(P047) A PROSPECTIVE STUDY USING WHOLE EXOME SEQUENCING (WES) IN A CANADIAN POPULATION WITH HYPERTROPHIC CARDIOMYOPATHY.

Background: An increasing number of genes are being identified as causes of hypertrophic cardiomyopathy (HCM). A human genome consists of about 20,000 genes - whole exome sequencing (WES) is an analysis of the coding region of these genes. The diagnostic evaluation of HCM in Canadian centres exclusively consists of a ‘gene panel’ which is an arbitrary list of a small number of genes (~0.1%) compared to WES. There are no prospective studies on Canadians on the utility of WES for genetic cardiomyopathy.

METHODS AND RESULTS: We prospectively performed WES in 132 samples in ambulatory patients who had HCM in Calgary, Alberta. Patients were identified with HCM on cardiac magnetic resonance imaging (CMRI), the absence of systemic hypertension, significant valvular disease, ischemic heart disease or any prior genetic testing. A diagnostic result was obtained in 22.7 % of cases (with a pathogenic; P; or likely pathogenic variant; LP), a genetic cause was suspected in 30.3 % had a variant of uncertain significance (VUS) and there was a negative result in 47.0 % of patients. We compared these results to a subset of 22 cases in our database without HCM and a there were no P or LP variants but 13/22 cases (59%) had a VUS in an HCM gene. A number of genes on WES were not covered on gene panels.

Conclusion: Data analysis is ongoing and more samples and controls will be analyzed. We conclude that 1. WES is more comprehensive than a gene panel when evaluating for hypertrophic cardiomyopathy 2. The VUS detection rate in an unaffected population is high and family studies are likely required in those patients before attributing a genetic diagnosis in patients with a VUS. WES data in unaffected individuals may help refine how to interpret VUS findings in patients with HCM.