The relationship between FOXRED1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of October 14, 2019. Variants in FOXRED1 were first reported in humans with Leigh syndrome spectrum as early as 2010 (PMID: 20818383). Four unique variants predicted to cause a loss of or reduced function of the protein have been reported in ClinVar, suggesting loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Two probands with confirmed FOXRED1 mutations demonstrating a Leigh syndrome spectrum phenotype have been reported in 2 publications (PMIDs: 26022995, 20818383) to reach a case-level evidence score of 4. This gene-disease association is further supported by FOXRED1’s protein interaction and shared function with other genes associated with Leigh syndrome spectrum, mitochondrial alterations in patient cell lines, and a FOXRED1 mouse model exhibiting a neuropathological and behavioral phenotype, reaching an experimental score of 5 pts. In summary, there is moderate evidence to support the relationship between FOXRED1 and autosomal recessive Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 14, 2019 (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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