Generalized epilepsy with febrile seizures plus (GEFS+) is a familial autosomal dominant entity characterized by the association of febrile and afebrile seizures. Mutations in 3 genes—the sodium channel α1 subunit gene (SCN1A), the sodium channel β1 subunit gene (SCN1B), and the γ2 GABA receptor subunit gene (GABRG2)—and linkage to 2 other loci on 2p24 and 21q22 have been identified in families with GEFS+, indicating genetic heterogeneity.
To localize by means of linkage analysis a new gene for GEFS+ in a large family with 11 affected members and to test the new locus in 4 additional families with GEFS+.
Family-based linkage analysis.
Five French families with GEFS+ and at least 7 available affected members with autosomal dominant transmission. All the patients had febrile seizures and/or afebrile generalized tonic-clonic seizures or absence epilepsy.
Main Outcome Measures
We analyzed 380 microsatellite markers and conducted linkage analysis.
In the largest family, a 10-cM-density genomewide scan revealed linkage to a 13-Mb (megabase) interval on chromosome 8p23-p21 with a maximum pairwise logarithm of odds (LOD) score of 3.00 (at Θ = 0) for markers D8S351 and D8S550 and a multipoint LOD score of 3.23. A second family with GEFS+ was also possibly linked to chromosome 8p23-p21 and the region was narrowed to a 7.3-Mb candidate interval, flanked by markers D8S1706 and D8S549. We have not, so far, identified mutations in the coding exons of 6 candidate genes (MTMR9, MTMR7, CTSB, SGCZ, SG223, and ATP6V1B2) located in the genetic interval.
We report a sixth locus for GEFS+ on chromosome 8p23-p21. Because no ion channel genes are located in this interval, identification of the responsible gene will probably uncover a new mechanism of pathogenesis for GEFS+.