Epidemiology of malignant hyperthermia in the UK 1988-2025: implications for prevalence, mode of inheritance, relative risk associated with <i>RYR1</i> genotypes and <i>in vitro</i> contracture test phenotype

Abstract Background There is disparity between the incidence of malignant hyperthermia (MH) reactions and the prevalence of variants in the RYR1 gene associated with susceptibility to MH (where susceptibility is determined by in vitro contracture tests). Our aims were to use clinical and genetic data from the UK to explain this disparity and to examine if these data are consistent with the clinical risk of MH being inherited as an autosomal dominant trait. Methods Clinical MH and genotyping data were extracted from the UK MH registry. The numbers of general anaesthetics delivered in the UK were estimated from national surveys and reports, with population data obtained from government statistics. The prevalence of RYR1 variants in the UK population was estimated using UK Biobank data. The incidence of MH reactions 1988-93 was used to estimate the prevalence of the clinical risk of MH in the UK. Bayesian modelling, calibrated against actual data, was used to evaluate the likely mode of inheritance of the clinical risk of MH and the relative risk of clinical MH associated with different RYR1 variants. Results The probability of index cases developing MH with each general anaesthetic can be expressed as a constant hazard of 0.46 (95% CI 0.42 – 0.50, n=375). We used peak incidence data (1988-93) to estimate the prevalence of the risk of MH as 1 in 44,000 (95% credibility interval, 1 in 40,000 to 1 in 48,000). The incidence of MH has declined over the past 22 years but the rate of decline is inconsistent with autosomal dominant inheritance ( P &lt; 10 -10 ). The risk of MH varied by up to 150-fold between carriers of 28 recurrent RYR1 variants. Conclusion These findings support a threshold inheritance model for clinical MH and have implications for diagnostics, both genotyping and in vitro contracture test phenotyping.