A Novel Locus for Generalized Epilepsy With Febrile Seizures Plus in French Families

Background 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. Objectives 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 + . Design Family-based linkage analysis. Setting University hospital. Patients 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. Results 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. Conclusions 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 + .