Miyoshi Hirotsugu, Mukaida Keiko, Otsuki Sachiko, Kido Kenshiro, Sumii Ayako, Ikeda Tsuyoshi, Xia Guoqiang, Noda Yuko, Ishii Tomomi, Kamiya Satoshi, Narasaki Soshi, Niinai Hiroshi, Tsutsumi Yasuo M
Department of Anesthesiology and Critical Care, Hiroshima University, Hiroshima 34-8551, Japan.
Genes (Basel). 2025 Aug 11;16(8):944. doi: 10.3390/genes16080944.
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle triggered by certain anesthetic agents. While Ryanodine Receptor 1 () and Calcium Voltage-Gated Channel Subunit Alpha1 S () are well-established susceptibility genes, the complete genetic basis of MH remains unclear, particularly in Asian populations.
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.
Candidate pathogenic variants were identified in 118 families (48.2%), including 73 (29.8%) in , 16 (6.5%) in , and 62 (25.3%) in other genes. Among CICR-positive families, and variants were detected in 42.0% and 5.3% of cases, respectively. In individuals with high CGS scores (Ranks 5-6), and variants were observed in 56.0% and 12.0%, respectively. Variants in other genes such as , , , , and were also detected.
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.
恶性高热（MH）是一种由某些麻醉剂引发的骨骼肌药物遗传紊乱疾病。虽然兰尼碱受体1（RYR1）和钙电压门控通道亚基α1S（CACNA1S）是公认的易感基因，但MH的完整遗传基础仍不清楚，尤其是在亚洲人群中。
我们对来自247个疑似或确诊为MH的日裔家庭的338名个体进行了针对24个钙相关基因的基因panel检测。对变异进行逐个基因分析，并使用计算机预测工具评估其致病性。此外，根据钙诱导钙释放（CICR）试验结果和临床分级量表（CGS）评分将患者分为亚组。
在118个家庭（48.2%）中鉴定出候选致病变异，包括RYR1中的73个（29.8%）、CACNA1S中的16个（6.5%）以及其他基因中的62个（25.3%）。在CICR阳性家庭中，分别在42.0%和5.3%的病例中检测到RYR1和CACNA1S变异。在CGS评分高（5 - 6级）的个体中，分别在56.0%和12.0%的个体中观察到RYR1和CACNA1S变异。还检测到其他基因如ANK2、CASQ1、FKBP1A、NCAM2、STAC3和TRDN中的变异。
我们的研究结果证实了RYR1和CACNA1S在日本人群MH易感性中的主要作用，并突出了可能导致该病的其他候选基因。有必要进行更广泛的基因筛查和功能验证研究，以进一步阐明MH的多基因性质。
