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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
1 HHMI - Howard Hughes Medical Institute [Boston]
2 Boston Children's Hospital
3 HMS - Harvard Medical School [Boston]
4 BROAD INSTITUTE - Broad Institute of MIT and Harvard
5 Harvard University [Cambridge]
6 MBRU - Mohammed Bin Rashid University of Medicine and Health Sciences
7 MSSM - Icahn School of Medicine at Mount Sinai [New York]
8 PITT - University of Pittsburgh
9 Nagoya University
10 Hospital General Universitario "Gregorio Marañón" [Madrid]
11 UCM - Universidad Complutense de Madrid [Madrid]
12 CIBER-SAM - Centro de Investigación Biomédica en Red Salud Mental [Madrid]
13 USC - Universidade de Santiago de Compostela [Spain]
14 CIBER de Enfermedades Raras (CIBERER)
15 Grupo de Medicina Xenómica - Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain]
16 King Abdulaziz University
17 Karolinska Institutet [Stockholm]
18 UCSF - University of California [San Francisco]
19 Goethe-University Frankfurt am Main
20 NPS-01 - Génétique de l'autisme = Genetics of Autism
NPS - Neurosciences Paris Seine
21 SickKids - The Hospital for sick children [Toronto]
22 University of Toronto
23 McLaughlin Centre for Population Health Risk Assessment
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sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies.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
Contributor : Catalina Betancur Connect in order to contact the contributor
Submitted on : Monday, February 8, 2021 - 9:16:01 PM
Last modification on : Thursday, September 2, 2021 - 8:14:03 AM

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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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