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Autism and Developmental Disorders Colloquium Series

“Genome Wide Analysis of Copy Number Variation in Autism”

Jonathan Sebat, Ph.D.
Assistant Professor, Cold Spring Harbor Laboratory

6:00 p.m., Wednesday, September 5, 2007
MIT Building 46-3002 (auditorium), followed by a reception

Building Address: 43 Vassar Street, Cambridge, MA 02139

Hosted by the Brain Development and Disorders Project at MIT

Supported by the Simons Foundation, the Anne and Paul Marcus Family Foundation, and the Autism Treatment Network

Colloquia sponsored by the Autism Consortium

Please RSVP to lmavros@mit.edu

Autism spectrum disorders (ASDs) are characterized by language impairments, social and communicative deficits and repetitive behaviors. Due in part to a high degree of genetic and phenotypic heterogeneity, traditional gene mapping approaches have had little success in identifying loci that have an effect on autism susceptibility. Cytogenetic techniques have been used to identify chromosomal abnormalities in 5-7% of patients, but these microscopic lesions contain many genes and it is uncertain which are clinically relevant. It is plausible that submicroscopic chromosomal variants contribute to the genetic basis of autism. Therefore, new methodologies with increased sensitivity to detect genomic imbalances are a promising approach to identifying genetic risk factors. We tested the hypothesis that spontaneous copy number variation ( CNV) is associated with autism spectrum disorders (ASD). We performed comparative genomic hybridization (CGH) on a large sample of families with idiopathic ASD, and examined the genomes of patients and unaffected subjects for CNVs not present in their parents. Candidate regions were validated by higher resolution CGH, paternity testing, cytogenetics, FISH analysis and micro-satellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P=0.0005). Such CNVs were identified in 12/118 (10%) of sporadic cases and in 2/77 (2%) of patients with an affected first-degree relative. De novo CNVs were detected in 2/196 (1.0 %) of unaffected controls. Spontaneous variants identified in this study ranged in size from 99 kb to 10 Mb, and included mutations of single genes. These findings implicate novel genes in the pathophysiology of autism.