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

Abstract

Idiopathic generalized epilepsy (IGE) is a common, complex disease with an almost exclusively genetic etiology but with variable phenotypes. Clinically, IGE can be divided into different syndromes. Varying lines of evidence point to the involvement of several interacting genes in the etiology of IGE. We performed a genome scan in 91 families ascertained through a proband with adolescent-onset IGE. The IGEs included juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and epilepsy with generalized tonic clonic seizures (EGTCS). Our linkage results support an oligogenic model for IGE, with strong evidence for a locus common to most IGEs on chromosome 18 (lod score 4.4/5.2 multipoint/two-point) and other loci that may influence specific seizure phenotypes for different IGEs: a previously identified locus on chromosome 6 for JME (lod score 2.5/4.2), a locus on chromosome 8 influencing non-JME forms of IGE (lod score 3.8/2.5), and, more tentatively, two newly discovered loci for absence seizures on chromosome 5 (lod 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 classification of these subforms of IGE. We hypothesize that interactions of different combinations of these loci produce the related heterogeneous phenotypes seen in IGE families.

Phenotypic concordance in 70 families with IGE-implications for genetic studies of epilepsy

“…Similarly, linkage studies have identified loci linked with specific IGE subtypes (Greenberg et al, 1988; Liu et al, 1996) and others loci linked to cohorts with a variety of IGE syndromes (Sander et al, 2000c; Kinirons et al, 2008). Under a more complex model, these findings could reflect the possibility that individuals within some families may possess additional genetic variants which influence phenotypic expression, a hypothesis previously suggested by Durner et al (2001).…”

“…A large amount of recent research has thus focused on the use of both association and linkage studies to detect pre-disposing variants and loci. Although a number of positive associations (Sander et al, 1997a, 2000a, 2000b, 2002; Steinlein et al, 1997; Chioza et al, 2001, 2002; Chen et al, 2003; Pal et al, 2003; Vijai et al, 2003; Gu et al, 2004) and loci (Sander et al, 1995, 1997b, 2000c; Durner et al, 1991, 1999, 2001; Liu et al, 1996; Serratosa et al, 1996; Pinto et al, 2004; Zara et al, 1995; Puranam et al, 2005; Elmslie et al, 1997; Greenberg et al, 1988, 2000, 2005) have been reported, few have been replicated with any consistency. In addition, recent work by Hempelmann et al (2007) using 126 multiplex IGE families suggested heterogenous configurations of susceptibility loci associated with different IGE subtypes and seizure types, further highlighting the likely complexity of the situation.…”

Mutations and polymorphisms of the CLCN2 gene in idiopathic epilepsy

“…3 Mutations in a voltage-gated chloride channel gene (CLCN2) 4 in the 3q26 region were subsequently found in three families, one with epilepsy with grand mal seizures on awakening (EGMA) and juvenile myoclonic epilepsy (JME), one with EGMA and childhood absence epilepsy (CAE), and one with juvenile absence epilepsy (JAE). Susceptibility loci for idiopathic generalized epilepsy (IGE) have been mapped to chromosomes 3q26, 2q36.1, 14q23 2 and 18q21.1, 6p21.2, 8p11.2.…”

Idiopathic generalized epilepsies

“…JAE may be linked to chromosome 8, 21, 18, and probably 5 (Sander et al, 1997;Durner et al, 1999Durner et al, , 2001. JAE may be linked to chromosome 8, 21, 18, and probably 5 (Sander et al, 1997;Durner et al, 1999Durner et al, , 2001.…”