Characterization of a 8q21.11 microdeletion syndrome associated with intellectual disability and a recognizable phenotype.

Abstract

We report eight unrelated individuals with intellectual disability and overlapping submicroscopic deletions of 8q21.11 (0.66-13.55 Mb in size). The deletion was familial in one and simplex in seven individuals. The phenotype was remarkably similar and consisted of a round face with full cheeks, a high forehead, ptosis, cornea opacities, an underdeveloped alae, a short philtrum, a cupid's bow of the upper lip, down-turned corners of the mouth, micrognathia, low-set and prominent ears, and mild finger and toe anomalies (camptodactyly, syndactyly, and broadening of the first rays). Intellectual disability, hypotonia, decreased balance, sensorineural hearing loss, and unusual behavior were frequently observed. A high-resolution oligonucleotide array showed different proximal and distal breakpoints in all of the individuals. Sequencing studies in three of the individuals revealed that proximal and distal breakpoints were located in unique sequences with no apparent homology. The smallest region of overlap was a 539.7 kb interval encompassing three genes: a Zinc Finger Homeobox 4 (ZFHX4), one microRNA of unknown function, and one nonfunctional pseudogen. ZFHX4 encodes a transcription factor expressed in the adult human brain, skeletal muscle, and liver. It has been suggested as a candidate gene for congenital bilateral isolated ptosis. Our results suggest that the 8q21.11 submicroscopic deletion represents a clinically recognizable entity and that a haploinsufficient gene or genes within the minimal deletion region could underlie this syndrome.

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REPORT
Characterization of a 8q21.11 Microdeletion
Syndrome Associated with Intellectual Disability
and a Recognizable Phenotype
Marı ´a Palomares,1,2,* Alicia Delicado,2,3Elena Mansilla,2,3Marı ´a Luisa de Torres,2,3Elena Vallespı ´n,1,2
Luis Fernandez,2,3Victor Martinez-Glez,1,2Sixto Garcı ´a-Min ˜aur,2,4Julia ´n Nevado,1,2
Fernando Santos Simarro,2,4Victor L. Ruiz-Perez,2,5Sally Ann Lynch,6Freddie H. Sharkey,7
Ann-Charlotte Thuresson,8Go ¨ran Annere ´n,8Elga F. Belligni,9Marı ´a Luisa Martı ´nez-Ferna ´ndez,2,10
Eva Bermejo,2,10,11Beata Nowakowska,12,13Anna Kutkowska-Kazmierczak,12Ewa Bocian,12
Ewa Obersztyn,12Marı ´a Luisa Martı ´nez-Frı ´as,2,10,11Raoul C.M. Hennekam,14,15
and Pablo Lapunzina2,4,15
We report eight unrelated individuals with intellectual disability and overlapping submicroscopic deletions of 8q21.11 (0.66–13.55 Mb
in size). The deletion was familial in one and simplex in seven individuals. The phenotype was remarkably similar and consisted of
a round face with full cheeks, a high forehead, ptosis, cornea opacities, an underdeveloped alae, a short philtrum, a cupid’s bow of
the upper lip, down-turned corners of the mouth, micrognathia, low-set and prominent ears, and mild finger and toe anomalies (camp-
todactyly, syndactyly, and broadening of the first rays). Intellectual disability, hypotonia, decreased balance, sensorineural hearing loss,
and unusual behavior were frequently observed. A high-resolution oligonucleotide array showed different proximal and distal break-
points in all of the individuals. Sequencing studies in three of the individuals revealed that proximal and distal breakpoints were located
in unique sequences with no apparent homology. The smallest region of overlap was a 539.7 kb interval encompassing three genes:
a Zinc Finger Homeobox 4 (ZFHX4), one microRNA of unknown function, and one nonfunctional pseudogen. ZFHX4 encodes a transcrip-
tion factor expressed in the adult human brain, skeletal muscle, and liver. It has been suggested as a candidate gene for congenital bilat-
eral isolated ptosis. Our results suggest that the 8q21.11 submicroscopic deletion represents a clinically recognizable entity and that
a haploinsufficient gene or genes within the minimal deletion region could underlie this syndrome.
