Research in context
Evidence before this study
The genetic underpinnings of common epilepsies are largely unknown, especially the relative contributions of common variants of small effect size versus rare variants of large effect, for which opportunities for novel therapeutic strategies might be greater. We searched PubMed with the terms “exome sequencing” and “common epilepsy” for reports published before June 28, 2016, with no language restrictions. There were no reports of exome sequencing of large case collections of common complex epilepsies. Although exome sequencing studies have been successful in implicating numerous genes and finding the relevant mutations for individuals with rare, severe, paediatric epilepsies, including epileptic encephalopathies, estimating the risk contribution from the ultra-rare protein-coding variants has been less clear for many of the common epilepsy syndromes.
Added value of this study
We used whole exome sequencing on a large collection of data from patients with one of two common epilepsy syndromes, genetic generalised epilepsy and non-acquired focal epilepsy, to search for ultra-rare deleterious qualifying variants, and compared the qualifying variant rates found in these cases to background rates estimated from sequenced controls. Among familial index cases sampled from the common epilepsies, we found a significant excess of ultra-rare deleterious variation within known epileptic encephalopathy genes. We also show that the epilepsy risk signal observed in the known epilepsy genes is accounted for by the ultra-rare class of variants that are absent among large reference control cohorts, such as the Exome Aggregate Consortium and Exome Variant Server. Variants in known epilepsy genes that were predicted to be deleterious, but found at very low frequencies in the population reference cohorts, showed no evidence of contribution to epilepsy risk.
Implications of all the available evidence
The present findings provide three key conclusions for our understanding of the common epilepsies. First, the identification of significant enrichment of ultra-rare deleterious variants in established epilepsy genes show that there are risk associations that can be identified through this methodology. Second, we showed that the precision medicine framework that is emerging for rare epilepsies can be expected to find applications also in more common epilepsies. Finally, we showed that risk in the common complex forms of epilepsy is associated with the rarest variants in the human population, providing the clearest insight available at present into the genetic variants underlying this common complex disorder. Further research is warranted to translate these findings into clinical practice.