Introduction: Expansion of genetic testing in Dilated Cardiomyopathy (DCM) has increased mutation detection in patients. Nevertheless, genotype-phenotype correlations are still poorly understood.
Hypothesis: To explore the genetic landscape of a large DCM cohort, assessing the effect of carrier status and association between specific genotypes and outcomes.
Methods: Four hundred eighty-seven patients with available genetic testing analysis were analyzed and grouped into “gene clusters” with similar functions. Primary prognostic measures included all causes of mortality, heart transplantation or ventricular assist device implantation (D/HTx/VAD). Two secondary end-points were also considered: heart failure (HF)-related death/HTx/VAD (DHF/HTx/VAD) and sudden death (SCD)/major ventricular arrhythmias (MVA).
Results: A total of 186 pathogenic/likely pathogenic variants were found in 180 patients (37%). The genetic clusters identified were: 55 (11%) TTNtv; 19 (4%) LMNA; 24 (5%) Structural Cytoskeleton-Z Disk genes; 16 (3%) Desmosomal genes; 47 (10%) Sarcomeric genes, 8 (2%) ionic channels genes, 11 (2%) “others”. The overall survival rate free from HTx/VAD was not significantly different between mutation carriers and non-carriers (p=0.17). However, the trajectory of events was characterized by an earlier occurrence of the primary endpoint in mutation positive patients with a 37% (95%CI 54-72%) observed rate at the age of 50 years vs 21% (95%CI 73-84%) in mutation negatives. They also presented a significantly higher rate of SCD/MVAs (p=0.005). Among the gene clusters, desmosomal mutations, along with the LMNA subgroup, experienced the highest rate of SCD/MVAs regardless of the left ventricular (LV) ejection fraction.
Conclusions: Despite an apparent neutral effect of mutation status on the overall mortality in DCM, patients with positive genetic testing experienced earlier D/HT and a higher risk of life-threatening arrhythmias. Desmosomal mutations showed an increased rate of arrhythmic events, independently from LV systolic function.