EP154: Predictive genomic medicine for thoracic aortic aneurysm and dissection

Abstract

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition for which the first detectable clinical sign is often a catastrophic event, such as dissection or rupture. TAAD can be the manifestation of a Mendelian disorder and can include additional syndromic features, but these are subtle and difficult to recognize for many clinicians. The detection of a pathogenic variant offers the potential to identify disease in an at-risk individual, but the penetrance of variants associated with TAAD is not certain. We sought to measure the clinical yield of Pathogenic and Likely Pathogenic variants (PLPVs) when identified in a phenotypically unselected population. We evaluated sequence data from a cohort of 3,052 adults who had volunteered for a genome sequencing research study. Individuals were recruited to the cohort through routine healthcare appointments without suspicion of genomic disease. We limited our search to 15 genes with strong evidence of association with syndromic or non-syndromic TAAD, seven of which are on the ACMG v3.0 recommended list for reporting of secondary findings. We assessed all missense and predicted loss of function variants identified by genome sequencing in these 15 genes and applied ACMG standards and guidelines to identify PLPVs. Pathogenicity assessment included manual curation and was not informed by phenotypic data from participants. Individuals who harbored PLPVs were recontacted for targeted reverse phenotyping including diagnostic testing, genetic counseling, and return of genetic results. We identified seven unique PLPVs in our cohort, for a rate of 7/3,052 or 0.23% (95% CI 0.00092 - 0.0047). Among these seven PLPVs, four were found in genes not on the ACMG secondary findings list. None of the participants identified had undergone clinical sequencing outside of the research study and none were previously aware of the molecular finding. Preliminary results from recontact and reverse phenotypic evaluation revealed that three individuals had a personal or family history highly suggestive of a Mendelian form of TAAD, but the option for clinical sequencing had not been addressed by the individuals’ providers. Another individual had a previously suspected connective tissue disorder without clear manifestation of aortic disease. Of the remaining individuals, aspects of their personal or family histories were potentially consistent with a TAAD-associated phenotype. Additional phenotypic evaluation of individuals with PLPVs including cascade testing of family members is ongoing. Our study is the first that we know of to use a strict genome first approach followed by targeted reverse phenotyping to evaluate the clinical yield of TAAD associated PLPVs in a phenotypically unselected population. The process of re-contact and reverse phenotyping highlights the benefits of identifying such variants (even in individuals with a previously known personal or family history of aneurysm). This study pilots predictive genomic medicine for TAAD, and additional research can use a similar framework to assess this approach on a larger scale.