Cited by 537Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersGenomic variations and chromosomal abnormalities

Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders

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Bakkaloglu, Betul, O'Roak, Brian J., Louvi, Angeliki, Gupta, Abha R., Abelson, Jesse F., Morgan, Thomas M., Chawarska, Katarzyna, Klin, Ami +11 more·2008·The American Journal of Human Genetics

Abstract

Autism spectrum disorders (ASD) are a group of related neurodevelopmental syndromes with complex genetic etiology. 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; the recent finding of rare homozygous mutations in CNTNAP2 leading to intractable seizures and autism; 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. Nonetheless, when viewed in light of two independent studies published in this issue of AJHG showing a relationship between ASD and common CNTNAP2 alleles, 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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Crossref · 10.1016/j.ajhg.2007.09.017

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Authors
Bakkaloglu, B., O'Roak, B. J., Louvi, A., Gupta, A. R., Abelson, J. F., Morgan, T. M., Chawarska, K., Klin, A., Ercan-Sencicek, A. G., Stillman, A. A., Tanriover, G., Abrahams, B. S., Duvall, J. A., Robbins, E. M., Geschwind, D. H., Biederer, T., Gunel, M., Lifton, R. P., & State, M. W.
Affiliations
  • Yale University (US)
  • Washington University in St. Louis (US)
  • University of California, Los Angeles (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
State, Matthew W.
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2008-01
Volume
82
Issue
1
Pages
165-173
ISSN
0002-9297 (ISSN-L)
OpenAlex
W2002938212
Cited by
537
References
34
Citations by year
2026: 7 · 2025: 9 · 2024: 11 · 2023: 14 · 2022: 14 · 2021: 26 · 2020: 14 · 2019: 16 · 2018: 18 · 2017: 25 · 2016: 25 · 2015: 40 · 2014: 31 · 2013: 47 · 2012: 55
FWCI
31.35
Type
journal article
Language
en
Update notices
addendum (2008-06-06)
Open access
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Hacettepe University Institutional Repository (hacettepe.edu.tr) (submittedVersion, other-oa)
Funders
  • National Institute of Mental Health (R01MH64547, R01MH064547)
  • National Institute on Drug Abuse (R01DA018928)
  • National Center for Research Resources (K23RR016118, K23 RR16118-04)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
autism spectrum disorder, CNTNAP2, CNTN4, AUTS2, rare variants, non-synonymous mutations, synaptic plasma membrane, genetic etiology of autism, neurodevelopmental delay
MeSH terms
Animals, Autistic Disorder, Child, Female, Humans, Male, Membrane Proteins, Nerve Tissue Proteins, RNA, Messenger, Temporal Lobe, Genetic Predisposition to Disease, Rats

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