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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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