Genotype-phenotype associations in 1018 individuals with SCN1A-related epilepsies

Objective: SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype–phenotype associations remain poorly understood. Methods: We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype. Results: DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p <.001). In silico variant scores were higher in DS versus GEFS+ (p <.001). Patients with missense variants in functionally important regions (conserved N-terminus, S4–S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p =.003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p =.036) and were more likely to have GEFS+ (15/29, χ2 = 19.16, p <.001). A minority of protein-truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p <.001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p =.001) and GEFS+ (8.0 vs. 11.0 months, p =.043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS. Significance: Understanding genotype–phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS.