Abstract 4147885: Aortic Growth Mapping to Examine Genotype-Phenotype Correlations in Heritable Thoracic Aortic Disease and Variants of Unknown Significance

Introduction: Methods to define genotype-phenotype correlations are needed to advance precision medicine in heritable thoracic aortic disease (HTAD), particularly for variants of unknown significance (VUS), where evidence is sparse. Vascular deformation mapping (VDM) - an image analysis tool - provides accurate, three-dimensional (3D) aortic growth mapping, to better define disease severity and phenotypes. Research Question: Does the extent of 3D aortic growth mapping vary among patients evaluated for HTAD according to their genetic test results? Methods: We included adults undergoing genetic testing for HTAD with at least 2 CT angiograms spanning ≥2 year interval. VDM quantified the 3D thoracic aortic growth over the longest interval. Results: We analyzed 122 patients (imaging follow-up 5.0 years ± 3.2), a median age of 62.5 years (range: 26-87), 33.6% females, 50% with a history of aneurysm and/or dissection in first-degree relatives, 32% with prior ascending aortic replacement (AAR). Genetic testing results were pathogenic/likely pathogenic (P/LP) in 17%, negative or benign/likely benign (B/LB) in 59%, and VUS in 46%. Among those with negative genetic testing, 80% had no growth by VDM. Among P/LP patients, 65% had at least one affected segment (6% showing growth without AAR; 24% with prior AAR; 35% with growth beyond AAR). Among VUS patients, 44% exhibited no aortic growth and 56% demonstrated aortic growth by VDM (30% with growth and native aorta; 26% with growth beyond the prior AAR). During follow-up, 10 VUS mutations were re-classified as B/LB or P/LP and VDM growth severity assessments were concordant with the re-classified category in 6 (60%). Among those with growth of the native aorta distal to AAR, 50% showed growth at non-dilated (<30 mm) diameters. Conclusion: HTAD presents with variable aortic enlargement patterns that are effectively characterized by VDM, providing an avenue for patient-specific risk assessment and decision-making, especially for VUS cases.