The relationship between NDUFAF6 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of April 20, 2020. The NDUFAF6 gene encodes NADH:ubiquinone oxidoreductase (complex I) assembly factor 6. Defects of this protein lead to a complex I deficiency.
The NDUFAF6 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2008 (PMID: 18614015). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included eight unique variants identified in seven cases from seven publications (PMIDs: 18614015, 30642748, 29531337, 27623250, 28639102, 31967322, 32020600). Segregation data includes 3 affected individuals from one kindred (PMID: 30642748). Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, expression data, and rescue in patient cells (PMIDs: 22019594, 25613900, 26741492).
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 April 20, 2020 (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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