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.
in this study. We thank Dr. M. Ramocki for helpful discussion.
Amor DJ, Burgess T, Tan TY, Pertile M. 2012. QuestionableQ8pathoge-
nicity of FOXG1 duplication. Eur J Hum Genet in press.
Bahi-Buisson N, Girard B, Gautier A, Nectoux J, Fichou Y, Saillour Y,
Poirier K, Chelly J, Bienvenu T. 2010. Epileptic encephalopathy in a girl
with an interstitial deletion of Xp22 comprising promoter and exon 1
of the CDKL5 gene. Am J Med Genet B Neuropsychiatr Genet 153B:
Bahi-Buisson N, Guttierrez-Delicado E, Soufflet C, Rio M, Daire VC,
ML, Edery P, Novelli A, Bernardini L, Dulac O, Nabbout R, Plouin P,
Battaglia A. 2008. Spectrum of epilepsy in terminal 1p36 deletion
syndrome. Epilepsia 49:509–515.
Ballif BC, Hornor SA, Jenkins E, Madan-Khetarpal S,Surti U, Jackson KE,
LG. 2007. Discovery of a previously unrecognized microdeletion syn-
drome of 16p11.2-p12.2. Nat Genet 39:1071–1073.
Bartnik M, Derwinska K, Gos M, Obersztyn E, Kolodziejska KE, Erez A,
GA, Reimschisel T, Bocian E, Mazurczak T, Cheung SW, Stankiewicz P.
2011. Early-onset seizures due to mosaic exonic deletions of CDKL5 in
a male and two females. Genet Med 13:447–452.
Battaglia A, Guerrini R. 2005. Chromosomal disorders associated with
epilepsy. Epileptic Disord 7:181–192.
Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas
W, Engel J, French J, Glauser TA, Mathern GW, Moshe SL, Nordli D,
Plouin P, Scheffer IE. 2010. Revised terminology and concepts for
organization of seizures and epilepsies: Report of the ILAE Commission
on Classification and Terminology, 2005–2009. Epilepsia 51:676–685.
BhallaK,LuoY,BuchanT, BeachemMA,Guzauskas GF,LaddS,Bratcher
SJ, Schroer RJ, Balsamo J, DuPont BR, Lilien J, Srivastava AK. 2008.
Alterations in CDH15 and KIRREL3 in patients with mild to severe
intellectual disability. Am J Hum Genet 83:703–713.
Boone PM, Bacino CA, Shaw CA, Eng PA, Hixson PM, Pursley AN, Kang
SH, Yang Y, Wiszniewska J, Nowakowska BA, del Gaudio D, Xia Z,
Simpson-Patel G, Immken LL, Gibson JB, Tsai AC, Bowers JA,
Reimschisel TE, Schaaf CP, Potocki L, Scaglia F, Gambin T, Sykulski
M, Bartnik M, Derwinska K, Wisniowiecka-Kowalnik B, Lalani SR,
P. 2010. Detection of clinically relevant exonic copy-number changes by
array CGH. Hum Mutat 31:1326–1342.
SR, Graham B, Lee B, Shinawi M, Shen J, Kang SH, Pursley A, Lotze T,
Kennedy G, Lansky-Shafer S, Weaver C, Roeder ER, Grebe TA, Arnold
GL, Hutchison T, Reimschisel T, Amato S, Geragthy MT, Innis JW,
Stankiewicz P, Cheung SW, Patel A. 2008. Recurrent reciprocal 1q21.1
deletions and duplications associated with microcephaly or macroce-
phaly and developmental and behavioral abnormalities. Nat Genet
Brunetti-Pierri N, Paciorkowski AR, Ciccone R, Mina ED, Bonaglia
MC, ‘Borgatti R, Schaaf CP, Sutton VR, Xia Z, Jelluma N, Ruivenkamp
8AMERICAN JOURNAL OF MEDICAL GENETICS PART B
D’Arrigo S, Hughes J, Cheung SW, Zuffardi O, Stankiewicz P. 2011.
Duplications of FOXG1 in 14q12 are associated with developmental
epilepsy, mental retardation, and severe speech impairment. Eur J Hum
Eur J Hum Genet in press.
