A multicenter study with participation from the Institut de Recerca Sant Pau (IR Sant Pau) has delved deeper into the genetic mechanisms of encephalopathy associated with the SYNGAP1 gene. This rare disease is characterized by epilepsy, intellectual disability, psychomotor delay, and, in numerous instances, autism. The study, published in Neurobiology of Disease, shows that disease severity does not depend solely on the primary mutation but also on other genetic factors that may modulate its clinical expression.
The research, led by teams from the University of Barcelona, the Sant Joan de Déu Research Institute, and CIBER, also includes participation from IR Sant Pau, with Dr. Àlex Bayés, head of the Molecular Physiology of the Synapse group at this center, as corresponding author of the study.
“This work shows that, even in diseases considered monogenic, the biological reality is more complex than previously thought,” says Dr. Bayés. “Clinical variability among patients cannot be explained solely by the mutation in SYNGAP1, but rather by the presence of other genetic factors that significantly influence disease progression.”
SYNGAP1 encephalopathy is caused by alterations in a key gene for brain development and cognitive function. Despite this well-defined origin, its clinical manifestations are highly heterogeneous, which complicates both prognosis and clinical management of patients.
In this context, the study analyzed a cohort of 44 patients from 16 hospitals across Spain, all carrying dominant mutations in SYNGAP1. A detailed genotype–phenotype analysis confirmed that patients with alterations in the same gene can present very different clinical profiles. “We are not dealing with a simple cause-and-effect relationship,” notes Dr. Bayés. “These results require a more nuanced interpretation of genetic information, considering the complexity of the genome as a whole.”
The study identified four new variants of the SYNGAP1 gene that had not been previously described, expanding knowledge of the genetic basis of this encephalopathy. Beyond this finding, massive sequencing analysis also revealed alterations in other genes that interact with the SYNGAP1 protein, such as SHANK1, SHANK3, or NLGN2, pointing to the existence of modifier genes capable of influencing the clinical expression of the disease.
In this regard, the results reinforce the idea that the patient’s overall genetic context plays a relevant role in the observed variability. “Identifying variants in genes that are part of the same synaptic network suggests that the patient’s global genetic context plays a determining role,” explains Dr. Bayés. “This allows progress toward a more integrated understanding of these disorders.”
Another aspect addressed in the study was the potential relationship between mutation characteristics and the severity of the clinical picture. The results indicated that the location of the variant within the gene may be a relevant factor and that certain regions are associated with distinct clinical manifestations.
In particular, variants located in the PH domain were associated with milder forms of the disease, with less language impairment, lower frequency of epilepsy, and overall lower severity. However, this relationship is partial and does not allow for conclusive prediction of individual patient outcomes, reinforcing the complexity of the genotype–phenotype relationship.
“It is not enough to identify the mutation; it is necessary to understand its location and the genetic context in which it appears,” says Dr. Bayés. “This approach is key to advancing toward more personalized medicine.”
The study’s findings have relevant implications for the clinical management of this encephalopathy, as identifying genetic patterns associated with different levels of severity could help anticipate disease progression and better guide therapeutic decision-making. At the same time, the work reinforces the classification of SYNGAP1 encephalopathy as one of the monogenic forms of autism spectrum disorder, present in approximately two-thirds of patients.
Overall, these findings contribute to redefining the understanding of rare genetic diseases and open new lines of research aimed at identifying biomarkers and potential therapeutic targets. “Advancing knowledge of the factors that modulate these diseases is essential to improve their diagnosis and, in the future, their treatment,” concludes Dr. Bayés.
Aranda S, Ribeiro-Constante J, Tristán-Noguero A, Moreno-Ruiz N, Arenas C, Calvo FFM, Ibañez-Mico S, Segura JLP, Ramos-Fernández JM, Del Carmen Moyano Chicano M, León RC, Soto-Insuga V, González-Alguacil E, Dávila CV, Fernández-Jaén A, Plans L, Camacho A, Visa-Reñé N, Del Pilar Martin-Tamayo Blázquez M, Paredes-Carmona F, Marti-Carrera I, Ginot-Julià G, Hernández-Fabián A, Davi MT, Sanchez MC, Herraiz LC, Pita PF, Gonzalez TB, O’Callaghan M, Iglesias Santa Polonia FF, Cazorla MR, Lucas MTF, González-Meneses A, Sala-Coromina J, Macaya A, Lasa-Aranzasti A, Anna M, Cueto-González, Párraga FV, Plana JC, Serrano M, Alonso X, Palafoll MIV, Monteagudo E, Alonso-Colmenero I, Capdevila OS, Casals F, Cormand B, García-Cazorla A, Bayés À, Mitjans M. Genotype-Phenotype Correlations and Putative Modifier Genes in SYNGAP1 Encephalopathy. Neurobiology of Disease. 2026 Mar 17;107357. https://doi.org/10.1016/j.nbd.2026.107357
