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

Elaine Lim 1, 2, 3, 4, 5 Mohammed Uddin 6 Silvia de Rubeis 7 Yingleong Chan 4, 5 Anne Kamumbu 1, 2, 3, 4 Xiaochang Zhang 1, 2, 3, 4 Alissa d'Gama 1, 2, 3, 4 Sonia Kim 1, 2, 3, 4 Robert Sean Hill 1, 2, 3, 4 Arthur Goldberg 7 Christopher Poultney 7 Nancy Minshew 8 Itaru Kushima 9 Branko Aleksic 9 Norio Ozaki 9 Mara Parellada 10, 11, 12 Celso Arango 10, 11, 12 Maria Penzol 10, 12 Angel Carracedo 13, 14, 15, 16 Alexander Kolevzon 7 Christina Hultman 17 Lauren Weiss 18 Menachem Fromer 7 Andreas Chiocchetti 19 Christine Freitag 19 Catalina Betancur 20 George Church 4, 5 Stephen Scherer 21, 22, 23 Joseph Buxbaum 7 Christopher Walsh 1, 2, 3, 4
Abstract : 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sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies.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.
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https://www.hal.inserm.fr/inserm-03135341
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Submitted on : Monday, February 8, 2021 - 9:16:01 PM
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Elaine Lim, Mohammed Uddin, Silvia de Rubeis, Yingleong Chan, Anne Kamumbu, et al.. Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Nature Neuroscience, Nature Publishing Group, 2017, 20 (9), pp.1217-1224. ⟨10.1038/nn.4598⟩. ⟨inserm-03135341⟩

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