Abrahams BS, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A,
Berney T, Bolshakova N, Bolton PF, Bourgeron T, Brennan S, Cali P,
Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Green J,
Guter SJ, Hakonarson H, Holt R, Hughes G, Hus V, Igliozzi R, Kim C,
Klauck SM, Kolevzon A, Lamb JA, Leboyer M, Le Couteur A, Leventhal
BL, Lord C, Lund SC, Maestrini E, Mantoulan C, Marshall CR, McCo-
nachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A,
G, Pagnamenta AT, Papanikolaou K, Parr JR, Parrini B, Pickles A, Pinto
D, Piven J, Posey DJ, Poustka A, Poustka F, Ragoussis J, Roge B, Rutter
ML, Sequeira AF, Soorya L, Sousa I, Sykes N, Stoppioni V, Tancredi R,
Tauber M, Thompson AP, Thomson S, Tsiantis J, Van Engeland H,
Vincent JB, Volkmar F, Vorstman JA, Wallace S, Wang K, Wassink TH,
White K, Wing K, Wittemeyer K, Yaspan BL, Zwaigenbaum L, Betancur
C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Gesch-
Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P,
Vieland VJ, Wijsman EM, Green A, Gill M, Gallagher L, Vicente A,
Ennis S. 2011. AQ10novel approach of homozygous haplotype sharing
identifies candidate genes in autism spectrum disorder. Hum Genet
[Epub ahead of print].
Chioza B, Osei-Lah A, Wilkie H, Nashef L, McCormick D, Asherson P,
Makoff AJ. 2002. Suggestive evidence for association of two potassium
channel genes with different idiopathic generalised epilepsy syndromes.
Epilepsy Res 52:107–116.
answers, more questions. Epilepsia 48(Suppl2):42–50.
de Kovel CG, Trucks H, Helbig I, Mefford HC, Baker C, Leu C, Kluck C,
Muhle H, von Spiczak S, Ostertag P, Obermeier T, Kleefuss-Lie AA,
Hallmann K, Steffens M, Gaus V, Klein KM, Hamer HM, Rosenow F,
Brilstra EH, Trenite DK, Swinkels ME, Weber YG, Unterberger I,
Zimprich F, Urak L, Feucht M, Fuchs K, Moller RS, Hjalgrim H, De
Jonghe P, Suls A, Ruckert IM, Wichmann HE, Franke A, Schreiber S,
Eichler EE, Sander T. 2010. Recurrent microdeletions at 15q11.2 and
16p13.11 predispose to idiopathic generalized epilepsies. Brain 133:
Trucks H, Obermeier T, Wittig M, Franke A, Caglayan H, Yapici Z,
Sander T, Eichler EE, Scheffer IE, Mulley JC, Berkovic SF. 2009. Familial
and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy:
Precedent for disorders with complex inheritance. Hum Mol Genet
Erez A, Patel AJ, Wang X, Xia Z, Bhatt SS, Craigen W, Cheung SW, Lewis
RA, Fang P, Davenport SL, Stankiewicz P, Lalani SR. 2009. Alu-specific
microhomology-mediated deletions in CDKL5 in females with early-
onset seizure disorder. Neurogenetics 10:363–369.
Gajecka M, Mackay KL, Shaffer LG. 2007. Monosomy 1p36 deletion
syndrome. Am J Med Genet C Semin Med Genet 145C:346–356.
epilepsy. J Neurol 247:327–334.
Gonzalez W, Bautista RE. 2009. Seizures and EEG findings in an adult
patient with DiGeorge syndrome: A case report and review of the
literature. Seizure 18:648–651.
genes, copy number alterations, and gene regulation. Arch Neurol 64:
Gurnett CA, Veile R, Zempel J, Blackburn L, Lovett M, Bowcock A. 2008.
complex partial epilepsy and mental retardation. Arch Neurol 65:
Hauser WA, Annegers JF, Rocca WA. 1996. Descriptive epidemiology of
epilepsy: Contributions of population-based studies from Rochester,
Minnesota. Mayo Clin Proc 71:576–586.
Heilstedt HA, Burgess DL, Anderson AE, Chedrawi A, Tharp B, Lee O,
Kashork CD, Starkey DE, Wu YQ, Noebels JL, Shaffer LG, Shapira SK.
2001. Loss of the potassium channel beta-subunit gene, KCNAB2, is
associated with epilepsy in patients with 1p36 deletion syndrome.
