Genetic basis of dilated cardiomyopathy: recent evidence and further challenges

Abstract

Abstract. Dilated cardiomyopathy (DCM) is a heterogeneous disorder of cardiac muscle leading to a common phenotype, characterized by dilatation of the left or both ventricles and reduced contractile function. This type of cardiomyopathy is the most common, often leading to clinically manifested heart failure and sudden cardiac death. In recent years, a wide range of pathogenic variants in genes related to the pathogenesis of DCM have been identified through genetic studies. There are several major groups of genes involved, depending on the functional belonging and cellular compartmentalization: genes encoding sarcomeric, cytoskeletal, mitochondrial proteins, and the nuclear envelope. A significant portion of the genetic variations leading to DCM is located in the TTN gene, which encodes the large sarcomeric protein titin. Despite advances in next-generation sequencing technologies that facilitate extensive genetic testing in patients with DCM, challenges exist regarding interpreting genetic variants and correlating them with certain phenotypic expression and clinical courses. In addition, epigenetic factors modify the genetic predisposition and complicate clinical presentation, highlighting the complexity of DCM and the need for more detailed study of genotype-phenotype relationships. Future therapeutic directions in DCM emphasize precision medicine approaches, including genome editing technologies, such as CRISPR/Cas9, gene therapy, and pharmacogenomics, that aim to target specific genetic and molecular causes of disease.