Myofibrillar myopathy 4

Summary

Myofibrillar myopathy 4 (MONDO:0012277) is a disease caused by LDB3 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LDB3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 1,180
• Phenotypes (HPO): 21

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		11	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0008954	Intrinsic hand muscle atrophy	Frequent (30-79%)
HP:0009073	Progressive proximal muscle weakness	Frequent (30-79%)
HP:0030198	Fatigable weakness of distal limb muscles	Frequent (30-79%)
HP:0001626	Abnormality of the cardiovascular system	Occasional (5-29%)
HP:0008969	Leg muscle stiffness	Occasional (5-29%)
HP:0009005	Weakness of the intrinsic hand muscles	Occasional (5-29%)
HP:0009077	Weakness of long finger extensor muscles	Occasional (5-29%)
HP:0031189	Wrist drop	Occasional (5-29%)
HP:0031374	Ankle weakness	Occasional (5-29%)
HP:0002505	Loss of ambulation	Excluded (0%)
HP:0001288	Gait disturbance	Very rare (<1-4%)
HP:0001638	Cardiomyopathy	Very rare (<1-4%)
HP:0003324	Generalized muscle weakness	Very rare (<1-4%)
HP:0003325	Limb-girdle muscle weakness	Very rare (<1-4%)
HP:0005162	Abnormal left ventricular function	Very rare (<1-4%)
HP:0008997	Proximal muscle weakness in upper limbs	Very rare (<1-4%)
HP:0009027	Foot dorsiflexor weakness	Very rare (<1-4%)
HP:0009072	Decreased Achilles reflex	Very rare (<1-4%)
HP:0009830	Peripheral neuropathy	Very rare (<1-4%)
HP:0011808	Decreased patellar reflex	Very rare (<1-4%)
HP:0012722	Heart block	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	myofibrillar myopathy 4
Mondo ID	MONDO:0012277
MeSH	C563718
OMIM	609452
Orphanet	98912
DOID	DOID:0080095
UMLS	C4721886
MedGen	1648314
GARD	0001886
Is cancer (heuristic)	no

Also known as: LDB3 myofibrillar myopathy (disease) · LDB3-related myofibrillar myopathy · MFM4 · myofibrillar myopathy (disease) caused by mutation in LDB3 · myofibrillar myopathy type 4 · myopathy, myofibrillar, 4 · myopathy, myofibrillar, type 4 · ZASP-related myofibrillar myopathy

Data availability: 1,180 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › myofibrillar myopathy 4

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

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:

313 uncertain significance, 180 likely benign, 74 conflicting classifications of pathogenicity, 19 benign/likely benign, 13 pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1058214	NM_007078.3(LDB3):c.319A>T (p.Lys107Ter)	LDB3	Pathogenic	criteria provided, single submitter
1175152	NM_007078.3(LDB3):c.59del (p.Gly20fs)	LDB3	Pathogenic	criteria provided, single submitter
1425088	NM_007078.3(LDB3):c.1439dup (p.Ala482fs)	LDB3	Pathogenic	criteria provided, single submitter
1430730	NM_007078.3(LDB3):c.289dup (p.Gln97fs)	LDB3	Pathogenic	criteria provided, single submitter
1431435	NM_007078.3(LDB3):c.1653C>A (p.Cys551Ter)	LDB3	Pathogenic	criteria provided, single submitter
1473224	NM_007078.3(LDB3):c.1968C>A (p.Tyr656Ter)	LDB3	Pathogenic	criteria provided, single submitter
1501667	NM_007078.3(LDB3):c.1806T>A (p.Tyr602Ter)	LDB3	Pathogenic	criteria provided, single submitter
2034482	NM_007078.3(LDB3):c.785_818dup (p.Ser274fs)	LDB3	Pathogenic	criteria provided, single submitter
2699041	NM_007078.3(LDB3):c.1343del (p.Ser448fs)	LDB3	Pathogenic	criteria provided, single submitter
2703332	NM_007078.3(LDB3):c.1074dup (p.Asp359fs)	LDB3	Pathogenic	criteria provided, single submitter
2720857	NM_007078.3(LDB3):c.566C>A (p.Ser189Ter)	LDB3	Pathogenic	criteria provided, single submitter
2733907	NM_007078.3(LDB3):c.59dup (p.Lys21fs)	LDB3	Pathogenic	criteria provided, single submitter
2791443	NM_007078.3(LDB3):c.1086-247_1231+2del	LDB3	Pathogenic	criteria provided, single submitter
1002404	NM_007078.3(LDB3):c.2037C>T (p.Gly679=)	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1009580	NM_007078.3(LDB3):c.944C>T (p.Pro315Leu)	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1011083	NM_007078.3(LDB3):c.1812A>G (p.Gln604=)	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027637	NM_007078.3(LDB3):c.422C>T (p.Thr141Ile)	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043971	NM_007078.3(LDB3):c.992C>T (p.Ala331Val)	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1052977	NM_007078.3(LDB3):c.1313C>A (p.Thr438Asn)	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1054802	NM_007078.3(LDB3):c.1446G>A (p.Ala482=)	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1090672	NM_007078.3(LDB3):c.645G>A (p.Gln215=)	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1176551	NM_007078.3(LDB3):c.1538C>A (p.Thr513Asn)	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1179890	NM_007078.3(LDB3):c.11G>A (p.Ser4Asn)	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1433678	NM_007078.3(LDB3):c.1618G>T (p.Glu540Ter)	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1490672	NM_007078.3(LDB3):c.1565C>T (p.Thr522Ile)	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1531293	NM_007078.3(LDB3):c.1231+7G>A	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1572844	NM_007078.3(LDB3):c.1827G>A (p.Leu609=)	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
163829	NM_007078.3(LDB3):c.655C>T (p.Arg219Ter)	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
163841	NM_007078.3(LDB3):c.860-15C>T	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
163845	NM_007078.3(LDB3):c.1036G>A (p.Ala346Thr)	LDB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 6 · 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
LDB3	Strong	Autosomal dominant	myofibrillar myopathy 4	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LDB3	Orphanet:154	Familial isolated dilated cardiomyopathy
LDB3	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
LDB3	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
LDB3	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
LDB3	Orphanet:54260	Left ventricular noncompaction
LDB3	Orphanet:98912	Late-onset distal myopathy, Markesbery-Griggs type

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
LDB3	HGNC:15710	ENSG00000122367	O75112	LIM domain-binding protein 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LDB3	LIM domain-binding protein 3	May function as an adapter in striated muscle to couple protein kinase C-mediated signaling via its LIM domains to the cytoskeleton.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LDB3	Transcription factor	no		PDZ, Znf_LIM, Zasp-like_motif

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
apex of heart	1
hindlimb stylopod muscle	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LDB3	247	broad	marker	skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LDB3	1,275

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LDB3	O75112	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
muscle structure development	1	1404.3×	0.003	LDB3
sarcomere organization	1	383.0×	0.005	LDB3
actin cytoskeleton organization	1	79.1×	0.013	LDB3
heart development	1	78.8×	0.013	LDB3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LDB3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	LDB3

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)
LDB3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.