Identification of molecular profiles in the Rare Genetic Syndrome associated with SYNGAP1 in isogenic neuronal models

Abstract

Epileptic encephalopathies (EEs) are epileptic conditions characterized by epileptiform abnormalities associated with progressive brain dysfunction. One of the genes related to EEs is the SYNGAP1 gene, which is related to the synaptic activity of excitatory neurons, so that haploinsufficiency of this gene impairs neuronal development. In this proposal, we will establish a large-scale CRISPR-based genomic engineering platform that allows simultaneous genome edits. We will apply this genome editing platform to human induced pluripotent stem cell (hiPSC) lineages aiming the introduction of variants in SYNGAP1. These cellular models will be differentiated into neural stem cells and cortical glutamatergic neurons in order to interrogate the molecular consequences of these genetic perturbations. Our aims are: Aim1: To determine the molecular impact (global transcriptional and neuroinflammatory profile) of genetic variations introduced by CRISPR by investigating hiPSC-derived neuronal models. Aim 2: To evaluate physiological (sleep pattern), molecular (inflammatory profile) and cognitive (social interaction and learning) aspects of patients with variants in SYNGAP1. Aim 3: To correlate clinical assessments performed in patients with assessments performed in in vitro neuronal models containing variants, aiming at Precision Medicine approaches. This study will therefore implement new technologies, generate neuronal models, and integrate datasets to identify convergence points in molecular signatures caused by EE, which in future studies may constitute targets for pharmacological manipulations. (AU)