桑格测序
基因
生物
遗传学
疾病
主动脉夹层
候选基因
转录组
DNA测序
生物信息学
医学
主动脉
基因表达
病理
内科学
作者
Zongzhe Li,Chengming Zhou,Lun Tan,Peng Chen,Yanyan Cao,Xianqing Li,Jiangtao Yan,Hesong Zeng,Dao-Wu Wang,Dao Wen Wang
标识
DOI:10.1007/s11427-018-9382-0
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 next-generation 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 loss-of-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.
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