King-Denborough syndrome

Summary

King-Denborough syndrome (MONDO:0020485) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 612

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		18	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	King-Denborough syndrome
Mondo ID	MONDO:0020485
MeSH	C536883, C537504
OMIM	619542
Orphanet	99741
SNOMED CT	764957003
UMLS	C1840365
MedGen	327082
GARD	0008433
Is cancer (heuristic)	no

Also known as: anesthetic-induced malignant hyperpyrexia in children · King Denborough syndrome · Koussef-Nichols syndrome · Kousseff Nichols syndrome · Noonan like contracture myopathy hyperpyrexia

Data availability: 612 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › multiple congenital anomalies/dysmorphic syndrome › multiple congenital anomalies/dysmorphic syndrome-variable intellectual disability syndrome › King-Denborough syndrome

Related subtypes (68): acromegaloid facial appearance syndrome, Hypoglossia-hypodactyly syndrome, Brachymorphism-onychodysplasia-dysphalangism syndrome, campomelic dysplasia, cerebrocostomandibular syndrome, autosomal dominant popliteal pterygium syndrome, Pallister-Hall syndrome, autosomal dominant primary microcephaly, microgastria-limb reduction defect syndrome, Mobius syndrome, oculodentodigital dysplasia, Char syndrome, Prader-Willi syndrome, Silver-Russell syndrome, ulnar-mammary syndrome, short stature-wormian bones-dextrocardia syndrome, ablepharon macrostomia syndrome, Goodman syndrome, anophthalmia/microphthalmia-esophageal atresia syndrome, microphthalmia with limb anomalies, Antley-Bixler syndrome, campomelia, Cumming type, CHARGE syndrome, Toriello-Carey syndrome, Donnai-Barrow syndrome, lethal faciocardiomelic dysplasia, hypertrichotic osteochondrodysplasia Cantu type, hypomandibular faciocranial dysostosis, isotretinoin-like syndrome, split hand-foot malformation 3, oculotrichoanal syndrome, Hennekam-Beemer syndrome, Mietens syndrome, Schinzel-Giedion syndrome, SHORT syndrome, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, occipital horn syndrome, hydrocephalus-costovertebral dysplasia-Sprengel anomaly syndrome, Potocki-Shaffer syndrome, Marshall-Smith syndrome, PHACE syndrome, Noonan syndrome-like disorder with loose anagen hair, branchiogenic deafness syndrome, combined immunodeficiency with faciooculoskeletal anomalies, chromosome 1p32-p31 deletion syndrome, Malan overgrowth syndrome, dysmorphism-conductive hearing loss-heart defect syndrome, TELO2-related intellectual disability-neurodevelopmental disorder, short stature-heart defect-craniofacial anomalies syndrome, arachnodactyly-intellectual disability-dysmorphism syndrome, polyvalvular heart disease syndrome, Kallmann syndrome-heart disease syndrome, Meier-Gorlin syndrome, symptomatic form of Coffin-Lowry syndrome in female carriers, Prader-Willi-like syndrome, contractures-developmental delay-Pierre Robin syndrome, 22q11.2 deletion syndrome, Noonan syndrome, Carpenter syndrome, Bosley-Salih-Alorainy syndrome, Sotos syndrome, Robinow syndrome, Weiss-Kruszka syndrome, retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome, omphalocele-diaphragmatic hernia-cardiovascular anomalies-radial ray defect syndrome, 4q25 proximal deletion syndrome, restrictive dermopathy 1, mosaic SMO syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

373 uncertain significance, 79 conflicting classifications of pathogenicity, 41 benign, 26 likely pathogenic, 22 likely benign, 21 benign/likely benign, 18 pathogenic/likely pathogenic, 11 pathogenic, 5 pathogenic; drug response, 3 likely pathogenic; drug response, 1 pathogenic/likely pathogenic; drug response

