congenital muscular dystrophy due to LMNA mutation

disease

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Also known as congenital muscular dystrophy caused by mutation in LMNAL-CMDLMNA congenital muscular dystrophyLMNA-related congenital muscular dystrophyMDCLmuscular dystrophy Congenital, LMNA-relatedmuscular dystrophy, congenitalmuscular dystrophy, congenital, LMNA-related

Summary

congenital muscular dystrophy due to LMNA mutation (MONDO:0013178) is a disease with 1 cohort gene and 1 clinical trial.

At a glance

Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
Cohort genes: 1
ClinVar variants: 280
Phenotypes (HPO): 22
Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		23	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0002421	Poor head control	Very frequent (80-99%)
HP:0003327	Axial muscle weakness	Very frequent (80-99%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001371	Flexion contracture	Frequent (30-79%)
HP:0001376	Limitation of joint mobility	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003306	Spinal rigidity	Frequent (30-79%)
HP:0003307	Hyperlordosis	Frequent (30-79%)
HP:0003457	EMG abnormality	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0000774	Narrow chest	Occasional (5-29%)
HP:0001522	Death in infancy	Occasional (5-29%)
HP:0001558	Decreased fetal movement	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0001883	Talipes	Occasional (5-29%)
HP:0004326	Cachexia	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0001382	Joint hypermobility	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital muscular dystrophy due to LMNA mutation
Mondo ID	MONDO:0013178
MeSH	C567708
OMIM	613205
Orphanet	157973
DOID	DOID:0110640
NCIT	C148369
UMLS	C2750785
MedGen	413043
GARD	0012585
Is cancer (heuristic)	no

Also known as: congenital muscular dystrophy caused by mutation in LMNA · L-CMD · LMNA congenital muscular dystrophy · LMNA-related congenital muscular dystrophy · MDCL · muscular dystrophy Congenital, LMNA-related · muscular dystrophy, congenital · muscular dystrophy, congenital, LMNA-related

Data availability: 280 ClinVar variants · 1 GenCC gene-disease record · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › congenital muscular dystrophy › congenital muscular dystrophy due to LMNA mutation

Related subtypes (22): Ullrich congenital muscular dystrophy, Bethlem myopathy, arthrogryposis due to muscular dystrophy, congenital muscular dystrophy-infantile cataract-hypogonadism syndrome, muscular dystrophy, congenital, with rapid progression, congenital myasthenic syndrome 10, megaconial type congenital muscular dystrophy, congenital muscular dystrophy 1B, congenital merosin-deficient muscular dystrophy 1A, congenital muscular dystrophy due to integrin alpha-7 deficiency, congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome, congenital myopathy, Paradas type, autosomal recessive myogenic arthrogryposis multiplex congenita, muscular dystrophy-dystroglycanopathy, congenital muscular dystrophy with hyperlaxity, muscle-eye-brain disease, rigid spine syndrome, congenital muscular dystrophy with cataracts and intellectual disability, SNUPN-related muscular dystrophy with or without multi-system involvement, congenital muscular dystrophy caused by variation in POMGNT2, collagen 6-related congenital muscular dystrophy, congenital muscular dystrophy without intellectual disability

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

280 retrieved; paginated sample, class counts are floors:

127 uncertain significance, 80 conflicting classifications of pathogenicity, 18 likely benign, 15 pathogenic/likely pathogenic, 15 pathogenic, 10 benign/likely benign, 7 likely pathogenic, 4 benign, 3 uncertain significance/uncertain risk allele, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
14478	NM_170707.4(LMNA):c.1357C>T (p.Arg453Trp)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14489	NM_170707.4(LMNA):c.1444C>T (p.Arg482Trp)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14495	NM_170707.4(LMNA):c.1130G>A (p.Arg377His)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
14523	NM_170707.4(LMNA):c.1139T>C (p.Leu380Ser)	LMNA	Pathogenic	no assertion criteria provided
14524	NM_170707.4(LMNA):c.745C>T (p.Arg249Trp)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14525	NM_170707.4(LMNA):c.1072G>A (p.Glu358Lys)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
1457399	NM_170707.4(LMNA):c.822del (p.Arg275fs)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
200941	NM_170707.4(LMNA):c.768G>A (p.Val256=)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
216958	NM_170707.4(LMNA):c.810+1G>C	LMNA	Pathogenic	criteria provided, single submitter
2503449	NM_170707.4(LMNA):c.95A>C (p.Lys32Thr)	LMNA	Pathogenic	no assertion criteria provided
3595598	NM_170707.4(LMNA):c.5del (p.Glu2fs)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
36473	NM_170707.4(LMNA):c.1003C>T (p.Arg335Trp)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36475	NM_170707.4(LMNA):c.1381-2A>G	LMNA	Pathogenic	criteria provided, single submitter
476837	NM_170707.4(LMNA):c.94A>G (p.Lys32Glu)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
48031	NM_170707.4(LMNA):c.1129C>T (p.Arg377Cys)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
48070	NM_170707.4(LMNA):c.607G>A (p.Glu203Lys)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
48096	NM_170707.4(LMNA):c.961C>T (p.Arg321Ter)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
66762	NM_170707.4(LMNA):c.1045C>T (p.Arg349Trp)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66778	NM_170707.4(LMNA):c.1130G>T (p.Arg377Leu)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66800	NM_170707.4(LMNA):c.1294C>T (p.Gln432Ter)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66817	NM_170707.4(LMNA):c.1380+1G>A	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
66850	NM_170707.4(LMNA):c.1583C>G (p.Thr528Arg)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66853	NM_170707.4(LMNA):c.1608+1G>A	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
66908	NM_170707.4(LMNA):c.568C>T (p.Arg190Trp)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
66924	NM_170707.4(LMNA):c.694G>C (p.Gly232Arg)	LMNA	Pathogenic	criteria provided, single submitter
66931	NM_170707.4(LMNA):c.746G>A (p.Arg249Gln)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
949101	NM_170707.4(LMNA):c.1147G>A (p.Glu383Lys)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14510	NM_170707.4(LMNA):c.428C>T (p.Ser143Phe)	LOC126805877	Pathogenic	no assertion criteria provided
218376	NM_170707.4(LMNA):c.91_93del (p.Glu31del)	LOC129931597	Pathogenic	criteria provided, single submitter
66960	NM_170707.4(LMNA):c.94_96del (p.Lys32del)	LOC129931597	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 40 · Orphanet: 21 · 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
LMNA	Definitive	Semidominant	Emery-Dreifuss muscular dystrophy 2, autosomal dominant	40

