Children's Hospital Boston Genotype Phenotype Study Group: Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders

Division of Developmental Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.42). 06/2010; 153B(4):937-47. DOI: 10.1002/ajmg.b.31063
Source: PubMed


Research has implicated mutations in the gene for neurexin-1 (NRXN1) in a variety of conditions including autism, schizophrenia, and nicotine dependence. To our knowledge, there have been no published reports describing the breadth of the phenotype associated with mutations in NRXN1. We present a medical record review of subjects with deletions involving exonic sequences of NRXN1. We ascertained cases from 3,540 individuals referred clinically for comparative genomic hybridization testing from March 2007 to January 2009. Twelve subjects were identified with exonic deletions. The phenotype of individuals with NRXN1 deletion is variable and includes autism spectrum disorders, mental retardation, language delays, and hypotonia. There was a statistically significant increase in NRXN1 deletion in our clinical sample compared to control populations described in the literature (P = 8.9 x 10(-7)). Three additional subjects with NRXN1 deletions and autism were identified through the Homozygosity Mapping Collaborative for Autism, and this deletion segregated with the phenotype. Our study indicates that deletions of NRXN1 predispose to a wide spectrum of developmental disorders.


Available from: Rachel Hundley
Deletions of NRXN1 (Neurexin-1) Predispose to a
Wide Spectrum of Developmental Disorders
Michael S.L. Ching,
Yiping Shen,
Wen-Hann Tan,
Shafali S. Jeste,
Eric M. Morrow,
Xiaoli Chen,
Nahit M. Mukaddes,
Seung-Yun Yoo,
Ellen Hanson,
Rachel Hundley,
Christina Austin,
Ronald E. Becker,
Gerard T. Berry,
Katherine Driscoll,
Elizabeth C. Engle,
Sandra Friedman,
James F. Gusella,
Fuki M. Hisama,
Mira B. Irons,
Tina Lafiosca,
Elaine LeClair,
David T. Miller,
Michael Neessen,
Jonathan D. Picker,
Leonard Rappaport,
Cynthia M. Rooney,
Dean P. Sarco,
Joan M. Stoler,
Christopher A. Walsh,
Robert R. Wolff,
Ting Zhang,
Ramzi H. Nasir,
* Bai-Lin Wu
** on behalf of the Children’s Hospital Boston
Genotype Phenotype Study Group
Division of Developmental Medicine, Children’s Hospital Boston, Boston, Massachusetts
Harvard Medical School, Boston, Massachusetts
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
Division of Genetics, Children’s Hospital Boston, Boston, Massachusetts
Department of Neurology, Children’s Hospital Boston, Boston, Massachusetts
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island
Department of Laboratory Medicine, Children’s Hospital Boston, Boston, Massachusetts
Department of Molecular Immunology, Capital Institute of Pediatrics, Beijing, China
Istanbul Faculty of Medicine, Department of Child Psychiatry, Istanbul University, Istanbul, Turkey
Children’s Hospital Boston, Howard Hughes Medical Institute, Boston, Massachusetts
Manton Center for Orphan Disease Research, Children’s Hospital Boston, Boston, Massachusetts
Department of Ophthalmology, Children’s Hospital Boston, Boston, Massachusetts
Department of Genetics, Harvard Medical School, Boston, Massachusetts
Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Children’s Hospital and Institutes of Biomedical Science, Fudan University, Shanghai, China
Received 1 July 2009; Accepted 15 December 2009
Additional Supporting Information may be found in the online version of
this article.
The Children’s Hospital Boston Genotype Phenotype Study Group also
includes Omar S. Khwaja, Annapurna Poduri, Mustafa Sahin and Magdi
Sobeih, Department of Neurology, Children’s Hospital Boston, Harvard
Medical School, Boston, Massachusetts.
Grant sponsors: Nancy Lurie Marks Family Foundation; Simons
Foundation; Autism Speaks; NIH; Grant numbers: 5K23MH080954-02,
M.S.L. Ching and Y. Shen contributed equally to this work.
*Correspondence to:
Ramzi H. Nasir, Division of Developmental Medicine, Children’s Hospital
Boston, Harvard Medical School. 300 Longwood Ave., Boston, MA 02115.
**Correspondence to:
Bai-Lin Wu, Departments of Laboratory Medicine and Pathology,
Children’s Hospital Boston, Harvard Medical School. 300 Longwood
Ave., Boston, MA 02115. E-mail:
Published online 7 April 2010 in Wiley InterScience
DOI 10.1002/ajmg.b.31063
2010 Wiley-Liss, Inc. 937
Neuropsychiatric Genetics
Page 1
Research has implicated mutations in the gene for neurexin-1
(NRXN1) in a variety of conditions including autism, schizo-
phrenia, and nicotine dependence. To our knowledge, there have
been no published reports describing the breadth of the pheno-
type associated with mutations in NRXN1. We present a medical
record review of subjects with deletions involving exonic
sequences of NRXN1. We ascertained cases from 3,540 individ-
uals referred clinically for comparative genomic hybridization
testing from March 2007 to January 2009. Twelve subjects were
identified with exonic deletions. The phenotype of individuals
with NRXN1 deletion is variable and includes autism spectrum
disorders, mental retardation, language delays, and hypotonia.
There was a statistically significant increase in NRXN1 deletion
in our clinical sample compared to control populations
described in the literature (P ¼ 8.9 10
). Three additional
subjects with NRXN1 deletions and autism were identified
through the Homozygosity Mapping Collaborative for Autism,
and this deletion segregated with the phenotype. Our study
indicates that deletions of NRXN1 predispose to a wide spectrum
of developmental disorders.
