Pathogenetics of Cardiomyopathy

The review summarizes the current knowledge on the role that genetic factors play in primary or Mendelian cardiomyopathies (CMs) and certain secondary CM forms. Dozens of genes with pathogenic or likely pathogenic variants were described for primary CMs. The spectrum of causal genetic variants is specific to particular CMs in most cases, but common genes and variants were also discovered. Genetic causes of the disease remain unknown in part of primary CM cases, and pathogenic variants of Mendelian disease genes are found in secondary CMs as well. The genetic component in the development of both primary and secondary CMPs was additionally established in genome-wide association studies (GWASs). Single nucleotide polymorphisms (SNPs) associated with primary and secondary CMs are, in most cases, specific to different CM types and contribute little to an individual’s overall risk. Certain SNPs were associated with electrocardiogram or echocardiogram features of the morphologically normal heart in humans. Most of the CMs-associated SNPs are in noncoding genome regions, but have a regulatory potential, acting as loci that affect the level of expression (eQTLs), splicing (sQTLs) or epigenetic modifications in the heart. It is noteworthy that the effects of eQTL and sQTL genotypes are not equivalent in different anatomical regions of the heart in some cases. The phenotype and clinical presentation of CMs in general can be determined by a wide range of rare pathogenic or likely pathogenic variants with a strong effect and common polymorphisms with a small effect and modified by epigenetic factors.