Genetic Panel Testing for Malignant Hyperthermia in Japan: Discovery of Novel Variants and Clinical Implications

Abstract

Background: Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle triggered by certain anesthetic agents. While Ryanodine Receptor 1 (RYR1) and Calcium Voltage-Gated Channel Subunit Alpha1 S (CACNA1S) are well-established susceptibility genes, the complete genetic basis of MH remains unclear, particularly in Asian populations. Methods: We conducted gene panel testing targeting 24 calcium-related genes in 338 individuals from 247 Japanese families with suspected or confirmed MH. Variants were analyzed on a gene-by-gene basis, and their pathogenicity was assessed using in silico prediction tools. Additionally, patients were classified into subgroups based on the results of the calcium-induced calcium release (CICR) assay and the Clinical Grading Scale (CGS) score. Results: Candidate pathogenic variants were identified in 118 families (48.2%), including 73 (29.8%) in RYR1, 16 (6.5%) in CACNA1S, and 62 (25.3%) in other genes. Among CICR-positive families, RYR1 and CACNA1S variants were detected in 42.0% and 5.3% of cases, respectively. In individuals with high CGS scores (Ranks 5–6), RYR1 and CACNA1S variants were observed in 56.0% and 12.0%, respectively. Variants in other genes such as STAC3, CASQ1, ATP2A1, ASPH, HRC and TRPV1 were also detected. Conclusions: Our findings confirm the predominant role of RYR1 and CACNA1S in MH susceptibility in the Japanese population and highlight additional candidate genes that may contribute to the condition. Broader genetic screening and functional validation studies are warranted to further elucidate the polygenic nature of MH.