A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21-q33

Abstract

We report a clinical and genetic study of a family with a phenotype resembling generalized epilepsy with febrile seizures plus (GEFS+), described by Berkovic and colleagues. Patients express a very variable phenotype combining febrile seizures, generalized seizures often precipitated by fever at age >6 years, and partial seizures, with a variable degree of severity. Linkage analysis has excluded both the beta 1 subunit gene (SCN1B) of a voltage-gated sodium (Na+) channel responsible for GEFS+ and the two loci, FEB1 and FEB2, previously implicated in febrile seizures. A genomewide search, under the assumption of incomplete penetrance at 85% and a phenocopy rate of 5%, permitted identification of a new locus on chromosome 2q21-q33. The maximum pairwise LOD score was 3.00 at recombination fraction 0 for marker D2S2330. Haplotype reconstruction defined a large (22-cM) candidate interval flanked by markers D2S156 and D2S2314. Four genes coding for different isoforms of the alpha-subunit voltage-gated sodium channels (SCN1A, SCN2A1, SCN2A2, and SCN3A) located in this region are strong candidates for the disease gene.

Figure 1

Partial pedigree of a French family with GEFS+, showing haplotype reconstruction for chromosome 2q markers. Deduced haplotypes are bracketed. Microsatellite markers are ordered, according to the Généthon genetic map, from centromere (top) to telomere (bottom). The haplotype segregating with the disease is boxed. Observed recombinations are indicated by arrows.

Figure 2

Multipoint analysis with chromosome 2q markers in the French family with GEFS+. The genetic distances are represented as on the Généthon chromosome 2 map. Horizontal dotted lines indicate the limit of exclusion (LOD score −2) and of significant linkage (LOD score 3).