Genetics of the epilepsies: where are we and where are we going?

Abstract

Purpose of review: We aim to review the most recent advances in the field of epilepsy genetics with particular focus on the progress in gene discovery in monogenic epilepsies, identification of risk genes in complex genetic epilepsies and recent findings in the field of epilepsy pharmacogenomics.

Recent findings: During the last 12 months, the use of massive parallel sequencing technologies has allowed for the discovery of several genes for monogenic epilepsies. Most importantly, PRRT2 was identified as the long-sought gene for benign familial infantile seizures. Mutations in KCNT1 were found in two seemingly unrelated monogenic epilepsies including malignant migrating partial seizures of infancy and severe autosomal dominant nocturnal frontal lobe epilepsy. A genome-wide association study in idiopathic generalized epilepsy revealed the first common risk variants for human seizure disorders including variants in VRK2, PNPO and SCN1A. Furthermore, a landmark study provided evidence that screening for the HLA-B1502 variant may prevent carbamazepine CBZ-induced side effects in the Taiwanese population. Also, HLA-A3101 variants were identified as a risk factor for carbamazepine side effects in Europeans.

Summary: Novel technologies and an unprecedented level of international collaboration have resulted in identification of novel genes for monogenic and complex genetic epilepsies as well as risk factors for side effects of antiepileptic drugs. This review provides an overview of the most relevant studies in the last year and highlights the future direction of the field.

Figure 1

The dimensions of the genetic architecture of the epilepsies Effect size refers to the increase in risk carried by a given genetic variant. While the effect size is very high for monogenic variants, common genetic variants such as Single Nucleotide Polymorphism (SNPs) usually confer a very small risk. Rare genetic variants located between both extremes currently pose a major problem for genetic research, as established frameworks to interpret this variant are still lacking. Variants can be frequent or rare in the general and patient population, and there is usually an inverse correlation between effect size and frequency. A variant with a strong effect is usually rare. This inverse correlation, however, only applies to disease risk variants, as the low frequency of the disease in the population only permits such a correlation. In genetic risk factors for medication side effects, for example, both the frequency and effect size can be high, which allows for these studies to be performed with a modest sample size.

Figure 2

The history of gene identifications in epilepsy research The history of gene discovery in epilepsy began in 1995 with the discovery of CHRNA4 as the causative gene in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). After a series of gene discoveries in monogenic epilepsies, it was found that most causative genes were ion channel genes, postulating the Channelopathy concept of human epilepsy. However, subsequent association studies mainly on ion channel genes have failed, and the initial hope for rapid detection of further risk variants (gray) has diminished. The field entered a period of association studies, which largely were not replicable. Finally, with the discovery of epilepsy-related microdeletions, the first risk genes for common epilepsies were identified. With the advent of Next-Generation Sequencing technologies (NGS), more gene discovery is likely. The expectations of this technology, however, parallel a typical “bubble phenomenon” and first indications from other neurodevelopmental disorders suggest that only a small subset of genes can be identified.