The relationship between ACO2 and autosomal recessive primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 19, 2023. ACO2 encodes mitochondrial aconitase, an iron-dependent mitochondrial enzyme involved in the citric acid cycle (catalyzes the isomerization of citrate to isocitrate via cis-aconitate), iron homeostasis, oxidative stress defense, and mitochondrial DNA maintenance.
The first case reports of ACO2 being associated with autosomal recessive primary mitochondrial disease were in 2012 (PMID: 22405087) in a consanguineous Arab Muslim family with infantile ataxia, cerebellar atrophy, athetosis, retinal dystrophy, and optic atrophy. This phenotype has been described as “infantile cerebellar-retinal degeneration” and is consistent with a primary mitochondrial disease phenotype. Subsequent cases have shown similar phenotypes ranging in age of onset and including cerebellar disease with or without optic atrophy, retinal disease, and epilepsy, as well as a cerebellar disease with spastic paraplegia. As per criteria outlined by the ClinGen Lumping and Splitting Working Group, these phenotypes were consistent with primary mitochondrial disease as agreed upon by the Mitochondrial Disease Gene Curation Expert Panel.
Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 11 unique missense variants, two nonsense variants, and three frameshift or splicing variants from 11 probands across six publications. Affected individuals presented with a similar cerebellar phenotype often with seizures and retinal dystrophy or optic atrophy (PMIDs: 22405087, 25351951, 30689204, 31106992). More cases are reported, but case evidence maximum was reached.
This gene-disease association is also supported by functional alteration and rescue in patient cells (PMIDs: 26992325, 29564393, 29577077) as well as a Drosophila melanogaster RNAi knockdown model of Acon, an ACO2 ortholog (PMID: 23438437).
In summary, there is definitive evidence to support the relationship between ACO2 and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. 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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