Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.

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.

Department

Description

Provenance

Subjects

Adolescent, Autistic Disorder, Case-Control Studies, Cell Adhesion Molecules, Neuronal, Child, Child, Preschool, Cohort Studies, Exons, Female, Gene Dosage, Gene Duplication, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Nerve Tissue Proteins, Pedigree, Sequence Deletion, Ubiquitin-Protein Ligases, Young Adult

Citation

Published Version (Please cite this version)

10.1371/journal.pgen.1000536

Publication Info

Bucan, Maja, Brett S Abrahams, Kai Wang, Joseph T Glessner, Edward I Herman, Lisa I Sonnenblick, Ana I Alvarez Retuerto, Marcin Imielinski, et al. (2009). Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet, 5(6). p. e1000536. 10.1371/journal.pgen.1000536 Retrieved from https://hdl.handle.net/10161/13928.

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Scholars@Duke

Dawson

Geraldine Dawson

William Cleland Distinguished Professor

Geraldine Dawson is the William Cleland Distinguished Professor of Psychiatry and Behavioral Sciences at Duke University, where she also is a Professor of Pediatrics and Psychology & Neuroscience.  Dawson also is the Founding Director of the Duke Center for Autism and Brain Development, an NIH Autism Center of Excellence, which is an interdisciplinary research program and clinic, aimed to improve the lives of those diagnosed with autism through research, education, clinical services, and policy. Dawson received a Ph.D. in Developmental and Child Clinical Psychology from the University of Washington and completed a clinical internship at the UCLA Neuropsychiatric Institute.

Dawson's work focuses on improving methods for early detection and intervention for autism, understanding brain function in autism, and validation of autism EEG biomarkers. She co-developed the Early Start Denver Model, an empirically-validated early autism intervention that is used worldwide. She collaborates with colleagues in the departments of computer science and engineering, pediatrics, and biostatistics to develop novel digital health approaches to autism screening and outcome monitoring. 

Dawson previously served as Director of the Duke Institute for Brain Sciences, President of the International Society for Autism Research, and was appointed by the US Secretary of Health as a member of the NIH Interagency Autism Coordinating Committee (IACC) which develops the federal strategic plan for autism research, services, and policy. Dawson is a member of the American Academy of Arts and Sciences. She was Founding Director of the University of Washington (UW) Autism Center and the Duke Center for Autism and Brain Development. Dawson's awards include the American Psychological Association Distinguished Career Award (Div53); Association for Psychological Science Lifetime Achievement Award; Clarivate Top 1% Cited Researcher Across All Scientific Fields; among others. Dawson is a Fellow of the International Society for Autism Research, the American Psychological Society, and the American Psychological Association. 


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