The relationship between PDSS2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of July 13, 2020. The PDSS2 gene encodes prenyl diphosphate synthase subunit 2, which is important early in the coenzyme Q10 biosynthesis pathway. Coenzyme Q10 is critical for many processes in the cell, including in the mitochondrial respiratory chain transferring electrons from complexes I and II to complex III.
The PDSS2 gene was first reported in association with autosomal recessive Leigh syndrome spectrum in 2006 (PMID: 17186472). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two variants identified in one cases from one publications (PMID: 17186472), as well as a case reported in a book chapter (Quinzii C, Loos M. Multisystemic Infantile CoQ10 Deficiency with Renal Involvement. In: Russell P. Saneto, Sumit Parikh and Bruce H. Cohen, editors. Mitochondrial Case Studies Underlying Mechanisms and Diagnosis. Academic Press; 2016. pp 299-04). 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, functional alteration in patient cells, functional alteration in non-patient cells, and animal models (PMIDs: 27977873, 21139605, 17186472, 29967258, 18437205, 23150520).
In summary, there is moderate 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 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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