{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T04:56:09Z","timestamp":1785387369951,"version":"3.55.0"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T00:00:00Z","timestamp":1630368000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T00:00:00Z","timestamp":1630368000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Hum Genet"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Malignant hyperthermia (MH) susceptibility is a rare life-threatening disorder that occurs upon exposure to a triggering agent. MH is commonly due to protein-altering variants in <jats:italic>RYR1<\/jats:italic> and <jats:italic>CACNA1S<\/jats:italic>. The American College of Medical Genetics and Genomics recommends that when pathogenic and likely pathogenic variants in <jats:italic>RYR1<\/jats:italic> and <jats:italic>CACNA1S<\/jats:italic> are incidentally found, they should be reported to the carriers. The detection of actionable variants allows the avoidance of exposure to triggering agents during anesthesia. First, we report a 10-year-old Icelandic proband with a suspected MH event, harboring a heterozygous missense variant NM_000540.2:c.6710G&gt;A r.(6710g&gt;a) p.(Cys2237Tyr) in the <jats:italic>RYR1<\/jats:italic> gene that is likely pathogenic. The variant is private to four individuals within a three-generation family and absent from 62,240 whole-genome sequenced (WGS) Icelanders. Haplotype sharing and WGS revealed that the variant occurred as a somatic mosaicism also present in germline of the proband\u2019s paternal grandmother. Second, using a set of 62,240 Icelanders with WGS, we assessed the carrier frequency of actionable pathogenic and likely pathogenic variants in <jats:italic>RYR1<\/jats:italic> and <jats:italic>CACNA1S<\/jats:italic>. We observed 13 actionable variants in <jats:italic>RYR1<\/jats:italic>, based on ClinVar classifications, carried by 43 Icelanders, and no actionable variant in <jats:italic>CACNA1S<\/jats:italic>. One in 1450 Icelanders carries an actionable variant for MH. Extensive sequencing allows for better classification and precise dating of variants, and WGS of a large fraction of the population has led to incidental findings of actionable MH genotypes.<\/jats:p>","DOI":"10.1038\/s41431-021-00954-2","type":"journal-article","created":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T01:02:19Z","timestamp":1630371739000},"page":"1819-1824","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Sequence variants in malignant hyperthermia genes in Iceland: classification and actionable findings in a population database"],"prefix":"10.1038","volume":"29","author":[{"given":"Run","family":"Fridriksdottir","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnar J.","family":"Jonsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brynjar O.","family":"Jensson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4824-6785","authenticated-orcid":false,"given":"Kristinn O.","family":"Sverrisson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6571-423X","authenticated-orcid":false,"given":"Gudny A.","family":"Arnadottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigurbjorg J.","family":"Skarphedinsdottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hildigunnur","family":"Katrinardottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steinunn","family":"Snaebjornsdottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hakon","family":"Jonsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0139-5107","authenticated-orcid":false,"given":"Ogmundur","family":"Eiriksson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gudjon R.","family":"Oskarsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4606-5163","authenticated-orcid":false,"given":"Asmundur","family":"Oddsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adalbjorg","family":"Jonasdottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aslaug","family":"Jonasdottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisli H.","family":"Sigurdsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Einar P.","family":"Indridason","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1036-2008","authenticated-orcid":false,"given":"Stefan B.","family":"Sigurdsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyda","family":"Bjornsdottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jona","family":"Saemundsdottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olafur