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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

Estimating the Prevalence of Malignant Hyperthermia Susceptibility Based on Causative RYR1 and CACNA1S Variants

  • Ekaterina Efremova1,2
  • Elena Baranova1,2
  • Anton Esibov3,4
  • Anastasiia Rozhkova3,4
  • Ekaterina Rutkovskaya3,4
  • Julia Krupinova3,4,5
  • Olga Mityaeva3,4
  • Mary Woroncow6
  • Sherzod Abdullaev1
  • Karin Mirzaev1,2
  • Viktor Bogdanov3,4
  • Pavel Volchkov3,4
1 more authors
  • Dmitry Sychev1,2
6 affiliations
  1. 1Petrovsky National Research Center of Surgery, Moscow 119435, Russia
  2. 2Russian Medical Academy of Continuous Professional Education, Moscow 125993, Russia
  3. 3Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow 125315, Russia
  4. 4Moscow Center for Advanced Studies, Moscow 123592, Russia
  5. 5Loginov Moscow Clinical Scientific Center, the Moscow Healthcare Department, Moscow 111123, Russia
  6. 6Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow 119991, Russia
Open at sourceDOICite

Abstract

Malignant hyperthermia susceptibility (MHS; OMIM 145600, 601887) is a pharmacogenetic condition in which exposure to volatile anesthetics and/or succinylcholine can trigger a potentially life-threatening hypermetabolic crisis of skeletal muscle. MHS is predominantly associated with pathogenic variants in RYR1, whereas CACNA1S contributes a substantially smaller proportion of genetically confirmed cases. Estimating the population prevalence of MHS is challenging because manifestation requires exposure to a triggering agent, penetrance is incomplete, and the evidentiary strength supporting individual variants varies considerably. In this study, MHS-associated RYR1 and CACNA1S variants were compiled from four complementary resources—EMHG, ClinGen MHS VCEP, HGMD, and ClinVar—and subjected to source-specific pathogenicity and phenotype filtering. A total of 13,918 unique reported variants were initially identified. Progressive evidence-based curation generated three nested variant tiers: a high-confidence Expert tier comprising 102 variants; an expanded HGMD-inclusive tier comprising 446 variants; and a full expanded ClinVar-inclusive tier comprising 593 variants. Population allele frequencies were evaluated using gnomAD v4.1.0 and the Russian GDB v1.3.4 database. The high-confidence Expert tier yielded genetically inferred MHS frequencies of approximately 1 in 807 in gnomAD and 1 in 1078 in GDB. Inclusion of HGMD-derived variants increased the corresponding estimates to approximately 1 in 50 and 1 in 104, respectively.

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Cite

BibTeXRIS
BibTeX
@article{efremova2026estimating,
  title = {{Estimating the Prevalence of Malignant Hyperthermia Susceptibility Based on Causative RYR1 and CACNA1S Variants}},
  author = {Ekaterina Efremova and Elena Baranova and Anton Esibov and Anastasiia Rozhkova and Ekaterina Rutkovskaya and Julia Krupinova and Olga Mityaeva and Mary Woroncow and Sherzod Abdullaev and Karin Mirzaev and Viktor Bogdanov and Pavel Volchkov and Dmitry Sychev},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = sep,
  doi = {10.3390/ijms27188327},
  url = {https://www.mdpi.com/1422-0067/27/18/8327},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Estimating the Prevalence of Malignant Hyperthermia Susceptibility Based on Causative RYR1 and CACNA1S Variants
AU  - Ekaterina Efremova
AU  - Elena Baranova
AU  - Anton Esibov
AU  - Anastasiia Rozhkova
AU  - Ekaterina Rutkovskaya
AU  - Julia Krupinova
AU  - Olga Mityaeva
AU  - Mary Woroncow
AU  - Sherzod Abdullaev
AU  - Karin Mirzaev
AU  - Viktor Bogdanov
AU  - Pavel Volchkov
AU  - Dmitry Sychev
PY  - 2026
DA  - 2026/09/19
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27188327
UR  - https://www.mdpi.com/1422-0067/27/18/8327
AB  - Malignant hyperthermia susceptibility (MHS; OMIM 145600, 601887) is a pharmacogenetic condition in which exposure to volatile anesthetics and/or succinylcholine can trigger a potentially life-threatening hypermetabolic crisis of skeletal muscle. MHS is predominantly associated with pathogenic variants in RYR1, whereas CACNA1S contributes a substantially smaller proportion of genetically confirmed cases. Estimating the population prevalence of MHS is challenging because manifestation requires exposure to a triggering agent, penetrance is incomplete, and the evidentiary strength supporting individual variants varies considerably. In this study, MHS-associated RYR1 and CACNA1S variants were compiled from four complementary resources—EMHG, ClinGen MHS VCEP, HGMD, and ClinVar—and subjected to source-specific pathogenicity and phenotype filtering. A total of 13,918 unique reported variants were initially identified. Progressive evidence-based curation generated three nested variant tiers: a high-confidence Expert tier comprising 102 variants; an expanded HGMD-inclusive tier comprising 446 variants; and a full expanded ClinVar-inclusive tier comprising 593 variants. Population allele frequencies were evaluated using gnomAD v4.1.0 and the Russian GDB v1.3.4 database. The high-confidence Expert tier yielded genetically inferred MHS frequencies of approximately 1 in 807 in gnomAD and 1 in 1078 in GDB. Inclusion of HGMD-derived variants increased the corresponding estimates to approximately 1 in 50 and 1 in 104, respectively.
SN  - 1422-0067
ER  -