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Early onset or syndromic epilepsy v8.83 UNC13A Achchuthan Shanmugasundram Added comment: 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.
Early onset or syndromic epilepsy v8.83 UNC13A Achchuthan Shanmugasundram Mode of inheritance for gene: UNC13A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.82 UNC13A Achchuthan Shanmugasundram edited their review of gene: UNC13A: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.82 UNC13A Achchuthan Shanmugasundram Publications for gene: UNC13A were set to 28192369; 39634123
Early onset or syndromic epilepsy v8.81 UNC13A Achchuthan Shanmugasundram Tag Q1_26_MOI tag was added to gene: UNC13A.
Early onset or syndromic epilepsy v8.81 UNC13A Achchuthan Shanmugasundram edited their review of gene: UNC13A: Added comment: 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).; Changed publications to: 28192369, 39634123, 41125872; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.61 BSN Helen Lord gene: BSN was added
gene: BSN was added to Early onset or syndromic epilepsy. Sources: Other
Mode of inheritance for gene: BSN was set to Unknown
Publications for gene: BSN were set to PMID: 36600631; 39616287; 40393460
Phenotypes for gene: BSN were set to Seizures - different types
Penetrance for gene: BSN were set to unknown
Review for gene: BSN was set to AMBER
Added comment: There are a lot of cases to support an AD phenotype but unsure as to whether there is also an AR pheontype associated with disease...

PMID:36600631 - Ye et al, 2023:
BSN gene encodes the Bsssoon protein which is highly expressed in the mammalian brain especially the cerebral cortex and the hippocampus.
WES in 313 trios with epilepsies of unknown causes novel BSN variants identifed in 5 cases and 3 additional variants identified in 3 cases from different centres:
Cases 1-4 compound het - variants shown to be inherited in trans
Cases 5-8 - het variants idenitied in case 5 & 6 inherited from affected parent (febrile seizure in these parents) and in cases 7 & 8 - arise de novo.
The 9 variants present in low or no allele freq in all populations or East Asian populations - no hom in gnomAD. No other pathogenic/likely pathogenic variants in other epilepsy genes identiifed.
Fig 3:
B:The 2 nonsense variants in exon 5 thought to result in the truncation of the basson protein and trigger NMD. Both de novo. They state LOF and haploinsuffucency of BSN are potentially pathogenic.
C: 6/9 missense variants led to hydrogen bond alterations - mostly creation of hydrogen bonds which were not predicted orignally. 5/9 missense variants clustered in the C-terminus. Among the 4 pairs of compound het variants at least 1 variant in each pair had hydrogen bond alterations.
In the discussion they state LOF of Bassoon is potentially the underlying mechanism of pathogenicity of BSN variants, which is consistent with the pathogenisi of other genes encoding CAZ proteins such as UNC13A and UNC13B; however, the functional effects of BSN variants warrants further investigation.
In het BSN knockout mice - no phenotype; however, hom knockout mice null led to spontaneous seizures and partial preamture lethality. Clinically the patients with monoallelic BSN missense variants achieved seizure free status without treatment or under monotherapy; whereas, the majority of patients with biallelic missense variants required combination therapy, possible correlation between genotype and phenotype severity.

PMID 39616287: Yacoub et al, 2025: WES in 10 JME (juvenille myoclonic epilepsy) patients - P4 found to have a het BSN missense variant - c.2534G>A p.(Arg845Gln), also identified in her affected brother who has GTCs, but also detected in an unaffected brother. Presumably also inherited from an unaffected pedogree (pedigree included - no mention of parental testing).

PMID: 40393460 Guzman et al, 2025: cohort of 29 individuals with BSN variants including 14 with de novo vairants, 13 individuals with PTVs (protein truncating variants) of unknown inheritance and 2 individuals with PTVs with paternal inheritance. Affected individuals had diverse neurodevelopmental phenotypes including behavioural abnormalities; delayed speech, learning difficulties and variable seizure types.
Recruitment: 2/29 - enrolled in the Epilepsy genetics research project at Childrens Hospital Philadelphia (CHOP) confirmed de novo; 14/29 identified via gene matcher - 9/14 confirmed de novo by respective institutions; 7/29 identified through Penn medicine biobank; 1/29 missense de novo BSN variant identified from birth defects biorepositary at CHOP; 3/29 BSN PTVs idenitifed through the center for applied genomics at CHOP and a lit review identified 2/29 previously reported individuals with de novo PTVs in BSN.
Table 1 details the 14 individuals with de novo BSN variants - 8/14 had seizures (different types); 12/14 had developmental features.
They suggest haploinsuffucency as as a likely mechanism.
Sources: Other
Early onset or syndromic epilepsy v8.23 UNC13A Achchuthan Shanmugasundram Classified gene: UNC13A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.23 UNC13A Achchuthan Shanmugasundram Added comment: 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.
Early onset or syndromic epilepsy v8.23 UNC13A Achchuthan Shanmugasundram Gene: unc13a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.22 UNC13A Achchuthan Shanmugasundram gene: UNC13A was added
gene: UNC13A was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_25_promote_green tags were added to gene: UNC13A.
Mode of inheritance for gene: UNC13A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UNC13A were set to 28192369; 39634123
Phenotypes for gene: UNC13A were set to developmental and epileptic encephalopathy, MONDO:0100620
Review for gene: UNC13A was set to GREEN
Added comment: 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