MT-CO1

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010779

Submitter: Orphanet

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between MT-CO1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of May 17, 2021. The MT-CO1 gene encodes cytochrome c oxidase (complex IV) subunit 1. Defects of this protein lead to complex IV deficiency. The MT-CO1 gene was first reported in relation to maternally inherited Leigh syndrome in 2014 (PMID: 24956508). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 3 variants (m.6547T>C, m.6579G>A, m.7402del) in 3 cases from 3 publications (PMIDs: 24956508, 30743023; the case with m.6547T>C was reported in a manuscript with no PMID - Pereira et al. (2019): Journal of Inborn Errors of Metabolism and Screening 2019, Volume 7: e20180003. DOI:10.1590/2326-4594-JIEMS-2018-0003). Of note, several cases had overlap in brain imaging findings between Leigh syndrome spectrum and MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes). Other variants in the MT-CO1 gene are associated with non-Leigh syndrome spectrum phenotypes. Segregation information is scored as case level evidence according to criteria established by the Mitochondrial Disease Gene Curation Expert Panel. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known protein interaction, expression, and animal models (PMIDs: 30030519, 25613900, 18276892). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 17, 2021 (SOP Version 8).

Inheritance Pattern: AR

Disease ID:MONDO:0009068

Submitter: Orphanet

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MT-CO1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 5, 2023. The *MT-CO1* gene encodes the cytochrome c oxidase (complex IV) subunit 1, which is one of 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-CO1* was first reported in relation to maternally-inherited primary mitochondrial disease in 1999 in an individual with cerebellar ataxia, progressive visual loss, and muscle weakness (PMID: 10441567). Other associated features have been reported over time. While various names could be given to the constellation of features seen in those with *MT-CO1*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MT-CO1* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *MT-CO1* 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-CO1* and primary mitochondrial disease includes case-level data and experimental data. This curation includes eight variants (m.5920G>A, m.6328C>T, m.6579G>A, m.6597C>A, m.6698del, m.6708G>A, m.6930G>A, m.7402del) in eight probands in eight publications (PMIDs: 10441567, 10980727, 15751226, 16284789, 18977334, 22832341, 24956508, 30743023). Single fiber testing and cybrid analyses further supported the pathogenicity of several of these variants (PMIDs: 10441567, 10980727, 22832341, 24956508). Age of onset in affected individuals ranged from infancy to adolescence. Clinical features in affected individuals included LSS, cognitive decline, exercise intolerance, myoglobinuria, stroke-like episodes, myoclonic epilepsy, cerebellar ataxia, muscle weakness, muscle atrophy, cataracts, optic atrophy, sensorineural hearing loss, and left ventricular hypertrophy. Brain imaging was variable and ranged from normal to findings consistent with LSS, cerebellar atrophy, and cortical atrophy. Muscle biopsies showed ragged red fibers, COX-deficient fibers, and complex IV deficiency. Metabolic laboratory investigations revealed normal to elevated lactate and creatine kinase (CK). Heteroplasmy levels in affected individuals were highest in muscle when multiple tissues were assessed (61-95% in muscle, undetectable to 30% in blood, undetectable to 40% in skin fibroblasts, undetectable in hair follicles when tested, and 15-70% 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, in vitro functional assays, and a mouse model, all of which demonstrate altered mitochondrial function as a result of variants in *MT-CO1* (PMIDs: 10441567, 18276892, 30030519). In summary, there is definitive evidence to support the relationship between *MT-CO1* and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on on June 5, 2023.

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010789

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0020504

Submitter: Orphanet