Baker, Gordon et al. present the first international case series describing the neurodevelopmental disorder associated with Synaptotagmin 1 (SYT1) de novo missense mutations. Key features include movement abnormalities, severe intellectual disability, and hallmark EEG alterations. Expression of patients’ SYT1 mutations in mouse neurons disturbs presynaptic vesicle dynamics in a mutation-specific manner.

Neuronal communication relies on the tightly controlled fusion of synaptic vesicles at nerve terminals, which results in the release of neurotransmitters with strict temporal and quantal precision. At rest, synaptic vesicle fusion is inhibited (Brunger et al., 2018). Action potential-mediated opening of voltage-gated Ca 2+ channels results in Ca 2+ influx into the nerve terminal, creating a Ca 2+ nanodomain that triggers the fusion of vesicles that are docked and primed at the plasma membrane, thereby evoking fast synchronous neurotransmitter release (Chanaday & Kavalali, 2018;Sudhof, 2013).Vesicles can additionally fuse asynchronously following evoked synchronous release and some spontaneous fusion of vesicles also occurs, though this is clamped (Chanaday & Kavalali, 2018).These processes are under exquisite regulatory control, preventing excessive neurotransmitter release and ensuring high-fidelity neuronal communication (Brunger et al., 2019;Rizo, 2018;; perturbation of this regulation can lead to a breakdown in neurotransmission.A range of presynaptic proteins are required to orchestrate these precision events. The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex, composed of the vesicular SNARE protein (v-SNARE) synaptobrevin and the target membrane SNARE proteins (t-SNAREs) syntaxin-1 and SNAP-25 (synaptosomal-associated protein-25), is the core fusion machinery that provides the energy required for fusion of synaptic vesicles with the plasma membrane (Weber et al., 1998). Several other key components regulate synaptic vesicle exocytosis in physiological environments (Brunger et al., 2019;Sudhof, 2014). SNARE complex assembly is orchestrated by Munc13 and Munc18, and further

Synaptotagmin-1 (SYT1) is a critical mediator of neurotransmitter release in the central nervous system. Previously reported missense SYT1 variants in the C2B domain are associated with severe intellectual disability, movement disorders, behavioral disturbances, and electroencephalogram abnormalities. In this study, we expand the genotypes and phenotypes and identify discriminating features of this disorder. Methods: We describe 22 individuals with 15 de novo missense SYT1 variants. The evidence for pathogenicity is discussed, including the American College of Medical Genetics and Genomics/ Association for Molecular Pathology criteria, known structure-function relationships, and molecular dynamics simulations. Quantitative behavioral data for 14 cases were compared with other monogenic neurodevelopmental disorders. Results: Four variants were located in the C2A domain with the remainder in the C2B domain. We classified 6 variants as pathogenic, 4 as likely pathogenic, and 5 as variants of uncertain significance. Prevalent clinical phenotypes included delayed developmental milestones, abnormal eye physiology, movement disorders, and sleep disturbances. Discriminating behavioral characteristics were severity of motor and communication impairment, presence of motor stereotypies, and mood instability. Conclusion: Neurodevelopmental disorder-associated SYT1 variants extend beyond previously reported regions, and the phenotypic spectrum encompasses a broader range of severities than initially reported. This study guides the diagnosis and molecular understanding of this rare neurodevelopmental disorder and highlights a key role for SYT1 function in emotional regulation, motor control, and emergent cognitive function.