Molecular Cytogenetic Analysis and Resequencing of Contactin Associated Protein-Like 2 in Autism Spectrum Disorders

Betul Bakkaloglu, Brian J. O'Roak, Angeliki Louvi, Abha R. Gupta, Jesse F. Abelson, Thomas M. Morgan, Katarzyna Chawarska, Ami Klin, A. Gulhan Ercan-Sencicek, Althea A. Stillman, Gamze Tanriover, Brett S. Abrahams, Jackie A. Duvall, Elissa M. Robbins, Daniel H. Geschwind, Thomas Biederer, Murat Gunel, Richard P. Lifton, Matthew W. State

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)165-173
Number of pages9
JournalAmerican Journal of Human Genetics
Volume82
Issue number1
DOIs
StatePublished - Jan 10 2008
Externally publishedYes

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Contactins
Cytogenetic Analysis
Proteins
Autistic Disorder
Contactin 2
Synaptic Membranes
Mutation
Prosencephalon
Computational Biology
Cytogenetics
Autism Spectrum Disorder
Seizures
Chromosomes
Alleles
Cell Membrane
Brain

ASJC Scopus subject areas

  • Genetics

Cite this

Bakkaloglu, B., O'Roak, B. J., Louvi, A., Gupta, A. R., Abelson, J. F., Morgan, T. M., ... State, M. W. (2008). Molecular Cytogenetic Analysis and Resequencing of Contactin Associated Protein-Like 2 in Autism Spectrum Disorders. American Journal of Human Genetics, 82(1), 165-173. https://doi.org/10.1016/j.ajhg.2007.09.017

Molecular Cytogenetic Analysis and Resequencing of Contactin Associated Protein-Like 2 in Autism Spectrum Disorders. / Bakkaloglu, Betul; O'Roak, Brian J.; 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 journalArticle

Bakkaloglu, B, O'Roak, BJ, Louvi, A, Gupta, AR, Abelson, JF, Morgan, TM, Chawarska, K, Klin, A, Ercan-Sencicek, AG, Stillman, AA, Tanriover, G, Abrahams, BS, Duvall, JA, Robbins, EM, Geschwind, DH, Biederer, T, Gunel, M, Lifton, RP & State, MW 2008, 'Molecular Cytogenetic Analysis and Resequencing of Contactin Associated Protein-Like 2 in Autism Spectrum Disorders', American Journal of Human Genetics, vol. 82, no. 1, pp. 165-173. https://doi.org/10.1016/j.ajhg.2007.09.017
Bakkaloglu, Betul ; O'Roak, Brian J. ; 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. / Molecular Cytogenetic Analysis and Resequencing of Contactin Associated Protein-Like 2 in Autism Spectrum Disorders. In: American Journal of Human Genetics. 2008 ; Vol. 82, No. 1. pp. 165-173.
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AU - Bakkaloglu, Betul

AU - O'Roak, Brian J.

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.

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