Heinzen EL, Radtke RA, Urban TJ, Cavalleri GL, Depondt C, Need AC,
Walley NM, Nicoletti P, Ge D, Catarino CB, Duncan JS, Kasperaviciute
Gumbs CE, Smith J, Cronin KD, Maia JM, Doherty CP, Pandolfo M,
Leppert D, Middleton LT, Gibson RA, Johnson MR, Matthews PM,
Hosford D, Kalviainen R, Eriksson K, Kantanen AM, Dorn T, Hansen J,
Kramer G, Steinhoff BJ, Wieser HG, Zumsteg D, Ortega M, Wood NW,
Huxley-Jones J, Mikati M, Gallentine WB, Husain AM, Buckley PG,
Stallings RL, Podgoreanu MV, Delanty N, Sisodiya SM, Goldstein DB.
2010. Rare deletions at 16p13.11 predispose to a diverse spectrum of
sporadic epilepsy syndromes. Am J Hum Genet 86:707–718.
H, de Kovel C, Baker C, von Spiczak S, Kron KL, Steinich I, Kleefuss-Lie
AA, Leu C, Gaus V, Schmitz B, Klein KM, Reif PS, Rosenow F, Weber Y,
Visscher F, de Haan GJ, Moller RS, Hjalgrim H, Luciano D, Wittig M,
BP, Lindhout D, Stephani U, Schreiber S, Eichler EE, Sander T. 2009.
15q13.3 microdeletions increase risk of idiopathic generalized epilepsy.
Nat Genet 41:160–162.
Huang N, Lee I, Marcotte EM, Hurles ME. 2010. CharacterisingQ11and
predicting haploinsufficiency in the human genome. PLoS Genet
Jozwiak S, Lason W, Bijak M, Katulska K. 2005. Research advances in
molecular genetics of epilepsies. Neurol Neurochir Pol 39:497–508.
Craddock N, Owen MJ, O’Donovan MC. 2009. Support for the involve-
Hum Mol Genet 18:1497–1503.
J, Bourquin T, Lewis L, Villasana D, Morgan M, Muzny D, Gibbs R,
profiles confounding personal risk assessment in epilepsy. Cell 145:
Koolen DA, Pfundt R, de Leeuw N, Hehir-Kwa JY, Nillesen WM, Neefs I,
Scheltinga I, Sistermans E, Smeets D, Brunner HG, van Kessel AG,
Veltman JA, de Vries BB. 2009. Genomic microarrays in mental retar-
dation: A practical workflow for diagnostic applications. Hum Mutat
Malafosse A.2010. Genetic linkagestudyof anautosomal recessive form
of juvenile myoclonic epilepsy in a consanguineous Tunisian family.
Epilepsy Res 90:33–38.
Bonneau P, Guichet A, Barth M, Charollais A, Journel H, Auvin S,
Frebourg T, Dubourg C, Andrieux J, Bonneau D. 2010. MEF2C
BARTNIK ET AL.
mutation is responsible for severe mental retardation with stereotypic
movements, epilepsy and/or cerebral malformations. J Med Genet 47:
cytogenetic diagnosis of constitutional disorders. Nat Genet 39:S48–
Ludes-Meyers JH, Kil H, Nunez MI, Conti CJ, Parker-Thornburg J, Bed-
ford MT, Aldaz CM. 2007. WWOX hypomorphic mice display a higher
incidence of B-cell lymphomas and develop testicular atrophy. Genes
Chromosomes Cancer 46:1129–1136.
Maestrini E, Pagnamenta AT, Lamb JA, Bacchelli E, Sykes NH, Sousa I,
Toma C, Barnby G, Butler H, Winchester L, Scerri TS, Minopoli F,
Reichert J, Cai G, Buxbaum JD, Korvatska O, Schellenberg GD, Dawson
2010. High-density SNP association study and copy number variation
analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4
gene region in autism susceptibility. Mol Psychiatry 15:954–968.
Magri C, Piovani G, Pilotta A, Michele T, Buzi F, Barlati S. 2011. De novo
deletion of chromosome 2q24.2 region in a mentally retarded boy with
muscular hypotonia. Eur J Med Genet 54:361–364.
