New ideas in epilepsy genetics: novel epilepsy genes, copy number alterations, and gene regulation.

The majority of genes associated with epilepsy syndromes to date are ion channel genes. Selection bias may have allowed us to establish their role in epilepsy based on a priori knowledge of the significance of these proteins in regulating neuronal excitability. There are, however, more than 3000 genes expressed at the synapse, as well as many other genes expressed nearby in supporting cells and glia that can likewise regulate excitability. Identification of new genes involved in epilepsy may arise from studying the targets of anticonvulsant medications, ascertainment of an epileptic phenotype in mice, or as a result of positional cloning efforts. There are several loci for idiopathic focal and generalized epilepsies that lie in chromosomal regions that are devoid of known ion channels; therefore, the number of novel genes involved in epilepsy is likely to increase. Establishing the role of these novel genes in the pathogenesis of epilepsy has not been an easy task compared with the relative ease with which ion channel mutations can be studied. This review will describe several novel epilepsy genes and will then discuss other genetic causes of epilepsy, including alterations of chromosomal copy number and gene regulatory elements.