Abstracts

Rationale: Genetic etiologies are increasingly recognized in the epilepsies and form the basis of modern attempts at precision medicine. However, the variability of genetic data often complicates the interpretation of genetic results. Standardized yet disease-specific criteria are needed to interpret the clinical significance of individual genes and the specific variants within genes for a given phenotype. Over the last several years, members of the Genetics Commission of the International League Against Epilepsy have worked with the ClinGen consortium to establish the Clinical Domain Working Group for Early Onset Epileptic Encephalopathies with the intention to create a framework that enables the assessment of gene validity for epilepsy genes, taking into account both formal criteria for gene validity and domain-specific expertise in the epilepsy field. We will describe the process of building a framework within our joint collaborative.  Methods: We established the ClinGen Clinical Domain Working Group for Early Onset Epileptic Encephalopathies as the interface between the epilepsy community, the ClinGen consortium and the International League Against Epilepsy Genetics Commission. We recruited a network of curators with clinical, acadamic and laboratory expertise to perform gene-level review of clinical validity, pathogenicity, and utility.  Results: We defined a joint framework to evaluate three main domains pertaining to genetic information in the context of epilepsy including gene validity (“Is this gene associated with epilepsy?”), variant pathogenicity (“Is this variant pathogenic?”), and clinical utility (“Is this information actionable?”). We identified a short list of 25 genes related to epilepsy to refine validity, pathogenicity, and utility criteria and to pilot the collaboration of review of epilepsy-related data within the formal context of the ClinGen framework.  Conclusions: We describe the process of building a formal framework to assess validity, pathogenicity, and utility criteria for genetic causes involving all major initiatives and stakeholders, fulfilling stringent and formal criteria for gene curation used in the genomics field. We identify possibilities and limitations of our framework and suggest solutions for sustainability of our gene curator network through systematic training and involvement of young researchers in the field.  Funding: NIH U01HG007437