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Science China Life Sciences

, Volume 61, Issue 12, pp 1545–1553 | Cite as

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

  • Zongzhe Li
  • Chengming Zhou
  • Lun Tan
  • Peng Chen
  • Yanyan Cao
  • Xianqing Li
  • Jiangtao Yan
  • Hesong Zeng
  • Dao-Wu Wang
  • Dao-Wen WangEmail author
Research Paper

Abstract

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.

Keywords

aortic dissection next-generation sequencing genetic diagnosis 

Notes

Acknowledgements

This work was supported by National Natural Science Foundation of China (81700413) and National Key Basic Research Program of China (2012CB518004, 2012CB517801).

Supplementary material

11427_2018_9382_MOESM1_ESM.doc (296 kb)
Supplementary material, approximately 296 KB.
11427_2018_9382_MOESM2_ESM.doc (752 kb)
Table S5 The gene reads of the two samples performing transcriptome sequencing

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Copyright information

© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Zongzhe Li
    • 1
    • 2
  • Chengming Zhou
    • 1
    • 2
  • Lun Tan
    • 1
    • 2
  • Peng Chen
    • 1
    • 2
  • Yanyan Cao
    • 1
    • 2
  • Xianqing Li
    • 1
    • 2
  • Jiangtao Yan
    • 1
    • 2
  • Hesong Zeng
    • 1
    • 2
  • Dao-Wu Wang
    • 3
  • Dao-Wen Wang
    • 1
    • 2
    Email author
  1. 1.Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological DisordersWuhanChina
  3. 3.State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine and Department of Cardiology, the First Affiliated HospitalNanjing Medical UniversityNanjingChina

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