{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:03:27Z","timestamp":1790863407499,"version":"4.1.0"},"reference-count":28,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"publisher","award":["075-15-2025-463"],"award-info":[{"award-number":["075-15-2025-463"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"publisher","award":["#FGFG-2026-0003"],"award-info":[{"award-number":["#FGFG-2026-0003"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>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\u2014EMHG, ClinGen MHS VCEP, HGMD, and ClinVar\u2014and 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.<\/jats:p>","DOI":"10.3390\/ijms27188327","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:18:26Z","timestamp":1790860706000},"page":"8327","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Estimating the Prevalence of Malignant Hyperthermia Susceptibility Based on Causative RYR1 and CACNA1S Variants"],"prefix":"10.3390","volume":"27","author":[{"given":"Ekaterina","family":"Efremova","sequence":"first","affiliation":[{"name":"Petrovsky National Research Center of Surgery, Moscow 119435, Russia"},{"name":"Russian Medical Academy of Continuous Professional Education, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Elena","family":"Baranova","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Center of Surgery, Moscow 119435, Russia"},{"name":"Russian Medical Academy of Continuous Professional Education, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Anton","family":"Esibov","sequence":"additional","affiliation":[{"name":"Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow 125315, Russia"},{"name":"Moscow Center for Advanced Studies, Moscow 123592, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7876-1223","authenticated-orcid":false,"given":"Anastasiia","family":"Rozhkova","sequence":"additional","affiliation":[{"name":"Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow 125315, Russia"},{"name":"Moscow Center for Advanced Studies, Moscow 123592, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Ekaterina","family":"Rutkovskaya","sequence":"additional","affiliation":[{"name":"Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow 125315, Russia"},{"name":"Moscow Center for Advanced Studies, Moscow 123592, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Julia","family":"Krupinova","sequence":"additional","affiliation":[{"name":"Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow 125315, Russia"},{"name":"Moscow Center for Advanced Studies, Moscow 123592, Russia"},{"name":"Loginov Moscow Clinical Scientific Center, the Moscow Healthcare Department, Moscow 111123, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9252-1601","authenticated-orcid":false,"given":"Olga","family":"Mityaeva","sequence":"additional","affiliation":[{"name":"Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow 125315, Russia"},{"name":"Moscow Center for Advanced Studies, Moscow 123592, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Mary","family":"Woroncow","sequence":"additional","affiliation":[{"name":"Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9001-1499","authenticated-orcid":false,"given":"Sherzod","family":"Abdullaev","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Center of Surgery, Moscow 119435, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Karin","family":"Mirzaev","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Center of Surgery, Moscow 119435, Russia"},{"name":"Russian Medical Academy of Continuous Professional Education, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6377-9056","authenticated-orcid":false,"given":"Viktor","family":"Bogdanov","sequence":"additional","affiliation":[{"name":"Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow 125315, Russia"},{"name":"Moscow Center for Advanced Studies, Moscow 123592, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9794-6297","authenticated-orcid":false,"given":"Pavel","family":"Volchkov","sequence":"additional","affiliation":[{"name":"Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, Moscow 125315, Russia"},{"name":"Moscow Center for Advanced Studies, Moscow 123592, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4496-3680","authenticated-orcid":false,"given":"Dmitry","family":"Sychev","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Center of Surgery, Moscow 119435, Russia"},{"name":"Russian Medical Academy of Continuous Professional Education, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"key":"ref_1","unstructured":"Adam, M.P., Bick, S., Mirzaa, G.M., Wallace, S.E., and Amemiya, A. (2026, September 14). Nonsyndromic Malignant Hyperthermia Susceptibility, GeneReviews\u00ae [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1146\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6","DOI":"10.17116\/anaesthesiology20230616","article-title":"Malignant hyperthermia due to anaesthesia","volume":"202","author":"Lebedinskii","year":"2023","journal-title":"Russ. J. Anesthesiol. Reanimatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"78","DOI":"10.24884\/2078-5658-2023-20-2-78-84","article-title":"Malignant hyperthermia (literature review)","volume":"20","author":"Tukhvatullina","year":"2023","journal-title":"Messenger Anesthesiol. Resusc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"391","DOI":"10.4097\/kjae.2012.63.5.391","article-title":"Malignant hyperthermia","volume":"63","author":"Kim","year":"2012","journal-title":"Korean J. Anesthesiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1097\/ALN.0000000000004786","article-title":"Evaluation of Malignant Hyperthermia Features in Patients with Pathogenic or Likely Pathogenic RYR1 Variants Disclosed through a Population Genomic Screening Program","volume":"140","author":"Yu","year":"2024","journal-title":"Anesthesiology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1038\/s41436-021-01125-w","article-title":"Variant curation expert panel recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility","volume":"23","author":"Johnston","year":"2021","journal-title":"Genet. