Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We 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; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABA A receptor genes were enriched for missense variants across all three classes of epilepsy, whereas 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 DEEs 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 lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.

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Summary: Purpose:To provide an overview of the evidence comparing carbamazepine (CBZ) and valproate (VPA) monotherapy for epilepsy, investigating whether existing data support the current practice of preferring CBZ for partial-onset and VPA for generalized-onset seizures.Methods: We performed meta-analysis of randomized controlled trials by using individual patient data. Our strategy included searches of (a) Medline, 1966Medline, -2000 The Cochrane Library 2000, issue 4; and (c) the pharmaceutical industry. Outcome measures were time to discontinuation of allocated treatment, time to 12-month remission, and time to first seizure after randomization. Results are expressed as hazard ratios (HRs; 95% CI), where HR 1 indicates that an event is more likely with VPA. A test for an interaction between treatment and seizure type (partial vs. generalized onset) also was undertaken.Results: Data were available for 1,265 patients from five trials. Overall results (HR, 95% CI) were Time to treatment discontinuation, 0.97 (0.79-1.18); 12-Month remission, 0.87 (0.74-1.02); and First seizure, 1.09 (0.96-1.25), suggesting no overall difference for these outcomes. The test for an interaction between Treatment and Seizure type was significant for time to first seizure, but for no other outcome. The age distribution of adults classified as having generalized seizures indicated that significant numbers of patients may have had their seizures misclassified. Conclusions:We found some evidence to support the preference of CBZ for partial-onset seizures, but no evidence to support the preference of VPA for generalized-onset seizures. Confidence intervals are too wide to infer equivalence. Misclassification of patients may have confounded our results and has important implications for future trials. Key Words: Carbamazepine-Valproate-Meta-analysis.Carbamazepine (CBZ) and valproate (VPA) are considered first-line treatments for epilepsy in Europe and the United States, with VPA the treatment of choice for generalized-onset seizures (generalized tonic-clonic, absence, and myoclonic seizures) and epilepsy syndromes, and CBZ, the treatment of choice for partial-onset seizures (simple partial, complex partial, and secondarily generalized tonic-clonic seizures) (1) and epilepsy syndromes. Despite this apparent consensus in treatment policy, there is little in the way of evidence from randomized controlled trials to support it. What evidence does exist is anecdotal, predominantly from case reports and case series. There are reports of a dramatic response of juvenile myoclonic epilepsy to VPA (2-4) and reports of efficacy for VPA against absence seizures (5,6). There also are reports of CBZ exacerbating myoclonic seizures (7,8) and absence seizures (7-9). The only randomized controlled trial (RCT) that found a significant difference between CBZ and VPA was conducted by the Veterans Administration Group (VA) (10) and recruited 480 patients with partial-onset seizures, making it the largest trial comparing CBZ and VPA to date. Patients with pred...

Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5–3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.