Congenital myaesthenic syndrome

Gene: UNC13A

Green List (high evidence)

Comment on list classification: There are 2 unrelated individuals with biallelic putative LoF variants in UNC13A who presented with congenital hypotonia and sever muscle weakness. Additionally, knockout mouse models show that Unc13A deficiency interferes with the synaptic maturation process. In contrast, 4 unrelated individuals with heterozygous missense variants in UNC13A presented with intellectual disability and seizures. Hence, there are two distinct disease entities, with different MOIs, associated with this gene. Based on the available evidence, UNC13A should be promoted to Green for Congenital myaesthenic syndrome at the next GMS update.

Created: 12 Nov 2025, 2:16 p.m. | Last Modified: 12 Nov 2025, 2:16 p.m.

Panel Version: 5.1

BIALLELIC CASES:
PMID: 27648472 Engel et al., 2016
Report of a native American girl, born prematurely at 32 weeks - hypotonic at birth, needed ventilatory support, developed aspiration pneumonia; died at age 50 months due to respiratory failure; EMG studies revealed abnormally low-amplitude CMAPs at rest; histochemical studies of the anconeus muscle revealed marked type 2 fiber atrophy and type 1 fiber hypertrophy; homozygous for NM_001080421.2; c.304C>T, p.(Gln102*) in UNC13A - variant extremely rare in gnomAD v4.1.0., no homozygotes; method: WES.

PMID: 36447687 Mullins et al., 2022
Case report of a female infant with congenital encephalopathy and a severe neuromuscular phenotype - delivered at 40 weeks due to abnormal heart rate and reduced fetal movement; she had mildly dysmorphic features, alternating hypertonia and hypotonia, extreme generalized muscle weakness, severe kyphoscoliosis and hernias. She died at 8 months due to bronchopneumonia. Homozygous for c.1188delC p.(Asp397Thrfs*107) in UNC13A - variant extremely rare in gnomAD v4.1.0., no homozygotes; method: WES.

MONOALLELIC: 4 heterozygous cases harbouring missense variants in UNC13A have been detailed previously by Tom Hodgkinson (see below) - individuals presented with seizures and intellectual disability, NOT myaesthenic syndrome.

FUNCTIONAL EVIDENCE:
PMID: 10440375 Augustin et al., 1999: In glutamatergic hippocampal neurons from Unc13A -/- mice the synaptic-vesicle cycle is arrested at the maturation step, stopping transmitter release from the synapses.
PMID: 15988013 Frédérique Varoqueaux et al., 2005: Triple knockout of Unc13A/B/C in the mouse results in paralysis and death; double knockout Unc13B/C mice were viable and fertile - thus, Unc13A was highlighted as crucial for CNS development and function.

This gene is not yet associated with a phenotype in OMIM (accessed 12th Nov 2025).

Created: 12 Nov 2025, 1:54 p.m. | Last Modified: 12 Nov 2025, 2:07 p.m.

Panel Version: 5.1

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
congenital myasthenic syndrome, MONDO:0018940

Publications

• 27648472
• 28192369
• 39634123

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 submitted for UNC13A for Intellectual disability panel.

Created: 28 Jul 2025, 2:22 p.m. | Last Modified: 28 Jul 2025, 2:22 p.m.

Panel Version: 5.1

Publications

• PMID: 28192369
• 39634123.

Red List (low evidence)

Review and rating from Michael Oldridge (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust), submitted by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group.

Created: 30 Apr 2019, 9:30 a.m.

Red List (low evidence)

Called MUNC13-1. Engel et al described single patient homozygous for nonsense mutn. EMG showed presynaptic NMJ defect. Missense variants associated with ALS phenotype (HGMD). Not enough evidence.

Created: 29 Apr 2019, 4:33 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 27648472