The RYR1 gene encodes the ryanodine receptor isoform 1, a calcium channel.1 RYR1 is the primary locus for the pharmacogenetic trait of malignant hyperthermia (MH), a condition that is predisposition to a hypermetabolic reaction triggered by any of the potent volatile anesthetics (except nitrous oxide and xenon) or the depolarizing muscle relaxant succinylcholine.1,2
The diagnosis of MH susceptibility (MHS) is made by one of two criteria: (i) positive response to an in vitro muscle bioassay, such as the in vitro contracture test (IVCT), or the caffeine- halothane contracture test (CHCT), as it is known in the United States; or (ii) the presence of a pathogenic variant in RYR1 or CACNA1S found by molecular genetic testing.3 Both the CHCT and IVCT can be difficult to perform, as it requires a muscle biopsy at a specialized MH biopsy testing center. According to the Malignant Hyperthermia Association of the United States (MHAUS), there are only four testing centers in the United States.34 Both the MHAUS and the European Malignant Hyperthermia Group (EMHG) consider the genetic testing of RYR1 and CACNA1S to be a viable diagnostic approach for MHS. The MHS is inherited in an autosomal-dominant pattern, and a heterozygous genotype of a pathogenic variant in RYR1 and CACNA1S can be considered as diagnostic for the trait. The CPIC guideline recommends that only non-triggering anesthetic agents are used in any individual thought to have MHS.3
It is worth noting that the American College of Medical Genetics and Genomics has included RYR1 and CACNA1S in its list of genes for which pathogenic variants should be returned as secondary findings.5 RPRD’s WPS testing only screens for specific variants associated with PGx function and a negative/normal test result does not rule out the presence of other possible pathogenic variants in these genes.