2010 Wiley-Liss, Inc.
Key words: NRXN1 (neurexin-1); developmental disorders;
array CGH; NRXN1 exonic deletions; CNV
Neurexins are a group of highly polymorphic cell surface proteins
involved in synapse formation and signaling [Ushkaryov et al.,
1992; Missler and Sudhof, 1998; Missler et al., 2003; Graf et al., 2004;
Nam and Chen, 2005]. There are three human neurexin genes
(NRXN1, NRXN2, and NRXN3), each of which has two indepen-
dent promoters resulting in an a and a b neurexin for each gene
[Ushkaryov et al., 1992; Ichtchenko et al., 1996]. Multiple alterna-
tive splicing leads to the possibility of greater than a thousand
distinct neurexin isoforms [Ullrich et al., 1995]. Their expression is
believed to be spatially and temporally regulated throughout
development [Puschel and Betz, 1995; Zeng et al., 2006].
Structure and Function of NRXN1
NRXN1, located on chromosome 2p16.3, is one of the largest
known human genes (1.1 Mb with 24 exons) [Tabuchi and Sudhof,
2002]. It is subject to relatively frequent disruption including
missense changes, translocation, whole gene deletion, and intra-
genic copy number alterations [Feng et al., 2006; Szatmari et al.,
2007; International Schizophrenia Consortium, 2008; Kim et al.,
2008; Kirov et al., 2008; Marshall et al., 2008; Morrow et al., 2008;
Yan et al., 2008; Zahir et al., 2008; Glessner et al., 2009; Rujescu et al.,
The longer transcript, NRXN1-a, encodes an N-terminal signal
peptide with three repeats of two laminin/neurexin/sex hormone-
binding globulin (LNS) domains separated by an EGF-like
sequence (Fig. 1). Following these repeats, there is an O-glycosyla-
tion sequence, a transmembrane domain, and a cytoplasmic tail of
55 amino acids.
Neurexin-1-a has been shown to interact with certain neuroligin
isoforms and neurexin-binding proteins known as neurexophilins.
This presynaptic molecule is also required for calcium-triggered
neurotransmitter release and the function of voltage-gated calcium
channels in the synapses of the brainstem and neocortex [Missler
et al., 2003; Zhang et al., 2005; Dudanova et al., 2006]. Mouse
knockouts of all three a-neurexin genes do not demonstrate
major abnormalities of axonal pathfinding during development
[Dudanova et al., 2007], although synaptic function is severely
impaired. Mice with knockouts of individual a-neurexin genes
have modestly decreased postnatal viability, while double knockout
mice have greatly decreased postnatal survival. Triple knockout
mice do not survive past the first day of life [Missler et al., 2003].
Neurexin-1-b is much shorter than Neurexin-1-a, as five of the
six LNS domains and the intervening EGF sequences are replaced
with a short b-neurexin-specific sequence (Fig. 1) [Missler and
Sudhof, 1998]. Neurexin-1-b has been shown to interact with the
postsynaptic neuroligin family of cell adhesion molecules and
dystroglycans [Ichtchenko et al., 1995; Sugita et al., 2001; Arac
et al., 2007; Comoletti et al., 2007; Chen et al., 2008]. No mouse
models with knockouts of NRXN1-b, alone or in combination with
NRXN1-a, have yet been analyzed [Sudhof, 2008]. For each of
Neurexin-1-a and Neurexin-1-b, multiple protein coding isoforms
of NRXN1 have been identified, whose structure and functions are
not well understood.
NRXN1 Mutations in Humans
There is increasing evidence that NRXN1 disruptions [Kim et al.,
2008], point mutations [Feng et al., 2006; Yan et al., 2008], and
deletions [Glessner et al., 2009; Marshall et al., 2008; Morrow et al.,
2008; Szatmari et al., 2007] are associated with autism spectrum
disorders. NRXN1 has also been found to be associated with autism
in a large genome-wide single nucleotide polymorphism associa-
tion study [Wang et al., 2009].
NRXN1 deletions have also been associated with a variety
of other conditions including schizophrenia [International
Schizophrenia Consortium, 2008; Kirov et al., 2008; Vrijenhoek
et al., 2008; Walsh et al., 2008; Need et al., 2009; Rujescu et al., 2009],
nicotine dependence [Bierut et al., 2007; Nussbaum et al., 2008],
How to Cite this Article:
Ching MSL, Shen Y, Tan W-H, Jeste SS,
Morrow EM, Chen X, Mukaddess NM, Yoo
S-Y, Hanson E, Hundley R, Austin C, Becker
RE, Berry GT, Driscoll K, Engle EC, Friedman
S, Gusella JF, Hisama FM, Irons MB, Lafiosca
T, LeClair E, Miller DT, Neessen M, Picker JD,
Rappaport L, Rooney CM, Sarco DP, Stoler
JM, Walsh CA, Wolff RR, Zhang T, Nasir RH,
Wu B-L, on behalf of the Children’s Hospital
Boston Genotype Phenotype Study Group.
2010. Deletions of NRXN1 (Neurexin-1)
Predispose to a Wide Spectrum of
Developmental Disorders.
Am J Med Genet Part B 153B:937947.
Page 2
and other physical manifestations such as vertebral anomalies
[Zahir et al., 2008].
Prior reports of abnormalities in NRXN1 have focused on
populations with specic diagnoses (e.g., autism, schizophrenia).