Historically
syndromes was established after the identification of
similar submicroscopic deletions in a collection of individ-
uals with a common phenotype. The introduction of
whole-genome scanning technologies such as array-based
comparative genomic hybridization (aCGH) enables the
identification of novel imbalances in large cohorts of indi-
vidualswith apparentlyno
a common cytogenetic etiology is established, the clinical
features of these new conditions are delineated. Recently
array-based techniques have led to the discovery of several
novel recurrent disease-causing microdeletions or micro-
duplications.1
Here we report eight nonrelated individuals with an
intellectual disability and an unusual phenotype who
have overlapping submicroscopic deletions of 8q21.11
(0.66–13.55 Mb in size). The phenotype was proven to be
recognizable in a family with five affected persons and
thecytogeneticbasisofmicrodeletion
specificfeatures.Once
published recently as a hitherto unreported entity,2of
whom one member is studied here. The other seven indi-
viduals are simplex cases. The phenotype is remarkably
similar despite the difference in the deletion size and con-
sisted of a round face with full cheeks, a high forehead,
ptosis, cornea opacities, an underdeveloped alae, a short
philtrum, a cupid’s bow of the upper lip, down-turned
corners of the mouth, micrognathia, low-set and promi-
nent ears, and mild finger and toe anomalies (camptodac-
tyly, syndactyly, and broadening of the first rays). Intellec-
tual disability, hypotonia, decreased balance, sensorineural
hearing loss, and unusual behavior were frequently
observed. The clinical findings of all individuals are
summarized in Table 1 and illustrated in Figure 1.
Individuals 1–3 and 7 were referred for genetic assess-
ment because of intellectual disability and an unusual
phenotype. They were studied by classical cytogenetics
and array comparative genomic hybridization (aCGH).
1Section of Functional and Structural Genomics, Instituto de Gene ´tica Me ´dica y Molecular (INGEMM), Instituto de Investigacio ´n Sanitaria (IdiPAZ),
Hospital Universitario La Paz, Madrid 28046, Spain;2Centro de Investigacio ´n Biome ´dica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos
III (ISCIII), Madrid 28029, Spain;3Cytogenetics, INGEMM, IdiPAZ, Hospital Universitario La Paz, Madrid 28046, Spain;4Clinical Genetics, INGEMM,
IdiPAZ, Hospital Universitario La Paz, Madrid 28046, Spain;5Instituto de Investigaciones Biome ´dicas (IIB) de Madrid, Centro Superior Investigaciones
Cientı ´ficas (CSIC), Universidad Auto ´noma de Madrid (UAM), Madrid 28046 Spain;6National Centre for Medical Genetics, Our Lady’s Childrens Hospital,
Crumlin, Dublin 12, Ireland;7Microarray Unit, Cytogenetics Laboratory, Western General Hospital Edinburgh, Edinburgh EH4 2XU, UK;8Department of
Immunology, Genetics and Pathology, Uppsala University Rudbeck Laboratory, Dag Hammarskjo ¨ldsv, Uppsala SE-751 85, Sweden;
Pediatrics, University of Torino, 10124 Torino, Italy;10Estudio Colaborativo Espan ˜ol de Malformaciones Conge ´nitas (ECEMC), ISCIII, Madrid 28029, Spain;
11Instituto de Investigacio ´n de Enfermedades Raras (IIER), ISCIII, Madrid 28029, Spain;12Department of Medical Genetics, Institute of Mother and
Child, 01-211 Warsaw, Poland;13Center for Human Genetics, Katholieke Universiteit Leuven, University Hospital Gasthuisberg, 3000 Leuven, Belgium;
14Department of Pediatrics, Academic Medical Center, Universiteit van Amsterdam, 1100 DD Amsterdam, The Netherlands
15These authors contributed equally to this work
*Correspondence: mpalomares.hulp@salud.madrid.org
DOI 10.1016/j.ajhg.2011.06.012. ?2011 by The American Society of Human Genetics. All rights reserved.
9Department of
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Individuals 1 and 2 had de novo apparently balanced
chromosome translocations involving 8q21; individual 3
was found to have a de novo Robertsonian translocation
of chromosome 21; and individual 7 had a normal karyo-
type (Table 2). Individual 4 was recruited through the
DECIPHER database3(ID 2121). Samples from individuals
5 and 6, who also had de novo 8q21 microdeletions,
were obtained from colleagues in Ireland and Poland.
Table 1.Clinical Data in Presently Reported Individuals With a 8q21.11 Microdeletion
12345678
Gender (M/F)MFMFMFFM
Age (yr)76 6 s 17.516 13152
Growth and development
Growth failureNDþ
þ
?
þ
þ
þ
?
þ
?
þ (mild)
þ
þ
?
