title: A novel susceptibility locus at 2p24 for generalised epilepsy with febrile seizures plus.
abstract: Generalised epilepsy with febrile seizures plus (GEFS+) is a clinically and genetically heterogeneous epilepsy syndrome. Using positional cloning strategies, mutations in SCN1B, SCN1A, and GABRG2 have been identified as genetic causes of GEFS+. In the present study, we describe a large four generation family with GEFS+ in which we performed a 10 cM density genome-wide scan. We obtained conclusive evidence for a novel GEFS+ locus on chromosome 2p24 with a maximum two point logarithm of the odds (LOD) score of 4.22 for marker D2S305 at zero recombination. Fine mapping and haplotype segregation analysis in this family delineated a candidate region of 3.24 cM, corresponding to a physical distance of 4.2 Mb. Linkage to 2p24 was confirmed (p = 0.007) in a collection of 50 nuclear and multiplex families with febrile seizures and epilepsy. Transmission disequilibrium testing and association studies provided further evidence (p < 0.05) that 2p24 is a susceptibility locus for febrile seizures and epilepsy. Furthermore, we could reduce the candidate region to a 2.14 cM interval, localised between D2S1360 and D2S2342, based upon an ancestral haplotype. Identification of the disease gene at this locus will contribute to a better understanding of the complex genetic aetiology of febrile seizures and epilepsy.
authors.affiliation: Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Audenaert
authors.forename: L
authors.initials: L
authors.lastname: Claes
authors.forename: K G
authors.initials: KG
authors.lastname: Claeys
authors.forename: L
authors.initials: L
authors.lastname: Deprez
authors.forename: T
authors.initials: T
authors.lastname: Van Dyck
authors.forename: D
authors.initials: D
authors.lastname: Goossens
authors.forename: J
authors.initials: J
authors.lastname: Del-Favero
authors.forename: W
authors.initials: W
authors.lastname: Van Paesschen
authors.forename: C
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: P
authors.initials: P
authors.lastname: De Jonghe
mesh_terms: D002889:Chromosomes, Human, Pair 2; D004827:Epilepsy / Q000235:genetics*; D005192:Family Health; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D016678:Genome; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008126:Lod Score; D008297:Male; D010375:Pedigree; D011995:Recombination, Genetic; D003294:Seizures, Febrile / Q000235:genetics*
chemical_list: D005819:Genetic Markers