Submission Details

SCN1A encompasses a variety of phenotypes from Generalized epilepsy with febrile seizures plus (GEFS+) to Dravet syndrome. An additional distinct phenotype for this gene, Early Infantile Epileptic Encephalopathy, has been described in the literature, distinguished by increased severity, and earlier age of onset. Individuals with this phenotype typically begin to have seizures at <3months of age, have profound developmental impairment and have been reported with movement disorders including choreoathetosis, dystonia and perioral hyperkinesia. Epileptic spasms are also noted. Missense variants have been primarily reported in association with this phenotype, most notably p.Thr226Met (c.677C>T), a recurrent variant identified as de novo in several individuals with similar features (PMIDs:24776920, 26482601, 28794249, 31257984, 31176277). Evidence supporting this gene-disease pair includes case-level and experimental data. Supporting experimental evidence has been reported in a patch-clamp cell culture model (PMID: 30779207). Of note, identification of this phenotype is recent; as such, this association has not been clearly demonstrated over time. Instances of this phenotype may be present in the literature but not clearly highlighted within the clinical descriptions of the reported individuals. In summary, SCN1A is strongly associated with this autosomal dominant early infantile epileptic encephalopathy (EIEE). This has been demonstrated in both research and clinical diagnostic settings.