Br J Anaesth. 2025 Dec 2:S0007-0912(25)00745-7. Revista: 10.1016/j.bja.2025.10.025. Online ahead of print.

BACKGROUND: Muscle biopsy and in vitro contracture testing remain the gold standard for presymptomatic diagnosis of malignant hyperthermia susceptibility. DNA analysis can be used when a familial variant is classified as pathogenic or likely pathogenic. For this, variants must meet a range of criteria, one of which is functional analysis in an approved system that demonstrates hypersensitivity of calcium release when exposed to an appropriate agonist.

METHODS: Seven patients with a clinical history of malignant hyperthermia were screened for the presence of variants in RYR1 by amplicon or whole exome sequencing. Six variants in RYR1 were subsequently introduced into the cDNA encoding the human ryanodine receptor and tested in human embryonic kidney cells for their effect on calcium release from intracellular stores in response to 4-chloro-m-cresol using fura-2 as a calcium indicator. Each variant was subjected to in silico curation using the European Malignant Hyperthermia Group (EMHG) scoring matrix and ClinGen RYR1 Variant Curation Expert Panel guidelines.

RESULTS: All six RYR1 variants studied (p.Gln464Lys, p.Asp2431Val, p.Val2354Met, p.Ser2542Asn, p.Val2627Leu, and p.Pro4973Leu) were hypersensitive to 4-chloro-m-cresol. Using the EMHG scoring matrix, four variants (p.Gln464Lys, p.Asp2431Val, p.Val2354Met, and p.Val2627Leu) were reclassified as pathogenic, one variant (p.Pro4973Leu) was upgraded from likely pathogenic to pathogenic, and one variant (p.Ser2542Asn) remained as ‘uncertain significance’.

CONCLUSIONS: Four additional RYR1 variants can be added to the list of RYR1 disease-associated variants managed by the EMHG and can therefore be used diagnostically in the future. One variant can be upgraded from likely pathogenic to pathogenic, whereas one remains as a variant of unknown significance.

PubMed:41339169 | Revista:10.1016/j.bja.2025.10.025