EMQN Best Practice Guidelines for Genetic Testing and Reporting in RYR1-related disorders

Here, we present EMQN Best Practice Guidelines for Genetic Testing and Reporting in RYR1-related disorders. They aim is to aid clinical genetic laboratories in testing, and unequivocal and comprehensive reporting of RYR1 variants for the benefit of patients and their relatives. These guidelines are supported by experts in the field of anaesthesia, (paediatric) neurology, clinical genetics and clinical laboratory genetics. The ryanodine receptor type 1 is a large calcium channel that regulates calcium release from the sarcoplasmic reticulum resulting in muscle contraction. This receptor is encoded by the RYR1 gene and expressed predominantly in skeletal muscle. Pathogenic RYR1 variants are associated with several allelic disorders: malignant hyperthermia, a hypermetabolic reaction to certain anaesthetics in otherwise healthy individuals, exertional rhabdomyolysis and both autosomal dominant and recessive congenital myopathies. In general, RYR1 gain-of-function variants are associated with malignant hyperthermia susceptibility, whereas dominant-negative and loss-of-function variants are associated with dominant and recessive myopathies, respectively. However, a small subset of RYR1 variants is associated with a combination of dominant malignant hyperthermia susceptibility with either a dominant or a recessive myopathy or exertional rhabdomyolysis. The apparent discrepancy between molecular mechanisms and different phenotypes is currently poorly understood. As a consequence, the context-dependent interpretation of RYR1 variants is challenging in diagnostic genetic testing. In particular, it is not trivial to assign a possible associated risk for an allelic disorder for an individual or their relatives, which is especially relevant in family planning.