Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder

Elaine T. Lim, Mohammed Uddin, Silvia De Rubeis, Yingleong Chan, Anne S. Kamumbu, Xiaochang Zhang, Alissa M. D'Gama, Sonia N. Kim, Robert Sean Hill, Arthur P. Goldberg, Christopher Poultney, Nancy J. Minshew, Itaru Kushima, Branko Aleksic, Norio Ozaki, Mara Parellada, Celso Arango, Maria J. Penzol, Angel Carracedo, Alexander KolevzonChristina M. Hultman, Lauren A. Weiss, Menachem Fromer, Andreas G. Chiocchetti, Christine M. Freitag, George M. Church, Stephen W. Scherer, Joseph D. Buxbaum, Christopher A. Walsh

Research output: Contribution to journalArticlepeer-review

182 Scopus citations


We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.

Original languageEnglish
Pages (from-to)1217-1224
Number of pages8
JournalNature Neuroscience
Issue number9
StatePublished - 1 Sep 2017


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