Genetics of inherited cardiomyopathy

Abstract

During the past two decades, numerous disease-causing genes for different cardiomyopathies have been identified. These discoveries have led to better understanding of disease pathogenesis and initial steps in the application of mutation analysis in the evaluation of affected individuals and their family members. As knowledge of the genetic abnormalities, and insight into cellular and organ biology has grown, so has appreciation of the level of complexity of interaction between genotype and phenotype across disease states. What were initially thought to be one-to-one gene-disease correlates have turned out to display important relational plasticity dependent in large part on the genetic and environmental backgrounds into which the genes of interest express. The current state of knowledge with regard to genetics of cardiomyopathy represents a starting point to address the biology of disease, but is not yet developed sufficiently to supplant clinically based classification systems or, in most cases, to guide therapy to any significant extent. Future work will of necessity be directed towards elucidation of the biological mechanisms of both rare and common gene variants and environmental determinants of plasticity in the genotype-phenotype relationship with the ultimate goal of furthering our ability to identify, diagnose, risk stratify, and treat this group of disorders which cause heart failure and sudden death in the young.

Figure 1

Classification of familial cardiomyopathies (adapted from Elliott et al.).

Figure 2

Risk factors for sudden cardiac death in hypertrophic cardiomyopathy.

Figure 3

Variance component analysis allows for breakdown of a disease state into its core components.  Heritability quantifies the likelihood of familial transmission of a given trait. Transmission of a trait is dependent on both genetic and environmental components. Genetic components of transmission are determined by the variable effects of a primary mutation and associated modifier genes (modified from Sen-Chowdhry et al.).