Genetics of dilated cardiomyopathy

Abstract

Purpose of review: Dilated cardiomyopathy (DCM), which include genetic and nongenetic forms, is the most common form of cardiomyopathy. DCM is characterized by left ventricular or biventricular dilation with impaired contraction. In the United States, DCM is a burden to healthcare that accounts for approximately 10,000 deaths and 46,000 hospitalizations annually. In this review, we will focus on the genetic forms of DCM and on recent advances in the understanding of cytoskeletal, sarcomeric, desmosomal, nuclear membrane, and RNA binding genes that contribute to the complexity and genetic heterogeneity of DCM.

Recent findings: Although mutations in TTN remain the most common identifiable cause of genetic DCM, there is a growing appreciation for arrhythmogenic-prone DCM due to mutations in LMNA, desmosomal genes, and the recently described FLNC gene encoding the structural filamin C protein. Mutations in RBM20 highlight the relevance of RNA splicing regulation in the pathogenesis of DCM. Although expanded genetic testing has improved access to genetic diagnostic studies for many patients, the molecular mechanisms in the pathogenesis of the disease remained largely unknown.

Summary: : The identification of the molecular causes and subsequent insight into the molecular mechanisms of DCM is expanding our understanding of DCM pathogenesis and highlights the complexity of DCM and the need to develop multifaceted strategies to treat the various causes of DCM.

Figure 1

DCM associated Gene-Gene Interaction Network. This network of DCM associated gene evidenced the complexity of DCM genetic architecture that hindered the identification of causal genes as well as molecular mechanisms in the pathogenesis of DCM. Abbreviation: DCM, dilated cardiomyopathy.

Fig. 2.. Frequency and distribution of causal genes in DCM, and effect on outcome.

The left top shows the distribution of P/LP variants in a large DCM cohort, with a yield of genetic testing of 37%, and TTN as most frequent gene identified. The left bottom shows the distribution by gene or gene cluster. The top right shows the higher incidence of SCD/VT/VF in variant-positive versus variant-negative (p = 0.062). The right bottom Kaplan-Meier survival curves for SCD/VT/VF shows the similar rate of SCD/VT/VF desmosomal and LMNA variant carriers, which was significantly different compared with the other patients (p = 0.006). CIF = cumulative incidence function; SCD/VT/VF= sudden cardiac death/ventricular tachycardia/ventricular fibrillation. From Gigli et al., J Am Coll Cardiol 2019 with permission).