ORIGINAL ARTICLE

CNTNAP2 gene dosage variation is associated with
schizophrenia and epilepsy
JI Friedman1,8, T Vrijenhoek2,8, S Markx3, IM Janssen2, WA van der Vliet2, BHW Faas2, NV Knoers2,

W Cahn4,5, RS Kahn4,5, L Edelmann1, KL Davis1, JM Silverman1, HG Brunner2, A Geurts van Kessel2,

C Wijmenga6,7, RA Ophoff5,6 and JA Veltman2

1Departments of Psychiatry and Human Genetics, Mount Sinai School of Medicine, New York, NY, USA; 2Department of
Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen,
The Netherlands; 3Department of Psychiatry, Columbia University, New York, NY, USA; 4Department of Psychiatry, Utrecht
University, Utrecht, The Netherlands; 5Rudolf Magnus Institute of Neuroscience, Utrecht University, Utrecht, The Netherlands;
6Department of Medical Genetics, Utrecht University, Utrecht, The Netherlands and 7Department of Genetics, University
Medical Centre Groningen, Groningen, The Netherlands

A homozygous mutation of the CNTNAP2 gene has been associated with a syndrome of focal
epilepsy, mental retardation, language regression and other neuropsychiatric problems in
children of the Old Order Amish community. Here we report genomic rearrangements resulting
in haploinsufficiency of the CNTNAP2 gene in association with epilepsy and schizophrenia.
Genomic deletions of varying sizes affecting the CNTNAP2 gene were identified in three non-
related Caucasian patients. In contrast, we did not observe any dosage variation for this gene
in 512 healthy controls. Moreover, this genomic region has not been identified as showing
large-scale copy number variation. Our data thus confirm an association of CNTNAP2 to
epilepsy outside the Old Order Amish population and suggest that dosage alteration of this
gene may lead to a complex phenotype of schizophrenia, epilepsy and cognitive impairment.
Molecular Psychiatry (2008) 13, 261–266; doi:10.1038/sj.mp.4002049; published online 24 July 2008

Keywords: epilepsy; schizophrenia; CNTNAP2; copy number variation

Introduction

Investigations of complex brain disorders such as
schizophrenia (MIM 181500) and epilepsy have
demonstrated considerable heterogeneity of the ge-
netic and pathophysiological components of these
illnesses. Moreover, the phenotypic manifestations of
schizophrenia are numerous and variable, and may
include delusions, disordered thought, hallucina-
tions, negative symptoms, and cognitive and func-
tional impairment.1 In addition, many distinct
epilepsy syndromes do exist, which are defined by
seizure characteristics, location and age of onset.
These factors have complicated the identification of
genes and their products that serve as vulnerability
factors for these disorders. Linkage and association
studies have yielded several candidate genes for
schizophrenia2,3 and epilepsy,4 but despite these
successes the genetic mechanisms underlying the

comprehensive pathophysiology of these brain dis-
orders remain poorly understood.
Technical developments in microarray-based gen-

ome profiling have facilitated the routine genome-
wide detection of genomic copy number variation
(CNV) with a resolution of up to B100 kb.5,6 As a
result, subtle CNVs have been linked to the patho-
genesis of a number of diseases, ranging from rare
monogenic to complex disorders.7–14 Moreover, lim-
ited evidence suggests a role for CNVs in the
susceptibility to psychiatric disease such as schizo-
phrenia.15

In the current study, we used both genome-wide
and targeted genomic approaches to investigate CNVs
in patients with epilepsy and schizophrenia. These
approaches revealed the presence of unique CNVs on
chromosome 7q34–36.1 in three unrelated patients
with epilepsy and schizophrenia, all affecting the
CNTNAP2 gene. CNTNAP2 variation has previously
been associated with epilepsy,16 but not with schizo-
phrenia. CNTNAP2 encodes Caspr2 (contactin-asso-
ciated protein 2), a member of the neurexin
superfamily, a group of transmembrane proteins that
mediate cell–cell interactions in the nervous system.
Caspr2 is predominantly expressed in the nervous
system in the juxtaparanodal region of axons of
myelinated neurons and in oligodendrocytes.17

Received 10 April 2007; revised 14 June 2007; accepted 27 June
2007; published online 24 July 2008

Correspondence: Dr JA Veltman, Department of Human Genetics,
Nijmegen Center for Molecular Life Sciences, Radboud University
Nijmegen Medical Center, Geert Grooteplein 10, PO Box 9101,
6500 HB Nijmegen, The Netherlands.
E-mail: j.veltman@antrg.umcn.nl
8These authors contributed equally to this work.

