title: The contribution of de novo coding mutations to autism spectrum disorder.
abstract: Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Iossifov
authors.affiliation: 1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA [2] Molecular &Medical Genetics, Oregon Health &Science University, Portland, Oregon 97208, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Roak
authors.affiliation: 1] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA [2] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ronemus
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: Niklas
authors.initials: N
authors.lastname: Krumm
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Levy
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: Holly 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: Kali 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: Laura
authors.initials: L
authors.lastname: Vives
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: Karynne E
authors.initials: KE
authors.lastname: Patterson
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Paeper
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Jeanselle
authors.initials: J
authors.lastname: Dea
authors.affiliation: 1] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Dong
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Gonzalez
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Mandell
authors.affiliation: Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Shrikant M
authors.initials: SM
authors.lastname: Mane
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Murtha
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Sullivan
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Walker
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Zainulabedin
authors.initials: Z
authors.lastname: Waqar
authors.affiliation: 1] Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China [2] National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Wei
authors.affiliation: 1] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA [2] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: A Jeremy
authors.initials: AJ
authors.lastname: Willsey
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Yamrom
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Yoon-ha
authors.initials: YH
authors.lastname: Lee
authors.affiliation: 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] New York Genome Center, New York, New York 10013, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Grabowska
authors.affiliation: 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] Department of Medical Biology, Bulent Ecevit University School of Medicine, 67600 Zonguldak, Turkey.
authors.forename: Ertugrul
authors.initials: E
authors.lastname: Dalkic
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Zihua
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Marks
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Andrews
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Leotta
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Jude
authors.initials: J
authors.lastname: Kendall
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Inessa
authors.initials: I
authors.lastname: Hakker
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Rosenbaum
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Beicong
authors.initials: B
authors.lastname: Ma
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Rodgers
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Troge
authors.affiliation: 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] New York Genome Center, New York, New York 10013, USA.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Narzisi
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Seungtai
authors.initials: S
authors.lastname: Yoon
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Schatz
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Kenny
authors.initials: K
authors.lastname: Ye
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: W Richard
authors.initials: WR
authors.lastname: McCombie
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: Jay
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, Seattle, Washington 98195, USA.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.affiliation: 1] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA [2] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA [4] Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: State
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wigler
mesh_terms: D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D016000:Cluster Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D005796:Genes; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007361:Intelligence Tests; D008297:Male; D009154:Mutation / Q000235:genetics*; D016366:Open Reading Frames / Q000235:genetics*; D015203:Reproducibility of Results