A locus for simple pure febrile seizures maps to chromosome 6q22-q24

Febrile seizures (FS) syndromes exhibit major clinical and genetic heterogeneity. We report a clinical and genetic study of three families with simple FS segregating as an autosomal dominant (AD) trait with high penetrance. All affected members presented a homogeneous phenotype of simple FS. The FS ceased before the age of 5 years. Among the 29 affected family members, only one patient presented two afebrile seizures, and none of the others developed concomitant or subsequent epilepsy. The phenotype differs from that previously reported in families presenting FS or generalized epilepsy with febrile seizures plus (GEFS+). After exclusion of already known loci for FS and GEFS+, we performed a genome-wide scan in the largest family. It led to the identification of a new locus on chromosome 6q22-q24 spanning 6.4 cM between D6S1620 and D6S975. For one of the other two families, the trait also segregated with this locus, but linkage studies could not restrict the candidate region further. The absence of linkage in the third family supports genetic heterogeneity of the AD form of pure simple FS. Sequence analysis excluded the implication of five candidate genes [A kinase anchoring protein 18 (AKAP18), syntaxin 7, putative neurotransmitter receptor (PNR), G protein receptor 57 (GPR57) and G protein receptor 58 (GPR58)] in the interval based on function. The locus mapping to 6q22-q24 seems to be the first identified locus responsible for pure simple FS, the most frequent form of FS. Studies are ongoing to identify the gene.