A targeted sequencing approach to find novel pathogenic genes associated with sporadic aortic dissection
| Autor: | Lun Tan, Jiangtao Yan, Zongzhe Li, Xianqing Li, Dao Wen Wang, Yanyan Cao, Dao-Wu Wang, Peng Chen, Hesong Zeng, Chengming Zhou |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adult Male Candidate gene Ubiquitin-Protein Ligases Disease 030204 cardiovascular system & hematology Biology Models Biological General Biochemistry Genetics and Molecular Biology DNA sequencing Pathogenesis 03 medical and health sciences symbols.namesake 0302 clinical medicine Loss of Function Mutation Databases Genetic Exome Sequencing medicine Humans Genetic Predisposition to Disease Gene Genetic Association Studies General Environmental Science Aged Sanger sequencing Aortic dissection Genetics Adenosine Triphosphatases Genetic Variation High-Throughput Nucleotide Sequencing Sequence Analysis DNA Middle Aged medicine.disease Aortic Dissection 030104 developmental biology symbols Female General Agricultural and Biological Sciences Genetic diagnosis |
| Zdroj: | Science China. Life sciences. 61(12) |
| ISSN: | 1869-1889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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