Malignant hyperthermia susceptibility (MHS; OMIM 145600, 601887) is a pharmacogenetic condition in which exposure to volatile anesthetics and/or succinylcholine can trigger a potentially life-threatening hypermetabolic crisis of skeletal muscle. MHS is predominantly associated with pathogenic variants in RYR1, whereas CACNA1S contributes a substantially smaller proportion of genetically confirmed cases. Estimating the population prevalence of MHS is challenging because manifestation requires exposure to a triggering agent, penetrance is incomplete, and the evidentiary strength supporting individual variants varies considerably. In this study, MHS-associated RYR1 and CACNA1S variants were compiled from four complementary resources—EMHG, ClinGen MHS VCEP, HGMD, and ClinVar—and subjected to source-specific pathogenicity and phenotype filtering. A total of 13,918 unique reported variants were initially identified. Progressive evidence-based curation generated three nested variant tiers: a high-confidence Expert tier comprising 102 variants; an expanded HGMD-inclusive tier comprising 446 variants; and a full expanded ClinVar-inclusive tier comprising 593 variants. Population allele frequencies were evaluated using gnomAD v4.1.0 and the Russian GDB v1.3.4 database. The high-confidence Expert tier yielded genetically inferred MHS frequencies of approximately 1 in 807 in gnomAD and 1 in 1078 in GDB. Inclusion of HGMD-derived variants increased the corresponding estimates to approximately 1 in 50 and 1 in 104, respectively.

The article considers key factors affecting choice of patients in favor of or against genetic testing. The emphasis is made upon such psychological aspects as fear of results, impact on self-identity and health perception. The survey of 699 patients established emotional hesitations they experience at making decision on behalf of genetic testing. The study results demonstrate that many patients encounter internal conflicts related to possible consequences of testing for their health and future. The article emphasizes importance of support from medical workers and psychologists in the decision-making process regarding genetic testing. The emphasis is also made upon necessity of development of information programs that will help patients to better understand consequences of their choices and to improve communication with relatives. It is important that patients have access to high-quality information and emotional support that will permit them to approach more consciously to issues of genetic testing and to make decisions corresponding to their personal values and expectations. This approach can significantly increase level of satisfaction and trust in patients.