However, the clinical signicance of copy number variants (CNV),
such as deletion involving one or more exons of NRXN1, and the
range of phenotypic manifestations of subjects with NRXN1 dele-
tion CNV remains unclear. We describe here a group of subjects
with NRXN1 deletions who demonstrate a wide range of physical
and developmental phenotypes.
Clinical Cohort Record Review
From March 2007 to January 2009, a total of 3,540 subjects at
Childrens Hospital Boston were evaluated for genomic imbalance
(deletion and duplication) using the Agilent 244K human genome
oligonucleotide comparative genomic hybridization (CGH) mi-
croarrays (G4411B, Agilent Technologies, Palo Alto, CA) according
to the manufacturers instructions [Oligonucleotide Array-Based
CGH for Genomic DNA Analysis protocol version 3 (Agilent
Technologies)]. The majority of the referrals were for clinical
features of developmental disorders (developmental delay, autism
spectrum disorders, mental retardation) or multiple congenital
malformations as determined by specialists in Clinical Genetics,
Neurology, and Developmental Medicine.
One hundred thirty probes cover the 1.12 Mb region of the
NRXN1 gene on the Agilent 244K CGH array. The average interp-
robe space within the NRXN1 gene is 8.6 kb. This permits the
reliable detection of small intragenic deletions down to 43 kb in size.
Images were captured by Agilent scanner and quantied using
Feature Extraction software v9.0 (Agilent Technologies). CGH
Analytics Software v3.4 (Agilent Technologies) was subsequently
used for data normalization, quality evaluation and data visualiza-
tion. Copy number aberration was indicated using the Aberration
Detection Method 2 (ADM-2) algorithm. Deletions involving ve
or more consecutive probes were considered as true CNV.
For two larger deletions, uorescent in situ hybridization (FISH)
testing using probe RP11-800C7 was carried out for deletion
conrmation and parental testing. The smaller deletions were
conrmed by PCR-based breakpoint mapping methods. The pri-
mers used for each case are listed in the Supplementary Material.
Subjects with deletions involving exonic sequence of NRXN1
were included in our review. Two developmental behavioral pedia-
tricians (RHN, MSLC), a clinical geneticist (WHT), and a pediatric
neurologist (SSJ) reviewed each of the medical records. The clinical
history, physical examination, laboratory data, and radiological
reports of each subject were reviewed.
Additional Report of Cases With NRXN1 Deletion
and Autism
Cases with exonic and intragenic NRXN1 deletions were also
contributed from the Homozygosity Mapping Collaborative for
Autism (HMCA) which utilized the Affymetrix GeneChip Human
Mapping 500K Array Set using CNV detection methods previously
described [Morrow et al., 2008].
This work was approved by the Institutional Review Boards at
the corresponding hospitals.
Clinical Cohort Record Review
We identied 12 subjects through Childrens Hospital Boston with
deletions involving exonic sequences of NRXN1 (Table I and Fig. 1).
The deletions reported here range from 65 kb to 5 Mb and most of
these cases are predicted to affect the initial structural domains of
the protein (Fig. 1).
FIG. 1. Illustrates the size and range of the 12 deletion CNVs in relation to the exons and protein domains of NRXN1-a and -b in the UCSC Genome
Browser ( [Kent et al.,2002].Thetop track showsthe genomic position and size ofthe 12 deletion CNVs.The middle tracks
show the gene annotations in RefSeq and Ensembl. The Refseq Genes show the a and b isoforms of the NRXN1 gene; the Ensembl gene prediction
shows several other minor isoforms of the NRXN1 gene. The bottom panel shows the protein domains of the NRXN1-a gene product. SP, signal
peptide; LNS, laminin/neurexin/sexhormone-binding globulin domain; EGF, epithelium growthfactor like domain;OS, O-glycosylation sequence; TM,
transmembrane domain; CT, cytoplasmic tail. tail. [Color gure can be viewed in the online issue, which is available at]
Page 3
TABLE I. Deletions Within NRXN1 in Our Sample
Patient Deletion location (hg18 build)
Size of
deletion (kb) Inheritance Exonsintrons deleted
Other genetic tests and results
(additional imbalance) Indication for testing
1 46,938,68552,015,885 5,077 Maternal FISH normal; paternal
study unavailable
All Karyotyping and Fragile X test: normal
(contiguous deletion including
Moderate mental retardation FISH
2 50,128,25654,050,713 3,923 De novo All except the last two exons None Global developmental delays,
suspected autism
3 50,897,00251,212,385 315 Paternal Exon 15; partial intron 5 Karyotyping and chromosome 15
methylation: normal
Gross motor delay, hypotonia PCR
4 50,936,91451,167,934 231 Paternal Exon 15; partial intron 5 Karyotyping, fragile X test,
mutation test: normal
PDD-NOS, hypotonia PCR
5 50,920,08251,059,469 139 De novo Exon 3, 4, 5; partial introns 2, 5 None VACTERL Not done
6 51,059,41051,316,396 257 Maternal Exon 1, 2; partial intron 2 Karyotyping and fragile X test: normal PDD-NOS, motor coordination
7 51,090,50451,212,385 122 Paternal Exon 13; partial intron 3 Karyotyping, Fragile X test, and
mutation test: normal
Autism, moderate mental
8 50,522,89250,827,767 305 De novo Exon 617; partial introns 5, 17
Fragile X test: normal (deletion at 3p24.3from
21492764 to 21806824, maternally
Mild mental retardation PCR
9 50,689,28050,853,329 164 Unknown (foster family) Exon 68; partial introns 5, 8
Karyotyping: normal Language delay, prenatal
substance exposure
10 50,714,29750,853,329 139 De novo Intron 5
Karyotyping and fragile X test: normal PDD-NOS PCR
11 50,735,49950,811,018 76 Maternal Intron 5
mutation tests:
normal (duplications at 5p13.2 from
37241141 to 37758854, paternally
inherited; at 15q26.3 from 98059710 to
