A splice site variant in the sodium channel gene SCN1A confers risk of febrile seizures.
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).
Schlachter
K
K
Department of Pediatrics, LKH Bregenz, Austria.
Gruber-Sedlmayr
U
U
Stogmann
E
E
Lausecker
M
M
Hotzy
C
C
Balzar
J
J
Schuh
E
E
Baumgartner
C
C
Mueller
J C
JC
Illig
T
T
Wichmann
H E
HE
Lichtner
P
P
Meitinger
T
T
Strom
T M
TM
Zimprich
A
A
Zimprich
F
F
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
D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C568242:SCN1A protein, human; D015222:Sodium Channels