Background/Objectives: Malignant hyperthermia (MH) is a pharmacogenetic hypermetabolic syndrome triggered by halogenated agents/succinylcholine. Most families present variants in the RYR1 and, rarely, in other genes (CACNA1S/STAC3/ASPH). However, each country or region presents differences in the type and frequency of MH variants. Objective: To present the genetic characteristics of Brazilian individuals with MH history. Methods: We reviewed clinical and laboratory data from all families referred for evaluation in the Brazilian MH unit due to a personal or family history of MH during anesthesia. Demographic and clinical data were collected, as well as serum creatine kinase (CK) levels, in vitro contracture test (IVCT) results, and the results of anatomopathological studies of skeletal muscle. Molecular analysis was performed using whole-exome sequencing (WES). Patients with and without variants were compared. Results: WES analysis was available for 61 patients (29 patients who survived an MH crisis and 32 relatives). Variants in the RYR1 were found in 38 patients (62.2%), and no variants were identified in 20 patients (32.7%). More than one variant in the RYR1 was found in six individuals. Variants in the CACNA1S were found in three patients (4.9%), all of them with concomitant variants in the RYR1. Three patients presented variants in the STAC3 (4.9%). Comparing the groups of patients with variants in the RYR1 with the one with no variants in this gene, it was observed that the first group showed higher levels of serum CK, a greater frequency of ptosis, strabismus, and cores, and a higher amplitude of contracture in the IVCT after caffeine or halothane. Conclusion: In this preliminary evaluation of Brazilian individuals with MH history, the frequency of RYR1 variants was similar to those of previous reports in other countries, but there was a higher frequency of STAC3 and CACNA1S variants.

Background/Objectives: Variants in the RYR1 gene are associated mainly with Malignant Hyperthermia. Missense variants are largely the most common, while insertions and duplications account for less than 10%. We aimed to investigate the effect of a rare duplication in the RYR1 gene with the variability of the Malignant Hyperthermia susceptibility phenotype. Methods: We used exome variant screening, in vitro contracture test, anatomopathological examination of the muscle biopsy, RT-qPCR analysis for RYR1 relative expression. Results: We identified a family with two affected siblings carrying an insertion of 18 pair bases in exon 91 of the RYR1 gene, resulting in an in-frame duplication of 6 amino acids (c.12835_12852 dupGAGGGCGCGGCGGGGCTC: 162 p.G4279_T4284insAAGLEG). This variant was found at a frequency of 0.0007% in gnomAD and was absent in 1200 Brazilian controls. First classified as a Variant of Uncertain Significance (VUS), with the molecular and physiological data from our family, we were able to reclassify it, reaching 5 points, which is still a VUS but borderline likely pathogenic. Muscle relative mRNA expression of RYR1 in the two patients identified a ~50% reduction, suggesting a possible hypomorphic allele. Conclusions: The pathomechanisms of RYR1 gene variants in Malignant Hyperthermia are mainly associated with gain-of-function mechanisms, but small insertions can often lead to loss of function or improper folding protein. This study adds evidence to the possibility that duplication in this region can cause structural defects and a more severe phenotype in the patients.