The relationship between ACO2 and autosomal dominant primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 19, 2023. ACO2 encodes an iron-dependent mitochondrial enzyme involved in the citric acid cycle, iron homeostasis, oxidative stress defense, and mitochondrial DNA maintenance.
The first case reports of ACO2 in relation to autosomal dominant primary mitochondrial disease were in 2020 (PMID: 33028849) in a German family with optic atrophy. Numerous additional cases have been reported, some with reduced penetrance and with variable age of onset (PMID: 34056600). This gene has also been implicated in autosomal recessive primary mitochondrial disease (please see separate curation).
Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included nine unique nonsense and frameshift variants predicted to result in protein truncation and loss of function from eight probands. There are >50 families reported with autosomal dominant ACO2-related disorders with reduced penetrance. At least 16 cases are reported with predicted null alleles (PMID: 34056600). Missense variants have also been reported and were reviewed but were not included in scoring given lack of functional evidence of variant impact resulting in loss-of-function.
This gene-disease association is also supported by functional alteration in patient cells and by a rescue study performed in yeast (PMIDs: 33028849, 34056600).
In summary, there is strong evidence to support the relationship between ACO2 and autosomal dominant primary mitochondrial disease. 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 October 19, 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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