{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:13:50Z","timestamp":1788344030624,"version":"build-2803163510"},"reference-count":17,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T00:00:00Z","timestamp":1761264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo\u2014Centro de Pesquisa, Inova\u00e7\u00e3o e Difus\u00e3o","award":["2013\/8028-1"],"award-info":[{"award-number":["2013\/8028-1"]}]},{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo\u2014Centro de Pesquisa, Inova\u00e7\u00e3o e Difus\u00e3o","award":["2021\/06180-7"],"award-info":[{"award-number":["2021\/06180-7"]}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"crossref","award":["465355\/2014-5"],"award-info":[{"award-number":["465355\/2014-5"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]},{"name":"CAPES\u2014Coordena\u00e7\u00e3o de aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","award":["001"],"award-info":[{"award-number":["001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/genes16111252","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T07:41:35Z","timestamp":1761291695000},"page":"1252","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Rare Duplication in the RYR1 Gene Causing Malignant Hyperthermia and Clinical Variability"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7066-262X","authenticated-orcid":false,"given":"Brandow W.","family":"Souza","sequence":"first","affiliation":[{"name":"Human Genome and Stem Cells Research Center, Institute of Biosciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-090, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilherme L.","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cells Research Center, Institute of Biosciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-090, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabela A.","family":"Zogbi","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cells Research Center, Institute of Biosciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-090, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela V.","family":"Andrade","sequence":"additional","affiliation":[{"name":"Malignant Hyperthermia Center, Department of Anesthesiology, Pain and Intensive Care, Federal University of S\u00e3o Paulo, S\u00e3o Paulo 04039-032, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joilson M.","family":"Santos","sequence":"additional","affiliation":[{"name":"Malignant Hyperthermia Center, Department of Anesthesiology, Pain and Intensive Care, Federal University of S\u00e3o Paulo, S\u00e3o Paulo 04039-032, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia N.","family":"Feitosa","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cells Research Center, Institute of Biosciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-090, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6986-4937","authenticated-orcid":false,"given":"Acary S. B.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Malignant Hyperthermia Center, Department of Anesthesiology, Pain and Intensive Care, Federal University of S\u00e3o Paulo, S\u00e3o Paulo 04039-032, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora R.","family":"Bertola","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cells Research Center, Institute of Biosciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-090, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soledad","family":"Levano","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8641-4006","authenticated-orcid":false,"given":"Thierry","family":"Girard","sequence":"additional","affiliation":[{"name":"Clinic for Anaesthesia, Intermediate Cre, Prehosptial Emergency Medicine and Pain Therapy, University Hospital Basel, University of Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9372-7019","authenticated-orcid":false,"given":"Helga C. A.","family":"Silva","sequence":"additional","affiliation":[{"name":"Malignant Hyperthermia Center, Department of Anesthesiology, Pain and Intensive Care, Federal University of S\u00e3o Paulo, S\u00e3o Paulo 04039-032, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2797-0782","authenticated-orcid":false,"given":"Mariz","family":"Vainzof","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cells Research Center, Institute of Biosciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-090, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,24]]},"reference":[{"key":"ref_1","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. 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