title: Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.
abstract: It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected β-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Roak
authors.forename: Laura
authors.initials: L
authors.lastname: Vives
authors.forename: Santhosh
authors.initials: S
authors.lastname: Girirajan
authors.forename: Emre
authors.initials: E
authors.lastname: Karakoc
authors.forename: Niklas
authors.initials: N
authors.lastname: Krumm
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Coe
authors.forename: Roie
authors.initials: R
authors.lastname: Levy
authors.forename: Arthur
authors.initials: A
authors.lastname: Ko
authors.forename: Choli
authors.initials: C
authors.lastname: Lee
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.forename: Emily H
authors.initials: EH
authors.lastname: Turner
authors.forename: Ian B
authors.initials: IB
authors.lastname: Stanaway
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vernot
authors.forename: Maika
authors.initials: M
authors.lastname: Malig
authors.forename: Carl
authors.initials: C
authors.lastname: Baker
authors.forename: Beau
authors.initials: B
authors.lastname: Reilly
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Akey
authors.forename: Elhanan
authors.initials: E
authors.lastname: Borenstein
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Raphael
authors.initials: R
authors.lastname: Bernier
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D058851:GPI-Linked Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007797:Laminin / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics; D000075385:Netrins; D010290:Parents; D017354:Point Mutation / Q000235:genetics*; D060066:Protein Interaction Maps / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D015203:Reproducibility of Results; D035781:Siblings; D015398:Signal Transduction; D015222:Sodium Channels / Q000235:genetics; D013269:Stochastic Processes; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C523331:CHD8 protein, human; D004268:DNA-Binding Proteins; D058851:GPI-Linked Proteins; C504218:LAMC3 protein, human; D007797:Laminin; D062550:NAV1.1 Voltage-Gated Sodium Channel; C121001:NR2B NMDA receptor; C463082:NTNG1 protein, human; D009419:Nerve Tissue Proteins; D000075385:Netrins; D016194:Receptors, N-Methyl-D-Aspartate; C568242:SCN1A protein, human; D015222:Sodium Channels; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin