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Over 1,500 gene mutations are known to cause hypertrophic cardiomyopathy (HCM). Previous studies suggest that cardiac β-myosin heavy chain ( MYH7)  gene mutations are commonly associated with a more severe phenotype, compared to cardiac myosin binding protein-C ( MYBPC3)  gene mutations with milder phenotype, incomplete penetrance and later age of onset. Compound mutations can worsen the phenotype. This study aimed to validate these comparative differences in a large cohort of individuals and families with HCM. We performed genome-phenome correlation among 80 symptomatic HCM patients, 35 asymptomatic carriers and 35 non-carriers, using an 18-gene clinical diagnostic HCM panel. A total of 125 mutations were identified in 14 genes.  MYBPC3  and  MYH7  mutations contributed to 50.0% and 24.4% of the HCM patients, respectively, suggesting that  MYBPC3  mutations were the most frequent cause of HCM in our cohort. Double mutations were found in only nine HCM patients (7.8%) who were phenotypically indistinguishable from single-mutation carriers. Comparisons of clinical parameters of  MYBPC3  and  MYH7  mutants were not statistically significant, but asymptomatic carriers had high left ventricular ejection fraction and diastolic dysfunction when compared to non-carriers. The presence of double mutations increases the risk for symptomatic HCM with no change in severity, as determined in this study subset. The pathologic effects of  MYBPC3  and  MYH7  were found to be independent of gene mutation location. Furthermore, HCM pathology is independent of protein domain disruption in both  MYBPC3  and  MYH7 . These data provide evidence that  MYBPC3  mutations constitute the preeminent cause of HCM and that they are phenotypically indistinguishable from HCM caused by  MYH7  mutations.

Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage