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Nat Neurosci. 2017 Sep;20(9):1217-1224. doi: 10.1038/nn.4598. Epub 2017 Jul 17.

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

Author information

1
Division of Genetics and Genomics, Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts, USA.
2
Departments of Pediatrics and Neurology, Harvard Medical School, Boston, Massachusetts, USA.
3
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
4
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA.
5
Mohammed Bin Rashid University of Medicine and Health Sciences, College of Medicine, Dubai, United Arab Emirates.
6
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai,New York, New York, USA.
7
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
8
Department of Psychiatry, Center For Excellence in Autism Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
9
Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
10
Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, Madrid, Spain.
11
Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, Madrid, Spain.
12
Grupo de Medicina Xenomica, Universidade de Santiago de Compostela, Centro Nacional de Genotipado-Plataforma de Recursos Biomoleculares y Bioinformaticos-Instituto de Salud Carlos III (CeGen-PRB2-ISCIII), Santiago de Compostela, Spain.
13
Grupo de Medicina Xenomica, CIBERER, Fundacion Publica Galega de Medicina Xenomica-SERGAS, Santiago de Compostela, Spain.
14
Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
15
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
16
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
17
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
18
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
19
Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.
20
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
21
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Autism Research and Intervention Center of Excellence, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany.
22
The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
23
Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, Ontario, Canada.
24
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
25
McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada.

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.

PMID:
28714951
PMCID:
PMC5672813
DOI:
10.1038/nn.4598
[Indexed for MEDLINE]
Free PMC Article

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