title: Patterns and rates of exonic de novo mutations in autism spectrum disorders.
abstract: Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.forename: Yan
authors.initials: Y
authors.lastname: Kou
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Avi
authors.initials: A
authors.lastname: Ma'ayan
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Samocha
authors.forename: Aniko
authors.initials: A
authors.lastname: Sabo
authors.forename: Chiao-Feng
authors.initials: CF
authors.lastname: Lin
authors.forename: Christine
authors.initials: C
authors.lastname: Stevens
authors.forename: Li-San
authors.initials: LS
authors.lastname: Wang
authors.forename: Vladimir
authors.initials: V
authors.lastname: Makarov
authors.forename: Paz
authors.initials: P
authors.lastname: Polak
authors.forename: Seungtai
authors.initials: S
authors.lastname: Yoon
authors.forename: Jared
authors.initials: J
authors.lastname: Maguire
authors.forename: Emily L
authors.initials: EL
authors.lastname: Crawford
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Campbell
authors.forename: Evan T
authors.initials: ET
authors.lastname: Geller
authors.forename: Otto
authors.initials: O
authors.lastname: Valladares
authors.forename: Chad
authors.initials: C
authors.lastname: Schafer
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.forename: Tuo
authors.initials: T
authors.lastname: Zhao
authors.forename: Guiqing
authors.initials: G
authors.lastname: Cai
authors.forename: Jayon
authors.initials: J
authors.lastname: Lihm
authors.forename: Ruth
authors.initials: R
authors.lastname: Dannenfelser
authors.forename: Omar
authors.initials: O
authors.lastname: Jabado
authors.forename: Zuleyma
authors.initials: Z
authors.lastname: Peralta
authors.forename: Uma
authors.initials: U
authors.lastname: Nagaswamy
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Reid
authors.forename: Irene
authors.initials: I
authors.lastname: Newsham
authors.forename: Yuanqing
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authors.lastname: Wu
authors.forename: Lora
authors.initials: L
authors.lastname: Lewis
authors.forename: Yi
authors.initials: Y
authors.lastname: Han
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Voight
authors.forename: Elaine
authors.initials: E
authors.lastname: Lim
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rossin
authors.forename: Andrew
authors.initials: A
authors.lastname: Kirby
authors.forename: Jason
authors.initials: J
authors.lastname: Flannick
authors.forename: Menachem
authors.initials: M
authors.lastname: Fromer
authors.forename: Khalid
authors.initials: K
authors.lastname: Shakir
authors.forename: Tim
authors.initials: T
authors.lastname: Fennell
authors.forename: Kiran
authors.initials: K
authors.lastname: Garimella
authors.forename: Eric
authors.initials: E
authors.lastname: Banks
authors.forename: Ryan
authors.initials: R
authors.lastname: Poplin
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.forename: Mark
authors.initials: M
authors.lastname: DePristo
authors.forename: Jack R
authors.initials: JR
authors.lastname: Wimbish
authors.forename: Braden E
authors.initials: BE
authors.lastname: Boone
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Levy
authors.forename: Catalina
authors.initials: C
authors.lastname: Betancur
authors.forename: Shamil
authors.initials: S
authors.lastname: Sunyaev
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.forename: Bernie
authors.initials: B
authors.lastname: Devlin
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Kathryn
authors.initials: K
authors.lastname: Roeder
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: James S
authors.initials: JS
authors.lastname: Sutcliffe
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005091:Exons / Q000235:genetics*; D005192:Family Health; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D020412:Multifactorial Inheritance / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D016012:Poisson Distribution; D060066:Protein Interaction Maps; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C523331:CHD8 protein, human; D004268:DNA-Binding Proteins; D014157:Transcription Factors