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).
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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