Myopathy, myofibrillar, 9, with early respiratory failure

Summary

Myopathy, myofibrillar, 9, with early respiratory failure (MONDO:0011362) is a disease caused by TTN (GenCC Strong), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TTN (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 3,618
• Phenotypes (HPO): 24

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002091	Restrictive ventilatory defect	Frequent (30-79%)
HP:0002094	Dyspnea	Frequent (30-79%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Frequent (30-79%)
HP:0002792	Reduced vital capacity	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003555	Muscle fiber splitting	Frequent (30-79%)
HP:0003557	Increased variability in muscle fiber diameter	Frequent (30-79%)
HP:0003722	Neck flexor weakness	Frequent (30-79%)
HP:0003803	Type 1 muscle fiber predominance	Frequent (30-79%)
HP:0003805	Rimmed vacuoles	Frequent (30-79%)
HP:0008800	Limited hip movement	Frequent (30-79%)
HP:0008978	Necrotizing myopathy	Frequent (30-79%)
HP:0009027	Foot dorsiflexor weakness	Frequent (30-79%)
HP:0012764	Orthopnea	Frequent (30-79%)
HP:0031237	Internally nucleated skeletal muscle fibers	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Occasional (5-29%)
HP:0003701	Proximal muscle weakness	Occasional (5-29%)
HP:0008963	Tibialis muscle weakness	Occasional (5-29%)
HP:0008981	Calf muscle hypertrophy	Occasional (5-29%)
HP:0100293	Muscle fiber hypertrophy	Occasional (5-29%)
HP:0002527	Falls	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	myopathy, myofibrillar, 9, with early respiratory failure
Mondo ID	MONDO:0011362
MeSH	C564377, C566343
OMIM	603689, 607569
Orphanet	178464, 34521
DOID	DOID:0111188
SNOMED CT	702373006, 733490006
UMLS	C1863599
MedGen	350930
GARD	0012591
Is cancer (heuristic)	no

Also known as: ADMERF · distal myopathy with early respiratory muscle involvement · Edstrom myopathy · Edström myopathy · hereditary inclusion body myopathy with early respiratory failure · hereditary proximal myopathy with early respiratory failure · HIBM-ERF · HMERF · HMERF-ERF · myofibrillar myopathy with early respiratory failure · myopathy, distal, with early respiratory failure, autosomal dominant · myopathy, proximal, with early respiratory muscle involvement

Data availability: 3,618 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › muscular dystrophy › progressive muscular dystrophy › myopathy, myofibrillar, 9, with early respiratory failure

Related subtypes (12): facioscapulohumeral muscular dystrophy, congenital fibrosis of extraocular muscles, Bethlem myopathy, oculopharyngeal muscular dystrophy, X-linked myopathy with excessive autophagy, progressive scapulohumeroperoneal distal myopathy, symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers, myotonic dystrophy, Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, oculopharyngodistal 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 conflicting classifications of pathogenicity, 205 uncertain significance, 70 benign/likely benign, 33 likely benign, 15 benign, 13 likely pathogenic, 10 pathogenic/likely pathogenic, 5 pathogenic, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067013	NM_001267550.2(TTN):c.69421_69422insAAAAG (p.Gly23141fs)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12652	NM_001267550.2(TTN):c.107780_107790delinsTGAAAGAAAAA (p.Glu35927_Trp35930delinsValLysGluLys)	TTN	Pathogenic	criteria provided, multiple submitters, no conflicts
132133	NM_001267550.2(TTN):c.95134T>C (p.Cys31712Arg)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
132134	NM_001267550.2(TTN):c.95185T>C (p.Trp31729Arg)	TTN	Pathogenic	criteria provided, single submitter
132135	NM_001267550.2(TTN):c.95186G>T (p.Trp31729Leu)	TTN	Pathogenic	no assertion criteria provided
132136	NM_001267550.2(TTN):c.95187G>C (p.Trp31729Cys)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
132137	NM_001267550.2(TTN):c.95195C>T (p.Pro31732Leu)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
132138	NM_001267550.2(TTN):c.95358C>G (p.Asn31786Lys)	TTN	Pathogenic	no assertion criteria provided
1329193	NM_001267550.2(TTN):c.73939C>T (p.Arg24647Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1508786	NM_001267550.2(TTN):c.80380C>T (p.Gln26794Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
165720	NM_001267550.2(TTN):c.94180delinsTCTAGCAG (p.Pro31394fs)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
179411	NM_001267550.2(TTN):c.49648+2del	TTN	Pathogenic	criteria provided, multiple submitters, no conflicts
179759	NM_001267550.2(TTN):c.81321C>G (p.Tyr27107Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068361	NM_001267550.2(TTN):c.96669G>A (p.Trp32223Ter)	TTN-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180573	NM_001267550.2(TTN):c.67495C>T (p.Arg22499Ter)	TTN-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1793398	NM_001267550.2(TTN):c.53026_53027del (p.Val17676fs)	LOC126806425	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048771	NM_001267550.2(TTN):c.826C>T (p.Gln276Ter)	TTN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066962	NM_001267550.2(TTN):c.56051-1G>A	TTN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067018	NM_001267550.2(TTN):c.62337_62340del (p.Thr20780fs)	TTN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067630	NM_001267550.2(TTN):c.51449del (p.Pro17150fs)	TTN	Likely pathogenic	criteria provided, single submitter
1285374	NM_001267550.2(TTN):c.23685del (p.Glu7896fs)	TTN	Likely pathogenic	criteria provided, single submitter
1297705	NM_001267550.2(TTN):c.83324dup (p.Arg27776fs)	TTN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325260	NM_001267550.2(TTN):c.101642C>G (p.Ser33881Ter)	TTN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325263	NM_001267550.2(TTN):c.53728G>T (p.Glu17910Ter)	TTN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1497348	NM_001267550.2(TTN):c.60455_60456del (p.Thr20152fs)	TTN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
165975	NM_001267550.2(TTN):c.54638G>A (p.Trp18213Ter)	TTN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
167754	NM_001267550.2(TTN):c.104092C>T (p.Arg34698Ter)	TTN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1678136	NM_001267550.2(TTN):c.77185A>T (p.Lys25729Ter)	TTN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
166320	NM_001267550.2(TTN):c.4396T>C (p.Phe1466Leu)	LOC101927055	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130687	NM_001267550.2(TTN):c.100315T>C (p.Trp33439Arg)	LOC126806420	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 17 · 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
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
CORIN	Orphanet:275555	Preeclampsia
LRP4	Orphanet:3152	Sclerosteosis
LRP4	Orphanet:3258	Cenani-Lenz syndrome
LRP4	Orphanet:98913	Postsynaptic congenital myasthenic syndrome

