Submission Details

DNM2 was first reported in relation to autosomal dominant Charcot-Marie-Tooth disease in 2005 (Zuchner et al., PMID: 15731758). At least 10 unique variants (e.g. missense, in-frame indel, frameshift, large deletion, etc) 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 twelve probands in eight publications (PMIDs: 15731758, 18394888, 28971531, 19502294, 17636067, 18560793, 22091729, 25259927). Variants in this gene also segregated with disease in 55 additional family members, totaling a LOD score of 18.29 and the maximum segregation evidence. The mechanism for disease is currently under investigation, however deleterious impact on clathrin-mediated endocytosis is likely involved for at least many of the known CMT variants. Of note, this gene has also been implicated in both a lethal autosomal recessive disorder and a dominant centronuclear myopathy. The latter has been assessed separately by the Congenital Myopathy GCEP. This gene-disease association is supported by expression studies identifying all four isoforms of human DNM2 in the skeletal muscle and schwann cells of all ages and several functional assays demonstrating functional alteration to specifically clathrin-mediated endocytosis as well as myelination and cell survival when mutants are expressed. There are also several models that express DNM2 mutants in mice, however given the physiological differences it is difficult to fully model the heterozygous disorder as the mice seem to require a greater proportion of mutant protein to recapitulate the observed phenotypes. In summary, DNM2 is definitively associated with autosomal dominant Charcot-Marie-Tooth disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.