PATIENT-SPECIFIC NEURODEVELOPMENTAL PHENOTYPES AND PHARMACOLOGICAL STRATEGIES IN SYNGAP1 SYNDROME

SYNGAP1 encodes SynGAP, a Ras GTPase-activating protein with a central role in excitatory synapse formation, maturation, and plasticity. Beyond these established synaptic functions, emerging evidence indicates a broader involvement of SynGAP in early neurodevelopment. Consistent with this, de novo heterozygous variants in SYNGAP1 cause SYNGAP1 syndrome, a rare neurodevelopmental disorder characterized by intellectual disability, developmental epileptic encephalopathy, autism spectrum disorder, and additional comorbidities. Despite this growing understanding, how SYNGAP1 dysfunction translates into the observed clinical heterogeneity remains largely unresolved.
Here, we hypothesize that distinct SYNGAP1 mutations differentially impact neurodevelopmental processes, contributing to the clinical heterogeneity of the disorder, and we aim to dissect these effects in parallel with the experimental evaluation of therapeutic approaches.
To address this, we employed human iPSC-based models carrying distinct SYNGAP1 mutations to generate 2D and 3D in vitro systems modeling early neurodevelopment and neural circuit formation, on which we tested pharmacological compounds targeting distinct signaling pathways to evaluate their effects on patient-specific phenotypes.
In 2D cortical neuron cultures, two distinct SYNGAP1 mutations were associated with divergent neurodevelopmental timing, with mutation-specific shifts toward accelerated or delayed developmental trajectories, together with alterations in mitochondrial morphology and dynamics. Furthermore, we observed in early brain organoids variant-dependent disruptions in neural rosette organization and progenitor proliferation, which were significantly ameliorated by pharmacological treatment.
Together, these findings indicate that distinct SYNGAP1 mutations differentially shape early neurodevelopmental trajectories, including mitochondrial dynamics, and that associated phenotypes can be differentially modulated by distinct pharmacological compounds.