Submission Details

The relationship between COA8 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 11, 2023. This gene was first reported to encode mitochondrial apoptogenic protein 1 (APOPT1) however subsequent studies have not shown evidence for a pro-apoptotic role. Rather, this gene is now known to encode cytochrome c oxidase assembly factor 8 (COA8) and functions in protecting the nascent COX holoenzyme from oxidative damage, particularly during metal insertion into the enzyme’s catalytic sites (PMID: 31555154). Defects of this protein lead to complex IV deficiency.

COA8 was first reported in relation to autosomal recessive primary mitochondrial disease in 2014 (PMID: 25175347), in several individuals with cavitating leukodystrophy and complex IV deficiency. While various names have been given to the constellation of features seen in those with COA8-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the COA8 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included seven unique variants (three nonsense, one intronic, two exonic deletions, one missense) identified in eight affected individuals from seven kindreds reported in three publications (PMIDs: 25175347, 29577824, 32637636). Affected individuals have a broad spectrum of features ranging from acute neurometabolic decompensation in late infancy to mild neurologic features in adolescence. Also seen were encephalopathic episodes (acute loss of developmental milestones, somnolence, seizures, pyramidal signs progressing to spastic tetraparesis) that tended to stabilize or improve over time. Age of onset varied from two to five years old, with one adult reported with minimal neurologic features (PMID: 32637636). The outcomes were variable, ranging from death to stabilization/improvement. Muscle biopsies showed complex IV deficiency. Brain imaging showed a cavitating leukodystrophy predominantly involving the posterior cerebral white matter and the corpus callosum in the acute stage after which the abnormalities partially improved and then stabilized in some affected individuals. Metabolic screening labs were not routinely reported.

This gene-disease association is also supported by its known biochemical function (PMID: 33340416), model organisms including a drosophila knockdown (PMID: 31555154) and mouse knockout (PMID: 30552096), and functional alteration in human cells (PMIDs: 25175347, 30552096).

In summary, there is definitive evidence to support the relationship between COA8 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 July 11, 2023 (SOP Version 9).