Abstracts

Rationale: Disease-causing variants in SYNGAP1 are associated with a wide range of phenotypic presentations including generalized epilepsy in up to 80% and intellectual disability in almost all reported individuals. However, overlapping phenotypes and the clinical heterogeneity within SYNGAP1-related disorders complicate recognition of clear subgroups.

Methods: Here, we assessed genetic and clinical data across 51 individuals with SYNGAP1-related disorders previously reported in the literature. Clinical presentations were analyzed across 1,992 derived phenotypic terms, leveraging our previously published Human Phenotype Ontology-based framework for computational analysis of disease phenotypes. In addition, epilepsy phenotypes including seizure onset and epilepsy syndrome were assessed for all individuals.

Results: SYNGAP1-related disorders are characterized by neurodevelopmental abnormalities in 98% of individuals and generalized-onset seizures in up to 86% of individuals. The median age of study inclusion was 8.0 years (IQR 5.0 – 10.1 years). In our cohort, 96% of individuals were documented to have intellectual disability, 78% had behavioral abnormalities, and 70% had hypotonia. The variant spectrum of our cohort focused on individuals with protein-truncating variants (PTV) in SYNGAP1 and included 28 individuals with nonsense variants and 23 individuals with frameshift variants. PTVs were distributed all along the SYNGAP1 gene, although 10 individuals (20%) were noted to have a PTV in Exon 5. Seizure onset was primarily in the second year of life, with a median of 24 months (n=45 individuals, IQR 16 months – 2.5 years). When assessing epilepsy syndromes in our cohort, 13 individuals had overlapping epilepsy with eyelid myoclonia (EME) and epilepsy with myoclonic-atonic seizures (MAE), while 10 individuals had EME only and four had MAE only. Additionally, nine patients were reported as having developmental and epileptic encephalopathies (DEEs) and 9 had genetic generalized epilepsies.

Conclusions: We provide a brief overview of the phenotypic landscape of SYNGAP1-related disorders, assessing clinical histories across 51 individuals through standardized HPO-based analysis. Further efforts to map the landscape of SYNGAP1-related disorders will remain critical for identifying genotype-phenotype associations and disease-specific clinical signatures that will inform tailored clinical care and prognosis and improve patient outcomes for affected individuals.

Funding: Children's Hospital of Philadelphia; National Institute of Neurological Disorders and Stroke