Selena Aranda, Juliana Ribeiro-Constante, Alba Tristán-Noguero, Nerea Moreno-Ruiz, C. Arenas, Fernando Francisco Martínez Calvo, Salvador Ibañez-Mico, José Luis Peña Segura, José Miguel Ramos-Fernández, María del Carmen Moyano Chicano, Rafael Camino León, Victor Soto-Insuga, Elena González-Alguacil, Carlos Valera Dávila, Alberto Fernandez-Jaen, Laura Plans, Ana Camacho, Nuria Visa-Reñé, María del Pilar Martin-Tamayo Blázquez, Fernando Paredes-Carmona, Itxaso Martí-Carrera, Guillem Ginot-Julia, Aránzazu Hernández-Fabián, Meritxell Tomas Davi, Merce Casadesus Sanchez, Laura Cuesta Herraiz, P Fuentes-Pita, Teresa Bermejo Gonzalez, Mar O'Callaghan, Federico Felipe Iglesias Santa Polonia, María Rosario Cazorla, María Teresa Ferrando Lucas, Antonio González-Meneses, Júlia Sala-Coromina, Alfons Macaya, Amaia Lasa-Aranzasti, Anna Ma Cueto-González, F. Valera Párraga, Campistol Plana J, Mercedes Serrano, Xènia Alonso, Maria Irene Valenzuela Palafoll, Eines Monteagudo, Itziar Alonso-Colmenero, Óscar Sans Capdevila, Ferrán Casals, Bru Cormand, Ángeles García‐Cazorla, Àlex Bayés, Marina Mitjans
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.