by 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, Jiří Zeman 5, Tomáš Paleček 6, Josef Houštěk 7, Zdeněk Drahota 7, Hana Nůsková 7, Jana Mikešová 7, Josef Zámečník 8, Milan Macek, Jr. 9, Petr Ridzoň 10, Jana Malusková 11, Viktor Stránecký 3, Vojtěch Melenovský 1, Hendrik Milting 4 and Stanislav Kmoch 3
1 Department of Cardiology, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
2 Institute of Physiology, First Faculty of Medicine, Charles University, 11636 Prague, Czech Republic
3 Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, 11636 Prague, Czech Republic
4 Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, 32545 Bad Oeynhausen, Germany
5 Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12108 Prague, Czech Republic
6 2nd Department of Medicine–Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12108 Prague, Czech Republic
7 Institute of Physiology, Czech Academy of Sciences, 11720 Prague, Czech Republic
8 Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University, 11636 Prague, Czech Republic
9 Department of Biology and Medical Genetics, Second Faculty of Medicine, Charles University, 11636 Prague, Czech Republic
10 Department of Neurology, Thomayer’s Hospital, 14059 Prague, Czech Republic
11 Department of Pathology, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
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.
