Autosomal recessive centronuclear myopathy

Summary

Autosomal recessive centronuclear myopathy (MONDO:0015705) is a disease with 4 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 4
• ClinVar variants: 2
• Phenotypes (HPO): 36

Clinical features

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0000218	High palate	Frequent (30-79%)
HP:0000278	Retrognathia	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0002515	Waddling gait	Frequent (30-79%)
HP:0003323	Progressive muscle weakness	Frequent (30-79%)
HP:0003391	Gowers sign	Frequent (30-79%)
HP:0003551	Difficulty climbing stairs	Frequent (30-79%)
HP:0003700	Generalized amyotrophy	Frequent (30-79%)
HP:0009046	Difficulty running	Frequent (30-79%)
HP:0010628	Facial palsy	Frequent (30-79%)
HP:0000160	Narrow mouth	Occasional (5-29%)
HP:0000193	Bifid uvula	Occasional (5-29%)
HP:0000276	Long face	Occasional (5-29%)
HP:0000411	Protruding ear	Occasional (5-29%)
HP:0000597	Ophthalmoparesis	Occasional (5-29%)
HP:0000602	Ophthalmoplegia	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0001349	Facial diplegia	Occasional (5-29%)
HP:0001618	Dysphonia	Occasional (5-29%)
HP:0001654	Abnormal heart valve morphology	Occasional (5-29%)
HP:0001712	Left ventricular hypertrophy	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0001762	Talipes equinovarus	Occasional (5-29%)
HP:0001999	Abnormal facial shape	Occasional (5-29%)
HP:0003273	Hip contracture	Occasional (5-29%)
HP:0003307	Hyperlordosis	Occasional (5-29%)
HP:0003403	EMG: decremental response of compound muscle action potential to repetitive nerve stimulation	Occasional (5-29%)
HP:0003687	Centrally nucleated skeletal muscle fibers	Occasional (5-29%)
HP:0003691	Scapular winging	Occasional (5-29%)
HP:0003803	Type 1 muscle fiber predominance	Occasional (5-29%)
HP:0100807	Long fingers	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive centronuclear myopathy
Mondo ID	MONDO:0015705
Orphanet	169186
DOID	DOID:0111216
ICD-11	1844602815
SNOMED CT	240081004
UMLS	C3645536
MedGen	771131
GARD	0012718
Is cancer (heuristic)	no

Also known as: AR-CNM · centronuclear myopathy, autosomal recessive

Data availability: 2 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › centronuclear myopathy › autosomal recessive centronuclear myopathy

Related subtypes (4): autosomal dominant centronuclear myopathy, X-linked myotubular myopathy, congenital myopathy with internal nuclei and atypical cores, myopathy, centronuclear, 6, with fiber-type disproportion

Subtypes (2): myopathy, centronuclear, 2, myopathy, centronuclear, 5

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

2 retrieved; paginated sample, class counts are floors:

2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1043872	NM_001267550.2(TTN):c.107797G>C (p.Gly35933Arg)	TTN	Uncertain significance	criteria provided, multiple submitters, no conflicts
466818	NM_001267550.2(TTN):c.13940A>G (p.Asp4647Gly)	TTN	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 55 · Orphanet: 28 · 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
BIN1	Definitive	Autosomal recessive	myopathy, centronuclear, 2	6
RYR1	Definitive	Autosomal dominant	RYR1-related myopathy	22
SPEG	Definitive	Autosomal recessive	myopathy, centronuclear, 5	6
TTN	Definitive	Autosomal recessive	early-onset myopathy with fatal cardiomyopathy	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
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
BIN1	Orphanet:169186	Autosomal recessive centronuclear myopathy
BIN1	Orphanet:169189	Autosomal dominant centronuclear myopathy
SPEG	Orphanet:169186	Autosomal recessive centronuclear 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
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	gencc,clinvar
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	gencc
BIN1	HGNC:1052	ENSG00000136717	O00499	Myc box-dependent-interacting protein 1	gencc
SPEG	HGNC:16901	ENSG00000072195	Q15772	Striated muscle preferentially expressed protein kinase	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
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.
BIN1	Myc box-dependent-interacting protein 1	Is a key player in the control of plasma membrane curvature, membrane shaping and membrane remodeling.
SPEG	Striated muscle preferentially expressed protein kinase	Isoform 3 may have a role in regulating the growth and differentiation of arterial smooth muscle cells.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.75

