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 < 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.

PMH is President of the European Malignant Hyperthermia Group and a member of the Editorial Board of BJA. JGB is Treasurer of the European Malignant Hyperthermia Group, a paid advisor to Norgine Pharmaceuticals and a member of the Editorial board of the BJA Education.

Genetic data included in this study have been collected over the past 35 years. The following grants have contributed to the funding of this work: UK Department of Health Pharmacogenetics Research Grant Programme. (PMH, MAS, RLR). 2004-2008 Big Lottery Fund (RLR, PMH). 2005-2008 National Institutes of Health; US National Institute of Arthritis and Musculoskeletal and Skin Diseases (2P01 AR-05235 to PMH). 2012-2017 The opinions expressed in this article are the authors own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services or the United States government. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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