MEGF10 was first reported in relation to autosomal recessive MEGF10-related myopathy, historically known as early-onset myopathy-areflexia-respiratory distress-dysphagia (EMARDD) in 2011 (Logan et al., PMID: 22101682). At least 11 variants (e.g. missense, nonsense, frameshift, deletions) have been reported in humans. 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 nine probands in four publications (PMIDs: 22101682, 22371254, 23453856, 27460346). Variants in this gene segregated with disease in two additional family members plus several sibling pairs. More evidence is available in the literature, but the maximum score for genetic evidence has been reached.The mechanism for disease is homozygous loss of function, with MEGF10 deficency reducing the proliferation and migration of muscle sattelite cells, impeding muscle repair, and supporting premature differentiation in myoblasts during development. Of note, this gene has also been implicated in a form of multiminicore myopathy with generally reduced phenotypic severity and later age of onset. This entity is considered part of the MEGF10-related myopathy spectrum. This gene-disease association is supported by two animal models, expression studies, biochemical function evidence, and myoblast alteration. Models in both zebrafish and mice displayed some phenotypes of MEGF10 myopathy, but were ultimately limited in scope. Expression data showed clear expression in myoblasts during development and sattelite cells in mature organisms further supporting the disease mechanism. Biochemical function studies demonstrated the MEGF10 pathogenic mechanism. Mouse myoblasts were altered and found to have reduced migration, proliferation, and premature differentiation in the absence of MEFG10. In summary, MEGF10 is definitively associated with autosomal recessive MEGF10-related myopathy. This has been demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Myopathies Working Group on 01/27/20 (SOP Version 7).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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