Commentary

Epileptic encephalopathies are a heterogeneous group of catastrophic epilepsies characterized by treatment-resistant seizures, behavioral and neurocognitive deficits, and a poor prognosis. Until recently, the causes of epileptic encephalopathies were largely unknown; however, emerging data from recent studies indicate that genetic factors are likely to account for a substantial percentage of cases (1–7).

Two recent studies that are the focus of this commentary provide further support for the genetic basis of epileptic encephalopathies. These studies used different but complementary genetic screening methods, namely, whole-exome sequencing (WES) and targeted resequencing. WES is an unbiased approach to disease gene discovery in which the protein coding regions of almost all the genes in the genome are sequenced and then compared with reference sequences. Targeted resequencing typically involves the application of high-throughput methods to perform comprehensive sequence analysis on pre-selected known or candidate disease genes in large numbers of samples.

Veeramah et al. (2013) performed WES on ten trios, each consisting of an affected child and both unaffected parents. Inclusion of the parents provided an efficient strategy to identify potentially disease-causing de novo mutations that, by definition, would only be present in the child. The ten children all shared histories of treatment-resistant epilepsy, but their seizure types and associated comorbid features differed. Of importance, despite the small number of patients and their range of clinical presentations, de novo mutations in known epilepsy genes or plausible candidate genes were identified in seven probands. Four probands had mutations in three genes previously associated with severe epilepsy: the voltage-gated sodium channel SCN1A, cyclin-dependent kinase-like 5 (CDKL5), and EEF1A2, encoding the eukaryotic translation factor 1 alpha 2. New candidate epilepsy genes that emerged from this study included a voltage-gated potassium channel (KCNH5), a voltage-dependent 2Cl⁻/H⁺ exchanger (CLCN4), and the Rho guanine nucleotide exchange factor 15 (ARHGEF15 or Ephexin5). Not surprising, several variants of unclear functional significance were also identified.

Carvill et al. (2013) performed high-throughput targeted sequencing of 19 known and 46 candidate epilepsy genes in 500 individuals with a range of epileptic encephalopathy phenotypes. The authors identified pathogenic or likely pathogenic mutations in 10% of the patients. Sixteen genes were found to harbor potentially disease-causing mutations. Of interest, multiple patients had mutations in CHD2, which encodes a member of the chromodomain helicase DNA-binding family of proteins, and SYNGAP1, a RAS/RAP GTP-activating protein. These genes, not previously implicated in epileptic encephalopathies, each accounted for approximately 1% of cases and are therefore likely to be important causal genes. Furthermore, the six patients with CHD2 mutations shared distinctive clinical features, raising the possibility that a better understanding of the underlying genetic architecture of epileptic encephalopathies might eventually help uncover discrete clinical subtypes. In addition, several genes that were previously associated with other epilepsy disorders, for example, the SCN2A voltage-gated sodium channel, were found to also significantly contribute to epileptic encephalopathies.

Taken together, the findings from these two studies, along with several other recent reports (1–7), have already established that genetic factors (gene mutations as well as pathogenic copy number variants) are responsible for at least 20% of epileptic encephalopathies. Clearly, as more studies are conducted, the contribution of genetics to this class of epilepsies will continue to increase. The observation that a large percentage of identified causal variants are de novo mutations is significant, since in a clinical setting, an underlying genetic cause would typically only be suspected in patients with a family history of epilepsy. However, the significant contribution of de novo mutations to the epileptic encephalopathies suggests that genetic analysis should be considered in all cases of unknown etiology. The routine application of genetics-based diagnoses is likely to become more feasible as advances in sequencing technologies lead to lower costs. Nevertheless, several challenges remain. Comprehensive sequence analysis of each DNA sample also results in the identification of large numbers of nonpathogenic genetic variants. Recognition of the disease-causing mutation against this background of genetic variation is akin to finding the proverbial needle in the haystack. While improvements in bioinformatic algorithms and strategies will continue to improve the efficiency of analyzing sequence data, at the present time, comprehensive sequence analysis is primarily only feasible in research settings. Furthermore, as illustrated by these two studies, sequence analysis reveals large numbers of variants of unknown significance, as well as putative disease genes with unclear roles in epilepsy. Extensive basic research efforts will therefore be required to definitively establish disease-causing roles for many identified variants. Eventually, more comprehensive panels of epileptic encephalopathy genes will be developed, thereby facilitating cost-effective and rapid identification of causal mutations. Genetics-based diagnosis of epileptic encephalopathies holds the promise for the identification of more discrete epilepsy subtypes, and ultimately the selection of more gene-specific treatment strategies.

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