Abstract Body (Do not enter title and authors here): Introduction: Pathogenic (P) or likely pathogenic (LP) aortopathy gene variants cause hereditary thoracic aortic aneurysm and dissection, but P/LP variants only explain approximately 20% of cases of thoracic aortic disease. Variants of unknown significance (VUS) are frequently identified among individuals undergoing genetic testing for thoracic aortic disease, however managing patients with VUSs remains clinically challenging.
Hypothesis: Bioinformatic tools can be used to determine thresholds above which VUSs may be considered “high-risk.”
Methods: Primary analyses were performed in the Penn Medicine Biobank (PMBB) which is composed of 43,731 participants who volunteered to have clinical information linked to biospecimen data including DNA which has undergone whole exome sequencing. PMBB participants were screened for VUSs in one of 11 aortopathy genes. VUS REVEL, AlphaMissense and minor allele frequency (MAF) high-risk thresholds were derived using cutpointR, a statistical package to optimize continuous variable thresholds based on binary outcomes. These thresholds were applied to VUS carriers in the PMBB and two independent validation cohorts. Logistic regression analysis was performed to test the association of high-risk VUSs with prevalent thoracic aortic disease.
Results: There were 11,925 individuals in PMBB who carried at least one missense VUS. Carrying a VUS was associated with a modest increased risk of thoracic aortic aneurysm (TAA: OR=1.14, 95% confidence interval [CI] 1.01 to 1.29, P=0.034) but no increased risk of thoracic aortic dissection (OR=1.04, 95%CI 0.55 to 2.00, P=0.896). As VUS REVEL or AlphaMissense increased, or MAF decreased, the association between VUSs and thoracic aortic disease became statistically significant. Using cutpointR, we derived REVEL (>0.649), AlphaMissense (>0.2543), and MAF (<8.16x10^-6) thresholds that together identified 435 high-risk VUSs robustly associated with prevalent dissection (OR=7.85, 95%CI 4.73 to 13.03, P<0.001), though the association with TAA was attenuated (OR=2.35, 95%CI 1.62 to 3.42, P<0.001). Similar results were observed in the UK Biobank (UKB) and Early Onset Sporadic Thoracic Aortic Dissection (ESTAD) cohorts.
Conclusions: VUSs that met high-risk bioinformatic thresholds were strongly associated with prevalent aortic dissection in the PMBB, UKB and ESTAD. Future investigation is warranted to determine if these thresholds can instruct clinical care of individuals carrying aortopathy gene VUSs.