Molecular Psychiatry (2008) 13, 261–266
& 2008 Nature Publishing Group All rights reserved 1359-4184/08 $30.00

www.nature.com/mp

http://dx.doi.org/10.1038/sj.mp.4002049
mailto:j.veltman@antrg.umcn.nl
http://www.nature.com/mp


Caspr2 is essential for the localization of voltage-
activated Kþ channels in the juxtaparanodal region of
axons, which may function to stabilize conduction
and help to maintain the intermodal resting poten-
tial.18 Targeted disruption of Caspr2 results in marked
reduction in the accumulation of Kþ channels at
the juxtaparanodes in both central and peripheral
nervous systems.19

This is the first study demonstrating an association
between the CNTNAP2 gene and schizophrenia.
Moreover, this study is the first to demonstrate the
presence of dosage variations at this gene, resulting in
both epilepsy and schizophrenia.

Materials and methods

Patient material
Genomic DNA from ethylenediaminetetraacetic acid
venous blood was obtained from three independent
sources. Patient 1 was brought to the diagnostics
department at the Radboud University Nÿmegen
Medical Center for routine karyotyping with a clinical
presentation of severe mental retardation, epilepsy
and language development problems among other
findings (see Table 1 for details). Patient 2, who
presented with schizophrenia and epilepsy, was
identified from a cohort of 23 patients with syndro-
mal schizophrenia (for example schizophrenia ac-
companied by numerous minor physical anomalies,
mental retardation, seizure disorder and other med-
ical problems) recruited from Pilgrim Psychiatric
Center, W Brentwood, NY, USA, and referred to the
Department of Human Genetics, Radboud University
Nijmegen Medical Centre for array-based comparative
genomic hybridization (array CGH) analysis. Patient 3
was identified from a cohort of 312 schizophrenic
patients recruited at the Department of Psychiatry,
Utrecht University, the Netherlands for targeted single
nucleotide polymorphism (SNP) array analysis. These
were analyzed together with 312 healthy individuals
of Dutch origin as a control set. The cohorts were
collected following institutional review board ap-
proval and after obtaining signed informed consent.

Array-based comparative genomic hybridization
Array CGH was performed as described previously10

using a tiling-resolution BAC array. All data were
mapped on the National Center for Biotechnology
Information (NCBI) build 35 of the UCSC Genome
Browser hg 17 (http://genome.ucsc.edu/).

Singe nucleotide polymorphism assay
To assess genetic variation in the genomic region
around CNTNAP2, we developed a targeted SNP
assay for the Illumina GoldenGate Bead Array
(Illumina Inc., San Diego, CA, USA). The assay
consisted of 194 haplotype-tagging SNPs in the
CNTNAP2 locus (chromosome 7: 145 444 787–
148 582 400; NCBI build 35 of the UCSC Genome
Browser hg17 (http://genome.ucsc.edu/); average spa-
cing between two SNPs was 16 kb). We performed a

straightforward w2 test for association of individual
SNPs with schizophrenia. We also checked for copy
number changes by simultaneous measurement of
both signal intensity variations (log2 R) and changes
in allelic composition.20

Multiplex ligation-dependent probe amplification
To confirm the microarray analysis, samples were
screened with multiplex ligation-dependent probe
amplification (MLPA), essentially as described pre-
viously.21 MLPA probes were designed for exons 2, 3,
4, 5, 14, 24 (one probe for each exon) and intron 3 of
CNTNAP2 (three different probes), and for exon 3 of
PDIA4 and exon 14 of NOS3 (one probe for each exon
of both). Sequences of test and control probes are in
Supplementary Table S1. Probes were developed in
accordance with a protocol provided by MRC-Holland
(Amsterdam, The Netherlands). Ten probes were
combined in one MLPA assay, in combination with
three standard control probes. Equal amounts of
probe mix and hybridization buffer were added to
100–200 ng of DNA from each sample, followed by
heat denaturation and overnight incubation at 601C.
Ligation products were amplified by regular PCR with
the use of a 6-FAM-labeled primer set. Amplification
products were identified and quantified by capillary
electrophoresis on an ABI 3730 genetic analyzer
(Applied Biosystems, Foster City, CA, USA). Data
were normalized by dividing each probe’s signal
strength by the average signal strength of the sample.
This normalized peak pattern was divided by the
average peak pattern of all samples in the same
experiment. Values for control wild-type peaks were
centered at 1.0. A copy number loss was defined as
that below a fixed threshold value of 0.7.

