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Classifications

Harrison's Part

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Inheritance

1

Autosomal Dominant HP:0000006

CMD1A is transmitted as an autosomal dominant trait. Affected individuals are heterozygous for a pathogenic LMNA variant and each child has a 50% chance of inheriting it. Penetrance is age-dependent - young carriers may be entirely normal - but becomes high by mid-adulthood, and expressivity is variable both between and within families.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:20301717 SUPPORT Human Clinical

"LMNA-related DCM is inherited in an autosomal dominant manner."

GeneReviews statement of the mode of inheritance.

PMID:29095976 SUPPORT Human Clinical

"Asymptomatic LMNA genotype-positive family members (age 31 ± 15 years) had a 9% annual incidence of a newly documented cardiac phenotype and 61% (19/31) of cardiac penetrance during 4.4 ± 2.9 years of follow-up."

Quantifies the age-dependent, incomplete-at-young-age but rapidly accumulating penetrance that governs family screening intervals.

PMID:20301717 SUPPORT Human Clinical

"Each child of an individual with LMNA-related DCM has a 50% chance of inheriting the pathogenic variant."

Evidences the 50% per-child transmission risk stated in this block's description, which the mode-of-inheritance statement alone does not cover.

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Mechanistic Hypotheses

2

Mechanical nuclear fragility model

mechanical_nuclear_fragility_model CANONICAL

In this model the primary defect is structural. A mutant lamina is mechanically weak, so cardiomyocyte nuclei - uniquely subject to the repetitive strain of contraction - deform abnormally, bleb, and rupture, and the nucleoskeleton-to-cytoskeleton coupling that transmits force across the nuclear surface is lost. Cardiomyocyte dysfunction and death follow from that mechanical failure. The structural evidence is direct: focal disruptions, blebs, and nuclear pore clustering in patient myocardium, and detachment of the desmin network from the nuclear surface in lamin A/C-null mice.

Pathograph links

LMNA Variant and Nuclear Lamina Assembly Defect -> Cardiomyocyte Nuclear Envelope Fragility and Rupture DIRECT

Cardiomyocyte Nuclear Envelope Fragility and Rupture -> Cardiomyocyte Loss and Myocardial Fibrosis INDIRECT UNKNOWN INTERMEDIATES

Signalling and gene-expression dysregulation model

signalling_and_gene_expression_model ALTERNATIVE

In this model the lamina's role as a signalling and chromatin platform is what matters. Mutant lamin A/C perturbs lamina-associated heterochromatin and activates intracellular cascades - ERK1/2 and p38 MAPK, AKT-mTOR with impaired autophagy, the DNA damage response and TP53, and PDGF receptor signalling - and it is this altered signalling and transcriptional output, not mechanical failure per se, that drives cardiomyocyte loss and fibrosis. The strongest support is temporal: MAPK activation is detectable in mutant mouse hearts before any clinical or molecular sign of cardiomyopathy, and pharmacological or genetic interruption of these cascades partially rescues the phenotype.

The two models are not mutually exclusive and are curated as parallel arms rather than competitors: nuclear rupture is itself a plausible upstream activator of the DNA damage response, and both arms converge on the same cardiomyocyte-loss and fibrosis nodes. They are separated here because the therapeutic implications differ, and because the failure of a p38 MAPK inhibitor in phase 3 (REALM-DCM) leaves the causal weight of the signalling arm in human disease unresolved.

Pathograph links

LMNA Variant and Nuclear Lamina Assembly Defect -> Chromatin and Lamina-Associated Domain Disorganization DIRECT

LMNA Variant and Nuclear Lamina Assembly Defect -> MAPK Cascade Activation INDIRECT UNKNOWN INTERMEDIATES

LMNA Variant and Nuclear Lamina Assembly Defect -> PDGF Receptor Signalling Activation INDIRECT UNKNOWN INTERMEDIATES

Cardiomyocyte Nuclear Envelope Fragility and Rupture -> DNA Damage Response and TP53 Pathway Activation INDIRECT UNKNOWN INTERMEDIATES

Chromatin and Lamina-Associated Domain Disorganization -> Cardiomyocyte Loss and Myocardial Fibrosis INDIRECT UNKNOWN INTERMEDIATES

MAPK Cascade Activation -> DUSP4-Mediated AKT-mTOR Activation with Impaired Autophagy DIRECT DUSP4 is transcriptionally induced by ERK1/2, which is the reported link between the MAPK and AKT-mTOR arms.

MAPK Cascade Activation -> Cardiomyocyte Loss and Myocardial Fibrosis INDIRECT UNKNOWN INTERMEDIATES

DUSP4-Mediated AKT-mTOR Activation with Impaired Autophagy -> Cardiomyocyte Loss and Myocardial Fibrosis INDIRECT UNKNOWN INTERMEDIATES

DNA Damage Response and TP53 Pathway Activation -> Cardiomyocyte Loss and Myocardial Fibrosis DIRECT

PDGF Receptor Signalling Activation -> Aberrant Cardiomyocyte Calcium Handling INDIRECT UNKNOWN INTERMEDIATES

Mitochondrial Dysfunction and Oxidative Stress -> Aberrant Cardiomyocyte Calcium Handling DIRECT

Aberrant Cardiomyocyte Calcium Handling -> Arrhythmogenic Substrate INDIRECT UNKNOWN INTERMEDIATES

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Discussions and Knowledge Gaps

2

Which of the mechanistic arms downstream of the lamina defect - mechanical nuclear rupture, chromatin/LAD disorganisation, MAPK and AKT-mTOR signalling, DNA damage response/TP53, or PDGF signalling - carries the dominant causal weight in human CMD1A, and are they sequential or parallel?

KNOWLEDGE GAP lmna_dcm_dominant_mechanistic_arm

Attached to

pathophysiology#MAPK Cascade Activation pathophysiology#DUSP4-Mediated AKT-mTOR Activation with Impaired Autophagy pathophysiology#Cardiomyocyte Nuclear Envelope Fragility and Rupture pathophysiology#DNA Damage Response and TP53 Pathway Activation

Each arm is supported by a model-system rescue experiment, which is exactly what makes the question hard: temsirolimus, Tp53 deletion, autophagy/ER stress modulation and PDGF inhibition all partially rescue their respective models, so none is excluded and none is established as rate-limiting. The only human test of any arm - selective p38-alpha MAPK inhibition in REALM-DCM - failed for futility, which argues against the MAPK arm being sufficient as a therapeutic target in symptomatic disease but does not resolve its contribution to pathogenesis, nor rank the others. Curating these as parallel arms feeding a shared cardiomyocyte-loss node is therefore an honest representation of the current state rather than an evasion.