98842423, maternally inherited; at
17p11.2 from 21147675 to 21442522
maternally inherited)
Hypotonia, muscle weakness,
large birth weight
12 50,735,49950,801,233 66 Maternal Intron 5
None Poor weight gain, mild craniofacial
, follicle-stimulating hormone receptor;
, luteinizing hormone/choriogonadotropin receptor;
Stoned B
-like factor; PDD-NOS, pervasive developmental disorder, not otherwise specified; VACTERL, vertebral anomalies, anal atresia, cardiac
malformations, tracheoesophageal fistula, renal anomalies, and limb anomalies;
, sal-like 1 (Drosophila);
, chromodomain helicase DNA-binding protein 7;
, phosphatase and tensin homolog;
, nuclear receptor-binding SET domain protein
Deletions of intron 5 in these patients involve an exon of a minor isoform of
Page 4
Of these 12 deletions, 4 were de novo CNV not identied in either
parent, 3 were maternally inherited, 3 were paternally inherited,
and the parental samples for 1 (subject 9) were not available. In
subjects 1, paternal samples were not available but the deletion was
not identied in maternal testing.
In subjects 19, the deletions involved at least two exons of
NRXN1-a, while in subjects 1012, the deletions involved only an
exon of a minor expressed NRXN1 isoform. The genomic imbal-
ances involving NRXN1 are summarized in Table I and the clinical
manifestations are summarized in Tables II and III. Further clinical
data are available in the Supplementary Material.
Detailed clinical records were available from geneticists in 9 out
of 12 subjects, developmental-behavioral pediatricians in 6/12,
psychologists in 6/12, and neurologists in 4/12. Four of the 12
subjects (4, 6, 7, and 10) were diagnosed with autism spectrum
disorders; in each positive case, this diagnosis was supported by the
Autism Diagnostic Observation Schedule. Another subject (2) was
suspected of having autism but the evaluation was not available for
review; he also had global developmental delays. Two subjects had
mental retardation without a diagnosis of an autism spectrum
disorder (1 and 8). Subject 1, in addition, had absence seizures and
an EEG consistent with a primary generalized epilepsy. One subject
(3) was too young to ascertain for an autism spectrum disorder or
cognitive delays. Nine subjects had clinical documentation of
expressive or receptive language delays.
Mild dysmorphic features were present in seven subjects (2, 3, 4,
7, 8, 9, and 12); three subjects had hemangiomas (2, 6, and 10).
Hypotonia was present in four subjects (3, 4, 9, and 11). Two
subjects (5 and 12) had ventricular septal defects.
Medical record review also revealed the following characteristics
in the six parents from whom the NRXN1 deletion was inherited.
Subject 4, who had pervasive developmental disorder, not other-
wise specied (PDD-NOS) and hypotonia, inherited his deletion
from his father who is also reported to be socially awkward. Subject
6, who had PDD-NOS and coordination issues, inherited the
deletion from a mother with a history of language delay and social
skill difculties. Subject 11, who has hypotonia, weakness, and
Poland anomaly, inherited the deletion from a mother who has a
history of joint hypermobility, osteoarthritis, mitral valve prolapse,
severe migraines, and severe breast asymmetry. The father of subject
3 (hypotonia, gross motor delay), the father of subject 7 (autism,
mental retardation) and the mother of subject 12 (poor weight gain,
craniofacial dysmorphism) are reported to be healthy without
developmental or medical concerns.
Additional Report of Cases With NRXN1 Deletion
and Autism
In addition to the Childrens Hospital Boston cases, we report here
three cases from two families ascertained through the HMCA
[Morrow et al., 2008]. The NRXN1 deletions in each were discov-
ered to segregate with IQ below 70 in these pedigrees (Fig. 2). All
three affected children were carriers and unaffected children were
not. The deletions were inherited from fathers who were found to
have ASD symptoms and IQ between 60 and 70, while non-carrier
mothers were not on the autism spectrum and with IQs in the
normal range. The deletion for the subject in the rst family is
exonic and intragenic, while the deletion for the two siblings in the
second family is upstream and may affect gene expression. Further
investigation is necessary to substantiate this as a functional dele-
tion, even though it segregates with disease.
Signicance Test
To establish the relevance of these CNV, we compared the frequency
of deletions involving NRXN1-a exons in our Childrens Hospital
Boston population, in whom CGH testing was considered to be
clinically indicated, to the frequency of similar deletions detected by
array genomic proling of equivalent resolution in normal pop-
ulations. Itsara et al. [2009] detected three deletions involving
NRXN1-a exons in 2,493 normal individuals. The International
Schizophrenia Consortium [2008] reported two exonic deletion
cases in 3,181 normal controls. Another large-scale schizophrenia
study identied ve deletion cases among 33,746 normal controls
[Rujescu et al., 2009]. Recently, Glessner et al. [2009]
reported no deletion CNV involving NRXN1-a among 1,409
Autism CaseControl (ACC) control samples and 1,110 Autism
Genetic Resource Exchange (AGRE) controls. Collectively, the
frequency of exonic deletion of NRXN1-a in control populations
is 10/51,939 (0.019%); this differs signicantly from the frequency
of exonic deletion CNV we observed in our clinically referred
population (9/3,540) (0.25%; P ¼ 8.9 10
, two-tailed Fishers
exact test). There are no available data on the frequency of minor
isoform exonic deletions in control populations and thus these
subjects (n ¼ 3) were excluded from the signicance test.
