UNC13A encodes a presynaptic protein essential for synaptic vesicle priming and neurotransmitter release, particularly at excitatory/glutamatergic synapses. The protein facilitates vesicle maturation during exocytosis and maintains synaptic active zones by enabling vesicle docking and priming 1. UNC13A is critically regulated by TDP-43, which normally represses cryptic exon inclusion in UNC13A mRNA 23. In neurodegenerative diseases like ALS and FTD, loss of nuclear TDP-43 function leads to aberrant cryptic exon splicing in UNC13A, resulting in nonsense-mediated decay and protein depletion 34. This mechanism is enhanced by common intronic polymorphisms (including rs12608932) that overlap TDP-43 binding sites and potentiate cryptic splicing 35. These variants represent major genetic risk factors for ALS/FTD and modify disease phenotype, correlating with bulbar onset, cognitive impairment, and shorter survival 5. Germline coding variants in UNC13A cause a distinct neurodevelopmental syndrome characterized by developmental delay, intellectual disability, seizures, and movement disorders through mechanisms including reduced protein expression, gain-of-function effects, or impaired second messenger regulation 1. UNC13A is also implicated in congenital myasthenic syndromes affecting neuromuscular junction function 6.