Abstracts

Rationale: KCNQ2 variants lead to a spectrum of early onset epilepsies that includes self-limiting forms transmitted in an autosomal dominant pattern, and KCNQ2 encephalopathy, characterized by more severe forms with persistent seizures and global developmental impairment. Factors accounting for differences in outcome are incompletely understood, as is the natural history at all points along the severity spectrum. Because KCNQ2 related epilepsy is uncommon, broad geographic collaboration is especially helpful for hastening research addressing these issues. Objectives of KCNQ2 variant curation include improving understanding of genotype-phenotype relationships, enabling clinical research needed for developing better outcome measures, and identifying subgroups that may require different therapeutic approaches.Methods: Under an approved IRB protocol, KCNQ2 variants enter the database via four pathways: (A) Variants published by others are entered by our staff; (B) Variants of “registered” patients (that self-refer and provide informed consent to us) are entered by our staff; (C) Variants of patients enrolled by their treating physicians (after informed consent to them) are reported to our database; (D) Variants disclosed by genetics testing labs or aggregation sites (e.g., ClinVar) are entered by our staff. The data collected via all pathways include clinical history, family history, test results, therapeutic trials and responses, as available. Each entry is reviewed by a multi-institutional, multidisciplinary expert panel. A gene-specific scoring matrix for pathogenicity and prognosis has been developed, based on American College of Medical Genetics and Genomics guidelines. An online scoring calculator is being developed to optimize the reliability of variant classification (as non-pathogenic, likely non-pathogenic, uncertain significance, likely pathogenic/self-limiting, likely pathogenic/epileptic encephalopathy, pathogenic/self-limiting, or pathogenic/epileptic encephalopathy). Scores are reported on a locus specific website (www.rikee.org) and to ClinVar (www.ncbi.nlm.nih.gov/clinvar/).Results: We have so far provisionally classified the disorders in 106 individuals as KCNQ2 encephalopathy, and classified 100 unrelated cases (or pedigrees) as self-limiting neonatal or infantile epilepsy. An additional 28 cases have recently entered via pathway B and C and not yet classified. Correlations have been identified between phenotype and variant characteristics, including; variant type, variant genetic location, and molecular functional change in the variant.Conclusions: We have used an interdisciplinary approach to develop a comprehensive KCNQ2 database/registry and website. Systematic classification is proving useful for understanding genotype-phenotype relationships and pathophysiology. Such understanding is needed for developing targeted treatments for individuals with KCNQ2 encephalopathy, an uncommon but very disabling condition. Our work provides a model for addressing challenges in collaborative investigation of rare disease. Support: AES EF Research Infrastructure Grant; The Jack Pribaz Foundation