title: SCN1A clinical spectrum includes the self-limited focal epilepsies of childhood.
abstract: Amongst autosomal dominant genetic epilepsy with febrile seizures plus (GEFS+) families, SCN1A variants are the most common genetic cause. Initially regarded as a generalized form of epilepsy, the GEFS+ spectrum is now known to include some focal epilepsies, but it is generally not conceptualized as extending to the self-limited focal epilepsies of childhood, such as Panayiotopoulos syndrome. There are, however, three reports of SCN1A variants in Panayiotopoulos syndrome. We describe the variable clinical phenotypes that include the self-limited focal epilepsies of childhood, present in a large GEFS+ family, segregating a heterozygous SCN1A missense variant.
  
  
  
  Electro-clinical details on all putatively affected family members were sought and blood samples were taken for genetic analysis. Two individuals were chosen for SCN1A testing. All 26 exons and exon-intron junctions were amplified, sequenced and analyzed. This was followed by pedigree segregation analysis of the variant identified.
  
  
  
  A pathogenic heterozygous SCN1A (c.2624C>A; p.Thr875Lys) variant was identified. Sixteen of the 18 variant positive family members were affected (88% penetrance): 8 with febrile seizures, 2 febrile seizures plus, 1 unclassified seizures and 5 with self-limited focal epilepsy of childhood. Of these, one was diagnosed with atypical childhood epilepsy with centrotemporal spikes and four with Panayiotopoulos syndrome.
  
  
  
  By characterizing the heterogeneous clinical phenotypes in a large, SCN1A mutation positive GEFS+ family, we conclude that the GEFS+ spectrum can extend to the self-limited focal epilepsies of childhood, including Panayiotopoulos syndrome, and in turn highlight the complex genotype-phenotype correlations associated with SCN1A-related epilepsies.
authors.affiliation: Epilepsy Unit, Schneider Children's Medical Center of Israel, Petah Tiqvah, Israel.
authors.forename: Sara
authors.initials: S
authors.lastname: Kivity
authors.affiliation: Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, Australia.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Oliver
authors.affiliation: Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, Israel.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Afawi
authors.affiliation: Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Damiano
authors.affiliation: Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, Australia.
authors.forename: Todor
authors.initials: T
authors.lastname: Arsov
authors.affiliation: Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.affiliation: Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, Australia. Electronic address: s.berkovic@unimelb.edu.au.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004828:Epilepsies, Partial / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D010375:Pedigree; D055815:Young Adult
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human
keywords: Consanguinity; GEFS+; Panayiotopoulos syndrome; SCN1A