YIELD OF GENETIC TESTING FOR HYPERTROPHIC CARDIOMYOPATHY ACCORDING TO CONTEMPORARY VARIANT INTERPRETATION GUIDELINES: RESULTS FROM A LARGE CANADIAN REFERRAL CENTRE

Abstract

The yield of genetic testing for hypertrophic cardiomyopathy (HCM) has been reported to be between 30% and 60%. Differences in populations studied are likely to be one explanation for this wide variation. Changes in the way we interpret genetic variants is likely to be a contributing factor. We aimed to analyze the genetic results from a large Canadian referral centre interpreted according to contemporary guidelines in order to examine the yield of genetic testing in the Canadian population. HCM index cases who underwent genetic testing between 2005 and January 2018 were included. All variants were re-classified according to the guidelines of the American College of Medical Genetics (ACMG) and subsequent gene-specific adaptations. Of 1,730 cases tested 393 (23%) were tested for 5 sarcomeric genes and 1,337 (77%) were tested for 8. In 325 patients (19%) a pathogenic (P) or likely pathogenic (LP) variant was identified and variants of unknown significance in 247 (14%). The majority (57%) of P/LP variants were found in the MYBPC3 gene, followed by the MYH7 gene (31%). The yield of TNNI3, TPM1 and TNNT2 genes was 4%, 3% and 2%, respectively. The 3 remaining genes combined (MYL2, MYL3 and ACTC1) were accountable for 3% of P/LP variants. Of the MYBPC3 variants 89% were loss-of-function (nonsense, frameshift or splice-site), one was an in-frame deletion and the rest (11%) missense. The yield of genetic testing in our centre was lower than previously reported. Possible explanations include lack of a founder mutation in the heterogenous Canadian population and higher referral rates of non-familial cases which are less likely to be gene-positive. Finally, using current and stricter guidelines for variant interpretation may have led to less variants being classified as P/LP, and may also explain the higher percentage of MYBPC3 variants among gene-positive cases. Further studies are required in order to determine whether this reflects the true genetic landscape of HCM or the limitations of current variant interpretation methods.