Genotype-phenotype correlations and putative modifier genes in SYNGAP1 Encephalopathy

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.

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Journal
Neurobiology of Disease
Published
2026-03-17
DOI
https://doi.org/10.1016/j.nbd.2026.107357
Primary Topic
Glycogen Storage Diseases and Myoclonus
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article

Genotype-phenotype correlations and putative modifier genes in SYNGAP1 Encephalopathy

Federico Felipe Iglesias Santa Polonia, Alfons Macaya, María Rosario Cazorla, José Luis Peña Segura et al.
Neurobiology of Disease
Glycogen Storage Diseases and Myoclonus
article

Genotype-phenotype correlations and putative modifier genes in SYNGAP1 Encephalopathy

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

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.

Neurobiology of DiseaseVol. 222
Universidad Complutense de Madrid (ES), Universitat Autònoma de Barcelona (ES), Hospital Sant Joan de Déu Barcelona (ES), University of the Basque Country (ES), Universitat Pompeu Fabra (ES), Hospital de Sant Pau (ES), Barcelona Biomedical Research Park (ES), Hospital Universitari Arnau de Vilanova (ES), Research Institute Hospital 12 de Octubre (ES), Centro de Investigación Biomédica en Red de Salud Mental (ES), Althaia (ES), Complejo Hospitalario Universitario de Santiago (ES), Complejo Hospitalario de Salamanca (ES), Biogipuzkoa Health Research Institute (ES), Hospital Universitario Puerta de Hierro Majadahonda (ES), Hospital Regional Universitario de Málaga (ES), Hospital Universitario Quirónsalud Madrid (ES), Hospital Infantil Universitario Niño Jesús (ES), Hospital Universitario Miguel Servet (ES), Centro de Investigación Biomédica en Red (ES), Hospital Universitario de Burgos (ES), Hospital Arnau de Vilanova (ES), Hospital de Manises (ES), Hospital Universitario Reina Sofía (ES), Institut de Biologia Evolutiva (ES), Hospital Universitario Virgen de la Arrixaca (ES), Hospital Universitario Virgen del Rocío (ES), Hospital Jerez Puerta del Sur (ES), Instituto de Investigación de Enfermedades Raras (ES), Instituto de Investigación Biomédica de Málaga (ES), Universitat de Barcelona (ES), Universidad de Sevilla (ES)
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