The relationship between COQ2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 30, 2023. The COQ2 gene encodes the 4-hydroxybenzoate polyprenyltransferase protein. This enzyme is required for the synthesis of coenzyme Q10 (CoQ10), which acts as an electron shuttle between enzyme complexes of the mitochondrial respiratory chain.
The COQ2 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2006 (PMID: 16400613). While various names have been given to the constellation of features seen in those with COQ2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the COQ2 phenotype has been lumped into one disease entity according to per the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included nine variants in eight probands across six publications (PMIDs: 16400613, 17855635, 17332895, 23631824, 15564041, 29637272). Common clinical manifestations include renal involvement (steroid-resistant nephrotic syndrome), hypotonia, cerebral/cerebellar atrophy, encephalopathy and optic atrophy. Age of onset is typically in the first few years of life. Reduced levels of CoQ10 and reduced activities of complex I+III and II+III are commonly observed in patient tissues and cells. No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease relationship is also supported by known biochemical function, a Drosophila model, and in vitro functional assays in patient cells demonstrating oxidative phosphorylation deficiencies due to variants in COQ2 (PMIDs: 33340416, 27493029, 21703546, 20495179, 26922674).
In summary, there is definitive evidence to support the relationship between COQ2 and autosomal recessive primary mitochondrial disease. More than three years have elapsed since the first assertion of this gene-disease relationship, and no contradictory evidence has emerged. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 30, 2023 (SOP Version 9).
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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