Multiminicore myopathy

Summary

Multiminicore myopathy (MONDO:0018948) is a disease (an umbrella term covering 5 Mondo subtypes) with 4 cohort genes and 2 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 17
• Phenotypes (HPO): 21
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0003198	Myopathy	Very frequent (80-99%)
HP:0003789	Minicore myopathy	Very frequent (80-99%)
HP:0003560	Muscular dystrophy	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001387	Joint stiffness	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Frequent (30-79%)
HP:0003306	Spinal rigidity	Frequent (30-79%)
HP:0003457	EMG abnormality	Frequent (30-79%)
HP:0004303	Abnormal muscle fiber morphology	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0008994	Proximal muscle weakness in lower limbs	Frequent (30-79%)
HP:0008997	Proximal muscle weakness in upper limbs	Frequent (30-79%)
HP:0000544	External ophthalmoplegia	Occasional (5-29%)
HP:0002047	Malignant hyperthermia	Occasional (5-29%)
HP:0002460	Distal muscle weakness	Occasional (5-29%)
HP:0002804	Arthrogryposis multiplex congenita	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	multiminicore myopathy
Mondo ID	MONDO:0018948
Orphanet	598
DOID	DOID:0080991
SNOMED CT	55133004
UMLS	C0270962
MedGen	75731
GARD	0016536
Is cancer (heuristic)	no

Also known as: MmD · multicore disease · multicore myopathy · multiminicore disease

Data availability: 17 ClinVar variants · 1 cell line.

Disease family

An umbrella term covering 5 Mondo subtypes.

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

Related subtypes (1): rigid spine syndrome

Subtypes (5): congenital multicore myopathy with external ophthalmoplegia, 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

17 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 3 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
161368	NM_000540.3(RYR1):c.2119G>A (p.Gly707Ser)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
161370	NM_000540.3(RYR1):c.3800C>G (p.Pro1267Arg)	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
870629	NM_001267550.2(TTN):c.85818T>A (p.Tyr28606Ter)	TTN	Pathogenic	criteria provided, single submitter
440962	NM_000540.3(RYR1):c.3877C>A (p.Pro1293Thr)	RYR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
290291	NM_001267550.2(TTN):c.102795TAA[1] (p.Asn34266del)	TTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
828055	NM_005087.4(FXR1):c.1603+733del	FXR1	Uncertain significance	criteria provided, single submitter
1050940	NM_000540.3(RYR1):c.1475G>A (p.Arg492His)	LOC129391106	Uncertain significance	reviewed by expert panel
1009361	NM_000540.3(RYR1):c.5962G>A (p.Ala1988Thr)	RYR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
544410	NM_000540.3(RYR1):c.3043C>T (p.Arg1015Cys)	RYR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
544446	NM_000540.3(RYR1):c.13069C>A (p.Leu4357Met)	RYR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
548498	NM_000540.3(RYR1):c.11687A>T (p.Asn3896Ile)	RYR1	Uncertain significance	criteria provided, single submitter
660051	NM_000540.3(RYR1):c.6891+3G>T	RYR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
948541	NM_000540.3(RYR1):c.5179C>G (p.Arg1727Gly)	RYR1	Uncertain significance	criteria provided, single submitter
2674590	NM_014370.4(SRPK3):c.749-2A>G	SRPK3	Uncertain significance	criteria provided, single submitter
2674602	NC_000002.12:g.178532523del	TTN	Uncertain significance	criteria provided, single submitter
133043	NM_000540.3(RYR1):c.12884C>T (p.Ala4295Val)	RYR1	Benign	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 25 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure
TTN	Orphanet:289377	Early-onset myopathy with fatal cardiomyopathy
TTN	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TTN	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TTN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TTN	Orphanet:324604	Classic multiminicore myopathy
TTN	Orphanet:334	Hereditary atrial fibrillation
TTN	Orphanet:466921	Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
TTN	Orphanet:609	Tibial muscular dystrophy
TTN	Orphanet:707983	Early-onset autosomal recessive TTN-related distal myopathy

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	clinvar
SRPK3	HGNC:11402	ENSG00000184343	Q9UPE1	SRSF protein kinase 3	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
FXR1	HGNC:4023	ENSG00000114416	P51114	RNA-binding protein FXR1	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.
SRPK3	SRSF protein kinase 3	Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
FXR1	RNA-binding protein FXR1	mRNA-binding protein that acts as a regulator of mRNAs translation and/or stability, and which is required for various processes, such as neurogenesis, muscle development and spermatogenesis.