þ Intellectual diabilityþ
Face
Round faceþ
þ
Mi, SC, C, S
þ
þ
PR, S
þ
þ
Mi, SC
þ
?
?
?
?
?
?
?
þ
?
þ
þ
þ
?
þ
þ
?
þ
þ
SC, S
Squareþ
?
D, S
þ
þHigh foreheadþ
þ
þ
?
þ
þ
þ
þ
þa
þ
þ
þ
þ
þ
þ
?
Eyes
Hypertelorism?
?
þ
þ
þ
þ
þ
þ
þ
þ
ND
þ
þ
þ
þ
?
þ
þ
þ
þ
þ
þ
þ
þ
þ
ND?
þ
?
þ
þ
?
þ
?
?
þ
?
þ
þ
þ
?
þ
þ
þ
þ
?
?
þ
þ
?
?
?
þ
?
?
?
þ
þ
?
þ
þ
þ
þ
?
CP
Downslanting palpebral fissuresþ
þ
þ
þ
þ
þ
þ
þ
þ
?
þ
þ
þ
Short palpebral fissures
Ptosis
Epicanthal Folds
Wide nasal bridge
Underdeveloped alae
Short philtrum
Cupid’s bow
Down-turned corners mouth
Highly arched palate
Micrognathia þ
þ
þ
?
þ
?
Prominent, low-set ears
Short neck
Neurology
Hypotoniaþ
þ
þ
þ
þ
autism
?
Nl
þ
Nl
?
unusually
pleasant
þ
Nl
?
NlBehavior
Magnetic resonance imagingUCC, GADMUCC, GA,
DM, OA
NlNlNlUCC
HearingNlhyperacusis hearing losshearing loss NlNlNl hearing loss
Balance Nl NlNl impairedNl NlNl impaired
Other
Fingers þ Nl Ca4th and 5th toe
abnormalities
ND longCa Sy, B, SM
Abnormal palmar creasesþ
CM, Cr, SP
þ
AD
þ
Cr
?
E
?
LU
þ??
DS Various
The following abbreviations are used: M, male; F, female; ND, no data available; Mi, microphthalmia; C, cataract; SC, sclerocornea; S, strabismus; PR, pigmentary
retina degeneration; D, Duane anomaly; CP, cleft palate; Nl, normal; UCC, underdeveloped corpus callosum; GA, gyration abnormalities; DM, decreased myeli-
nation; Ca, camptodactyly; Sy, syndactyly 3–4 finger; B, broad first ray; SM, short metacarpals; CM, capillary malformation; Cr, cryptorchidism; SP, small penis;
AD, abnormal dentition; E, eczema; LU, lozenge shaped umbilicus; DS, decreased sense of smell.
aThis individual also had agenesis nasal cartilage; which had been surgically corrected before the picture was taken.
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One of them (individual 6) had been published.4Indi-
vidual 8 was recently published as part of a four-generation
family suggested to have a hitherto unrecognized entity
characterized by intellectual disability and an unusual
phenotype2. He had a previous normal aCGH result at
a 0.7 Mb resolution. The resemblance to individuals 1–7
was recognized and samples obtained. The study received
ethical approval from the ethical committee of the Univer-
sity Hospital La Paz and, after a complete description of
the study to the participants, written informed consent
was obtained. In individuals 1–7, overlapping 8q21 dele-
tions were ascertained by aCGH with the Agilent Kit
105A (Figure 2). Individual 8, who had a previous normal
result with a commercial aCGH platform, was directly
analyzed with a high-density custom oligonucleotide array
for the 8q21 region. The deletions were confirmed by
fluorescent in situ hybridization (FISH), multiplex liga-
tion-dependent probe amplification, or microsatellite
analysis (Figure 3). The 8q21.11 deletion region has not
been reported to show copy number variation (CNV) in
normal individuals. No other potentially pathogenic
copy number alterations were observed elsewhere in the
genome (data not shown).
In order to define more precisely the breakpoint interval
of the deletions, we designed a high-density targeted oligo-
nucleotide array with a 140 bp average probe spacing
spanning a 20 Mb interval of 8q13.3-q21.3 (AMADID
029896, Agilent Technologies, Santa Clara, CA, USA).
Results demonstrated that all eight individuals carried
overlapping deletions defining a minimal region of
539.77 kb (hg 19, chromosome 8: 77226464–77766239)
(Table 2, illustrated in Figure 2 and Figure S1, available
online). In addition individual 1 showed a complex
genomic rearrangement with a pattern consistent with
two deletions close to one another and involving the
8q21 region (Figure 2 and Figure S1).
