Genetic variations and associated pathophysiology in the management of epilepsy

John C Mulley^1,2, Leanne M Dibbens^3
1Department of Genetic Medicine, Directorate of Genetics and Molecular Pathology, SA Pathology at Women’s and Children’s Hospital, North Adelaide, Australia; ²School of Paediatrics and Reproductive Health, and School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, Australia; ³School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia

Abstract: The genomic era has enabled the application of molecular tools to the solution of many of the genetic epilepsies, with and without comorbidities. Massively parallel sequencing has recently reinvigorated gene discovery for the monogenic epilepsies. Recurrent and novel copy number variants have given much-needed impetus to the advancement of our understanding of epilepsies with complex inheritance. Superimposed upon that is the phenotypic blurring by presumed genetic modifiers scattering the effects of the primary mutation. The genotype-first approach has uncovered associated syndrome constellations, of which epilepsy is only one of the syndromes. As the molecular genetic basis for the epilepsies unravels, it will increasingly influence the classification and diagnosis of the epilepsies. The ultimate goal of the molecular revolution has to be the design of treatment protocols based on genetic profiles, and cracking the 30% of epilepsies refractory to current medications, but that still lies well into the future. The current focus is on the scientific basis for epilepsy. Understanding its genetic causes and biophysical mechanisms is where we are currently positioned: prizing the causes of epilepsy “out of the shadows” and exposing its underlying mechanisms beyond even the ion-channels.

Keywords: array CGH, copy number variants, epilepsy, ion channels, massively parallel sequencing, next generation sequencing, susceptibility genes