ApplicationQ1of Array Comparative Genomic
Hybridization in 102 Patients With Epilepsy and
Additional Neurodevelopmental Disorders
Magdalena Bartnik,1El_ zbieta Szczepanik,2Katarzyna Derwi? nska,1Barbara Wis ´niowiecka-Kowalnik,1
Tomasz Gambin,3Maciej Sykulski,4Kamila Ziemkiewicz,1Marta Ke ˛dzior,1Monika Gos,1
Dorota Hoffman-Zacharska,1Tomasz Mazurczak,2Anetta Jeziorek,2Dorota Antczak-Marach,2
Mariola Rudzka-Dybała,2Hanna Mazurkiewicz,2Alicja Goszcza? nska-Ciuchta,2
Zofia Zalewska-Miszkurka,2Iwona Terczy? nska,2Małgorzata Sobierajewicz,5Chad A. Shaw,6
Anna Gambin,4,7Hanna Mierzewska,2Tadeusz Mazurczak,1Ewa Obersztyn,1Ewa Bocian,1
and Paweł Stankiewicz1,6*
1Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
2Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland
3Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland
4Institute of Informatics, University of Warsaw, Warsaw, Poland
5Child Neurology Outpatient Clinic, Leszno, Poland
6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
7Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
Manuscript Received: 3 February 2012; Manuscript Accepted: 2 July 2012
Copy-number variants (CNVs) collectively represent an impor-
tant cause of neurodevelopmental disorders such as develop-
mental delay (DD)/intellectual disability (ID), autism, and
epilepsy. In contrast to DD/ID, for which the application of
microarray techniques enables detection of pathogenic CNVs
in ?10–20% of patients, there are only few studies of the role of
CNVs in epilepsy and genetic etiology in the vast majority of
cases remains unknown. We have applied whole-genome exon-
targeted oligonucleotide array comparative genomic hybridiza-
tion (aCGH) to a cohort of 102 patients with various types of
epilepsy withor without additionalneurodevelopmental abnor-
malities. Chromosomal microarray analysis revealed 24 non-
polymorphic CNVs in 23 patients, among which 10 CNVs
are known to be clinically relevant. Two rare deletions in
genetic loci and 12 CNVs are of unknown clinical significance.
Our results further support thenotion that rare CNVs can cause
different types of epilepsy, emphasize the efficiency of detecting
the clinical application of aCGH should be extended to patients
with unexplained epilepsies.
? 2012 Wiley Periodicals, Inc.
How to Cite this Article:
Bartnik M, Szczepanik E, Derwi? nska K,
Wis ´niowiecka-Kowalnik B, Gambin T,
Sykulski M, Ziemkiewicz K, Ke ˛dzior M, Gos
M, Hoffman-Zacharska D, Mazurczak T,
Jeziorek A, Antczak-Marach D, Rudzka-
Dybała M, Mazurkiewicz H, Goszcza? nska-
Ciuchta A, Zalewska-Miszkurka Z,
Terczy? nska I, Sobierajewicz M, Shaw CA,
Gambin A, Mierzewska H, Mazurczak T,
Obersztyn E, Bocian E, Stankiewicz P. 2012.
Application of array comparative genomic
hybridization in 102 patients with epilepsy
and additional neurodevelopmental
Am J Med Genet Part B 9999:1–11.
Grant sponsor: Polish Ministry of Science and Higher Education; Grant
number: R13-0005-04/2008; Grant sponsor: Foundation for Polish
The authors have no conflicts of interest to declare.
Paweł Stankiewicz, M.D., Ph.D., Department of Molecular and Human
Genetics, Baylor College of Medicine, One Baylor Plaza, Rm R809,
Houston, TX 77030. E-mail: firstname.lastname@example.org
Article first published online in Wiley Online Library
(wileyonlinelibrary.com): 00 Month 2012
? 2012 Wiley Periodicals, Inc.
