Submission Details

ACO2 is a nuclear gene that encodes a mitochondrial aconitase belonging to the family of iron-sulfur [4Fe- 4S]-containing dehydratases. The protein product is involved in cellular metabolism through the tricarboxylic acid (TCA) cycle.

ACO2 was first reported in 2012 in relation to optic atrophy (OPA) in patients with infantile cerebellar-retinal degeneration (ICRD) (Spiegel et al., PMID: 22405087). Whole exome sequencing detected a homozygous variant encoding p.Ser112Arg in ACO2 in eight affected individuals from two consanguineous families. The variant was found in the heterozygous state in one unaffected sibling and ten unaffected parents and absent from three additional healthy siblings. A subsequent study (Metodiev et al., 2014, PMID: 25351951) investigating the causative variants for either isolated or syndromic optic neuropathy identified biallelic variants in ACO2 in patients with optic neuropathy with or without extraocular features. By resequencing gene panels dedicated to the molecular diagnosis of inherited optic neuropathies (IONs), a large cohort study (Charif et al., 2021, PMID: 64056600), including about 1000 molecularly undiagnosed cases with isolated optic neuropathy, identified 61 affected individuals carrying suspected disease-causing variants in ACO2, of which majority of cases (50/61) were autosomal dominant. Disease-causing ACO2 variants were also reported in individuals with optic atrophy/visual loss and spastic paraplegia (Marwlli et al., 2018, PMID 29564393, Tozawa et al., 2021, PMID 33500398).

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, the molecular mechanism (ACO2 loss of function) was found to be consistent among patients with optic atrophy with or without extraocular features. The phenotypic variability between patients appears to represent a spectrum of disease rather than separate disease entities and the mechanism of pathogenicity appears to be loss of function with underlying aconitase enzyme deficiency as a shared feature. Therefore, the following disease entities, ICRD (OMIM:614559), Optic atrophy 9 (OMIM: 616289), and optic atrophy and hereditary spastic paraplegia, have been lumped for the purposes of this curation into a single disease entity, referred to as ACO2-related optic atrophy with or without extraocular features, with a semidominant mode of inheritance.

Over 150 ACO2 variants including missense, nonsense, frameshift, and small insertions and deletions have been reported in more than 20 publications in association with optic atrophy with or without extraocular features. Majority of them are rare unique variants. This curation includes and scores twenty one variants identified in fifteen probands and reported in ten publications, including six variants identified in dominant OPA, six in recessive OPA, two in classic ICRD, and seven in OPA with extraocular features (PMIDs: 22405087, 25351951, 26992325, 29564393, 30118607, 31765440, 32449285, 33028849, 34056600, 37460232).

This gene-disease relationship is also supported by experimental evidence (PMID: 29577077, 29564393, 25351951, 26992325, 31106992, 33028849, 34056600, 22405087). ACO2 variants identified in affected individuals displayed adverse impact on aconitase enzyme activity and, under growth conditions requiring the TCA cycle, failed to complement a yeast strain in which the aconitase gene was deleted (∆aco1). Fibroblasts derived from the affected individuals displayed a deficiency in cellular respiration and mitochondrial DNA depletion (PMID: 26992325, 33028849). Further study is needed to directly illustrate the role of ACO2 deficiency in oxidative stress and cell death related to optic nerve atrophy.

In summary, ACO2 is definitively associated with ACO2-related optic atrophy with or without extraocular features. This has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel and the ClinGen Mitochondrial Diseases Gene Curation Expert Panel on ______, 2024 (SOP Version 9).