MORC2 was first reported in relation to Charcot-Marie-Tooth type 2Z (CMT2Z) in 2016 (Sevilla et al., PMID: 26497905; Albulym et al PMID: 26659848)). CMT2Z is allelic with ‘developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy’ (DIGFAN). These diseases illustrate the diverse range of phenotypical expressions associated with MORC2, varying both in terms of age of onset and overall clinical presentation. Based on these extremely distinct disease presentations, we decided to split and curate the CMT2Z – MORC2 assertion. Patients with CMT2Z present with an axonal (sensori)motor peripheral neuropathy with varying inter- and intrafamilial severity. Complex features, such as central nervous system involvement, or more proximal weakness (non-5Q SMA presentation) are rarely reported (Jacquier et al., PMID 35904125). MORC2 encodes the Microrchidia (MORC) family CW-type zinc finger 2 protein, a DNA-dependent ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation (Sancho et al., 2019, PMID: 30624633). Extensive genetic evidence is present to support the gene-disease relationship. In total, we scored evidence for 12 different missense variants in 27 probands, of which the mutation was found to be de novo in 9 probands. (Sevilla et al., PMID:26497905, Albulym et al., PMID: 26659848, Zhao et al., PMID: 27329773, Ando et al., PMID: 28771897, Duan et al., PMID: 34059105, Hyun et al., PMID: 27105897, Lassuthova et al., PMID: 26912637, Jacquier et al., PMID: 35904125, Sivera et al., PMID: 34189813, Vujovic et al., PMID: 33844363, Wang et al., PMID: 35332768). A summed LOD score of 9,72, calculated in three families, added substantially to the segregation evidence. Furthermore, experimental evidence supports the gene-disease relationship. The recurrent p.Arg252Trp mutation has been found to hyperactivate the HUSH complex, leading to a transcriptional repression of target genes. (Tchasovnikarova IA, et al., PMID: 28581500). These results were confirmed through transcriptome analysis in patient-derived fibroblasts (Sancho et al,PMID: 30624633). In summary, MORC2 is DEFINETIVELY associated with autosomal dominant axonal Charcot-Marie-Tooth disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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