摘要
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.
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) in exonic (1.37×10) and 3’-UTR regions (1.42×10) was revealed in comparison with that of whole genome (1.05×10).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.
作者
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
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(Institute of Genomic Medicine,Wenzhou Medical University,Wenzhou 325000,China;BGI-Shenzhen,Shenzhen 518083,China;Department of Child Healthcare,Children's Hospital of Fudan University,Shanghai 200032,China;State Key Laboratory of Medical Genetics,Central South University,Changsha 410078,China;Beijing Institutes of Life Science,Chinese Academy of Sciences,Beijing 100101,China;Department of Pediatrics and Neurobiology,Duke University School of Medicine,Durham,NC 27710,USA)
基金
supported by the grants from the Major State Basic Research Development Program of China(2012CB517902 and 2012CB517904)
National Key Technology Research and Development Program of China(2012BAI03B00)
Special Research Program of National Health and Family Planning Commission of China(201302002)
International S&T Cooperation Program of China(2011DFA30670)
National Natural Science Foundation of China(31571357/31771404)
supported in part by research funding from AstraZeneca Innovation Center China and Wenzhou Medical University
