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CACNA1S encodes the α1S subunit of the dihydropyridine receptor (DHPR), a voltage‐gated calcium channel essential for excitation–contraction coupling in skeletal muscle. Malignant hyperthermia susceptibility type 5 (MHS5; MONDO:0011163) is inherited in an autosomal dominant manner with incomplete penetrance and is characterized by a life‐threatening hypermetabolic response to volatile anesthetics and succinylcholine. Genetic testing can identify at‐risk individuals to guide anesthetic management.
Genetic evidence for CACNA1S‐MHS5 includes six distinct missense variants identified in six unrelated probands presenting with positive in vitro contracture test responses (PMID:28011884). Among these, c.3257G>T (p.Arg1086Leu) segregates with MH susceptibility in a multigenerational family (PMID:16163667). A large UK cohort study of 50 RYR1-negative MH patients identified a single potentially pathogenic CACNA1S variant p.Arg174Trp, underscoring locus heterogeneity (PMID:19825159).
All reported CACNA1S variants in MHS5 are protein‐altering missense changes clustering in domains critical for DHPR function. Recurrent variants include p.Arg1086Leu and p.Arg1086His in the S4 voltage sensor of domain III. Haplotype analysis demonstrated diverse background alleles across European populations, arguing against a simple founder effect.
Functional concordance is supported by pharmacogenetic studies showing that DHPR variants alter calcium release kinetics in muscle contracture assays, consistent with pathogenic gain‐of‐function. However, direct biophysical analyses of individual MHS5-associated CACNA1S variants in recombinant systems remain limited.
No studies have refuted the association, but incomplete penetrance and the requirement for modifier loci (e.g., RYR1 variants) necessitate cautious interpretation of solitary CACNA1S findings. Genetic heterogeneity in MH implicates both RYR1 and CACNA1S and underscores the need for comprehensive screening.
In summary, CACNA1S meets ClinGen Strong clinical validity criteria for MHS5 based on multiple unrelated families, segregation of key variants, and concordant pharmacogenetic data. Routine CACNA1S testing in MH workups enhances risk stratification and informs perioperative management.
Key Take-home: CACNA1S variant screening is clinically actionable for malignant hyperthermia risk mitigation.
Gene–Disease AssociationStrongSix unrelated families with CACNA1S pathogenic variants associated with positive in vitro contracture tests ([PMID:28011884]), including segregation of p.Arg1086Leu ([PMID:16163667]), and functional concordance in pharmacogenetic assays Genetic EvidenceModerateSix distinct pathogenic missense variants identified in six probands with MH susceptibility across independent families, with segregation documented for p.Arg1086Leu ([PMID:16163667]) Functional EvidenceLimitedContracture testing demonstrates abnormal calcium release in variant carriers, but direct mechanistic studies of CACNA1S variants in MH5 are lacking |