Clinical signatures of SYNGAP1-related disorders through data integration.

Abstract

Purpose: SYNGAP1 is a genetic neurodevelopmental disorder characterized by generalized epilepsy, autism, and intellectual disability. Despite a comparatively high prevalence, the longitudinal landscape remains relatively unexplored, and complete characterization is essential for clinical trial readiness.

Methods: We combined electronic medical record data (n=158) with insurance claims data (n=246) to evaluate longitudinal progression of symptoms.

Results: Phenotypes associated with SYNGAP1 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), autism (OR 12.23, CI 9.29-16.24), and a developmental profile with prominent deficits in verbal skill acquisition. Several 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 were significantly increased (OR 4.05, CI 2.02-7.59) after 3 years of age and persisted over time. Valproic acid and clobazam were commonly used for epilepsy treatment, while risperidone, aripiprazole, and guanfacine were commonly used for behavior management. Valproate and lamotrigine were more effective at reducing seizure frequencies or maintaining seizure freedom than other anti-seizure medications.

Conclusion: We delineated the seizure, developmental, and behavioral trajectories in SYNGAP1-related disorders, to improve diagnosis, prognosis, and clinical care, as well as facilitating clinical trial readiness.