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.

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. AJTR