[POS-2] Defining Natural History and Genotype-Phenotype Relationships in KCNQ2 Encephalopathy through Broad Interdisciplinary Collaboration
KCNQ2/3 variants lead to a spectrum of early onset epilepsies, including a self-limiting form transmitted in an autosomal dominant pattern (BFNE), and KCNQ2/3 epileptic encephalopathy (EE), which includes a range of phenotypes with more persistent seizures and developmental impairment. Factors affecting outcome are incompletely understood, as is the natural history at all points along the severity spectrum. Objectives of our research include improving understanding of genotype-phenotype relationships, enabling clinical research needed for developing better outcome measures in therapeutic trials. We established an integrated informatics system incorporating a patient registry, a variant curation platform and a public website, www.RIKEE.org. Patients diagnosed with KCNQ2/3 variants enter the database via four pathways: (A) publication; (B) family self-registration; (C) physician referral; (D) clinical genetics lab disclosure. Data collected include clinical and family history, test results, and therapeutic responses, as available. Each entry is reviewed by a multi-institutional, multidisciplinary curation panel, responsible for a “variant summary” providing classification of pathogenicity and severity. Variants are prioritized for in vitro studies and development of animal models based on recurrence frequency and potential novelty of pathogenic mechanism or phenotype. Recent progress supports the conclusion that in most patients with pathogenic KCNQ2/3 variants and impaired development (i.e., outside the range of BFNE), dominant negative suppression of channel function is the underlying molecular mechanism. KCNQ2/3 gain-of-function variants, presenting either as severe neonatal encephalopathy without seizures or as West Syndrome in mid-infancy, are found in about 5% of patients. Gain-of-function and dominant-negative variant groups likely require very different therapeutic approaches.