Chinese HCM patients have a higher rare variant proportion (52.8% vs 13.6%) and specific variants c.3624del (2.9%) in MYBPC3 and c.300C>G (1.5%) in TNNT2 are East Asian-specific.
Does the rare variant genetic architecture of hypertrophic cardiomyopathy differ between Chinese and UK cohorts?
Chinese patients with HCM have a higher proportion of rare variants but are less likely to have them classified as pathogenic/likely pathogenic compared to European ancestry patients, highlighting ethnic differences in HCM genetic architecture.
Absolute Event Rate: 0% vs 0%
Abstract Backgroud: The genetic architecture of hypertrophic cardiomyopathy (HCM) is complex and genetic data from Chinese patients are scant. Purpose: To compare the rare variant genetic architecture of HCM between Chinese and United Kingdom (UK) cohorts. Methods: This cross-sectional study included prospective Chinese patients (n = 593) with HCM and controls (n = 491) who underwent clinical phenotyping and whole exome sequencing. Rare variants in 16 validated HCM genes were assessed and compared with a UK HCM cohort (n = 1,232) and controls (n = 344,745). Rare variants were collected from the HCM cohorts, and filtered to identify likely deleterious mutations, and genes were classified as pathogenic (P), likely pathogenic (LP), uncertain significance (VUS), likely benign (LB) or benign (B). Mutational burden per gene was tested between cases and controls. Also, potential digenic or oligogenic relationships were identified by joint presence in an individual. Results: Chinese HCM patients have a higher proportion of rare variants compared to the UK cohort (52.8% versus 13.6%, P 0.001). Statistic testing of the mutational load of each gene also differed between cohorts. Both had a significant association for the genes MYBPC3 from truncating variants (P=1.01E-26 Chinese; P=7.72E-29 UK), MYH7 non-truncating variants (P=2.41E-23 Chinese;P=2.99E-7 UK) and ALPK3 (P=1.49E-3 Chinese; P=2.65E-5 UK). However, in the Chinese cohort there were additional associations with the combined Thin Filament genes (P=1.29E-9) and Myosin Light Chain genes (P=4.43E-3). The UK cohort had a significant association with MYBPC3 non-truncating variants (P=2.99E-7). In addition, by classifying variants using the tool genebe, the proportion of variants of uncertain significance (VUS) was minimalized to 46.8% compared to other tools (63.3% by Intervar; 91.3% by CardioClassifier). Finally, we report that c.3624del in MYBPC3 and c.300CG in TNNT2 account for 2.9% and 1.5% of all HCM cases in the Chinese (17/593; 9/593) cohort respectively, which are predominantly present in patients of East Asian ancestry. Conclusions: 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 ancestry due to differences in genetic architecture and a lack of representation of Chinese ancestry in clinical data sets. The variants of c.3624del in MYBPC3 and c.300CG in TNNT2 appear to be specific to East Asians and provide important insights into the ethnic differences of HCM genetic architecture.Figure 1 Figure 2
Wang et al. (Sat,) reported a other. Chinese HCM patients have a higher rare variant proportion (52.8% vs 13.6%) and specific variants c.3624del (2.9%) in MYBPC3 and c.300C>G (1.5%) in TNNT2 are East Asian-specific.
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