Dilated Cardiomyopathy: Genetic Determinants and Mechanisms

Abstract

Nonischemic dilated cardiomyopathy (DCM) often has a genetic pathogenesis. Because of the large number of genes and alleles attributed to DCM, comprehensive genetic testing encompasses ever-increasing gene panels. Genetic diagnosis can help predict prognosis, especially with regard to arrhythmia risk for certain subtypes. Moreover, cascade genetic testing in family members can identify those who are at risk or with early stage disease, offering the opportunity for early intervention. This review will address diagnosis and management of DCM, including the role of genetic evaluation. We will also overview distinct genetic pathways linked to DCM and their pathogenetic mechanisms. Historically, cardiac morphology has been used to classify cardiomyopathy subtypes. Determining genetic variants is emerging as an additional adjunct to help further refine subtypes of DCM, especially where arrhythmia risk is increased, and ultimately contribute to clinical management.

Keywords: cardiomyopathy, dilated; genetic testing; heart failure; mutation; sarcomeres; therapeutics.

Figure 1. Echocardiography demonstrates forms of cardiomyopathy

Left ventricular noncompaction cardiomyopathy (LVNC) is shown in the upper right (arrows indicate deep trabeculations in the left ventricle (LV). Dilated cardiomyopathy (DCM) is defined by enlarged LV diameters (dashed double sided arrow). Hypertrophic cardiomyopathy (HCM) is defined with a thickened LV, including the septum (marked with double sided arrow).

Figure 2. Algorithm for the management of a patient with nonischemic DCM

CMR: cardiac magnetic resonance, CK: creatine kinase. DCM patients should undergo an accurate family history examination. A comprehensive exam should include serum CK to evaluate skeletal muscle involvement. Genetic testing and genetic counseling should be offered to DCM patients, regardless of family history; 1^st degree relatives should be examined (physical exam, ECG, echocardiogram). A positive genetic testing in the proband offers the possibility of a confirmatory genetic testing in relatives, which may guide follow up and need of further testing. Adapted from^{, , ,}

Figure 3. DCM gene panels are used for genetic testing

Shown is a list of 111 genes offered from multiple commercial testing laboratories for the evaluation of DCM. Those shown in black are commonly found on DCM panels from multiple sources, while those shown in gray are found on only some panels reflecting their role in syndromic cardiomyopathy such as Noonan syndrome, neuromuscular disease and/or mitochondrial myopathies.

Figure 4

A typical DCM pedigree is shown highlighting variable expressivity. Most DCM is inherited in an autosomal dominant pattern. Affected individuals with DCM are shown in black. A gene panel revealed the previously reported pathogenic TPM1 E54K variant. The proband (arrow) presented in early life requiring heart transplant during early childhood. Other members of the family are in their 3^rd to 6^th decade with LVEF 45%, demonstrating variable expressivity of the primary mutation. Environmental and additional genetic factors may contribute to variable expressivity.

Figure 5

Shown in the top is a schematic of the sarcomere with the position of the thick myosin-containing filaments and the thin actin-containing filaments. Titin is considered a third filament of the sarcomere since its spans from Z disk to M band. The lower schematics show the major splice forms of titin (N2-BA, N2-B, N2-A). The green box represents a unique sequence domain. The PEVK region is named for the repetitive amino acid sequences (proline, glutamine, valine, lysine).

Figure 6

Shown are major components within the cardiomyocyte with emphasis on compartments that contribute to genetically mediated DCM. The extracellular matrix is shown in gray. The dystrophin complex that includes the sarcoglycans (green) is mutated in forms of DCM with neuromuscular disease. The sarcomeres (pink) include components that are mutated in both HCM and DCM. Z band (dark red) is a mechanosensing hub that serves to transmit force from the sarcomeres. Mutations in both mitochondrially encoded (purple) and nuclear encoded mitochondria proteins lead to cardiomyopathy. The nuclear lamina include lamins A and C, and the gene LMNA is commonly mutated in DCM.

Figure 7. Sudden cardiac death and life-threatening ventricular arrhythmias in DCM

Cox-estimated event-free survival stratified by 2 risk factors, family history of SCD or ventricular arrhythmias (SVT or VF) and AR-DCM diagnosis, in a cohort of 285 DCM patients. The AR-DCM phenotype (p=0.02) and family history of SCD or ventricular arrhythmias (SCD/SVT/VF) (p=0.038) showed an additive prognostic effect on mortality for arrhythmic events. AR-DCM: Arrhythmogenic Dilated Cardiomyopathy; SCD/SVT/VF: sudden cardiac death, sustained ventricular tachycardia and ventricular fibrillation. From Spezzacatene et al., with permission.