The relationship between NAXE and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of March 24, 2021. The NAXE gene encodes NAD(P)X epimerase that catalyzes the conversion of R-NAD(P)HX to S-NAD(P)HX, which are toxic cellular metabolites, so that S-NAD(P)HX can be reconverted to S-NAD(P)H by the dehydratase NAXD, thus preventing the accumulation of toxic metabolites.
The NAXE gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2016 (PMID: 27616477). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four variants identified in two cases in two publications (PMIDs: 27616477, 32020600). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by expression and functional alteration in patient cells (PMIDs: 25613900, 27616477).
In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 24, 2021 (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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