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Molecular Genetics of Malignant Hyperthermia Susceptibility and Related Diseases
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Molecular Genetics of Malignant Hyperthermia Susceptibility and Related Diseases

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (5 August 2025) | Viewed by 4738

Special Issue Editor

Dr. Nyamkhishig Sambuughin

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Guest Editor
Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA
Interests: molecular genetics of muscle disorders specifcally triggarable muscle disorders to inlcude malignant hyperthermia; exertional rahdbomyolysis and exercise intolerance

Special Issue Information

Dear Colleagues,

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that manifests as a hypermetabolic reaction in susceptible individuals upon exposure to halogenated inhalational anesthetic or succinylcholine.  Susceptibility to MH has been associated with pathogenic variants in RYR1, CACNA1S, and STAC3 genes. Of those, dominant variants in RYR1 account for about 70% of MH cases. RYR1 encodes the skeletal muscle calcium-release channel, which plays a central role in muscle Ca2+ regulation, linking surface membrane potential to muscle contraction. Although not common, non-anesthesia-related environmental factors such as exercise, heat, or both may trigger MH. This led to finding RYR1 variants in environmentally triggerable conditions such as exertional rhabdomyolysis and exertional heat illness. Dominant and recessive variants in RYR1 have also been associated with various non-dystrophic myopathies that include central core disease, multi-minicore disease, centronuclear myopathy, and congenital fiber type disproportion. Collectively, these disorders are considered to be RYR1-related disorders. This Special Issue is focused on the genetic contribution to MH susceptibility, and RYR1-related disorders.

Dr. Nyamkhishig Sambuughin
Guest Editor

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Keywords

  • malignant hyperthermia
  • malignant hyperthermia susceptibility
  • RYR1
  • CACNA1S
  • STAC3
  • RYR1 related congenital myopathies
  • exertional rhabdomyolysis
  • exertional heat illness

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Published Papers (5 papers)

