title: Using exome data to identify malignant hyperthermia susceptibility mutations.
abstract: BACKGROUND
  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 RYR1 and CACNA1S genes.
  
  
  METHODS
  Exome sequencing was performed on 870 volunteers not ascertained for MHS. Variants in RYR1 and CACNA1S 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.
  
  
  RESULTS
  The authors identified 70 RYR1 and 53 CACNA1S variants among 870 exomes. Sixty-three RYR1 and 41 CACNA1S variants passed the quality and frequency metrics but the authors excluded synonymous variants. In RYR1, the authors identified 65 missense mutations, one nonsense, two that affected splicing, and one non-frameshift indel. In CACNA1S, 48 missense, one frameshift deletion, one splicing, and one non-frameshift indel were identified. RYR1 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: * Research Associate, † Clinical Specialty Consultant, ‡ Staff Scientist, ‡‡ Branch Chief, Genetic Disease Research Branch, †† Director, National Institutes of Health Intramural Sequencing Center, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, Maryland. # Research Associate, ** Professor of Human Molecular Genetics, Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom. § 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. ‖ Members of the National Institutes of Health Intramural Sequencing Center group are listed in the appendix.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Gonsalves
authors.forename: David
authors.initials: D
authors.lastname: Ng
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Johnston
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Teer
authors.forename: Peter D
authors.initials: PD
authors.lastname: Stenson
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
mesh_terms: D000368:Aged; D015220:Calcium Channels / Q000235:genetics; D020746:Calcium Channels, L-Type; D015331:Cohort Studies; D030541:Databases, Genetic; D059472:Exome / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics* / Q000502:physiology*; D020125:Mutation, Missense / Q000235:genetics / Q000502:physiology; D019683:Penetrance; D011237:Predictive Value of Tests; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics
chemical_list: C412223:CACNA1S protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel