ClinGen Expert Curation Panel for the Epilepsies

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PROJECT SUMMARY/ABSTRACT Over the past decade, more than 100 genetic etiologies have been identified in the epilepsies, turning a group of previously poorly understood conditions into distinct genetic etiologies that can be identified in up to 30-40% of affected individuals. Information about genetic etiology is and will be increasingly used to make treatment decisions and to develop novel therapies. This is especially true in the developmental and epileptic encephalopathies, which are severe, treatment resistant, early-onset epilepsies that are frequently associated with additional neurological and non-neurological co-morbidities. Genetic testing in the epilepsies is performed at scale with > 25,000 individuals having undergone diagnostic gene-panel testing in the last few years. A comprehensive understanding of whether a given gene – as well as specific variants in that gene – is in fact disease-causing is critical, but this information is frequently not available. Using the ClinGen framework, we propose to perform systematic curation of genes that are reported associated with epilepsy and are frequently testing in clinical laboratories. For a subset of genes, we will also carefully evaluate specific variants to determine clinical relevance. We will engage physicians, molecular geneticists and genetic counselors with expertise in epilepsy genetics to develop appropriate guidelines and apply them systematically to the gene and variant curation effort. In our preliminary work on epilepsy gene curation, we identified 10 genes that are commonly included on clinical gene panels that lack evidence for a role as a disease gene, including genes such as EFHC1 or SCN9A that have extensively researched. Likewise, in a separate study, we found that a substantial number of relevant genes are not tested for routinely in a diagnostic setting. The situation is even magnified when assessing variants, most of which have never been curated by expert panels. Given that disease-causing variants in epilepsy genes are increasingly used for clinical and therapeutic decision-making, we aim to address this critical gap and assess the validity of gene-disease relationships in the epilepsies and curate the spectrum of variants in these genes.