T.","family":"Magnusson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans T.","family":"Bjornsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Unnur","family":"Thorsteinsdottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodor S.","family":"Sigurdsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7123-6123","authenticated-orcid":false,"given":"Patrick","family":"Sulem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin I.","family":"Sigurdsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1676-864X","authenticated-orcid":false,"given":"Kari","family":"Stefansson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,31]]},"reference":[{"key":"954_CR1","doi-asserted-by":"crossref","unstructured":"Klingler W, Heiderich S, Girard T, Gravino E, Heffron JJA, Johannsen S, et al. Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study. Orphanet J Rare Dis. 2014;9:8.","DOI":"10.1186\/1750-1172-9-8"},{"key":"954_CR2","doi-asserted-by":"crossref","unstructured":"Hopkins PM, R\u00fcffert H, Snoeck MM, Girard T, Glahn KPE, Ellis FR, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2015;115:531\u20139.","DOI":"10.1093\/bja\/aev225"},{"key":"954_CR3","doi-asserted-by":"crossref","unstructured":"Fiszer D, Shaw MA, Fisher NA, Carr IM, Gupta PK, Watkins EJ, et al. Next-generation sequencing of RYR1 and CACNA1S in malignant hyperthermia and exertional heat illness. Anesthesiology. 2015;122:1033\u201346.","DOI":"10.1097\/ALN.0000000000000610"},{"key":"954_CR4","doi-asserted-by":"crossref","unstructured":"Riazi S, Kraeva N, Hopkins PM. Malignant hyperthermia in the post-genomics era: new perspectives on an old concept. Anesthesiology. 2018;128:168\u201380.","DOI":"10.1097\/ALN.0000000000001878"},{"key":"954_CR5","doi-asserted-by":"crossref","unstructured":"Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013;15:565\u201374.","DOI":"10.1038\/gim.2013.73"},{"key":"954_CR6","doi-asserted-by":"crossref","unstructured":"Claussnitzer M, Cho JH, Collins R, Cox NJ, Dermitzakis ET, Hurles ME, et al. A brief history of human disease genetics. Nature. 2020;577:179\u201389.","DOI":"10.1038\/s41586-019-1879-7"},{"key":"954_CR7","doi-asserted-by":"crossref","unstructured":"Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018;562:203\u20139.","DOI":"10.1038\/s41586-018-0579-z"},{"key":"954_CR8","doi-asserted-by":"crossref","unstructured":"Turnbull C, Scott RH, Thomas E, Jones L, Murugaesu N, Pretty FB, et al. The 100 000 Genomes Project: bringing whole genome sequencing to the NHS. BMJ. 2018;361:k1687. https:\/\/pubmed.ncbi.nlm.nih.gov\/29691228\/.","DOI":"10.1136\/bmj.k1687"},{"key":"954_CR9","doi-asserted-by":"crossref","unstructured":"Carey DJ, Fetterolf SN, Davis FD, Faucett WA, Kirchner HL, Mirshahi U, et al. The Geisinger MyCode community health initiative: an electronic health record-linked biobank for precision medicine research. Genet Med. 2016;18:906\u201313.","DOI":"10.1038\/gim.2015.187"},{"key":"954_CR10","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1038\/ng.3247","volume":"47","author":"DF Gudbjartsson","year":"2015","unstructured":"Gudbjartsson DF, Helgason H, Gudjonsson SA, Zink F, Oddson A, Gylfason A, et al. Large-scale whole-genome sequencing of the Icelandic population. Nat Genet. 2015;47:435\u201344.","journal-title":"Nat Genet"},{"key":"954_CR11","doi-asserted-by":"crossref","unstructured":"Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285\u201391.","DOI":"10.1038\/nature19057"},{"key":"954_CR12","doi-asserted-by":"crossref","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405\u201324.","DOI":"10.1038\/gim.2015.30"},{"key":"954_CR13","unstructured":"Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. 2013 Mar 16 [cited 2021 Aug 28]; Available from: https:\/\/arxiv.org\/abs\/1303.3997v2."},{"key":"954_CR14","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1101\/gr.107524.110","volume":"20","author":"A McKenna","year":"2010","unstructured":"McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297\u2013303.","journal-title":"Genome Res"},{"key":"954_CR15","doi-asserted-by":"crossref","unstructured":"McLaren W, Pritchard B, Rios D, Chen Y, Flicek P, Cunningham F. Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics. 2010;26:2069\u201370.","DOI":"10.1093\/bioinformatics\/btq330"},{"key":"954_CR16","doi-asserted-by":"crossref","unstructured":"Kong A, Masson G, Frigge ML, Gylfason A, Zusmanovich P, Thorleifsson G, et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nat Genet. 2008;40:1068\u201375.","DOI":"10.1038\/ng.216"},{"key":"954_CR17","doi-asserted-by":"crossref","unstructured":"J\u00f3nsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, et al. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519\u201322.","DOI":"10.1038\/nature24018"},{"key":"954_CR18","doi-asserted-by":"crossref","unstructured":"J\u00f3nsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, et al. Data descriptor: whole genome characterization of sequence diversity of 15,220 Icelanders. Sci Data. 2017;4:170115.","DOI":"10.1038\/sdata.2017.115"},{"key":"954_CR19","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/j.nmd.2005.06.008","volume":"15","author":"S Treves","year":"2005","unstructured":"Treves S, Anderson AA, Ducreux S, Divet A, Bleunven C, Grasso C, et al. Ryanodine receptor 1 mutations, dysregulation of calcium homeostasis and neuromuscular disorders. Neuromuscul Disord. 2005;15:577\u201387.","journal-title":"Neuromuscul Disord"},{"key":"954_CR20","doi-asserted-by":"crossref","unstructured":"Brislin RP, Theroux MC. Core myopathies and malignant hyperthermia susceptibility: a review. Paediatr Anaesth. 2013;23:834\u201341.","DOI":"10.1111\/pan.12175"},{"key":"954_CR21","doi-asserted-by":"crossref","unstructured":"Glahn KPE, Bendixen D, Girard T, Hopkins PM, Johannsen S, R\u00fcffert H, et al. Availability of dantrolene for the management of malignant hyperthermia crises: European Malignant Hyperthermia Group guidelines. Br J Anaesth. 2020;125:133\u201340.","DOI":"10.1016\/j.bja.2020.04.089"},{"key":"954_CR22","doi-asserted-by":"crossref","unstructured":"Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology. 1994;80:771\u20139.","DOI":"10.1097\/00000542-199404000-00008"},{"key":"954_CR23","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","volume":"99","author":"NM Ioannidis","year":"2016","unstructured":"Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 2016;99:877\u201385.","journal-title":"Am J Hum Genet"},{"key":"954_CR24","unstructured":"Scoring matrix of mh variants\u2014European Malignant Hyperthermia Group. 2015. https:\/\/www.emhg.org\/genetic-scoring-matrix. Accessed 26 Apr 2021."},{"key":"954_CR25","doi-asserted-by":"crossref","unstructured":"Johnston JJ, Dirksen RT, Girard T, Gonsalves SG, Hopkins PM, Riazi S, et al. Variant curation expert panel recommendations for RYR1 pathogenicity assertions in malignant hyperthermia susceptibility. Genet Med. 2021;23:1288\u201395.","DOI":"10.1038\/s41436-021-01125-w"}],"container-title":["European Journal of Human Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41431-021-00954-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41431-021-00954-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41431-021-00954-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T01:09:52Z","timestamp":1638320992000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41431-021-00954-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,31]]},"references-count":25,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["954"],"URL":"https:\/\/doi.org\/10.1038\/s41431-021-00954-2","relation":{},"ISSN":["1018-4813","1476-5438"],"issn-type":[{"value":"1018-4813","type":"print"},{"value":"1476-5438","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,31]]},"assertion":[{"value":"26 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 August 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 August 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Authors affiliated with deCODE Genetics\/Amgen declare competing interests as employees. The remaining authors declare no competing financial interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The study was approved by the National Bioethics Committee in Iceland. Written, informed consent to participate was obtained for all participants, or their guardians, before blood samples were drawn. All participants, or their guardians, provided written informed consent for publication of medical data, medical imaging, and genetic data.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}]}}