Association between Genetic Variants of Uncertain Significance in Thoracic Aortic Disease and Outcomes Following Aortic Surgery.

BACKGROUND: Genetic testing increasingly identifies variants of uncertain significance (VUS) in patients with thoracic aortic disease. Treated as benign, VUS impact on outcomes remains unclear. We evaluated associations between genetic variants and surgical outcomes in patients undergoing aortic surgery. METHODS: This single-center retrospective study evaluated adults with thoracic aortic aneurysm or dissection who underwent genetic testing between 2012-2023. Patients were classified as having pathogenic variants, VUS, or variant-negative in the 11 primary genes for thoracic aortic disease. The primary outcome was a composite of death or reoperation. Cox regression assessed genetic status with variant-negative as reference, adjusting for age, sex, bicuspid aortic valve, dissection type, and aneurysm type. RESULTS: Among 1,004 patients, 866 (86.3%) were variant-negative, 107 (10.7%) had VUS, and 31 (3.1%) had pathogenic variants. Overall, there were 713 surgical patients with median follow-up of 57.4 (39.5-82.0) months. VUS were independently associated with a twofold increased risk of death or reoperation compared with variant-negative (HR 2.13, 95% CI 1.35-3.37, p=0.001). Pathogenic variants showed no significant association (HR 0.99, 95% CI 0.38-2.58, p=0.99). Other significant predictors included type A dissection (HR 3.37), type B dissection (HR 4.06), descending aneurysm (HR 2.04), arch aneurysm (HR 1.92), and greater age at surgery (HR 1.04). CONCLUSIONS: VUS status in validated thoracic aortic disease genes conferred twofold increased risk of death or reoperation, suggesting current management treating these variants as benign may be inadequate. Further prospective studies are needed to refine risk stratification for patients with VUS.