Submission Details

The relationship between MT-CO2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 11, 2023. The MT-CO2 gene encodes cytochrome c oxidase (complex IV) subunit 2, which is one of the three core subunits of the mitochondrial respiratory chain complex IV holoenzyme and is required for both complex assembly and catalysis. Defects of this protein lead to complex IV deficiency.

MT-CO2 was first reported in relation to maternally-inherited primary mitochondrial disease in 1999 in an individual with progressive gait ataxia, bilateral optic atrophy, pigmentary retinopathy, and distal muscle wasting (PMID: 10205264). Other associated features have been reported over time. While various names have been given to the constellation of features seen in those with MT-CO2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-CO2 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, MT-CO2 was first curated by this GCEP for its association with Leigh syndrome spectrum (LSS) on May 17, 2021 (SOP v8), with a final classification of limited. This current curation for the association with primary mitochondrial disease includes cases with LSS.

Evidence supporting the gene-disease relationship between MT-CO2 and primary mitochondrial disease includes case-level data and experimental data. This curation includes eight variants (m.7587T>C, m.7671T>A, m.7896G>A, m.7630del, m.8156dup, m.8156del, m.8163A>G, m.8088del) in eight probands in eight publications (PMIDs: 10205264, 10486321, 11558799, 18245391, 23616164, 28521807, 30315213, 31167410). Single fiber testing further supported the pathogenicity of several of these variants (PMIDs: 31167410, 28521807, 23616164, 11558799, 10486321, 10205264 ). Age of onset in affected individuals ranged from childhood to the mid-40s. Clinical features in affected individuals included LSS, myopathy, muscle wasting, ataxia, epilepsy, stroke-like episodes, global developmental delay, cognitive decline, psychosis, axonal sensorimotor neuropathy, sensorineural hearing loss, retinitis pigmentosa, cataracts, optic atrophy, and left ventricular hypertrophy. Brain imaging was variable and ranged from normal to findings consistent with LSS, cerebral and cerebellar atrophy, and agenesis of the corpus callosum. Muscle biopsies showed ragged red fibers, COX-deficient fibers, lipid accumulation, subsarcolemmal accumulation of mitochondria, and complex IV deficiency. Metabolic screening labs showed elevated lactate. Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed (56-95% in muscle, undetectable to 67% in blood, 33-49% in buccal, undetectable to 89% in skin fibroblasts, and undetectable to 49% in urine). Segregation evidence is scored as case-level data according to the criteria established by the Mitochondrial Disease Gene Curation Expert Panel. The mechanism of pathogenicity appears to be loss of function resulting in specific loss of complex IV activity. This gene-disease relationship is also supported by known biochemical function and in vitro functional assays demonstrating altered mitochondrial function as a result of variants in MT-CO2 (PMIDs: 23965802, 30030519).

In summary, there is definitive evidence to support the relationship between MT-CO2 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 July 11, 2023 (SOP Version 9).