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Analysis of the contribution of 129 candidate genes to thoracic aortic aneurysm or dissection of a mixed cohort of sporadic and familial cases in South China.

ABSTRACT: Thoracic aortic aneurysm or dissection (TAAD) is a group of life-threatening complex diseases after symptomatic onset with genetic heterogeneity accounting for approximately 20% of cases. Previously, we identified 40 rare variants in 11 TAAD-related core genes among 70 TAAD patients by next-generation sequencing. In this study, we further analyzed the variants in the disease-causing genes in 129 cases of sporadic TAAD and 22 familial cases by whole-exome sequencing. A total of 116 variants in 47 TAAD-related genes were identified, 64.7% (75/116) of which occurred in sporadic TAAD without syndromes, and among these genes, FBN1 was the most common TAAD-related gene. Of the 26.7% (31/116) that were pathogenic or likely pathogenic, almost one third were from sporadic cases without syndromes involving FBN1, SMAD3, SMAD6, MYH11, TGFBR1, MYLK, LOX and LTBP3. Interestingly, the novel VUS (variant of uncertain significance) *879Glu in MCTP2 occurred in two unrelated probands with sporadic acute aortic dissection without a bicuspid aortic valve. Furthermore, more than one variant was detected in 24 patients, and 70.8% (17/24) occurred in sporadic cases. Younger individuals were more likely to carry P/LP (pathogenic or likely pathogenic) variants and harbor more variants. P/LP carriers seem to have a larger aortic diameter, lower D-dimer levels, and a shorter ICU length of stay but longer hospitalization time. In conclusion, we expanded the candidate gene profile of TAAD, especially for sporadic cases without syndromic features. VUSs need further clarification.

SUBMITTER: Li Y

PROVIDER: S-EPMC8205813 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Thoracic aortic aneurysms progressively enlarge and predispose to acute aortic dissections. Up to 25% of individuals with thoracic aortic disease harbor an underlying Mendelian pathogenic variant. An evidence-based strategy for selection of genes to test in hereditary thoracic aortic aneurysm and dissection (HTAAD) helps inform family screening and intervention to prevent life-threatening thoracic aortic events. OBJECTIVES:The purpose of this study was to accurately identify genes that predispose to HTAAD using the Clinical Genome Resource (ClinGen) framework. METHODS:We applied the semiquantitative ClinGen framework to assess presumed gene-disease relationships between 53 candidate genes and HTAAD. Genes were classified as causative for HTAAD if they were associated with isolated thoracic aortic disease and were clinically actionable, triggering routine aortic surveillance, intervention, and family cascade screening. All gene-disease assertions were evaluated by a pre-defined curator-expert pair and subsequently discussed with an expert panel. RESULTS:Genes were classified based on the strength of association with HTAAD into 5 categories: definitive (n = 9), strong (n = 2), moderate (n = 4), limited (n = 15), and no reported evidence (n = 23). They were further categorized by severity of associated aortic disease and risk of progression. Eleven genes in the definitive and strong groups were designated as "HTAAD genes" (category A). Eight genes were classified as unlikely to be progressive (category B) and 4 as low risk (category C). The remaining genes were recent genes with an uncertain classification or genes with no evidence of association with HTAAD. CONCLUSIONS:The ClinGen framework is useful to semiquantitatively assess the strength of gene-disease relationships for HTAAD. Gene categories resulting from the curation may inform clinical laboratories in the development, interpretation, and subsequent clinical implications of genetic testing for patients with aortic disease.

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Analysis of the contribution of 129 candidate genes to thoracic aortic aneurysm or dissection of a mixed cohort of sporadic and familial cases in South China.

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