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Hundreds of novel candidate human epilepsy-associated genes have been identified thanks to advancements in next-generation sequencing and large genome-wide association studies, but establishing genetic etiology requires functional validation. We generated a list of >2,200 candidate epilepsy-associated genes, of which 48 were developed into stable loss-of-function (LOF) zebrafish models. Of those 48, evidence of seizure-like behavior was present in 5 (, , , , and ). Further characterization provided evidence for epileptiform activity via electrophysiology in and mutants. Additionally, and mutants showed a decrease in the number of inhibitory interneurons in the optic tectum of larval animals. Further, RNA sequencing (RNA-seq) revealed convergent transcriptional abnormalities between mutant lines, consistent with their developmental defects and hyperexcitable phenotypes. These zebrafish models provide strongest experimental evidence supporting the role of , , and in human epilepsy and further demonstrate the utility of this model system for evaluating candidate human epilepsy genes.