INVESTIGATING EARLY NEURODEVELOPMENTAL DISRUPTIONS IN <EM>SYNGAP1</EM> PATIENT IPSC-DERIVED NEURAL MODELS

SYNGAP1 developmental and epileptic encephalopathy (DEE) is a severe neurodevelopmental disorder characterised by intellectual disability, developmental delay, and drug-resistant epilepsy, caused by heterozygous mutations in SYNGAP1, which encodes synaptic Ras GTPase-activating protein 1. While SYNGAP1 is well established as a regulator of synaptic plasticity, its role in early human neurodevelopment remains poorly understood. Here, we investigated how a pathogenic p.Leu150Valfs6 SYNGAP1 variant affects early human neurodevelopment and neuronal excitability using patient-derived iPSC neural rosettes and induced 2D neurons. Morphological analysis of neural rosettes revealed significant disruptions in rosette architecture. This included enlarged lumen area and altered rosette organisation in patient rosettes, which is consistent with the emerging role for SYNGAP1 in regulating cytoskeletal remodelling at apical end feet during early neuroepithelial patterning. Transcriptomic profiling of patient-derived neurons identified dysregulation of ion channel, neurodevelopmental, and synaptic genes, with gene ontology analysis highlighting enriched pathways related to neural crest migration, cell adhesion, cytoskeletal organisation, and synaptic development. Functional characterisation using whole-cell patch-clamp electrophysiology demonstrated increased neuronal excitability, including altered action potential kinetics, increased firing rates, and changes in inward and outward current densities. Together, these findings indicate that SYNGAP1 variants exert effects on neuronal development and cell-autonomous excitability prior to synaptogenesis. Our results support a non-canonical role for SYNGAP1 in early brain development, consistent with recent reports of its expression in radial glial populations. Understanding both the neurodevelopmental and synaptic functions of SYNGAP1 is essential for advancing therapeutic strategies for SYNGAP1 DEE.