A new study published in Precision Clinical Medicine examined the genetic architecture of hypertrophic cardiomyopathy (HCM) in individuals of Chinese and UK ancestry – and found notable differences in genetic variation between the two populations.
Researchers analyzed whole-exome sequencing data from 593 Chinese patients with HCM and 491 controls and compared them with a UK cohort of 1,232 patients and 344,745 controls. Sixteen validated HCM-associated genes were assessed, including MYBPC3, MYH7, and other sarcomeric and non-sarcomeric genes related to cardiac muscle function.
The findings showed that 53 percent of Chinese patients carried rare variants in HCM genes compared with 14 percent of UK patients (P < 0.001). However, both groups had a similar proportion of pathogenic or likely pathogenic variants – 52 percent and 23 percent in Chinese patients versus 42 percent and 17 percent in UK patients, respectively.
In Chinese participants, additional associations were found with thin filament genes (ACTC1, TNNC1, TNNI3, TNNT2, TPM1) and myosin light chain genes (MYL2, MYL3), while UK cases were linked with non-truncating MYBPC3 variants. Two variants – MYBPC3 c.3624del and TNNT2 c.300C>G – were identified in 3 percent and 2 percent of Chinese HCM cases, respectively, but were not observed in the UK cohort. These appear to be specific to individuals of East Asian ancestry.
The study also evaluated the accuracy of variant classification tools used in diagnostics. When applying the genebe platform, variants of uncertain significance were reduced to 47 percent, compared with 63 percent using InterVar and 91 percent using CardioClassifier, improving the interpretability of genetic findings in clinical contexts.
The authors noted that reference databases such as gnomAD are primarily based on European populations, limiting accurate variant interpretation for other ancestries. The inclusion of population-specific data could improve diagnostic precision and risk assessment for HCM in underrepresented groups.
Overall, the researchers concluded that Chinese patients with HCM show a higher frequency of rare variants in disease-associated genes, though the proportion of pathogenic variants remains similar to that of European patients. The identification of ancestry-specific variants such as MYBPC3 c.3624del and TNNT2 c.300C>G could aid in refining diagnostic criteria and enhance the clinical interpretation of HCM across diverse populations.
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