**Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction**

**Miloš Kubánek 1,\*, Tereza Schimerová 1,2, Lenka Piherová 3, Andreas Brodehl 4, Alice Krebsová 1, Sandra Ratnavadivel 4, Caroline Stanasiuk 4, Hana Hansíková 5, Jiˇrí Zeman 5, Tomáš Paleˇcek 6, Josef Houšt ˇek 7, Zden ˇek Drahota 7, Hana N ˚usková 7, Jana Mikešová 7, Josef Zámeˇcník 8, Milan Macek Jr. 9, Petr Ridzo ˇn 10, Jana Malusková 11, Viktor Stránecký 3, Vojt ˇech Melenovský 1, Hendrik Milting <sup>4</sup> and Stanislav Kmoch <sup>3</sup>**


Received: 13 February 2020; Accepted: 24 March 2020; Published: 29 March 2020

**Abstract: Background:** The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. We aimed to describe the prevalence, phenotypic expression, and mitochondrial function of individuals with putative disease-causing desmin (DES) variants identified in patients with an unexplained etiology of cardiomyopathy. **Methods:** A total of 327 Czech patients underwent whole exome sequencing and detailed phenotyping in probands harboring DES variants. **Results:** Rare, conserved, and possibly pathogenic DES variants were identified in six (1.8%) probands. Two DES variants previously classified as variants of uncertain significance (p.(K43E), p.(S57L)), one novel DES variant (p.(A210D)), and two known pathogenic DES variants (p.(R406W), p.(R454W)) were associated with characteristic desmin-immunoreactive aggregates in myocardial and/or skeletal biopsy samples. The individual with the novel DES variant p.(Q364H) had a decreased myocardial expression of desmin with absent desmin aggregates in myocardial/skeletal muscle biopsy and presented with familial left ventricular non-compaction cardiomyopathy (LVNC), a relatively novel

phenotype associated with desminopathy. An assessment of the mitochondrial function in four probands heterozygous for a disease-causing DES variant confirmed a decreased metabolic capacity of mitochondrial respiratory chain complexes in myocardial/skeletal muscle specimens, which was in case of myocardial succinate respiration more profound than in other cardiomyopathies. **Conclusions:** The presence of desminopathy should also be considered in individuals with LVNC, and in the differential diagnosis of mitochondrial diseases.

**Keywords:** desmin; dilated cardiomyopathy; mitochondrial dysfunction; myopathy; non-ischemic cardiomyopathy; whole exome sequencing
