title: De novo SCN1A pathogenic variants in the GEFS+ spectrum: Not always a familial syndrome.
abstract: Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by heterogeneous phenotypes ranging from mild disorders such as febrile seizures to epileptic encephalopathies (EEs) such as Dravet syndrome (DS). Although DS often occurs with de novo SCN1A pathogenic variants, milder GEFS+ spectrum phenotypes are associated with inherited pathogenic variants. We identified seven cases with non-EE GEFS+ phenotypes and de novo SCN1A pathogenic variants, including a monozygotic twin pair. Febrile seizures plus (FS+) occurred in six patients, five of whom had additional seizure types. The remaining case had childhood-onset temporal lobe epilepsy without known febrile seizures. Although early development was normal in all individuals, three later had learning difficulties, and the twin girls had language impairment and working memory deficits. All cases had SCN1A missense pathogenic variants that were not found in either parent. One pathogenic variant had been reported previously in a case of DS, and the remainder were novel. Our finding of de novo pathogenic variants in mild phenotypes within the GEFS+ spectrum shows that mild GEFS+ is not always inherited. SCN1A screening should be considered in patients with GEFS+ phenotypes because identification of pathogenic variants will influence antiepileptic therapy, and prognostic and genetic counseling.
authors.affiliation: Department of Medicine, Epilepsy Research Centre, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.|Department of Pediatrics, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Myers
authors.affiliation: Department of Medicine, Epilepsy Research Centre, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Rosemary
authors.identifier: 0000-0002-2664-4395
authors.initials: R
authors.lastname: Burgess
authors.affiliation: Tel-Aviv University Medical School, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Afawi
authors.affiliation: Department of Medicine, Epilepsy Research Centre, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Damiano
authors.affiliation: Department of Medicine, Epilepsy Research Centre, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.affiliation: Department of Medicine, Epilepsy Research Centre, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hildebrand
authors.affiliation: Department of Medicine, Epilepsy Research Centre, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.|Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, Flemington, Victoria, Australia.|The Florey Institute of Neuroscience and Mental Health, Heidelberg, Victoria, Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000235:genetics*; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D003294:Seizures, Febrile / Q000235:genetics*; D055815:Young Adult
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human
keywords: 
  SCN1A
  ; De novo pathogenic variant; Dravet syndrome; Febrile seizures; Genetic epilepsy with febrile seizures plus