Comparative Risks of Initial Aortic Events Associated With Genetic Thoracic Aortic Disease

Area of Science:

• Cardiovascular Genetics
• Aortic Diseases
• Medical Genomics

Background:

• Heritable thoracic aortic disease (HTAD) is linked to pathogenic variants in 11 genes.
• Limited data exist to stratify aortic event risks associated with specific HTAD genes.

Purpose of the Study:

• To compare the risk of first aortic events (thoracic aortic aneurysm surgery or dissection) among 7 HTAD genes.
• To analyze risk differences based on variant types within each gene.

Main Methods:

• Retrospective cohort study of 1,028 probands and relatives with rare variants in 7 HTAD genes.
• Assessment of aortic event risk stratified by gene, variant type, sex, proband status, and recruitment location.

Main Results:

• Significant differences in aortic event risk were found among smooth muscle contraction genes (ACTA2, MYLK, PRKG1) and Loeys-Dietz syndrome genes (SMAD3, TGFB2, TGFBR1, TGFBR2).
• Variants in ACTA2, MYLK, PRKG1, and SMAD3 showed higher cumulative incidence of type A aortic dissection than surgery.
• Variants in ACTA2, PRKG1, and TGFBR2 had higher cumulative incidence of type B aortic dissection.
• Specific ACTA2 and TGFBR2 variants were linked to higher aortic event risk with childhood onset, even after adjustments.

Conclusions:

• Gene- and variant-specific data are crucial for managing HTAD.
• Findings support personalized aortic surveillance and clinical management strategies for individuals with HTAD.