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Intellectual disability v11.42 ACO2 Ida Ertmanska changed review comment from: 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: 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).; to: 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).
Intellectual disability v8.97 FUK Sarah Leigh Tag watchlist was removed from gene: FUK.
Tag Q3_24_promote_green was removed from gene: FUK.
Intellectual disability v8.97 FUK Sarah Leigh reviewed gene: FUK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.97 FUK Sarah Leigh Source NHS GMS was added to FUK.
Source Expert Review Green was added to FUK.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v6.61 FUK Achchuthan Shanmugasundram Phenotypes for gene: FUK were changed from Seizures; Generalized hypotonia; Feeding difficulties; Intellectual disability; Global developmental delay; Congenital disorder of glycosylation with defective fucosylation 2, 618324 to Congenital disorder of glycosylation with defective fucosylation 2, OMIM:618324
Intellectual disability v6.60 FUK Achchuthan Shanmugasundram Classified gene: FUK as Amber List (moderate evidence)
Intellectual disability v6.60 FUK Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated families reported with ID (severe in three families and mild in one). Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v6.60 FUK Achchuthan Shanmugasundram Gene: fuk has been classified as Amber List (Moderate Evidence).
Intellectual disability v6.59 FUK Achchuthan Shanmugasundram Publications for gene: FUK were set to 30503518
Intellectual disability v6.58 FUK Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: FUK.
Intellectual disability v6.58 FUK Achchuthan Shanmugasundram reviewed gene: FUK: Rating: GREEN; Mode of pathogenicity: None; Publications: 35718084, 36426412; Phenotypes: Congenital disorder of glycosylation with defective fucosylation 2, OMIM:618324; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.981 FUK Catherine Snow Tag watchlist tag was added to gene: FUK.
Intellectual disability v2.978 FUK Catherine Snow Source Expert Review was added to FUK.
Source Expert Review Amber was added to FUK.
Added phenotypes Congenital disorder of glycosylation with defective fucosylation 2, 618324 for gene: FUK
Rating Changed from No List (delete) to Amber List (moderate evidence)
Intellectual disability v2.800 SNAP25 Konstantinos Varvagiannis gene: SNAP25 was added
gene: SNAP25 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: SNAP25 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SNAP25 were set to 29491473; 28135719; 29100083; 25381298; 25003006
Phenotypes for gene: SNAP25 were set to ?Myasthenic syndrome, congenital 18, 616330
Penetrance for gene: SNAP25 were set to Complete
Review for gene: SNAP25 was set to GREEN
gene: SNAP25 was marked as current diagnostic
Added comment: Probably 9 individuals with heterozygous SNAP25 pathogenic variants have been reported to date, most summarized in the first reference (NM_130811.2 used as reference for all variants below):
- Fukuda et al. (2018 - PMID: 29491473) 2 sibs (~11 and 2.5 y.o) with seizures and cerebellar ataxia but not ID. harboring c.176G>C (p.Arg59Pro) variant which was inherited from a mosaic unaffected parent.
- DDD study (2017 - PMID: 28135719) [also in Heyne et al. 2018 - PMID: 29942082] 3 inividuals (11 m - 7 y of age) with DD and seizures due to c.118A>G (p.Lys40Glu), c.127G>C (p.Gly43Arg) and c.520C>T (p.Gln174*) de novo variants.
- Hamdan et al. (2017 - PMID: 29100083) a 23 y.o. male with epilepsy and ID and c.496G>T (p.Asp166Tyr) de novo variant
- Shen et al. (2014 - PMID: 25381298) a 11 y.o. female with epilepsy and ID and c.200T>A (p.Ile67Asn) de novo variant
- Rohena et al. (2013 - PMID: 25003006) a 15 y.o. female with epilepsy and ID and c.142G>T (p.Val48Phe) de novo variant
- Decipher patient 292139, a male with c.212T>C (p.Met71Thr) with hypotonia, DD, poor coordination and additional features (epilepsy not reported).

Seizures of variable type [absence seizures, generalized tonic-clonic (most), focal clonic, myoclonic, etc] have been reported for most (8/9) of these individuals. DD was a feature in several subjects and intellectual outcome has been specifically commented on for 5 (2 without and 3 with ID - moderate/severe/not further specified).

