Identification of novel potentially causative RYR1 variants in individuals with malignant hyperthermia susceptibility

Malignant Hyperthermia Susceptibility (MHS) is a pharmacogenetic disorder triggered by volatile anesthetics and muscle relaxants, leading to a hypermetabolic reaction in skeletal muscle that can be fatal if untreated. Diagnosis relies on an in vitro contracture test (IVCT) on muscle biopsy and/or genetic testing for pathogenic variants in the RYR1 gene, which accounts for most cases; less frequently, variants are found in CACNA1S and STAC3. However, unlike the IVCT, genetic testing is limited by the large number of RYR1 variants classified as of uncertain significance (VUS), preventing it from fully replacing the IVCT. We report data from 250 MHS individuals followed over 20 years, in whom 100 RYR1 and 3 CACNA1S variants were identified. Among the RYR1 variants, 81 were previously reported and 19 were novel, all classified as VUS according to European Malignant Hyperthermia Group (EMHG) and Variant Curation Expert Panel (VCEP) criteria. Similarly, of the 3 CACNA1S variants, 1 was previously reported and 2 were classified as VUS. The reporting of novel variants is crucial for improving the accuracy and consistency of variant classification, thereby supporting a more precise interpretation of their clinical significance.