By M. Elizabeth Ross, MD, PhD

Nathan E. Cumming Professor of Neurology and Neuroscience, Chair, Neuroscience Graduate Program, Weill Cornell Medical College

Dr. Ross reports no financial relationships relevant to this field of study.

SYNOPSIS: In the first study with genome sequencing in the common forms of epilepsy, ultra-rare genetic mutations of known epilepsy genes were over-represented in the epilepsy population, compared to controls.

SOURCE: Epi4K consortium; Epilepsy Phenome/Genome Project. Ultra-rare genetic variation in common epilepsies: A case-control sequencing study. Lancet Neurol 2017;16:135-143.

Heritability studies have identified dozens of genes in which mutations can lead to rare, severe epilepsies that are clinically syndromic. However, two critical questions arise with regard to common epilepsies: First, what is the extent to which these genes may contribute to common epileptic encephalopathies, and second, do rare-occurring mutations — whether inherited or de novo — have large effects on the emergence of seizures, or do common variants with small effect on gene function converge to result in common epilepsies? A report in the Feb. 16 issue of Lancet Neurology tackles these questions using exome sequencing in a case-control study of a large seizure cohort, collected through two major consortia funded by the National Institute of Neurological Disorders and Stroke (NINDS) and Epilepsy Research UK.

The study group separately analyzed 640 cases of familial generalized epilepsy, 525 cases of familial idiopathic focal epilepsy, and 622 cases of sporadic non-acquired focal epilepsy. These were compared with data from 3,877 seizure-free control subjects, all of European ancestry. This is the first genome sequencing report of a large case collection of common complex epilepsies. The study focused on ultra-rare DNA sequence variants that occur with a mean allele frequency (MAF) < 0.05% in cases and controls combined. In addition, filtered variants were expected to have a MAF = 0% in the publicly accessible databases of the exome aggregate consortium (ExAC) and the exome variant server (EVS), together totaling more than 65,000 sequences. Through a number of statistical treatments, the authors examined whether the occurrence of loss of function variants (those causing a premature stop in the protein sequence or frame shift loss of function mutations or predicted deleterious amino acid substitutions) occurred more frequently in cases than expected compared with control subjects. A stringent threshold for significance across the study of P = 8.9 x 10-7 was invoked to guard against false positives due to multiple sampling error.

For familial generalized epilepsy, no single gene rose to significance study-wide. However, of the 76,313 variants that fulfilled the selection criteria of ultra-rare, three known epilepsy genes (KCNQ2, GABRG2, and SCN1A) were in the top 10 that were enriched in cases over controls. Intriguingly, 43 known dominant epilepsy genes were over-represented in cases. In the familial focal epilepsy group, DEPDC5 variants reached study-wide significance and another four (LGI1, PCDH19, SCN1A, and GRIN2A) made up the next nearest rank. That five known epilepsy genes should be found as the most highly enriched among this minimally targeted analysis is unlikely to occur by chance. Finally, among the 622 sporadic cases of non-acquired focal epilepsy, no single gene achieved study-wide significance and no enrichment of loss of function/deleterious variants was detected.


This study is only a beginning for genomic investigation into complex epilepsies, but it provides several important insights. First, genome sequencing can be used in a non-hypothesis-driven approach to discovery of genetic factors contributing to epilepsy. Second, rare, and especially ultra-rare or private genetic variants, can be identified as risk factors for complex epileptic encephalopathies. Third, this implies that a precision medicine approach to treatment of common epilepsies may indeed be a fruitful avenue for clinical care in the foreseeable future. Directions for subsequent research no doubt will include collecting sequences on further enlarging case-control cohorts, similar to those that have been mined from schizophrenia cohorts of 50,000 persons or more. As these datasets grow, it will be possible to examine patterns of genetic variant interactions that may identify risk with increasing accuracy. In the not-too-distant future, sequence data sets from the entire genome, not just the coding exons that make up only 2% of the genome, will enable interrogation of the regulatory variations that also may contribute to epilepsy predisposition. Greater knowledge of the genetic underpinnings of each patient's seizure susceptibility will lead to more individualized strategies of anti-epileptic drug selection.