title: Recurrent de novo mutations implicate novel genes underlying simplex autism risk.
abstract: Autism spectrum disorder (ASD) has a strong but complex genetic component. Here we report on the resequencing of 64 candidate neurodevelopmental disorder risk genes in 5,979 individuals: 3,486 probands and 2,493 unaffected siblings. We find a strong burden of de novo point mutations for these genes and specifically implicate nine genes. These include CHD2 and SYNGAP1, genes previously reported in related disorders, and novel genes TRIP12 and PAX5. We also show that mutation carriers generally have lower IQs and enrichment for seizures. These data begin to distinguish genetically distinct subtypes of autism important for aetiological classification and future therapeutics.
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: O'Roak
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Stessman
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Boyle
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Witherspoon
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: B
authors.initials: B
authors.lastname: Martin
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: C
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: L
authors.initials: L
authors.lastname: Vives
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: C
authors.initials: C
authors.lastname: Baker
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Hiatt
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bernier
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: J
authors.initials: J
authors.lastname: Shendure
authors.affiliation: 1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA [2] Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005190:Family; D020022:Genetic Predisposition to Disease; D006801:Humans; D007360:Intelligence / Q000235:genetics; D007361:Intelligence Tests; D009154:Mutation; D051757:PAX5 Transcription Factor / Q000235:genetics; D012306:Risk; D017422:Sequence Analysis, DNA; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D020703:ras GTPase-Activating Proteins / Q000235:genetics
chemical_list: C575189:CHD2 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; C484739:SYNGAP1 protein, human; D020703:ras GTPase-Activating Proteins; C530813:TRIP12 protein, human; D044767:Ubiquitin-Protein Ligases