The contribution of de novo coding mutations to autism spectrum disorder

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, Bryan Paeper, Deborah A. Nickerson, Jeanselle Dea, Shan Dong, Luis E. Gonzalez, Jeffrey D. Mandell, Shrikant M. Mane, Michael T. Murtha, Catherine A. Sullivan, Michael F. Walker, Zainulabedin Waqar, Liping Wei, A. Jeremy Willsey, Boris Yamrom, Yoon-ha Lee, Ewa Grabowska, Ertugrul Dalkic, Zihua Wang, Steven Marks, Peter Andrews, Anthony Leotta, Jude Kendall, Inessa Hakker, Julie Rosenbaum, Beicong Ma, Linda Rodgers, Jennifer Troge, Giuseppe Narzisi, Seungtai Yoon, Michael C. Schatz, Kenny Ye, W. Richard McCombie, Jay Shendure (), Evan E. Eichler (), Matthew W. State () and Michael Wigler ()
Additional contact information
Ivan Iossifov: Cold Spring Harbor Laboratory
Brian J. O’Roak: University of Washington School of Medicine
Stephan J. Sanders: University of California, San Francisco, San Francisco, California 94158, USA
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
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
A. Jeremy Willsey: University of California, San Francisco, San Francisco, California 94158, USA
Boris Yamrom: Cold Spring Harbor Laboratory
Yoon-ha Lee: Cold Spring Harbor Laboratory
Ewa Grabowska: Cold Spring Harbor Laboratory
Ertugrul Dalkic: Cold Spring Harbor Laboratory
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
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
Matthew W. State: University of California, San Francisco, San Francisco, California 94158, USA
Michael Wigler: Cold Spring Harbor Laboratory

Nature, 2014, vol. 515, issue 7526, 216-221

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13908

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