"The goal of this proposal is to identify the major genes and gene variants that cause human epilepsies and their comorbid traits of cognitive and behavioral impairments. The common epilepsies are complex disorders caused by a combination of susceptibility genes. To date we have identified major genes for three main classes of epilepsy that account for 30% of the population total. In this proposal we aim to (1) Search for sequence and structural variations in identified genes ELP4, BRD2 and ME2 that predispose to disease; (2) Repeat genomewide screens and fine-mapping studies for additional susceptibility loci that act in combination with identified genes; (3) Develop animal models to delineate functional effects of gene variants. The significance of this proposal is manifold. First, trait susceptibility genes discovered through study of epilepsies may contribute to common neurodevelopmental impairments in the general population, eg for reading disability. Second, genes for common epilepsies may be shared with less common but more catastrophic neuroregressive conditions. Third, our discoveries will also significantly contribute to our understanding of the mechanisms of normal and abnormal postnatal brain development. Last, we anticipate that genetic discoveries will lead to better diagnostic screening tests, prediction of risk in presymptomatic individuals, and gene-based therapeutic strategies that not only avoid the adverse effect profiles of the current generation of antiepileptic agents but also may result in cure and prevention."