Syndrome-associatednonrecurrent
usually share a common genomic region of overlap (the
smallest region of overlap [SRO]) encompassing the locus
associated with the genomic disorder. We analyzed the
rearrangements
Figure 1.
(A) Individual 1 at age 4 (left) and 7 years (right).
(B) Individual 3 at age 1 month (left) and 6 years (middle and right).
(C) Individual 2 at age 6 months.
(D) Individual 4 at age 17 years (left and right).
(E) Individual 5 at age 12 years (left and right).
(F) Individual 6 at age 20 months (left) and 9 years (right).
(G) Individual 7 at age 15 years (left and right) and (H) individual 8 at age 3 years.
Facial Views of Individuals Included in the Present Study
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present individuals with 8q21 rearrangements by using
high-density arrays to narrow the SRO to a 539.77 kb
interval. In the minimal region of overlap only one gene,
Zinc Finger Homeobox 4 (ZFHX4 [MIM 606940]); one micro-
RNA of unknown function (LOC100192378); and one
nonfunctional pseudogen (Mitochondrial Ribosomal Protein
L9 Pseudogene 1 [MRPL9P1]) were mapped (Figure 2).
ZFHX4 belongs to the family of zinc-finger homeodomain
transcription factors. This gene has been suggested to regu-
late neural and mesenchymal cell differentiation.5Hemmi
et al.6demonstrated that ZFHX4 is expressed in the human
adult brain, muscle, and liver and that Zfhx4 is expressed
in the brain and in developing muscle during embryogen-
esis of the mouse. Because ZFHX4 is 90% homologous to
mouse Zfhx4 in the genomic structure, amino acid
sequence, and expression profile, the authors suggest
that ZFHX4 plays a role in human neuronal and muscle
differentiation comparable to that in mice. Levels of the
ZFHX4 protein were high in the brainstem at embryonic
and neonatal periods and in the midbrain and dienceph-
alon in the neonatal rat brain. An immunolocalization
study showed that postmitotic neurons in the brainstem
were the major site of ZFHX4 localization, and the levels
of protein varied depending on age and anatomical sites.
Table 2.Results of aCGH and Classical Cytogenetic Studies of Eight 8q21 Microdeletions
DeletionSize (Mb)StartEndNomenclatureKaryotype
18q21.11q21.3
8q21.2q21.3
9.79
1.50
74915253
86536728
84715130
88037242
arr 8q21.11q21.3 (74915253-84715130)x1 dn
arr 8q21.2q21.3 (86536728-88037242)x1 dn
46,XY,t(4;8;7)(q13;q13;q11.2)dn.
ish del (8)(q21.11)(RP11-48D4-)
28q21.11q21.29.807436243884172022 arr 8q21.11q21.2(74362438-84172022)x1 dn46,XX,t(8;15)(q13;q15)dn.
ish del(8) (q21.1)(RP11-48D4-)
3 8q21.11q21.13 4.747717923381924253 arr 8q21.11q21.13 (77179233-81924253)x1 dn45,XY,der(21;21)(q10,q10)dn.
ish del(8)(q21.11)(RP11-48D4-)
4 8q21.113.58 74487194 78073108arr 8q21.11 (74487194-78073108)x1 dn 46, XX
5 8q21.11q21.313.55 7722025390774646arr 8q21.11q21.3 (77220253-90774646)x1 dn 46, XY
64
8q21.11q21.13 5.697460027180291446arr 8q21.11q21.13 (74600271-80291446)x1 dn46, XX
78q21.11q21.135.117722646482338741arr 8q21.11q21.13 (77226464-82338741)x1 dn46, XX, ish del(8) (q21.1)(RP11-48D4-)
82
8q21.110.667709887777766239arr 8q21.11(77098877-77766239)x146, XY
Data are from the UCSC Genome Browser (February 2009 assembly: hg19, NCBI Build 37).
Figure 2.
The minimal region of overlap shown includes hg 19, chromosome 8: 77226464-77766239.
