Molecular Characterization and Genotype-phenotype Correlations of SYNGAP1 Variants in a Polish Pediatric Cohort With Neurodevelopmental Disorders
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background Pathogenic variants in SYNGAP1 are a major cause of developmental and epileptic encephalopathy, typically presenting with intellectual disability, epilepsy, and autism spectrum disorder. Despite increasing recognition worldwide, genotype–phenotype data from Central and Eastern Europe remain limited. Methods We conducted a nationwide study of 30 unrelated Polish pediatric patients carrying pathogenic or likely pathogenic SYNGAP1 variants. Variant classification followed ACMG/ClinGen guidelines. Clinical phenotyping used a structured numerical scoring system. Genotype–phenotype relationships were explored with non-metric multidimensional scaling and PERMANOVA. Results We identified 30 pathogenic or likely pathogenic variants, including truncating, splice-site, and missense substitutions; 50% were novel. Haploinsufficiency emerged as the main pathogenic mechanism, though some missense variants suggested additional effects. Phenotypic analysis showed marked heterogeneity, but severe global developmental delay, intellectual disability, and epilepsy were consistently observed. Epilepsy affected > 80% of patients and frequently required polytherapy. Genotype–phenotype clustering demonstrated broader symptom variability in missense carriers compared with truncating or splice-site variants. Conclusion This first national cohort study from Poland broadens the SYNGAP1 mutational spectrum and highlights the consistently severe neurodevelopmental phenotype, particularly epilepsy and intellectual disability. Our results refine genotype–phenotype correlations, emphasize the clinical impact of haploinsufficiency, and provide a framework for patient stratification in future trials and emerging therapeutic approaches.
