Abstract
Autism spectrum disorders (ASD) are a group of related neurodevelopmental syndromes with complex genetic etiology.1 We identified a de novo chromosome 7q inversion disrupting Autism susceptibility candidate 2 (AUTS2) and Contactin Associated Protein-Like 2 (CNTNAP2) in a child with cognitive and social delay. We focused our initial analysis on CNTNAP2 based on our demonstration of disruption of Contactin 4 (CNTN4) in a patient with ASD;2 the recent finding of rare homozygous mutations in CNTNAP2 leading to intractable seizures and autism;3 and in situ and biochemical analyses reported herein that confirm expression in relevant brain regions and demonstrate the presence of CNTNAP2 in the synaptic plasma membrane fraction of rat forebrain lysates. We comprehensively resequenced CNTNAP2 in 635 patients and 942 controls. Among patients, we identified a total of 27 nonsynonymous changes; 13 were rare and unique to patients and 8 of these were predicted to be deleterious by bioinformatic approaches and/or altered residues conserved across all species. One variant at a highly conserved position, I869T, was inherited by four affected children in three unrelated families, but was not found in 4010 control chromosomes (p = 0.014). Overall, this resequencing data demonstrated a modest nonsignificant increase in the burden of rare variants in cases versus controls. Nonethless, when viewed in light of two independent studies published in this issue of AJHG showing a relationship between ASD and common CNTNAP2 alleles,4,5 the cytogenetic and mutation screening data suggest that rare variants may also contribute to the pathophysiology of ASD, but place limits on the magnitude of this contribution.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 165-173 |
| Number of pages | 9 |
| Journal | American Journal of Human Genetics |
| Volume | 82 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 10 2008 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Genetics
Cite this
Molecular Cytogenetic Analysis and Resequencing of Contactin Associated Protein-Like 2 in Autism Spectrum Disorders. / Bakkaloglu, Betul; O'Roak, Brian; Louvi, Angeliki; Gupta, Abha R.; Abelson, Jesse F.; Morgan, Thomas M.; Chawarska, Katarzyna; Klin, Ami; Ercan-Sencicek, A. Gulhan; Stillman, Althea A.; Tanriover, Gamze; Abrahams, Brett S.; Duvall, Jackie A.; Robbins, Elissa M.; Geschwind, Daniel H.; Biederer, Thomas; Gunel, Murat; Lifton, Richard P.; State, Matthew W.
In: American Journal of Human Genetics, Vol. 82, No. 1, 10.01.2008, p. 165-173.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Molecular Cytogenetic Analysis and Resequencing of Contactin Associated Protein-Like 2 in Autism Spectrum Disorders
AU - Bakkaloglu, Betul
AU - O'Roak, Brian
AU - Louvi, Angeliki
AU - Gupta, Abha R.
AU - Abelson, Jesse F.
AU - Morgan, Thomas M.
AU - Chawarska, Katarzyna
AU - Klin, Ami
AU - Ercan-Sencicek, A. Gulhan
AU - Stillman, Althea A.
AU - Tanriover, Gamze
AU - Abrahams, Brett S.
AU - Duvall, Jackie A.
AU - Robbins, Elissa M.
AU - Geschwind, Daniel H.
AU - Biederer, Thomas
AU - Gunel, Murat
AU - Lifton, Richard P.
AU - State, Matthew W.
PY - 2008/1/10
Y1 - 2008/1/10
N2 - Autism spectrum disorders (ASD) are a group of related neurodevelopmental syndromes with complex genetic etiology.1 We identified a de novo chromosome 7q inversion disrupting Autism susceptibility candidate 2 (AUTS2) and Contactin Associated Protein-Like 2 (CNTNAP2) in a child with cognitive and social delay. We focused our initial analysis on CNTNAP2 based on our demonstration of disruption of Contactin 4 (CNTN4) in a patient with ASD;2 the recent finding of rare homozygous mutations in CNTNAP2 leading to intractable seizures and autism;3 and in situ and biochemical analyses reported herein that confirm expression in relevant brain regions and demonstrate the presence of CNTNAP2 in the synaptic plasma membrane fraction of rat forebrain lysates. We comprehensively resequenced CNTNAP2 in 635 patients and 942 controls. Among patients, we identified a total of 27 nonsynonymous changes; 13 were rare and unique to patients and 8 of these were predicted to be deleterious by bioinformatic approaches and/or altered residues conserved across all species. One variant at a highly conserved position, I869T, was inherited by four affected children in three unrelated families, but was not found in 4010 control chromosomes (p = 0.014). Overall, this resequencing data demonstrated a modest nonsignificant increase in the burden of rare variants in cases versus controls. Nonethless, when viewed in light of two independent studies published in this issue of AJHG showing a relationship between ASD and common CNTNAP2 alleles,4,5 the cytogenetic and mutation screening data suggest that rare variants may also contribute to the pathophysiology of ASD, but place limits on the magnitude of this contribution.
AB - Autism spectrum disorders (ASD) are a group of related neurodevelopmental syndromes with complex genetic etiology.1 We identified a de novo chromosome 7q inversion disrupting Autism susceptibility candidate 2 (AUTS2) and Contactin Associated Protein-Like 2 (CNTNAP2) in a child with cognitive and social delay. We focused our initial analysis on CNTNAP2 based on our demonstration of disruption of Contactin 4 (CNTN4) in a patient with ASD;2 the recent finding of rare homozygous mutations in CNTNAP2 leading to intractable seizures and autism;3 and in situ and biochemical analyses reported herein that confirm expression in relevant brain regions and demonstrate the presence of CNTNAP2 in the synaptic plasma membrane fraction of rat forebrain lysates. We comprehensively resequenced CNTNAP2 in 635 patients and 942 controls. Among patients, we identified a total of 27 nonsynonymous changes; 13 were rare and unique to patients and 8 of these were predicted to be deleterious by bioinformatic approaches and/or altered residues conserved across all species. One variant at a highly conserved position, I869T, was inherited by four affected children in three unrelated families, but was not found in 4010 control chromosomes (p = 0.014). Overall, this resequencing data demonstrated a modest nonsignificant increase in the burden of rare variants in cases versus controls. Nonethless, when viewed in light of two independent studies published in this issue of AJHG showing a relationship between ASD and common CNTNAP2 alleles,4,5 the cytogenetic and mutation screening data suggest that rare variants may also contribute to the pathophysiology of ASD, but place limits on the magnitude of this contribution.
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UR - http://www.scopus.com/inward/citedby.url?scp=38749099110&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2007.09.017
DO - 10.1016/j.ajhg.2007.09.017
M3 - Article
C2 - 18179895
AN - SCOPUS:38749099110
VL - 82
SP - 165
EP - 173
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 1
ER -