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J Genet Genomics. 2018 Oct 20;45(10):527-538. doi: 10.1016/j.jgg.2018.09.002. Epub 2018 Oct 21.

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

Author information

1
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China.
2
BGI-Shenzhen, Shenzhen 518083, China.
3
Department of Child Healthcare, Children's Hospital of Fudan University, Shanghai 200032, China.
4
State Key Laboratory of Medical Genetics, Central South University, Changsha 410078, China.
5
Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.
6
Department of Pediatrics and Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA.
7
State Key Laboratory of Medical Genetics, Central South University, Changsha 410078, China. Electronic address: xiakun@sklmg.edu.cn.
8
Department of Pediatrics and Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: yong-hui.jiang@duke.edu.
9
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China; Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: sunzs@mail.biols.ac.cn.

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.

KEYWORDS:

Autism spectrum disorders; De novo mutations; Microcephaly-associated genes; Whole-genome sequencing

PMID:
30392784
DOI:
10.1016/j.jgg.2018.09.002

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