Ingo Helbig, M.D.
Ed Cooper, M.D., Ph.D.
Our Center is performing a systematic functional analysis of ion channel variants related to human epilepsy using high-throughput studies (Project 1) and detailed analysis of selected variants in cellular systems (Project 2) and animal models (Project 3). Genetic changes in ion channel genes represent the most common genetic causes for human epilepsy and provide a potential avenue into future therapies. However, the genetic landscape of channelopathy-associated epilepsy is extremely heterogeneous at the variant level. Given the vast amount of existing genetic data on human genetic variants in ion channel genes, a robust strategy to select candidate variants for functional studies is required.
The major goals of Core A are to create a comprehensive database of variants in the epilepsy-associated voltage-gated ion channel genes (Aim 1), to prioritize variants for functional studies by Projects 1, 2 and 3 (Aim 2), and to curate genetic, functional, and clinical data to improve variant classification and diagnostic criteria for channelopathy-associated epilepsy genes (Aim 3). The proposed activities of Core A are significant because they will focus the limited resources and finite investigator bandwidth for functional studies on the most important and informative variants, and will amplify the clinical impact of in vitro and in vivo functional studies through a rigorous process of data analysis, curation, and dissemination in formats designed for consumption by geneticists, clinicians, and drug developers who are not ion channel specialists. Core A provides an effective interface with existing NIH resources such as ClinVar and ClinGen to curate the data generated by the Center in a clinical diagnostic context.
Core A performs three services. First, the Core catalogues, classifies and prioritizes ion channel gene variants for functional studies. We are cataloging genetic and phenotypic information from diverse sources including publications, locus-specific databases, previously undisclosed data from diagnostic laboratories (~30,000 patients) and research studies (~20,000 subjects). We store this information in a secure database accessible to Center investigators using a web-based portal. These efforts are establishing a unique ion channel variant dataset to support Center projects, which will be more comprehensive than any publicly or privately held resource. Second, Core A is prioritizing up to 200 variants per year for functional studies, with an emphasis on selecting variants representative of diverse phenotypes including a significant fraction of variants of uncertain significance for high-throughput models in Project 1 and high confidence variants for cellular and animal models in Projects 2 and 3. Third, Core A will curate variants and submit to ClinVar along with revised classifications and supporting functional data. Core A is collaborating with ClinVar to implement standardized data fields for functional data to create added value to this publically accessible resource.
Lastly, Core A is using the functional data and revised variant classifications generated by the Center to suggest gene-specific curation rules. Importantly, the Core A co-directors are both members of the ClinGen Pediatric Neurology Working Group, and Dr. Helbig is Co-leader of the ClinGen Epilepsy Group. This will facilitate the development of diagnostic criteria for the genes we study, with the ultimate goal of developing a gene/variant-based taxonomy of early onset epilepsy that harmonizes with ILAE epilepsy syndrome classification schemes. This Core activity will help bring together genetic and clinical information in a new diagnostic construct that will promote selection of subjects for future clinical trials based on the presence of specific genes/variants rather than specific seizure phenotypes. These services allow the Center to use laboratory-derived functional data to iteratively refine variant classifications and clinical diagnostic criteria.
Highlights of Core A:
• Existing computational platform for variant classification and curation
• Access to expansive resources for cataloging variants
• Partnership with GeneDx combined with ClinVar collaboration and ClinGen leadership
Parthasarathy S, et al. 2022. A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism. Am J Hum Genet (Dec 2022)
Seiffert S, et al. 2022. Modulating effects of FGF12 variants on Na1.2 and Na1.6 being associated with developmental and epileptic encephalopathy and Autism spectrum disorder: A case series. EBioMedicine (Sep 2022)