The relationship between SLC25A46 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of August 17, 2020. The SLC25A46 gene encodes a member of the SLC25 family of mitochondrial carrier proteins. The SLC25A46 protein is involved in mitochondrial dynamics, interacting with OPA1, MFN2, and mitochondrial contact site and cristae organizing system (MICOS) complex, and is likely important for lipid transfer from the endoplasmic reticulum to the mitochondrion, and for mitochondrial fission. Pathogenic variants in SLC25A46 have been associated with other phenotypes outside the Leigh syndrome spectrum including pontocerebellar hypoplasia, optic atrophy, and parkinsonism.
The SLC25A46 gene has been reported in relation to autosomal recessive Leigh syndrome spectrum in a single publication in 2016 (PMID: 27390132). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous variant identified in one case in one publication (PMID: 27390132). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, expression data, functional alteration in patient cells, and model systems (PMIDs: 26168012, 25613900, 26951855, 28376086, 28934388, 28376083).
In summary, there is limited evidence to support this gene-disease relationship. Although the total score (7) falls in the moderate range, only one case with Leigh syndrome spectrum has been reported, therefore this gene-disease association can only reach a limited classification at this time. 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 July 13, 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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