Marini C, Scheffer IE, Nabbout R, Mei D, Cox K, Dibbens LM, McMahon
JM, Iona X, Carpintero RS, Elia M, Cilio MR, Specchio N, Giordano L,
Striano P, Gennaro E, Cross JH, Kivity S, Neufeld MY, Afawi
Z, Andermann E, Keene D, Dulac O, Zara F, Berkovic SF, Guerrini R,
Mulley JC. 2009. SCN1A duplications and deletions detected in
Dravet syndrome: Implications for molecular diagnosis. Epilepsia 50:
Marshall CR, Young EJ, Pani AM, Freckmann ML, Lacassie Y, Howald C,
Fitzgerald KK, Peippo M, Morris CA, Shane K, Priolo M, Morimoto M,
Kondo I, Manguoglu E, Berker-Karauzum S, Edery P, Hobart HH,
Mervis CB, Zuffardi O, Reymond A, Kaplan P, Tassabehji M, Gregg
RG, Scherer SW, Osborne LR. 2008. Infantile spasms is associated with
A, Malafosse A, Genton P, Thomas P, Gurnett CA, Schreiber S, Bassuk
AG, Guipponi M, Stephani U, Helbig I, Eichler EE. 2010. Genome-wide
generalized and focal epilepsies. PLoS Genet 6:e1000962.
Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S,
Hennekam RC, Male A, Gaunt L, Clayton-Smith J, Simonic I, Park SM,
Mehta SG, Nik-Zainal S, Woods CG, Firth HV, Parkin G, Fichera M,
Reitano S, Lo Giudice M, Li KE, Casuga I, Broomer A, Conrad B,
Schwerzmann M, Raber L, Gallati S, Striano P, Coppola A, Tolmie JL,
Tobias ES, Lilley C, Armengol L, Spysschaert Y, Verloo P, De Coene A,
Goossens L, Mortier G, Speleman F, van Binsbergen E, Nelen MR,
Hochstenbach R, Poot M, Gallagher L, Gill M, McClellan J, King MC,
Regan R, Skinner C, Stevenson RE, Antonarakis SE, Chen C, Estivill X,
JR, Barber JC, Willatt L, Tassabehji M, Eichler EE. 2008. Recurrent
rearrangements of chromosome 1q21.1 and variable pediatric pheno-
types. N Engl J Med 359:1685–1699.
Mefford HC, Yendle SC, Hsu C, Cook J, Geraghty E, McMahon JM, Eeg-
Freeman JL, Andermann E, Pelakanos JT, Andrews I, Wallace G, Eichler
EE, Berkovic SF, Scheffer IE. 2011. Rare copy number variants are an
important cause of epileptic encephalopathies. Ann Neurol 70:974–985.
MeiD, Marini C,Novara F,Bernardina BD, Granata T, Fontana E,Parrini
E, Ferrari AR, Murgia A, Zuffardi O, Guerrini R. 2010. Xp22.3 genomic
deletions involving the CDKL5 gene in girls with early onset epileptic
encephalopathy. Epilepsia 51:647–654.
Ravel T, Van Vooren S, Balikova I, Backx L, Janssens S, De Paepe A, De
Moor B, Moreau Y, Marynen P, Fryns JP, Mortier G, Devriendt K,
Speleman F, Vermeesch JR. 2006. Emerging patterns of cryptic chromo-
somal imbalance in patients with idiopathic mental retardation and
published reports. J Med Genet 43:625–633.
MillerDT,Adam MP,AradhyaS,BieseckerLG,Brothman AR,CarterNP,
Church DM, Crolla JA, Eichler EE, Epstein CJ, Faucett WA, Feuk L,
Friedman JM, Hamosh A, Jackson L, Kaminsky EB, Kok K, Krantz ID,
Kuhn RM, Lee C, Ostell JM, Rosenberg C, Scherer SW, Spinner NB,
Stavropoulos DJ, Tepperberg JH, Thorland EC, Vermeesch JR, Wagg-
oner DJ, Watson MS, Martin CL, Ledbetter DH. 2010. Consensus
statement: Chromosomal microarray is a first-tier clinical diagnostic
lies. Am J Hum Genet 86:749–764.
CH, Reimschisel T, Roeder E, Malphrus AD, Eng PA, Hixson PM, Kang
of copy number variation in chromosome 16p13.11. Eur J Hum Genet
Nowakowska BA, Obersztyn E, Szymanska K, Bekiesinska-Figatowska M,
Scott DA, Cheung SW, Bohan TP, Stankiewicz P. 2010. Severe mental
retardation, seizures, and hypotonia due to deletions of MEF2C. Am J
Med Genet B Neuropsychiatr Genet 153B:1042–1051.
