title: Susceptibility genes for complex epilepsy.
abstract: Common idiopathic epilepsies are, clinically and genetically, a heterogeneous group of complex seizure disorders. Seizures arise from periodic neuronal hyperexcitability of unknown cause. The genetic component is mostly polygenic, where each susceptibility gene in any given individual is likely to represent a small component of the total heritability. Two susceptibility genes have been so far identified, where genetic variation is associated with experimentally demonstrated changes in ion channel properties, consistent with seizure susceptibility. Rare variants and a polymorphic allele of the T-type calcium channel CACNA1H and a polymorphic allele and a rare variant of the GABA(A) receptor delta subunit gene have differential functional effects. We speculate that these and other as yet undiscovered susceptibility genes for complex epilepsy could act as 'modifier' loci, affecting penetrance and expressivity of the mutations of large effect in those 'monogenic' epilepsies with simple inheritance that segregate through large families. Discovery of epilepsy-associated ion channel defects in these rare families has opened the door to the discovery of the first two susceptibility genes in epilepsies with complex genetics. The susceptibility genes so far detected are not commonly involved in complex epilepsy suggesting the likelihood of considerable underlying polygenic heterogeneity.
authors.affiliation: Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
authors.forename: John C
authors.initials: JC
authors.lastname: Mulley
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.forename: Louise A
authors.initials: LA
authors.lastname: Harkin
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Dibbens
mesh_terms: D000483:Alleles; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000502:physiology; D004827:Epilepsy / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D020412:Multifactorial Inheritance; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology
chemical_list: C479952:CACNA1H protein, human; D020747:Calcium Channels, T-Type; C464500:GABRD protein, human; D007473:Ion Channels; D011963:Receptors, GABA-A