The recent recognition of genomic imbalance in many chromo-
somal regions that are associated with autism, mental retardation,
and schizophrenia is due to the increasing use of whole genome
high-resolution array CGH in the evaluation of individuals with
these disorders. Our clinical subjects with NRXN1 deletion were
ascertained through a patient population presenting with a broad
range of referring diagnoses.
Through a careful review of medical records, we identied in our
subjects a number of clinical features that had not been previously
associated with NRXN1 deletions. These include language delays,
mental retardation without autism, hypotonia, and hemangiomas.
In addition, two of our subjects (5 and 12) had ventricular
septal defects. Interestingly, the human cDNA homologous to rat
NRXN1-a has been isolated in both brain and heart tissues suggest-
ing a potential role for Neurexin-1 in both brain and heart devel-
opment [Nagase et al., 1998]. One of these subjects (5) also had
evidence of multiple congenital anomalies including vertebral
anomalies in the form of a VACTERL association. Vertebral
anomalies have also been reported in one other case in the literature
[Zahir et al., 2008].
A previous report showed the presence of a seizure disorder in
two unrelated individuals sharing the same missense variant in exon
1ofNRXN1-b [Feng et al., 2006]. In our cohort, only one subject
had a seizure disorder (subject 1), although his 5 Mb deletion
encompassed the entire NRXN1 gene as well as the genes
for follicle-stimulating hormone receptor (FSHR), luteinizing
Page 5
TABLE II. Neurological and Developmental Characteristics
Subject Sex
Age at
Autism spectrum
ndings Language delay Motor involvement
History of seizures/
EEG results MRI-brain Behavioral features
1 M 16 y No MR; SB5: FSIQ 44; VIQ 44; NVIQ 48;
(CA 14 y)
Expressive and
Walked at 18
History of seizures;
abnormal EEG
Normal Inattention,
2 M 2 y Autism suspected,
no formal
Global developmental delays Expressive and
Not documented Not documented Not performed or
not documented
Not documented
3 F 10 mo Not suspected No concerns reported. Testingnot
No Mild gross motor
delay, hypotonia
None Not performed or
not documented
Not documented
4 M 4 y PDD-NOS (ADOS) WPPSI-III VIQ 77, PIQ 98 (CA 4 y) Expressive Hypotonia EEG Normal Not performed or
not documented
Attention concerns
5 F 6 y No No concerns reported. Testing not
6 month receptive
Normal Not documented Not performed or
not documented
Not documented
6 F 7 y PDD-NOS (ADOS) Bayley II mental scale 91, 29 mo
(CA 31 mo)
Expressive Motor coordination
None Not performed or
not documented
Not documented
7 M 14 y Autism (ADOS) MR: SB5: FSIQ 47; VIQ 46; NVIQ 53 Expressive and
Normal EEG normal Not performed or
not documented
8 F 11 y No MR: WISC-IV: VCI 67, PRI 63, WMI
59, PSI 75, FSIQ 58 (CA 11 y)
Expressive and
Normal None Normal Inattention, dgety,
9 F 4 y No Academic delays reported.
Testing not documented
Expressive and
Hypotonia None Normal Impulsivity and
10 M 2 y PDD-NOS (ADOS) Bayley III cognitive score 95
Expressive and
Normal Not documented Not performed or
not documented
Not documented
11 M 8 y No No concerns reported.
Testing not documented
No Proximal and distal
None Not performed or
not documented
Not documented
12 F 19 mo Not documented Not documented Not documented Normal None Not performed or
not documented
Not documented
ADOS, autismdiagnostic observation schedule; BayleyII,BayleyScales of Infant Development, secondedition; Bayley III, Bayley scales ofinfant and toddler development, thirdedition; CA, chronological age at testing;MR,mental retardation; SB5, Stanford-Binet
intelligence scales, fth edition; FSIQ, full scale IQ; VIQ, verbal IQ; NVIQ, non verbal IQ; PIQ, performance IQ; WPPSI-III, Wechsler preschool and primary scale of intelligence, third edition; WISC-IV, Wechsler intelligence scale for children, fourth edition; VCI, verbal
comprehension index, PRI, perceptual reasoning index; WMI, working memory index; PSI, processing speed index; y, years; mo, months.
