Background: Febrile seizures (FSs) are the most common form of childhood seizures, and genetic factors play a role in susceptibility to FS.
Objective: To identify novel loci and genes associated with susceptibility to FS.
Methods: Study participants were the FS probands and family members of 59 Japanese nuclear families (223 members including 112 affected children). Forty-eight of these families had at least two affected children for which genome-wide linkage screening was carried out. The Genehunter software was used to perform nonparametric multipoint linkage analysis. Mutational and association analyses were conducted in all 59 Japanese FS families.
Results: Genotyping data of 407 microsatellite markers suggested linkage of FSs to chromosome 18p11.2 (non-parametric linkage score = 3.68, p = 0.0001). This region includes the IMPA2 gene, which encodes myo-inositol monophosphatase (IMPase) 2. In the phosphatidylinositol-signaling pathway, IMPase is inhibited by lithium, which has a proconvulsant effect, and is stimulated by carbamazepine, an anticonvulsant. A systematic search was performed for mutations in IMPA2 in 24 unrelated randomly selected Japanese FS patients; seven variants were detected. Haplotype analysis revealed an association of a common haplotype in IMPA2 with FSs (p = 0.0009).
Conclusion: The authors found a novel locus on chromosome 18p11.2 for febrile seizures (FSs). IMPA2 is likely to be an FS susceptibility gene.