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Research

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9 pages, 765 KB  
Article
Rare Duplication in the RYR1 Gene Causing Malignant Hyperthermia and Clinical Variability
by Brandow W. Souza, Guilherme L. Yamamoto, Isabela A. Zogbi, Pamela V. Andrade, Joilson M. Santos, Leticia N. Feitosa, Acary S. B. Oliveira, Debora R. Bertola, Soledad Levano, Thierry Girard, Helga C. A. Silva and Mariz Vainzof
Genes 2025, 16(11), 1252; https://doi.org/10.3390/genes16111252 - 24 Oct 2025
Viewed by 688
Abstract
Background/Objectives: Variants in the RYR1 gene are associated mainly with Malignant Hyperthermia. Missense variants are largely the most common, while insertions and duplications account for less than 10%. We aimed to investigate the effect of a rare duplication in the RYR1 gene [...] Read more.
Background/Objectives: Variants in the RYR1 gene are associated mainly with Malignant Hyperthermia. Missense variants are largely the most common, while insertions and duplications account for less than 10%. We aimed to investigate the effect of a rare duplication in the RYR1 gene with the variability of the Malignant Hyperthermia susceptibility phenotype. Methods: We used exome variant screening, in vitro contracture test, anatomopathological examination of the muscle biopsy, RT-qPCR analysis for RYR1 relative expression. Results: We identified a family with two affected siblings carrying an insertion of 18 pair bases in exon 91 of the RYR1 gene, resulting in an in-frame duplication of 6 amino acids (c.12835_12852 dupGAGGGCGCGGCGGGGCTC: 162 p.G4279_T4284insAAGLEG). This variant was found at a frequency of 0.0007% in gnomAD and was absent in 1200 Brazilian controls. First classified as a Variant of Uncertain Significance (VUS), with the molecular and physiological data from our family, we were able to reclassify it, reaching 5 points, which is still a VUS but borderline likely pathogenic. Muscle relative mRNA expression of RYR1 in the two patients identified a ~50% reduction, suggesting a possible hypomorphic allele. Conclusions: The pathomechanisms of RYR1 gene variants in Malignant Hyperthermia are mainly associated with gain-of-function mechanisms, but small insertions can often lead to loss of function or improper folding protein. This study adds evidence to the possibility that duplication in this region can cause structural defects and a more severe phenotype in the patients. Full article
(This article belongs to the Special Issue Molecular Genetics of Malignant Hyperthermia Susceptibility and Related Diseases)
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15 pages, 1225 KB  
Article
Genetic Characteristics of Brazilian Patients with MH History
by Helga C. A. Silva, Daniela C. Mendonça, Brandow W. Souza, Joilson M. Santos, Lucas S. Souza, Antonio F. R. Junior, Felipe T. G. R. Vasconcelos, Pamela V. Andrade, Acary S. B. Oliveira and Mariz Vainzof
Genes 2025, 16(10), 1127; https://doi.org/10.3390/genes16101127 - 25 Sep 2025
Cited by 1 | Viewed by 571
Abstract
Background/Objectives: Malignant hyperthermia (MH) is a pharmacogenetic hypermetabolic syndrome triggered by halogenated agents/succinylcholine. Most families present variants in the RYR1 and, rarely, in other genes (CACNA1S/STAC3/ASPH). However, each country or region presents differences in the type and [...] Read more.
Background/Objectives: Malignant hyperthermia (MH) is a pharmacogenetic hypermetabolic syndrome triggered by halogenated agents/succinylcholine. Most families present variants in the RYR1 and, rarely, in other genes (CACNA1S/STAC3/ASPH). However, each country or region presents differences in the type and frequency of MH variants. Objective: To present the genetic characteristics of Brazilian individuals with MH history. Methods: We reviewed clinical and laboratory data from all families referred for evaluation in the Brazilian MH unit due to a personal or family history of MH during anesthesia. Demographic and clinical data were collected, as well as serum creatine kinase (CK) levels, in vitro contracture test (IVCT) results, and the results of anatomopathological studies of skeletal muscle. Molecular analysis was performed using whole-exome sequencing (WES). Patients with and without variants were compared. Results: WES analysis was available for 61 patients (29 patients who survived an MH crisis and 32 relatives). Variants in the RYR1 were found in 38 patients (62.2%), and no variants were identified in 20 patients (32.7%). More than one variant in the RYR1 was found in six individuals. Variants in the CACNA1S were found in three patients (4.9%), all of them with concomitant variants in the RYR1. Three patients presented variants in the STAC3 (4.9%). Comparing the groups of patients with variants in the RYR1 with the one with no variants in this gene, it was observed that the first group showed higher levels of serum CK, a greater frequency of ptosis, strabismus, and cores, and a higher amplitude of contracture in the IVCT after caffeine or halothane. Conclusion: In this preliminary evaluation of Brazilian individuals with MH history, the frequency of RYR1 variants was similar to those of previous reports in other countries, but there was a higher frequency of STAC3 and CACNA1S variants. Full article
(This article belongs to the Special Issue Molecular Genetics of Malignant Hyperthermia Susceptibility and Related Diseases)
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10 pages, 214 KB  
Article
