Genotype-Phenotype Correlations and Putative Modifier Genes in SYNGAP1 Encephalopathy

Abstract

Synaptic Ras GTPase-Activating Protein 1 (SynGAP) is a key regulator of synaptic plasticity, neurodevelopment, and neuronal circuit function. It is encoded by the SYNGAP1 gene, in which de novo dominant pathogenic variants are a major cause of SYNGAP1 Encephalopathy, a rare neurodevelopmental disorder characterized by intellectual disability, epilepsy, autistic traits, and other clinical manifestations. While some genetic studies have reported genotype-phenotype correlations in this condition, our understanding of how specific genetic variants contribute to the heterogeneous clinical symptoms remain limited. Here, we analysed a cohort of 44 cases extensively characterised at the phenotypic level to investigate the impact of genetic variants in SYNGAP1 and in potentially modulatory genes on the clinical features of SYNGAP1 Encephalopathy. Our results indicate that patients with variants in the PH domain of SynGAP exhibited milder phenotypes than other individuals. Moreover, missense variants were associated with a higher prevalence of autistic traits compared to loss-of-function variants. Autistic traits also showed a suggestive positive correlation with the predicted length of the encoded protein. Finally, patients harbouring rare or low-frequency variants in SYNGAP1- related genes tended to present with higher global severity. Taken together, these findings suggest that both the location and nature of SYNGAP1 variants, along with additional genetic modifiers, may contribute to the variability in clinical presentation and severity. Further studies involving larger cohorts and functional validation are needed to refine genotype-phenotype correlations and support the development of personalized management strategies.