The relationship between NDUFS2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of November 23, 2020. The NDUFS2 gene encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit S2. Defects of this protein lead to complex I deficiency.
The NDUFS2 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2001 (PMID: 11220739). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 6 variants in 5 cases from 3 publications (PMIDs: 11220739, 20819849, 22036843). Of note, the c.875T>C (p.Met292Thr) variant is speculated to be a hypomorphic allele (found in 2 homozygotes in gnomAD at the time of this gene review). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known protein interactions, expression, functional alterations in patient cells, and model organisms (PMIDs: 27509854, 25613900, 14749350, 29526616, 31297047).
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 November 23, 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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