Letter to the Editor: A Scalable Alternative to In Vitro Contracture Testing for Incidentally Discovered Genetic Variants for Malignant Hyperthermia

Abstract

Keywords

Bayesian prediction European Malignant Hyperthermia Group calcium voltage-gated channel subunit alpha 1S in vitro contracture testing malignant hyperthermia ryanodine receptor 1 variant of uncertain significance

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References

Ellinas

Albrecht

. Malignant hyperthermia update. Anesthesiol Clin. 2020;38(1):165-181. doi:10.1016/j.anclin.2019.10.010.

Richards

Aziz

Bale

, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi:10.1038/gim.2015.30.

Riazi

Watt

Plester

Biesecker

. A proposed North American approach for genetic testing of individuals at risk for malignant hyperthermia. Anesthesiology. 2026;144(4):776-783. doi:10.1097/ALN.0000000000005849.

Johnston

Dirksen

Girard

, et al. Updated variant curation expert panel criteria and pathogenicity classifications for 251 variants for RYR1-related malignant hyperthermia susceptibility. Hum Mol Genet. 2022;31(23):4087-4093. doi:10.1093/hmg/ddac145.

Ruffert

Gillies

Hopkins

, et al. European malignant hyperthermia group 2025 guidelines for the investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2026;136(2):653-661. doi:10.1016/j.bja.2025.11.006.

Roberts

Bastarache

, et al. Updating probability of pathogenicity for RYR1 and CACNA1S exon variants in individuals without malignant hyperthermia after exposure to triggering anesthetics. Pharmacogenet Genomics. 2025;35(2):65-72. doi:10.1097/FPC.0000000000000551.

Johnston

Dirksen

Girard

, et al. Variant curation expert panel recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility. Genet Med. 2021;23(7):1288-1295. doi:10.1038/s41436-021-01125-w.

Hoppe

Jurkat-Rott

Kranepuhl

, et al. Relevance of pathogenicity prediction tools in human RYR1 variants of unknown significance. Sci Rep. 2021;11(1):3445. doi:10.1038/s41598-021-82024-7.

Chen

Francioli

Goodrich

, et al. A genomic mutational constraint map using variation in 76,156 human genomes. Nature. 2024;625(7993):92-100. doi:10.1038/s41586-023-06045-0.

10.

Bastarache

Tinker

Schuler

, et al. Characterizing trends in clinical genetic testing: a single-center analysis of EHR data from 1.8 million patients over two decades. Am J Hum Genet. 2025;112(5):1029-1038. doi:10.1016/j.ajhg.2025.03.009.

11.

Litman

Rosenberg

. Malignant hyperthermia: update on susceptibility testing. JAMA. 2005;293(23):2918-2924. doi:10.1001/jama.293.23.2918.

12.

Riazi

Biesecker

Rosenberg

, et al. Nonsyndromic malignant hyperthermia susceptibility. In: Adam

Bick

Mirzaa

, et al., eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993.

13.

Ibarra Moreno

Kraeva

, et al. An assessment of penetrance and clinical expression of malignant hyperthermia in individuals carrying diagnostic ryanodine receptor 1 gene mutations. Anesthesiology. 2019;131(5):983-991. doi:10.1097/ALN.0000000000002813.