Journal
NATURE MEDICINE
Volume 21, Issue 2, Pages 185-191Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3792
Keywords
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Funding
- Autism Speaks
- Autism Speaks Canada
- Neurodevelopment Network (NeuroDevNet)
- Canadian Institutes for Advanced Research
- University of Toronto McLaughlin Centre
- Genome Canada and Ontario Genomics Institute
- government of Ontario
- Canadian Institutes of Health Research
- Hospital for Sick Children Foundation
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Autism spectrum disorder (ASD) is genetically heterogeneous, with evidence for hundreds of susceptibility loci. Previous microarray and exome-sequencing studies have examined portions of the genome in simplex families (parents and one ASD-affected child) having presumed sporadic forms of the disorder. We used whole-genome sequencing (WGS) of 85 quartet families (parents and two ASD-affected siblings), consisting of 170 individuals with ASD, to generate a comprehensive data resource encompassing all classes of genetic variation (including noncoding variants) and accompanying phenotypes, in apparently familial forms of ASD. By examining de novo and rare inherited single-nucleotide and structural variations in genes previously reported to be associated with ASD or other neurodevelopmental disorders, we found that some (69.4%) of the affected siblings carried different ASD-relevant mutations. These siblings with discordant mutations tended to demonstrate more clinical variability than those who shared a risk variant. Our study emphasizes that substantial genetic heterogeneity exists in ASD, necessitating the use of WGS to delineate all genic and non-genic susceptibility variants in research and in clinical diagnostics.
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