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

dc.contributor.author Abrahams, BS
dc.contributor.author Alvarez Retuerto, AI
dc.contributor.author Bradfield, JP
dc.contributor.author Bucan, M
dc.contributor.author Buxbaum, JD
dc.contributor.author Cantor, RM
dc.contributor.author Cook, EH
dc.contributor.author Coon, H
dc.contributor.author Dawson, Geraldine
dc.contributor.author Geschwind, DH
dc.contributor.author Gidaya, NB
dc.contributor.author Glessner, JT
dc.contributor.author Grant, Struan FA
dc.contributor.author Hadley, D
dc.contributor.author Hakonarson, H
dc.contributor.author Herman, EI
dc.contributor.author Hutman, T
dc.contributor.author Imielinski, M
dc.contributor.author Kim, C
dc.contributor.author Kim, J
dc.contributor.author Kustanovich, V
dc.contributor.author Lajonchere, CM
dc.contributor.author Li, M
dc.contributor.author Lindquist, I
dc.contributor.author McMahon, WM
dc.contributor.author Minshew, NJ
dc.contributor.author Nurnberger, JI
dc.contributor.author Owley, T
dc.contributor.author Schellenberg, GD
dc.contributor.author Sigman, Marian
dc.contributor.author Singleton, A
dc.contributor.author Sonnenblick, LI
dc.contributor.author Sutcliffe, JS
dc.contributor.author Sweeney, JA
dc.contributor.author Wang, K
dc.contributor.author Wassink, TH
dc.coverage.spatial United States
dc.date.accessioned 2017-04-02T19:29:40Z
dc.date.available 2017-04-02T19:29:40Z
dc.date.issued 2009-06
dc.identifier https://www.ncbi.nlm.nih.gov/pubmed/19557195
dc.identifier.uri https://hdl.handle.net/10161/13928
dc.description.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.
dc.language eng
dc.relation.ispartof PLoS Genet
dc.relation.isversionof 10.1371/journal.pgen.1000536
dc.subject Adolescent
dc.subject Autistic Disorder
dc.subject Case-Control Studies
dc.subject Cell Adhesion Molecules, Neuronal
dc.subject Child
dc.subject Child, Preschool
dc.subject Cohort Studies
dc.subject Exons
dc.subject Female
dc.subject Gene Dosage
dc.subject Gene Duplication
dc.subject Genetic Predisposition to Disease
dc.subject Genome-Wide Association Study
dc.subject Humans
dc.subject Male
dc.subject Nerve Tissue Proteins
dc.subject Pedigree
dc.subject Sequence Deletion
dc.subject Ubiquitin-Protein Ligases
dc.subject Young Adult
dc.title Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.
dc.type Journal article
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/19557195
pubs.begin-page e1000536
pubs.issue 6
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Institute for Brain Sciences
pubs.organisational-group Institutes and Provost's Academic Units
pubs.organisational-group Pediatrics
pubs.organisational-group Psychiatry, Child & Family Mental Health and Developmental Neuroscience
pubs.organisational-group Psychiatry & Behavioral Sciences
pubs.organisational-group Sanford School of Public Policy
pubs.organisational-group Sanford School of Public Policy - Secondary Group
pubs.organisational-group School of Medicine
pubs.organisational-group University Institutes and Centers
pubs.publication-status Published
pubs.volume 5
dc.identifier.eissn 1553-7404


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