The Genetic Bases of Cardiomyopathies

Abstract

Cardiomyopathies represent an important cause of cardiovascular morbidity and mortality due to heart failure, arrhythmias, and sudden death. A majority of hypertrophic cardiomyopathies (HCM) and at least 30% of dilated cardiomyopathies (DCM) are familial forms, with most often an autosomal dominant mode of inheritance. Over the last 15 years, our knowledge on the genetic bases of these diseases has considerably improved. Cardiomyopathies are characterized by a great genetic heterogeneity at both allelic and non-allelic levels. Hypertrophic cardiomyopathies are mainly linked to mutations on genes encoding sarcomeric proteins, and beta myosin heavy chain and myosin binding protein C gene mutations account for about 80% of genotyped cases. Familial DCM is associated with mutations in genes encoding sarcomeric proteins but also other proteins of the myocyte, such as cytoskeletal or nuclear membrane proteins. Due to the genetic heterogeneity and the variable clinical expressivity of these diseases, the relations between genotype and phenotype remain complex, but the age of onset, the clinical severity, or associated phenotypes may be, at least in part, related to the precise gene mutations. Therefore, besides a better understanding of the molecular basis for cardiac remodeling and heart failure, the genetic analysis of cardiomyopathies is going to play an increasing role in the routine management of these patients in the following years, particularly in HCM. (J Am Coll Cardiol 2006;48:A79 -89)

Mutation of V896M in cardiac myosin binding protein-c gene in two Chinese families with hypertrophic cardiomyopathy

“…Taken together, the results suggest that the phenotype becomes more malignant with increasing age. Thus, in the present study the V896M mutation was found to exhibit similar features to those reported by Richard et al (13), including the delayed onset of clinical symptoms, slow development and a benign phenotype.…”

“…only one was confirmed to be a healthy carrier through electrocardiographic and echocardiographic examinations. However, this one (EⅢ:3) is a 15-year-old boy, and studies have shown that patients with MYBPC3 mutations usually have a delayed age of onset (13). long-term follow-up is therefore essential in this patient.…”

A985G Polymorphism of the Endothelin-2 Gene and Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy

“…[9][10][11][12][13] Additional genetic factors, such as angiotensin-converting enzyme (ACE) genotypes, partially account for the variability in the phenotypic expression of the disease. 14, 15 We previously showed that a genotype that resulted in inhibition of the renin -angiotensinaldosterone (RAA) system (the ACE insertion/insertion genotype) turned out to be a significant risk factor for AF in patients with HCM, 16 contrary to the previous notion that the ACE deletion/deletion genotype of increased activation of the RAA system may be a predisposing factor for hypertension, AF, and other organic heart diseases.…”

Evidence for CTLA4 as a susceptibility gene for dilated cardiomyopathy

“…In particular, genes encoding cytoskeletal, sarcomeric, and nuclear proteins, which are engaged in extracellular anchorage or myocardial contractility, have been linked to DCM. 3,4 Besides base substitutions in the mitochondrial genome, which can also cause a DCM-type disease, 5 these mutations critically diminish force generation, transduction, and/or transmission within the contractile apparatus of the myocardium and lead to impaired systolic function. However, these sarcomeric gene defects explain the disease only in some families, leaving other forms of inherited DCM subentities unresolved.…”