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

Bucan, M and Abrahams, BS and Wang, K and Glessner, JT and Herman, EI and Sonnenblick, LI and Alvarez Retuerto, AI and Imielinski, M and Hadley, D and Bradfield, JP and Kim, C and Gidaya, NB and Lindquist, I and Hutman, T and Sigman, M and Kustanovich, V and Lajonchere, CM and Singleton, A and Kim, J and Wassink, TH and McMahon, WM and Owley, T and Sweeney, JA and Coon, H and Nurnberger, JI and Li, M and Cantor, RM and Minshew, NJ and Sutcliffe, JS and Cook, EH and Dawson, G and Buxbaum, JD and Grant, SFA and Schellenberg, GD and Geschwind, DH and Hakonarson, H (2009) Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genetics, 5 (6). ISSN 1553-7390

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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 = 2.3×10-5). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10-4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10-39), 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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Bucan, M
Abrahams, BS
Wang, K
Glessner, JT
Herman, EI
Sonnenblick, LI
Alvarez Retuerto, AI
Imielinski, M
Hadley, D
Bradfield, JP
Kim, C
Gidaya, NB
Lindquist, I
Hutman, T
Sigman, M
Kustanovich, V
Lajonchere, CM
Singleton, A
Kim, J
Wassink, TH
McMahon, WM
Owley, T
Sweeney, JA
Coon, H
Nurnberger, JI
Li, M
Cantor, RM
Minshew, NJnminshew@pitt.eduNMINSHEW
Sutcliffe, JS
Cook, EH
Dawson, G
Buxbaum, JD
Grant, SFA
Schellenberg, GD
Geschwind, DH
Hakonarson, H
ContributionContributors NameEmailPitt UsernameORCID
Date: 1 June 2009
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 5
Number: 6
DOI or Unique Handle: 10.1371/journal.pgen.1000536
Refereed: Yes
ISSN: 1553-7390
MeSH Headings: Adolescent; Autistic Disorder/genetics; 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/genetics; Pedigree; Sequence Deletion; Ubiquitin-Protein Ligases/genetics; Young Adult
PubMed Central ID: PMC2695001
PubMed ID: 19557195
Date Deposited: 30 Jul 2012 22:09
Last Modified: 22 Jun 2021 13:56


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