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

Miloš Kubánek,Tereza Schimerová,Alice Krebsová,Sandra Ratnavadivel,Vojtěch Melenovský,Jana Mikešová,Hendrik Milting,Petr Ridzoň,Stanislav Kmoch,Lenka Piherová,Hana Nůsková,Viktor Stránecký,Caroline Stanasiuk,Tomáš Paleček,Josef Zámečnı́k ,Jana Malušková ,J Houštěk ,Milan Maçek ,Z Drahota ,Hana Hansı́ková ,Jiřı́ Zeman

doi:10.3390/jcm9040937

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.

Highlights

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]
Two missense variants were identified within the non-helical head domain of desmin, i.e., in P1 with biventricular form of ACM (NM_001927.3: c.127A > G; NP_001918.3: p.(K43E)) and in P2 with dilated cardiomyopathy (DCM) (NM_001927.3: c.170C > T; NP_001918.3: p.(S57L)) (Figure 1, Tables S2 and S3)
Two novel variants were found in the highly conserved central α-helical rod domain, i.e., in P3 with familial DCM located in the 1B helical domain (NM_001927.3:c.629C > A; NP_001918.3: p.(A210D)) and in P4 with familial left ventricular non-compaction cardiomyopathy (LVNC) in combination with skeletal myopathy located in the 2B helical domain (NM_001927.3: c.1092G>T; NP_001918.3: p.(Q364H)) (Figure 1, Tables S2 and S3)

Summary

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]. Cardiomyopathy, cardiac conduction disease, and progressive skeletal myopathy are the most common clinical presentations of desminopathy. 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. 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 be considered in individuals with LVNC, and in the differential diagnosis of mitochondrial diseases

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Conclusion