Generalized epilepsy with febrile seizures plus (GEFS+) is a recently recognized but relatively common form of inherited childhood-onset epilepsy with heterogeneous epilepsy phenotypes. We genotyped 41 family members, including 21 affected individuals, to localize the gene causing epilepsy in a large family segregating an autosomal dominant form of GEFS+. A genomewide search examining 197 markers identified linkage of GEFS+ to chromosome 2, on the basis of an initial positive LOD score for marker D2S294 (Z = 4.4, recombination fraction [θ] = 0). A total of 24 markers were tested on chromosome 2q, to define the smallest candidate region for GEFS+. The highest two-point LOD score (Z(max) = 5.29; θ = 0) was obtained with marker D2S324. Critical recombination events mapped the GEFS+ gene to a 29-cM region flanked by markers D2S156 and D2S311, with the idiopathic generalized epilepsy locus thereby assigned to chromosome 2q23-q31. The existence of the heterogeneous epilepsy phenotypes in this kindred suggests that seizure predisposition determined by the GEFS+ gene on chromosome 2q could be modified by other genes and/or by environmental factors, to produce the different seizure types observed.662698701Blair, L.A., Levitan, E.S., Marshall, J., Dionne, V.E., Barnard, E.A., Single sub-units of the GABAA receptor form ion channels with properties of the native receptor (1988) Science, 242, pp. 577-579Baulac, S., Gourfinkel-An, I., Picard, F., Rosenberg-Bourgin, M., Prud'homme, J.-F., Baulac, M., Brice, A., A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21-q33 (1999) Am J Hum Genet, 65, pp. 1078-1085Berkovic, S.F., Scheffer, I.E., Genetics of the epilepsies (1999) Curr Opin Neurol, 12, pp. 177-182Bievert, C., Schoeder, B.C., Kubisch, C., Berkovic, S.F., Propping, P., Jentsch, T.J., Steinlein, O.K., A potassium channel mutation in neonatal human epilepsy (1998) Science, 279, pp. 403-406Bu, D.F., Tobin, A.J., The exon-intron organization of the genes (GAD1 and GAD2) encoding two human glutamate decarboxylases (GAD67 and GAD65) suggests that they derive from a common ancestral GAD (1994) Genomics, 21, pp. 222-228Proposal for revised clinical and electroencephalographic classification of epileptic seizures (1981) Epilepsia, 22, pp. 489-501Gyapay, G., Morissette, J., Vignal, A., Dib, C., Fizames, C., Millasseau, P., Marc, S., The 1993-94 Généthon human genetic linkage map (1994) Nat Genet, 7, pp. 246-339Hauser, W.A., Annegers, J.F., Kurland, L.T., Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984 (1993) Epilepsia, 34, pp. 453-468Lathrop, G.M., Lalouel, J.M., Easy calculations of LOD scores and genetic risks on small computers (1984) Am J Hum Genet, 36, pp. 460-465Lopes-Cendes, I., Scheffer, I.E., Berkovic, S.F., Rousseau, M., Andermann, E., Rouleau, G.A., Mapping a locus for idiopathic generalized epilepsy in a large multiplex family (1996) Epilepsia, 37 (SUPPL. 5), p. 127Moulard, B., Guipponi, M., Chaigne, D., Mouthon, D., Buresi, C., Malafosse, A., Identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+) on chromosome 2q24-q33 (1999) Am J Hum Genet, 65, pp. 1396-1400Peiffer, A., Thompson, J., Charlier, C., Otterud, B., Varvil, T., Pappas, C., Barnitz, C., A locus for febrile seizures (FEB3) maps to chromosome 2q23-24 (1999) Ann Neurol, 46, pp. 671-678Sambrook, J., Fritsch, E.F., Maniatis, T., (1989) Molecular Cloning: A Laboratory Manual, 2d Ed., pp. E3-E4. , Cold Spring Harbor Laboratory, Cold Spring Harbor, NYScheffer, I.E., Berkovic, S.F., Generalized epilepsy with febrile seizures plus: A genetic disorder with heterogeneous clinical phenotypes (1997) Brain, 120, pp. 479-490Singh, N.A., Charlier, C., Stauffer, D., DuPont, B.R., Leach, R.J., Melis, R., Ronen, G.M., A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns (1998) Nat Genet, 18, pp. 25-29Singh, R., Scheffer, I.E., Crossland, K., Berkovic, S.F., Generalized epilepsy with febrile seizures plus (GEFS+): A common, childhood-onset, genetic epilepsy syndrome (1999) Ann Neurol, 45, pp. 75-81Steinlein, O.K., Mulley, J.C., Propping, P., Wallace, R.H., Phillips, H.A., Sutherland, G.R., Scheffer, I.E., A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy (1995) Nat Genet, 11, pp. 201-203Wallace, R.H., Wang, D.W., Sing, R., Scheffer, I.E., George A.I., Jr., Phillips, H.A., Saar, K., Febrile seizures and generalized epilepsy associated with a mutation in the Na +-channel β1 subunit gene SCN1B (1998) Nat Genet, 19, pp. 366-370