title: 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.
authors: Autism Genetic Resource Exchange, Autism Speaks, Los Angeles, California, United States of America.
authors: Maja
authors: M
authors: Bucan
authors: Brett S
authors: BS
authors: Abrahams
authors: Kai
authors: K
authors: Wang
authors: Joseph T
authors: JT
authors: Glessner
authors: Edward I
authors: EI
authors: Herman
authors: Lisa I
authors: LI
authors: Sonnenblick
authors: Ana I
authors: AI
authors: Alvarez Retuerto
authors: Marcin
authors: M
authors: Imielinski
authors: Dexter
authors: D
authors: Hadley
authors: Jonathan P
authors: JP
authors: Bradfield
authors: Cecilia
authors: C
authors: Kim
authors: Nicole B
authors: NB
authors: Gidaya
authors: Ingrid
authors: I
authors: Lindquist
authors: Ted
authors: T
authors: Hutman
authors: Marian
authors: M
authors: Sigman
authors: Vlad
authors: V
authors: Kustanovich
authors: Clara M
authors: CM
authors: Lajonchere
authors: Andrew
authors: A
authors: Singleton
authors: Junhyong
authors: J
authors: Kim
authors: Thomas H
authors: TH
authors: Wassink
authors: William M
authors: WM
authors: McMahon
authors: Thomas
authors: T
authors: Owley
authors: John A
authors: JA
authors: Sweeney
authors: Hilary
authors: H
authors: Coon
authors: John I
authors: JI
authors: Nurnberger
authors: Mingyao
authors: M
authors: Li
authors: Rita M
authors: RM
authors: Cantor
authors: Nancy J
authors: NJ
authors: Minshew
authors: James S
authors: JS
authors: Sutcliffe
authors: Edwin H
authors: EH
authors: Cook
authors: Geraldine
authors: G
authors: Dawson
authors: Joseph D
authors: JD
authors: Buxbaum
authors: Struan F A
authors: SF
authors: Grant
authors: Gerard D
authors: GD
authors: Schellenberg
authors: Daniel H
authors: DH
authors: Geschwind
authors: Hakon
authors: H
authors: Hakonarson
mesh_terms: D000293:Adolescent; D001321:Autistic Disorder / Q000235:genetics*; D002135:Calcium-Binding Proteins; D016022:Case-Control Studies; D015816:Cell Adhesion Molecules, Neuronal; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005091:Exons; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D019006:Neural Cell Adhesion Molecules; D010375:Pedigree; D017384:Sequence Deletion; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D055815:Young Adult
chemical_list: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases