Specific Genetic Variants Clinically Important in Heritable Thoracic Aortic Disease

Sonogram of an aortic dissection
Sonogram of an aortic dissection
Researchers sought to determine the relationship between risk for first aortic event and 7 specific genes related to heritable thoracic aortic disease.

A study published in the Journal of the American College of Cardiology supports personalized aortic surveillance and clinical management strategies on the basis of genetics among patients with heritable thoracic aortic disease (HTAD).

Patients (N=1028) with HTAD caused by inherited rare variants in 1 of 7 genes (ACTA2, MYLK, PRKG1, TGFBR1, TGFBR2, SMAD3, and TGFB2) and their relatives were included in this analysis. Risk for aortic events were evaluated on the basis of genetic- and variant-specific factors.

The study population comprised 51% men, aged median 33 (IQR, 19-49) years, 78% had a missense substitution, 12% a truncating variant resulting in premature codon termination and nonsense-mediated decay, and 9% had a truncating variant resulting in premature codon termination and escape of nonsense-mediated decay. The gene that most patients carried a rare variant in was ACTA2 (n=306), followed by TGFBR2 (n=236), SMAD3 (n=211), TGFBR1 (n=141), MYLK (n=55), TGFB2 (n=42), and PRKG1 (n=37). All PRKG1 variants were observed among patients recruited in North America and no patients recruited from Australia or Japan had MYLK, SMAD3, or TGFB2 variants.

Stratified by gene and age, the cumulative incidence of composite aortic event was 15% by 25 years of age and 69% by 65 years of age among patients with an ACTA2 variant. Compared with ACTA2, the incidence of an aortic event tended to be higher among patients with PRKG1 variants (cumulative incidence, 25 years: 27%; 65 years: 86%; P =.051) and was significantly lower among patients with SMAD3 (cumulative incidence, 25 years: 1%; 65 years: 66%; P =.001) or MYLK (cumulative incidence, 25 years: 4%; 65 years: 47%; P =.019) variants.

Stratified by event, significant group differences for elective aneurysm procedure were observed among patients with TGFB2 (P <.001), TGFBR1 (P <.001), TGFBR2 (P <.001), PRKG1 (P =.018), and SMAD3 (P =.035)variants; for type A aortic dissection among patients with TGFBR2 (P =.049) variants; and for type B aortic dissection among patients with PRKG1 (P =.009), SMAD3 (P =.01), and TGFBR1 (P =.017) variants compared with the ACTA2 variant cohort.

In the multivariate analysis which adjusted for gender and location of recruitment, risk of an aortic event was higher among men with ACTA2, TGFBR1, TGFB2 and TGFBR2 variants compared with women. Risk for an event was higher for Europeans with MYLK and lower for Europeans with SMAD3 variants compared with individuals recruited from North America.

This study may be limited by not examining additional risk factors, such as family history, comorbidities, or medications.

“The accumulating data on gene- and variant-specific aortic outcomes for HTAD genes may be used to develop algorithms for incorporating molecular diagnosis, along with clinical features and family history, into medical decision-making to improve outcomes and minimize costs for the care of patients with HTAD,” the study authors wrote.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Regalado ES, Morris SA, Braverman AC, et al. Comparative risks of initial aortic events associated with genetic thoracic aortic disease. J Am Coll Cardiol. Published online August 22, 2022. doi:10.1016/j.jacc.2022.05.054