143 A pivotal role for NRF2 in endothelial detachment–implications for endothelial erosion of stenotic plaques

Abstract

defines a diagnostic yield of just 8/536 (6%) in this patient group, using known aortopathy gene panels. Surprisingly, none of these variants were found in probands under 30 at disease onset. There were 68 classic trios in this cohort (proband + mother and father). However, just one of these has a clearly pathogenic de novo variant identified (in MYH11). There were just 2 Tier 2 variants of uncertain significance (VUS) in aortopathy genes in other trios. 10 larger family structures have yielded no clear pathogenic candidates to date. The majority of the cohort are recruited as singletons. 75 Tier 2 variants have been identified to date in 19 aortopathy genes (see figure 1). Just 1 of these (in LOX) can be classified as likely pathogenic. The remainder are VUSs. Conclusion In this genetically pre-screened cohort with FTAAD, genetic diagnosis remains elusive. The variety of genes in which protein-altering variants are found highlights the genetic heterogeneity of this condition. We plan further systematic studies of the family structures available in the 100,000 Genomes Project and case:control studies to further elucidate the genetic architecture of FTAAD. The negative findings to date, particularly in probands with young-onset aortopathy, make it likely that responsible genes are yet to be discovered in many cases. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project.