Genetic Testing for Malignant Hyperthermia Susceptibility—Threading the Needle in the Haystack

Malignant hyperthermia (MH) is a rare pharmacogenetic disorder triggered by volatile anesthetics and succinylcholine, most often linked to pathogenic variants in RYR1, CACNA1S, and STAC3. The advent of next-generation sequencing (NGS) has transformed MH diagnostics, offering new opportunities for perioperative risk assessment as caffeine-halothane contracture testing declines. However, challenges remain, including incomplete penetrance, variable pathogenicity of variants, limited access to functional confirmatory testing, and cost. Genetic testing also raises important questions. What is the clinical utility of finding a variant of unknown significance? What are the broader implications of MH susceptibility beyond the operating room? Emerging evidence connects MH susceptibility loci to exertional heat illness (EHI), exertional rhabdomyolysis (ERM), and heat-related mortality, highlighting the need for a broader framework for genetic risk assessment. This review synthesizes historical advances, current consensus, and future directions concerning MH to guide anesthesiologists and perioperative clinicians in leveraging molecular diagnostics for personalized care and improved patient safety.