Abstract

BACKGROUND: Arrhythmogenic Cardiomyopathy (AC) is a heritable myocardial disorder and a major cause of sudden cardiac death. It is typically caused by mutations in desmosomal genes. Desmin gene (DES) variants have been previously reported in AC, but with insufficient evidence to support their pathogenicity. METHODS: We aimed to assess a large AC patient cohort for DES mutations and describe a unique phenotype associated with a recurring variant in three families. A cohort of 138 probands with a diagnosis of AC and no identifiable desmosomal gene mutation were prospectively screened by whole exome sequencing. RESULTS: A single DES variant (p.Leu115Ile, c.343C>A) was identified in three index patients (2%). We assessed the clinical phenotypes within their families and confirmed co-segregation. One carrier required heart transplantation, two died suddenly and one died of non-cardiac causes. All cases had right and left ventricular (LV) involvement. LV late gadolinium enhancement was present in all and circumferential sub-epicardial distribution was confirmed on histology. A significant burden of ventricular arrhythmias was noted. Desmin aggregates were not observed macroscopically but analysis of the desmin filament formation in transfected cardiomyocytes derived from induced pluripotent stem cells and SW13 cells revealed cytoplasmic aggregation of mutant desmin. Atomic force microscopy revealed that the mutant form accumulates into short proto-filaments and small fibrous aggregates. CONCLUSIONS: DES p.Leu115Ile leads to disruption of the desmin filament network and causes a malignant biventricular form of AC, characterized by LV dysfunction and a circumferential subepicardial distribution of myocardial fibrosis.