The relationship between MT-ND3 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of March 24, 2021. The MT-ND3 gene encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit ND3. Defects of this protein lead to complex I deficiency.
The MT-ND3 gene was first reported in relation to maternally inherited Leigh syndrome spectrum in 2003 (PMID: 14684687). Evidence supporting the gene-disease relationship between MT-ND3 and Leigh syndrome spectrum includes case-level data and experimental data. This curation included 5 variants in 14 cases (1 with m.10134C>A, 5 with m.10158T>C, 3 with m.10191T>C, 4 with m.10197G>A, 1 with m.10254G>A) from 7 publications (PMIDs: 14684687, 14705112, 14764913, 17152068, 20202874, 25118196, 25384404). Of note, while Gene Curation SOP Version 8 maxes case level missense variant total score at 7, the Mitochondrial Disease Gene Curation Expert Panel agreed the maximum score would be 12 given that the majority of pathogenic mitochondrial DNA variants are missense variants (the total score for genetic level evidence in this curation was 19.5). Segregation information is scored as case level evidence according to the criteria established by the Mitochondrial Disease Gene Curation Expert Panel. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known protein interaction and functional alteration in patient cells (PMIDs: 27509854, 14705112).
In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 24, 2021 (SOP Version 8).
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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