Proposed experiments

Staged intervention in a single inducible cardiomyocyte model

lmna_dcm_staged_arm_interruption

Use one inducible, cardiomyocyte-restricted mutant-lamin model to interrupt each arm separately and in combination at matched disease stages, with identical structural and functional endpoints, so the arms can be ranked within a single system rather than compared across models with different alleles, zygosities and expression levels.

Show evidence (2 references)

PMID:38979608 SUPPORT Human Clinical

"REALM-DCM was terminated after a planned interim analysis suggested futility."

The only human test of any single mechanistic arm failed, which is what leaves the relative causal weight of the arms open rather than settled by the model-system rescue experiments.

PMID:22837537 SUPPORT Model Organism

"Emerging evidence suggests that LMNA mutations cause disease by altering cell signaling pathways, but the specific mechanisms are poorly understood."

States the gap directly. PARTIAL because it frames the open question rather than resolving it.

Do the two workhorse model systems for this disease - homozygous mutant or null mice and iPSC-derived cardiomyocytes - reproduce the human heterozygous, adult-onset, mechanically loaded disease faithfully enough for their mechanistic conclusions to transfer?

HUMAN MODEL MISMATCH lmna_dcm_model_fidelity

Attached to

pathophysiology#Cardiomyocyte Nuclear Envelope Fragility and Rupture

Human CMD1A is a heterozygous dominant disease of adult, chronically loaded myocardium. The mouse models that generated most of the mechanism are homozygous - either null or knock-in - and develop disease over months rather than decades; the null in particular models absence of lamin A/C rather than the dominant-negative action of a mutant protein that human myocardial western blots suggest. iPSC cardiomyocytes are genotypically faithful and support isogenic comparison, but are developmentally immature and are not subjected to the sustained mechanical load that the mechanical-fragility model says is the proximate cause of nuclear failure - so the arm they are least able to test is the one with the strongest human ultrastructural support. The clinical consequence is not hypothetical: the one mechanism taken from these models into a phase 3 trial did not translate.

Proposed experiments

Heterozygous knock-in under physiological load

lmna_dcm_heterozygous_knockin_load

Characterise heterozygous knock-in mice carrying a recurrent human CMD1A allele, with and without imposed haemodynamic load, and compare nuclear rupture frequency and signalling activation against homozygous animals and against human myocardial samples.

Maturation-matched engineered heart tissue

lmna_dcm_engineered_heart_tissue

Study patient and isogenic-control iPSC cardiomyocytes in maturation-promoting engineered heart tissue under chronic auxotonic load, testing whether nuclear rupture emerges once the mechanical environment is restored.

Show evidence (3 references)

PMID:38718107 SUPPORT Model Organism

"in mice, mutations in both alleles of Lmna are required for the disease penetrance, whereas in humans, the vast majority of LMNA cardiomyopathy is autosomal dominant."

States the zygosity mismatch at the heart of this discussion directly, rather than leaving it to be inferred from a model's genotype.

PMID:15548545 SUPPORT Model Organism

"At adulthood, male homozygous mice display reduced locomotion activity with abnormal stiff walking posture and all of them die by 9 months of age."

A concrete instance of that mismatch: the knock-in phenotype is reported in homozygotes, whereas human CMD1A is heterozygous and adult-onset over decades rather than months.

PMID:11897440 SUPPORT Human Clinical

"Western blot protein analyses of three hearts with different mutations showed an additional 30-kDa band, suggesting a degrading effect of mutated on wild-type protein."

Human myocardial evidence for a dominant-negative action on wild-type protein, which a homozygous-null model by construction cannot represent.

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Pathophysiology

17

LMNA Variant and Nuclear Lamina Assembly Defect

A heterozygous pathogenic LMNA variant is the initiating lesion. LMNA encodes lamin A and lamin C by alternative splicing; both assemble into the nuclear lamina, a filamentous meshwork on the nucleoplasmic face of the inner nuclear membrane. Disease-associated variants are distributed across the gene with no single hotspot and include missense changes concentrated in the central alpha-helical rod domain as well as nonsense, frameshift and splice-affecting alleles. Missense alleles are thought to act largely by incorporating into and destabilising the meshwork (a dominant-negative effect), consistent with the reduced or absent nuclear lamin A/C immunostaining and the aberrant degradation product seen in patient myocardium; non-missense alleles behave differently in the clinic, conferring earlier conduction disease and higher arrhythmic risk.

Mechanical nuclear fragility model Signalling and gene-expression dysregulation model

Cardiomyocyte CL:0000746

LMNA hgnc:6636

Genetic context LMNA hgnc:6636 variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE

Applies to the missense alleles, which are modelled as co-assembling into and destabilising the lamina. Non-missense alleles are equally represented in CMD1A and behave differently in the clinic, with earlier conduction disease and higher arrhythmic risk; for those, haploinsufficiency through nonsense-mediated decay is the competing mechanism, and this entry does not claim a single functional mechanism across the whole allelic spectrum.

Nuclear envelope organization GO:0006998 ⚠ ABNORMAL

Nuclear lamina GO:0005652

Myocardium UBERON:0002349

Downstream

Cardiomyocyte Nuclear Envelope Fragility and Rupture

Chromatin and Lamina-Associated Domain Disorganization

MAPK Cascade Activation

PDGF Receptor Signalling Activation

Show evidence (5 references)

PMID:10580070 SUPPORT Human Clinical

"Five novel missense mutations were identified: four in the alpha-helical-rod domain of the lamin A/C gene, and one in the lamin C tail domain."

The founding CMD1A observation, establishing LMNA rod-domain missense variants as the causal lesion in autosomal dominant DCM with conduction-system disease.

PMID:11897440 SUPPORT Human Clinical

"Western blot protein analyses of three hearts with different mutations showed an additional 30-kDa band, suggesting a degrading effect of mutated on wild-type protein."

Direct human myocardial evidence that mutant lamin A/C acts on the wild-type protein rather than simply being absent, which is the biochemical basis for modelling the trigger as a dominant-negative lamina assembly defect.

CGGV:assertion_132ea1ec-caa9-409a-8670-3edb2ec9c889-2025-05-30T160000.000Z SUPPORT Other

ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies the LMNA-DCM gene-disease relationship as Definitive with autosomal dominant inheritance.

