Genetics and disease of ventricular muscle

Abstract

Cardiomyopathies are a heterogeneous group of heart muscle diseases associated with heart failure, arrhythmias, and death. Genetic variation has a critical role in the pathogenesis of cardiomyopathies, and numerous single-gene mutations have been associated with distinctive cardiomyopathy phenotypes. Contemporaneously with these discoveries, there has been enormous growth of genome-wide sequencing studies in large populations, data that show extensive genomic variation within every individual. The considerable allelic diversity in cardiomyopathy genes and in genes predicted to impact clinical expression of disease mutations indicates the need for a more nuanced interpretation of single-gene mutation in cardiomyopathies. These findings highlight the need to find new ways to interpret the functional significance of suites of genetic variants, as well as the need for new disease models that take global genetic variant burdens, epigenetic factors, and cardiac environmental factors into account.

Figure 1.

Schematic showing potential roles of genetics and other factors that are intrinsic and extrinsic to the cardiomyocyte as determinants of cardiomyopathy phenotype.

Figure 2.

Effects of cardiac gene mutations in zebrafish. (A) Lateral view of embryonic zebrafish hearts at 3 d postfertilization. (Top panel) Wild-type (wt) heart; (lower panel) heart of a mainsqueeze (msq) mutant showing pericardial edema because of loss of ventricular contractility. A, atrium; V, ventricle. Genetic studies of the ENU-generated msq mutant identified an L308P variant in the integrin-linked kinase (ilk) gene (Bendig et al. 2006). ILK mutations have subsequently been associated with human DCM. (B) ECG tracings from anesthetized adult zebrafish. (Top panel) Normal sinus rhythm in a wild-type zebrafish. (Middle and lower panels) 2:1 Atrioventricular block and sinus bradycardia with pauses, respectively, in transgenic zebrafish expressing the human SCN5A D1275N mutation (Huttner et al. 2013).