The relationship between PDHX and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of July 13, 2020. The PDHX gene encodes the E3 binding protein 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.
The PDHX gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2003 (PMID: 12557299). Evidence supporting this gene-disease relationship includes case-level data and experimental data.
This curation included six variants identified in five cases in five publications (PMIDs: 12557299, 14518830, 15303005, 16566017, 25087164). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression, and functional alteration in patient cells (PMIDs: 27977873, 21139605, 14518830).
In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the gene-disease association. 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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