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Intellectual disability

Gene: ACO2

Green List (high evidence)
ACO2 (aconitase 2)
EnsemblGeneIds (GRCh38): ENSG00000100412
EnsemblGeneIds (GRCh37): ENSG00000100412
OMIM: 100850, Gene2Phenotype
ACO2 is in 11 panels

6 reviews

Ida Ertmanska (Genomics England Curator)

Green List (high evidence)

Comment on mode of inheritance: There are numerous patients reported with both mono- and bi-allelic variants in ACO2. Individuals with heterozygous ACO2 variants present with isolated optic atrophy, while those with biallelic variants may present with either syndromic or non-syndromic optic atrophy. Syndromic presentation usually involves cerebellar-retinal degeneration, ataxia, seizures, ID, and developmental delays. Hence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal for Intellectual disability.
Created: 8 Oct 2026, 4:55 p.m. | Last Modified: 8 Oct 2026, 4:55 p.m.
Panel Version: 11.42
PMID: 34056600 Charif et al., 2021
Study identified 61 cases harbouring variants in ACO2. 50/61 harboured heterozygous ACO2 variants. 52 individuals had isolated optic atrophy. "27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy (...) with a single case showing hearing loss (P38) and two cases showing a late-onset cerebellar ataxia (P19 and P53)."
However, extraocular features in the dominant cases were not consistent and mostly did not match the AR Infantile cerebellar-retinal degeneration disease entity associated with ACO2 - probably incidental findings.
P19 - somewhat consistent - het for ACO2 p.Gly463Arg and had cerebellar ataxia. Among recessive cases, 1 individual had epilepsy with onset at 22 yrs (comp het for ACO2 c.36+5delG and p.(Gly240Ala)). Another patient presented with kinetic and static cerebellar syndrome with cerebellar atrophy; episode of dysarthria at 45 y - comp het for ACO2 p.(Leu74Val) and p.(Glu464*). No mention of intellectual disability in this cohort.

PMID: 32519519 Blackburn et al., 2020
Report of five patients with biallelic pathogenic variants in ACO2:
Case 1 & 2 - Two sibs with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities.
Case 3 - proband presented with the classic form with cerebellar hypoplasia, ataxia, seizures, moderate‐to‐severe intellectual disability, optic atrophy, and retinitis pigmentosa.
Case 4 - proband demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months.
Case 5 - proband presented with ataxia, severe developmental and motor delays, and seizures; developed severe progressive spastic quadriplegia.
Mostly missense variants; Case 5 had biallelic frameshift variants in ACO2.

PMID: 31106992 Fukada et al., 2019
Report of a Japanese female patient with progressive cerebellar and cerebral atrophy, hypotonia, ataxia, seizure disorder, developmental delay, ophthalmological abnormalities and hearing loss. WES detected comp het missense variants (c.1534G>A, p.Asp512Asn and c.1997G>C, p.Gly666Ala) in ACO2. Parents were healthy and unrelated, confirmed to be het for a variant each.

PMID: 25351951 Metodiev et al., 2014
Study of 5 patients from 3 unrelated families with homozygous or compound heterozygous missense and frameshift mutations in ACO2, with either isolated or syndromic optic neuropathy.

PMID: 22405087 Spiegel et al., 2012
Studied eight individuals from two unrelated families of Arab Muslim origin who presented at 2–6 months of age with truncal hypotonia and athetosis, seizure disorder, profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Six individuals older than 2 years were profoundly intellectually disabled. All patients were homozygous for ACO2 p.Ser112Arg. Method: homozygosity mapping and WES. Ten parents and one of the healthy sibs were confirmed to be heterozygous.

