Abstracts

Rationale: SYNGAP1-related neurodevelopmental disorder is one of the more common monogenic causes of generalized epilepsy, including myoclonic-astatic epilepsy (MAE, or Doose Syndrome), intellectual disability, and autism spectrum disorder. The SYNGAP1protein forms an indispensable part of the postsynaptic density of excitatory glutamatergic neurons, and loss of function variants in this gene typically lead to disease. The clinical variation in individuals with SYNGAP1-related disorder is wide, but poorly understood, and no clear genotype-phenotype relationship has been established to date.

Methods: We assessed clinical data across 32 individuals with SYNGAP1-related neurodevelopmental disorder, including 15 individuals followed at our center and 17 individuals reported in the scientific literature. We reconstructed the epilepsy histories of 15 individuals with SYNGAP1-related disorder across 1354 patient months and retrieved 168 anti-seizure medication (ASM) prescriptions from the electronic medical records. We used a novel comparative effectiveness framework previously developed by our group to assess seizure patterns and ASM response in individuals with SYNGAP1-related disorder.

Results: The overall phenotypic landscape in SYNGAP1-related neurodevelopmental disorder is characterized by developmental delays or intellectual disability in 100% and seizures in 84% of individuals. 95% of individuals had seizure onset before age 5 years, with a median age of onset of 26 months of age (IQR, 24-36 months). We performed detailed seizure reconstructions in monthly time increments in 15 individuals. Seizures are usually generalized, including absence, myoclonic and atonic. The most commonly prescribed ASMs are lamotrigine, clobazam and valproate with medication-specific effects on overall seizure burden, seizure types, and reduction of seizure frequency versus maintenance of seizure freedom. Autism spectrum disorder is prevalent and has been formally diagnosed in 73% and suspected but not yet diagnosed in another 13%. Notably, behavioral concerns are common, including self-injurious behavior, aggression, impulsivity, and sleep disturbances, and are reported as distressing by caregivers in 53% of individuals. Ninety-one percent of the variants identified are protein-truncating, either nonsense, frameshift, or splice site, with missense variants representing the remaining 9%.

Conclusions: We utilized a novel data-driven approach to assess phenotypic patterns, identify clinically significant genotype-phenotype correlations, and demonstrate the dynamic pattern of seizures and drug response in individuals with SYNGAP1-related disorder. Elucidating the full clinical spectrum in SYNGAP1-related disorder will be critically important for understanding the disease mechanism, developing disease-specific outcome measures and guiding future precision medicine efforts.

Funding: Children’s Hospital of Philadelphia, National Institute of Neurological Disorders and Stroke, The Hartwell Foundation