The relationship between COX4I2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 18, 2024. The COX4I2 gene encodes an isoform of a subunit of cytochrome c oxidase (COX) that is expressed in lung and pancreatic acinar cells.
COX4I2 was first reported in relation to autosomal recessive primary mitochondrial disease in 2009 (PMID: 19268275) in two unrelated probands with exocrine pancreatic insufficiency, dyserythropoeitic anemia, and calvarial hyperostosis. While various names have been given to the constellation of features seen in those with COX4I2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the COX4I2 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 missense variant seen in both probands. Of note, this variant has a relatively high allele frequency in gnomAD v4.0.0 (allele frequency 0.0003940, including two homozygotes). This Expert Panel elected to include these cases at minimal scoring given that the variant frequency did not seem sufficiently high enough to entirely exclude the variants as causative and the shared phenotype of exocrine pancreatic insufficiency and dyserythropoeitic anemia is unique.
The mechanism of disease is loss of function This gene-disease association is also supported by its known biochemical function of COX4I2 as a subunit of complex IV, functional alteration in non-patient cells (PMID: 32075102), and a knockout mouse model (PMID: 22730437).
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/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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