{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T21:28:00Z","timestamp":1790285280273,"version":"4.1.0"},"reference-count":40,"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>About half of malignant hyperthermia (MH) cases are associated with skeletal muscle ryanodine receptor 1 (<jats:italic toggle=\"yes\">RYR1<\/jats:italic>) and calcium channel, voltage-dependent, L type, \u03b11S subunit (<jats:italic toggle=\"yes\">CACNA1S<\/jats:italic>) gene mutations, leaving many with an unknown cause. The authors chose to apply a sequencing approach to uncover causal variants in unknown cases. Sequencing the exome, the protein-coding region of the genome, has power at low sample sizes and identified the cause of over a dozen Mendelian disorders.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>The authors considered four families with multiple MH cases lacking mutations in <jats:italic toggle=\"yes\">RYR1<\/jats:italic> and <jats:italic toggle=\"yes\">CACNA1S<\/jats:italic> by Sanger sequencing of complementary DNA. Exome sequencing in two affecteds per family, chosen for maximum genetic distance, were compared. Variants were ranked by allele frequency, protein change, and measures of conservation among mammals to assess likelihood of causation. Finally, putative pathogenic mutations were genotyped in other family members to verify cosegregation with MH.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>Exome sequencing revealed one rare <jats:italic toggle=\"yes\">RYR1<\/jats:italic> nonsynonymous variant in each of three families (Asp1056His, Val2627Met, Val4234Leu), and one <jats:italic toggle=\"yes\">CACNA1S<\/jats:italic> variant (Thr1009Lys) in the fourth family. These were not seen in variant databases or in our control population sample of 5,379 exomes. Follow-up sequencing in other family members verified cosegregation of alleles with MH.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>The authors found that using both exome sequencing and allele frequency data from large sequencing efforts may aid genetic diagnosis of MH. In a sample selected by the authors, this technique was more sensitive for variant detection in known genes than Sanger sequencing of complementary DNA, and allows for the possibility of novel gene discovery.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1097\/aln.0b013e3182a8a998","type":"journal-article","created":{"date-parts":[[2013,9,7]],"date-time":"2013-09-07T02:30:03Z","timestamp":1378521003000},"page":"1054-1065","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":56,"title":["Exome Sequencing Reveals Novel Rare Variants in the Ryanodine Receptor and Calcium Channel Genes in Malignant Hyperthermia Families"],"prefix":"10.1097","volume":"119","author":[{"given":"Jerry H.","family":"Kim","sequence":"first","affiliation":[{"name":"Assistant Professor, Department of Anesthesiology and Pain Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail 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