{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:24Z","timestamp":1790899224622,"version":"4.1.0"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Malignant hyperthermia susceptibility (MHS) is a life-threatening, inherited disorder of muscle calcium metabolism, triggered by anesthetics and depolarizing muscle relaxants. An unselected cohort was screened for MHS mutations using exome sequencing. The aim of this study was to pilot a strategy for the <jats:italic toggle=\"yes\">RYR1<\/jats:italic> and <jats:italic toggle=\"yes\">CACNA1S<\/jats:italic> genes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Exome sequencing was performed on 870 volunteers not ascertained for MHS. Variants in <jats:italic toggle=\"yes\">RYR1<\/jats:italic> and <jats:italic toggle=\"yes\">CACNA1S<\/jats:italic> were annotated using an algorithm that filtered results based on mutation type, frequency, and information in mutation databases. Variants were scored on a six-point pathogenicity scale. Medical histories and pedigrees were reviewed for malignant hyperthermia and related disorders.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>The authors identified 70 <jats:italic toggle=\"yes\">RYR1<\/jats:italic> and 53 <jats:italic toggle=\"yes\">CACNA1S<\/jats:italic> variants among 870 exomes. Sixty-three <jats:italic toggle=\"yes\">RYR1<\/jats:italic> and 41 <jats:italic toggle=\"yes\">CACNA1S<\/jats:italic> variants passed the quality and frequency metrics but the authors excluded synonymous variants. In <jats:italic toggle=\"yes\">RYR1<\/jats:italic>, the authors identified 65 missense mutations, one nonsense, two that affected splicing, and one non\u2013frameshift indel. In <jats:italic toggle=\"yes\">CACNA1S<\/jats:italic>, 48 missense, one frameshift deletion, one splicing, and one non\u2013frameshift indel were identified. <jats:italic toggle=\"yes\">RYR1<\/jats:italic> variants predicted to be pathogenic for MHS were found in three participants without medical or family histories of MHS. Numerous variants, previously described as pathogenic in mutation databases, were reclassified by the authors as being of unknown pathogenicity.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Exome sequencing can identify asymptomatic patients at risk for MHS, although the interpretation of exome variants can be challenging. The use of exome sequencing in unselected cohorts is an important tool to understand the prevalence and penetrance of MHS, a critical challenge for the field.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1097\/aln.0b013e3182a8a8e7","type":"journal-article","created":{"date-parts":[[2013,8,24]],"date-time":"2013-08-24T12:12:03Z","timestamp":1377346323000},"page":"1043-1053","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":79,"title":["Using Exome Data to Identify Malignant Hyperthermia Susceptibility Mutations"],"prefix":"10.1097","volume":"119","author":[{"given":"Stephen G.","family":"Gonsalves","sequence":"first","affiliation":[{"name":"Research Associate"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Ng","sequence":"additional","affiliation":[{"name":"Clinical Specialty Consultant"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J.","family":"Johnston","sequence":"additional","affiliation":[{"name":"Staff Scientist"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie K.","family":"Teer","sequence":"additional","affiliation":[{"name":"Postdoctoral Fellow, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health. Current position: Assistant Member, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter D.","family":"Stenson","sequence":"additional","affiliation":[{"name":"Research Associate"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David N.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Professor of Human Molecular Genetics, Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James C.","family":"Mullikin","sequence":"additional","affiliation":[{"name":"Director, National Institutes of Health Intramural Sequencing Center, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie G.","family":"Biesecker","sequence":"additional","affiliation":[{"name":"Branch Chief, Genetic Disease Research Branch"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-20241226","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1097\/00000542-200606000-00008","article-title":"Malignant hyperthermia in Japan: Mutation screening of the entire ryanodine receptor type 1 gene coding region by direct sequencing.","volume":"104","year":"2006","journal-title":"Anesthesiology"},{"key":"R2-20241226","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1097\/00000542-200503000-00007","article-title":"Screening of the entire ryanodine receptor type 1 coding region for sequence variants associated with malignant hyperthermia susceptibility in the north american population.","volume":"102","year":"2005","journal-title":"Anesthesiology"},{"key":"R3-20241226","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1002\/humu.9442","article-title":"Frequency and localization of mutations in the 106 exons of the RYR1 gene in 50 individuals with malignant hyperthermia.","volume":"27","year":"2006","journal-title":"Hum Mutat"},{"key":"R4-20241226","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1097\/00000542-200211000-00007","article-title":"Presence of two different genetic traits in malignant hyperthermia families: Implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility.","volume":"97","year":"2002","journal-title":"Anesthesiology"},{"key":"R5-20241226","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1002\/humu.20356","article-title":"Mutations in RYR1 in malignant hyperthermia and central core disease.","volume":"27","year":"2006","journal-title":"Hum Mutat"},{"key":"R6-20241226","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1034\/j.1399-0004.2001.590306.x","article-title":"Identification of the Arg1086His mutation in the alpha subunit of the voltage-dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia.","volume":"59","year":"2001","journal-title":"Clin Genet"},{"key":"R7-20241226","first-page":"65ra4","article-title":"Carrier testing for severe childhood recessive diseases by next-generation sequencing.","volume":"3","year":"2011","journal-title":"Sci Transl Med"},{"key":"R8-20241226","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1101\/gr.092841.109","article-title":"The ClinSeq Project: Piloting large-scale genome sequencing for research in genomic medicine.","volume":"19","year":"2009","journal-title":"Genome