ACO2

Inheritance Pattern: AD

Disease ID:MONDO:0044970

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0013802

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014571

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013802

Submitter: G2P

Inheritance Pattern: Unknown

Disease ID:MONDO:0014571

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013802

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0014571

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0014753

Submitter: Orphanet

Inheritance Pattern: SD

Disease ID:MONDO:0014571

Submitter: ClinGen

*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).

Inheritance Pattern: SD

Disease ID:MONDO:0014571

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0013802

Submitter: PanelApp Australia