The relationship between COQ4 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 30, 2023. The COQ4 gene encodes ubiquinone biosynthesis protein COQ4, which functions as part of the coenzyme Q10 (CoQ10) biosynthetic pathway.
The COQ4 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2015 (PMID: 25658047). While various names have been given to the constellation of features seen in those with COQ4-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the COQ4 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included eleven unique variants (eight missense, one stop-gained, one frameshift, and one in-frame deletion variant) identified in seven individuals from four publications (PMIDs: 25658047, 30225196, 28540186, 30659264). Affected individuals have a broad spectrum of features that range from an early onset multisystem encephalopathy with myopathy and cardiac involvement to a less severe, later onset ataxia-spasticity disorder. 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 for scoring. The mechanism of disease appears to be loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, and specifically coenzyme Q10 deficiency; early embryonic lethality in a knockout mouse model; wild-type rescue of growth and COQ synthesis defects in a null yeast model; and wild-type rescue of mitochondrial dysfunction in patient-derived iPSCs and differentiated myocytes (PMIDs: 33340416, 18474229, 29539633, 28472853).
In summary, there is definitive evidence to support the relationship between COQ4 and autosomal recessive primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. 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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