{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T13:47:46Z","timestamp":1784036866599,"version":"3.55.0"},"reference-count":26,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:sec>\n            <jats:title>Objectives<\/jats:title>\n            <jats:p>We aimed to classify genetic variants in <jats:italic toggle=\"yes\">RYR1<\/jats:italic> and <jats:italic toggle=\"yes\">CACNA1S<\/jats:italic> associated with malignant hyperthermia using biobank genotyping data in patients exposed to triggering anesthetics without malignant hyperthermia phenotype.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We identified individuals who underwent surgery and were exposed to triggering anesthetics without malignant hyperthermia phenotype and who had <jats:italic toggle=\"yes\">RYR1<\/jats:italic> or <jats:italic toggle=\"yes\">CACNA1S<\/jats:italic> genotyping data available in our biobank. We classified all variants in the cohort using a Bayesian framework of the American College of Medical Genetics and Genomics and the Association of Molecular Pathologists guidelines for variant classification and updated the posterior probabilities from this model with the new information from our biobank cohort.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We identified 253 patients with 95 <jats:italic toggle=\"yes\">RYR1<\/jats:italic> variants and 12 <jats:italic toggle=\"yes\">CACNA1S<\/jats:italic> variants. After applying a Bayesian framework, we classified 17 variants as benign (B), 31 as likely benign (LB), 57 as uncertain (VUS), and 2 as likely pathogenic (LP). When we incorporated evidence about unique exposures to malignant hyperthermia triggering anesthetic agents, 48 of 107 (45%) variants were downgraded (9 to B, 37 to LB, and 2 to VUS). Notably, 41 (72%) of 57 VUSs were downgraded to B or LB. When repeat anesthetics in the same individual were counted as one exposure, 42 of 107 (39%) of variants were downgraded (5 to B, 35 to LB, and 2 to VUS). Specifically, 37 (65%) of 57 VUSs were downgraded to LB.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Deidentified biorepositories linked with anesthetic data offer a new method of integrating clinical evidence into the assessment of variant probability of pathogenicity.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1097\/fpc.0000000000000551","type":"journal-article","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T15:05:09Z","timestamp":1730300709000},"page":"65-72","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":4,"title":["Updating probability of pathogenicity for RYR1 and CACNA1S exon variants in individuals without malignant hyperthermia after exposure to triggering anesthetics"],"prefix":"10.1097","volume":"35","author":[{"given":"David A.","family":"Roberts","sequence":"first","affiliation":[{"name":"Division of Pediatric Anesthesiology, Monroe Carell Jr. Children\u2019s Hospital"},{"name":"Department of Anesthesiology, Vanderbilt University Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Bastarache","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine, Department of Biomedical Informatics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"He","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine, Department of Biomedical Informatics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Lewis","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine, Department of Biomedical Informatics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida T.","family":"Aka","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine, Department of Biomedical Informatics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew S.","family":"Shotwell","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Vanderbilt University Medical Center"},{"name":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srijaya K.","family":"Reddy","sequence":"additional","affiliation":[{"name":"Division of Pediatric Anesthesiology, Monroe Carell Jr. Children\u2019s Hospital"},{"name":"Department of Anesthesiology, Vanderbilt University Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk J.","family":"Hogan","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie G.","family":"Biesecker","sequence":"additional","affiliation":[{"name":"Center for Precision Health Research, National Human Genome Institute, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miklos D.","family":"Kertai","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Vanderbilt University Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2025,1,2]]},"reference":[{"key":"R1-20250102","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s13023-015-0310-1","article-title":"Malignant hyperthermia: a review.","volume":"10","author":"Rosenberg","year":"2015","journal-title":"Orphanet J Rare Dis"},{"key":"R2-20250102","first-page":"157","article-title":"Temperature sensors in the brain [proceedings].","volume":"26","author":"Nakayama","year":"1976","journal-title":"Med J Osaka 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The European Malignant Hyperthermia Group.","volume":"41","author":"Ording","year":"1997","journal-title":"Acta Anaesthesiol Scand"},{"key":"R26-20250102","doi-asserted-by":"crossref","first-page":"3445","DOI":"10.1038\/s41598-021-82024-7","article-title":"Relevance of pathogenicity prediction tools in human RYR1 variants of unknown significance.","volume":"11","author":"Hoppe","year":"2021","journal-title":"Sci Rep"},{"key":"R27-20250102","doi-asserted-by":"crossref","first-page":"989","DOI":"10.2217\/pgs-2019-0055","article-title":"Bayesian modeling to predict malignant hyperthermia susceptibility and pathogenicity of RYR1, CACNA1S and STAC3 variants.","volume":"20","author":"Sadhasivam","year":"2019","journal-title":"Pharmacogenomics"}],"container-title":["Pharmacogenetics and Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/10.1097\/FPC.0000000000000551","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T16:00:52Z","timestamp":1735833652000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1097\/FPC.0000000000000551"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,2]]},"references-count":26,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025]]}},"URL":"https:\/\/doi.org\/10.1097\/fpc.0000000000000551","relation":{},"ISSN":["1744-6872","1744-6880"],"issn-type":[{"value":"1744-6872","type":"print"},{"value":"1744-6880","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,2]]}}}