A Locus for Generalized Tonic-Clonic Seizure Susceptibility Maps to Chromosome

Inheritance patterns in twins and multiplex families led us to hypothesize that two loci were segregating in subjects with juvenile myoclonic epilepsy (JME), one predisposing to generalized tonic-clonic seizures (GTCS) and a second to myo-clonic seizures. We tested this hypothesis by performing genome-wide scan of a large family (Family 01) and used the results to guide analyses of additional families. A locus was identified in Family 01 that was linked to GTCS (10q25-q26). Model-based multipoint analysis of the 10q25-q26 locus showed a logarithm of odds (LOD) score of 2.85; similar results were obtained with model-free analyses (maximum nonparametric linkage [NPL] of 2.71; p 0.0019). Analyses of the 10q25-q26 locus in 10 additional families assuming heterogeneity revealed evidence for linkage in four families; model-based and model-free analyses showed a heterogeneity LOD (HLOD) of 2.01 ( 0.41) and maximum NPL of 2.56 (p 0.0027), respectively, when all subjects with GTCS were designated to be affected. Combined analyses of all 11 families showed an HLOD of 4.04 ( 0.51) and maximum NPL score of 4.20 (p 0.000065). Fine mapping of the locus defined an interval of 4.45Mb. These findings identify a novel locus for GTCS on 10q25-q26 and support the idea that distinct loci underlie distinct seizure types within an epilepsy syndrome such as JME. Ann Neurol 2005;58:449–458 Epilepsy, characterized by recurrent seizures, is a com-mon and complicated group of disorders. The geneti