Early onset or syndromic epilepsy

Gene: GLUL

Green List (high evidence)

Comment on mode of inheritance: There are >10 unrelated individuals reported with developmental and epileptic encephalopathy and monoallelic GLUL variants. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.

Created: 7 Jan 2026, 11:18 a.m. | Last Modified: 7 Jan 2026, 11:18 a.m.

Panel Version: 8.88

PMID:38579670 (2024) reported nine unrelated individuals with severe global developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry. The epilepsy was characterized as generalized (4 individuals), combined general and focal (3), focal (1), or unknown (1). Most individuals had a developmental and epileptic encephalopathy, with one individual meeting diagnostic criteria for infantile epileptic spasms syndrome. They were identified with heterozygous de novo variants in GLUL gene via whole-exome sequencing. Seven out of nine were start-loss variants and two out of nine disrupted 5' UTR splicing resulting in splice exclusion of the initiation codon.

PMID:39985170 (2025) reported a male proband with a phenotype of refractory focal and generalized seizures and developmental delays and identified with a heterozygous de novo start-codon-disrupting variant in GLUL (c.-13-2A>G).

PMID:41083803 (2025) reported three additional unrelated patients with heterozygous de novo GLUL variants identified via trio whole-exome sequencing and with developmental and epileptic encephalopathy.

Both monoallelic and biallelic variants in this gene have been associated with relevant phenotypes in OMIM (MIMs #610015 & #620806, last accessed 07 January 2026) and ClinGen (both AR and AD diseases with 'moderate' rating). Only biallelic variants are currently associated with phenotype in Gene2Phenotype ('definitive' rating on DD panel).

Created: 7 Jan 2026, 11:11 a.m. | Last Modified: 7 Jan 2026, 11:22 a.m.

Panel Version: 8.88

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Glutamine deficiency, congenital, OMIM:610015; Developmental and epileptic encephalopathy 116, OMIM:620806; congenital brain dysgenesis due to glutamine synthetase deficiency, MONDO:0012393; developmental and epileptic encephalopathy 116, MONDO:0970945

Publications

• 38579670
• 39985170
• 41083803

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Glutamine deficiency, congenital, 610015

Publications

• 21353613
• 16267323

Comment on publications: Added publications to support upgrading of the gene to Green

Created: 20 Nov 2018, 11:25 a.m.

Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association.

Created: 20 Nov 2018, 11:22 a.m.

Comment on mode of inheritance: changed MOI from OMIM and publication PMID:16267323

Created: 16 Nov 2018, 4:19 p.m.

Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel

Created: 16 Nov 2018, 4:18 p.m.

Green List (high evidence)

Seizures are part of the phenotype.

Created: 14 Aug 2018, 10:52 a.m.

Phenotypes
Glutamine deficiency, congenital, MIM#610015

Variants in this GENE are reported as part of current diagnostic practice