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Study Description

Malignant hyperthermia (MH) is a genetic disorder that causes a profound metabolic derangement following exposure to certain anesthetics. While approximately half of all cases are associated with ryanodine receptor-1 gene (RYR1) mutations, many cases have an unknown genetic cause. We sought to identify rare variants in novel MH candidate genes by sequencing the protein-coding regions of the genomes of individuals whose disease was either ruled in or out by the gold-standard diagnostic test. We also carefully selected individuals from well-characterized families to use gene-sharing information and maximize efficiency in the study design. Exome sequencing has helped identify the causes of over a dozen Mendelian disorders, has high power at low sample sizes, and is cost-efficient compared to whole-genome sequencing.

  • Study Type: Case Set
  • Number of study subjects that have individual level data available through Authorized Access: 13

Authorized Access
Publicly Available Data (Public ftp)

Connect to the public download site. The site contains release notes and manifests. If available, the site also contains data dictionaries, variable summaries, documents, and truncated analyses.

Study Inclusion/Exclusion Criteria

Inclusion Criteria:

  • Positive IVCT biopsy
  • Positive family history for MH

Exclusion Criteria:

  • Minor aged subject
  • Genetic variant in known causal gene
  • Other familial muscle or metabolic disorders

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Exome Sequencing Illumina Genome Analyzer IIX N/A N/A
Exome Sequencing Illumina HiSeq 2000 N/A N/A
Study History

This cohort represents subjects with familial history of MH who underwent an in vitro contracture test (IVCT), the gold-standard diagnostic test, at the University of Leeds (Leeds, UK). In the test a sample is extracted from the vastus lateralis muscle on the side of the upper leg and contraction strength is measured following exposure to both halothane and caffeine in the laboratory. The muscle contracture is measured that is attributed to exposure to halothane, caffeine or both. Once a diagnosis of MH susceptibility was made, the known causal genes (RYR1 and CACNA1S) were sequenced using cDNA derived from the muscle samples. Certain subjects who lacked a mutation in a known gene were selected for exome sequencing and high-density single nucleotide polymorphism (SNP) genotyping by the Leeds and University of Washington teams. These samples were de-identified and transferred to Seattle, WA, USA, for sequencing and genotyping. Analysis of the first set of sequences is underway, as is recruitment of additional samples for sequencing.

Selected publications
Diseases/Traits Related to Study (MESH terms)
Links to Related Resources
Authorized Data Access Requests
Study Attribution
  • Principal Investigator
    • Jerry Kim, MD. Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA, USA
  • Co-Principal Investigator
    • Gail Jarvik, MD, PhD. Department of Medicine, Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA, USA
  • Co-Investigator
    • Philip Hopkins, MD. Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
  • Genetic Statistician
    • Brian Browning, PhD. Department of Medicine, Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA, USA
  • Funding Source
    • Grant 265508. Washington State Life Sciences Discovery Fund
  • Funding Source (PI: Nora Disis, University of Washington, Seattle, WA, USA)
    • NIH KL2 RR025015. National Institutes of Health, Bethesda, MD, USA
  • Sequencing Center
    • Northwest Genomics Center (NWGC; Director: Deborah Nickerson). University of Washington, Seattle, WA, USA
  • Funding Source for Sequencing
    • HG005608. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA