Chipping away at the common epilepsies with complex genetics: the 15q13.3 microdeletion shows the way

Helbig and colleagues [1] have recently described the most common inherited cause of epilepsy detected so far. Such progress has reminded us of Ryan's eloquent 1995 review [2] on the mapping of genes for familial idiopathic epilepsies to chromosomes, which he likened to creating "chinks in the(ir) armor". The 'armor' he was referring to was the enormity of the human genome, which effectively shields the underlying molecular defects from detection. The timing of Ryan's article was impeccable: epilepsy gene hunters, assisted by rapid technological developments in molecular genetics and bioinformatics as the Human Genome Project gained momentum, were at the threshold of uncovering the channelopathy paradigm for the familial epilepsies showing Mendelian inheritance. The first genes for the monogenic idiopathic epilepsies were about to be identified [3-7].Most of the known pathogenic culprits in epileptogenesis are mutations in genes encoding components of neuronal ion channels [8]. The question from the beginning was whether knowledge of the genes underlying these familial epilepsies would provide the clues to uncover the susceptibility genes for common, polygenic or multifactorial epilepsies, with their complex genetics and complex genotype-environment interactions.Gargus [9] suggested that multiple neuronal ion channels might be involved in seizure susceptibility through the additive effects of genetic variants that contribute to the channelopathy load. Even the simple 'monogenic' epilepsies show a certain level of genetic complexity, as they are genetically heterogeneous [8]. Add to this the incomplete penetrance of mutations and variable expressivity, and one can imagine a continuum between the apparently monogenic and the polygenic epilepsies [8].A few rare and polymorphic variants in ion channel genes have been identified that result in changes to channel properties consistent with an increased predisposition to seizures [8,10]. To this list of susceptibility gene