Abstract 554: The Association Of Multiple Variants In The TNXB Gene With Vascular Aneurysms And Dissections

Pathogenic variants in the Tenascin-XB (TNXB) gene are associated with autosomal recessive Ehlers Danlos Syndrome (classical-like). Here, we report the association of two or more TNXB variants with aneurysms and/or dissections in different arterial beds. We compared case and control data from exome sequencing (ES) or multigene panel testing (MGPT). Statistical analysis was performed by Fisher’s exact test. From 350 cases of vascular aneurysm and/or dissection referred for genetic testing by ES, we identified 5 individuals with two or more rare missense variants in the TNXB gene (1.4%) versus 16 individuals with two or more TNXB variants from 10, 968 matched controls (0.14%, p<.0.01). In a replication cohort of 1844 individuals undergoing multigene panel testing (MGPT) for connective tissue disorders including aneurysms and dissections, we identified 27 individuals with two or more TNXB variants (1.5%, p<0.01); 19 of these individuals (70.3%, n= 19/27) had a personal history of aneurysm and/or dissection and had no other identifiable pathogenic or likely pathogenic variants. Interestingly, 3 (15.7%, n=3/19) had a diagnosis of bicuspid aortic valve (BAV), a 10-fold higher prevalence compared to the general population incidence of BAV. An additional 158 individuals with BAV who underwent ES also showed a higher prevalence of multiple TNXB variants compared to controls (1.8% vs 0.14%, p<0.01). This data strongly supports an association between multiple TNXB variants and vascular aneurysms and dissections.