Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders.
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.
Bakkaloglu
Betul
B
Program on Neurogenetics, Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
O'Roak
Brian J
BJ
Louvi
Angeliki
A
Gupta
Abha R
AR
Abelson
Jesse F
JF
Morgan
Thomas M
TM
Chawarska
Katarzyna
K
Klin
Ami
A
Ercan-Sencicek
A Gulhan
AG
Stillman
Althea A
AA
Tanriover
Gamze
G
Abrahams
Brett S
BS
Duvall
Jackie A
JA
Robbins
Elissa M
EM
Geschwind
Daniel H
DH
Biederer
Thomas
T
Gunel
Murat
M
Lifton
Richard P
RP
State
Matthew W
MW
D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger; D051381:Rats; D013702:Temporal Lobe / Q000378:metabolism
C403049:CNTNAP2 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger