Submission Details

DES was first reported in relation to semidominant Myofibrillar Myopathy in 1998 (Goldfarb et al. 1998, PMID: 9697706). Myofibrillar myopathy is a subset of inherited muscle diseases primarily characterized by progressive muscle weakness, atrophy, respiratory abnormalities, and cardiomyopathy. Over 100 variants, mostly missense and small in-frame indels, have been reported in human probands. Although this disorder largely segregates in an autosomal dominant manner, many confirmed cases of autosomal recessive probands have been characterized. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 11 probands in 7 publications (PMIDs; 17221859, 23687351, 19105189, 10717012, 9697706, 10545598, 11061256). Variants in this gene segregated with disease in 13 additional family members in 3 families. Significantly more evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. Although the primary mechanism for pathogenic DES variants is a gain-of-function causing desmin aggregates and clumping in the muscle fibers, there is evidence for some variants disrupting the desmin fiberous network or for a loss-of-function when multiple null variants are inherited in an autosomal recessive manner (PMIDs: 16217025, 31718026) This gene has historically been implicated in a form of recessive limb-girdle muscular dystrophy, but as of 2018 the association was reclassified as a type of myofibrillar myopathy (PMIDs: 23687351, 30055862). This gene-disease association is additionally supported by many animal models, expression studies, and in vitro functional assays. There are several models that recapitulate either the entirety of phenotypes observed in human probands or a partial aspect, such as the skeletal myopathy or cardiomyopathy phenotypes. These models vary in the pathogenic mechanism, however they all provide strong evidence supporting the pathogenicity of DES null and other variants. DES is uniquely expressed in all types of muscle, further implicating this gene as related to the cardiac and skeletal myopathy phenotypes. A functional assay evaluating the effect of 14 different DES variants was conducted with all of them showing altered function, whether that be disrupting the proper assembly of sarcomeres and z-discs or forming aggregates that impairs the contration and relaxation of the muscle fibers. In summary, DES is definitively associated with semidominant Myofibrillar Myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease-inheritance association was recurated according to ClinGen's recuration guidelines (last curation publication date 09/25/17, SOP Version 5).