Eur J Hum Genet. 2026 Jun 3. doi: 10.1038/s41431-026-02145-3. Online ahead of print.
ABSTRACT
Thoracic aortic dissection (TAD) is a life-threatening condition with a significant genetic contribution. This study evaluated the clinical implications of diagnostic screening of 368 TAD patients for (likely) pathogenic (LPP) variants in 23 TAD-associated genes and sought to identify genotype-phenotype correlations. Clinically relevant causative variants were identified in 12.5% of patients. Most patients were explained by LPP variants in FBN1 (n = 13), ACTA2 (n = 8), COL3A1 (n = 6), and TGFBR1 (n = 5), and all identified LPP variants were found in the genes identified by the ClinGen Aortopathy Expert Panel to be definitively or strongly associated with heritable aortopathy. LPP patients had a significantly younger age at dissection and had almost a two-fold increase in risk of dissection at any age compared to those without a rare genetic variant (HR, 1.98; 95% CI, 1.4-2.8; p < 0.001). COL3A1 LPP variant-harboring patients were particularly young, with a median age at dissection of 22 years. Patients with more than one variant of uncertain significance (VUS) experienced dissection at younger ages compared to single VUS-harboring individuals (p = 0.002). Presence of the MYH11 NM_001040113.2:c.3787_3789del (p.Lys1263del) VUS was indicative of a younger age at dissection. In conclusion, our study demonstrated the clinical utility of current genetic testing in TAD patients. Yet, it highlights the need for improved VUS interpretation and their consideration as risk factors. Further improvements in the screening approaches are needed to increase clinical utility and, hence, mitigate TAD morbidity and mortality by identification of at-risk individuals.
PMID:42236916 | DOI:10.1038/s41431-026-02145-3