The relationship between COX20 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 17, 2022. COX20 encodes a Cytochrome c oxidase (complex IV) assembly factor.
COX20 was first reported in relation to autosomal recessive mitochondrial disease in 2013 (PMID: 23125284). While various names have been given to the constellation of features seen in those with COX20-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *COX20 *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, including one nonsense (occurring in the last exon, 4/4), two intronic, and four missense variants, in 16 probands across seven publications from 2013-2021 (PMIDs: 23125284, 30656193, 32606554, 24202787, 31079202, 32999401, 33751098). Of note, the p.Arg14Lys and p.Thr52Pro variants appear to be founder variants, in the Eastern Chinese and Turkish populations, respectively, while the c.157+3G>C and p.Trp74Cys variants appear to be recurrent. COX20 pathogenic variants were first reported in a child with ataxia, hypotonia, developmental delay, and short stature in the setting of complex IV deficiency in muscle and skin. Subsequent publications have shown expansion of the phenotypic spectrum that ranges from childhood to adolescent onset sensory neuropathy, dystonia, and sensory ataxia, as well as muscle weakness, intellectual disability, and cerebellar atrophy. 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 cells, functional alteration in non-patient cells, rescue in patient cells, and model systems (PMIDs: 22095077, 24403053, 23125284).
In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 17, 2022 (SOP Version 8).
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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