title: Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.
abstract: Exome sequencing studies of autism spectrum disorders (ASDs) have identified many de novo mutations but few recurrently disrupted genes. We therefore developed a modified molecular inversion probe method enabling ultra-low-cost candidate gene resequencing in very large cohorts. To demonstrate the power of this approach, we captured and sequenced 44 candidate genes in 2446 ASD probands. We discovered 27 de novo events in 16 genes, 59% of which are predicted to truncate proteins or disrupt splicing. We estimate that recurrent disruptive mutations in six genes-CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1-may contribute to 1% of sporadic ASDs. Our data support associations between specific genes and reciprocal subphenotypes (CHD8-macrocephaly and DYRK1A-microcephaly) and replicate the importance of a β-catenin-chromatin-remodeling network to ASD etiology.
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Roak
authors.forename: Laura
authors.initials: L
authors.lastname: Vives
authors.forename: Wenqing
authors.initials: W
authors.lastname: Fu
authors.forename: Jarrett D
authors.initials: JD
authors.lastname: Egertson
authors.forename: Ian B
authors.initials: IB
authors.lastname: Stanaway
authors.forename: Ian G
authors.initials: IG
authors.lastname: Phelps
authors.forename: Gemma
authors.initials: G
authors.lastname: Carvill
authors.forename: Akash
authors.initials: A
authors.lastname: Kumar
authors.forename: Choli
authors.initials: C
authors.lastname: Lee
authors.forename: Katy
authors.initials: K
authors.lastname: Ankenman
authors.forename: Jeff
authors.initials: J
authors.lastname: Munson
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Hiatt
authors.forename: Emily H
authors.initials: EH
authors.lastname: Turner
authors.forename: Roie
authors.initials: R
authors.lastname: Levy
authors.forename: Diana R
authors.initials: DR
authors.lastname: O'Day
authors.forename: Niklas
authors.initials: N
authors.lastname: Krumm
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Coe
authors.forename: Beth K
authors.initials: BK
authors.lastname: Martin
authors.forename: Elhanan
authors.initials: E
authors.lastname: Borenstein
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.forename: Dan
authors.initials: D
authors.lastname: Doherty
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Akey
authors.forename: Raphael
authors.initials: R
authors.lastname: Bernier
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
mesh_terms: D002508:Cephalometry; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D002675:Child, Preschool; D042002:Chromatin Assembly and Disassembly; D015331:Cohort Studies; D015342:DNA Probes; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D058627:Megalencephaly / Q000235:genetics; D008831:Microcephaly / Q000235:genetics; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D020825:T-Box Domain Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D015342:DNA Probes; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D018160:Receptors, Cytoplasmic and Nuclear; D016194:Receptors, N-Methyl-D-Aspartate; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D051176:beta Catenin; D000097603:Dyrk Kinases; C523331:CHD8 protein, human; C121001:NR2B NMDA receptor; C473691:TBL1XR1 protein, human; C574705:TBR1 protein, human; C494929:PTEN protein, human