Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, researchers performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of European ancestry.

The study focused on three phenotypic groups; the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE).

Researchers observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, they found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE.

Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2, and GABRG2for GGE and LGI1, TRIM3, and GABRG2 for NAFE.

Researchers state their study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.

Article featuring the work of CURE Grantee Dr. Annapurna Poduri, Supported by the Isaiah Stone Foundation Award

Objective: To compare the cost-effectiveness of genetic testing strategies in patients with epilepsy of unknown etiology.

Methods: This meta-analysis and cost-effectiveness study compared strategies involving 3 genetic tests: chromosomal microarray (CMA), epilepsy panel (EP) with deletion/duplication testing, and whole-exome sequencing (WES) in a cost-effectiveness model, using “no genetic testing” as a point of comparison.

Results: Twenty studies provided information on the diagnostic yield of CMA (8 studies), EP (9 studies), and WES (6 studies). The diagnostic yield was highest for WES: 0.45 (95% confidence interval [CI]: 0.33–0.57) (0.32 [95% CI: 0.22–0.44] adjusting for potential publication bias), followed by EP: 0.23 (95% CI: 0.18–0.29), and CMA: 0.08 (95% CI: 0.06–0.12). The most cost-effective test was WES with an incremental cost-effectiveness ratio (ICER) of $15,000/diagnosis. However, after adjusting for potential publication bias, the most cost-effective test was EP (ICER: $15,848/diagnosis) followed by WES (ICER: $34,500/diagnosis). Among combination strategies, the most cost-effective strategy was WES, then if nondiagnostic, EP, then if nondiagnostic, CMA (ICER: $15,336/diagnosis), although adjusting for potential publication bias, the most cost-effective strategy was EP ± CMA ± WES (ICER: $18,385/diagnosis). While the cost-effectiveness of individual tests and testing strategies overlapped, CMA was consistently less cost-effective than WES and EP.

Conclusion: Whole-exome sequencing and epilepsy panel are the most cost-effective genetic tests for epilepsy. Our analyses support, for a broad population of patients with unexplained epilepsy, starting with these tests. Although less expensive, chromosomal microarray has lower yield, and its use as the first-tier test is thus not supported from a cost-effectiveness perspective.

A genome-wide analysis of nearly 45,000 people has identified 16 regions of DNA associated with epilepsy, 11 of which are newly identified.

The International League Against Epilepsy (ILAE) Consortium on Complex Epilepsies did the analysis, which involved DNA from 15,212 people with epilepsy and 29,677 people without the condition. It is the largest study of its kind. The analysis was published in the Dec 10, 2018 issue of Nature Communications.

Most of these identified genes are associated with generalized epilepsy. The genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin B6 metabolism enzyme.

Compared with focal epilepsies, generalized epilepsies appear to have a stronger heritable component. However, fewer single genes have been implicated in generalized epilepsies.

Precision medicine is the treatment of patients with therapy targeted to their specific pathophysiology. This lofty ideal currently has limited application in clinical practice. However, new technological advances in epilepsy models and genomics suggest that the precision medicine revolution is closer than ever before. We are gaining an improved understanding of the true complexity underlying the pathophysiology of genetic epilepsies and the sources of phenotypic variation that continue to frustrate efforts at genotype–phenotype correlation.

Conventional experimental models of epilepsy, such as mouse models and heterologous expression systems, have provided many of the advances in our understanding of genetic epilepsies, but fail to account for some of these complexities. Novel high-throughput models of epilepsy such as zebrafish and induced pluripotent stems cells can be combined with CRISPR–Cas9 gene editing techniques to explore the pathogenesis of a specific gene change and rapidly screen drug libraries for potential therapeutics.

The knowledge gained from these models must be combined with thorough natural history studies to determine appropriate patient populations for pragmatic clinical trials. Advances in the ‘omics’, genetic epilepsy models and deep-phenotyping techniques have revolutionary translational research potential that can bring precision medicine to the forefront of clinical practice in the coming decade.

Epileptic seizures caused by disturbances in the activity of a specific type of nerve cell called an inhibitory neuron were prevented by the reactivation of the UBE3A gene in young mice with Angelman syndrome features, a study shows.

The study, “Ube3a reinstatement mitigates epileptogenesis in Angelman syndrome model mice,” was published in The Journal of Clinical Investigation.

The disorder is frequently associated with epileptic seizures — estimated to affect between 80% and 95% of patients — that usually fail to respond to anti-epileptic medications. However, the reason why genetic mutations in UBE3A seem to increase patients’ risk of developing epileptic seizures is not yet fully understood.

Although there is no cure for Angelman syndrome, recent studies in mouse models based on UBE3A gene replacement or reactivation in neurons hold great therapeutic potential, including for the treatment of epilepsy.