Abstracts

Rationale: Generalized epilepsy with genetic etiology (GGE) is the most common type of inherited epilepsy characterized by absence, myoclonic and generalized tonic-clonic seizures typically occurring with generalized spike-and-wave discharges on electroencephalography. Despite its high heritability of 80%, the genetic background is still largely unknown. Methods: We performed whole exome sequencing in a cohort of 196 familial index cases with GGE and 605 ethnically matched controls. We designed a targeted enrichment panel comprising all 19 GABAA receptor genes for replication. Functional investigations were performed for variants using automated two-microelectrode voltage clamping in Xenopus oocytes. Results: A significant burden of variants in the ensemble of GABAA receptor encoding genes was detected. Candidate gene panel sequencing in an independent cohort of 635 familial and sporadic GGE index cases confirmed a burden of variants in the same genes. Five of the seven variants in GABRB2 and GABRA5 showed significant loss-of-function effects with reduced current amplitudes in mutant compared to respective wildtype receptors. Conclusions: Our results suggest that functionally relevant variants in a GABAA receptor subunit encoding gene-set constitute a significant risk factor for common forms of GGE. Funding: No specific funding was received for this abstract. The primary funding studies were the ESF project EuroEPINOMICS CoGIE, the FP6 project Epicure and the Rotterdam Study.