COX10

Inheritance Pattern: AR

Disease ID:MONDO:0033635

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0009068

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between COX10 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of April 22, 2019. 14 articles were reviewed. COX10 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2003 (Antonicka et al., PMID: 12928484). Six unique variants predicted to cause a loss of or reduced function of the protein have been reported in ClinVar. Complex IV deficiency is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 2 probands with Leigh syndrome spectrum in 2 different publications (PMID 12928484, 15455402). This gene-disease association is further supported by the function of the gene product, expression, and studies in patient cell lines and COX10 mouse models. In summary, there is moderate evidence to support the relationship between COX10 and autosomal recessive Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 22, 2019 (SOP Version 6).

Inheritance Pattern: AR

Disease ID:MONDO:0033635

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0033635

Submitter: Natera