Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes

Year: 2009

Type: article

Abstract: The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.

Source: PLoS Genetics

DOI: 10.1371/journal.pgen.1000536

Institutions: Autism Speaks, University of Pennsylvania, University of California, Los Angeles, Children's Hospital of Philadelphia, University of Southern California, National Institutes of Health, National Institute on Aging, University of Iowa, University of Utah, University of Illinois Chicago, Indiana University Indianapolis, University of Pittsburgh, Vanderbilt University, University of North Carolina at Chapel Hill, Icahn School of Medicine at Mount Sinai

Language: English

Topic: Autism Spectrum Disorder Research

Subfield: Cognitive Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,043

Funders: U.S. Department of Health and Human Services, Autism Speaks, Massachusetts General Hospital, Yale University, Children's Hospital of Philadelphia, University of Pennsylvania, Emory University, George Washington University, National Alliance for Research on Schizophrenia and Depression, Cotswold Foundation, National Institutes of Health, National Institute on Aging, National Institute of Mental Health, National Institute of General Medical Sciences, National Center for Research Resources, Eunice Kennedy Shriver National Institute of Child Health and Human Development

Awards: Comparative Approaches to Bio-knowledge Discovery, Center for Genomic and Phenomic Studies in Autism, G3976977953, Institutional Clinical and Translational Science Award, A Comprehensive Approach to Identification of Autism Susceptibility Genes, Heterogeneity in Autism Spectrum Disorders: Biological Mechanisms, Trajectories, and Treatment Response, Mentorship Program Patient-Oriented Research on Aging, Genome wide SNP analysis in Parkinson's disease, G91145486

OpenAlex ID: W2125432692