Genomic landscapes of Chinese sporadic autism spectrum disorders revealed by whole-genome sequencing. (20th October 2018)

• Record Type: Journal Article
• Authors: Wu, Jinyu; Yu, Ping; Jin, Xin; Xu, Xiu; Li, Jinchen; Li, Zhongshan; Wang, Mingbang; Wang, Tao; Wu, Xueli; Jiang, Yi; Cai, Wanshi; Mei, Junpu; Min, Qingjie; Xu, Qiong; Zhou, Bingrui; Guo, Hui; Wang, Ping; Zhou, Wenhao; Hu, Zhengmao; Li, Yingrui; Cai, Tao; Wang, Yi; Xia, Kun; Jiang, Yong-Hui; Sun, Zhong Sheng
• Is Part Of: Journal of genetics and genomics. Volume 45:Number 10(2018)
• Page Start: 527
• Page End: 538
• Publication Date: 2018-10-20
• Subjects: Autism spectrum disorders -- De novo mutations -- Microcephaly-associated genes -- Whole-genome sequencing; Genetics -- Periodicals; Genomics -- Periodicals; 576.505
• DOI: 10.1016/j.jgg.2018.09.002
• Languages: English
• ISSNs: 1673-8527

Abstract

Abstract: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with considerable clinical and genetic heterogeneity. In this study, we identified all classes of genomic variants from whole-genome sequencing (WGS) dataset of 32 Chinese trios with ASD, including de novo mutations, inherited variants, copy number variants (CNVs) and genomic structural variants. A higher mutation rate (Poisson test, P < 2.2 × 10 −16 ) in exonic (1.37 × 10 −8 ) and 3′-UTR regions (1.42 × 10 −8 ) was revealed in comparison with that of whole genome (1.05 × 10 −8 ). Using an integrated model, we identified 87 potentially risk genes ( P < 0.01) from 4832 genes harboring various rare deleterious variants, including CHD8 and NRXN2, implying that the disorders may be in favor to multiple-hit. In particular, frequent rare inherited mutations of several microcephaly-associated genes ( ASPM, WDR62, and ZNF335 ) were found in ASD. In chromosomal structure analyses, we found four de novo CNVs and one de novo chromosomal rearrangement event, including a de novo duplication of UBE3A -containing region at 15q11.2-q13.1, which causes Angelman syndrome and microcephaly, and a disrupted TNR due to de novo chromosomal translocation t(1; 5)(q25.1; q33.2). Taken together, our results suggest that abnormalities of centrosomal function and chromatin remodeling of the microcephaly-associated genes may be implicated in pathogenesis of ASD. Adoption of WGS as a new yet efficient technique to illustrate the full genetic spectrum in complex disorders, such as ASD, could provide novel insights into pathogenesis, diagnosis and treatment.