Key words: seizures; array CGH; copy-number variants;
KCNJ3, WWOX; CDH15; IMMP2L
Advancesinmolecular cytogenetic techniques,such asarrayCGH,
have improved diagnostic power and allowed the detection of
clinically significant submicroscopic
(CNVs), in patients with multiple congenital anomalies, dysmor-
phic features, developmental delay (DD)/intellectual disability
(ID), autism, and schizophrenia at 100–1,000 times higher reso-
lution than conventional karyotype analysis [Lee et al., 2007;
Shinawi and Cheung, 2008; Kirov et al., 2009; Miller et al., 2010;
ID has been extensively investigated and the detection rate of
clinically relevant imbalances is estimated to be ?10–20%
[Menten et al., 2006; Stankiewicz and Beaudet, 2007; Koolen
et al., 2009]. Recently, more attention has been paid to identifica-
tion of CNVs in other neurodevelopmental disorders, including
Epilepsy is one of the most common neurological disorders
affecting up to 1% of the population. It has been estimated that up
to 40% of epilepsies are genetically determined and can be divided
into Mendelian, non-Mendelian (‘‘complex’’) diseases, and chro-
mosomal disorders [Hauser et al., 1996; Gardiner, 2000; Jozwiak
in which epilepsy is part of the clinical condition, but not the
primary feature. Over the past two decades, the progress in under-
standing mechanisms and causes of epilepsy has been spectacular
[Crino, 2007; Ottman et al., 2010]. Most of the rare monogenic
epilepsies are caused by mutations in genes encoding subunits of
ment [Sanchez-Carpintero Abad et al., 2007; Berg et al., 2010;
Ottman et al., 2010; Klassen et al., 2011].
Different types of epilepsy have been reported in patients with
chromosomal imbalances, including 1p36 deletion (Chromosome
1p36 deletion syndrome), 4p16.3 deletion (Wolf–Hirschhorn
syndrome), ring chromosome
(Angelman syndrome), inv dup (15) chromosome, deletion
17p13.3 (Miller–Dieker syndrome), ring chromosome 20, and
trisomy 21 (Down syndrome) [Singh et al., 2002; Battaglia and
Guerrini, 2005]. Application of molecular cytogenetic techniques
such as fluorescence in situ hybridization (FISH) and microarrays
have enabled identification of several novel smaller-sized patho-
genic CNVs, for example: deletions of CDKL5 (cyclin-dependent
et al., 2010; Mei et al., 2010], deletions and duplications of SCN1A
(sodium channel, neuronal type 1, alpha subunit; OMIM 182389;
2q24.3) in patients with Dravet syndrome (OMIM 607208)
[Marini et al., 2009], deletions of MAGI2 (membrane-associated
guanylate kinase inverted-2; OMIM 606382; 7q11.23–q21) in
subjects with infantile spasms [Marshall et al., 2008], deletions
of MEF2C (mads box transcription enhancer factor 2, polypeptide
C; OMIM 600662; 5q14.3) in patients with severe ID, seizures, and
hypotonia [Le Meur et al., 2010; Nowakowska et al., 2010; Zweier
14, deletion 15q11.2q12
et al., 2010], deletions of STXBP1 (syntaxin-binding protein 1;
OMIM 602926; 9q34.11) in patients with early infantile epileptic
encephalopathy (OMIM 612164) [Saitsu et al., 2008], deletions of
ARX (aristaless-related homeobox, X-linked; OMIM 300382;
Xp21.3) in patients with early infantile epileptic encephalopathy
1 (EIEE1; OMIM 308350), as well as duplications of MECP2
with Lubs syndrome (OMIM 300260) [Van Esch et al., 2005], and
duplications of FOXG1 (forkhead box G1; OMIM 164874; 14q12)
in patients with developmental epilepsy, mental retardation, and
severe speech impairment [Brunetti-Pierri et al., 2011]. Moreover,
recently, several recurrent CNVs have been identified in patients
with seizures, including microdeletions of chromosomal regions
1q21.1 [Brunetti-Pierri et al., 2008; Mefford et al., 2008], 7q11.23
[Ramocki et al., 2010], 10q11.21q11.23 [Stankiewicz et al.,
2012]; 15q11.2 [de Kovel et al., 2010; Mefford et al., 2010],
15q13.3 [Dibbens et al., 2009; Helbig et al., 2009; Shinawi et al.,
2009; Mefford et al., 2010], 16p11.2 [Ballif et al., 2007; Shinawi
et al., 2010], 16p13.11 [de Kovel et al., 2010; Heinzen et al.,
2010; Mefford et al., 2010], and 22q11.2 [Ryan et al., 1997;
Gonzalez and Bautista, 2009] and reciprocal microduplications
[Stankiewicz et al., 2012], and 16p11.2 [Shinawi et al., 2010;
Mefford et al., 2011].
Despite increasing interest in the genetics of epilepsy, only a few
genome-wide studies of CNVs have been performed in patients
with epilepsy [Battaglia and Guerrini, 2005; Heinzen et al., 2010;
Mefford et al., 2010, 2011; Paciorkowski et al., 2011; Sisodiya and
Here, we report the results of chromosomal microarray analysis
(CMA) in 102 patients with idiopathic generalized epilepsy (IGE)
or epilepsy with other neurodevelopmental disorders. We show
that CNVs significantly contribute to the genetic etiology of
MATERIALS AND METHODS
We studied 102 patients with different types of epilepsy, including
juvenile myoclonic epilepsy (JME), West syndrome, idiopathic
generalized epilepsy (IGE), and unclassified syndromes of refrac-
tory epilepsy with different types of seizures. The epilepsy was
either isolated or epilepsy accompanied by DD/ID, dysmorphy,
or other neurological signs (epilepsy plus). We applied array
CGH to detect copy number changes in 50 individuals with
isolated IGE and in 52 patients with different types of epilepsy
had normal karyotype using GTG banding analysis with at least
Genomic DNA was extracted from peripheral blood cells using a
Puregene DNA Blood Kit (Qiagen, Gentra Systems, Minneapolis,
samples were obtained from phenotypically normal male and
2AMERICAN JOURNAL OF MEDICAL GENETICS PART B
Chromosomal Microarray Analysis (CMA)
ics Laboratories at Baylor College of Medicine (BCM; http://
www.bcm.edu/geneticlabs/cma/tables.html) in cooperation with
Department of Medical Genetics at the Institute of Mother and
V8.0 and V8.1 OLIGO (180K) arrays have genome-wide coverage
as well as exon coverage for over 1,700 genes with an average of 4.2
2010]. Digestion, labeling, and hybridization were performed
following the manufacturer’s instructions. The BCM web-based
used for genomic copy-number analysis. All genomic coordinates
are based on the March 2006 assembly of the reference genome
(NCBI36/hg18). When available, blood samples were obtained
from patient’s parents, and array CGH was done to investigate
To verify genomic gains and losses identified by array CGH,
depending on CNV size, we used GTG-banding, FISH, multiplex
Conventional Karyotype Analysis
Peripheral blood lymphocytes were cultured and GTG-banding
analysis was performed according to the standard protocol. The
metaphases with 550-band resolution were analyzed.
FISH analyses were carried out by standard procedures in phyto-
hemagglutinin-stimulated peripheral blood lymphocytes using
probes derived from bacterial artificial chromosomes (BACs).
When available, blood samples were obtained from the patient’s
parents, and FISH analysis using the same probes was done to
investigate the inheritance of the CNVs.
MLPA, PCR, and DNA Sequencing
MLPA experiments (Patients 1 and 2) were preformed according
the manufacturer’s instruction with the kit SALSA MLPA P189
GeneMarker v1.8 software (SoftgeneticsQ2, LLC). To characterize
the breakpoint in the CDKL5 gene, PCR reaction was performed
with Expand Long Template PCR System (RocheQ3Diagnostics)
according to the manufacturer’s instructions. The reaction prod-
ucts were separated by agarose gel electrophoresis. The smaller
product was cut out from the gel and after DNA extraction (Gel-
reaction (BigDye Terminator v.3.1 Cycle Sequencing Kit, Life
TechnologiesQ5) with primers used for the product amplification.
The sequences were analyzed with FinchTV v.1.4.0 and compared
to the reference sequence NG_008475.1.
Overall, 24 non-polymorphic (not reported in CNV databases of
healthy individuals) copy-number changes were found in 23
(isolated epilepsy in 12 and epilepsy plus in 11) of 102 patients
(23.5%), ranging in size from 1kb to 10.35Mb. We divided the
detected CNVs into three groups. The first group contains CNVs
in seven patients and duplications in three patients (Table I). We
identified five patients with known recurrent CNVs at hotspots:
15q11.2 (BP1/BP2), 16p11.2, 16p13.11, 22q11.21, and 7q11.23 (pt
3 was described elsewhere, Ramocki et al., 2010] and five patients
with different-sized non-recurrent CNVs: two girls with exonic
deletions of the CDKL5 gene at chromosome Xp22.13 (pt 1 was
duplication CNVs at Xq28 harboring the MECP2 and IDS
(iduronate 2-sulfatase; OMIM 300823) genes and a heterozygous
NPHP1 (nephrocystin 1; OMIM 607100) deletion at 2q13, one
individual with a deletion at 1p36.21p36.32 associated with a
balanced paracentric inversion at 1p32p34.3 detected by conven-
tional karyotyping (data not shown), and one subject with a
duplication of 14q12 encompassing the FOXG1 gene.
