Heterogeneous contribution of microdeletions in the development of common generalised and focal epilepsies.

BACKGROUND: Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement 'hotspot' loci. However, microdeletion burden not overlapping these regions or within different epilepsy subtypes has not been ascertained. OBJECTIVE: To decipher the role of microdeletions outside hotspots loci and risk assessment by epilepsy subtype. METHODS: We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases. Microdeletions were assessed in a combined and subtype-specific approaches against 6746 controls. RESULTS: When hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted p=1.06×10-6,OR 1.89, 95% CI 1.51 to 2.35). Epilepsy subtype-specific analyses showed that hotspot microdeletions in the GGE subgroup contribute most of the overall signal (adjusted p=9.79×10-12, OR 7.45, 95% CI 4.20-13.5). Outside hotspots , microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted p=9.13×10-3,OR 2.85, 95% CI 1.62-4.94). No additional signal was observed for RE and AFE. Still, gene-content analysis identified known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes across epilepsy subtypes that were not deleted in controls. CONCLUSIONS: Our results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor contribution in the aetiology of RE and AFE.

Lack of association between ABCC2 gene variants and treatment response in epilepsy.

AIM: The aim of this study was to replicate a previously reported association between drug resistance in epilepsy patients and the 24C>T variant of the ABCC2 gene that codes for the drug efflux transporter MRP2. PATIENTS & METHODS: We genotyped 381 Caucasian epileptic patients (337 drug resistant and 44 drug responsive) and 247 healthy controls for the ABCC2 gene -24C>T polymorphism (rs717620) and two other nearby SNPs in linkage disequilibrium (1249G>A and 3972C>T). Genotype, allele and three-SNP-haplotype frequencies were compared between groups. Patients were further stratified into four groups according to their degree of drug resistance (as measured by seizure frequency under medication) to perform regression analysis against genotypes and haplotpyes. RESULTS: We detected no significant differences in the distribution of any of the tested alleles, genotypes or haplotypes between the investigated groups. Neither was there an association between genotypes or haplotypes and degree of drug resistance. This study was adequately powered to detect genotype relative risks of above two. CONCLUSION: Although adequately powered to detect the previously reported effect size and although our definition of drug resistance, following the International League Against Epilepsy guidelines, was slightly stricter than in the original study, we failed to confirm an association between the 24C>T variant in the ABCC2 gene and drug resistance in epilepsy.