The relationship between PDHA1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of March 25, 2019. 31 articles were reviewed. PDHA1 was first reported in relation to X-linked Leigh syndrome spectrum in 1993 (Matthews et al., PMID 8498846). Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in numerous probands in numerous publications (PMIDs 7887409, 8962591, 8664900, 9187674, 9671272, 10679936, 12621116, 15384102, 20002461, 21914562). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by the known biochemical function, protein interaction, functional studies in patient cell lines, and animal models. PDHA1 encodes the E1 alpha subunit of the pyruvate dehydrogenase complex (PDC). PDC catalyzes conversion of pyruvate into acetyl-CoA, thus is the link between glycolysis and the citric acid cycle. PDC deficiency leads to impaired energy metabolism. In summary, there is definitive evidence to support the relationship between PDHA1 and X-linked Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 25, 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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