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

Develop and Pilot Genomic Screening Techniques

A future is coming where large numbers of individuals undergo genome-wide screening that encompasses many disease and pharmacogenetic susceptibilities: it is essential to develop evidence to support this approach on a disease-by-disease basis. We propose that a trial of preoperative screening for MH susceptibility would serve as a proof of principle to test the applicability and utility of extracting MH-associated variants from genomic or exomic data. Once a suitable set of pathogenic variants is identified, genomic screening for MH susceptibility could be piloted on a population of individuals scheduled for elective surgery. The size and power analysis of such a study will require more accurate estimates of prevalence and the diagnostic yield of a given set of pathogenic variants. We propose that this could be fruitful, even without a clear understanding of penetrance of the variants, because one could eliminate MH reactions if every person with an at-risk genotype was administered a nontriggering agent. While general population screening for MH susceptibility will likely not be practical for some time, an ever-increasing number of individuals with variants in RYR1 and CACNA1S are being identified through secondary findings from exome and genome sequencing.[20,21] These individuals provide opportunities to study and pilot approaches to presymptomatic diagnosis. When MH-susceptible individuals are identified through preoperative screening or secondary findings, and there is no personal or family history of suspected MH, the presence of the variant represents the only known risk factor for MH susceptibility in the family. Identifying an individual with MH susceptibility is an opportunity to classify all members within a family, where the risk of having MH (50% for first-degree relatives) is orders of magnitude greater than the general population. Prospective determination of risk of relatives can therefore be made by testing for the single variant, which is simpler to perform and interpret than is exome, panel, or even full gene testing as the laboratory does not need to interpret other variants.