The contribution of de novo coding mutations to autism spectrum disorder

Autor: Stephen Sanders, Deborah A. Nickerson, Michael Ronemus, Luis E. Gonzalez, Michael F. Walker, Kali Witherspoon, Shan Dong, Niklas Krumm, Jeffrey D. Mandell, Catherine A.W. Sullivan, Laura Vives, Giuseppe Narzisi, Boris Yamrom, Brian J. O'Roak, A. Jeremy Willsey, Jude Kendall, Jay Shendure, Karynne E. Patterson, Ewa A. Grabowska, Jeanselle Dea, Ivan Iossifov, Michael Wigler, Inessa Hakker, Michael C. Schatz, Dan Levy, Ertugrul Dalkic, Zainulabedin Waqar, Bryan W. Paeper, Beicong Ma, Jennifer Troge, Kenny Ye, Matthew W. State, Anthony Leotta, Peter Andrews, Linda Rodgers, Zihua Wang, Yoon-ha Lee, Holly A.F. Stessman, Seungtai Yoon, Evan E. Eichler, Joshua D. Smith, Steven Marks, Michael T. Murtha, Julie Rosenbaum, Liping Wei, Shrikant Mane, W. Richard McCombie
Přispěvatelé: Zonguldak Bülent Ecevit Üniversitesi
Rok vydání: 2014
Předmět:
Zdroj: Nature. 515:216-221
ISSN: 1476-4687
0028-0836
Popis: 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. © 2014 Macmillan Publishers Limited. All rights reserved.
National Institutes of Health: P30CA016359 National Institutes of Health: R01MH101221 National Institutes of Health: RC2HL102923 National Institutes of Health: RC2HL102924 National Institutes of Health: RC2HL102925 National Institutes of Health: RC2HL102926 National Institutes of Health: RC2HL103010 National Institutes of Health: T32GM007266 National Institutes of Health: U54HD083091 National Institutes of Health: UC2HL102923 National Institutes of Health: UC2HL102924 National Institutes of Health: UC2HL102925 National Institutes of Health: UC2HL102926 National Institutes of Health: UC2HL103010 National Institutes of Health: UL1TR000142
Databáze: OpenAIRE
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