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

• DOI: 10.1038/nn.4598
• Publication Date: 2017-07-17T15:05:45Z
• Authors: 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 Kolevzon; Christina M Hultman; Lauren A Weiss; Menachem Fromer; Andreas G Chiocch...; Christine M Freitag; ; George M Church; Stephen W Scherer; Joseph D Buxbaum; Christopher A Walsh
• Keywords: Nonsynonymous substitution; Proband

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sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies.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.