Statement of Purpose: Epilepsy is a chronic condition of recurrent seizures which affects approximately one percent of the general population. Though several causative genes have already been identified, these account for only a small percentage of all the genetically caused cases of epilepsy. Further, even when genes are identified, we lack tractable animal models to rapidly translate these findings into mechanistic insights and ultimately new anti-epileptic therapies. For this reason, the zebrafish is increasingly being used as a model of epilepsy due to its high genetic and physiologic homology to humans and its seizure-like behavior in response to various pharmacological and genetic manipulations. Using High throughput sequencing, a significant number of gene variants are being identified, yet their role in the disease state remain unknown. My project utilizes the zebrafish and focuses on characterizing the functional role of 15 genes in the NIH Undiagnosed Diseases Program for which mutations have been associated with epilepsy, and for which zebrafish orthologues have been identified. Methods: I isolated the zebrafish orthologues and characterized gene expression patterns by RTPCR and whole mount in situ hybridization techniques. We previously demonstrated that knockdown of Prickle (PK), a gene associated with human epilepsy, sensitizes zebrafish to seizure-inducing drugs through the use of larval motility assays. To facilitate high-throughput in vivo screens, I adapted this approach and developed a code to rapidly and efficiently analyze the generated data sets. This allowed for the characterization of the 15 candidate genes in the context of seizure sensitization. Results: Of the fifteen candidates, I found five: syne1b, sms, ccdc89, wscd1, and nid2a, to result in seizure sensitization when knocked down in the zebrafish. I show that each of these genes is expressed in specific regions in the brain during critical times of neuronal development. Further, I find genes expressed in the retina result in axon defects when knocked down.