The relationship between RMND1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 7, 2022.The RMND1 gene encodes required for meiotic nuclear division 1 homolog, which functions in mitochondrial translation.
The RMND1 gene was first reported in relation to primary mitochondrial disease in 2012 (PMID 23022099). While various names have been given to the constellation of features seen in those with RMND1-related disease, including autosomal recessive combined oxidative phosphorylation deficiency 11 (MIM 614922), pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the RMND1 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included eight unique variants (two missense, two frameshift, two consensus splice-site, one stop-gained and one extension variant) from six cases across four publications (PMIDs: 23022099, 25058219, 26395190, 27412952). The mechanism of disease appears to be loss of function. This gene-disease relationship is also supported by a biochemical function to anchor or stabilize the mitochondrial ribosome near the sites of mRNA maturation, shRNA knockdown of RMND1 in HeLa cells showed significantly decreased complex I, III and IV activities and diminished mitochondrial protein synthesis (PMIDs: 23022099, 25604853).
In summary, there is definitive evidence to support the relationship between RMND1 and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 7, 2022 (SOP Version 9).
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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