MORC2

Inheritance Pattern: AD

Disease ID:MONDO:0030835

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0014736

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014736

Submitter: ClinGen

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.

Inheritance Pattern: AD

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between MORC2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of March 24, 2021. The MORC2 gene encodes Microrchidia family CW-type zinc finger 2, a DNA-dependent ATPase that has several important roles including in chromatin remodeling, DNA repair and regulating transcription. The MORC2 gene was first reported in relation to de novo dominant Leigh syndrome spectrum in 2019 (PMID: 30624633). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two de novo variants identified in two cases in one publication (PMID: 30624633). No segregation data were available. MORC2 variants have also been reported to be associated with Charcot-Marie-Tooth disease type 2Z and a syndrome of developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (DIGFAN). Haploinsufficiency is implicated as the mechanism of disease but this is still being studied. This gene-disease association is also supported by expression (PMID: 25613900). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 24, 2021 (SOP Version 7).

Inheritance Pattern: AD

Disease ID:MONDO:0030835

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014736

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0014736

Submitter: PanelApp Australia