A targeted sequencing approach to find novel pathogenic genes associated with sporadic aortic dissection  

作　　者：Zongzhe Li Chengming Zhou Lun Tan Peng Chen Yanyan Cao Xianqing Li Jiangtao Yan Hesong Zeng Dao-Wu Wang Dao-Wen Wang 

机构地区：[1]Division of Cardiology,Departments of Internal Medicine and Genetic Diagnosis Center,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China [2]Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders,Wuhan 430030,China [3]State Key Laboratory of Reproductive Medicine,Clinical Center of Reproductive Medicine and Department of Cardiology,the First Affiliated Hospital,Nanjing Medical University,Nanjing 210029,China

出　　处：《Science China(Life Sciences)》2018年第12期1545-1553,共9页中国科学（生命科学英文版）

基　　金：supported by National Natural Science Foundation of China (81700413);National Key Basic Research Program of China (2012CB518004, 2012CB517801)

摘　　要：Aortic dissection(AD) is a heterogeneous genetic disease of the aorta with high mortality and poor prognosis. However, only few genetic causes of AD have been explored till date. After conducting a broad literature review focused on identifying potential pathogenic pathways, we designed a panel containing 152 AD-associated genes to conduct massively parallel targeted nextgeneration sequencing of 702 sporadic aortic dissection patients and 163 matched healthy controls. After validation by Sanger sequencing, we identified 21 definitely pathogenic and 635 likely pathogenic variants in 61.25%(430/702) of patients. In these patients, 34.88%(150/430) harbored more than one variant that was either definitely or likely to be pathogenic. Among the candidate genes, we identified 546 likely pathogenic variants in 47.72%(335/702) of patients. Importantly, we identified 94 lossof-function(LOF) variants in 45 genes in AD patients, but only five LOF variants in the controls(P=1.34×10^(-4)). With a burden test, we highlighted RNF213 as an important new gene for AD pathogenesis. We also performed transcriptome sequencing of human aorta tissues to evaluate the expression levels of these newly identified genes. Our study has compiled a comprehensive genetic map of sporadic AD in the Han Chinese population. We believe it will facilitate risk predicting and genetic diagnosis of this severe disease in the future.Aortic dissection(AD) is a heterogeneous genetic disease of the aorta with high mortality and poor prognosis. However, only few genetic causes of AD have been explored till date. After conducting a broad literature review focused on identifying potential pathogenic pathways, we designed a panel containing 152 AD-associated genes to conduct massively parallel targeted nextgeneration sequencing of 702 sporadic aortic dissection patients and 163 matched healthy controls. After validation by Sanger sequencing, we identified 21 definitely pathogenic and 635 likely pathogenic variants in 61.25%(430/702) of patients. In these patients, 34.88%(150/430) harbored more than one variant that was either definitely or likely to be pathogenic. Among the candidate genes, we identified 546 likely pathogenic variants in 47.72%(335/702) of patients. Importantly, we identified 94 lossof-function(LOF) variants in 45 genes in AD patients, but only five LOF variants in the controls(P=1.34×10^(-4)). With a burden test, we highlighted RNF213 as an important new gene for AD pathogenesis. We also performed transcriptome sequencing of human aorta tissues to evaluate the expression levels of these newly identified genes. Our study has compiled a comprehensive genetic map of sporadic AD in the Han Chinese population. We believe it will facilitate risk predicting and genetic diagnosis of this severe disease in the future.

关 键 词：AORTIC DISSECTION next-generation SEQUENCING genetic diagnosis 

分 类 号：Q[生物学]