• Dorota Fiszer, Marie-Anne Shaw, Nickla A Fisher, Ian M Carr, Pawan K Gupta, Elizabeth J Watkins, Daniel Roiz de Sa, Jerry H Kim, and Philip M Hopkins.
• From the Leeds Institute of Biomedical & Clinical Sciences, School of Medicine, University of Leeds, Leeds, United Kingdom (D.F., M.-A.S., I.M.C., P.M.H.); Malignant Hyperthermia Investigation Unit, St. James's University Hospital, Leeds, United Kingdom (D.F., M.-A.S., N.A.F., P.K.G., E.J.W., P.M.H.); Environmental Medicine and Science Division, Institute of Naval Medicine, Alverstoke, Hampshire, United Kingdom (D.R.d.S.); and Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington (J.H.K.).
• Anesthesiology. 2015 May 1; 122 (5): 103310461033-46.

BackgroundVariants in RYR1 are associated with the majority of cases of malignant hyperthermia (MH), a form of heat illness pharmacogenetically triggered by general anesthetics, and they have also been associated with exertional heat illness (EHI). CACNA1S has also been implicated in MH. The authors applied a targeted next-generation sequencing approach to identify variants in RYR1 and CACNA1S in a cohort of unrelated patients diagnosed with MH susceptibility. They also provide the first comprehensive report of sequencing of these two genes in a cohort of survivors of EHI.MethodsDNA extracted from blood was genotyped using a "long" polymerase chain reaction technique, with sequencing on the Illumina GAII or MiSeq platforms (Illumina Inc., USA). Variants were assessed for pathogenicity using bioinformatic approaches. For further follow-up, DNA from additional family members and up to 211 MH normal and 556 MH-susceptible unrelated individuals was tested.ResultsIn 29 MH patients, the authors identified three pathogenic and four novel RYR1 variants, with a further five RYR1 variants previously reported in association with MH. Three novel RYR1 variants were found in the EHI cohort (n = 28) along with two more previously reported in association with MH. Two other variants were reported previously associated with centronuclear myopathy. The authors found one and three rare variants of unknown significance in CACNA1S in the MH and EHI cohorts, respectively.ConclusionsTargeted next-generation sequencing proved efficient at identifying diagnostically useful and potentially implicated variants in RYR1 and CACNA1S in MH and EHI.

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