Congenital myopathy with myasthenic-like onset

Summary

Congenital myopathy with myasthenic-like onset (MONDO:0018528) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 1
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0003473	Fatigable weakness	Very frequent (80-99%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0002047	Malignant hyperthermia	Frequent (30-79%)
HP:0002058	Myopathic facies	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002828	Multiple joint contractures	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0003388	Easy fatigability	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003691	Scapular winging	Frequent (30-79%)
HP:0003701	Proximal muscle weakness	Frequent (30-79%)
HP:0003789	Minicore myopathy	Frequent (30-79%)
HP:0003803	Type 1 muscle fiber predominance	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0003201	Rhabdomyolysis	Excluded (0%)
HP:0003236	Elevated circulating creatine kinase concentration	Excluded (0%)
HP:0040191	Rectus femoris muscle atrophy	Excluded (0%)
HP:0000602	Ophthalmoplegia	Very rare (<1-4%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myopathy with myasthenic-like onset
Mondo ID	MONDO:0018528
Orphanet	424107
SNOMED CT	763315005
UMLS	C4706390
MedGen	1642781
GARD	0021783
Is cancer (heuristic)	no

Also known as: congenital myopathy with myasthenic-like onset

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

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › RYR1-related myopathy › congenital myopathy with myasthenic-like onset

Related subtypes (4): central core myopathy, congenital multicore myopathy with external ophthalmoplegia, King-Denborough syndrome, rhabdomyolysis-myalgia 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

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1334959	NM_001135254.2(PAX7):c.587-8G>A	PAX7	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · Orphanet: 13 · 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
PAX7	Orphanet:99756	Alveolar rhabdomyosarcoma

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	gencc
PAX7	HGNC:8621	ENSG00000009709	P23759	Paired box protein Pax-7	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.
PAX7	Paired box protein Pax-7	Transcription factor that is involved in the regulation of muscle stem cells proliferation, playing a role in myogenesis and muscle regeneration.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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	55.8×	0.036
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
PAX7	Transcription factor	no		HD, Paired_dom, OAR_dom

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
gluteal muscle	1
hindlimb stylopod muscle	1
nasal cavity epithelium	1
nasal cavity mucosa	1
olfactory segment of nasal mucosa	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
PAX7	61	tissue_specific	marker	olfactory segment of nasal mucosa, nasal cavity epithelium, nasal cavity mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAX7	2,847
RYR1	2,177

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RYR1	P21817	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PAX7	P23759	63.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Specification of the neural plate border	1	317.2×	0.022	PAX7
Ion homeostasis	1	102.0×	0.029	RYR1
Stimuli-sensing channels	1	68.0×	0.029	RYR1
Cardiac conduction	1	54.4×	0.029	RYR1
Ion channel transport	1	48.0×	0.029	RYR1
Muscle contraction	1	38.6×	0.030	RYR1
Transport of small molecules	1	12.6×	0.078	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
skeletal muscle satellite cell commitment	1	8426.0×	0.004	PAX7
regulation of cell fate commitment	1	2808.7×	0.005	PAX7
response to caffeine	1	1203.7×	0.005	RYR1
muscle tissue morphogenesis	1	1203.7×	0.005	PAX7
skeletal muscle satellite cell differentiation	1	1053.2×	0.005	PAX7
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	842.6×	0.005	RYR1
cellular response to caffeine	1	766.0×	0.005	RYR1
regulation of chromatin organization	1	766.0×	0.005	PAX7
ossification involved in bone maturation	1	702.2×	0.005	RYR1
positive regulation of myoblast proliferation	1	702.2×	0.005	PAX7
spinal cord association neuron differentiation	1	648.1×	0.005	PAX7
skeletal muscle tissue regeneration	1	443.5×	0.006	PAX7
striated muscle contraction	1	421.3×	0.006	RYR1
dorsal/ventral neural tube patterning	1	401.2×	0.006	PAX7
neuron fate commitment	1	401.2×	0.006	PAX7
skeletal muscle fiber development	1	271.8×	0.008	RYR1
skin development	1	221.7×	0.009	RYR1
embryonic skeletal system development	1	195.9×	0.009	PAX7
regulation of cytosolic calcium ion concentration	1	191.5×	0.009	RYR1
release of sequestered calcium ion into cytosol	1	172.0×	0.010	RYR1
outflow tract morphogenesis	1	153.2×	0.011	RYR1
cartilage development	1	125.8×	0.012	PAX7
protein homotetramerization	1	118.7×	0.012	RYR1
muscle contraction	1	104.0×	0.014	RYR1
cellular response to calcium ion	1	100.3×	0.014	RYR1
calcium ion transport	1	90.6×	0.014	RYR1
anatomical structure morphogenesis	1	69.6×	0.018	PAX7
response to hypoxia	1	47.9×	0.025	RYR1
chromatin remodeling	1	36.5×	0.032	PAX7
transcription by RNA polymerase II	1	35.3×	0.032	PAX7

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
PAX7	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: 2; 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	1	PAX7

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RYR1	16	—
PAX7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.