Congenital multicore myopathy with external ophthalmoplegia

Summary

Congenital multicore myopathy with external ophthalmoplegia (MONDO:0009712) is a disease caused by RYR1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: RYR1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1,066
• Phenotypes (HPO): 44

Clinical features

Signs & symptoms

Clinical features (HPO)

44 HPO clinical features (Orphanet curated; top 44 by frequency):

HPO ID	Term	Frequency
HP:0000544	External ophthalmoplegia	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001558	Decreased fetal movement	Frequent (30-79%)
HP:0002058	Myopathic facies	Frequent (30-79%)
HP:0002795	Abnormal respiratory system physiology	Frequent (30-79%)
HP:0003327	Axial muscle weakness	Frequent (30-79%)
HP:0003557	Increased variability in muscle fiber diameter	Frequent (30-79%)
HP:0003560	Muscular dystrophy	Frequent (30-79%)
HP:0003701	Proximal muscle weakness	Frequent (30-79%)
HP:0003803	Type 1 muscle fiber predominance	Frequent (30-79%)
HP:0009025	Increased connective tissue	Frequent (30-79%)
HP:0010628	Facial palsy	Frequent (30-79%)
HP:0011805	Abnormal skeletal muscle morphology	Frequent (30-79%)
HP:0011807	Type 1 muscle fiber atrophy	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0031237	Internally nucleated skeletal muscle fibers	Frequent (30-79%)
HP:0100293	Muscle fiber hypertrophy	Frequent (30-79%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000046	Small scrotum	Occasional (5-29%)
HP:0000054	Micropenis	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000275	Narrow face	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000969	Edema	Occasional (5-29%)
HP:0001349	Facial diplegia	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0001561	Polyhydramnios	Occasional (5-29%)
HP:0002090	Pneumonia	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0003547	Shoulder girdle muscle weakness	Occasional (5-29%)
HP:0003798	Nemaline bodies	Occasional (5-29%)
HP:0008850	Severe postnatal growth retardation	Occasional (5-29%)
HP:0009046	Difficulty running	Occasional (5-29%)
HP:0010804	Tented upper lip vermilion	Occasional (5-29%)
HP:0011399	Tibialis atrophy	Occasional (5-29%)
HP:0012036	Sternocleidomastoid amyotrophy	Occasional (5-29%)
HP:0031139	Frog-leg posture	Occasional (5-29%)
HP:0040191	Rectus femoris muscle atrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital multicore myopathy with external ophthalmoplegia
Mondo ID	MONDO:0009712
OMIM	255320
Orphanet	98905
NCIT	C150608
UMLS	C1850674
MedGen	340597
GARD	0010316
Is cancer (heuristic)	no

Also known as: minicore myopathy, antenatal onset, with arthrogryposis · multicore myopathy with external ophthalmoplegia

Data availability: 1,066 ClinVar variants · 2 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › qualitative or quantitative protein defects in neuromuscular diseases › neuromuscular disease caused by qualitative or quantitative defects of selenoprotein N1 › multiminicore myopathy › congenital multicore myopathy with external ophthalmoplegia

Related subtypes (4): rigid spine muscular dystrophy 1, moderate multiminicore disease with hand involvement, antenatal multiminicore disease with arthrogryposis multiplex congenita, classic multiminicore myopathy

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:

247 uncertain significance, 173 conflicting classifications of pathogenicity, 46 benign/likely benign, 37 likely pathogenic, 35 benign, 21 pathogenic, 18 likely benign, 10 pathogenic/likely pathogenic, 7 pathogenic; drug response, 4 likely pathogenic; drug response, 1 uncertain significance; drug response, 1 drug response

ClinVar	Variant (HGVS)	Gene	Classification	Review
2627379	NM_000540.3(RYR1):c.[11941C>T;8342_8343del]		Pathogenic	no assertion criteria provided
29876	NM_000540.2(RYR1):c.[5726_5727delAG;9242T>C]		Pathogenic	no assertion criteria provided
1030857	NM_000540.3(RYR1):c.177dup (p.Asp60fs)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066833	NM_000540.3(RYR1):c.3223C>T (p.Arg1075Trp)	RYR1	Pathogenic/Likely 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
12976	NM_000540.3(RYR1):c.6502G>A (p.Val2168Met)	RYR1	Pathogenic; drug response	reviewed by expert panel
12977	NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met)	RYR1	Pathogenic	reviewed by expert panel
12983	NM_000540.3(RYR1):c.10579C>T (p.Pro3527Ser)	RYR1	Pathogenic	no assertion criteria provided
12987	NM_000540.2(RYR1):c.14647-1449A>G	RYR1	Pathogenic	no assertion criteria provided
12990	NM_000540.3(RYR1):c.14365-2A>T	RYR1	Pathogenic	no assertion criteria provided
12996	NM_000540.3(RYR1):c.13013_13032del (p.Ala4338fs)	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
133116	NM_000540.3(RYR1):c.2455C>T (p.Arg819Ter)	RYR1	Pathogenic	criteria provided, multiple submitters, no conflicts
133183	NM_000540.3(RYR1):c.7063C>T (p.Arg2355Trp)	RYR1	Pathogenic; drug response	reviewed by expert panel
133202	NM_000540.3(RYR1):c.7360C>T (p.Arg2454Cys)	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
161368	NM_000540.3(RYR1):c.2119G>A (p.Gly707Ser)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190957	NM_000540.3(RYR1):c.2097_2123del (p.Glu699_Gly707del)	RYR1	Pathogenic	no assertion criteria provided
199203	NM_000540.3(RYR1):c.12499G>T (p.Glu4167Ter)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
201146	NM_000540.3(RYR1):c.2989C>T (p.Arg997Ter)	RYR1	Pathogenic	criteria provided, multiple submitters, no conflicts
2039302	NM_000540.3(RYR1):c.6797-6_6798del	RYR1	Pathogenic	criteria provided, multiple submitters, no conflicts
2168903	NM_000540.3(RYR1):c.13041_13066del (p.Ala4348fs)	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

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	Definitive	Autosomal dominant	RYR1-related myopathy	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.