ClinVar	Variant (HGVS)	Gene	Classification	Review
590611	NM_000540.3(RYR1):c.8342_8343del (p.Ile2781fs)	LOC126862902	Pathogenic	criteria provided, multiple submitters, no conflicts
12964	NM_000540.3(RYR1):c.1840C>T (p.Arg614Cys)	RYR1	Pathogenic; drug response	reviewed by expert panel
12970	NM_000540.3(RYR1):c.7300G>A (p.Gly2434Arg)	RYR1	Pathogenic; drug response	reviewed by expert panel
12977	NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met)	RYR1	Pathogenic	reviewed by expert panel
132994	NM_000540.3(RYR1):c.10348-6C>G	RYR1	Pathogenic	reviewed by expert panel
133061	NM_000540.3(RYR1):c.14210G>A (p.Arg4737Gln)	RYR1	Pathogenic	reviewed by expert panel
133098	NM_000540.3(RYR1):c.14918C>T (p.Pro4973Leu)	RYR1	Pathogenic/Likely pathogenic	reviewed by expert panel
133102	NM_000540.3(RYR1):c.1597C>T (p.Arg533Cys)	RYR1	Pathogenic; drug response	reviewed by expert panel
133108	NM_000540.3(RYR1):c.1841G>T (p.Arg614Leu)	RYR1	Pathogenic; drug response	reviewed by expert panel
1431756	NM_000540.3(RYR1):c.4674dup (p.Asn1559fs)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454292	NM_000540.3(RYR1):c.14130-2A>G	RYR1	Pathogenic	criteria provided, multiple submitters, no conflicts
199203	NM_000540.3(RYR1):c.12499G>T (p.Glu4167Ter)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2168951	NM_000540.3(RYR1):c.2449C>T (p.Arg817Ter)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224998	NM_000540.3(RYR1):c.10347+1G>A	RYR1	Pathogenic	reviewed by expert panel
3024255	NM_000540.3(RYR1):c.14804G>A (p.Gly4935Asp)	RYR1	Pathogenic	criteria provided, single submitter
3583767	NM_000540.3(RYR1):c.718C>T (p.Gln240Ter)	RYR1	Pathogenic	criteria provided, single submitter
420588	NM_000540.3(RYR1):c.14761TTC[3] (p.Phe4924del)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
42098	NM_000540.3(RYR1):c.10204T>G (p.Cys3402Gly)	RYR1	Pathogenic	reviewed by expert panel
422691	NM_000540.3(RYR1):c.5340_5341del (p.Cys1781fs)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4277460	NM_000540.3(RYR1):c.6700C>A (p.Arg2234Ser)	RYR1	Pathogenic	criteria provided, single submitter
451330	NM_000540.3(RYR1):c.9472+1G>A	RYR1	Pathogenic	reviewed by expert panel
478201	NM_000540.3(RYR1):c.14833C>T (p.Arg4945Ter)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
478250	NM_000540.3(RYR1):c.6274+1G>A	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
497120	NM_000540.3(RYR1):c.8929_8932+4delinsAAGCGG	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523793	NM_000540.3(RYR1):c.9847C>T (p.Arg3283Ter)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
544398	NM_000540.3(RYR1):c.1250T>C (p.Leu417Pro)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
571022	NM_000540.3(RYR1):c.1342A>T (p.Ile448Phe)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
590394	NM_000540.3(RYR1):c.12063_12064dup (p.Met4022fs)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
590421	NM_000540.3(RYR1):c.12978del (p.Glu4327fs)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
590479	NM_000540.3(RYR1):c.15016G>A (p.Gly5006Ser)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · Orphanet: 12 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RYR1	Supportive	Autosomal dominant	King-Denborough syndrome	22

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RYR1	Orphanet:169186	Autosomal recessive centronuclear myopathy
RYR1	Orphanet:169189	Autosomal dominant centronuclear myopathy
RYR1	Orphanet:178145	Moderate multiminicore disease with hand involvement
RYR1	Orphanet:324581	Benign Samaritan congenital myopathy
RYR1	Orphanet:33108	Lethal multiple pterygium syndrome
RYR1	Orphanet:423	Malignant hyperthermia of anesthesia
RYR1	Orphanet:424107	Congenital myopathy with myasthenic-like onset
RYR1	Orphanet:466650	Exercise-induced malignant hyperthermia
RYR1	Orphanet:597	Central core disease
RYR1	Orphanet:700188	Calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy
RYR1	Orphanet:98905	Congenital multicore myopathy with external ophthalmoplegia
RYR1	Orphanet:99741	King-Denborough syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RYR1	Ryanodine receptor 1	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Ion channel	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
gluteal muscle	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RYR1	2,177

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RYR1	P21817	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Ion homeostasis	1	203.9×	0.016	RYR1
Stimuli-sensing channels	1	135.9×	0.016	RYR1
Cardiac conduction	1	108.8×	0.016	RYR1
Ion channel transport	1	96.0×	0.016	RYR1
Muscle contraction	1	77.2×	0.016	RYR1
Transport of small molecules	1	25.1×	0.040	RYR1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to caffeine	1	2407.4×	0.003	RYR1
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	1685.2×	0.003	RYR1
cellular response to caffeine	1	1532.0×	0.003	RYR1
ossification involved in bone maturation	1	1404.3×	0.003	RYR1
striated muscle contraction	1	842.6×	0.004	RYR1
skeletal muscle fiber development	1	543.6×	0.005	RYR1
skin development	1	443.5×	0.005	RYR1
regulation of cytosolic calcium ion concentration	1	383.0×	0.005	RYR1
release of sequestered calcium ion into cytosol	1	343.9×	0.005	RYR1
outflow tract morphogenesis	1	306.4×	0.005	RYR1
protein homotetramerization	1	237.3×	0.006	RYR1
muscle contraction	1	208.1×	0.006	RYR1
cellular response to calcium ion	1	200.6×	0.006	RYR1
calcium ion transport	1	181.2×	0.006	RYR1
response to hypoxia	1	95.8×	0.010	RYR1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RYR1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RYR1	16	Binding:13, Functional:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	RYR1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RYR1	16	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.