Malignant Hyperthermia in Slavonic cohort – clinical and genetic findings beyond standard diagnostics

Malignant Hyperthermia (MH) is a rare, hereditary, life-threatening pharmacogenetic disorder. The genetic background of MH was identified only in approximately half of MH-susceptible (MHS) patients, differing between geographical areas. Variants recognised as being sufficiently functionally characterised to be used in diagnostics for MH are on the “European Malignant Hyperthermia Group list of diagnostic variants”. However, the list may be a bit biased in the sense of rare variants in favour of better-described and published MHS cohorts. Also, the understanding of MH genetics is incomplete, with no variant identified in a significant number of cases. Aimed to investigate the clinical features, detected gene variants, and potential genotype-phenotype correlations in Slavonic patients with MH. Retrospective analysis of clinical data and molecular genetic characteristics was conducted on patients referred for possible MH during 20 + years of diagnostics at the Academic Centre for Malignant Hyperthermia of Masaryk University, Brno, Czech Republic. MH susceptibility was confirmed in 94 families, containing 254 individuals. 79% of our MHS probands were diagnosed based on MH-related adverse anaesthesia complications in personal/family history. Pathogenic/Likely-pathogenic MH variants in the RYR1 gene were detected in 48% of MHS families. In 18% of MHS patients, 14 variants of unclear significance (VUS) were detected. Three of these VUS were detected in more than one unrelated family - c.1589G>A p.(Arg530His), c.1598G>A p.(Arg533His), and c.6742C>T p.(Arg2248Cys). We detected five families with one example of genotype-phenotype discordance. Still, in 34% of MHS probands, no variants were detected. Expanded diagnostics with neuromuscular panels or exome sequencing did not provide any additional benefit. We also presented the list of five patients with detected VUS and MH-negative In Vitro Contracture Test (IVCT). This study presents the largest Slavonic cohort of patients investigated for risk of MH. Nearly half of the detected RYR1 variants were VUS, though most appear as likely pathogenic for MH in our cohort and could be considered for a change in pathogenicity criteria. Still, over a third of MHS patients lack a confirmed genetic basis and may benefit from future advances in molecular genetic diagnostics and new scientific knowledge. This is a retrospective observational national cohort study reported according to STROBE guidelines (https://www.strobe-statement.org/index.php?id=strobe-home). The study was registered on 05/09/2021 at ClinicalTrials.gov (ID: NCT05036148).