The relationship between COX6A1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 18, 2024. The COX6A1 gene encodes an isoform of a subunit of cytochrome c oxidase (COX).
COX6A1 was first reported in relation to autosomal recessive primary mitochondrial disease in 2014 (PMID: 25152455), in two Japanese probands with early childhood onset peripheral neuropathy. A third case with similar clinical features was reported in 2016 (PMID: 26302975). While various names have been given to the constellation of features seen in those with COX6A1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the COX6A1 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 one homozygous five base pair intronic deletion resulting in aberrant splicing and loss of function in all reported cases.
The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of COX6A1 as a subunit of complex IV, functional alteration in non-patient cells (PMID: 20307258), and a mouse model that recapitulates the clinical and biochemical phenotype seen in affected individuals (PMID: 25152455)
In summary, there is strong evidence to support the relationship between COX6A1 and autosomal recessive primary mitochondrial disease. While the three publications related to this gene-disease curation covered a span of six years (2010-2016), this Expert Panel elected to classify this association as strong given that a single variant only has been reported in the three unrelated probands, and two of these probands were from consanguineous families, raising the possibility other genetic etiologies could be present. We will re-evaluate this gene-disease relationship in the future to determine if an upgraded classification of Definitive is warranted. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 18, 2024 (SOP Version 10).
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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