Genetic architecture of hypertrophic cardiomyopathy in individuals of Chinese and United Kingdom ancestry

Background No studies have explored the genetic differences between the Chinese and other ethnic hypertrophic cardiomyopathy (HCM) populations. Methods This cross-sectional study included Chinese patients (n = 593) with HCM and controls (n = 491) who underwent whole-exome sequencing. Rare variants in 16 validated HCM genes were assessed and compared with a United Kingdom HCM cohort (n = 1 232) and controls (n = 344 745). Results Chinese HCM patients have a higher proportion of rare variants (52.8% vs 13.6%, P < 0.001) but have a similar proportion of pathogenic (P) or likely pathogenic (LP) variants compared to the UK cohort. In addition, the Chinese cohort had additional associations with the combined thin filament genes (P = 1.29E−9) and myosin light chain genes (P = 4.43E−3). The United Kingdom cohort was significantly associated with MYBPC3 non-truncating variants (P = 2.99E−7). By classifying variants using the tool genebe, the variants of uncertain significance were minimized to 46.8% compared to other tools (63.3% by Intervar; 91.3% by CardioClassifier). Furthermore, we report that c.3624del in MYBPC3 and c.300C > G in TNNT2 account for 2.9% and 1.5% of all Chinese HCM cases, respectively. Conclusion Our findings suggested that patients of Chinese ancestry with HCM have a higher proportion of rare variants but are less likely to be classified as P/LP variants in HCM genes than those of European origin. The variants of c.3624del in MYBPC3 and c.300C > G in TNNT2 were specific to Chinese individuals and provide important insights into the ethnic differences of HCM genetic architecture.