J, Zara F, Scheffer IE. 2010. Genetic testing in the epilepsies—Report of
the ILAE Genetics Commission. Epilepsia 51:655–670.
S, Chung WK, Marsh ED, Gentile M, Reggin JD, Wheless JW, Balasu-
bramanian S, Kumar R, Christian SL, Marini C, Guerrini R, Maltsev N,
Shaffer LG, Dobyns WB. 2011. Copy number variants and infantile
spasms: Evidence for abnormalities in ventral forebrain development
and pathways of synaptic function. Eur J Hum Genet 19:1238–1245.
epilepsy. Nat Rev Neurol 6:445–453.
A novel deletion in 2q24.1q24.2 in a girl with mental retardation and
generalized hypotonia: A case report. Mol Cytogenet 5:1.
2011. Translocation breakpoint at 7q31 associated with tics: Further
evidence for IMMP2L as a candidate gene for Tourette syndrome. Eur J
Hum Genet 19:634–639.
Petek E, Windpassinger C, Vincent JB, Cheung J, Boright AP, Scherer SW,
KroiselPM, WagnerK.2001.Disruption ofanovelgene(IMMP2L) bya
2011. 16p13.11 duplication is a risk factor for a wide spectrum of
neuropsychiatric disorders. J Hum Genet 56:541–544.
Ramocki MB, Bartnik M, Szafranski P, Kolodziejska KE, Xia Z, Bravo J,
zak T, Antczak-Marach D, Coldwell JG, Akman CI, McAlmon K, Cohen
E, Shaw CA, Cheung SW, Stankiewicz P. 2010. Recurrent distal 7q11.23
deletion including HIP1 and YWHAG identified in patients with intel-
10AMERICAN JOURNAL OF MEDICAL GENETICS PART B
lectual disabilities, epilepsy, and neurobehavioral problems. Am J Hum
Forster-Gibson C, Cilliers D, Hislop RG, Lamb A, Torchia B, Ballif BC,
Shaffer LG. 2010. Refinement of causative genes in monosomy 1p36
through clinical and molecular cytogenetic characterization of small
interstitial deletions. Am J Med Genet A 152A:1951–1959.
Ryan AK, Goodship JA, Wilson DI, Philip N, Levy A, Seidel H, Schuffen-
hauer S, Oechsler H, Belohradsky B, Prieur M, Aurias A, Raymond FL,
Clayton-Smith J, Hatchwell E, McKeown C, Beemer FA, Dallapiccola B,
Novelli G, Hurst JA, Ignatius J, Green AJ, Winter RM, Brueton L,
Brondum-Nielsen K, Scambler PJ, et al. 1997. Spectrum of clinical
features associated with interstitial chromosome 22q11 deletions: A
European collaborative study. J Med Genet 34: 798–804.
Kumada S, Nishiyama K, Nishimura A, Okada I, Yoshimura Y, Hirai S,
Kumada T, Hayasaka K, Fukuda A, Ogata K, Matsumoto N. 2008. De
novomutations in the geneencoding STXBP1 (MUNC18-1) cause early
infantile epileptic encephalopathy. Nat Genet 40:782–788.
Sanchez-Carpintero Abad R, Sanmarti Vilaplana FX, Serratosa Fernandez
JM. 2007. Genetic causes of epilepsy. Neurologist 13:S47–S51.
Shaikh TH, Gai X, Perin JC, Glessner JT, Xie H, Murphy K, O’Hara R,
Casalunovo T, Conlin LK, D’Arcy M, Frackelton EC, Geiger EA, Halde-
Dabaghyan E, Eckert A, Onyiah CC, Ostapenko S, Otieno FG, Santa E,
Shaner JL, Skraban R, Smith RM, Elia J, Goldmuntz E, Spinner NB,
Zackai EH, Chiavacci RM, Grundmeier R, Rappaport EF, Grant SF,
White PS, Hakonarson H. 2009. High-resolution mapping and analysis
of copy number variations in the human genome: A data resource for
clinical and research applications. Genome Res 19:1682–1690.
Drug Discov Today 13:760–770.