+ 2 more references

Cardiomyocyte Nuclear Envelope Fragility and Rupture

A lamina built from mutant subunits cannot bear the mechanical load imposed on a cardiomyocyte nucleus by repetitive contraction. Patient myocardium shows focal disruptions of the nuclear membrane, bleb formation and clustered nuclear pores; lamin A/C-null mouse cardiomyocytes show grossly abnormal nuclear shape and size with displaced and fragmented heterochromatin, and the desmin intermediate filament network detaches from the nuclear surface, so force is no longer transmitted between nucleoskeleton and cytoskeleton. Deleting Lmna in adult cardiomyocytes reproduces the nuclear abnormalities and adds perinuclear Golgi dilation and fragmentation with CREB3-mediated stress signalling before any fall in cardiac function.

Mechanical nuclear fragility model Signalling and gene-expression dysregulation model

Cardiomyocyte CL:0000746

Nuclear envelope organization GO:0006998 ⚠ ABNORMAL

Nuclear envelope GO:0005635

Myocardium UBERON:0002349

Animal models

Lamin A/C-null mouse Mouse recapitulates Demonstrates nuclear structural failure and loss of coupling between the nucleoskeleton and the cytoskeleton in cardiomyocytes.

Downstream

Cardiomyocyte Loss and Myocardial Fibrosis

DNA Damage Response and TP53 Pathway Activation

Mitochondrial Dysfunction and Oxidative Stress

Cardiac Conduction System Degeneration The primary route to conduction disease. Conduction tissue fails first, before ventricular remodeling exists to explain it: the H222P knock-in develops conduction defects as part of its cardiac phenotype, and in patients the electrical abnormality precedes structural disease by years.

Show evidence (8 references)

PMID:11897440 SUPPORT Human Clinical

"Focal disruptions, bleb formation and nuclear pore clustering were documented by electron microscopy of the myocyte nuclear membranes."

Ultrastructural evidence of nuclear envelope failure in the myocardium of LMNA-mutation carriers, in human tissue rather than a model system.

PMID:14755333 SUPPORT Model Organism

"Electron microscopy of Lmna(-/-) cardiomyocytes shows disorganization and detachment of desmin filaments from the nuclear surface with progressive disruption of the cytoskeletal desmin network."

Establishes loss of nucleoskeleton-cytoskeleton coupling as the structural correlate of the mechanical model.

PMID:14755333 SUPPORT Model Organism

"These findings suggest a model in which the primary pathophysiological mechanism in Lmna(-/-) mice is defective force transmission resulting from disruption of lamin interactions with the muscle-specific desmin network and loss of cytoskeletal tension."

States the mechanical force-transmission model this node represents.

+ 5 more references

Chromatin and Lamina-Associated Domain Disorganization

The lamina tethers peripheral heterochromatin, so a defective meshwork releases and redistributes it. Lamin A/C-null cardiomyocyte nuclei show central displacement and fragmentation of heterochromatin, and heterochromatin is dislocated in the hearts of H222P knock-in mice alongside activated Smad signalling. Loss of the correct chromatin-lamina arrangement is the presumed route by which a structural protein defect becomes a transcriptional one, including a failure to mount the compensatory hypertrophic gene programme that normally accompanies ventricular stress.

Signalling and gene-expression dysregulation model

Cardiomyocyte CL:0000746

Chromatin organization GO:0006325 ⚠ ABNORMAL

Downstream

Cardiomyocyte Loss and Myocardial Fibrosis

Show evidence (3 references)

PMID:14755333 SUPPORT Model Organism

"Lmna(-/-) LV myocyte nuclei have marked alterations of shape and size with central displacement and fragmentation of heterochromatin; these changes are present but less severe in left atrial nuclei."

Directly documents loss of peripheral heterochromatin organisation in lamin-deficient cardiomyocytes, and its chamber-dependent gradient.

PMID:14755333 SUPPORT Model Organism

"Alterations in nuclear architecture are associated with defective nuclear function evidenced by decreased SREBP1 import, reduced PPARgamma expression, and a lack of hypertrophic gene activation."

Links the architectural defect to a measurable transcriptional consequence, including failure of the compensatory hypertrophic programme.

PMID:15548545 SUPPORT Model Organism

"Histopathological analysis of the mice revealed muscle degeneration with fibrosis associated with dislocation of heterochromatin and activation of Smad signalling in heart and skeletal muscles."

Reproduces heterochromatin dislocation in a knock-in missense model rather than a null, showing it is not merely an artefact of complete lamin loss.

MAPK Cascade Activation

Mutant A-type lamins activate the ERK1/2, JNK and p38 MAPK branches in the heart. The timing is what makes this node upstream rather than reactive: activation is detectable in H222P knock-in mouse hearts before any clinical sign or molecular marker of cardiomyopathy, and expressing mutant lamin A in cultured cells is sufficient to reproduce it. The p38 branch was the explicit rationale for the ARRY-371797 clinical programme, which failed at phase 3 - so this node records a well-evidenced cascade whose causal weight in human disease is unsettled.

Signalling and gene-expression dysregulation model

Cardiomyocyte CL:0000746

MAPK cascade GO:0000165 ↑ INCREASED ERK1 and ERK2 cascade GO:0070371 ↑ INCREASED

Animal models

Lmna H222P knock-in mouse Mouse recapitulates The model in which MAPK activation was shown to precede cardiomyopathy and in which AKT-mTOR hyperactivation with defective autophagy was identified and pharmacologically reversed.

Downstream

DUSP4-Mediated AKT-mTOR Activation with Impaired Autophagy DUSP4 is transcriptionally induced by ERK1/2, which is the reported link between the MAPK and AKT-mTOR arms.

Cardiomyocyte Loss and Myocardial Fibrosis

Show evidence (2 references)

PMID:17446932 SUPPORT Model Organism

"Using real-time PCR, we showed that activation of MAPK pathways preceded clinical signs or detectable molecular markers of cardiomyopathy."

The temporal argument for this node: MAPK activation is upstream of, not a reaction to, established cardiomyopathy.

PMID:17446932 SUPPORT In Vitro

"Expression of H222P Lamin A in cultured cells activated MAPKs and downstream target genes."

Shows the mutant lamin is sufficient to drive the cascade in a cellular system, independent of the whole-organ context.

DUSP4-Mediated AKT-mTOR Activation with Impaired Autophagy

Downstream of the MAPK cascade, the AKT-mTOR axis is hyperactivated and macroautophagy is defective. DUSP4, induced by ERK1/2, is raised in LMNA cardiomyopathy hearts and its overexpression alone causes cardiac dysfunction through AKT-mTOR activation and impaired autophagy. Both halves of this node are pharmacologically reversible in mouse models: the rapalog temsirolimus restores autophagic flux and prevents functional deterioration, and modulating autophagy or ER stress in a separate cardiomyocyte-specific deletion model delays dysfunction and prolongs survival.

