Submission Details

The relationship between COX10 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 4, 2023. COX10 encodes cytochrome c oxidase (COX) assembly factor 10 heme A:farnesyltransferase. COX10 functions in the mitochondrial heme biosynthetic pathway by catalyzing the conversion of protoheme IX (heme B) and farnesyl diphosphate to heme O, via the farnesylation of a vinyl group at position C2 of heme B. Heme O is in turn converted to heme A, one of the prosthetic groups critical to COX function.

The COX10 gene was first reported in relation to primary mitochondrial disease in 2000 (PMID: 10767350), in a consanguineous African family with mitochondrial encephalopathy and COX deficiency. Subsequent publications reported eight additional probands with a similar early onset, severe, progressive mitochondrial disorder. One adult with later onset and a mild phenotype including myopathy, muscle weakness, and exercise intolerance has also been reported (PMID: 24100867). While various names have been given to the constellation of features seen in those with COX10-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the COX10 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, COX10 was previously curated by this GCEP on April 22, 2019 (SOP Version 6) as having a moderate association with Leigh Syndrome Spectrum (LSS). The scope of this current curation encompassed cases of primary mitochondrial disease, which includes LSS.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 13 unique variants reported in 10 cases from eight publications (PMIDs: 10767350; 12928484; 15455402; 24100867; 26741492; 27290639; 30588737; 32313153). Variants included 12 missense and one frameshift variant. Segregation could be scored in one large consanguineous family (PMID: 10767350). Reported individuals were generally severely affected with features including LSS, neurologic deterioration, ataxia, epilepsy, myopathy, hypertrophic cardiomyopathy, sensorineural hearing loss, macrocytic anemia, failure to thrive, lactic acidosis, and metabolic acidosis. There is one report of an adult who was more mildly affected with muscle weakness, exercise intolerance, demyelinating neuropathy, premature ovarian failure, short stature, renal failure, hearing loss, pigmentary maculopathy, and renal tubular dysfunction (PMID: 24100867). Skeletal muscle, fibroblasts, and/or liver showed decreased activities of mitochondrial respiratory chain complex IV.

This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, rescue of COX activity and heme A levels in patient derived fibroblast cell lines, and a conditional knockout mouse model that showed complex IV deficiency and a muscle myopathy phenotype (PMIDs: 12928484, 16103131, 33340416).

In summary, there is definitive evidence to support the relationship between COX10 and 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 December 4, 2023 (SOP Version 10).