Res"},{"key":"R9-20241226","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1101\/gr.106716.110","article-title":"Systematic comparison of three genomic enrichment methods for massively parallel DNA sequencing.","volume":"20","year":"2010","journal-title":"Genome Res"},{"key":"R10-20241226","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1093\/bioinformatics\/btr711","article-title":"VarSifter: Visualizing and analyzing exome-scale sequence variation data on a desktop computer.","volume":"28","year":"2012","journal-title":"Bioinformatics"},{"key":"R11-20241226","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.ajhg.2012.05.021","article-title":"Secondary variants in individuals undergoing exome sequencing: Screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.","volume":"91","year":"2012","journal-title":"Am J Hum Genet"},{"key":"R12-20241226","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1002\/humu.20880","article-title":"Sequence variant classification and reporting: Recommendations for improving the interpretation of cancer susceptibility genetic test results.","volume":"29","year":"2008","journal-title":"Hum Mutat"},{"key":"R13-20241226","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1136\/jmedgenet-2011-100305","article-title":"Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes.","volume":"48","year":"2011","journal-title":"J Med Genet"},{"key":"R14-20241226","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1002\/humu.22106","article-title":"A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome.","volume":"33","year":"2012","journal-title":"Hum Mutat"},{"key":"R15-20241226","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1002\/humu.20889","article-title":"Locus-specific databases and recommendations to strengthen their contribution to the classification of variants in cancer susceptibility genes.","volume":"29","year":"2008","journal-title":"Hum Mutat"},{"key":"R16-20241226","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ajhg.2011.01.011","article-title":"Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy.","volume":"88","year":"2011","journal-title":"Am J Hum Genet"},{"key":"R17-20241226","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/humu.22214","article-title":"Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions.","volume":"34","year":"2013","journal-title":"Hum Mutat"},{"key":"R18-20241226","first-page":"577","article-title":"Human Gene Mutation Database (HGMD): 2003 update.","volume":"21","year":"2003","journal-title":"Hum Mutat"},{"key":"R19-20241226","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1002\/humu.21438","article-title":"LOVD v.2.0: The next generation in gene variant databases.","volume":"32","year":"2011","journal-title":"Hum Mutat"},{"key":"R20-20241226","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.ymgme.2011.07.001","article-title":"Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies.","volume":"104","year":"2011","journal-title":"Mol Genet Metab"},{"key":"R21-20241226","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/0888-7543(91)90084-R","article-title":"A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia.","volume":"11","year":"1991","journal-title":"Genomics"},{"key":"R22-20241226","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1093\/bja\/aep204","article-title":"Genetic variation in RYR1 and malignant hyperthermia phenotypes.","volume":"103","year":"2009","journal-title":"Br J Anaesth"},{"key":"R23-20241226","first-page":"464","article-title":"Malignant hyperthermia genetic testing in North America Working Group Meeting. Bethesda, Maryland. September 4-5, 2002.","volume":"100","year":"2004","journal-title":"Anesthesiology"},{"key":"R24-20241226","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.nmd.2009.12.005","article-title":"Multi-minicore disease and atypical periodic paralysis associated with novel mutations in the skeletal muscle ryanodine receptor (RYR1) gene.","volume":"20","year":"2010","journal-title":"Neuromuscul Disord"},{"key":"R25-20241226","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1001\/archneurol.2011.188","article-title":"Muscle magnetic resonance imaging in congenital myopathies due to ryanodine receptor type 1 gene mutations.","volume":"68","year":"2011","journal-title":"Arch Neurol"},{"key":"R26-20241226","doi-asserted-by":"crossref","first-page":"2791","DOI":"10.1093\/hmg\/ddl221","article-title":"Characterization of recessive RYR1 mutations in core myopathies.","volume":"15","year":"2006","journal-title":"Hum Mol Genet"},{"issue":"Pt 8","key":"R27-20241226","first-page":"2024","article-title":"Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies.","volume":"130","year":"2007","journal-title":"Brain"},{"key":"R28-20241226","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1002\/humu.22056","article-title":"Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies.","volume":"33","year":"2012","journal-title":"Hum Mutat"},{"key":"R30-20241226","doi-asserted-by":"crossref","first-page":"C1345","DOI":"10.1152\/ajpcell.00008.2010","article-title":"Identification and functional characterization of malignant hyperthermia mutation T1354S in the outer pore of the Cavalpha1S-subunit.","volume":"299","year":"2010","journal-title":"Am J Physiol Cell Physiol"},{"key":"R31-20241226","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1213\/ANE.0b013e3181b5ae2d","article-title":"Core myopathies and risk of malignant hyperthermia.","volume":"109","year":"2009","journal-title":"Anesth Analg"},{"key":"R32-20241226","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1750-1172-2-21","article-title":"Malignant hyperthermia.","volume":"2","year":"2007","journal-title":"Orphanet J Rare Dis"}],"container-title":["Anesthesiology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/pubs.asahq.org\/anesthesiology\/article-pdf\/119\/5\/1043\/455178\/20131100_0-00015.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/anesthesiology.pubs.asahq.org\/article.aspx?volume=119&page=1043","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T15:23:13Z","timestamp":1735831393000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1097\/ALN.0b013e3182a8a8e7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,11]]},"references-count":31,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2013]]}},"URL":"https:\/\/doi.org\/10.1097\/aln.0b013e3182a8a8e7","relation":{},"ISSN":["0003-3022"],"issn-type":[{"value":"0003-3022","type":"print"}],"subject":[],"published":{"date-parts":[[2013,11]]}}}