The second group consists of two patients with rare larger-sized
deletions, at 2q24.1q24.3 (10.4Mb) and 9q21.13 (2.5Mb; Fig. 1)
that represent novel CNVs potentially causative for epilepsy
In the third group, we classified patients with four unique
deletions and eight duplications of unknown clinical significance
(Table III). Three of them map to recurrent hot spots; however,
duplication 16p13.11 in patient 21 is smaller in size than the
common ones and likely was not mediated by non-allelic homol-
ogous recombination (NAHR).
To determine the pathogenic role of the identified CNVs, we
considered their type (deletion or duplication) and size, gene
content, inheritance pattern, and available information from
BCM and public CNV databases. In general, we have divided the
consider as clinically relevant for epilepsy. The second group
consists of rare larger-sized deletions that could be novel CNVs
potentially causative for epilepsy. Finally, variants of unknown
clinical significance are listed in the third group.
isolated epilepsyandsevenpatients withepilepsyandother neuro-
developmental abnormalities (Table I). A number of studies have
suggested that increased dosage of FOXG1 mapping to chromo-
some 14q12 is pathogenic for developmental delay, cognitive
impairment with speech delay, and epilepsy [Yeung et al., 2009;
Brunetti-Pierri et al., 2011; Paciorkowski et al., 2011; Striano et al.,
2011; Tohyama et al., 2011]. However, recently, Amor et al. 
passing FOXG1, associated only with isolated hemifacial micro-
somia. Brunetti-Pierri et al.  suggested that this small
duplication may be devoid of FOXG1 distant up-regulating ele-
ments, thus not sufficiently increasing the gene dosage to manifest
the abnormal neurological phenotype. In addition, Amor et al.
 also identified an ?3Mb duplication of the 14q12 region,
including FOXG1 in a child enrolled as a control subject in the
BARTNIK ET AL.
TABLE I. Clinically Relevant CNVs Known to Be Pathogenic for Epilepsy
Refractory epilepsy with
different types of
seizures (GTCS, tonic,
Bartnik et al. 
Refractory epilepsy with
different types of
seizures (focal, tonic)
Erez et al. 
HIP1, YWHAG 1.658
Epilepsy with GTCS/JME
Ramocki et al. 
Mild ID, VCFS
JME (with myoclonus and
GTCS, and absences
with eyelid myoclonus)
Normal IQ, headache
de Kovel et al. 
West syndrome evolving
Brunetti-Pierri et al.
Refractory epilepsy with
Bahi-Buisson et al.
West syndrome evolving
into epilepsy with focal
seizures with hypsar-
rythmia in EEG
Dysmorphic, profound DD
West syndrome evolving
into epilepsy with tonic
Dysmorphic, profound DD,
Shinawi et al. 
DD, developmental delay; GTCS, generalized tonic–clonic seizures; ID, intellectual disability; JME, juvenile myoclonic epilepsy; mat, maternal; pat, paternal. VCFS, Velocardiofacial syndrome.
*Patient 7 had an additional balanced paracentric inversion 1p32p34.3. **Patient 8 had an additional heterozygous NPHP1 deletion at 2q13 and a 284kb duplication at Xq28 (148,240,624-148,524,326), harboring the IDS gene (Table III). The absence of
epilepsy in patient 8’s mother likely results from a skewed X-inactivation, which was not studied.
the pathogenicity of FOXG1 duplication. However, upon further
delay, which was not known before (H. Hakonarson, personalQ7
communication). Our data further support the pathogenicity of
FOXG1 duplication in epilepsy and DD.
The 8.5Mb interstitial deletion 1p36.21p36.32 identified in
patient 7 harbors the KCNAB2 gene encoding a beta subunit of
a voltage-gated potassium channel (OMIM 601142) but does not
includeKLHL17 (kelch-like 17)andGABRD (g-aminobutyric acid
Areceptordelta-subunit; OMIM 137163), three genes proposed as
syndrome (OMIM 607872) [Heilstedt et al., 2001; Bahi-Buisson
et al., 2008; Rosenfeld et al., 2010; Paciorkowski et al., 2011]. Our
data further emphasize the role of KCNAB2 in this syndrome
[Heilstedt et al., 2001; Gajecka et al., 2007].
