Advancing epilepsy genetics in the genomic era

Candace T. Myers, Heather C. Mefford

Epilepsy is a group of disorders characterized by recurrent seizures, and is one of the most common neurological conditions. The genetic basis of epilepsy is clear from epidemiological studies and from rare gene discoveries in large families. The three major classes of epilepsy disorders are genetic generalized, focal and encephalopathic epilepsies, with several specific disorders within each class. Advances in genomic technologies that facilitate genome-wide discovery of both common and rare variants have led to a rapid increase in our understanding of epilepsy genetics. Copy number variant and genome-wide association studies have contributed to our understanding of the complex genetic architecture of generalized epilepsy, while genetic insights into the focal epilepsies and epileptic encephalopathies have come primarily from exome sequencing. It is increasingly clear that epilepsy is genetically heterogeneous, and novel gene discoveries have moved the field beyond the known contribution of ion channels to implicate chromatin remodeling, transcriptional regulation and regulation of the mammalian target of rapamycin (mTOR) protein in the etiology of epilepsy. Such discoveries pave the way for new therapeutics, some of which are already being studied. In this review, we discuss the rapid pace of gene discovery in epilepsy, as facilitated by genomic technologies, and highlight several novel genes and potential therapies.