Signalling and gene-expression dysregulation model

Cardiomyocyte CL:0000746

TORC1 signaling GO:0038202 ↑ INCREASED Macroautophagy GO:0016236 ↓ DECREASED

Downstream

Cardiomyocyte Loss and Myocardial Fibrosis

Show evidence (4 references)

PMID:23048029 SUPPORT Model Organism

"Dusp4 expression is enhanced in hearts with LMNA cardiomyopathy, and its overexpression in mice causes it by activating AKT-mTOR signaling that impairs autophagy."

Supplies the molecular link from the MAPK cascade into this node. The paper's own conclusion is that DUSP4 "may contribute" to the disease, so this is a contributing arm rather than a sufficient cause.

PMID:22837537 SUPPORT Model Organism

"We show that the AKT-mammalian target of rapamycin pathway is hyperactivated in hearts of mice with cardiomyopathy caused by Lmna mutation and that in vivo administration of the rapamycin analog temsirolimus prevents deterioration of cardiac function."

Establishes the AKT-mTOR arm and provides the rescue experiment that makes it causal rather than correlative in the model.

PMID:22837537 SUPPORT Model Organism

"We also show defective autophagy in hearts of these mice and demonstrate that improvement in heart function induced by pharmacological interventions is correlated with enhanced autophagy."

Supports the impaired-autophagy component of this node and ties functional rescue to restored autophagic flux.

+ 1 more reference

DNA Damage Response and TP53 Pathway Activation

Mutant lamin A/C expression in cardiomyocytes activates an E2F-DNA damage response-TP53 axis. In a mouse model expressing a DCM-associated LMNA D300N protein in cardiac myocytes this axis is engaged alongside NF-kB and TGF-beta signalling, and the same DNA damage response/TP53 signature is present in RNA sequencing of human hearts with LMNA-associated DCM - a rare instance where a model-derived mechanism was confirmed in the target human tissue. Conditional deletion of Tp53 in cardiac myocytes partially rescues fibrosis, apoptosis and ventricular dysfunction, establishing the pathway as pathogenic rather than a bystander.

Signalling and gene-expression dysregulation model

Cardiomyocyte CL:0000746

DNA damage response GO:0006974 ↑ INCREASED Signal transduction by p53 class mediator GO:0072331 ↑ INCREASED

Animal models

Cardiomyocyte-restricted LMNA D300N mouse Mouse recapitulates The pathway identified in this model was independently confirmed by RNA sequencing of human LMNA-DCM hearts, and cardiomyocyte Tp53 deletion partially rescued the phenotype.

Downstream

Cardiomyocyte Loss and Myocardial Fibrosis

Show evidence (2 references)

PMID:30696354 SUPPORT Human Clinical

"RNA sequencing of human hearts with DCM associated with defined LMNA pathogenic variants corroborated activation of the DNA damage response/TP53 pathway in the heart."

Confirms the pathway is activated in human LMNA-DCM myocardium, not only in the mouse model that suggested it.

PMID:30696354 SUPPORT Model Organism

"Deletion of Tp53 partially rescued myocardial fibrosis, apoptosis, proliferation of nonmyocyte cells, left ventricular dilatation and dysfunction, and slightly improved survival."

The genetic rescue that makes TP53 activation causal for the downstream fibrosis and dysfunction nodes. Partial rescue is why the causal link is curated as contributory rather than sole.

PDGF Receptor Signalling Activation

Platelet-derived growth factor signalling is activated in patient-derived iPSC cardiomyocytes carrying an LMNA frameshift variant, relative to isogenic corrected controls. Inhibiting the pathway pharmacologically or molecularly abolishes the downstream arrhythmic phenotype, which is what makes the activation causal rather than incidental and nominates PDGFRB as a candidate target.

Signalling and gene-expression dysregulation model

Cardiomyocyte CL:0000746

Platelet-derived growth factor receptor signaling pathway GO:0048008 ↑ INCREASED

Downstream

Aberrant Cardiomyocyte Calcium Handling

Show evidence (2 references)

PMID:31316208 SUPPORT In Vitro

"Mechanistically, we show that the platelet-derived growth factor (PDGF) signalling pathway is activated in mutant iPSC-CMs compared to isogenic control iPSC-CMs."

The isogenic comparison establishing PDGF pathway activation as a consequence of the LMNA variant rather than of line-to-line variation.

PMID:31316208 SUPPORT In Vitro

"Conversely, pharmacological and molecular inhibition of the PDGF signalling pathway ameliorated the arrhythmic phenotypes of mutant iPSC-CMs in vitro."

The rescue arm that makes PDGF activation causal for the downstream arrhythmic phenotype in this system.

Mitochondrial Dysfunction and Oxidative Stress

A second, mechanistically distinct route from the lamina defect to arrhythmia, established in patient-derived iPSC cardiomyocytes. Mutant lamin A/C accelerates degradation of its interaction partner SIRT1, producing mitochondrial dysfunction and oxidative stress; the resulting reactive oxygen species activate the CaMKII-RYR2 axis and aggravate SUN1 accumulation, feeding both the calcium-handling and the nuclear-deformation phenotypes. Independent work on the H222P allele finds a converging mitochondrial lesion - reduced mitochondrial calcium uniporter expression with impaired mitochondrial calcium uptake - in a human cardiac organoid model.

Signalling and gene-expression dysregulation model

Cardiomyocyte CL:0000746

Response to oxidative stress GO:0006979 ↑ INCREASED

Mitochondrion GO:0005739

Downstream

Aberrant Cardiomyocyte Calcium Handling

Cardiomyocyte Nuclear Envelope Fragility and Rupture A feed-back arm rather than a forward step: ROS aggravates SUN1 accumulation and so worsens the nuclear deformation that lies upstream of it.

Show evidence (2 references)

PMID:39143095 SUPPORT In Vitro

"Mechanistically, lamin A interacts with sirtuin 1 (SIRT1) where mutant lamin A/C accelerates degradation of SIRT1, leading to mitochondrial dysfunction and oxidative stress."

Gives the molecular route from the mutant lamin to the mitochondrial and oxidative lesion this node represents.

PMID:42478871 SUPPORT In Vitro

"Transcriptomic analyses suggested a global mitochondrial dysfunction and in particular an impaired mitochondrial calcium uptake with a significantly decreased expression of the mitochondrial calcium uniporter (MCU)."

Independent convergence on a mitochondrial lesion, in a different LMNA allele and against a CRISPR-corrected isogenic control.

