Breakthrough study sheds light on the genetic landscape of hypertrophic cardiomyopathy in Chinese patients
Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young people and a condition shaped in large part by genetic variants in sarcomere-related genes. While much of the existing research has focused on European populations, a groundbreaking cross-sectional study from West China Hospital and the University of Birmingham expands the view to Chinese patients, revealing notable ethnic differences in the genetic architecture of HCM.
The researchers analyzed whole-exome sequencing data from 593 Chinese HCM patients and 1,232 UK (predominantly European) HCM patients, along with matched controls. The comparison revealed several striking findings about rare genetic variation and the distribution of pathogenic variants between the two groups.
Higher rare-variant burden in Chinese patients, with similar pathogenic rates
One of the most compelling outcomes was the significantly higher burden of rare genetic variants in the Chinese cohort. Specifically, 52.8% of Chinese individuals carried rare variants, compared with 13.6% in the UK group. Despite this stark difference in overall rarity, the proportion of pathogenic or likely pathogenic (P/LP) variants remained similar between the two populations. This suggests that while rare variants are more common in Chinese patients, many of these variants do not reach the threshold of pathogenicity, underscoring the need for careful interpretation in diverse populations.
Two Chinese-unique mutations identified: MYBPC3 and TNNT2
The study highlighted two mutations that appear to be specific to the Chinese cohort: MYBPC3 c.3624del and TNNT2 c.300C>G. These variants accounted for 2.9% and 1.5% of Chinese HCM cases, respectively. Their absence or rarity in UK data points to population-specific mutational spectra, which has important implications for genetic testing panels and personalized risk assessment in Chinese patients. Clinicians should be aware of such ancestry-enriched variants to avoid misclassification or under- interpretation of genetic results.
Shifts in gene associations: thin filament and myosin light chain prominence in China
The analysis also revealed that Chinese patients showed stronger associations with genes encoding thin filament and myosin light chain components. This contrasts with the UK cohort, where differences leaned toward non-truncating variants in MYBPC3. These patterns may reflect underlying population-specific genetic architectures and could influence genotype-guided clinical management, including risk stratification and family screening strategies in Chinese HCM patients.
Improved variant interpretation with genebe
To tackle the persistent challenge of variants of uncertain significance (VUS), researchers employed a tool called genebe. This approach reduced the VUS rate to 46.8%, outperforming other classification frameworks. By improving the clarity of genetic findings, genebe enhances diagnostic confidence and supports more precise counseling for patients and their families, a crucial step in integrating genetic data into routine cardiology practice.
Clinical and research implications: ethnicity matters in HCM genetics
The study’s findings emphasize the value of ethnicity-specific genetic databases and interpretation pipelines. Relying on data derived primarily from European populations risks misclassification and reduced diagnostic yield when applied to Chinese patients. Establishing and expanding Chinese or East Asian genetic databases will help clinicians better distinguish pathogenic variants from benign rare changes and refine risk prediction models.
Beyond individual care, this research underscores the importance of inclusive studies that capture genetic diversity. The insights into population-specific mutation spectra may inform the development of targeted genetic testing panels and guide future functional studies to elucidate how these Chinese-specific variants influence sarcomere function and HCM phenotype.
Conclusion
As precision medicine advances, understanding how ethnicity shapes the genetic basis of hypertrophic cardiomyopathy is essential for accurate diagnosis, prognosis, and treatment. The identification of Chinese-specific mutations and the shift in gene associations call for broader, more representative genetic resources and validated interpretation tools to ensure equitable care across diverse populations.
