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RYR2 encodes the cardiac ryanodine receptor, a sarcoplasmic reticulum Ca²⁺ release channel essential for excitation–contraction coupling. Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy in the absence of abnormal loading conditions and is most often inherited in an autosomal dominant pattern. While RYR2 is well established in arrhythmia syndromes, its role in primary HCM remains underexplored.
No definitive RYR2 pathogenic variants have been reported in unrelated HCM probands, and large HCM cohorts have not identified RYR2 as a sarcomeric or channelopathy gene, suggesting limited human genetic evidence for a direct association (PMID:39803791). Molecular autopsy and family studies of idiopathic left ventricular hypertrophy have similarly failed to detect RYR2 variants in individuals meeting HCM criteria, distinguishing idiopathic LVH from HCM (PMID:32011662).
Functional overlap is suggested by studies of left ventricular noncompaction, revealing enrichment of RYR2 exon deletions in phenotypic spectra that include HCM-like hypertrophy (PMID:33500567). Cellular models of RYR2 mutations (e.g., E3987A) demonstrate altered Ca²⁺ sensitivity and channel gating, providing mechanistic plausibility for hypertrophic remodeling through disrupted Ca²⁺ homeostasis (PMID:11429443).
Extensive in vitro and animal model work illustrates that RYR2 gain- and loss-of-function mutations provoke calcium dysregulation, with downstream effects on cardiomyocyte growth and survival. Mutations in the central and C-terminal domains disrupt inter-domain interactions, leading to abnormal Ca²⁺ release events analogous to those driving myocardial hypertrophy (PMID:16339485).
Conflicting evidence arises from idiopathic LVH studies, where broad channelopathy screening did not uncover RYR2 involvement, indicating that RYR2 is unlikely a common HCM gene. Given the absence of segregation or case–control data in bona fide HCM, clinical testing of RYR2 for HCM is not currently supported.
In summary, RYR2 has compelling functional plausibility for hypertrophic remodeling but lacks human genetic validation in HCM cohorts. Additional proband-level studies and segregation analyses are required to clarify its clinical utility in HCM diagnosis.
Key Take-home: Functional data support RYR2 as a modifier of cardiomyocyte calcium signaling, but current human genetic evidence for primary HCM is limited, precluding routine diagnostic testing.
Gene–Disease AssociationLimitedNo unrelated HCM probands; association inferred from review and cohort studies without direct RYR2 HCM variants Genetic EvidenceLimitedAbsence of pathogenic RYR2 variants in HCM case series and lack of segregation data Functional EvidenceModerateMultiple in vitro and animal models demonstrate RYR2 mutations disrupt Ca²⁺ handling relevant to myocardial hypertrophy |