The relationship between NDUFS1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of March 12, 2019. NDUFS1 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2001 (Benit et al., PMID 11349233). Several pathogenic variants have been reported in ClinVar, and loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data (PMIDs 15824269, 21203893, 11349233, 20382551, 22200994, 19167255, 21458341, 24952175, 25615419) to reach a maximal case-level evidence score of 12 points. This gene-disease association is further supported by the function of the gene product, complex I alterations in patient cell lines, expression studies, and animal models reaching an experimental score of 4.5 points. The mechanism for disease is complex I deficiency. In summary, NDUFS1 is definitively associated with autosomal recessive Leigh syndrome spectrum. More than three years have elapsed from the first proposal of the association to reach a definitive classification. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on June 10, 2019 (SOP Version 6).
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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