Fluorescent in situ hybridization analysis
Fluorescent in situ hybridization (FISH) experiments
were performed for de novo checking on metaphase
spreads prepared from patient-derived lymphoblast
cell lines using routine procedures. Probe labeling,
slide preparation and hybridization were carried out
as described elsewhere,14 using probes listed in
Supplementary Table S2.

Sequence analysis
To sequence all 24 exons of the CNTNAP2 gene, we
designed primers in the intronic region surrounding
each exon using Primer3,22 and performed standard
PCR reactions. Primer sequences and conditions are
in Supplementary Table S3.

Results

We identified a hemizygous deletion involving chro-
mosome region 7q34–7q36.1 in patient 1 by routine
chromosome analysis (data not shown). Patient 1 is a
severely mentally retarded 21-year-old Caucasian
male born to healthy non-consanguineous parents.
No other family members were reported to have
mental retardation or epilepsy. At the age of 2, the

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262

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http://genome.ucsc.edu/
http://genome.ucsc.edu/


patient suffered from seizures, first noticed by the
parents and later confirmed by electroencephalogram
(EEG). Anticonvulsant medication (carbamazepine)
was initiated and has remained necessary until today
(Table 1). We confirmed this deletion by using both
FISH and MLPA (Figure 1b). FISH analysis of both
parents failed to reveal any chromosome 7 aberra-
tions, indicating that the deletion occurred de novo in
the patient. We also used tiling-resolution genome-
wide array CGH to characterize the deletion in detail
(Figure 1a). By doing so, we found this deletion to be
10.7 Mb in size and to encompass 58 known genes, of
which only EPHB6, EZH2 and CNTNAP2 are ex-
pressed in the brain.

We identified a second hemizygous deletion invol-
ving CNTNAP2 in patient 2 by tiling-resolution array

CGH. This 1.5 Mb deletion was identified at the 7q35–
7q36.1 locus and was found to encompass four genes:
CUL1, EZH2, PDIA4 and CNTNAP2 (Figure 1c). The
microdeletion was confirmed by MLPA analysis
(Figure 1b). The patient is a 50-year-old Caucasian
female diagnosed with schizophrenia (age of on-
set = 18), epilepsy and severe cognitive impairment
as indicated by a WAIS III full-scale intelligence
quotient (IQ) = 63 (Table 1). She completed 10 years of
mainstream education and was assessed to have a pre-
morbid IQ = 94 (derived from WRAT-R Reading score),
indicating a significant decrement in cognitive ability
subsequent to the onset of schizophrenia. She also
experienced a significant deterioration in communi-
cative and self-care abilities requiring prolonged
institutionalization. Her mother and both of the

Table 1 Overview of clinical characteristics of the three patients with a deletion in chromosome 7q34–7q36.1

Patient 1 Patient 2 Patient 3

Deletion
Size 11 Mb 1.5 Mb 220 kb
Number of genes 58 4 1
Inheritance De novo Unknown Unknown; healthy sister does

not show deletion

Patient details
Gender Male Female Female
Year of birth 1979 1955 1973
Ethnicity Caucasian Caucasian Caucasian

Status at birth Premature birth, severe
respiratory problems,
neonatal sepsis

Normal Premature birth, dizygotic
twin, severe respiratory
problems

Family history
Schizophrenia — — Aunt with bipolar disorder
Epilepsy — — Father’s cousin with epilepsy
Physical illness — Mother and two maternal

aunts with chronic severe
mental illness

Epilepsy
Age of first seizure 2 34 16
Type Focal right frontotemporal

epilepsia with secondary
generalization

General tonic-clonic seizure Brainstem regulation disorder

EEG Slow theta/delta Dysrythmic theta/delta Not determined
Therapy Carbamazepine Dilantin None

Schizophrenia
Age of onset Could not be determined 18 21
Type Paranoid Paranoid

Other features
Speech Almost absent Deteriorated Normal
Cognitive abilities Severe mental retardation Progressive cognitive

deterioration, IQ = 63 at
ascertainment

Normal IQ

Additional features Severely delayed
psychomotor development

Difficulties in
communication

Autistic features Mild cerebral atrophy

Abbreviations: EEG, electroencephalogram; IQ, intelligence quotient.

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mother’s siblings suffered from unspecified chronic
psychiatric illnesses requiring prolonged institutio-
nalization. All three of this patient’s male siblings
were free from psychiatric illness. At age 34, the
patient experienced her first and only-documented
seizure, characterized as generalized tonic-clonic. Her
EEG (16 channel) demonstrated slow dysrythmia in
theta and occasional delta, predominantly in the
frontal area (Table 1).