Page 6
TABLE III. Relevant Physical Characteristics
Subject Dysmorphic features Vertebral/skeletal Cardiac Skin
1 None Not documented Normal Not documented
2 Frontal bossing History of plagiocephaly Resolved heart murmur Hemangioma on neck
3 Epicanthal folds; hypertelorism smaller
bifrontal region
Prominent coronal sutures, feet: high arches
and somewhat small length
Normal Lighter than parents
4 Down-slanting palpebral ssures; anteverted
nares; mild retrognathia, pointed chin
Not documented Normal Normal
5 None Curved 2nd toes, incomplete fusion of ring of
rst cervical vertebra
Narrowed aortic arch, 2 VSDs Not documented
6 None Bilateral hip dysplasia Prolonged QTc (457 msec) Hemangioma on neck
7 Slightly deep set eyes, large ears Normal Normal Normal
8 Long face, malar hypoplasia, prominent tubular
nose with pointed nasal tip, hypoplastic alae
nase, long at philtrum, thin vermilion,
prominent chin, long slender ngers, thin toes
Not documented Normal Normal
9 Low nasal bridge, small jaw, very smooth
philtrum. Slightly at mid-face and prominent
Mild clinodactyly and uneven digit lengths Normal Not documented
10 Dolichocephaly (32-week premature infant) Not documented Normal Hemangioma on back
11 None Chest-right mild Poland anomaly Normal Eczema
12 Relative macrocephaly (head circumference
90%), cupping of left ear, frontal bossing
Open anterior fontanelle at 19 months Small muscular VSD, fenestration
in atrial septum, small PDA
Not documented
VSD, ventricular septal defect; PDA, patent ductus arteriosus; QTc, corrected QT interval (normal <440 msec).
Page 7
hormone/choriogonadotropin receptor (LHCGR), and Stoned
B-like factor (STN1). To our knowledge, none of these genes has
been associated with seizures or mental retardation in the literature.
Although we cannot be certain that these features are a direct
consequence of NRXN1 deletion, our observations suggest that the
phenotypic characteristics of NRXN1 deletion may be wider than
previously reported.
The mutations we have observed in our clinical cohort are
primarily in NRXN1-a. Subjects with small deletions (under 3 -
Mb) clustered into two groups (Fig. 1). One group (subjects 37)
had deletions involving part of the initial LNS and EGF domains-
encoding regions of NRXN1-a. Of these ve individuals, three had
autism spectrum disorders. One additional case from the HMCA
was also found to have a deletion in this region, which is similar to
the deletion in subject 7 from the clinically referred cohort.
A second group (subjects 812) had deletions that clustered
around a region further from the a promotor of the gene (Fig. 1). All
ve of these subjects deletions encompassed an exon of an isoform
whose function is not well understood. Furthermore, while two
subjects (8 and 9) had deletions involving other exons of NRXN1-a
as well as this minor isoform, three subjects deletions (1012)
contain only the exon of this minor isoform. This minor isoform
is an Ensembl annotated transcript, named ENST00000406859
(Fig. 1). It contains 13 exons with 2,590 bp transcription and
856 residues of translation length. The coded protein
(ENSP00000385681) consists of one LNS and EGF domain. Its
function is currently unknown.
One such subject (10) with a de novo deletion in this region has
been diagnosed with PDD-NOS, suggesting potential clinical rele-
vance for this isoform. This deletion in intron 5 has not to our
knowledge been previously reported as being associated with
abnormal development.
Neurexin-1-b mutations were less common. Two of the subjects
in our cohort had large deletions encompassing exons for NRXN1-
a and -b. Missense variants in NRXN1-b (R8P, L13F, S14L, and
T40S) have previously been identied in individuals with autism
[Feng et al., 2006; Kim et al., 2008]. Relatives of these individuals
with autism who shared these missense mutations demonstrated
some degree of learning or behavioral issues but did not appear to
meet full autism spectrum disorder criteria [Feng et al., 2006; Kim
et al., 2008]. This is consistent with our ndings of a mixed
phenotype associated with deletions in this region ranging from
autism spectrum disorders to hypotonia with carrier relatives who
are not as affected.
In addition to their NRXN1 deletions, subjects 8 and 11 had
additional genomic imbalances as described in Table I. These
genomic imbalances were all inherited from unaffected parents.
The two duplications on 15q26.3 and 17p11.2 in subject 11 overlap
FIG. 2. A: NRXN1-a deletions segregate with autism spectrum disorder (ASD) and mild mental retardation. Pedigree 1 shows co-segregation of a
hemizygous CNV between rs17041500 and rs17512199which deletes the rst threecoding exons(Del Ex1-3) of NRXN1-a. The CNV iscarried by all
subjects with ASD and diminished intelligence quotient (IQ), but not by a typically developing sibling. Pedigree 2 shows co-segregation of a
hemizygous CNV which deletes likely regulatory, genomic DNA upstream (Del 5
Reg) of NRXN1-a. PDD-NOS, pervasive development disorder, not
otherwise specied. þ, wild-type, non-deleted DNA. B: Mapping of inferred CN data SNP-by-SNP on the UCSC genome browser demonstrates the
extent across the NRXN1 locus. Vertical red lines indicate each SNP with copy number of 1 or 2. Horizontal green lines demarcate the extent of each
deletion. Alignment of annotated genes in the RefSeq database are shown as well as a representation of vertebrate conservation using multiz and
related tools in the UCSC/Penn State Bioinformatics comparative genomic alignment pipeline. Of note, Del 5
Reg deletes the last four exons of an
uncharacterized, spliced mRNA AK127244 that is expressed in brain. The gene is transcribed in the opposite direction as NRXN1-a yet the
transcription start site is within 3.5 kb suggesting that this mRNA may be transcribed coordinately with NRXN1-a. [Color gure can be viewed in the
online issue, which is available at]
Page 8
with known benign CNVs and are unlikely contributory factors to
the patients condition. The duplication at 5p13.2 in subject 11 and
deletion at 3p24.3 in subject 8 are not previously reported CNV but
contain no known genes associated with developmental disorders,
thus are considered as CNV of unknown signicance. Nevertheless,
it is unclear whether these CNVs modied the observed phenotype.
