Whole-genome sequencing of quartet families with autism spectrum disorder.

Bibliographic Collection: 
Publication Type: Journal Article
Authors: Yuen, Ryan K C; Thiruvahindrapuram, Bhooma; Merico, Daniele; Walker, Susan; Tammimies, Kristiina; Hoang, Ny; Chrysler, Christina; Nalpathamkalam, Thomas; Pellecchia, Giovanna; Liu, Yi; Gazzellone, Matthew J; D'Abate, Lia; Deneault, Eric; Howe, Jennifer L; Liu, Richard S C; Thompson, Ann; Zarrei, Mehdi; Uddin, Mohammed; Marshall, Christian R; Ring, Robert H; Zwaigenbaum, Lonnie; Ray, Peter N; Weksberg, Rosanna; Carter, Melissa T; Fernandez, Bridget A; Roberts, Wendy; Szatmari, Peter; Scherer, Stephen W
Year of Publication: 2015
Journal: Nat Med
Volume: 21
Issue: 2
Pagination: 185-91
Date Published: 2015 Feb
Publication Language: eng
ISSN: 1546-170X
Keywords: Adult, Child, Child Development Disorders, Pervasive, Female, Genetic Predisposition to Disease, Humans, Male, Parents, Sequence Analysis, DNA, Siblings

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.

DOI: 10.1038/nm.3792
Alternate Journal: Nat. Med.