Graphical Representation of the Deletions in All Individuals and Genes within the Minimal Region of Overlap
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Although ZFHX4 levels decreased after birth, the protein
was detected in the mature neurons. Thus, it has been
postulated that ZFHX4 participates in the regulation of
neural cell maturation or region-specific differentiation
of the brain.5Further support for this is provided by the
52% homology of ZFHX4 with Zinc Finger Homeobox 3
(ZFHX3 [MIM 104155]), involved in early development
of the central nervous system, maintenance of the undif-
ferentiated state of myoblasts, and regulation of various
genes important for cell cycle and growth.6ZFHX4 was
found to be disrupted in an individual with congenital
bilateral isolated ptosis (MIM 178300) and a de novo
balanced translocation t(1;8)(p34.3;q21.12).7The break-
point occurred in intron 4 of ZFHX4 and resulted in trun-
cation of this gene and its protein product. This person did
not have an intellectual disability or any other unusual
morphological characteristic. Levels of the protein Zfhx4
were high in the midbrain, including the oculomotor
nuclei, during embryogenesis in mice,5and the oculo-
motor nerves innervate the levator palpebrae superioris
that regulate the elevation of superior eyelid. Abnormal
protein levels of ZFHX4 might cause congenital bilateral
isolated ptosis.7Linkage studies did show linkage to 8q21
in several families, but subsequent sequencing failed
to show a mutation and no abnormal methylation of
ZFHX4 was found either.8The findings in the present indi-
viduals fit in well with the expression pattern of ZFHX4:
the intellectual disability, disturbed eye movements,
hearing and balance problems, and decreased sense of
smell fit in with an altered ZFHX4 function in brain devel-
opment, and the hypotonia fits in with ZFHX4 expression
in muscle. Detailed muscular studies have not been per-
formed in the present series of individuals and could
show interesting results. The absence of major malforma-
tions (except for the eye findings; see below) elsewhere
in the anatomy fits in with the expression pattern as
well. However, the fact that the individual reported by
McMullan et al.7showed no intellectual disability or
physical abnormalities other than the congenital bilateral
isolated ptosis makes it difficult to establish a direct associ-
ation between the haploinsufficiency for this gene and the
cause of the intellectual disability observed in these indi-
viduals. Moreover a CNV that partially affects ZFHX4
and the microRNA located in the SRO has been reported
in one apparently normal Yoruba individual from the
HapMap Project.9The significance of this observation is
unclear,and the identification of the genomic cause under-
lying this clinically recognizable entity is difficult at this
stage.
The deletions presented here show different sizes and
proximal and distal breakpoints in all cases. Breakpoint
junction sequencing analyses in individuals 3, 4, and 5
provided base pair resolution and showed that the break-
points were located in unique sequences with no apparent
homology (Figure S2). Thus nonallelic homologous recom-
bination between clusters of flanking low-copy repeats
or repetitive elements, the prevailing mechanism for recur-
rent rearrangements causing genomic disorders, seems not
to be the rearrangement mechanism underlying 8q21
microdeletions.
In addition to the common 8q21 microdeletion pheno-
type, individuals 1 and 3 presented with severe eye
abnormalities: severe microphthalmia, aphakia, cataracts,
atrophy of optic nerves, corneal opacity, and sclerocornea.
The individual reported by Taysi et al.10who had an inter-
stitial 8q12-q22 deletion also showed severe bilateral
microphthalmia. One might hypothesize that individuals
with 8q21 microdeletions have a contiguous gene syn-
drome because a gene for eye development might be
present in the deleted region. Because individuals 2 and
5–7 have a deletion that overlaps with the deleted regions
in individuals 1 and 3, this seems less likely. The 8q21
microdeletion might have a variable presentation, and
the extreme end of the spectrum might present with
eye development defects. Lastly, the 8q21 microdeletion
might unmask recessive mutations on the nondeleted
allele. It is of interest that two genes involved in eye
morphogenesis map close to 8q21 deletions. Eyes Absent
1 (EYA1 [MIM 601653]), mapping 2 Mb upstream from
the most proximal deletion breakpoint, encodes a member
of the eyes-absent family of proteins playing a role in the
developing kidneys, branchial arches, eyes, and ears.
Mutations of this gene have been associated with sporadic
cases of congenital cataracts and ocular anterior segment
anomalies. The Growth Differentiation Factor 6 (GDF6
[MIM 601147]) is located 6 Mb downstream from the
most distal breakpoint and encodes a member of the
bone morphogenetic protein family and the TGF-beta
Figure 3.
Individuals 1 (A), 2 (B), and 3 (C) are shown with BAC probe RP11-48D4 mapping to 8q21.11 (red).
