High-throughput functional evaluation of ion channel variants in epilepsy

Channelopathies, particularly those involving voltage-gated sodium (NaV) and potassium (KV) channel genes, are associated with a variety of epilepsy syndromes having diverse clinical severity. Further, NaV and KV channels are important targets for many approved and investigational anticonvulsant drugs. Among the many genes associated with epilepsy, those encoding NaV and KV channels have the highest cumulative variant burden (>2,000 variants in the Human Gene Mutation Database), accounting for approximately one third of all reported genetic variants associated with epilepsy and related neurodevelopmental disorders. But differentiating pathogenic from benign variants and establishing genotype-phenotype relationships has become increasingly challenging because of explosive growth in the number of variants discovered in research and clinical medicine. Channelopathy-associated epilepsies represent unique opportunities to meet the challenge of variant annotation because well-established in vitro functional assay paradigms exist for these proteins, coupled with extensive knowledge regarding their contributions to neuronal function and drug response. We propose creating a multi-institutional and interdisciplinary CHANNELOPATHY-ASSOCIATED EPILEPSY RESEARCH CENTER that will combine high-throughput technologies with high-content human neuron and animal model systems. The Center will be comprised of an integrated set of 3 research projects and 2 scientific cores involving a synergistic mixture of academic and industry scientists. Project 1 will conduct a large-scale functional and pharmacological evaluation of variants in genes encoding voltage-gated ion channels frequently associated with monogenic and curate findings in tandem with revised variant classifications. Project 2 will investigate human neuron models of channelopathy-associated epilepsy using conventional electrophysiological methods and using an especially innovative and novel optogenetic approach (Optopatch) to stimulate and record data from hundreds of neurons simultaneously with single-cell precision. Project 3 will develop and investigate new mouse models of channelopathy-associated epilepsy and compare variant ion channel dysfunction across model systems. A key objective of our Center is to determine to what extent non-neuronal cell models can predict effects of ion channel variants in neurons and brain. Our overarching goal is to promote transformative advances in our understanding of the functional consequences of genetic variants in channelopathy-associated epilepsy and to enable a paradigm shift to a gene/variant-based taxonomy of epilepsy that harmonizes with traditional syndromic classification schemes and informs the implementation of precision medicine for this common neurological disorder.