title: A splice site variant in the sodium channel gene SCN1A confers risk of febrile seizures.
abstract: OBJECTIVE
  Our aim was to investigate whether the risk of febrile seizures is influenced by a common functional polymorphism in the sodium channel gene SCN1A. This single nucleotide polymorphism (IVS5N+5 G>A, rs3812718) was shown to modify the proportion of two alternative transcripts of the channel.
  
  
  METHODS
  We performed an exploratory case-control association analysis in 90 adult epilepsy patients with childhood febrile seizures vs 486 epilepsy patients without a history of febrile seizures and also vs 701 population controls. In the replication step, we investigated children with febrile seizures without concomitant epilepsy at the time of their inclusion. We compared the genotypes of 55 of those children against population controls and performed a within-family association analysis in an additional 88 child-parent trios with febrile seizures.
  
  
  RESULTS
  We observed a significant association of the splice-site interrupting A-allele with febrile seizures (p value in the exploratory step: 0.000017; joint p value of the replication: 0.00069). Our data suggest that the A-allele of this variant confers a threefold genotype relative risk in homozygotes and accounts for a population attributable fraction of up to 50% for the etiology of febrile seizures.
  
  
  CONCLUSIONS
  The A-allele of the SCN1A single nucleotide polymorphism IVS5N+5 G>A (rs3812718) represents a common and relevant risk factor for febrile seizures. A limitation of the present study is that patients of the exploratory and replication steps differed in aspects of their phenotype (febrile seizures with and without additional epilepsy).
authors.affiliation: Department of Pediatrics, LKH Bregenz, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Schlachter
authors.forename: U
authors.initials: U
authors.lastname: Gruber-Sedlmayr
authors.forename: E
authors.initials: E
authors.lastname: Stogmann
authors.forename: M
authors.initials: M
authors.lastname: Lausecker
authors.forename: C
authors.initials: C
authors.lastname: Hotzy
authors.forename: J
authors.initials: J
authors.lastname: Balzar
authors.forename: E
authors.initials: E
authors.lastname: Schuh
authors.forename: C
authors.initials: C
authors.lastname: Baumgartner
authors.forename: J C
authors.initials: JC
authors.lastname: Mueller
authors.forename: T
authors.initials: T
authors.lastname: Illig
authors.forename: H E
authors.initials: HE
authors.lastname: Wichmann
authors.forename: P
authors.initials: P
authors.lastname: Lichtner
authors.forename: T
authors.initials: T
authors.lastname: Meitinger
authors.forename: T M
authors.initials: TM
authors.lastname: Strom
authors.forename: A
authors.initials: A
authors.lastname: Zimprich
authors.forename: F
authors.initials: F
authors.lastname: Zimprich
mesh_terms: D000328:Adult; D000483:Alleles; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics* / Q000502:physiology; D012306:Risk; D003294:Seizures, Febrile / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C568242:SCN1A protein, human; D015222:Sodium Channels