Heating Up: The Genetics of Febrile Seizures

Febrile seizures—seizures caused by a high fever—occur in as many as 5% of young children. Often the fever is a result of a viral illness, but vaccine-induced fevers can also cause seizures and are considered an adverse effect of immunization. Family and twin studies confirm a strong genetic component underlying risk for febrile seizures. Genes have been identified for some epilepsy syndromes, but genetic risk factors for “simple” or self-limited febrile seizures have been elusive. Two recent studies advance our understanding of genetic susceptibility to fever-related seizures. In the first study, Schubert and colleagues used exome sequencing in two large families with multiple affected individuals to identify rare variants that segregate with fever-related seizures. They identified mutations in STX1B in both families as well as in four unrelated, affected individuals. Rare variants in STX1B were associated with a broad range of seizures, ranging from simple febrile seizures to more severe epilepsy conditions, so further study is required to understand what role this gene plays in run-of-the-mill simple febrile seizures. The second study is a genome-wide association study (GWAS) by Feenstra and colleagues in which they identify common genetic variants associated with risk for simple febrile seizures. They compared three groups of individuals: 929 children who had a febrile seizure after receiving the measles-mumps-rubella (MMR) vaccine, 1070 who had febrile seizures unrelated to the MMR vaccine, and 1999 controls without febrile seizures. They identified four loci associated with risk of febrile seizures overall and confirmed the associations in an independent case-control cohort. Two risk variants lie within well-known epilepsy genes that encode sodium channel subunits, SCN1A and SCN2A , so these results are not entirely surprising. Notably, variants in a different gene, ANO3 , were associated with the highest risk of febrile seizures. Little is known about how this gene, which encodes a transmembrane protein that belongs to a family of chloride channels, might be related to seizure susceptibility. The discovery highlights new areas for research and, potentially, therapy. The fourth locus was not linked to a gene, but to a genomic region previously associated with magnesium levels—another area worthy of investigation. Perhaps most interesting, the authors identified two loci that are specific for risk of febrile seizures after the MMR vaccine, both of which are in genes that are involved in the immune response to infection: IFI44L and CD46 . These results suggest that MMR vaccine–related seizures may be a subtype of simple febrile seizures. Together, these studies demonstrate that genetic susceptibility to febrile seizures is heterogeneous and involves both rare and common variants. More important, the results point to new genes and pathways that can form the basis for investigations of potential targets for therapeutic intervention and for the identification of susceptible individuals. J. Schubert et al ., Mutations in STX1B , encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nat. Genet. 10.1038/ng.3130 (2014). [[Abstract]][1] B. Feenstra et al., Common variants associated with general and MMR vaccine–related febrile seizures. Nat. Genet. 10.1038/ng.3129 (2014). [ [Abstract]][2] [1]: http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3130.html [2]: http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3129.html