The above results prompted us to assess further
genetic variation in the minimal deleted region using
a targeted SNP assay. We genotyped the cohort of
312 patients with schizophrenia and a cohort of 312

Dutch control subjects for 194 haplotype-tagging
SNPs in the CNTNAP2 locus. The w2 test for
association revealed no SNP to be significantly
(P < 0.05) associated with schizophrenia. However, a
detailed copy number analysis of all data revealed a
hemizygous deletion involving CNTNAP2 in one
patient from the cohort of 312 schizophrenic patients
(patient 3), represented by 15 consecutive homo-
zygous SNPs with an average log2 R-value of �0.42
(Figure 1a). Subsequent MLPA analysis confirmed the
deletion, which encompasses 220 kb and affects only
intron 3 of the CNTNAP2 gene (Figure 1b). The
patient is a 32-year-old Caucasian female diagnosed

Figure 1 Genomic deletions of the CNTNAP2 locus in chromosome 7 in three patients. (a) Microarray-based chromosome 7
profiles for patients 1–3. The profiles for patients 1 and 2 were obtained from tiling-path resolution genome-wide arrays
containing 32 447 human BAC clones, indicated by small circles. These represent the log 2-transformed and normalized test-
over-reference intensity ratios. The clones are ordered from pter – qter on the basis of physical-mapping positions obtained
from NCBI build 35 of the UCSC genome browser hg17 http://genome.ucsc.edu/. The normalized ratios were analyzed for
loss and gain regions by a standard hidden Markov model,23 as indicated by the red line. The profiles show the 10.7 Mb
deletion of chromosomal region 7q34–7q36.1 in patient 1, and the 1.5 Mb deletion of chromosomal region 7q35–7q36.1 in
patient 2. The profile for patient 3 was obtained from an array that contained 194 haplotype-tagging SNPs in the CNTNAP2
locus, indicated by small circles. In the upper profile, the circles represent the log 2-transformed total intensity ratio log2 R of
both variants of an SNP. In the lower profile, they represent the B-allele frequency of the SNPs. The 220 kb deletion in
CNTNAP2 is represented by a simultaneous decrease in log2 R and shift from heterozygous to homozygous state of the SNPs.
(b) MLPA confirmation of the deletions in CNTNAP2 in all three patients. Different probe sets were used to confirm the
deletions, which varied in size. (c) Schematic overview of the deletions in all three patients. For each patient, the deleted
genomic region is shown in red. MLPA, multiplex ligation-dependent probe amplification; SNP, single nucleotide
polymorphism.

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with schizophrenia who suffered from epileptic
seizures starting from age 16. Her IQ is reported as
normal. Family history revealed one aunt with bipolar
disorder and a paternal cousin with epilepsy (Table
1). Analysis of the healthy dizygotic twin sister of the
patient did not reveal any deletion at this locus
(Figure 1b).

No CNVs larger than 10 kb have been reported in
the 7q34–7q36.1 chromosomal region, in which all
deletions observed in the present study occurred (see
the Database of Genomic Variants; http://projects.t-
cag.ca/variation/). In addition, we did not observe any
deletions in our cohort of 312 healthy controls tested
on the targeted SNP array, nor in an additional cohort
of 100 healthy individuals analyzed by MLPA. More-
over, no CNV has been observed at this genomic locus
in more than 500 mentally retarded patients and 100
unaffected parental samples tested on tiling-resolu-
tion BAC arrays in the diagnostics laboratory at the
Radboud University Nijmegen Medical Centre. Se-
quence analysis of all 24 exons of the CNTNAP2 gene
revealed no additional mutations in these three
patients.

