title: Variable neurologic phenotype in a GEFS+ family with a novel mutation in SCN1A.
abstract: OBJECTIVE
  To describe the spectrum of clinical disease in a mutliplex family with an autosomal dominant form of generalized epilepsy with febrile seizures plus (GEFS+) and determine its genetic etiology.
  
  
  METHODS
  Medical and family history was obtained on 11 clinically affected individuals and their relatives across three generations through medical chart review and home visits. A candidate gene approach including haplotype analysis and direct sequencing was used.
  
  
  RESULTS
  An epilepsy-associated haplotype was identified on 2q24. Direct sequencing of the entire SCN1A gene identified seven sequence variants. However, only one of these, c.1162 T>C, was not found in population controls. This transition in exon 8 of SCN1A predicts a substitution (Y388H) of a highly conserved tyrosine residue in the loop between transmembrane segments S5 and S6 of the sodium channel protein (Na(v)1.1). Clinical features in mutation carriers of this novel missense mutation were highly variable, ranging from febrile seizures to severe refractory epilepsy.
  
  
  CONCLUSIONS
  A novel missense mutation in the pore-forming region of the sodium channel gene SCN1A causes GEFS+ with a variable phenotype that includes mood and anxiety disorders, as well as ataxia, expanding the GEFS+ spectrum to include neuropsychiatric disease.
authors.affiliation: Clinical Epidemiology Unit, Faculty of Medicine, Memorial University, St. John's, NL, Canada. kmahoney@mun.ca
authors.forename: Krista
authors.initials: K
authors.lastname: Mahoney
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Moore
authors.forename: David
authors.initials: D
authors.lastname: Buckley
authors.forename: Muhammed
authors.initials: M
authors.lastname: Alam
authors.forename: Patrick
authors.initials: P
authors.lastname: Parfrey
authors.forename: Sharon
authors.initials: S
authors.lastname: Penney
authors.forename: Nancy
authors.initials: N
authors.lastname: Merner
authors.forename: Kathy
authors.initials: K
authors.lastname: Hodgkinson
authors.forename: Terry-Lynn
authors.initials: TL
authors.lastname: Young
mesh_terms: D000328:Adult; D001007:Anxiety / Q000209:etiology / Q000235:genetics; D001259:Ataxia / Q000209:etiology / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004829:Epilepsy, Generalized / Q000150:complications / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D003294:Seizures, Febrile / Q000150:complications / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels