Next Generation Mendelian Genetics: Malignant Hyperthermia

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.]]>
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 ]]>
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.]]>