Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders
Open accessAbstract
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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Common variants in CNTNAP2 have also been associated with ASD and specific-language impairment.
“Common variants in CNTNAP2 have also been associated with ASD (49–51) and specific-language impairment (52).”
From Individual common variants exert weak effects on the risk for autism spectrum disorders (2012) · cites this paper as [51]
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Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1
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Genetic basis of autism: is there a way forward?
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Self-citationAssociation and mutation analyses of 16p11.2 autism candidate genes
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Self-citationRecent advances in Tourette syndrome
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Self-citation
- 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.
- ORCID
- 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)
- PMC
- PMC2253974
- 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
- bronze
- doi.org
- Licence
- 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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