Protein-family classification

Druggable: 4 · 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
Complement	1	67.0×	0.022
Kinase	2	13.9×	0.022
Ion channel	1	27.9×	0.035

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
SRPK3	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
FXR1	Complement	yes		KH_dom, KH_dom_type_1, Agenet-like_dom

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	3
gluteal muscle	3
hindlimb stylopod muscle	3
biceps brachii	1
skeletal muscle tissue of biceps brachii	1
sperm	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
SRPK3	202	broad	marker	hindlimb stylopod muscle, gluteal muscle, gastrocnemius
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
FXR1	299	ubiquitous	marker	sperm, hindlimb stylopod muscle, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TTN	4,237
FXR1	4,128
RYR1	2,177
SRPK3	1,561

Intra-cohort edges

A	B	Sources
RYR1	TTN	intact

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
FXR1	P51114	3
RYR1	P21817	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SRPK3	Q9UPE1	80.61

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Striated Muscle Contraction	1	102.9×	0.043	TTN
Ion homeostasis	1	68.0×	0.043	RYR1
Signaling by BRAF and RAF1 fusions	1	56.8×	0.043	FXR1
Stimuli-sensing channels	1	45.3×	0.043	RYR1
Cardiac conduction	1	36.2×	0.043	RYR1
Ion channel transport	1	32.0×	0.043	RYR1
Platelet degranulation	1	29.3×	0.043	TTN
Muscle contraction	1	25.7×	0.043	RYR1
Transport of small molecules	1	8.4×	0.115	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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
striated muscle contraction	2	421.3×	5e-04	RYR1, TTN
muscle contraction	2	104.0×	0.004	RYR1, TTN
skeletal muscle myosin thick filament assembly	1	1404.3×	0.007	TTN
sarcomerogenesis	1	1404.3×	0.007	TTN
regulation of translation at presynapse, modulating synaptic transmission	1	1404.3×	0.007	FXR1
negative regulation of mRNA catabolic process	1	1404.3×	0.007	FXR1
nuclear pore localization	1	842.6×	0.008	FXR1
muscle tissue development	1	842.6×	0.008	SRPK3
skeletal muscle thin filament assembly	1	702.2×	0.008	TTN
response to caffeine	1	601.9×	0.008	RYR1
detection of muscle stretch	1	601.9×	0.008	TTN
regulation of circadian sleep/wake cycle, sleep	1	601.9×	0.008	FXR1
positive regulation of miRNA-mediated gene silencing	1	601.9×	0.008	FXR1
skeletal muscle organ development	1	526.6×	0.008	FXR1
positive regulation of long-term neuronal synaptic plasticity	1	468.1×	0.008	FXR1
cardiac muscle hypertrophy	1	421.3×	0.008	TTN
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	421.3×	0.008	RYR1
nuclear pore complex assembly	1	421.3×	0.008	FXR1
cellular response to caffeine	1	383.0×	0.008	RYR1
obsolete protein kinase A signaling	1	351.1×	0.008	TTN
ossification involved in bone maturation	1	351.1×	0.008	RYR1
cardiac muscle tissue morphogenesis	1	351.1×	0.008	TTN
cardiac myofibril assembly	1	324.1×	0.008	TTN
negative regulation of long-term synaptic potentiation	1	324.1×	0.008	FXR1
membraneless organelle assembly	1	280.9×	0.009	FXR1
muscle filament sliding	1	263.3×	0.009	TTN
mitotic chromosome condensation	1	247.8×	0.009	TTN
regulation of mRNA processing	1	221.7×	0.010	SRPK3
animal organ development	1	183.2×	0.012	FXR1
mRNA destabilization	1	168.5×	0.012	FXR1

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 4 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SRPK3	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SRPK3	18	4
RYR1	0	0
TTN	0	0
FXR1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	SRPK3
AXITINIB	4	SRPK3
RUXOLITINIB	4	SRPK3
BOSUTINIB	4	SRPK3
NINTEDANIB	4	SRPK3
SUNITINIB	4	SRPK3
ERLOTINIB	4	SRPK3
CRIZOTINIB	4	SRPK3
MIDOSTAURIN	4	SRPK3
DOVITINIB	3	SRPK3
LESTAURTINIB	3	SRPK3
RUBOXISTAURIN	3	SRPK3
SU-014813	2	SRPK3
TG100-115	2	SRPK3
R-406	2	SRPK3
TOZASERTIB	2	SRPK3
GSK-461364	1	SRPK3
KW-2449	1	SRPK3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
SRPK3	229	Binding:229
RYR1	16	Binding:13, Functional:3
FXR1	6	Binding:6
TTN	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SRPK3	2.7.11.1	non-specific serine/threonine protein kinase
TTN	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SRPK3	229

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

Chemical tractability of cohort targets

18 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.

Compound	Max phase	Cohort target (bioactivity)
FEDRATINIB	4	SRPK3
AXITINIB	4	SRPK3
RUXOLITINIB	4	SRPK3
BOSUTINIB	4	SRPK3
NINTEDANIB	4	SRPK3
SUNITINIB	4	SRPK3
ERLOTINIB	4	SRPK3
CRIZOTINIB	4	SRPK3
MIDOSTAURIN	4	SRPK3
DOVITINIB	3	SRPK3
LESTAURTINIB	3	SRPK3
RUBOXISTAURIN	3	SRPK3
SU-014813	2	SRPK3
TG100-115	2	SRPK3
R-406	2	SRPK3
TOZASERTIB	2	SRPK3
GSK-461364	1	SRPK3
KW-2449	1	SRPK3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SRPK3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	RYR1, TTN, FXR1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RYR1	16	—
TTN	1	—
FXR1	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00272883	Not specified	RECRUITING	Molecular and Genetic Studies of Congenital Myopathies
NCT06791369	Not specified	NOT_YET_RECRUITING	The Prevalence of RYR1-related Disease