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
Kinase	2	13.9×	0.022
Ion channel	1	27.9×	0.053
Scaffold/PPI	1	4.3×	0.212

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
BIN1	Scaffold/PPI	no		SH3_domain, Amphiphysin, Amphiphysin_2
SPEG	Kinase	yes		Prot_kinase_dom, Ig_sub2, Ig_sub

Expression context

Cohort genes with no expression data: 0.

3 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
gluteal muscle	2
gastrocnemius	2
hindlimb stylopod muscle	2
biceps brachii	1
skeletal muscle tissue of biceps brachii	1
skeletal muscle tissue of rectus abdominis	1
popliteal artery	1
right coronary artery	1
tibial artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle
BIN1	287	ubiquitous	marker	gastrocnemius, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis
SPEG	249	ubiquitous	yes	popliteal artery, tibial artery, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TTN	4,237
BIN1	3,571
RYR1	2,177
SPEG	1,107

Intra-cohort edges

A	B	Sources
RYR1	TTN	intact

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
BIN1	O00499	7
RYR1	P21817	2
SPEG	Q15772	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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×	0.053	TTN
Ion homeostasis	1	68.0×	0.053	RYR1
Stimuli-sensing channels	1	45.3×	0.053	RYR1
Cardiac conduction	1	36.2×	0.053	RYR1
Ion channel transport	1	32.0×	0.053	RYR1
Platelet degranulation	1	29.3×	0.053	TTN
Clathrin-mediated endocytosis	1	28.4×	0.053	BIN1
Muscle contraction	1	25.7×	0.053	RYR1
Membrane Trafficking	1	12.4×	0.092	BIN1
Vesicle-mediated transport	1	11.6×	0.092	BIN1
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×	4e-04	TTN, RYR1
muscle contraction	2	104.0×	0.004	TTN, RYR1
negative regulation of ventricular cardiac muscle cell action potential	1	4213.0×	0.004	BIN1
lipid tube assembly	1	2106.5×	0.007	BIN1
skeletal muscle myosin thick filament assembly	1	1404.3×	0.007	TTN
sarcomerogenesis	1	1404.3×	0.007	TTN
negative regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1	1053.2×	0.008	BIN1
skeletal muscle thin filament assembly	1	702.2×	0.008	TTN
T-tubule organization	1	702.2×	0.008	BIN1
response to caffeine	1	601.9×	0.008	RYR1
detection of muscle stretch	1	601.9×	0.008	TTN
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
quinolinate biosynthetic process	1	383.0×	0.008	BIN1
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
positive regulation of astrocyte differentiation	1	351.1×	0.008	BIN1
cardiac muscle tissue morphogenesis	1	351.1×	0.008	TTN
negative regulation of potassium ion transmembrane transport	1	351.1×	0.008	BIN1
cardiac myofibril assembly	1	324.1×	0.008	TTN
muscle filament sliding	1	263.3×	0.009	TTN
mitotic chromosome condensation	1	247.8×	0.009	TTN
regulation of cell cycle process	1	247.8×	0.009	BIN1
negative regulation of amyloid-beta formation	1	221.7×	0.010	BIN1
muscle cell differentiation	1	210.7×	0.010	SPEG
positive regulation of endocytosis	1	200.6×	0.010	BIN1
regulation of neuron differentiation	1	183.2×	0.011	BIN1
cardiac muscle cell development	1	156.0×	0.012	TTN
nucleus organization	1	140.4×	0.013	BIN1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
TTN	0	0
RYR1	0	0
BIN1	0	0
SPEG	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RYR1	16	Binding:13, Functional:3
TTN	1	Binding:1

Cohort enzymes (BRENDA EC)

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

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

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	3	TTN, RYR1, SPEG
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	BIN1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TTN	1	—
RYR1	16	—
BIN1	0	—
SPEG	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.