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

Yuen RK1, Thiruvahindrapuram B1, Merico D1, Walker S1, Tammimies K2, Hoang N3, Chrysler C4, Nalpathamkalam T1, Pellecchia G1, Liu Y5, Gazzellone MJ1,D'Abate L1, Deneault E1, Howe JL1, Liu RS1, Thompson A4, Zarrei M1, Uddin M1, Marshall CR6, Ring RH7, Zwaigenbaum L8, Ray PN9, Weksberg R10, Carter MT11, Fernandez BA12, Roberts W13, Szatmari P14, Scherer SW15.

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Abstract

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.