Intellectual disability
Gene: UNC13A

UNC13A (unc-13 homolog A)
EnsemblGeneIds (GRCh38): ENSG00000130477
EnsemblGeneIds (GRCh37): ENSG00000130477
OMIM: 609894, Gene2Phenotype
UNC13A is in 6 panels

4 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

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 GDD/ ID, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Created: 2 Jan 2026, 10:20 p.m. | Last Modified: 2 Jan 2026, 10:20 p.m.

Panel Version: 9.215

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, 10:17 p.m. | Last Modified: 2 Jan 2026, 10:17 p.m.

Panel Version: 9.213

Comment on list classification: There are three unrelated patients reported with three different monoallelic UNC13A variants and with intellectual disability/ developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Created: 14 Aug 2025, 12:53 p.m. | Last Modified: 14 Aug 2025, 12:53 p.m.

Panel Version: 9.64

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 has a nonverbal IQ of 70, suggesting borderline-mild intellectual disability.

PMID:39634123 (2024) reported three unrelated patients with epileptic encephalopathy 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. The two patients under the age of two had DQ of 49 and 47), while 7-year-old male patient had IQ of <40.

More information can be found on the review by Tom Hodgkinson (see below).
Created: 14 Aug 2025, 12:48 p.m. | Last Modified: 14 Aug 2025, 12:48 p.m.

Panel Version: 9.61

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
developmental and epileptic encephalopathy, MONDO:0100620

Publications

Created: 14 Aug 2025, 12:48 p.m.
Last Modified: 14 Aug 2025, 12:48 p.m.
Panel version: 9.213

Tom Hodgkinson (Leeds Teaching Hospitals NHS Trust)

I don't know

PMID: 28192369
Single patient with c.2441C>T p.(Pro814Leu) denovo variant with developmental delay, dyskinetic movement disorder, febrile seizures, ASD and ADHD. WES of DNA extracted from blood for proband and parents was performed and confirmed by sanger as denovo in proband. UNC13A variation on neurotransmission studied using neuronal cultures variant on double knockout mice and other model organisms. Single point mutations identified as having deleterious consequences for synaptic transmission and highly likely to affect neuronal network activity and lead to complex psychiatric and neurological deficits as observed in the patient.

PMID: 39634123
3 denovo heterozygous missense variants in UNC13A (c.1892T>A/p.Met631Lys, c.1945T>C/p.Phe649Leu, and c.2441C>T/p.Pro814Leu in NM_001080421.3) in three unrelated probands with epileptic encephalopathies and intellectual disability based on exome sequencing. 3 probands had consistent clinical phenotypes of developmental and epileptic encephalopathies, presenting with a history of status epilepticus, focal onset seizures in both febrile and afebrile states, and intellectual disability. CRISPR/Cas9 zebrafish mutants used to investigate UNC13A pathogenesis in epilepsy. Results suggest UNC13A variants are associated with epileptic encephalopathies and intellectual disability.

UNC13A c.2441C>T (p.Pro814Leu) appears 3 times in Clinvar, associated with delayed speech and language development, ataxia, tremor, febrile seizure. Clinvar submissions contacted with only 1 response from Victorian Clinical genetics service. Observed there in 1 individual… ‘Trio exome sequencing was performed which showed the variant to be de novo in the proband, who presented with a history of global developmental delay, focal seizures, speech apraxia, tremor, aortic root aneurysm, dilatation of the renal pelvis and Arnold-Chiari type I malformation’. All 3 submissions on Clinvar classified as Likely pathogenic.

Limited evidence reported on Clingen for gene-disease relationship (2021).
Same evidence also submitted for UNC13A on Congenital myaesthenic syndrome panel.
Created: 28 Jul 2025, 2:18 p.m. | Last Modified: 28 Jul 2025, 2:18 p.m.

Panel Version: 9.45

Phenotypes
ASD; dyskinetic movement disorder; febrile seizures; developmental delay; intellectual disability; ataxia

Publications

PMID: 8192369
39634123

Mode of pathogenicity
Other

Created: 28 Jul 2025, 2:18 p.m.
Last Modified: 28 Jul 2025, 2:18 p.m.
Panel version: 9.45

Louise Daugherty (Genomics England Curator)

Comment on list classification: New gene added by external expert review. This maybe a disease-modifying gene, but there is not enough evidence to date to rate this gene other than Red for now
Created: 16 Jul 2018, 2:52 p.m.

Created: 16 Jul 2018, 2:52 p.m.

Panel version: 2.158

Zornitza Stark (Australian Genomics)

Red List (low evidence)

Single family reported, consider inclusion as Red.
Created: 22 Jun 2018, 3:01 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

28192369

Created: 22 Jun 2018, 3:01 p.m.

Panel version: 2.109

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

Expert Review Amber
Victorian Clinical Genetics Services

Phenotypes

developmental and epileptic encephalopathy, MONDO:0100620

Tags

Q3_25_promote_green Q1_26_MOI Q3_25_NHS_review

OMIM

609894

Clinvar variants

Variants in UNC13A

Penetrance

None

Publications

Panels with this gene