Aberrant Cardiomyocyte Calcium Handling

Two upstream arms converge here. PDGF pathway activation and ROS-driven CaMKII-RYR2 activation both disturb calcium homeostasis in LMNA-mutant human cardiomyocytes, producing arrhythmia at the single-cell level. This is a cell-autonomous route to arrhythmogenesis that does not require prior structural remodeling, which matters because sudden death in this disease can precede any fall in ejection fraction.

Signalling and gene-expression dysregulation model

Cardiomyocyte CL:0000746

Intracellular calcium ion homeostasis GO:0006874 ⚠ ABNORMAL

Experimental models

Patient-derived LMNA-mutant iPSC cardiomyocytes IPSC DERIVED MODEL A human cell system with isogenic controls that reproduces arrhythmogenesis cell-autonomously and identifies a druggable pathway.

Downstream

Arrhythmogenic Substrate

Show evidence (2 references)

PMID:31316208 SUPPORT In Vitro

"Electrophysiological studies showed that the mutant iPSC-CMs displayed aberrant calcium homeostasis that led to arrhythmias at the single-cell level."

Establishes the cell-autonomous arrhythmic phenotype in human LMNA-mutant cardiomyocytes, independent of chamber remodeling.

PMID:39143095 SUPPORT In Vitro

"Elevated reactive oxygen species (ROS) then activates the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-ryanodine receptor 2 (RYR2) pathway and aggravates the accumulation of SUN1 in mutant iPSC-CMs, contributing to arrhythmias and NE deformation, respectively."

Names the second, oxidative route into this node and the CaMKII-RYR2 effector through which it becomes arrhythmogenic.

Cardiomyocyte Loss and Myocardial Fibrosis

The convergence point of every upstream arm. Cardiomyocytes are lost by apoptosis and replaced by fibrotic extracellular matrix, and the surviving myocardium cannot mount the compensatory hypertrophic response that normally offsets myocyte loss. Mutant-lamin mouse hearts show severe myocardial fibrosis and apoptosis, and muscle degeneration with fibrosis is a histological hallmark of the H222P knock-in. In patients the correlate is late gadolinium enhancement on cardiac magnetic resonance, typically in a non-ischaemic midmyocardial or subepicardial distribution, present in over half of imaged variant carriers.

Cardiomyocyte CL:0000746 Cardiac fibroblast CL:0002548

Cardiac muscle cell apoptotic process GO:0010659 ↑ INCREASED Extracellular matrix organization GO:0030198 ↑ INCREASED

Myocardium UBERON:0002349

Downstream

Cardiac Conduction System Degeneration A late, additional contributor only - not the origin of the conduction phenotype, which precedes structural disease. Once replacement fibrosis is established it further disrupts impulse propagation; myocardial enhancement on cardiac magnetic resonance is associated with conduction abnormality.

Arrhythmogenic Substrate

Left Ventricular Dilation and Systolic Dysfunction

Show evidence (6 references)

PMID:30696354 SUPPORT Model Organism

"Expression of LMNAD300N led to severe myocardial fibrosis, apoptosis, cardiac dysfunction, and premature death."

Cardiomyocyte-restricted expression of a mutant lamin is sufficient to produce the fibrosis-and-apoptosis phenotype this node represents.

PMID:15548545 SUPPORT Model Organism

"Histopathological analysis of the mice revealed muscle degeneration with fibrosis associated with dislocation of heterochromatin and activation of Smad signalling in heart and skeletal muscles."

Independent knock-in model showing degeneration with fibrosis in cardiac and skeletal muscle.

PMID:40689545 SUPPORT Human Clinical

"Among the 72/116 (62%) LMNA variant-positive patients with cardiac magnetic resonance imaging data, LGE was observed in 40/72 (56%) cases."

Human in-vivo evidence that myocardial fibrosis is present in the majority of imaged LMNA variant carriers.

+ 3 more references

Cardiac Conduction System Degeneration

The specialised conduction tissue - sinoatrial node, atrioventricular node and His-Purkinje system - fails earlier and more consistently than the working myocardium, which is the defining feature of this cardiomyopathy. Clinically this appears as sinus bradycardia, progressive first- to third-degree atrioventricular block, and atrial fibrillation or flutter, typically years before ventricular dilation. Conduction defects are reproduced in the H222P knock-in mouse, confirming that they follow from the lamin defect rather than from advanced heart failure.

Sinoatrial node pacemaker cell CL:1000477 Atrioventricular node myocyte CL:1000410

Cardiac conduction GO:0061337 ⚠ ABNORMAL

Cardiac conduction system UBERON:0002350

Animal models

Lmna H222P knock-in mouse Mouse recapitulates Reproduces the combined conduction-defect-plus-dilation cardiac phenotype that defines the human disease.

Downstream

Arrhythmogenic Substrate

Progressive Heart Failure and End-Stage Disease

Intracardiac Thrombus Formation Via atrial fibrillation: loss of organised atrial contraction produces the flow stasis on which an atrial thrombus forms.

Show evidence (3 references)

PMID:10580070 SUPPORT Human Clinical

"Each mutation caused heritable, progressive conduction-system disease (sinus bradycardia, atrioventricular conduction block, or atrial arrhythmias) and dilated cardiomyopathy."

Establishes progressive conduction-system disease as an obligate, heritable component of the CMD1A phenotype across five independent mutations.

PMID:20301717 SUPPORT Human Clinical

"LMNA-related dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and/or reduced systolic function preceded (sometimes by many years) by or accompanied by conduction system disease and/or arrhythmias."

The GeneReviews definition of the disease, which is exactly the temporal ordering this node encodes.

PMID:15548545 SUPPORT Model Organism

"As for cardiac phenotype, they develop chamber dilation and hypokinesia with conduction defects."

Recapitulation of the combined conduction-plus-dilation phenotype in a knock-in mouse.

Arrhythmogenic Substrate

Replacement fibrosis, conduction-tissue disease and cell-autonomous calcium mishandling combine to create a myocardial substrate that supports reentrant and triggered activity. The substrate matures out of step with pump failure, which is the feature that separates this disease from other dilated cardiomyopathies. In imaged carriers, myocardial enhancement is associated with conduction abnormality, tying the fibrotic and electrical components of the substrate together in the same tissue.

Cardiac conduction GO:0061337 ⚠ ABNORMAL

Myocardium UBERON:0002349

Downstream

Malignant Ventricular Arrhythmia

Show evidence (2 references)

PMID:21689390 SUPPORT Human Clinical

"Patients had LV myocardial fibrosis in 88% of cases. Segmental wall motion abnormalities correlated strongly with the degree of enhancement. Myocardial enhancement was associated with conduction abnormalities."

Links the fibrotic and electrical components of the substrate in the same imaged myocardium.