Cohort genes → proteins

4 cohort genes, 3 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
CORIN	HGNC:19012	ENSG00000145244	Q9Y5Q5	Atrial natriuretic peptide-converting enzyme	clinvar
TTN-AS1	HGNC:44124	ENSG00000237298		TTN antisense RNA 1	clinvar
LRP4	HGNC:6696	ENSG00000134569	O75096	Low-density lipoprotein receptor-related protein 4	clinvar

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.
CORIN	Atrial natriuretic peptide-converting enzyme	Serine-type endopeptidase involved in atrial natriuretic peptide (NPPA) and brain natriuretic peptide (NPPB) processing.
LRP4	Low-density lipoprotein receptor-related protein 4	Mediates SOST-dependent inhibition of bone formation.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · 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
Protease	1	9.2×	0.205
Kinase	1	6.9×	0.205
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
CORIN	Protease	yes		SRCR, Trypsin_dom, LDrepeatLR_classA_rpt
TTN-AS1	Other/Unknown	no
LRP4	Other/Unknown	no		LDLR_classB_rpt, EGF, EGF-like_Ca-bd_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
biceps brachii	1
gluteal muscle	1
skeletal muscle tissue of biceps brachii	1
cardiac muscle of right atrium	1
heart right ventricle	1
myocardium	1
gastrocnemius	1
hindlimb stylopod muscle	1
right atrium auricular region	1
dorsal motor nucleus of vagus nerve	1
medial globus pallidus	1
ventricular zone	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
CORIN	176	tissue_specific	marker	cardiac muscle of right atrium, heart right ventricle, myocardium
TTN-AS1	174	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, right atrium auricular region
LRP4	242	ubiquitous	marker	ventricular zone, dorsal motor nucleus of vagus nerve, medial globus pallidus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TTN	4,237
CORIN	1,291
LRP4	1,250
TTN-AS1	0

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
LRP4	O75096	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CORIN	Q9Y5Q5	70.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Physiological factors	1	223.9×	0.022	CORIN
Striated Muscle Contraction	1	102.9×	0.024	TTN
ECM proteoglycans	1	50.1×	0.033	LRP4
Platelet degranulation	1	29.3×	0.042	TTN
Extracellular matrix organization	1	21.0×	0.047	LRP4

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of presynaptic membrane organization	1	5617.3×	0.005	LRP4
regulation of systemic arterial blood pressure by atrial natriuretic peptide	1	1872.4×	0.005	CORIN
skeletal muscle myosin thick filament assembly	1	1872.4×	0.005	TTN
sarcomerogenesis	1	1872.4×	0.005	TTN
synaptic assembly at neuromuscular junction	1	1872.4×	0.005	LRP4
regulation of renal sodium excretion	1	1404.3×	0.006	CORIN
skeletal muscle thin filament assembly	1	936.2×	0.006	TTN
detection of muscle stretch	1	802.5×	0.006	TTN
postsynaptic membrane assembly	1	802.5×	0.006	LRP4
amyloid-beta clearance by cellular catabolic process	1	702.2×	0.006	LRP4
skeletal muscle acetylcholine-gated channel clustering	1	624.1×	0.006	LRP4
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	624.1×	0.006	LRP4
cardiac muscle hypertrophy	1	561.7×	0.006	TTN
presynaptic membrane assembly	1	561.7×	0.006	LRP4
generation of neurons	1	510.7×	0.006	LRP4
obsolete protein kinase A signaling	1	468.1×	0.006	TTN
cardiac muscle tissue morphogenesis	1	468.1×	0.006	TTN
enzyme-linked receptor protein signaling pathway	1	432.1×	0.006	LRP4
negative regulation of axonogenesis	1	432.1×	0.006	LRP4
cardiac myofibril assembly	1	432.1×	0.006	TTN
muscle filament sliding	1	351.1×	0.007	TTN
mitotic chromosome condensation	1	330.4×	0.007	TTN
peptide hormone processing	1	312.1×	0.007	CORIN
striated muscle contraction	1	280.9×	0.007	TTN
regulation of cardiac conduction	1	280.9×	0.007	CORIN
proximal/distal pattern formation	1	216.1×	0.008	LRP4
positive regulation of Rac protein signal transduction	1	216.1×	0.008	LRP4
negative regulation of ossification	1	208.1×	0.008	LRP4
cardiac muscle cell development	1	208.1×	0.008	TTN
Rac protein signal transduction	1	187.2×	0.009	LRP4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
CORIN	0	0
TTN-AS1	0	0
LRP4	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
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: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

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	TTN
D	Druggable family + AlphaFold only, no drug	1	CORIN
E	Difficult family or no structure, no drug	2	TTN-AS1, LRP4

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	—
CORIN	0	—
TTN-AS1	0	—
LRP4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.