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LMNA	Orphanet:154	Familial isolated dilated cardiomyopathy
LMNA	Orphanet:157973	Congenital muscular dystrophy due to LMNA mutation
LMNA	Orphanet:1662	Restrictive dermopathy
LMNA	Orphanet:168796	Heart-hand syndrome, Slovenian type
LMNA	Orphanet:2229	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome
LMNA	Orphanet:2348	Familial partial lipodystrophy, Dunnigan type
LMNA	Orphanet:280365	Autosomal semi-dominant severe lipodystrophic laminopathy
LMNA	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
LMNA	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
LMNA	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
LMNA	Orphanet:300751	Familial dilated cardiomyopathy with conduction defect due to LMNA mutation
LMNA	Orphanet:363618	LMNA-related cardiocutaneous progeria syndrome
LMNA	Orphanet:54260	Left ventricular noncompaction
LMNA	Orphanet:675396	Epithelioid hemangioma
LMNA	Orphanet:740	Hutchinson-Gilford progeria syndrome
LMNA	Orphanet:79084	Familial partial lipodystrophy, Köbberling type
LMNA	Orphanet:79474	Atypical Werner syndrome
LMNA	Orphanet:90153	Mandibuloacral dysplasia with type A lipodystrophy
LMNA	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98855	Autosomal recessive Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98856	Charcot-Marie-Tooth disease type 2B1

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
LMNA	HGNC:6636	ENSG00000160789	P02545	Prelamin-A/C	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LMNA	Prelamin-A/C	Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LMNA	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf

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
mucosa of stomach	1
nipple	1
skin of abdomen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LMNA	295	ubiquitous	marker	nipple, mucosa of stomach, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMNA	7,173

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LMNA	P02545	28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Breakdown of the nuclear lamina	1	3806.7×	0.004	LMNA
Depolymerization of the Nuclear Lamina	1	761.3×	0.005	LMNA
Initiation of Nuclear Envelope (NE) Reformation	1	601.0×	0.005	LMNA
IRE1alpha activates chaperones	1	519.1×	0.005	LMNA
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	519.1×	0.005	LMNA
Nuclear Envelope Breakdown	1	456.8×	0.005	LMNA
Unfolded Protein Response (UPR)	1	356.9×	0.006	LMNA
Oncogenic MAPK signaling	1	248.3×	0.008	LMNA
XBP1(S) activates chaperone genes	1	215.5×	0.008	LMNA
Signaling by BRAF and RAF1 fusions	1	170.4×	0.009	LMNA
Meiotic synapsis	1	141.0×	0.010	LMNA
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.022	LMNA
Cellular responses to stress	1	36.8×	0.031	LMNA
Cellular responses to stimuli	1	31.5×	0.034	LMNA
Disease	1	13.1×	0.076	LMNA

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA double-strand break attachment to nuclear envelope	1	5617.3×	0.002	LMNA
establishment or maintenance of microtubule cytoskeleton polarity	1	4213.0×	0.002	LMNA
nuclear pore localization	1	3370.4×	0.002	LMNA
negative regulation of mesenchymal cell proliferation	1	2808.7×	0.002	LMNA
protein localization to nuclear envelope	1	2106.5×	0.002	LMNA
regulation of protein localization to nucleus	1	2106.5×	0.002	LMNA
negative regulation of cardiac muscle hypertrophy in response to stress	1	1872.4×	0.002	LMNA
ventricular cardiac muscle cell development	1	1532.0×	0.002	LMNA
nuclear envelope organization	1	991.3×	0.003	LMNA
regulation of telomere maintenance	1	842.6×	0.003	LMNA
negative regulation of release of cytochrome c from mitochondria	1	802.5×	0.003	LMNA
nuclear migration	1	732.7×	0.003	LMNA
double-strand break repair via nonhomologous end joining	1	421.3×	0.004	LMNA
negative regulation of extrinsic apoptotic signaling pathway	1	421.3×	0.004	LMNA
protein localization to nucleus	1	351.1×	0.005	LMNA
cellular senescence	1	295.6×	0.005	LMNA
heterochromatin formation	1	255.3×	0.006	LMNA
muscle organ development	1	166.8×	0.008	LMNA
regulation of cell migration	1	157.5×	0.008	LMNA
protein import into nucleus	1	144.0×	0.009	LMNA
regulation of protein stability	1	125.8×	0.009	LMNA
cellular response to hypoxia	1	121.2×	0.009	LMNA
intracellular protein localization	1	104.7×	0.010	LMNA
negative regulation of cell population proliferation	1	42.1×	0.025	LMNA
positive regulation of gene expression	1	38.7×	0.026	LMNA

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
LMNA	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	LMNA
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	LMNA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
LMNA	12	Binding:9, Functional:3

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

30 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)
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	LMNA
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	LMNA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LMNA
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05394506	Not specified	RECRUITING	Modifying Factors in Striated Muscle Laminopathies

Cohort genes: LMNA