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
aInstitute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China
bBGI-Shenzhen, Shenzhen 518083, China
cDepartment of Child Healthcare, Children's Hospital of Fudan University, Shanghai 200032, China
dState Key Laboratory of Medical Genetics, Central South University, Changsha 410078, China
eBeijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
fDepartment of Pediatrics and Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA
More InformationCorresponding 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.Keywords: Autism spectrum disorders,
Microcephaly-associated genes,
Whole-genome sequencing
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