SNAP25 encodes a (t-)SNARE protein essential for synaptic vesicle exocytosis. Mutations in genes for other components of the SNARE complex (eg. STXBP1) have been associated with epilepsy and/or ID.

SNAP25a and SNAP25b are the 2 major protein isoforms [corresponding transcripts: ENST00000304886 (NM_003081) and ENST00000254976 (NM_130811) respectively]. These isoforms are produced by utilization of alternative exons 5 (5a or 5b) though the amino-acid sequence encoded by these exons appears to be identical except for 9 residues. Most variants reported to date affect both transcripts (and protein isoforms) although 2 were specific for ENST00000254976 (or SNAP25b isoform - Fukuda et al. and Shen et al.).

Mouse Snap25 has also 2 isoforms. Both are predominantly localized in embryonic and adult mouse brains. Snap25a is produced before Snap25b though the latter becomes the major isoform early postnatally (by the second week) [PMIDs cited: 7878010, 21526988].

Based on the phenotype of some individuals with chromosome 20 deletions in Decipher (note: only 3 deletions spanning SNAP25 however appear currently, the phenotype is not specified and 2 of them are >4.5Mb) or the pLI of 0.96 in gnomAD, haploinsufficiency has been proposed as a likely mechanism. A dominant-negative effect was however suggested for the Ile67Asn studied by Shen et al. Functional studies have not been performed for other variants.

Animal models discussed:
- Snap25 null drosophila show complete loss of synaptic transmission upon electroretinogram recordings (PMID cited: 12242238).
- In mice, elimination of Snap25b expression resulted in developmental defects, seizures and impaired short-term synaptic plasticity (PMID cited: 19043548).
- Mice with a 4.6 Mb deletion encompassing 12 genes (incl. Snap25) display seizure predisposition (PMID cited: 23064108).
- Heterozygosity for Ile67Thr in (blind-drunk mutant) mice results in impaired vesicle trafficking, impaired sensorimotor gating and ataxia (PMID cited:17283335).

In OMIM, heterozygous SNAP25 mutations are associated with ?Myasthenic syndrome, congenital, 18 (with intellectual disability and ataxia). SNAP25 is part of the DD panel, associated with "Epilepsy and intellectual disability" (disease confidence: probable).

This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc). SNAP25 is among the genes discussed by Erger et al. (PMID: 30914295) as associated with ID in OMIM/HPO/G2P/SysID but not included in the current panel.

As a result SNAP25 can be considered for inclusion in the ID panel probably as green (3 individuals with ID, role of SNARES in "synaptopathies", supportive animal models) or amber (if functional studies for individual variants would be required).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.782 FUK Louise Daugherty commented on gene: FUK
Intellectual disability v2.782 FUK Louise Daugherty Tag new-gene-name tag was added to gene: FUK.
Intellectual disability v2.584 FUK Konstantinos Varvagiannis gene: FUK was added
gene: FUK was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FUK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FUK were set to 30503518
Phenotypes for gene: FUK were set to Feeding difficulties; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures
Penetrance for gene: FUK were set to Complete
Review for gene: FUK was set to AMBER
Added comment: Ng et al. (PMID: 30503518) report on 2 unrelated individuals with biallelic pathogenic variants in FUK. The common features consisted of feeding difficulties, hypotonia, global developmental delay with severe intellectual disability, seizures as well as visual impairment.

The first patient was compound heterozygous for 2 missense variants (Ser223Pro and Arg683Cys) while the second - born to consanguineous parents - was homozygous for Lys994Gln.

Significant reduction in the FUK protein amount was demonstrated upon Western blot for the first individual for whom fibroblast and lymphoblast cell lines were available.

Fucokinase (FUK) is an enzyme of the fucose salvage pathway, one of the mechanisms (the other and main contributor being the de novo pathway) for synthesis of GDP-fucose. GDP-fucose is a donor substrate for fucosylation, a form of glycosylation. Significant decrease of fucokinase activity was shown for this individual when compared to controls.

Cell lines from the second individual were not available for expression/functional studies.

Overall the authors suggest loss-of-function variants cause a congenital disorder of glycosylation with ID and seizures.

There are no further cases published in the literature.

FUK is not associated with any phenotype in OMIM nor in G2P.

As a result this gene can be considered for inclusion in this panel as amber.

[You might consider inclusion of this gene also in the CDG gene panel].
Sources: Literature