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1080\/23328940.2016.1153360","article-title":"Functional analysis of RYR1 variants linked to malignant hyperthermia","volume":"3","author":"Stephens","year":"2016","journal-title":"Temperature"},{"key":"ref_8","unstructured":"European Malignant Hyperthermia Group (2026, July 10). EMHG Homepage. Available online: http:\/\/www.emhg.org\/home\/."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"106296","DOI":"10.1016\/j.nmd.2025.106296","article-title":"Identification of novel potentially causative RYR1 variants in individuals with malignant hyperthermia susceptibility","volume":"58","author":"Rossi","year":"2026","journal-title":"Neuromuscul. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4087","DOI":"10.1093\/hmg\/ddac145","article-title":"Updated variant curation expert panel criteria and pathogenicity classifications for 251 variants for RYR1-related malignant hyperthermia susceptibility","volume":"31","author":"Johnston","year":"2022","journal-title":"Hum. Mol. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1002\/(SICI)1098-1004(200005)15:5<410::AID-HUMU2>3.0.CO;2-D","article-title":"Ryanodine receptor mutations in malignant hyperthermia and central core disease","volume":"15","author":"McCarthy","year":"2000","journal-title":"Hum. Mutat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1093\/hmg\/ddg121","article-title":"A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia","volume":"12","author":"Monnier","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","first-page":"34","article-title":"Clinical and Genetic Spectrum of RYR1-Related Disease","volume":"17","author":"Baydan","year":"2026","journal-title":"Mol. Syndromol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"15622","DOI":"10.1074\/jbc.RA120.013512","article-title":"The central domain of cardiac ryanodine receptor governs channel activation, regulation, and stability","volume":"295","author":"Guo","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"24528","DOI":"10.1074\/jbc.M116.756528","article-title":"Enhanced Cytosolic Ca2+ Activation Underlies a Common Defect of Central Domain Cardiac Ryanodine Receptor Mutations Linked to Arrhythmias","volume":"291","author":"Xiao","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_16","first-page":"145","article-title":"Predictive factors of the contracture test for diagnosing malignant hyperthermia in a Brazilian population sample: A retrospective observational study","volume":"73","author":"Andrade","year":"2023","journal-title":"Braz. J. Anesthesiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1097\/00000542-200405000-00008","article-title":"Molecular genetic testing for malignant hyperthermia susceptibility","volume":"100","author":"Girard","year":"2004","journal-title":"Anesthesiology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1097\/ALN.0b013e3182a8a8e7","article-title":"Using exome data to identify malignant hyperthermia susceptibility mutations","volume":"119","author":"Gonsalves","year":"2013","journal-title":"Anesthesiology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e461","DOI":"10.1016\/j.bja.2019.06.010","article-title":"Estimating prevalence of malignant hyperthermia susceptibility through population genomics data","volume":"123","author":"Mungunsukh","year":"2019","journal-title":"Br. J. Anaesth."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/ajmg.c.31887","article-title":"Leveraging population-based exome screening to impact clinical care: The evolution of variant assessment in the Geisinger MyCode research project","volume":"187","author":"Kelly","year":"2021","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Rozhkova, A.V., Rutkovskaya, E.A., Kadyshev, V.V., Esibov, A.A., Alsalloum, A., Kuznetsova, E.S., Krupinova, J.A., Mityaeva, O.N., Shefer, K.K., and Boiko, E.V. (2026). Bayesian Population-Based Prevalence Estimation of KCNV2-Associated Retinopathy: A Comparative Analysis of Disease-Associated Variant Frequencies in Russian and Global Populations. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27135911"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1056\/NEJMsr1406261","article-title":"ClinGen\u2014The Clinical Genome Resource","volume":"372","author":"Rehm","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"D862","DOI":"10.1093\/nar\/gkv1222","article-title":"ClinVar: Public Archive of Interpretations of Clinically Relevant Variants","volume":"44","author":"Landrum","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1007\/s00439-020-02199-3","article-title":"The Human Gene Mutation Database (HGMD\u00ae): Optimizing Its Use in a Clinical Diagnostic or Research Setting","volume":"139","author":"Stenson","year":"2020","journal-title":"Hum. Genet."},{"key":"ref_25","unstructured":"European Malignant Hyperthermia Group (EMHG) (2026, July 31). (Likely) Pathogenic Mutations. Available online: https:\/\/www.emhg.org\/diagnostic-mutations."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41586-023-06045-0","article-title":"A Genomic Mutational Constraint Map Using Variation in 76,156 Human Genomes","volume":"625","author":"Chen","year":"2024","journal-title":"Nature"},{"key":"ref_27","unstructured":"(2026, July 31). Database of Population Frequencies of Genetic Variants of the Population of the Russian Federation. Federal Medical-Biological Agency of Russia, Available online: https:\/\/gdbpop.nir.cspfmba.ru\/."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1007\/s00439-015-1551-8","article-title":"Prevalence Estimation for Monogenic Autosomal Recessive Diseases Using Population-Based Genetic Data","volume":"134","author":"Schrodi","year":"2015","journal-title":"Hum. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8327\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:28:32Z","timestamp":1790861312000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8327"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,19]]},"references-count":28,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27188327"],"URL":"https:\/\/doi.org\/10.3390\/ijms27188327","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,19]]}}}