Abstract Details

Variants in KCNQ2/3/5 lead to early onset illnesses including self-limiting forms transmitted in an autosomal dominant pattern (BFNE), and developmental and epileptic encephalopathy (DEE), which includes phenotypes with seizures, developmental impairment, and autism.  Factors affecting outcome are incompletely understood.

Our goals 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. 

We established a custom informatics system including patient registry, curation platform and website. Patients with KCNQ2/3/5 variants enter the database via (A) publication by others; (B) family self-registration; (C) physician referral; (D) clinical genetics lab disclosure (e.g., ClinVar). Data collected include clinical and family history, test results, and therapeutic responses. Each entry is reviewed by a multidisciplinary curation panel. Curation includes standardized abstraction of key clinical and laboratory data that ends in a “variant summary”. Scoring criteria for pathogenicity and severity are based on ACMG guidelines (Richards, 2015), customized based on gene-specific knowledge. An automated pathogenicity/severity calculator records score results. Parts of the evidence summary and pathogenicity and severity classification are reported online (www.rikee.org). 

Unrelated individuals and pedigrees total 784 (Oct 2020); 141 variants have been classified as BFNE (192 pedigrees) and 120 as DEE (375 individuals). Of the KCNQ2 DEE patients, 13.8% (52 individuals, 10 variants) are classified as gain-of-function.  Re-assessment of some variants previously published has led to re-classification. Correlations have been made between phenotype and variant characteristics, including type (e.g., missense vs. stop-gained), protein hotspot location, and in vitro function. For KCNQ2, 67.3%  of individuals (371/551) have recurrent variants, improving assessment security. 

Systematic classification enabled by this international  database is useful clinically, making diagnosis more rapid and secure, and relationships between genotype, pathophysiology, and phenotype clearer. This may guide development of targeted treatments, and facilitate qualification of patients for entrance into trials.