channel genes [Turnbull et al., 2005], mutations have been found
only in four genes, KCNQ2 (voltage-gated, KQT-like subfamily,
member 2; OMIM 602235; 20q13.3) and KCNQ3 (voltage-gated,
KQT-like subfamily, member 3; OMIM 602232; 8q24) in patients
with benign familial neonatal convulsions as well as in KCNA1
(voltage-gated, shaker-related subfamily, member 1; OMIM
176260; 12p13) in patients with partial epilepsy or episodic ataxia
type 1 (OMIM 160120) [Gurnett and Hedera, 2007]. In addition,
KCNMA1 (calcium-activated, large conductance, subfamily M,
alpha, member 1; OMIM 600150; 10q22) was found mutated in
patients with generalized epilepsy and paroxysmal dyskinesia
In two patients (11 and 12), we detected CNVs that were not
previouslyreported tobe associatedwith epilepsy andthat contain
Interestingly, patient 11 with refractory West syndrome and
profound DD had a 10.3Mb deletion in 2q24.1q24.3 (located
1.5Mb proximally to SCN1A), harboring two other potassium
FIG. 1. ArrayCGHanalyses(a)inpatient11,showingan?10.3Mbinthe2q24.1q24.3regionand(b)inpatient12,showingan?2.5Mbdeletionon
the deleted region on chromosome 9q21.13. e: Results of GTG-banding analysis of chromosome 2 in patient 11. Red arrow indicates the deleted
chromosome region. f: Results of the FISH analysis in patient 12 with the BAC clone RP11-243A1 (green) and Vysis CEP 9 Alpha (red) used as
controls. White arrow indicates the deleted chromosome region.
BARTNIK ET AL.
channel genes KCNJ3 (inwardly-rectifying channel, subfamily J,
member 3; OMIM 601534) and KCNH7 encoding a pore-forming
family 4 (sodium bicarbonate transporter-like), member 10;
OMIM 605556) (Fig. 1a,c,e). Disruption of SLC4A10 was reported
in a patient with a de novo apparently balanced chromosomal
translocation t(2;13; q24;q31) and complex partial epilepsy with
mental retardation [Gurnett et al., 2008]. However, an ?7.5Mb
deletion chr2:155.526.470–163.058.894, harboring SLC4A10 and
truncating KCNH7, but likely not involving KCNJ3 (max coor-
dinates: chr2:155.413.315–163.101.007), was found in a patient
2012] and an overlapping ?5.2Mb deletion chr2:159,618,452–
164,882,054, encompassing SLC4A10 and KCNH7, but leaving
KCNJ3 intact, was described in a mentally retarded boy with
muscular hypotonia and no evidence of epilepsy [Magri et al.,
2011]. Furthermore, Layouni et al.,  identified a region of
absence of heterozygosity containing KCNJ3 in a consanguineous
Tunisian family with an autosomal recessive form of juvenile
myoclonic epilepsy and Chioza et al.,  reported an associ-
ation of KCNJ3 with different idiopathic generalized epilepsy
of KCNJ3 contributes to epilepsy in our patient. In support of this
notion, DECIPHER patient 254867 with an overlapping deletion
chr2:156539025–158815118, not including KCNJ3 and KCNH7,
present with epilepsy.
A 2.5Mb deletion 9q21.13 in patient 12 (Fig. 1b,d,f) with
epilepsy with eyelid myoclonia and GTCS and autism involves
GDA (guanine deaminase; OMIM 139260), ZFAND5 (zinc finger,
AN1-type domain 5; OMIM 604761), TMC1 (transmembrane
ase 1 family, member A1; OMIM 100640), ANXA1 (annexin A1;
OMIM 151690), RORB (RAR-related orphan receptor B; OMIM
601972), and potentially TRPM6 (transient receptor potential
cation channel, subfamily M, member 6; OMIM 607009). Hetero-
zygous and homozygous mutations in TRPM6 are associated with
hypomagnesemia with secondary hypocalcemia, a rare condition
usually presenting in the newborn period as refractory seizures
the lower border (0.74 and 0.79mg/dl, normal 0.7–1.1mg/dl). His
calcemia was normal. In addition, heterozygous and homozygous
mutations in TMC1 have been associated with progressive post-
lingual hearing loss and profound prelingual deafness DFNA36
(OMIM 606705) and DFNB7 (OMIM 600974). No evidence of
deafness was observed in our patient. Of note, DECIPHER patient
2065 with a larger-sized ?10.3Mb deletion chr9:70318675–
80676552 had tonic/clonic (grand-mal) seizures and patient
2064 with an overlapping 6.4Mb deletion chr9:74281674–
80676552, excluding GDA and ZFAND5, also had seizures. Given
the large size, gene content and the fact that it arose de novo we
believe this deletion is causative for epilepsy in our patient.
