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NPJ Genom Med. 2016 Aug 3;1:160271-1602710.

Genome-wide characteristics of de novo mutations in autism.

Author information

1
The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
2
BGI-Shenzhen, Yantian, Shenzhen, China.
3
Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada.
4
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
5
Center of Neurodevelopmental Disorders (KIND), Pediatric Neuropsychiatry Unit, Karolinska Institutet, Stockholm, Sweden.
6
Google, Mountain View, California, USA.
7
Autism Speaks, Princeton, New Jersey, USA.
8
The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Molecular Genetics, Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
9
Bloorview Research Institute, University of Toronto, Toronto, Ontario, Canada.
10
Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
11
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
12
Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada; Provincial Medical Genetic Program, Eastern Health, St. John's, Newfoundland, Canada.
13
Autism Research Unit, The Hospital for Sick Children, Toronto, Ontario, Canada.
14
Autism Research Unit, The Hospital for Sick Children, Toronto, Ontario, Canada; Child Youth and Family Services, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
15
Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
16
The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada; McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada.

Abstract

De novo mutations (DNMs) are important in Autism Spectrum Disorder (ASD), but so far analyses have mainly been on the ~1.5% of the genome encoding genes. Here, we performed whole genome sequencing (WGS) of 200 ASD parent-child trios and characterized germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only (p=4.2×10-10). However, when clustered DNMs (those within 20kb) were found in ASD, not only did they mostly originate from the mother (p=7.7×10-13), but they could also be found adjacent to de novo copy number variations (CNVs) where the mutation rate was significantly elevated (p=2.4×10-24). By comparing DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases (p=8.0×10-9; OR=1.84), of which 15.6% (p=4.3×10-3) and 22.5% (p=7.0×10-5) were in the non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, boundaries involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD risk- and epigenetic- genes DNMT3A and ADNP. Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the etiology of ASD.

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