Genomic Screening for Malignant Hyperthermia Susceptibility

Leslie G. Biesecker, M.D.; Robert T. Dirksen, Ph.D.; Thierry Girard, M.D.; Philip M. Hopkins, M.D.; Sheila Riazi, M.D.; Henry Rosenberg, M.D.; Kathryn Stowell, Ph.D.; James Weber, Ph.D.


Anesthesiology. 2020;133(6):1277-1282. 

In This Article

Research to Identify all Genetic Loci That Cause or Contribute to MH Susceptibility

Genomic technologies are rapidly advancing, primarily due to chip-based DNA testing platforms[13] and next generation sequencing.[14] Whereas Sanger sequencing of RYR1 and CACNA1S has been, and remains, expensive, next generation sequencing panel tests that include these genes are now available at costs well below that of Sanger sequencing. Next generation exome and genome sequencing are increasingly available in many countries and becoming an affordable part of research and health care. These rapid advances and falling costs enable both research and clinical genomic testing that were inconceivable just a few years ago. They enable rapid identification of sequence variants in individuals with putative inherited diseases. However, these variants may number several thousand in each sample and predicting which variant(s) is(are) implicated in the disease can be challenging. In MH susceptibility where a single missense variant may be all that is required, once variants in RYR1, CACNA1S, and STAC3 have been excluded, this approach has proved fruitless to date. So far, relatively few samples from MH-susceptible individuals have undergone exome or genome sequencing. If a larger number can be sequenced, we will more likely be able to identify rare recurrent variants or genes that have an increased burden of rare variants. We propose that there should be a coordinated program of clinical and research testing such that every individual with an MH reaction or positive contracture test is evaluated by next generation sequencing to increase the chances of identifying the causative variant(s). This should be a mix of both clinical testing and clinical research testing. Clinical sequencing of known MH susceptibility–associated genes is available from a number of laboratories (see the appendix). Deidentified data from all who are sequenced and found to harbor a pathogenic, or likely pathogenic variant (determined as per Richards et al. and Harrison et al.[15,16]), should be deposited in a public repository, such as ClinVar or a dedicated MH database so that all can benefit from this knowledge. Individuals who are not found to have an unambiguously pathogenic variant should be referred to a clinical research program to be further evaluated to better understand the genetic basis of this disease. The pooling and organization of these cases and data will add immeasurably to efforts to fully catalog genetic variation associated with MH susceptibility.

Escalation to next generation sequencing may also prove useful in cases where MH susceptibility is apparently more genetically complex,[12,17] especially if combinations of rare variants are involved. However, if the genetic model involves combinations of several more common variants, sample sizes will need to be even larger and single nucleotide polymorphism chip genotyping is likely to be more cost-effective.