FISH Confirmation of the Heterozygous Deletion of 8q21 in Individuals
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superfamily of secreted signaling molecules. It is required
for normal formation of some bones and joints in the
limbs, skull, and axial skeleton. Mutations in this gene
also result in congenital abnormalities in ocular develop-
ment. Neither gene is directly disrupted or deleted by
8q21 rearrangements, but one cannot completely exclude
a position effect through the loss of regulatory sequences
because enhancer elements can regulate the expression
of a gene at large distance, even with other uninvolved
genes located within the genomic region separating the
enhancer and the regulated gene.
Three of the eight 8q21.11 deletion individuals had
corneal opacities. Seven of them had heterozygous dele-
tions of Peroxisomal Biogenesis Factor 2 (PEX2 [MIM
170993]) in addition to ZFHX4 deletions. PEX2 encodes
an integral peroxisomal membrane protein required for
peroxisome biogenesis. Mutations in this gene result in
Zellweger syndrome (ZS [MIM 214100]). Although carriers
of heterozygous mutations in PEX2 are normal, pheno-
typic effects of heterozygous mutations in parents of
four infants who had ZS have been reported,11describing
curvilinear, cortical lens opacities. One cannot exclude
a contribution of PEX2 haploinsufficiency to the pheno-
type in some of the present individuals.
Parent-of-origin studies were carried out by segregation
analysis of 18 sequence-tagged sites in samples from avail-
able parents of individuals 1–4, 6, and 7. Individual 8
belongs to a family in whom five members in four genera-
tions are affected, including his mother. Samples from
other family members were not available. These studies
revealed that the deletion occurred on the paternal chro-
mosome in five individuals (1–4 and 6), and on the
maternal chromosome in individual 7; individual 8 very
likely inherited the deletion from his mother. This could
suggest the existence of a parent-of-origin bias indicating
that the mechanisms that lead to this rearrangement occur
preferentially in the paternal germline, but the difference
could also well be coincidence. Parent-of-origin effects
in the phenotype were not observed; ZFHX4 was found
not to be imprinted,8and no other imprinted genes
have been described within the regions deleted in our
individuals.
Large interstitial deletions that also involve chromo-
some region 8q21 have been reported infrequently in the
literature.10,12–14Persons with these deletions showed
a phenotype, similar to the that in the 8q21.11 microdele-
tion reported here, that included a high forehead, a wide
nasal bridge, hypertelorism, down-turned corners of the
mouth, micrognathia, abnormally shaped ears, a short
neck, hypotonia, growth retardation, and intellectual
disability. At the time of description, these deletions could
be characterized only at the cytogenetic level, which
hampers using the individuals for further delineation of
the phenotype.
In summary, we have observed a characteristic common
phenotype in eight individuals with a microdeletion of
8q21.11, suggesting that this could potentially represent
a clinically recognizable entity, at least in retrospect. We
could narrowdown the SRO to a 539.77 kb interval encom-
passing ZFHX4, one microRNA of unknown function, and
one nonfunctional pseudogen. Our observations suggest
that the core phenotype of this microdeletion could be
due to a haploinsufficient gene or genes within the
minimal deletion. We cannot discard the existence within
the SRO of a hitherto not-annotated gene. Characteriza-
tion of additional 8q21 deletion patients might help refine
this critical region, potentially allowing the identification
of the underlying gene(s) by mutation analysis in pheno-
typically similar patients without a detectable deletion.
Supplemental Data
Supplemental Data include two figures and can be found with this
article online at http://www.cell.com/AJHG/.
Acknowledgments
We would like to thank all the individuals and families for their
participation in this study. This work was supported by a grant
from the Fondo de Investigaciones Sanitarias (PI081187) of the
Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacio ´n
of Spain.
Received: February 21, 2011
Revised: May 30, 2011
Accepted: June 20, 2011
Published online: July 28, 2011
Web Resources
The URLs for data presented herein are as follows:
Agilent eArray, https://earray.chem.agilent.com/earray/
Database of Genomic Variants, http://projects.tcag.ca/cgi-bin/
variation/gbrowse/hg19/
Database of Genomic Variants Archive, http://www.ebi.ac.uk/
dgva/
Database of Genomic Structural Variation (dbVAR), http://www.
ncbi.nlm.nih.gov/dbvar/
DECIPHER, http://decipher.sanger.ac.uk
Genomic Imprint, http://www.geneimprint.com
UCSC Genome Browser (build 37), http://genome.ucsc.edu
International Mouse Strain Resource, http://www.findmice.org/
Online Mendelian Inheritance in Man (OMIM), http://www.
omim.org/
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