Abstract
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.
Highlights
Hypertrophic cardiomyopathy (HCM) is a commonly inherited myocardial disease with an estimated prevalence of 1 in 200 [1]
hypertrophic cardiomyopathy (HCM) is characterized by abnormal thickening of the left ventricular wall that cannot be explained by abnormal loading conditions or metabolic disorder [2]
The study population was uniformly distributed in terms of age and left ventricular (LV) function with the exception of six patients who presented with HCM that had progressed to the decompensated stage (Fig 1C, black marks)
Summary
Hypertrophic cardiomyopathy (HCM) is a commonly inherited myocardial disease with an estimated prevalence of 1 in 200 [1]. In patients with HCM, cardiomyocytes enlarge, and interstitial fibrosis and myocardial disarray are apparent [3]. Clinical outcomes of HCM are highly variable such that many patients are asymptomatic, or mildly symptomatic, presenting with symptoms such as dyspnea, angina, syncope, lightheadedness, and heart palpitations [2]. HCM is potentially life- threatening and associated with high risk of heart failure, atrial fibrillation, stroke, and sudden death [4]. HCM is the leading cause of sudden cardiac death in young athletes [5]. Even among HCM, it is difficult to predict disease severity owing to the variable penetrance of the disease and insufficient genotype-phenotype correlation [6]
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