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.

Disclosures

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

In This Article

Establish the Pathogenicity of all Variants in Genes That Cause or Contribute to MH Susceptibility

Efforts are underway to comprehensively characterize the pathogenicity of reported variants in RYR1 and CACNA1S through the ClinGen Variant Curation Expert Panel process (https://www.clinicalgenome.org/affiliation/50038/, accessed August 25, 2020). This effort is initially focused on the variants proposed by the European Malignant Hyperthermia Group (https://www.emhg.org/, accessed August 25, 2020), with an adaptation of the American College of Medical Genetics and Genomics variant pathogenicity standards.[15] These standards, which must be adapted to take into account knowledge of the biology of RYR1 and malignant hyperthermia susceptibility, comprise 27 criteria including observations of inheritance, case-control studies, functional studies, and in silico predictors, and conforms to the current international standard for variant pathogenicity assertions. A major deficit in being able to assign pathogenic status is the small number of variants that have been robustly functionally characterized in relevant model systems. Current testing is robust, but low throughput. A recent revolution in functional genomics heralds a realistic prospect of overcoming this bottleneck. Prime editing, an adaptation of CRISPR technology,[18] coupled with strategies for high-throughput functional assays[19] have the potential to support highly robust functional assessments of all variants, even before they are detected in a human. If these technologies can be adapted to RYR1 and other genes implicated in MH susceptibility, they have the potential to provide for high-throughput, low-cost, functional in vitro assays for every potential variant. This task is not trivial, but it should be feasible. Even achieving a goal of assessing the pathogenicity of variants that can account for 80% of known cases of MH susceptibility would create a set of pathogenic variants that could be employed for clinical research to test the practicality of preoperative screening.

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