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RYR3 (ryanodine receptor 3) encodes a calcium‐release channel expressed in brain regions critical for neuronal excitability. Gain‐of‐function variants in RYR3 have been implicated in congenital myopathy type 20, and emerging evidence supports an autosomal dominant role in developmental and epileptic encephalopathy (DEE) (MONDO:0100062).
DEE due to RYR3 follows an autosomal dominant inheritance with de novo missense variants. A 10-month-old female presenting with West syndrome and global developmental delay harbored a novel heterozygous variant c.10943C>T (p.Thr3648Met) (PMID:39220738). Three additional unrelated DEE cases have been reported: two with de novo monoallelic missense variants and one compound heterozygote, all showing consistent infantile spasm syndrome and psychomotor impairment. In total, four unrelated probands support a recurrent genotype–phenotype correlation in RYR3‐related DEE.
No multigenerational transmission has been observed; all parents tested negative for the proband’s variant. The DEE‐associated RYR3 variants are exclusively missense, with c.10943C>T (p.Thr3648Met) being the first recurrent allele identified in classical infantile spasm syndrome. No loss‐of‐function or splice variants have been linked to DEE to date.
RYR3 forms homotetrameric Ca2+ release channels in hippocampus and cortex, modulating intracellular Ca2+ dynamics (PMID:8617786). Knockout of RyR3 in mice alters synaptic plasticity and social behavior, underscoring its role in neuronal network function (PMID:19503748). The DEE variants are hypothesized to confer a “leaky” gain‐of‐function effect on Ca2+ release channels, leading to neuronal hyperexcitability.
Collectively, four unrelated DEE cases with de novo or compound heterozygous RYR3 missense variants, coupled with functional studies demonstrating RYR3’s neuronal roles, support a Moderate ClinGen clinical validity classification for RYR3–related DEE. Additional studies are warranted to characterize variant‐specific channel dysfunction. Key take-home: screening for de novo RYR3 missense variants should be considered in unexplained infantile spasms and DEE.
Gene–Disease AssociationModerateFour unrelated probands with de novo or compound heterozygous missense RYR3 variants causing DEE with consistent clinical features Genetic EvidenceModerateFour unrelated probands harboring de novo or biallelic missense variants in RYR3 (including c.10943C>T (p.Thr3648Met)) Functional EvidenceLimitedGeneral RyR3 functional assays in brain models support role in Ca2+ homeostasis but no variant-specific studies |