The relationship between COQ8B and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 6, 2023. The COQ8B gene encodes the COQ8B protein, which is an atypical kinase that is expressed in the podocytes of the kidney and localizes to the mitochondrial matrix, where it participates in coenzyme Q10 synthesis. Of note, this gene was previously known as ADCK4.
The COQ8B gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2013 (PMID: 24270420). While various names have been given to the constellation of features seen in those with COQ8B-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the COQ8B phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.
Evidence supporting the gene-disease relationship between COQ8B and primary mitochondrial disease includes case-level data and experimental data. This curation includes eleven variants (five missense, two nonsense, three frameshift, and one in frame insertion) in eight probands in one publication (PMIDs: 24270420) although additional cases have been reported in the medical literature. Affected individuals typically experience early-onset severe kidney dysfunction (steroid-resistant nephrotic syndrome, or SRNS, that typically leads to end-stage kidney disease) although later onset has also been reported. Treatment with high dose Coenzyme Q10 supplementation early in the course of disease can be beneficial. Other features have been reported including seizures, intellectual disability, hypothyroidism, and retinitis pigmentosa. Loss of function is implicated as the mechanism of disease.
This gene-disease relationship is also supported by known biochemical function, a mouse model, a zebrafish model, and in vitro functional assays demonstrating oxidative phosphorylation deficiencies due to variants in COQ8B (PMIDs: 32381600, 24270420).
In summary, there is definitive evidence to support the relationship between COQ8B 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 February 6, 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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