ACO2 is associated with AR Infantile cerebellar-retinal degeneration, OMIM:614559 and AD Optic atrophy 9. OMIM:616289 in OMIM (accesssed 8th Oct 2026).
Created: 8 Oct 2026, 4:28 p.m. | Last Modified: 8 Oct 2026, 4:53 p.m.
Panel Version: 11.42

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Infantile cerebellar-retinal degeneration, OMIM:614559; Optic atrophy 9. OMIM:616289

Publications

Created: 8 Oct 2026, 4:28 p.m.
Last Modified: 8 Oct 2026, 4:53 p.m.
Panel version: 11.42

Arina Puzriakova (Genomics England Curator)

The mode of inheritance of this gene has been updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.
Panel Version: 4.53
Created: 30 Jan 2023, 5:50 p.m.
Last Modified: 30 Jan 2023, 5:50 p.m.
Panel version: 4.53

Sarah Leigh (Genomics England Curator)

New paper (34056600) describing ACO2 as a cause of autosomal dominant optic atrophy - update of inheritance needed.
Tom Cullup (Great Ormond Street Hospital), 17 Feb 2022
Created: 26 May 2022, 1:26 p.m. | Last Modified: 26 May 2022, 1:26 p.m.
Panel Version: 3.1593
PMID: 34056600 reports 61 cases of genetically unsolved inherited optic neuropathies who were harbouring variants in ACO2, of which 50 carried dominant variants (the remaining 11 cases were biallelic). The authors state that this is the first report of monoallelic pathogenic ACO2 variants resulting in dominant optic atrophy.
Created: 26 May 2022, 1:23 p.m. | Last Modified: 26 May 2022, 1:23 p.m.
Panel Version: 3.1593

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Created: 26 May 2022, 1:23 p.m.
Last Modified: 26 May 2022, 1:23 p.m.
Panel version: 3.1593

Caroline Wright (Sanger)

I don't know

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
INFANTILE CEREBELLAR-RETINAL DEGENERATION

Publications

Lu Raymond (university of cambridge )

I don't know

Created: 23 Feb 2016, 10 a.m.

Panel version: 0.306

Richard Scott (Genomics England Curator)

Comment on list classification: Multiple families now reported
Created: 29 Jan 2016, 4:39 p.m.

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • NHS GMS
  • Victorian Clinical Genetics Services
  • Expert Review Green
Phenotypes
  • Infantile cerebellar-retinal degeneration, OMIM:614559
  • Infantile cerebellar-retinal degeneration, MONDO:0013802
Tags
Q4_26_MOI
OMIM
100850
Clinvar variants
Variants in ACO2
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

8 Oct 2026, Gel status: 3

Added Tag

Ida Ertmanska (Genomics England Curator)

Tag Q4_26_MOI tag was added to gene: ACO2.

8 Oct 2026, Gel status: 3

Set publications

Ida Ertmanska (Genomics England Curator)

Publications for gene: ACO2 were set to 22405087; 25351951; 34056600

31 Jan 2023, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q2_22_MOI was removed from gene: ACO2.

30 Jan 2023, Gel status: 3

Added New Source, Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

Source NHS GMS was added to ACO2. Mode of inheritance for gene ACO2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

26 May 2022, Gel status: 3

Added Tag

Sarah Leigh (Genomics England Curator)

Tag Q2_22_MOI tag was added to gene: ACO2.

26 May 2022, Gel status: 3

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: ACO2 were set to 22405087; 25351951

1 Mar 2021, Gel status: 3

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: ACO2 were changed from INFANTILE CEREBELLAR-RETINAL DEGENERATION to Infantile cerebellar-retinal degeneration, OMIM:614559; Infantile cerebellar-retinal degeneration, MONDO:0013802

28 Sep 2018, Gel status: 4

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to ACO2.

12 Mar 2018, Gel status: 3

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

29 Jan 2016, Gel status: 4

Gene classified by Genomics England curator

Richard Scott (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

29 Jan 2016, Gel status: 4

Gene classified by Genomics England curator

Richard Scott (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

29 Jan 2016, Gel status: 4

Set publications

Richard Scott (Genomics England Curator)

Publications for ACO2 were set to 22405087; 25351951

29 Jan 2016, Gel status: 4

Gene classified by Genomics England curator

Richard Scott (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

ACO2 was added to Intellectual disabilitypanel. Sources: Expert Review Amber

13 Nov 2015, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

ACO2 was created by ellenmcdonagh