PO12 Genetic Findings in a Cohort of Over 2,300 Individuals with Clinically Suspected Heritable Thoracic Aortic Disease

Abstract Background Heritable thoracic aortic disease (HTAD) is associated with high disease burden and mortality; sudden cardiac death due to aortic dissection commonly presents as the first clinical feature. Purpose Despite being a heritable disease, the role of genetic testing in supporting the diagnosis of HTAD is not fully understood. In this work, we reviewed the genetic findings in a large cohort of individuals with clinical suspicion of HTAD to assess the relevance of genetic testing in this population. Material and Methods DNA samples from 2,358 consecutive individuals referred for genetic testing for suspected HTAD were sequenced with a next generation sequence panel including up to 53 genes associated with HTAD. Gene content varied due to the addition of genes to the panel over time. Sequence variant and copy number variant (CNV) interpretation was performed in accordance with modified ACMG/AMP guidelines. Results Pathogenic (P) or likely pathogenic (LP) variants consistent with the individual’s phenotype and disease inheritance were identified in 11.8% (278/2,358) cases. The positivity rate was similar in children (12.5% [35/281]) and adults (11.7% [243/2,077]) but was higher in deceased individuals (23.5% [8/34]) compared to living individuals (11.6% [270/2,324]). A total of 282 different LP/P variants were identified; 17 of these were CNVs. Of the total number of variants identified, 98.6% (278/282) were in genes associated with extracardiac features in addition to HTAD. Two LP/P variants in different autosomal dominant genes in the same individual were identified in 0.13% (3/2,358) of individuals in the cohort. The most common finding was an LP/P sequence variant in FBN1 (44.2% [123/278]), and the most common LP/P CNV was a duplication involving the ABCC6 and MYH11 genes (29.4% [5/17] of all CNVs). Conclusion The positivity rate of genetic testing in this cohort of individuals with suspected HTAD was 11.8% and this rate among deceased individuals was even higher, 23.5%. Establishing a genetic cause of HTAD allows management based on positive test result, which is especially of high relevance in deceased individuals allowing management for at-risk family members.