From Bedside to Bench: Drosophila Models of Baker-Gordon Syndrome (BAGOS)

De novo SYT1 mutations cause Baker-Gordon syndrome (BAGOS), yet the pathogenic mechanisms are not well understood, and no disease-modifying therapies exist. We identified a child carrying a newly described SYT1 variant, D310N, and compared this case to a previously reported D366E variant. Across all phenotypic domains evaluated, the D310N variant produced a consistently more severe clinical phenotype. To investigate the biological basis of these differences, we generated Drosophila models harboring each variant. Heterozygous D310N flies displayed substantially greater locomotor impairment, higher incidences of seizure-like activity, and more pronounced deficits in learning and memory than flies expressing D366E. At synapses, both variants disrupt synaptic vesicle (SV) recycling during repetitive stimulation. These fly models enable us to gain further insight into BAGOS otherwise not possible with cell culture. Namely, we have identified a mid-larval developmental window during which variant expression induces life-long locomotor abnormalities even though the mutant SYT1 protein is no longer detectable in adult flies. Yet, mutant SYT1 expressed in adult stage does not have a detectable effect on climbing for over 10 days, arguing that BAGOS is likely caused by developmentally disrupted networks rather than synaptic transmission alone. Finally, we show that cholinergic interneurons are major common drivers of the observed locomotor deficits whereas expression of mutant SYT1 in cholinergic and GABAergic neurons induces seizure-like activity. Together, these findings recapitulate core clinical manifestations and uncover variant-specific disruptions in SV recycling, developmental timing, and circuit-level contributions. This integrated human-fly analysis advances understanding of SYT1-associated neurodevelopmental disorders and highlights discrete developmental periods and neuronal subtypes as potential therapeutic targets.