PMID:40689545 SUPPORT Human Clinical

"During a median follow-up of 37 months, IgD variant presence independently predicted sudden cardiac death/major ventricular arrhythmia (hazard ratio, 2.391 [95% CI, 1.046-5.464]; P=0.039)."

Shows the substrate's arrhythmic consequence is variant-position dependent, i.e. that the substrate differs by genotype rather than being uniform.

Malignant Ventricular Arrhythmia

Sustained ventricular tachycardia and ventricular fibrillation arising on that substrate. The clinically decisive feature is that these events are decoupled from systolic function: sudden cardiac death can occur with minimal or no systolic dysfunction. Risk is therefore stratified by genotype and rhythm data rather than by ejection fraction alone - non-sustained ventricular tachycardia, LVEF below 45% at first contact, male sex and a non-missense variant are independent predictors, and the same variables plus atrioventricular block underpin the validated LMNA-risk VTA calculator.

Cardiac conduction GO:0061337 ⚠ ABNORMAL

Myocardium UBERON:0002349

Downstream

Sudden Cardiac Death

Show evidence (3 references)

PMID:20301717 SUPPORT Human Clinical

"Sudden cardiac death can occur, and in some instances is the presenting manifestation; sudden cardiac death may occur with minimal or no systolic dysfunction."

The decoupling of arrhythmic risk from systolic function, which is what makes this a distinct node rather than a consequence of pump failure.

PMID:22281253 SUPPORT Human Clinical

"Independent risk factors for MVA were nonsustained ventricular tachycardia, left ventricular ejection fraction <45% at the first clinical contact, male sex, and non-missense mutations (ins-del/truncating or mutations affecting splicing)."

The four independent predictors of malignant ventricular arrhythmia in LMNA carriers, from a 269-carrier multicentre cohort.

PMID:31155932 SUPPORT Human Clinical

"Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction"

The externally validated risk model, which adds atrioventricular block to the predictor set and is the basis of current ICD timing in this disease.

Left Ventricular Dilation and Systolic Dysfunction

Progressive myocyte loss and fibrosis degrade pump function, producing left ventricular enlargement with reduced ejection fraction. In CMD1A this step usually arrives after conduction disease is already established, and it is not universal at first presentation: roughly 45% of carriers have an LVEF below 50% at genetic diagnosis, rising with follow-up, and about a quarter of those with preserved function at index evaluation develop new dysfunction over the following years.

Cardiomyocyte CL:0000746

Cardiac muscle contraction GO:0060048 ↓ DECREASED

Left ventricle UBERON:0002084

Downstream

Progressive Heart Failure and End-Stage Disease

Intracardiac Thrombus Formation Via ventricular stasis: a dilated, hypokinetic left ventricle is the substrate for a mural thrombus.

Show evidence (2 references)

PMID:29237675 SUPPORT Human Clinical

"Of the 77 carriers, 71 (92%) were phenotypically affected and showed cardiac conduction disturbance (81%), low left ventricular ejection fraction (<50%; 45%), atrial arrhythmias (58%), and malignant ventricular arrhythmias (26%)."

Quantifies systolic dysfunction alongside the other cardiac manifestations in a genotyped multicentre cohort, and shows conduction disturbance is the more prevalent finding.

PMID:27884249 SUPPORT Human Clinical

"In patients without LVD at presentation, 24% developed new LVD, and 7% developed end-stage HF."

Documents incident systolic dysfunction in carriers who were structurally normal at first contact, supporting this as a progressive step rather than a fixed state.

Intracardiac Thrombus Formation

Two features of this disease converge on intracardiac stasis: atrial fibrillation arising from the diseased conduction system, and a dilated, hypokinetic left ventricle. Both supply the flow-stagnation limb of the Virchow triad, and a conventional fibrin-platelet thrombus forms on that substrate - as a left ventricular mural thrombus or in the fibrillating atrium. Embolus from a mural thrombus is recognised as one of the ways CMD1A first presents, and thromboembolic events are common enough in genotyped cohorts to differ measurably by variant position. Conformance is deliberately limited to the thrombus-formation node of the module: the downstream systemic embolization here is arterial and cardiac in origin, so it does not map to the module's venous-to-pulmonary embolic branch, and no local occlusion or ischemia is claimed.

Blood coagulation GO:0007596 ↑ INCREASED

Heart UBERON:0000948

Show evidence (2 references)

PMID:20301717 SUPPORT Human Clinical

"LMNA-related DCM usually presents in early to mid-adulthood with symptomatic conduction system disease or arrhythmias, or with symptomatic DCM including heart failure or embolus from a left ventricular mural thrombus."

Establishes left ventricular mural thrombus, and embolism from it, as a recognised presenting manifestation rather than a late complication.

PMID:40689545 SUPPORT Human Clinical

"In patients with clinically manifest disease (76/116), those with IgD-localizing variants had a lower prevalence of atrioventricular block (25% versus 72%, P=0.002) and atrial fibrillation (50% versus 81%, P=0.019) but higher rates of thromboembolic events (42% versus 16%, P=0.038)."

Quantifies thromboembolic events in a genotyped cohort. Note the dissociation it reports: the higher-risk group had *less* atrial fibrillation, so atrial stasis cannot be the whole explanation and the ventricular contribution is doing real work.

Progressive Heart Failure and End-Stage Disease

One of the disease's two exits. Pump failure progresses to end-stage disease requiring mechanical support or transplantation in around a fifth of carriers followed long term, and survival is materially worse than in non-LMNA dilated cardiomyopathy: event-free survival at age 45 was 31% in carriers versus 75% in non-carrier DCM patients.

Heart contraction GO:0060047 ⚠ ABNORMAL

Heart UBERON:0000948

Show evidence (3 references)

PMID:12628721 SUPPORT Human Clinical

"The LMNA mutation carriers had a significantly poorer cumulative survival compared with non-carrier DCM patients: event-free survival at the age of 45 years was 31% versus 75% in non-carriers."

Direct comparison establishing the worse natural history of LMNA-related DCM against other dilated cardiomyopathy.

PMID:29095976 SUPPORT Human Clinical

"Heart transplantation was performed in 15 of 79 (19%) LMNA patients during 7.8 ± 6.3 years of follow-up."

Quantifies the transplantation burden that defines this end state.

PMID:27884249 SUPPORT Human Clinical

"End-stage HF developed in 19% of patients, and 13% died."

Independent cohort giving concordant end-stage heart failure and mortality figures.

Sudden Cardiac Death

The disease's other exit, and the one that can come first. Arrhythmic death may be the presenting event, before heart failure and sometimes before any detectable systolic impairment. Keeping it as a node distinct from the heart failure end state is what the pathograph needs in order to represent a disease in which the two exits are not sequential.

