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The contribution of de novo coding mutations to autism spectrum disorder

Author

Listed:
  • Ivan Iossifov

    (Cold Spring Harbor Laboratory)

  • Brian J. O’Roak

    (University of Washington School of Medicine
    Molecular & Medical Genetics, Oregon Health & Science University)

  • Stephan J. Sanders

    (University of California, San Francisco, San Francisco, California 94158, USA
    Yale University School of Medicine)

  • Michael Ronemus

    (Cold Spring Harbor Laboratory)

  • Niklas Krumm

    (University of Washington School of Medicine)

  • Dan Levy

    (Cold Spring Harbor Laboratory)

  • Holly A. Stessman

    (University of Washington School of Medicine)

  • Kali T. Witherspoon

    (University of Washington School of Medicine)

  • Laura Vives

    (University of Washington School of Medicine)

  • Karynne E. Patterson

    (University of Washington School of Medicine)

  • Joshua D. Smith

    (University of Washington School of Medicine)

  • Bryan Paeper

    (University of Washington School of Medicine)

  • Deborah A. Nickerson

    (University of Washington School of Medicine)

  • Jeanselle Dea

    (University of California, San Francisco, San Francisco, California 94158, USA)

  • Shan Dong

    (Yale University School of Medicine
    Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University)

  • Luis E. Gonzalez

    (Child Study Center, Yale University School of Medicine)

  • Jeffrey D. Mandell

    (University of California, San Francisco, San Francisco, California 94158, USA)

  • Shrikant M. Mane

    (Yale Center for Genomic Analysis, Yale University School of Medicine)

  • Michael T. Murtha

    (Child Study Center, Yale University School of Medicine)

  • Catherine A. Sullivan

    (Child Study Center, Yale University School of Medicine)

  • Michael F. Walker

    (University of California, San Francisco, San Francisco, California 94158, USA)

  • Zainulabedin Waqar

    (Child Study Center, Yale University School of Medicine)

  • Liping Wei

    (Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University
    National Institute of Biological Sciences)

  • A. Jeremy Willsey

    (University of California, San Francisco, San Francisco, California 94158, USA
    Yale University School of Medicine)

  • Boris Yamrom

    (Cold Spring Harbor Laboratory)

  • Yoon-ha Lee

    (Cold Spring Harbor Laboratory)

  • Ewa Grabowska

    (Cold Spring Harbor Laboratory
    New York Genome Center)

  • Ertugrul Dalkic

    (Cold Spring Harbor Laboratory
    Bulent Ecevit University School of Medicine, 67600 Zonguldak, Turkey)

  • Zihua Wang

    (Cold Spring Harbor Laboratory)

  • Steven Marks

    (Cold Spring Harbor Laboratory)

  • Peter Andrews

    (Cold Spring Harbor Laboratory)

  • Anthony Leotta

    (Cold Spring Harbor Laboratory)

  • Jude Kendall

    (Cold Spring Harbor Laboratory)

  • Inessa Hakker

    (Cold Spring Harbor Laboratory)

  • Julie Rosenbaum

    (Cold Spring Harbor Laboratory)

  • Beicong Ma

    (Cold Spring Harbor Laboratory)

  • Linda Rodgers

    (Cold Spring Harbor Laboratory)

  • Jennifer Troge

    (Cold Spring Harbor Laboratory)

  • Giuseppe Narzisi

    (Cold Spring Harbor Laboratory
    New York Genome Center)

  • Seungtai Yoon

    (Cold Spring Harbor Laboratory)

  • Michael C. Schatz

    (Cold Spring Harbor Laboratory)

  • Kenny Ye

    (Albert Einstein College of Medicine)

  • W. Richard McCombie

    (Cold Spring Harbor Laboratory)

  • Jay Shendure

    (University of Washington School of Medicine)

  • Evan E. Eichler

    (University of Washington School of Medicine
    Howard Hughes Medical Institute)

  • Matthew W. State

    (University of California, San Francisco, San Francisco, California 94158, USA
    Yale University School of Medicine
    Child Study Center, Yale University School of Medicine
    Yale University School of Medicine)

  • Michael Wigler

    (Cold Spring Harbor Laboratory)

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.

Suggested Citation

  • Ivan Iossifov & Brian J. O’Roak & Stephan J. Sanders & Michael Ronemus & Niklas Krumm & Dan Levy & Holly A. Stessman & Kali T. Witherspoon & Laura Vives & Karynne E. Patterson & Joshua D. Smith & Brya, 2014. "The contribution of de novo coding mutations to autism spectrum disorder," Nature, Nature, vol. 515(7526), pages 216-221, November.
  • Handle: RePEc:nat:nature:v:515:y:2014:i:7526:d:10.1038_nature13908
    DOI: 10.1038/nature13908
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