Epilepsy genetics: Current knowledge, applications, and future directions

Abstract

The rapid pace of disease gene discovery has resulted in tremendous advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, and genomes are now available and have led to higher diagnostic rates and insights into the underlying disease processes. As such, the contribution to the care of patients by medical geneticists, neurogeneticists and genetic counselors are significant; the dysmorphic examination, the necessary pre- and post-test counseling, the selection of the appropriate next-generation sequencing-based test(s), and the interpretation of sequencing results require a care provider to have a comprehensive working knowledge of the strengths and limitations of the available testing technologies. As the underlying mechanisms of the encephalopathies and epilepsies are better understood, there may be opportunities for the development of novel therapies based on an individual's own specific genotype. Drug screening with in vitro and in vivo models of epilepsy can potentially facilitate new treatment strategies. The future of epilepsy genetics will also probably include other-omic approaches such as transcriptomes, metabolomes, and the expanded use of whole genome sequencing to further improve our understanding of epilepsy and provide better care for those with the disease.

Implementation of Epilepsy Multigene Panel Testing in Ontario, Canada

“…1,2 The condition is clinically heterogeneous and has diverse etiologies with age dependent presentation. 3 Twin and family studies show that epilepsy is a highly heritable condition, 4 and a proportion of affected individuals will develop epilepsy due to pathogenic variant(s) in a single gene (e.g., monogenic). These individually rare, highly penetrant disease-causing variants have previously been difficult to diagnose by molecular means until the advent of next-generation sequencing (NGS).…”

“…Several studies now show that NGS-based strategies can provide a molecular diagnosis in 15%-30% of individuals with epilepsy and, for specific clinical presentations, the rate can be higher. 4,5 As a result, the application of NGS has rapidly transformed the way in which genetic epilepsy is diagnosed. The sequencing of dozens to even hundreds of genes is now possible with a wide variety of "epilepsy panels" available through commercial laboratories.…”

Genetic factors and the risk of drug-resistant epilepsy in young children with epilepsy and neurodevelopment disability: A Prospective Study and Updated Meta-Analysis

“…Gene-related epilepsy involves various heterogenous seizure mechanisms that depend on the role of the genes. There are over 970 genes associated with epilepsy, and the number is increasing year by year [41,42]. Although the seizure mechanisms are complex and diverse between the causative genes, we could roughly categorize them into ion and nonion channel genes.…”

Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A

“…The significance of NMDARs is also well-demonstrated by the range of clinical phenotypes of patients with mutations in the genes encoding NMDAR subunits. Since the development of next generation sequencing methods in the mid-1990's there has been a steady rise in number of epilepsy-associated genes 35 with the addition of the GluN2A receptor gene, GRIN2A, to this list only a decade ago [36][37][38] . Published figures now show that >250 patients are known to have GRIN2A mutations, either de novo or transmitted with dominant inheritance 39,40 .…”