Clinical signatures of SYNGAP1-related disorders through data integration

ObjectiveTo characterize the longitudinal disease and treatment histories of individuals with SYNGAP1-related disorders. MethodsParticipants with SYNGAP1 were identified from a range data data sources, including insurance claims data by ICD-10 diagnosis codes (n=246), a specialized medical record registry and a local cohort followed at a single tertiatry health care institution (n=158). ResultsCompared to a broader population of individuals with epilepsy, phenotypes associated with SYNGAP1 disorders included behavioral abnormalities (Odds ratio (OR) 12.35, 95% CI 9.21-16.78), generalized-onset seizures (OR 1.56, CI 1.20-2.02), and autism (OR 12.23, CI 9.29-16.24). A wide range of clinical features showed distinct age-related patterns, such as a more than five-fold risk of autistic behavior emerging between 27 and 30 months. Generalized-onset seizures became significantly enriched (OR 4.05, CI 2.02-7.59) after 3 years of age and persisted over time. Valproic acid (OR 2.26, CI 1.29-3.70) and clobazam (OR 2.58, CI 1.55-4.09) were commonly used for epilepsy management, which contrasted significantly from treatment strategies in the broader epilepsy cohort. Furthermore, valproate and lamotrigine were more effective at reducing seizure frequencies or maintaining seizure freedom than other anti-seizure medications. Risperidone, aripiprazole, and guanfacine were commonly used for behavioral features. InterpretationPhenotypic features specific to SYNGAP1 included a predominance and age-dependence of generalized seizures, a more than ten-fold risk of behavioral abnormalities, and a developmental profile with prominent deficits in verbal skill acquisition. Clear delineation of trajectories of SYNGAP1-related disorders will improve diagnosis, prognosis, and clinical care, facilitating clinical trial readiness.