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

Jinyu Wu^{a, #},
Ping Yu^{a, #},
Xin Jin^{b, #},
Xiu Xu^{c, #},
Jinchen Li^d,
Zhongshan Li^a,
Mingbang Wang^b,
Tao Wang^a,
Xueli Wu^b,
Yi Jiang^a,
Wanshi Cai^e,
Junpu Mei^b,
Qingjie Min^a,
Qiong Xu^c,
Bingrui Zhou^c,
Hui Guo^d,
Ping Wang^f,
Wenhao Zhou^c,
Zhengmao Hu^d,
Yingrui Li^b,
Tao Cai^a,
Yi Wang^c,
Kun Xia^{d
, ,},
Yong-Hui Jiang^{f
, ,},
Zhong Sheng Sun^{a, e
, ,}

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

More Information

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)

These authors contributed equally to this work.

摘要

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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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doi: 10.1016/j.jgg.2018.09.002

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

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)

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doi: 10.1016/j.jgg.2018.09.002

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

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)

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