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 alpha 1 subunit gene ( SCN1A), the sodium channel beta 1 subunit gene ( SCN1B), and the gamma 2 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 affectedmemberswith autosomaldominanttransmission. 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 Theta= 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: Wereport 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(+).