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NEUROLOGY 2009;72:974-978
© 2009 American Academy of Neurology

A splice site variant in the sodium channel gene SCN1A confers risk of febrile seizures

K. Schlachter, MD, U. Gruber-Sedlmayr, MD, E. Stogmann, MD, M. Lausecker, MD, C. Hotzy, J. Balzar, MD, E. Schuh, C. Baumgartner, MD, J. C. Mueller, PhD, T. Illig, PhD, H. E. Wichmann, MD, PhD, P. Lichtner, PhD, T. Meitinger, MD, T. M. Strom, MD, A. Zimprich, MD and F. Zimprich, MD, PhD

From the Department of Pediatrics (K.S.), LKH Bregenz; Austria; Department of Pediatrics (U.G.-S.), Medical University of Graz; Austria; Department of Clinical Neurology (E.S., C.H., J.B., E.S., A.Z., F.Z.), Medical University of Vienna; Austria; G. v. Preyer’sches Kinderspital (M.L.), Vienna; Austria; 2nd Neurological Department (C.B.), General Hospital Hietzing with Neurological Center Rosenhuegel, Vienna, Austria; Max Planck Institute for Ornithology (J.C.M.), Department of Behavioural Ecology and Evolutionary Genetics, Seewiesen, Germany; Institute of Epidemiology (T.I., H.E.W.), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics (T.M., T.M.S.), Technische Universität München, Munich, Germany; and Institute of Human Genetics (P.L., T.M., T.M.S.), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Address correspondence and reprint requests to Dr. Fritz Zimprich, Universitaetsklinik fuer Neurologie, Allgemeines Krankenhaus der Stadt Wien, Waehringer Guertel 18-20, A-1090 Vienna, Austria friedrich.zimprich{at}meduniwien.ac.at

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).

Abbreviations: CI = confidence interval; Epi = epilepsy; FS = febrile seizures; GEFS+= generalized epilepsy with febrile seizures plus; GRR = genotype relative risk; PAF = population attributable fraction; SNP = single nucleotide polymorphism; TDT = transmission disequilibrium test.

*These authors contributed equally to the study.

The KORA research platform was initiated and financed by the GSF (National Research Centre for Environment and Health), which is funded by the German Federal Ministry of Education and Research (Berlin, Germany) and by the State of Bavaria. KORA-gen is partly funded by several projects of the NGFN (Nationales Genomforschungsnetz/German National Genome Research Network).

Disclosure: The authors report no disclosures.

Received September 15, 2008. Accepted in final form December 18, 2008.






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