DESCRIPTION (provided by applicant): Epilepsy is a common disease with significant heritability. For the past two decades a steady stream of gene discovery revealed some human epilepsy variants, and additional seizure-causing genes have been identified in animal models, but together these account for only a fraction of all human disease. In the past few years, rapid improvements in genome sequencing, along with a sophisticated understanding of how to use sequencing to mine variants in human populations, have begun to transform many medical research fields. Very recent individual and community-based sequencing efforts, including the NIH-funded Epi4k consortium, provide a first glimpse into what a discovery boom for epilepsy looks like. These efforts have mostly focused on a subset of disease - childhood epileptic encephalopathy (EE) - defined by intractable, seizures accompanied by cognitive decline, usually very severe. EE is not as common as idiopathic disease, but because of the severity and effect on children, it is a very motivating. Dominant EE variants are not usually heritable in the classical parent-to-child sense, but they can be detected as de novo or somatic mutations. The first wave of Epi4K results was very encouraging. Our conservative estimate suggests that more than 80 EE genes are now on the map from just these first efforts. Some genes were previously known in epilepsy, including ion channels and neurotransmitter receptors, but many are new. Standing between this unqualified success and successful therapies are several key questions, including: How do we know for sure which variants are causal and which are bystanders? Does this group of 80 (or more) genes imply that there are 80 (or more) ways to get disease, or do they instead converge onto a smaller number of pathological mechanisms? What is the relationship between seizures and cognitive decline - is co-dependence the rule or the exception? What neuron types/circuits are rate limiting for disease? Do milder alleles of EE genes also cause the genetically elusive, but more common, IGE? Mutant mice provide powerful models for human disease, and the field of mouse genetics which had also evolved linearly over the years, acquiring sophisticated tools such as conditional gene targeting and strain diversity panels, has also exploded due to both genomic technologies and much more efficient and rapid gene targeting. We think the time has come to aggressively model precise human epilepsy mutations in mice and use them to address key questions. In the next few years we will employ the latest gene targeting approaches along with the diverse toolkit of mouse genetics to make new models, study the etiology seizures and behaviors in these mice, and explore relationships between genes to identify convergent pathological mechanisms.