3 (GOLPH3), the myotubularin
p15 (SUB1 (PC4)) and the atrial natriuretic peptide clearance
receptor precursor (NPR3) (Fig. 4). The likely haploinsufficient
score of 67% suggests that MTMR12 is more likely to be a
haplosufficient gene than the other four candidate genes with
haploinsufficient scores of between 8% and 12% (Table I)
[Huang et al., 2010].
Variable Penetrance of the Cadherin Cluster
classical type II cadherin (CDH) precursors, which are cell–cell
adhesion molecules that play critical roles in brain development.
Three of these four (CDH12, 10, and 6) have tissue specific and/or
polymerase II transcrip-
tional coactivator p15
activators and thegeneral transcriptional
Atrial natriuretic peptide
Receptor for natriuretic
including atrial and
brain natriureticpeptides; possible
cause of salt resistant
Placenta, adult and
fetal kidney, andfetal heart.
Bold type has been used for G-dark bands, genes within the critical gene region (CGR) and genes with haploinsufficient scores of less than 10%.
aStart and end positions from NCBI35/hg17.
bThe likely haploinsufficient scores have been taken from DECIPHER version 5.0 [after Huang et al., 2010].
BARBER ET AL.
5p13.3 has been given the lowest haploinsufficient score of 6%
compared with CDH12 (42%), CDH10 (26%), and CDH9 (25%).
Thus, it is difficult to ignore the possibility that deletion of CDH6
itself, and/or other haploinsufficient members of the cadherin
cluster, might contribute to the cognitive phenotype in this and
other families, especially as cells expressing CDH6, CDH9, and
CDH10 are thought to interact with each other [Shimoyama et al.,
2000] and deletions of cadherin precursors in 16q21 (CDH8) and
16q24.3 (CDH15) have recently been implicated in autism and
mental and intellectual disability [Bhalla et al., 2008; Pagnamenta
et al., 2011]. The absence of a phenotype in the patients with the
benign 5p14 deletions might then be a novel type of chromosomal
genes within IDIII only become penetrant when flanking genes
proximal or distalto IDIII are also deleted. The proximal deletions
include those extending beyond IDIII into 5p13.3 [present family;
Walker et al., 1984; Keppen et al., 1992], and the distal deletions,
those CdCSpatientswithdeletionsofIDIand thegreater degree of
Modifiers of Gene Expression
ment and are thought to be enriched in pathogenic deletions
[Mart? ınez et al., 2010]. The ultraconserved element uc.151 is a
microRNA (hsa-miR-579) in intron 11 of the ZFR gene within the
expressivity of the Alagille syndrome phenotype [Ahluwalia et al.,
2009] and with the regulation, in trans, of several proteins in the
brains of patients with Down syndrome [Kuhn et al., 2010]. Hsa-
RNASEN gene in 5p13.3 which is a homologue of the Drosophila
syndrome critical region gene 8 (DGCR8) and is important for the
genesis of microRNAs [Gregory etal., 2004].However, thereis not
yet any information about the targets of hsa-mir-579, nor any
disease association in the miR2Disease database. No further
developmentally-associated conserved non-coding elements map
FIG. 4. UCSC genome browser (NCBI35/hg17) illustration ofthe short arm of chromosome 5 withthe detailed content from base pairs 15,363,238 in
ultraconserved microRNA locus (miR) and the upward vertical arrow indicates the approximate location of the highly conserved genomic element
6 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
the deleted region does contain 25 other non-coding RNAs in the
Ensembl genome browser (hg18).
Wang et al.  found six tagging single nucleotide poly-
morphisms (SNPs) in 5p14.1 associated with autistic spectrum
disorders (ASDs) and an 849 bp conserved genomic element
(HCGE) between CDH10 and CDH9 (Fig. 4). However, benign
overlapping copy number variations, and the relatively modest
odds ratios associating these SNPs with autism, suggest that com-
mon variants are unlikely to determine the cognitive phenotype
explaining phenotypic variation within and among families has
been suggested [Johnson et al., 2000; Zhang et al., 2005] but seems
less likely as the deletion has been transmitted on at least three
occasions from parents of both sexes in the present family (Fig. 2).
Hidden mosaicism [Bruder et al., 2008; Piotrowski et al., 2008],
unmasking of recessive alleles [Bisgaard et al., 2009], epigenetic
2007], or stochastic factors [Lansdorp, 2009] may be invoked to
less likely to explain the consistent presence or absence of a
phenotype in multiple members of unrelated families.
We conclude that the present family confirms that medial 5p
deletions, extending into 5p13.3, are associated with a relatively
mild phenotype that is compatible with fertility and family life but
also associated with learning and/or behavioral difficulties and, in
addition, microcephaly, mild dysmorphism, and short stature in
some deletion heterozygotes. Large, overlapping deletions with no
phenotypic effect indicate the need for caution in associating
variable phenotypes with sub-microscopic deletions within IDIII
1617, 1970, 2050 and 2054. In the meantime, larger data sets may
provide further clarification of the possible role of candidate genes
within 5p13.3, CDH6, the cadherin cluster or modifiers of gene
expression in the cognitive phenotype associated with deletions of
the medial short arm of chromosome 5.
CONDOR (Database of COnserved Non-coDing Orthologous
DECIPHER v5.0 (Database of Chromosomal Imbalance and
Phenotype in Humans Using Ensembl Resources): https://
Ensembl Genome Browser: http://www.ensembl.org/Homo_
miR2Disease Base: http://www.mir2disease.org/.
UCSC Web Browser: http://genome.ucsc.edu/.
Anomaly Collection: http://www.ngrl.org.uk/
We acknowledge Andrea Garner and members of the Wessex
Regional Genetics Laboratory for chromosome analysis of
the proband and other family members as well as Dr. James
MacPherson for molecular genetic analysis of the FRAXA and
FRAXE loci. We also thank ProfessorPeter Scamblerfor providing
cosmid H748. SH is supported as part of the National Genetics
Reference Laboratory (Wessex) by the UK Department of Health.
TABLE II. Phenotypic Features in Transmitted Interstitial Deletions of Medial 5p
et al. 
Zhang et al.
Hand et al.
Johnson et al.
Walker et al.
Keppen et al.
0/3 Learning difficulties/MR/
in some family
a1% normal cells in paternal skin.
b1/4 patients with mosaic trisomy 8 as well as del(5)(p13.3p14.3).
cNot assessable in neonates.
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