Perspective:

Multiple genetic abnormalities have been associated with HTAD, including pathogenic variants in FBN1 (associated with Marfan syndrome), variants in genes encoding proteins involved in the TGFß signaling pathway (associated with Loeys-Dietz syndrome), and variants in genes encoding proteins involved in smooth muscle contraction. This study used data from the Montalcino Aortic Consortium to evaluate probands and relatives with variants in seven genes for HTAD, including four genes associated with the TGFß signaling pathway and three associated with proteins involved in smooth muscle contraction.

The study found significant differences in risks between specific genetic groups, with higher aortic dissection risk compared to elective aneurysm surgery among people with smooth muscle contraction genetic variants compared to TGFß variants; significant differences in the cumulative risk of aortic events among people with various TGFß genetic variants; the highest burden of childhood-onset aortic events associated with two TGFß signaling pathway variants (TGFBR1 and TGFBR2); and a higher incidence of type B aortic dissection associated with two variants associated with smooth muscle contraction (ACTA2 and PRKG1) and one associated with the TGFß pathway (TGFBR2). With different clinical risks associated with different specific genetic variants, the findings raise the question of whether current syndromic classifications (e.g., labeling all TGFß genetic abnormalities as ‘Loeys-Dietz syndrome’) are appropriate. If the data from this study are reproducible, then clinical management might be best defined by recommendations specific to certain genetic variants.