Heart UBERON:0000948

Show evidence (2 references)

PMID:20301717 SUPPORT Human Clinical

"Sudden cardiac death can occur, and in some instances is the presenting manifestation; sudden cardiac death may occur with minimal or no systolic dysfunction."

Establishes that this exit is reachable without passing through the heart failure end state.

PMID:22281253 SUPPORT Human Clinical

"In a median follow-up period of 43 months (interquartile range: 17 to 101 months), 48 (18%) persons experienced a first episode of MVA: 11 persons received successful cardiopulmonary resuscitation, 25 received appropriate ICD treatment, and 12 persons died suddenly."

Quantifies malignant arrhythmic events, including 12 sudden deaths, in a 269-carrier cohort over a median 43 months.

✶

Histopathology

2

Reduced or Absent Nuclear Lamin A/C Immunostaining

Endomyocardial biopsy is not routine in this disease, but where myocardium has been examined the lamina is depleted: immunochemistry shows reduced or absent lamin A/C in myocyte nuclei, and electron microscopy shows focal membrane disruptions, blebs and clustered nuclear pores. These findings are the tissue-level correlate of the assembly defect and were absent in the disease and normal controls of the same series.

Show evidence (2 references)

PMID:11897440 SUPPORT Human Clinical

"The LMNA expression of the myocyte nuclei was reduced or absent."

The immunochemical finding in myocardium from LMNA-mutation carriers.

PMID:11897440 SUPPORT Human Clinical

"None of these changes and no mutations were found in the nine patients with DCM and increased sCPK or in the disease and normal controls."

Establishes the specificity of the finding against both disease and normal controls in the same study.

Myonuclear Elongation and Clustering with Sarcomeric Disorganisation

Reported in myocardium from carriers of both an LMNA and a TTN variant, compared with LMNA single heterozygotes from the same family - so the finding tracks the modifier genotype rather than the disease as such.

Show evidence (1 reference)

PMID:23463027 SUPPORT Human Clinical

"Myocardial specimens of doubly heterozygote individuals showed increased nuclear length, sarcomeric disorganization, and myonuclear clustering compared with samples from single heterozygotes."

The within-family histological comparison that ties these findings to the TTN modifier rather than to LMNA alone.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

15

Blood 1

Thromboembolic Events Thromboembolism HP:0001907

Show evidence (1 reference)

PMID:40689545 SUPPORT Human Clinical

"In patients with clinically manifest disease (76/116), those with IgD-localizing variants had a lower prevalence of atrioventricular block (25% versus 72%, P=0.002) and atrial fibrillation (50% versus 81%, P=0.019) but higher rates of thromboembolic events (42% versus 16%, P=0.038)."

Documents thromboembolic events in LMNA carriers and their variant-position dependence.

Cardiovascular 9

Cardiac Conduction Abnormality VERY_FREQUENT HP:0031546

Course: PROGRESSIVE

Show evidence (2 references)

PMID:29237675 SUPPORT Human Clinical

"Of the 77 carriers, 71 (92%) were phenotypically affected and showed cardiac conduction disturbance (81%), low left ventricular ejection fraction (<50%; 45%), atrial arrhythmias (58%), and malignant ventricular arrhythmias (26%)."

Reports conduction disturbance in 81% of genotyped carriers, supporting the VERY_FREQUENT band (80-99%). The figure sits just inside the band boundary and comes from a single 77-carrier cohort; the other cohort in this entry reports atrioventricular block alone at 46-57%, which is a narrower finding than "conduction abnormality" and is curated separately below.

PMID:10580070 SUPPORT Human Clinical

"Each mutation caused heritable, progressive conduction-system disease (sinus bradycardia, atrioventricular conduction block, or atrial arrhythmias) and dilated cardiomyopathy."

Supports the progressive clinical course qualifier and the range of conduction abnormalities seen.

Atrioventricular Block HP:0001678

Course: PROGRESSIVE

Show evidence (2 references)

PMID:11897440 SUPPORT Human Clinical

"The LMNA gene mutations account for 33% of the DCMs with AVB, all familial autosomal dominant."

Supports the diagnostic value of atrioventricular block in selecting DCM patients for LMNA testing.

PMID:27884249 SUPPORT Human Clinical

"The prevalence of clinical manifestations increased broadly from index evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to 34%; and LVD, 44% to 57%."

Documents both the prevalence of atrioventricular block and its progression over long-term follow-up.

Atrial Fibrillation FREQUENT HP:0005110

Show evidence (2 references)

PMID:27884249 SUPPORT Human Clinical

"The prevalence of clinical manifestations increased broadly from index evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to 34%; and LVD, 44% to 57%."

Atrial arrhythmia prevalence of 39-63% supports the FREQUENT band (30-79%).

PMID:39145700 SUPPORT Human Clinical

"Atrial fibrillation was present in 60% of patients; 79% of all patients had NYHA Class II and 21% had NYHA Class III HF symptoms at baseline."

Independent contemporary trial cohort giving an atrial fibrillation prevalence of 60%, concordant with the FREQUENT band.

Ventricular Tachyarrhythmia FREQUENT Ventricular tachycardia HP:0004756

Show evidence (2 references)

PMID:27884249 SUPPORT Human Clinical

"The prevalence of clinical manifestations increased broadly from index evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to 34%; and LVD, 44% to 57%."

Ventricular arrhythmia rises from 16% to 34% over follow-up; the follow-up figure supports the FREQUENT band (30-79%).

PMID:29095976 SUPPORT Human Clinical

"We clinically followed up 79 LMNA genotype-positive [age 42 ± 16 years, ejection fraction (EF) 45 ± 13%], including 44 (56%) with VT."

Ventricular tachycardia in 56% of a followed genotype-positive cohort, concordant with the FREQUENT band.

Ventricular Fibrillation HP:0001663

Show evidence (1 reference)

PMID:22281253 SUPPORT Human Clinical

"In this multicenter cohort of 269 LMNA mutation carriers, we evaluated risk factors for MVA, defined as sudden cardiac death, resuscitation, and appropriate implantable cardioverter-defibrillator (ICD) treatment."

Defines the malignant ventricular arrhythmia endpoint - resuscitated arrest and appropriate ICD therapy - which is the clinical footprint of ventricular fibrillation in these cohorts.

Sudden Cardiac Death HP:0001645

Show evidence (2 references)

PMID:20301717 SUPPORT Human Clinical

"Sudden cardiac death can occur, and in some instances is the presenting manifestation; sudden cardiac death may occur with minimal or no systolic dysfunction."

GeneReviews statement of both the occurrence of sudden death and its independence from systolic dysfunction.

