The relationship between NDUFS4 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of February 11, 2019. 18 articles were reviewed. NDUFS4 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 1998 (Van den Heuvel et al 1998 PMID: 9463323). At least 12 unique variants predicted to cause a loss of or reduced function of the protein have been reported in ClinVar, suggesting homozygous loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 6 probands with Leigh syndrome spectrum in 6 publications (PMID 27079373, 14765537, 27671926, 24020637, 22326555, 12616398). This gene-disease association is supported by protein interaction, expression, alterations in patient cell lines, and animal models. In summary, there is definitive evidence to support the relationship between NDUFS4 and 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 February 11, 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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