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RYR1 encodes the skeletal muscle ryanodine receptor, a Ca²⁺ release channel critical for excitation–contraction coupling. Heterozygous pathogenic variants in RYR1 cause malignant hyperthermia susceptibility type 1, an autosomal dominant pharmacogenetic disorder characterized by uncontrolled muscle contracture, hypermetabolism, and hyperthermia upon exposure to triggering anesthetics. Genetic heterogeneity and variable penetrance have been well documented, yet the RYR1 association meets Definitive ClinGen criteria based on extensive linkage, segregation, and functional data.
Early linkage analyses identified RYR1 on chromosome 19q13.1 with a lod score of 4.2 across 338 informative meioses, co-segregating with malignant hyperthermia in families and pigs, and pinpointed a C1843T (p.Arg615Cys) substitution as causative across species barriers (PMID:1341035). Subsequent human studies confirmed autosomal dominant inheritance with robust genotype–phenotype correlation in multiple pedigrees.
The c.1840C>T (p.Arg614Cys) variant co-segregated with malignant hyperthermia susceptibility in a German family, with 11 carriers (10 heterozygotes, 1 homozygote) exhibiting positive in vitro contracture tests and clinical crises (PMID:11493496). Larger mutation screens in 105 unrelated MH families identified 21 distinct RYR1 missense mutations, including hotspot regions in MH/CCD domains 1 (residues 35–614) and 2 (residues 2163–2458), with nearly perfect concordance between genetic results and contracture test phenotypes (PMID:10484775). In a Swiss cohort, RYR1 variants were found in 19 of 48 families (40%), with recurrent alleles such as p.Val2168Met and p.Thr2206Met reaching up to 27% frequency and correlating with more severe contracture responses (PMID:11668625).
To date, over 22 missense substitutions (Arg163Cys, Gly341Arg, Ile403Met, Arg552Gln/Trp, Arg614Leu/Cys/His, Gly2434Arg, Arg2435His/Cys, Arg2458His/Cys, Thr2206Met, Val2168Met/Leu/Ala, etc.) have been reported, with no truncating alleles, reflecting a gain-of-function mechanism. A recurrent founder variant, c.6617C>T (p.Thr2206Met), is prevalent in European MH cohorts (PMID:11668625).
Functional studies in heterologous systems and patient myotubes demonstrate that MH-associated RYR1 mutants show hypersensitivity to caffeine and halothane, increased resting Ca²⁺ leak, reduced Ca²⁺ inactivation, and altered [³H]ryanodine binding consistent with a hyperexcitable channel state (PMID:9030597; PMID:9334205). Animal models and contracture assays further corroborate the causal role of RYR1 gain-of-function in hypermetabolic crises.
No credible studies have refuted the RYR1–MH association, though genetic heterogeneity implies that other loci may also predispose to malignant hyperthermia. Current evidence saturates the ClinGen scoring framework, supporting a Definitive classification.
In conclusion, autosomal dominant RYR1 variants causing hyperactive Ca²⁺ release channels underlie malignant hyperthermia susceptibility type 1. Genetic testing of RYR1 provides a reliable noninvasive diagnostic tool to identify at-risk individuals and guide perioperative management.
Gene–Disease AssociationDefinitiveRobust linkage (lod 4.2, 338 meioses), multi‐family segregation and functional concordance Genetic EvidenceStrong11 segregating carriers in one pedigree; 21 missense variants in 105 MH families Functional EvidenceStrongMultiple heterologous and contracture assays show gain-of-function channel behavior |