COQ5 was first reported in relation to autosomal recessive coenzyme Q10 deficiency, a primary mitochondrial disease, in 2018 (Malicdan MCV, et al., PMID: 29044765). The COQ5 gene encodes coenzyme Q5, methyltransferase which is involved in mitochondrial ubiquinone (coenzyme Q10, CoQ10) biosynthesis. 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. CoQ10 deficiency is a multisystem primary mitochondrial disease characterized by variable clinical manifestations that include encephalopathy, seizures, movement disorder, hypotonia, nephrotic syndrome, hypertrophic cardiomyopathy, muscle weakness, exercise intolerance, retinopathy and sensorineural hearing loss. Laboratory findings include reduced CoQ10 biosynthesis and reduced activity of mitochondrial complex I+II and I+III and II+III (PMID: 28125198). Three variants (1 large tandem duplication, 1 canonical splice-site, 1 missense) that have been reported in 2 probands in 2 publications (PMIDs: 29044765, 37599337) are included in this curation. The mechanism of pathogenicity appears to be loss of function.
This gene-disease relationship is also supported by experimental evidence including the biochemical function of ubiquinone biosynthesis that is shared with other known genes in the disease of interest (PMIDs: 9083048, 33340416, 28125198), protein interaction with COQ4 which is another ubiquinone biosynthesis gene that has a definitive classification for mitochondrial disease (PMID: 25152161), and a human rescue model where high-dose oral supplementation of CoQ10 was shown to improve the clinical manifestations and Q10 levels in patients with COQ5-related coenzyme Q10 deficiency (PMID: 29044765).
In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Ataxia GCEP on the meeting date July 10, 2024 (SOP Version 10).
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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.