Genetic testing in thoracic aortic disease: diagnostic performance of the 2024 ESC algorithm

Heritable thoracic aortic diseases (HTAD) include Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), vascular Ehlers-Danlos syndrome (vEDS), and non-syndromic HTAD (ns-HTAD).1,2 HTAD are monogenic diseases, and genetic testing serves as gold standard for guiding surgical decisions. For atheromatous TAD, surgery is recommended for proximal aortic diameters of ≥ 55 mm. However, surgery is advised for smaller diameters of ≥ 40 mm in patients with high-risk HTAD associated with pathogenic or likely pathogenic variants in genes such as TGFBR1 and TGFBR2.3 Evidence-based genes for genetic testing include FBN1 for MFS, TGFBR1, TGFBR2, SMAD3, and TGFB2 for LDS, COL3A1 for vEDS, and ACTA2, MYH11, MYLK, LOX, and PRKG1 for ns-HTAD.4 Widely accepted, classical criteria for genetic testing of TAD patients5,6 comprise presence of syndromic features of MFS, LDS, or vEDS,7,8 age ≤ 60 years at diagnosis of TAD, and family history of HTAD, specified as the presence of TAD or peripheral or intracranial aneurysm or unexplained sudden death at age < 60 years in a first-degree relative.3 A recent ESC guideline proposed an algorithm for genetic testing of HTAD genes.3 We retrospectively evaluated the diagnostic performance of this algorithm in a large cohort of patients referred to the German hub of the Vascular European Reference Network (VASCERN-GE).