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.

2nd Department of Medicine Department of Cardiovascular Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague 12108 Prague Czech Republic

Department of Biology and Medical Genetics 2nd Faculty of Medicine Charles University 11636 Prague Czech Republic

Department of Cardiology Institute for Clinical and Experimental Medicine 14021 Prague Czech Republic

Department of Neurology Thomayer's Hospital 14059 Prague Czech Republic

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University 11636 Prague Czech Republic

Department of Pathology Institute for Clinical and Experimental Medicine 14021 Prague Czech Republic; Institute for Clinical and Experimental Medicine 14021 Prague Czech Republic

Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague 12108 Prague Czech Republic

Erich and Hanna Klessmann Institute Heart and Diabetes Center NRW University Hospital of the Ruhr University Bochum 32545 Bad Oeynhausen Germany

Institute of Physiology 1st Faculty of Medicine Charles University 11636 Prague Czech Republic

Institute of Physiology Czech Academy of Sciences 11720 Prague Czech Republic

Research Unit for Rare Diseases Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University 11636 Prague Czech Republic

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