utism spectrum disorder (ASD) is a neurodevelopmental disorder with considerable clinical and geneticheterogeneity. In this study, we identified all classes of genomic variants from whole-genome sequencing(WGS) dataset of 32 Chinese trios with ASD, includingde novomutations, inherited variants, copynumber variants (CNVs) and genomic structural variants. A higher mutation rate (Poisson test,P<2.21016) in exonic (1.37108) and 30-UTR regions (1.42108) was revealed in comparison withthat of whole genome (1.05108). Using an integrated model, we identified 87 potentially risk genes(P<0.01) from 4832 genes harboring various rare deleterious variants, includingCHD8andNRXN2,implying that the disorders may be in ... More
utism spectrum disorder (ASD) is a neurodevelopmental disorder with considerable clinical and geneticheterogeneity. In this study, we identified all classes of genomic variants from whole-genome sequencing(WGS) dataset of 32 Chinese trios with ASD, includingde novomutations, inherited variants, copynumber variants (CNVs) and genomic structural variants. A higher mutation rate (Poisson test,P<2.21016) in exonic (1.37108) and 30-UTR regions (1.42108) was revealed in comparison withthat of whole genome (1.05108). Using an integrated model, we identified 87 potentially risk genes(P<0.01) from 4832 genes harboring various rare deleterious variants, includingCHD8andNRXN2,implying that the disorders may be in favor to multiple-hit. In particular, frequent rare inherited mu-tations of several microcephaly-associated genes (ASPM,WDR62, andZNF335) were found in ASD. Inchromosomal structure analyses, we found fourde novoCNVs and onede novochromosomal rear-rangement event, including ade novoduplication ofUBE3A-containing region at 15q11.2-q13.1, whichcauses Angelman syndrome and microcephaly, and a disruptedTNRdue tode novochromosomaltranslocation t(1; 5)(q25.1; q33.2). Taken together, our results suggest that abnormalities of centrosomalfunction and chromatin remodeling of the microcephaly-associated genes may be implicated in patho-genesis of ASD. Adoption of WGS as a new yet efficient technique to illustrate the full genetic spectrum incomplex disorders, such as ASD, could provide novel insights into pathogenesis, diagnosis and treatment.Copyright©2018, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, andGenetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved
