28 Increasing the diagnostic yield of TAAD participants from the 100,000 genomes project

Thoracic aortic aneurysm and dissection (TAAD) can affect individuals across all age groups. A family history is present in as many as 20% of individuals with thoracic aortic disease. The genetic basis of TAAD remains poorly understood; many different genes have been identified which cause TAAD either as part of a syndrome (e.g. Marfan, Loeys-Dietz syndromes) or as non-syndromic isolated cases (e.g. ACTA2, MYLK), however, the majority of cases remain unsolved. The 100,000 Genomes Project conducted whole genome sequencing for patients with rare diseases and cancers, including those recruited for TAAD, and screened them against virtual gene panels to identify pathogenic variants. Here, we analysed clinical, phenotypic, and genetic data from the 100,000 Genomes Project to identify potentially pathogenic variants in 833 participants recruited for TAAD, including both isolated and syndromic cases. TAAD has one of the lowest diagnostic yields in the 100,000 Genomes Project, with a pathogenic variant being identified in only 3% of cases. We screened known TAAD genes in this cohort and identified potentially pathogenic variants in a further 14% of the unsolved cases, giving a maximum diagnostic yield of 17%. The majority of these variants are classified as variants of uncertain significance (VUS), and additional work is needed to confirm the functional impact of these variants. Copy number variants (CNVs) are known to play an important role in TAAD, so to gain further insight into our unsolved cases, we explored specific genes from the virtual gene panels and the literature in which CNVs are detected. Wider screening of TAAD genes could increase the diagnostic yield of the 100,000 Genomes Project for participants with TAAD. Exploring rare variants within this group will reveal new genes and genomic regions associated with TAAD, contributing to a better understanding of the genetic underpinnings of TAAD. The ability to conduct this research was facilitated by accessing the data derived from the 100,000 Genomes Project. Conflict of Interest NONE