ClinGen Expert Curation Panel for the Epilepsies

Children'S Hosp Of Philadelphia, Philadelphia PA

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY The epilepsies affect up to 1% of the global population and more than 150 genetic etiologies have been discovered over the last two decades. Genetic testing is emerging as a diagnostic standard and the diagnostic yield frequently approaches 30-40% for individuals with epilepsy who receive testing. Knowledge about the underlying genetic etiology is increasingly used for personalized medicine and a wide variety of gene-specific treatments with novel pharmacological compounds, gene-regulating strategies such as use of anti-sense oligonucleotides, and viral gene therapy are under development. However, information with regards to gene validity and variant pathogenicity is often not standardized. This highlights an ongoing, critical need to assess the validity of gene-disease relationships in the epilepsies, given that variant information is increasingly used for therapeutic decision-making. Our ClinGen Epilepsy Gene Curation Expert Panel (GCEP) already curated nearly 120 genetic etiologies for the epilepsies and our Epilepsy Sodium Channel Variant Curation Expert Panel (VCEP) has already modified ACMG/AMP variant criteria for ion channel-related epilepsies as the most important gene group in the epilepsies. The current project represents an urgently needed continuation of our gene and variant curation efforts, which we aim to accomplish through two aims. First, we will curate 100 gene-disease relationships in the epilepsies in newly defined etiologies (Aim #1) given the ongoing discovery of novel genetic etiologies in the epilepsies. We will use our previously developed epilepsy-specific Standard Operating Procedures (SOPs) with regards to phenotype-based pre-curation to capture relevant clinical subgroups, novel concepts for the inclusion of relevant model system data, and reassessment of prior curations based on updated literature. We expect that these SOPs will allow for evidence-based classification in 90% of all genetic etiologies according to different levels of certainty. Secondly, we will curate variants in synapse genes and continue curation for channelopathies (Aim #2). The overall frequency, disease burden, and heterogeneity of the disorders of the synapse has only become apparent in the last five years. We therefore will establish a new VCEP for synapse disorders (STXBP1, SYNGAP1, DNM1, and STX1B) and modify ACMG/AMP criteria. Combining variant curation in synapse disorders with our continued effort for variants curation in the ion channels, we plan to curate 1,500 variants, aiming for reduced VUS rates by >20%. By the end of the proposed research period, we will have addressed the lack of reliable, objectively reviewed information on the causative nature of newly identified epilepsy genes and will have re-categorized a significant proportion of disease variants in synapse disorders, jointly with our continued effort within the sodium channel VCEP. Combined with our prior work, this will provide a much-needed foundation for the emerging era of precision medicine in genetic epilepsies.