Overview
Hypertrophic cardiomyopathy (HCM) is a leading genetic heart disorder characterized by thickened heart muscle and an array of inherited mutations. While much of the genetic work on HCM has focused on European populations, a new cross-sectional study sheds light on how the condition presents in Chinese patients. Researchers from West China Hospital and the University of Birmingham analyzed whole-exome sequencing data from 593 Chinese and 1,232 UK HCM patients, alongside controls, to understand ethnic differences in the genetic architecture of HCM.
Key findings: higher rare-variant burden in Chinese patients
The study reveals a striking disparity: Chinese individuals with HCM carry a significantly higher burden of rare genetic variants than their UK counterparts (52.8% vs. 13.6%). Despite this elevated variant load, the proportion of pathogenic or likely pathogenic (P/LP) variants remained similar between the two groups. This suggests that while Chinese patients accumulate more rare changes, only a subset may drive disease, underscoring the complexity of interpreting genetic risk across populations.
Specific mutations tied to the Chinese cohort
Two mutations emerged as notably specific to the Chinese cohort. MYBPC3 c.3624del accounted for about 2.9% of Chinese HCM cases, and TNNT2 c.300C>G accounted for roughly 1.5%. These variants appear relatively uncommon in Western populations but may contribute meaningfully to HCM risk in Chinese patients. Their identification emphasizes how ethnicity can shape the mutational landscape of inherited heart diseases.
Differences in gene associations by ethnicity
The data also highlighted distinct gene-phenotype associations. In Chinese patients, there were stronger links between HCM and variants in thin filament and myosin light chain genes, suggesting a slightly different pathogenic emphasis compared with UK cohorts. Conversely, non-truncating variants in MYBPC3 were more prominent among UK patients, pointing to population-specific pathways that can influence disease expression and progression.
Improving interpretation with advanced classification tools
To tackle the challenge of variants of uncertain significance (VUS), researchers employed genebe, a classification tool designed to refine variant interpretation. The tool reduced the VUS rate to 46.8%, outperforming other available methods. This improvement translates into clearer genetic diagnoses, better risk stratification, and more informed clinical decisions for patients and their families.
Clinical and research implications
The findings carry several important implications for clinical practice and future research. First, they highlight the need for ethnicity-specific genetic databases to avoid misclassification of variants and to ensure accurate risk prediction. Second, they suggest that diagnostic pipelines for HCM should incorporate population-tailored interpretation frameworks, particularly for Chinese and other non-European populations. Finally, the study underscores the value of comprehensive data integration—combining whole-exome sequencing with robust variant classification tools—to enhance patient care.
Where this leaves patients and clinicians
For clinicians, the study reinforces the importance of considering ethnicity when evaluating genetic test results for HCM. While P/LP variant proportions were similar across groups, recognizing Chinese-specific mutations like MYBPC3 c.3624del and TNNT2 c.300C>G can inform targeted testing and family counseling. For researchers, the work invites deeper exploration into how rare variants contribute to HCM in diverse populations and how international collaboration can build richer, more inclusive genetic databases.
Conclusion
As genetics research expands beyond European cohorts, understanding ethnic nuances in hypertrophic cardiomyopathy becomes possible. The Chinese-specific mutations and the broader pattern of rare variant burden revealed in this study demonstrate why ethnicity-aware approaches are crucial for accurate diagnosis, prognosis, and personalized management of HCM globally.
