Genetic Basis of Idiopathic Cardiomyopathies

posted Jan 26, 2017, 1:33 AM by sourav ghosh
Madhu Khullar
Department of Experimental Medicine & Biotechnology, PGIMER, Chandigarh, India

Idiopathic cardiomyopathies are a heterogeneous group of diseases of the myocardium and are responsible for significant morbidity and mortality and leading indication for heart failure and transplant. Idiopathic cardiomyopathies are due to a variety of causes that frequently are genetic. Hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and estrictive cardiomyopathy (RCM) are the major types of cardiomyopathies caused by mutant sarcomeric and non sarcomeric genes. Myosin Heavy Chain (MYH7), Myosin Binding Protein C (MYBPC3), Troponin T (TNNT2) and Troponin I (TNNI3) are frequently mutated genes in cardiomyopathy. Several of the mutant genes linked to DCM encode the same contractile sarcomeric proteins that are responsible for HCM; however, mutations in other genes encoding cytoskeletal/sarcolemmal, nuclear envelope, sarcomere, and transcriptional coactivator proteins like lamin A/C, dystrophin, desmin, caveolin, sarcoglycan, as well as the mitochondrial respiratory chain gene have been also observed. Despite advances in technology for detection of gene variants such as next generation sequencing, causal genes of cardiomyopathies remain to be identified in approximately 1/3rd of patients. Genotype-phenotype studies have shown large clinical variability and genetic heterogeneity among cardiomyopathy patients which is not solely associated with the causal mutations. Clinical phenotypes are also likely to be modified by age, sex hormones, diet and polymorphisms in many genes. Characterization and mechanistic study of cardiomyopathies are therefore challenging due to the complex protein structures, the multitude of disease-causing mutations, and modulations of pathology by genetic background.