Discussion

Recently, a syndrome characterized by focal epilepsy,
macrocephaly, diminished deep tendon reflexes,
mental retardation and other neuropsychiatric dis-
turbances (designated as cortical dysplasia-focal
epilepsy syndrome) was described in association
with a homozygous mutation of the CNTNAP2 gene
in Old Order Amish children.16 The results of the
present study demonstrate an association between
dosage variation of the CNTNAP2 gene and epilepsy
outside the Old Order Amish community. Sequence
analysis of all 24 exons of the CNTNAP2 gene in all
three patients revealed no mutation in the remaining
allele, indicating that haploinsufficiency of this gene
leads to the disease. Given that these deletions are not
common events nor located in identified regions of
high CNV,5,6 these findings are unlikely to be coin-
cidental. Moreover, unlike the neuropsychiatric pre-
sentation suggestive of a pervasive development
disorder in the Amish children with a homozygous
mutation of CNTNAP2,16 two out of three subjects in
the present study presented with a diagnosis of
schizophrenia. To our knowledge, this is the first
report of an association between the CNTNAP2 gene
and schizophrenia. However, it is noteworthy that a
chromosomal translocation disrupting the CNTNAP2
locus seems to result in Gilles de la Tourette
syndrome (MIM 137580) and obsessive compulsive
disorder,24 although the causality of this translocation
was recently questioned.25 CNTNAP2 plays a role
in the organization of myelinated axons,17,19 and its
disruption affects neuroblast migration.16 Interest-
ingly, brains of schizophrenic patients show evidence
for myelin-related dysfunction26 and aberrant neuro-
nal migration.27,28 This may explain the observed

association between CNTNAP2 disruptions and sus-
ceptibility to schizophrenia.
Although the three patients in the present study

showed moderate clinical overlap, they exhibited
differences that may be related to the varying size of
the deletion. The deletion in patient 1 affected 57
other genes in addition to CNTNAP2. The more
severe phenotype observed in this patient as com-
pared to the other two (for example severe mental
retardation, multiple epileptic seizures, severely
delayed psychomotor development) may be the result
of an additive effect of one or more of these other
genes. Because of the severe mental retardation and
inability to communicate, a diagnosis of schizophre-
nia could not be determined in this patient. Similarly,
the deletion in patient 2 encompasses four additional
genes, among which are the Cullin-1 (CUL1) and
Enhancer of Zeste Homolog 2 (EZH2) genes, which
are involved in protein ubiquitination and histone
methylation, respectively.29,30 Although these genes
have been reported to be only indirectly involved in
brain function,29,30 they might have also contributed
to the phenotype of this patient. Patient 3 had the
smallest deletion encompassing only intron 3 of the
CNTNAP2 gene, and presented with the least severe
phenotype (normal IQ, normal speech and higher
levels of functioning), which still included epilepsy
and schizophrenia. Although no exons were affected
in the CNTNAP2 deletion found in patient 3,
regulatory motifs within this region may have affected
the expression of the CNTNAP2 gene. Alternatively,
there are examples of enhancers that act over long
distances, affecting other genes than those in which
they reside.31 Further functional analysis of this
intronic CNTNAP2 deletion was not possible in this
patient, owing to the restricted pattern of CNTNAP2
expression in the nervous system.17

Our study and that of others16 indicate that rare
point mutations and/or dosage variation at the
CNTNAP2 gene can cause both neurological and
psychiatric disorders. Examples of other rare muta-
tions of genes resulting in variable expression of
neurologic and psychiatric disease include mutations
in the KCNN3 gene32 as well as the SYNGR1 gene33 in
schizophrenia, and the association of rare variants of
the KCC3 gene with bipolar disorder.34 On the other
hand, CNV of genes in the 22q11 region, which results
in velo-cardio-facial syndrome, produces develop-
mental neurologic abnormalities and is one of the
most common known genetic risk factors for the
development of schizophrenia.35

In conclusion, this study confirms the recently
reported association between the CNTNAP2 gene
and epilepsy in patients outside the Old Order
Amish community and demonstrates an association
between CNTNAP2 and schizophrenia. Our results
highlight CNTNAP2 as a strong candidate gene for
epilepsy and schizophrenia. The results further
support the notion that CNV is a potentially important
source of genetic susceptibility to both complex brain
diseases.

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http://projects.tcag.ca/variation/
http://projects.tcag.ca/variation/


Acknowledgments

We thank R van’t Slot, E Strengman and D Lugtenberg
for their technical support. This work was supported
by grants from the Netherlands Organization for
Health Research and Development (to JAV, ZonMW
912-04-047 and 917-66-363) and Grant P50 MH
66392-01 awarded by the NIMH to Kenneth Davis.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://
www.nature.com/mp)

CNTNAP2 deletions
JI Friedman et al

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Molecular Psychiatry

http://www.nature.com/mp
http://www.nature.com/mp

	CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy
	Introduction
	Materials and methods
	Patient material
	Array-based comparative genomic hybridization
	Singe nucleotide polymorphism assay
	Multiplex ligation-dependent probe amplification
	Fluorescent in situ hybridization analysis
	Sequence analysis

	Results
	Discussion
	Acknowledgements
	Note
	References