Genome scan of idiopathic generalized epilepsy: Evidence for major susceptibility gene and modifying genes influencing the seizure type

Idiopathic generalized epilepsy (IGE) is a common, complex disease with an almost exclusively genetic etiology but with variable phenotypes. Clinicall y, IGE can be divided into different syndromes. Varying lines of evidence p oint to the involvement of several interacting genes in the etiology of IGE . We performed a genome scan in 91 families ascertained through a proband w ith adolescent-onset IGE. The IGEs included juvenile myoclonic epilepsy (JM E), juvenile absence epilepsy (JAE), and epilepsy with generalized tonic cl onic seizures (EGTCS). Our linkage results support an oligogenic model for IGE, with strong evidence for a locus common to most IGEs on chromosome 18 (Iod score 4.4/5.2 multipoint/two-point) and other loci that may influence specific seizure phenotypes for different IGEs: a previously identified loc us on chromosome 6 for JME (lod score 2.5/4.2), a locus on chromosome 8 inf luencing non-JME forms of IGE (Iod score 3.8/2.5), and, more tentatively, t wo newly discovered loci for absence seizures on chromosome 5 (Iod scores 3 .8/2.8 and 3.4/1.9). Our data also suggest that the genetic classification of different forms of IGE is likely to cut across the clinical classificati on of these subforms of IGE. We hypothesize that interactions of different combinations of these loci produce the related heterogeneous phenotypes see n in IGE families.