Date of Award

January 2025

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Prashanth Vallabhajosyula

Abstract

AimsThoracic aortic disease (TAD), including aneurysms and dissections, present a significant global health challenge due to its typically asymptomatic nature until the onset of critical complications that come with high morbidity and mortality. Effective risk stratification is crucial for early identification and management of patients and their families who are at heightened risk of disease progression. This study aims to evaluate the effectiveness of current genetic testing guidelines for patients with thoracic aortic aneurysms. Methods The study evaluated genetic tests for TAD from 2012 to 2023 in patients aged 18 and older with a thoracic aorta diameter greater than 4 cm. Mutation rates were compared by American College of Cardiology/American Heart Association testing criteria met by patients: age younger than 60 years, syndromic features of connective tissue diseases (CTDs), family history, or none. Results were classified as pathogenic, variants of uncertain significance (VUS), or negative. Genes tested were analyzed in 2 categories: primary (strongly associated with heritable diseases) or secondary (less strongly associated). Results In total, 1034 patients were included: 42.4% aged younger than 60 years, 19.1% with syndromic features of CTD, 41.8% with family history, and 30.7% meeting no criteria. Overall, 3.97% had pathogenic mutations, and 27.27% had VUS. Mutation rates were greatest in patients with syndromic features of CTD (13.2%), followed by patients aged younger than 60 years (5.48%), with a family history (4.63%), and with no criteria met (2.21%). Primary genes had pathogenic mutation rates of 3.29% and VUS rates of 12.19%. Secondary genes had lower pathogenic rates (0.68%) but greater VUS (17.5%). Mutation rates in primary genes peaked at 22% in patients meeting all criteria, whereas those younger than 60 years without family history or syndromic features of CTD had the lowest rate (0.54%). Conclusions This study underscores the evolving role of genetic testing in the risk stratification of patients with thoracic aortic aneurysms. We found that guidelines criteria are not uniformly effective for risk stratification and employing a comprehensive strategy that encompasses the ensemble of these criteria can significantly improve risk stratification. Furthermore, we found that testing genes weakly associated with aortic disease is of limited clinical utility due to high rates of VUS. We propose that refining genetic testing guidelines to incorporate multiple patient criteria could enhance risk stratification and support informed decision-making in genetic testing for TAD.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 05/14/2026

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