Genotype-phenotype correlations and putative modifier genes in SYNGAP1 Encephalopathy
Year: 2026
Type: article
Study design: Observational Study
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.
Source: Neurobiology of Disease
Authors: Selena Aranda, Juliana Ribeiro-Constante, Alba Tristán-Noguero, Nerea Moreno-Ruiz, Concepción Arenas, Fernando Francisco Martínez Calvo, Salvador Ibáñez-Micó, José Luis Peña Segura, José Miguel Ramos-Fernández, María del Carmen Moyano Chicano, Rafael Camino León, Víctor Soto-Insuga, Elena González-Alguacil, Carlos Valera Dávila, Alberto Fernández-Jaén, Laura Plans, Ana Camacho, Nuria Visa-Reñé, María del Pilar Martín-Tamayo Blázquez, Fernando Paredes-Carmona, Itxaso Marti-Carrera, Guillem Ginot-Julià, Aránzazu Hernández-Fabián, Meritxell Tomàs Daví, Mercè Casadesús Sànchez, Laura Cuesta Herraiz, Patricia Fuentes Pita, Teresa Bermejo González, 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, Francisca Valera Párraga, Jaume Campistol Plana, Mercedes Serrano, Xenia Alonso, Maria Irene Valenzuela Palafoll, Eines Monteagudo, Itziar Alonso-Colmenero, Oscar Sans Capdevila, Ferran Casals, Bru Cormand, Ángeles García-Cazorla, Àlex Bayés, Marina Mitjans
Institutions: Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona, Hospital Sant Joan de Déu Barcelona, Universitat Autònoma de Barcelona, Institut de Recerca Sant Pau, Universitat Pompeu Fabra, Barcelona Biomedical Research Park, Institut de Biologia Evolutiva, Hospital Universitario Miguel Servet, Hospital Universitario Virgen de la Arrixaca, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga, Hospital Universitario Reina Sofía, Hospital Infantil Universitario Niño Jesús, Hospital Universitario Quirónsalud Madrid, Universitat de Vic - Universitat Central de Catalunya, Althaia, Universidad Complutense de Madrid, Hospital Universitario 12 De Octubre, Hospital Universitari Arnau de Vilanova, Hospital Universitario de Jerez, University of the Basque Country, Biogipuzkoa Health Research Institute, Donostiako Unibertsitate Ospitalea, Complejo Hospitalario de Salamanca, Hospital de Manises, Complejo Hospitalario Universitario de Santiago, Hospital Universitario de Burgos, Hospital Universitario Puerta de Hierro Majadahonda, Hospital Universitario Virgen del Rocío, Vall d'Hebron Hospital Universitari, Instituto de Salud Carlos III, Centre for Biomedical Network Research on Rare Diseases, Institut de Recerca Sant Joan de Déu, Centro de Investigación Biomédica en Red de Salud Mental
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,180
Funders: Fundació la Marató de TV3, Ministerio de Ciencia, Innovación y Universidades, Centres de Recerca de Catalunya, European Commission, Generalitat de Catalunya, Ministerio de Economía y Competitividad, Institució Catalana de Recerca i Estudis Avançats, Ministerio de Ciencia e Innovación, Ministerul Cercetării şi Inovării, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, European Regional Development Fund, Agencia Estatal de Investigación
Awards: G1034919023, G1092484527, G1105844351, G1175115578, G121809054, G1235647790, G127167649, G1568148067, G1568717892, G1622782223, G1650125035, G1855990336, G2064873908, G2262748287, G2309174360, G24120701, G252646220, G2601397997, G2660406951, G2672435700, G288263039, G294895050, G2979234808, G3005324705, G300979063, G3288897321, G3369768856, G3387824582, G3461529875, G3480869486, G3681454997, G3979309726, G4042783231, G4045630229, G410571670, G4227480934, G425668148, G430777504, G4347677570, G451917667, G4663796273, G491712853, G5080475149, G5195188938, G523076202, G5421974903, G549596889, G5511869972, G5539308778, G5554424168, G5790171244, G5852091828, G593054264, G593623381, G5967599077, G6033112984, G6219869690, G6441318753, G647161945, G6644324421, G6656126374, G6909844768, G7084143925, G7805626310, G7863371703, G7866584213, G7868768884, G787121397, G8049708214, G8347645112, G8352616040, G8497050386, G8696694383, G8920660035, G99296377
OpenAlex ID: W7138340443