NRXN1 and Synapse Function
Prior studies have functionally linked other molecules that are
associated with NRXN1 to a range of neuropsychiatric disorders
including autism. These include neuroligins 3 and 4 (NLGN3,
NLGN4) and SH3 and multiple ankyrin repeat domains 3
(SHANK3) [Jamain et al., 2002; Laumonnier et al., 2004; Durand
et al., 2007; Moessner et al., 2007; Lawson-Yuen et al., 2008]. In
addition, CNTNAP2 (contactin associated protein-like 2) [Alarcon
et al., 2008; Arking et al., 2008; Bakkaloglu et al., 2008] and cadherin
10 (CDH10)and9(CDH9) have been also associated with autism
spectrum disorders [Wang et al., 2009]. Our nding that NRXN1 is
also associated with autism and developmental disorders adds
further evidence to the importance of this molecular family to the
development of neurodevelopmental disorders.
The function of NRXN1 in facilitating synaptic transmission
suggests that mutations in this gene may predispose to a neurologic
disconnection syndrome. Long-range disconnections between
neural networks have been hypothesized to be causative in some
populations with autism [Barnea-Goraly et al., 2004; Frith, 2004;
Just et al., 2004; Geschwind and Levitt, 2007]. The effects of NRXN1
on language development and hypotonia may likewise be related to
long-range connectivity within the brain.
Phenotypic Variation
Phenotypic variations may reect the highly pleiotropic effects
observed for specic CNVs such as those associated with NRXN1.
In addition, a number of our subjects inherited NRXN1 deletions
from their parents. The detailed phenotype of these parents were
not described in the medical records except in the family history,
but the parents were ostensibly less affected than their children.
This suggests that deletion in the NRXN1 gene may not be fully
penetrant, or interacts with other genes resulting in the variable
phenotype. Further research efforts to investigate such variable
phenotypes associated with this unstable genomic region will pro-
vide further insight into the role of NRXN1 in the development of
language delays, autism spectrum disorders, and physical features.
The accuracy and completeness of the clinical phenotype identied
in this study is entirely dependent on the clinical information that
was documented in the medical records of these subjects, often
before the NRXN1 deletions were identied in them. Because of the
clinical variability exhibited in our cohort, the subjects were seen by
a variety of specialists, which affected the completeness of data.
In addition, the parents were not formally assessed to ascertain
their cognitive, physical, and behavioral phenotypes. As noted
above, review of family history suggests that some parents may
have shared similar phenotypes to their children. We are conduct-
ing further testing on both the subjects and their parents to better
clarify developmental and/or social cognition issues in subjects and
their parents.
For the deletion CNV signicance test, we used the normal
control data generated by different genomic proling array plat-
forms as reference. Knowing that the sensitivity and specicity
differ from one array platform to another, this may not be an
optimal comparison. However, the effort was made to minimize the
detection bias between different array platforms. Here we have only
chosen recent studies using array platform of similar resolution as
ours. All these published articles reported the detection of smaller
CNV, suggesting that technically all these array platforms were able
to detect any CNV identied in this study. Thus this comparison,
although an approximation, is on the conservative side.
Finally we acknowledge that while our clinically ascertained
subjects were not drawn from a cohort with a single diagnosis such
as autism or schizophrenia, they were ascertained from a heteroge-
neously affected group in whom genetic testing was considered
clinically relevant. As a result, there is ascertainment bias and our
ndings may not reect the true distribution of physical and
developmental ndings in the NRXN1 deletion phenotype. Never-
theless, we have demonstrated that there are a number of other
phenotypic features present in this clinical population beyond what
has previously been identied in the literature.
We found a wide range of phenotypic features in a group of subjects
with NRXN1 deletions who were clinically referred for genetic
testing. These include subjects with autism spectrum disorders,
mental retardation, language delays, hypotonia, hemangiomas, and
the VACTERL association.
The authors gratefully acknowledge the assistance by our colleagues
from the DNA Diagnostics Lab: Va Lip, Xiaoming Sheng, Ann
Reinhard, Hong Fang, Siv Tang, Hong Shao, Haitao Zhu, Sam
Tang, and Andrew Cheng for technical support of array CGH;
Christopher A. Walsh Lab: Danielle Gleason and Daniel Rakiec for
technical support and Robert Sean Hill for bioinformatics support.
We are further grateful for the support from the Nancy Lurie Marks
Family Foundation (C.A.W.), the Simons Foundation (C.A.W. and
J.F.G.), Autism Speaks (J.F.G.), and the NIH (5K23MH080954-02
to E.M.M. and 1R01MH083565 to C.A.W). E.C.E. and C.A.W. are
Investigators of the Howard Hughes Medical Institute. Y.S. holds a
Young Investigator Award from the Childrens Tumor Foundation
and Catalyst Award from Harvard Medical School, E.M.M. holds a
Career Award for Medical Scientists from the Burroughs Wellcome
Fund, B.L.W. holds a Fudan Scholar Research Award from Fudan
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    • "In addition , compound heterozygous NRXN1 mutations consisting of a combination of exon-disrupting microdeletions and nonsense or splice-site mutations have recently been described in patients with severe early-onset epilepsy and profound ID (Harrison et al., 2011; Duong et al., 2012). Comorbid epilepsy has been reported in almost half of these cases (Ching et al., 2010; Gregor et al., 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: This report is regarding a Dutch female with microcephaly, mild intellectual disability (ID), gonadal dysgenesis and dysmorphic facial features with synophrys. Upon genotyping, an ∼455 kb de novo deletion encompassing the first exon of NRXN1 was found. Bidirectional sequencing of the coding exons of the NRXN1 alpha isoform was subsequently performed to investigate the possibility of a pathogenic mutation on the other allele, but we could not find any other mutation. Previously, many heterozygous mutations as well as microdeletions in NRXN1 were shown to be associated with ID, autism, schizophrenia, and other psychiatric and psychotic disorders. Our results are in agreement with other reports that show that NRXN1 deletions can lead to ID, microcephaly and mild dysmorphic features. However, this is the first report of gonadal dysgenesis being associated with such deletions. It is not clear whether there is a causal relationship between the NRXN1 deletion and gonadal dysgenesis, but it is of interest that the FSHR gene, which encodes the follicle-stimulating hormone receptor causative correlation that is mutated in ovarian dysgenesis, is located proximal to the NRXN1 gene. Given that most of the females carrying NRXN1 deletions have been diagnosed at a prepubertal age, gynecologic screening of female carriers of a NRXN1 deletion is warranted.
