Implications of Genetic Testing in Dilated Cardiomyopathy.

Background - Genetic analysis is a first-tier test in dilated cardiomyopathy (DCM). Electrical phenotypes are common in genetic DCM but their exact contribution to the clinical course and outcome is unknown. We determined the prevalence of pathogenic gene variants in a large unselected DCM population, and determined the role of electrical phenotypes in association with outcome. Methods - This study included 689 DCM patients from the Maastricht Cardiomyopathy Registry, undergoing genetic evaluation using a 48 cardiomyopathy-associated gene-panel, echocardiography, endomyocardial biopsies and Holter monitoring. Upon detection of a pathogenic variant in a DCM patient, familial segregation was performed. Outcome was defined as cardiovascular death, heart transplantation, heart failure hospitalization and/or occurrence of life-threatening arrthymias. Results - A (likely) pathogenic gene variant was found in 19% of patients, varying from 36% in familial to 13% in non-familial DCM. Family segregation analysis showed familial disease in 46% of DCM patients who were initially deemed non-familial by history. Overall, 18% of patients with a non-genetic risk factor had a pathogenic gene variant. Almost all pathogenic gene variants occurred in just 12 genes previously shown to have robust disease association with DCM. Genetic DCM was independently associated with electrical phenotypes such as atrial fibrillation (AF), non-sustained ventricular tachycardia (NSVT) and AV-block (AVB), and inversely correlated with the presence of a left bundle branch block(p<0.01). After a median follow-up of 4 years, event-free survival was reduced in genetic versus non-genetic DCM patients(p=0.01). This effect on outcome was mediated by the associated electrical phenotypes of genetic DCM(p<0.001). Conclusions - One in five patients with an established non-genetic risk factor or a non-familial disease still carries a pathogenic gene variant. Genetic DCM is characterized by a profile of electrical phenotypes (AF, NSVT and AVB), which carries increased risk for adverse outcomes. Based on these findings, we envisage a broader role for genetic testing in DCM.