**1. Introduction**

Desminopathy (OMIM # 601409) represents a group of autosomal inherited disorders caused by pathogenic variants in the disease-causing desmin (*DES*) gene, encoding the major muscle specific intermediate filament protein desmin (OMIM: #125660) [1]. Desmin is the major component of intermediate filaments in cardiac, skeletal, and smooth muscle cells, with a particularly high content in Purkinje fibers and diaphragmatic muscle cells [1]. Consequently, cardiomyopathy, cardiac conduction disease, and progressive skeletal myopathy are the most common clinical presentations of desminopathy. It may occur as an isolated cardiac disease or in variable combinations and with different onsets. As summarized in a meta-analysis [1], 49%, 60%, and 74% of individuals harboring a pathogenic *DES* variant develop cardiomyopathy, cardiac conduction disease, and skeletal myopathy, respectively. The most common form of myocardial involvement is dilated cardiomyopathy (DCM) [1–3], followed by restrictive (RCM) [4–7], arrhythmogenic (ACM) and hypertrophic cardiomyopathy (HCM), and arrhythmogenic cardiomyopathy pattern [8–11]. On the other hand, there is low evidence regarding an association between desminopathy and left ventricular noncompaction cardiomyopathy (LVNC). Importantly, intermediate filaments are essential not only for cellular integrity, organization, and differentiation, but also for a signal transduction and adequate mitochondrial function [12]. Accordingly, several experimental [12–14] and clinical [15,16] studies have proven a secondary mitochondrial dysfunction in desminopathy, which in one case even mimicked mitochondrial disease [16].

The pleomorphic clinical presentation makes the diagnosis of desminopathy challenging. Fortunately, massively parallel sequencing (MPS) utilizing either cardiomyopathy panels and/or even whole exome sequencing (WES) aid in the diagnosis of desminopathy regardless of its clinical presentation. Hereby, we aimed to describe the prevalence of desminopathy and their phenotypes in a large representative cohort of patients with cardiomyopathy of unexplained etiology using WES.
