RYR1 – King-Denborough Syndrome

King-Denborough syndrome is a rare congenital myopathy characterised by dysmorphic features, variable hypotonia, and susceptibility to malignant hyperthermia. Heterozygous missense variants in the skeletal muscle calcium release channel gene RYR1 have been implicated in King-Denborough syndrome (MONDO_0020485). Patients typically present with early hypotonia (HP:0001252) and myopathy (HP:0003198), often alongside facial dysmorphism and MH episodes.

A study of four unrelated families reported four heterozygous RYR1 missense mutations in three families and one novel allele in the fourth, with autosomal dominant inheritance and variable expressivity in King-Denborough syndrome. Protein analyses in two families showed marked reduction of RyR1 expression in skeletal muscle, supporting pathogenicity (PMID:21514828).

An additional case report described a child with congenital hypotonia and dysmorphic facies who developed malignant hyperthermia intraoperatively and was found to carry the recurrent RYR1 variant c.7522C>T (p.Arg2508Cys). This variant, previously associated with MH, was the first documented in King-Denborough syndrome and expanded the phenotypic spectrum of RYR1-related myopathies (PMID:27918309).

In a recent cohort of 67 Black African patients with congenital myopathy, 44 were diagnosed with King-Denborough syndrome and RYR1 biallelic variants were identified as one of the two predominant genetic causes, indicating autosomal recessive presentations alongside the classical dominant mode (PMID:39966651).

Functional assays across MH and core myopathy studies demonstrate that RYR1 missense mutations alter channel sensitivity to activating ligands (e.g., caffeine, halothane) and perturb calcium homeostasis, consistent with MH susceptibility and myopathic features. The concordance between in vitro contracture tests, calcium imaging, and protein expression studies underpins a plausible haploinsufficiency and leaky‐channel mechanism in King-Denborough syndrome.

Although some patients with clinical King-Denborough syndrome lack detectable RYR1 variants, indicating further genetic heterogeneity, the cumulative genetic and experimental data support a Moderate ClinGen clinical validity classification. Continued discovery in underrepresented populations and detailed segregation studies will refine risk estimates. Key take-home: RYR1 testing can inform diagnosis, perioperative management, and genetic counseling in King-Denborough syndrome.

References

• A & A case reports • 2017 • Intraoperative Presentation of Malignant Hyperthermia (Confirmed by RYR1 Gene Mutation, c.7522C>T; p.R2508C) Leads to Diagnosis of King-Denborough Syndrome in a Child With Hypotonia and Dysmorphic Features: A Case Report. PMID:27918309
• Neuromuscular disorders : NMD • 2011 • King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene. PMID:21514828
• European journal of human genetics : EJHG • 2025 • Biallelic variants in RYR1 and STAC3 are predominant causes of King-Denborough Syndrome in an African cohort. PMID:39966651

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