Shinawi M, Liu P, Kang SH, Shen J, Belmont JW, Scott DA, Probst FJ,
Craigen WJ, Graham BH, Pursley A, Clark G, Lee J, Proud M, Stocco A,
Rodriguez DL, Kozel BA, Sparagana S, Roeder ER, McGrew SG, Kurc-
AL, Cheung SW, Lupski JR. 2010. Recurrent reciprocal 16p11.2 rear-
rangements associated with global developmental delay, behavioural
Shinawi M, Schaaf CP, Bhatt SS, Xia Z, Patel A, Cheung SW, Lanpher B,
Nagl S, Herding HS, Nevinny-Stickel C, Immken LL, Patel GS, German
JR, Beaudet AL, Stankiewicz P. 2009. A small recurrent deletion within
15q13.3 is associated with a range of neurodevelopmental phenotypes.
Nat Genet 41:1269–1271.
Singh R, Gardner RJ, Crossland KM, Scheffer IE, Berkovic SF. 2002.
Chromosomal abnormalities and epilepsy: A review for clinicians and
gene hunters. Epilepsia 43:127–140.
Sisodiya SM, Mefford HC. 2011. Genetic contribution to common epi-
lepsies. Curr Opin Neurol 24:140–145.
Stankiewicz P, Beaudet AL. 2007. Use of array CGH in the evaluation of
dysmorphology, malformations, developmental delay, and idiopathic
mental retardation. Curr Opin Genet Dev 17:182–192.
TH, Xia Z, Pursley AN, Cooper ML, Shinawi M, Paciorkowski AR,
Martin AS, Madan-Khetarpal S, Hoover J, Medne L, Bonnemann CG,
Moeschler JB, Vallee SE,Parikh S,IrwinP, DalzellVP, Smith WE, Banks
VC, Flannery DB, Lovell CM, Bellus GA, Golden-Grant K, Gorski JL,
Kussmann JL, McGregor TL, Hamid R, Pfotenhauer J, Ballif BC, Shaw
repeats. Hum Mutat 33:165–179.
Striano P, Paravidino R, Sicca F, Chiurazzi P, Gimelli S, Coppola A,
Robbiano A, Traverso M, Pintaudi M, Giovannini S, Operto F, Vigliano
P, Granata T, Coppola G, Romeo A, Specchio N, Giordano L, Osborne
LR, Gimelli G, Minetti C, Zara F. 2011. West syndrome associated with
14q12 duplications harboring FOXG1. Neurology 76:1600–1602.
with lethal dwarfism and epilepsy. Genes Brain Behav 8:650–660.
Szafranski P, Schaaf CP, Person RE, Gibson IB, Xia Z, Mahadevan S,
Structures and molecular mechanisms for common 15q13.3 microdu-
plications involving CHRNA7: Benign or pathological. Hum Mutat
Tohyama J, Yamamoto T, Hosoki K, Nagasaki K, Akasaka N, Ohashi T,
Kobayashi Y, Saitoh S. 2011. West syndrome associated with mosaic
duplication of FOXG1 in a patient with maternal uniparental disomy of
chromosome 14. Am J Med Genet A 155A:2584–2588.
genetics of human epilepsy. Hum Mol Genet 14:Spec No. 2: 2491–2500.
Van Esch H, Bauters M, Ignatius J, Jansen M, Raynaud M, Hollanders K,
Lugtenberg D, Bienvenu T, Jensen LR, Gecz J, Moraine C, Marynen P,
cause of severe mental retardation and progressive neurological symp-
toms in males. Am J Hum Genet 77:442–453.
P, Harley V, Cools M, Looijenga L, Sinclair A. 2012. AQ12multi-exon
deletion within WWOX is associated with a 46,XY disorder of sex
development. Eur J Hum Genet. DOI: 10.1038/ejhg.2011.204.
Willemsen MH, Fernandez BA, Bacino CA, Gerkes E, de Brouwer AP,
Pfundt R, Sikkema-Raddatz B, Scherer SW, Marshall CR, Potocki L, van
as candidate genes for autism and variable cognitive impairment in the
novel 16q24.3 microdeletion syndrome. Eur J Hum Genet 18:429–
2009. 4.45 Mb microduplication in chromosome band 14q12 including
J Med Genet 52:440–442.
Holder SE, Zenker M, Rossier E, Grasshoff U, Johnson DS, Robertson L,
5q14.3q15microdeletion syndromeregion areafrequentcauseofsevere
mental retardation and diminish MECP2 and CDKL5 expression. Hum
BARTNIK ET AL.
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