Molecular genetics of idiopathic generalized epilepsies

Abstract

Most of idiopathic generalized epilepsies (IGEs) follow a complex genetic inheritance, with only a few rare, large families presenting with an autosomal dominant inheritance. During the past 20 years many genes associated with IGE were discovered, most of which encode ion channels or neurotransmitter receptors, but the question about the total number of existing genes is still unanswered. Novel technologies have resulted in the expansion of knowledge of normal variations in the human genome and enabled progress in the area of the molecular basis of IGE. New generation sequencing has become affordable and exom sequencing well established standard technology. The main result achieved was identification of copy number variations associated with IGE. But these rare variants could not be identified with genome-wide significance suggesting that genetic architecture of IGE is much more heterogeneous. The other achievement was identification of common genetic variants or Single Nucleotide Polymorphisms associated with IGE through genome-wide association studies, but not only in genes encoding the ion channels, moving the field of IGE genetics beyond the channelopathies. True measure of the success of these researches will be the possibility to translate genetic discoveries into a deeper mechanistic understanding of epilepsy in order to develop effective therapy.