On genetic and phenotypic variability of hypertrophic cardiomyopathy: nature versus nurture

Abstract

The seminal discovery of the R403Q mutation in the beta-myosin heavy chain (MyHC) gene as a cause of hypertrophic cardiomyopathy (HCM) by Dr. Thierfelder’s group a decade ago (1) ushered in a new era in the molecular genetics of HCM. To date, over 120 mutations in 10 genes, all encoding sarcomeric proteins, have been identified in patients with HCM (2), leading to the notion that HCM is a disease of contractile sarcomeric proteins (3). Mutations in nonsarcomeric genes, mitochondrial genome and genes responsible for the triplet repeat syndromes also have been found in patients with HCM (2). Although no large-scale systematic search has yet been performed, the existing data suggest that mutations in the beta-MyHC, myosin binding protein-C (MyBP-C) and cardiac troponin T (cTnT) are the most common causes of HCM, collectively accounting for approximately 60% to 70% of all HCM cases (2). It has also become evident that the frequency of each particular causal mutation in the HCM population is relatively low (<5%). Overall, genetic studies indicate significant allelic and nonallelic heterogeneity of HCM, an issue that complicates the feasibility of genetic diagnosis.