Early onset or syndromic epilepsy

Gene: FUK

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 5:59 p.m. | Last Modified: 24 Feb 2025, 5:59 p.m.

Panel Version: 7.39

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Comment on list classification: There are four unrelated patients reported with seizures and hence this gene can be promoted to green rating in the next GMS update.

Created: 19 Jul 2024, 3:01 p.m. | Last Modified: 19 Jul 2024, 3:01 p.m.

Panel Version: 5.26

PMID:35718084 reviewed three previously published cases including the two patients from PMID:30503518 and reported a new patient with biallelic variants in FCSK/ FUK gene. The newly reported patient of Iranian descent was identified with two novel homozygous variants. All four reported individuals presented with mild-severe intellectual disability, developmental delay and brain abnormalities, and three of four patients had seizures. All these phenotypes had their onset in childhood.

PMID:36426412 reported a new patient with a homozygous missense variant and had a milder phenotype. The patient presented with infantile spasm, but not with intellectual disability, developmental delay, or brain abnormalities.

This gene has been associated with relevant phenotypes in OMIM (MIM #618324) and Gene2Phenotype (with 'strong' rating on the DD panel).

Created: 19 Jul 2024, 2:58 p.m. | Last Modified: 19 Jul 2024, 2:58 p.m.

Panel Version: 5.24

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Congenital disorder of glycosylation with defective fucosylation 2, OMIM:618324

Publications

• 35718084
• 36426412

I don't know

Kept rating as Amber based on Amber post-Webex review from Helen Lord.

Created: 9 Sep 2019, 10:21 a.m. | Last Modified: 9 Sep 2019, 10:21 a.m.

Panel Version: 1.314

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

I don't know

AR CDGF2. Ng et al, 2018 (30503518) - 2 unrelated children aged 6 and 7 with a severe multisystem disorder apparent from early infancy. Both developed intractable seizures with epileptic encephalopathy. Hom/compound het missense variants detected. Immunoblot analysis of cells from patient 1 showed a 60-80% reduction in FUK levels and severely decreased FUK activity compared to controls - consistent with LOF. no cell lines available for patient 2.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

FCSK/FUK was added to the Genetic epilepsy syndromes panel and rated Amber by Konstantinos Varvagiannis. Ng et al. (PMID: 30503518) reported on 2 unrelated individuals with biallelic pathogenic variants in FUK. FUK has been added to OMIM and DDG2P based on this publications. No details were given at the age of onset of epilepsy. As there are no further cases or animal models to support these variants in the literature, inline with current guidelines, gene will remain Amber.

Created: 25 Jun 2019, 1:16 p.m. | Last Modified: 25 Jun 2019, 1:16 p.m.

Panel Version: 0.13

Added new-gene-name tag, new approved HGNC gene symbol for FUK is FCSK

Created: 1 Mar 2019, 4:11 p.m.

I don't know

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 that 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

Created: 13 Dec 2018, 7:38 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Feeding difficulties; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of vision

Publications

• 30503518