Submission Details

DNM2 was first reported in relation to autosomal dominant centronuclear myopathy in 2005 (Bitoun et al., 16227997). At least ten variants (e.g. missense, in-frame indel, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, experimental data. Variants in this gene have been reported in at least 17 probands in three publications (PMID: 17932957, 16227997, 26273216). Variants in this gene segregated with disease in 24 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. The mechanism for disease is heterozygous gain of function, with CNM DNM2 mutations interrupting the normal regulatory pathway and causing overexpression of DNM2 in the skeletal muscle resulting in myopathy phenotypes. Of note, this gene has also been implicated in Charcot-Marie-Tooth disease, dominant intermediate B and Lethal congenital contracture syndrome 5. These will be assessed separately. This gene-disease association is also supported by shared biochemical function with BIN1, another gene responsible for centronuclear myopathy apparently via DNM2 dysregulation as shown by mouse models. Skin fibroblasts in DNM2 patients also demonstrate modified endocytosis, another factor which can influence the progress of various myopathies. A mouse model displaying the most common CNM variant, R465W, clearly recapitulates the phenotypes observed in human probands. Lastly, expression of siRNAs to block expression of the variant in these same mice fully rescues the disease phenotype. In summary, DNM2 is definitively associated with autosomal dominant centronuclear myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.