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 characterised 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 include the identification of four previously unreported likely pathogenic SYNGAP1 variants associated with the disease. In our cohort, individuals carrying variants within the PH domain of SynGAP exhibit milder phenotypes compared with other patients. Finally, patients harbouring rare or low-frequency variants in SYNGAP1-related genes tend to present with higher global severity. Taken together, these findings suggest that the location of SYNGAP1 variants, together with additional genetic modifiers, may contribute to variability in clinical presentation and disease severity. Further studies in larger cohorts and functional validation are needed to refine genotype-phenotype correlations and to support the development of personalized management strategies.