99-Case Study of Sporadic Aortic Dissection by Whole Exome Sequencing Indicated Novel Disease-Associated Genes and Variants in Chinese Population

Abstract

Background. In this study, the whole exome sequencing in human aortic dissection, a highly lethal cardiovascular disease, was investigated to explore the aortic dissection-associated genes and variants in Chinese population. Methods. Whole exome sequencing was performed in 99 cases of aortic dissection. All single nucleotide polymorphisms (SNPs), insertions/deletions (InDels), and copy number variations (CNVs) were filtered to exclude the benign variants. Enrichment analysis and disease-gene correlation analysis were performed. Results. 3425873 SNPs, 685245 InDels, and 1177 CNVs were identified, and aortic dissection-associated SNPs, InDels, and CNVs were collected. After the disease correlation analysis, 20 candidate genes were identified. Part of these genes such as MYH11, FBN1, and ACTA2 were consistent with previous studies, while MLX, DAB2IP, EP300, ZFYVE9, PML, and PRKCD were newly identified as candidate aortic dissection-associated genes. Conclusion. The pathogenic and likely pathogenic variants in most of AD-associated genes (FBN1, MYH11, EFEMP2, TGFBR2, FBN2, COL3A1, and MYLK) were identified in our cohort study, and pathogenic CNVs involved in MYH11, COL family, and FBN were also identified which are not detectable by other NGS analysis. The correlation between MLX, DAB2IP, EP300, ZFYVE9, PML, PRKCD, and aortic dissection was identified, and EP300 may play a key role in AD.

Large Vessel Cell Heterogeneity and Plasticity: Focus in Aortic Aneurysms

“…DOI: 10.1161/ATVBAHA.121.316237 pathways is partly overlapping with the syndromic and nonsyndromic familial TAAs. 36,37 In AAA, genetic studies have identified 87 genes or loci with polymorphisms on AAA patients but only 10 of them with strong or moderate evidence for association with the disease. These are related to cholesterol metabolism, atherosclerosis, inflammation, and hypertension.…”

“…Even a broader range of somatic mutations have been detected in a sporadic TAA; although, a list of risk genes and affected signaling pathways is partly overlapping with the syndromic and nonsyndromic familial TAAs. 36,37…”

Fibrillin-1 Gene Polymorphisms (rs145233125, rs11070646, rs201170905) Are Associated With the Susceptibility and Clinical Prognosis of DeBakey Type III Aortic Dissection in Chinese Han Population

“…14,15 Previous research found that 2 SNPs in the FBN1 gene, rs2118181 and rs10519177, were found to be associated with thoracic aortic dissection (TAD), nonclamped thoracic aortic aneurysm (TAA), and TAAD in previous studies. 12,16 However, to our knowledge, no related research about the association between rs201170905 or rs11070646 of FBN1 gene and DeBakey type III AD has been reported. In this study, we observed that individuals with GG genotype of rs11070646 and rs201170905 were at an increased risk for DeBakey type III AD.…”

Tracking an Elusive Killer: State of the Art of Molecular-Genetic Knowledge and Laboratory Role in Diagnosis and Risk Stratification of Thoracic Aortic Aneurysm and Dissection

“…Concerning syndromic TAA in patients diagnosed as vEDS, few post-mortem cases were reported in 2010 [ 107 ], and 33 unrelated individuals or families were found to carry COL3A1 splicing mutations or small deletions partially removing splice-junctions sequences [ 108 ], and patients developing post-surgical or sudden aortic events are reported [ 109 , 110 , 111 ]. COL3A1 variants were additionally found to be associated with sporadic forms of TAAD in recent WES and case-control studies [ 112 , 113 ]. The type of variant involving the COL3A1 gene was also been suggested to correlate with the phenotype severity of vEDS; specifically, a subgroup of patients in a large European cohort bearing non-glycine missense and/or genetic variations at the C- and N-termini of type III procollagens was found to develop a later-onset and a milder phenotype with higher rates of aortic complications [ 114 ], while mutations at splice-donor sites were associated with higher mortality rates with respect to those involving the splice-acceptor sequences [ 115 ].…”