Rhabdomyolysis in the Era of Next-Generation Sequencing: Selecting Patients with a High Likelihood of a Genetic Susceptibility Using ‘RHABDO’ Features
by Nick Kruijt, Sanne A. J. H. van de Camp, Jasper J. Kramer, Luuk R. van den Bersselaar, Meyke Schouten, Thatjana Gardeitchik, Heinz Jungbluth, Salman Bhai, Anneke J. van der Kooi, Erik-Jan Kamsteeg and Nicol C. Voermans
Genes 2025, 16(9), 995; https://doi.org/10.3390/genes16090995 - 25 Aug 2025
Viewed by 1057
Abstract
Background/Objectives: Rhabdomyolysis is a potentially life-threatening condition characterized by acute skeletal muscle breakdown. In addition to well-described external triggers, a genetic contribution is increasingly recognized. We aimed to (I) review the genetic diagnostic approach of rhabdomyolysis, (II) evaluate the clinical characteristics indicative of [...] Read more.
Background/Objectives: Rhabdomyolysis is a potentially life-threatening condition characterized by acute skeletal muscle breakdown. In addition to well-described external triggers, a genetic contribution is increasingly recognized. We aimed to (I) review the genetic diagnostic approach of rhabdomyolysis, (II) evaluate the clinical characteristics indicative of a genetic susceptibility with the ‘RHABDO’ acronym, and (III) assess the predictive value of the presence RHABDO features for identifying genetic variants. Methods: In this retrospective two-center study, 122 patients underwent genetic testing for rhabdomyolysis since the introduction of whole exome sequencing (WES) in 2013. The presence of RHABDO features was compared between those with (likely) pathogenic variants and those with benign or no identified variants or variants of uncertain significance. Results: The testing methods included panel-based WES (82%), Sanger sequencing (49%), and full WES (24%), of which 52 patients (43%) underwent multiple methods. A (likely) pathogenic variant was identified in 13 patients (11%), in all of whom ≥2 RHABDO features were present. The positive predictive value for ≥2 features was 14%, while the negative predictive value was 100%. Conclusions: These results highlight the relevance of WES in further elucidating the genetic basis of rhabdomyolysis and demonstrated that RHABDO is a valuable tool for selecting patients who should undergo genetic testing. Full article
(This article belongs to the Special Issue Molecular Genetics of Malignant Hyperthermia Susceptibility and Related Diseases)
10 pages, 1191 KB  
Article
RNA Sequencing on Muscle Biopsies from Exertional Rhabdomyolysis Patients Revealed Down-Regulation of Mitochondrial Function and Enhancement of Extracellular Matrix Composition
by Mingqiang Ren, Luke P. Michaelson, Ognoon Mungunsukh, Peter Bedocs, Liam Friel, Kristen Cofer, Carolyn E. Dartt, Nyamkhishig Sambuughin and Francis G. O’Connor
Genes 2025, 16(8), 930; https://doi.org/10.3390/genes16080930 - 2 Aug 2025
Viewed by 862
Abstract
Background/Objective: Exertional rhabdomyolysis (ER) is primarily driven by mechanical stress on muscles during strenuous or unaccustomed exercise, often exacerbated by environmental factors like heat and dehydration. While the general cellular pathway involving energy depletion and calcium overload is understood in horse ER models, [...] Read more.
Background/Objective: Exertional rhabdomyolysis (ER) is primarily driven by mechanical stress on muscles during strenuous or unaccustomed exercise, often exacerbated by environmental factors like heat and dehydration. While the general cellular pathway involving energy depletion and calcium overload is understood in horse ER models, the underlying mechanisms specific to the ER are not universally known within humans. This study aimed to evaluate whether patients with ER exhibited transcriptional signatures that were significantly different from those of healthy individuals. Methods: This study utilized RNA sequencing on skeletal muscle samples from 19 human patients with ER history, collected at a minimum of six months after the most recent ER event, and eight healthy controls to investigate the transcriptomic landscape of ER. To identify any alterations in biological processes between the case and control groups, functional pathway analyses were conducted. Results: Functional pathway enrichment analyses of differentially expressed genes revealed strong suppression of mitochondrial function. This suppression included the “aerobic electron transport chain” and “oxidative phosphorylation” pathways, indicating impaired energy production. Conversely, there was an upregulation of genes associated with adhesion and extracellular matrix-related pathways, indicating active restoration of muscle function in ER cases. Conclusions: The study demonstrated that muscle tissue exhibited signs of suppressed mitochondrial function and increased extracellular matrix development. Both of these facilitate muscle recovery within several months after an ER episode. Full article
(This article belongs to the Special Issue Molecular Genetics of Malignant Hyperthermia Susceptibility and Related Diseases)
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Review

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10 pages, 222 KB  
Review
Genetic Testing for Malignant Hyperthermia Susceptibility—Threading the Needle in the Haystack
by Anjan K. Saha and Teeda Pinyavat
Genes 2025, 16(11), 1281; https://doi.org/10.3390/genes16111281 - 29 Oct 2025
Viewed by 735
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Molecular Genetics of Malignant Hyperthermia Susceptibility and Related Diseases)
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