    Full-text · Article · Oct 2015 · Genetics Research
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    • "One of the most exciting developments in research on the etiology of ASD has been the recent discovery that many cases of ASD are associated with rare deletions or duplications , termed copy number variants (CNVs), that directly or indirectly affect genes related neurodevelopment and/or synaptic functions32333435. Genes affected by CNVs linked to ASD include NRXN1 [36], NLGN4X [37], APBA2 [38], SYNGAP1 [35], DLGAP2 [35], SHANK2 [35,39], and SHANK3 [34]. DNA sequencing has also identified rare missense and nonsense mutations in several of these genes in ASD patients [10]. "
    [Show abstract] [Hide abstract] ABSTRACT: Currently, there is great interest in identifying genetic variants that contribute to the risk of developing autism spectrum disorders (ASDs), due in part to recent increases in the frequency of diagnosis of these disorders worldwide. While there is nearly universal agreement that ASDs are complex diseases, with multiple genetic and environmental contributing factors, there is less agreement concerning the relative importance of common vs rare genetic variants in ASD liability. Recent observations that rare mutations and copy number variants (CNVs) are frequently associated with ASDs, combined with reduced fecundity of individuals with these disorders, has led to the hypothesis that ASDs are caused primarily by de novo or rare genetic mutations. Based on this model, large-scale whole-genome DNA sequencing has been proposed as the most appropriate method for discovering ASD liability genes. While this approach will undoubtedly identify many novel candidate genes and produce important new insights concerning the genetic causes of these disorders, a full accounting of the genetics of ASDs will be incomplete absent an understanding of the contributions of common regulatory variants, which are likely to influence ASD liability by modifying the effects of rare variants or, by assuming unfavorable combinations, directly produce these disorders. Because it is not yet possible to identify regulatory genetic variants by examination of DNA sequences alone, their identification will require experimentation. In this essay, I discuss these issues and describe the advantages of measurements of allelic expression imbalance (AEI) of mRNA expression for identifying cis-acting regulatory variants that contribute to ASDs.
    Preview · Article · Sep 2015 · Science China. Life sciences
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    • "Sex differences, which were readily apparent in the rat, and the phenotypic difference between mono-and biallelic deletions must also be considered properly in an evaluation of translational validity. Multiple human studies have shown a significantly higher frequency of NRXN1 defects in patient populations in comparison to control populations, but NRXN1 alterations have also been identified in normal parents and healthy controls (Bucan et al., 2009; Ching et al., 2010; Feng et al., 2006; Hedges et al., 2012; Kirov et al., 2009; Rujescu et al., 2009; Sanders et al., 2011; Schaaf et al., 2012; Zweier et al., 2009). Therefore, there are clearly other genetic and/or environmental factors influencing the ultimate phenotype and degree of neurocognitive disabilities caused by defects in NRXN1 expression. "
    [Show abstract] [Hide abstract] ABSTRACT: Neurexins are neuronal presynaptic proteins that play a key role in mediation of synapse formation. Heterozygous partial deletions in the neurexin-1 gene (NRXN1, 2p16.3) have been observed in autism spectrum disorder (ASD) patients. NRXN1-α knockout (KO) mice present behavioral impairments that resemble some of the core ASD symptoms of social impairment and inflexibility/stereotypy. At present, a thorough assessment of cognitive function has yet to be completed. Rats, containing a biallelic deletion of the NRNX1-α gene on a Sprague Dawley background were compared to littermate wild types across a range of tasks designed to test functional domains disrupted in ASD and other neurodevelopmental disorders, including sensory perception (prepulse inhibition), attention (latent inhibition), associative learning (instrumental and Pavlovian conditioning), and memory (rewarded alternation T maze and spatial discrimination). NRXN1α KO rats were found to present with large and persistent nonsocial deficits, including hyperactivity, deficits in simple instrumental learning, latent inhibition, and spatial-dependent learning. No deficit in sensorimotor gating was observed, despite the presence of an exaggerated startle response. Although KO animals were also able to learn a simple Pavlovian conditioning discrimination, they did display impaired latent inhibition. The presence of pronounced impairments in several domains in NRXN1α KO rats clearly suggests that nonsocial cognitive deficits can also be measured in an animal model of ASD. Further exploration of those deficits, both clinically and preclinically, as planned in the Innovative Medicines Initiative's European Autism Interventions: A Multicenter Study for Developing New Medications program, may help to better understand the brain circuitry involved in ASD and therefore open new avenues to advance novel therapies. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
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