Genomic landscapes of Chinese sporadic autism spectrum disorders revealed by whole-genome sequencing

Jinyu Wu; Ping Yu; Xin Jin; Xiu Xu; Jinchen Li; Zhongshan Li; Mingbang Wang; Tao Wang; Xueli Wu; Yi Jiang; Wanshi Cai; Junpu Mei; Qingjie Min; Qiong Xu; Bingrui Zhou; Hui Guo; Ping Wang; Wenhao Zhou; Zhengmao Hu; Yingrui Li; Tao Cai; Yi Wang; Kun Xia; Yong-Hui Jiang; Zhong Sheng Sun

doi:10.1016/j.jgg.2018.09.002

Volume 45 Issue 10

Oct. 2018

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Article Navigation > Journal of Genetics and Genomics > 2018 > 45(10): 527-538

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Genomic landscapes of Chinese sporadic autism spectrum disorders revealed by whole-genome sequencing

doi: 10.1016/j.jgg.2018.09.002

a
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China
b
BGI-Shenzhen, Shenzhen 518083, China
c
Department of Child Healthcare, Children's Hospital of Fudan University, Shanghai 200032, China
d
State Key Laboratory of Medical Genetics, Central South University, Changsha 410078, China
e
Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
f
Department of Pediatrics and Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA

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Corresponding author: E-mail address: xiakun@sklmg.edu.cn (Kun Xia); E-mail address: yong-hui.jiang@duke.edu (Yong-Hui Jiang); E-mail address: sunzs@mail.biols.ac.cn (Zhong Sheng Sun)
Received Date: 2018-05-15
Accepted Date: 2018-09-09
Rev Recd Date: 2018-08-25

Available Online: 2018-10-21

Publish Date: 2018-10-20

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, includingCHD8 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.
- Autism spectrum disorders,
- Microcephaly-associated genes,
- Whole-genome sequencing

These authors contributed equally to this work.

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