CNVs in group 3 have been classified as of unknown clinical
data to suggest that they may be responsible for the observed
TABLE II. Novel CNVs Potentially Causative for Epilepsy
Profound DD, EPH
Epilepsy with eyelid
myoclonia and GTCS
DD, developmental delay; GTCS, generalized tonic–clonic seizures; mat, maternal.
6 AMERICAN JOURNAL OF MEDICAL GENETICS PART B
TABLE III. CNVs of Unknown Clinical Significance
West syndrome evolving
into epilepsy with focal
seizures with hypsar-
rythmia in EEG
JME with GTCS
Refractory epilepsy with
Profound DD, Rett-like
Mother normal, father
West syndrome evolving
into refractory epilepsy
Profound DD, cerebral
Mother normal, father
Epilepsy with absences
Epilepsy with GTCS and
Normal IQ, visual
arr Xp22.31 (7,801,120-
Father and brother
NDE1, ABCC1, ABCC6
JME (with absences with
eyelid myoclonia and
CSWS, continuous spikes and waves during slow wave sleep; DD, developmental delay; GTCS, generalized tonic–clonic seizures; JME, juvenile myoclonic epilepsy; mat, maternal; pat, paternal.
BARTNIK ET AL.
phenotypic abnormalities. In cases 13, 17–20, we classified the
identified CNVs in group III because, similar to the CMA sign out
guidelines used at Baylor College of Medicine, we report all
gene-free CNVs if larger than 500kb (patients 13) as well as
CNVs>300kb containing genes, even if their clinical significance
is unknown (patients 17–20).
[Nagamani et al., 2011; Ramalingam et al., 2011] presented with
generalized epilepsy. We believe that this duplication may also
contribute to JME in patients 21 and 22. Patient 14 with refractory
epilepsy with tonic seizures and electrographic continuous spikes
(Cadherin 15; OMIM 114019) inherited from his apparently
healthy father. Heterozygous point mutations in CDH15 have
been reported in patients with mild to severe ID [Bhalla et al.,
2008]. In addition, deletions of CDH15 have been observed in
four patients with neurodevelopmental abnormalities, including
epilepsy (16q24.3 microdeletion syndrome) [Willemsen et al.,
IMMP2L (IMP2 inner mitochondrial membrane peptidase-like
subunit 2; OMIM 605977) deleted in patient 15 with West syn-
disorders (ASDs) and Tourette syndrome [Petek et al., 2001;
Maestrini et al., 2010; Casey et al., 2011; Patel et al., 2011]. Little
is known about the function of the IMMP2L protein. However,
given its potential role in other neuropsychiatric disorders, we
cannot exclude its contribution to the abnormal phenotype in our
deletion of WWOX (WW domain containing oxidoreductase;
OMIM 605131). Interestingly, a 13-bp deletion in exon 9 of the
Wwox gene was observed in rats with lethal dwarfism and epilepsy
 bioinformatically predicted WWOX to be haploinsufficient
in humans. Recently, White et al.  reported a maternally
inherited exon 6–8 deletion in WWOX in a patient with a 46,XY
karyotype and ambiguous genitalia and gonadal dysgenesis but no
evidence of seizures or autism. This exonic deletion was predicted
at the C-terminus. Given the previous description of Wwox defi-
cientmice withgonadalabnormalities [Ludes-Meyersetal.,2007],
White et al.  suggested a role for WWOX in human gonad
development. However, no sex determination/differentiation
abnormalities were observed in our male patient, suggesting that
haploinsufficiency of WWOX may have different clinical
The role of CHRNA7 (cholinergic receptor, neuronal nicotinic,
alpha polypeptide 7; OMIM 118511) duplication in patient 23
microdeletions of CHRNA7 [Helbig et al., 2009; Shinawi et al.,
2009], it was present only in one of 11 patients with small micro-
duplications involving CHRNA7 [Szafranski et al., 2010].
and non-recurrent submicroscopic CNVs in the etiology of epi-
lepsy, demonstrate the usefulness of our approach to the identi-
in the genetic diagnosis of epilepsy.
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