Whole-genome sequencing of quartet families with autism spectrum disorder

• Published in: Nature medicine Vol. 21; no. 2; pp. 185 - 191
• Main 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2015; Nature Publishing Group
• Subjects: 45; 45/23; 631/208/212/2301; Adult; Autism; Biomedical and Life Sciences; Biomedicine; Cancer Research; Child; Child Development Disorders, Pervasive - genetics; DNA sequencing; Families & family life; Female; Genetic aspects; Genetic disorders; Genetic diversity; Genetic Predisposition to Disease; Genetic research; Genomes; Heterogeneity; Humans; Infectious Diseases; Male; Medical research; Metabolic Diseases; Molecular Medicine; Mutation; Neurosciences; Nucleotide sequencing; Parents; Pervasive developmental disorders; resource; Sequence Analysis, DNA; Siblings
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.3792

Whole-genome sequencing of 85 families with two affected siblings reveals considerable genetic heterogeneity in autism spectrum disorder. 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.