Early onset or syndromic epilepsy

Gene: UNC13A

Green List (high evidence)

Comment on mode of inheritance: As there is sufficient evidence available for the association of both monoallelic and biallelic UNC13A variants with seizures, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.

Created: 2 Jan 2026, 10:27 p.m. | Last Modified: 2 Jan 2026, 10:27 p.m.

Panel Version: 8.83

PMID:41125872 (2025) identified a neurodevelopmental syndrome caused by variants in the UNC13A gene. Systematic patient and variant characterisation enabled classification of three disease subtypes.

A first group of six patients (18 months to ~15 years old) presented with severe-to-profound global developmental delay (GDD) or intellectual disability (ID), hypotonia and seizures of different types (largely controllable with medication) or death in early childhood caused by respiratory failure after pneumonia in one case. UNC13A variants in these patients were homozygous or compound heterozygous missense, insertion–deletion or splice-site variants with gene-disrupting splicing effects proven by minigene assays.

A second group of 13 patients (21 months to 32 years old) harboured pathogenic, heterozygous de novo missense variants with multiple substitutions at amino acids 808, 811 and 814. They presented with variable degrees of GDD, hypotonia, seizures of different types (mainly refractory to treatment) and typically exhibited ataxia, tremor or dyskinetic movements rarely observed in other patients.

The third group of patients consisted of a family with at least four affected members across two generations (4 years to 35 years old) harbouring a pathogenic heterozygous missense variant (p.Cys587Phe) that caused learning difficulties to mild–moderate intellectual disability as well as controlled seizures.

Both monoallelic and biallelic UNC13A variants have been associated with relevant phenotypes in Gene2Phenotype (both with 'moderate' rating on the DD panel), but not yet in OMIM (last accessed 02 January 2026).

Created: 2 Jan 2026, 10:22 p.m. | Last Modified: 2 Jan 2026, 10:22 p.m.

Panel Version: 8.81

Comment on list classification: There is sufficient evidence available (four unrelated patients and functional studies) for the promotion of this gene to green rating in the next GMS update.

Created: 14 Aug 2025, 1:17 p.m. | Last Modified: 14 Aug 2025, 1:17 p.m.

Panel Version: 8.23

PMID:28192369 (2017) reported a 6-year-old male patient presenting with a disorder characterised by a dyskinetic movement disorder, developmental delay, and autism, and identified with a rare de novo heterozygous missense variant (p.Pro814Leu) in UNC13A gene. Sanger sequencing was done in parents and de novo inheritance was confirmed. This patient also presented with febrile seizures.

PMID:39634123 (2024) reported three unrelated patients presenting with clinical phenotypes consistent with developmental and epileptic encephalopathy including status epilepticus, focal onset seizures in both febrile and afebrile states, and intellectual disability. They were identified with three different de novo heterozygous missense variants (p.Met631Lys, p.Phe649Leu & p.Pro814Leu) based on trio exome sequencing. There is also functional evidence available from CRISPR/Cas9 zebrafish mutants in support of the association of UNC13A to epilepsy.

This gene is currently associated with congenital nervous system disorder (MONDO:0002320) in ClinGen with 'Limited' rating by Syndromic Disorders expert panel (https://search.clinicalgenome.org/CCID:008453)
Sources: Literature

Created: 14 Aug 2025, 1:15 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
developmental and epileptic encephalopathy, MONDO:0100620

Publications

• 28192369
• 39634123
• 41125872