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, Michael Wigler

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.