P.09 Comprehensive database for RYR1-related disorders: concept and progress update

Approximately 300 pathogenic RYR1 variants have been reported to date accounting for ∼30% of congenital myopathies. RYR1 encodes the type one ryanodine receptor (RyR1), a 2.2 megadalton ion channel expressed in skeletal muscle that tightly regulates intracellular calcium flux. Pathogenic RYR1 variants result in a wide spectrum of monoallelic and biallelic congenital, late-onset, and triggered neuromuscular disease phenotypes for which there is no approved treatment. Moreover, the >2000 RYR1 variants of uncertain significance (VUS) present a diagnostic challenge with a majority being uncharacterized in in vitro model systems and the limited utility of bioinformatic pathogenicity prediction tools for RYR1. In 2017, the RYR-1 Foundation provided seed funding to develop an international database of nonclinical and clinical data published on RYR1-related disorders to advance therapeutic development, support clinical interpretation, and inform the patient community. To date, two datasets have been developed (1) clinical genotype-phenotype dataset on 2500 patient cases, and (2) nonclinical dataset on cellular and animal model systems that includes >250 unique RYR1 variants. Using commercially available variant curation software, human phenotype ontologies linked to RYR1 variants are extracted from published works on an ongoing basis and organized by MedDRA system organ class. A Boolean search strategy is used to extract relevant non-clinical published works from PubMed and EMBASE. The database taxonomy also incorporates genetic, bioinformatic, structural, and model system data on each variant, as available. The long-term goal is to make these datasets publicly available via an online platform to encourage international research collaboration on RYR1-related disorders.