COX15

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *COX15* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 4, 2023. *COX15* encodes the cytochrome c oxidase assembly protein COX15 homolog protein, a transmembrane protein located at the mitochondrial inner membrane. *COX15* is a Complex IV assembly factor with is thought to be involved in the biosynthesis of heme A. Defects of this protein lead to complex IV deficiency. *COX15* was first reported in relation to autosomal recessive primary mitochondrial disease in 2003 in an individual with fatal, infantile hypertrophic cardiomyopathy (PMID: 12474143). While various names could be given to the constellation of features seen in those with *COX15*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *COX15* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *COX15* was previously curated by this GCEP on April 22, 2019 (SOP Version 6) as having a Limited association with Leigh Syndrome Spectrum (LSS). The scope of this current curation encompassed cases of primary mitochondrial disease, which includes LSS. Evidence supporting the gene-disease relationship between *COX15* and primary mitochondrial disease includes case-level data and experimental data. This curation includes six unique variants (four missense including the p.Arg217Trp variant that appears to be recurrent as it was scored in five probands from different populations, one nonsense, one splicing) in nine probands from nine publications (PMIDs: 15235026, 12474143, 15863660, 21412973, 26959537, 32232962, 33746038, 34440436, 31967322). Affected individuals present with a broad phenotypic spectrum of disease which may include seizures, hypotonia, ataxia, psychomotor retardation, vision loss, dysphagia, microcephaly, encephalopathy, and gliosis as well as cardiomyopathy. MRI findings are often consistent with LSS. The age of onset ranges from birth to early childhood. Where assessed, affected individuals present with persistent lactic acidosis and complex IV deficiency. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, functional alteration in patient fibroblasts, and a mouse model which recapitulates aspects of mitochondrial disease (PMIDs: 33340416, 12474143, 21723506, 26039449). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 4, 2023 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between COX15 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of April 22, 2019. 11 articles were reviewed. COX15 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2004 (Oquendo et al., PMID: 15235026). Five 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 1 proband with Leigh syndrome spectrum in 1 publication (PMID 15235026 ). This gene-disease association is further supported by the function of the gene product, expression, and studies in patient cell lines and a COX15 mouse model. In summary, there is limited evidence to support the relationship between COX15 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:0014051

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0014051

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0014051

Submitter: Labcorp Genetics (formerly Invitae)