PMID:22281253 SUPPORT Human Clinical

"In a median follow-up period of 43 months (interquartile range: 17 to 101 months), 48 (18%) persons experienced a first episode of MVA: 11 persons received successful cardiopulmonary resuscitation, 25 received appropriate ICD treatment, and 12 persons died suddenly."

Quantifies malignant arrhythmic events, including 12 sudden deaths, in a 269-carrier cohort over a median 43 months.

Dilated Cardiomyopathy FREQUENT HP:0001644

Course: PROGRESSIVE

Show evidence (2 references)

PMID:20301717 SUPPORT Human Clinical

"LMNA-related dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and/or reduced systolic function preceded (sometimes by many years) by or accompanied by conduction system disease and/or arrhythmias."

The defining clinical description, including the characteristic ordering relative to conduction disease.

PMID:27884249 SUPPORT Human Clinical

"The prevalence of clinical manifestations increased broadly from index evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to 34%; and LVD, 44% to 57%."

Left ventricular dysfunction in 44-57% of carriers supports the FREQUENT band (30-79%).

Reduced Left Ventricular Ejection Fraction FREQUENT HP:0012664

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:29237675 SUPPORT Human Clinical

"Of the 77 carriers, 71 (92%) were phenotypically affected and showed cardiac conduction disturbance (81%), low left ventricular ejection fraction (<50%; 45%), atrial arrhythmias (58%), and malignant ventricular arrhythmias (26%)."

Reports low ejection fraction in 45% of carriers, supporting the FREQUENT band (30-79%).

Congestive Heart Failure HP:0001635

Course: PROGRESSIVE

Show evidence (2 references)

PMID:27884249 SUPPORT Human Clinical

"End-stage HF developed in 19% of patients, and 13% died."

Quantifies progression to end-stage heart failure in a long-term multicentre cohort.

PMID:20301717 SUPPORT Human Clinical

"LMNA-related DCM usually presents in early to mid-adulthood with symptomatic conduction system disease or arrhythmias, or with symptomatic DCM including heart failure or embolus from a left ventricular mural thrombus."

Names symptomatic heart failure as one of the typical presenting syndromes.

Musculoskeletal 2

Skeletal Muscle Involvement Proximal muscle weakness HP:0003701

Show evidence (2 references)

PMID:12628721 SUPPORT Human Clinical

"There was significant phenotypic variability, but the presence of skeletal muscle involvement (p < 0.001), supraventricular arrhythmia (p = 0.003), conduction defects (p = 0.01), and "mildly" DCM (p = 0.006) were predictors of LMNA mutations."

Establishes skeletal muscle involvement as part of the spectrum and as a statistically significant clinical predictor of LMNA mutation status.

PMID:10580070 SUPPORT Human Clinical

"No family members with mutations had either joint contractures or skeletal myopathy."

Shows skeletal involvement is not obligate: in the founding CMD1A families it was entirely absent. PARTIAL because it bounds rather than supports the phenotype.

Joint Contractures HP:0034392

Show evidence (2 references)

PMID:10580070 SUPPORT Human Clinical

"Mutations in the head or tail domain of this gene cause Emery-Dreifuss muscular dystrophy, a childhood-onset disease characterized by joint contractures and in some cases by abnormalities of cardiac conduction during adulthood."

Establishes contractures as the hallmark of the allelic Emery-Dreifuss phenotype. PARTIAL because the quote describes the allelic disorder, not CMD1A.

PMID:10580070 REFUTE Human Clinical

"No family members with mutations had either joint contractures or skeletal myopathy."

A negative finding in the founding CMD1A families, recorded as REFUTE because it argues against contractures being a feature of the cardiomyopathy-predominant presentation.

Other 3

Sinus Bradycardia and Sinus Node Dysfunction HP:0001688

Show evidence (1 reference)

PMID:10580070 SUPPORT Human Clinical

"Each mutation caused heritable, progressive conduction-system disease (sinus bradycardia, atrioventricular conduction block, or atrial arrhythmias) and dilated cardiomyopathy."

Names sinus bradycardia explicitly among the conduction-system manifestations segregating with LMNA mutations.

Myocardial Fibrosis FREQUENT HP:0001685

Show evidence (2 references)

PMID:40689545 SUPPORT Human Clinical

"Among the 72/116 (62%) LMNA variant-positive patients with cardiac magnetic resonance imaging data, LGE was observed in 40/72 (56%) cases. Most exhibited a nonischemic, midmyocardial or subepicardial pattern (73%), and 6/40 (15%) showed a unique "pseudo-infarct" transmural pattern, predominantly..."

Gives both the 56% prevalence supporting the FREQUENT band and the distribution patterns described.

PMID:21689390 SUPPORT Human Clinical

"Patients had LV myocardial fibrosis in 88% of cases. Segmental wall motion abnormalities correlated strongly with the degree of enhancement. Myocardial enhancement was associated with conduction abnormalities."

An independent, higher fibrosis prevalence in a small carrier series, and the observation that enhancement tracks with conduction abnormality - the tissue link between the fibrotic and electrical phenotypes.

Left Ventricular Mural Thrombus with Systemic Embolism Left ventricular thrombus HP:0040412

Show evidence (1 reference)

PMID:20301717 SUPPORT Human Clinical

"LMNA-related DCM usually presents in early to mid-adulthood with symptomatic conduction system disease or arrhythmias, or with symptomatic DCM including heart failure or embolus from a left ventricular mural thrombus."

Identifies left ventricular mural thrombus with embolism as a recognised presenting manifestation.

🧬

Genetic Associations

2

LMNA

Gene: LMNA hgnc:6636 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:10580070 SUPPORT Human Clinical

"Genetic defects in distinct domains of the nuclear-envelope proteins lamin A and lamin C selectively cause dilated cardiomyopathy with conduction-system disease or autosomal dominant Emery-Dreifuss muscular dystrophy."

Establishes LMNA as the causal gene and the domain-dependent split between the cardiomyopathy-predominant and muscular-dystrophy phenotypes.

PMID:29237675 SUPPORT Human Clinical

"The onset of cardiac disorders indicated that subjects with truncation mutations had an earlier occurrence of cardiac conduction disturbance and low left ventricular ejection fraction, than those with missense mutations."

Supports the genotype-phenotype gradient by variant class that drives risk stratification in this disease.

PMID:11897440 SUPPORT Human Clinical

"Western blot protein analyses of three hearts with different mutations showed an additional 30-kDa band, suggesting a degrading effect of mutated on wild-type protein."

Biochemical support for modelling the missense lesion as dominant-negative: mutant protein acting on wild-type rather than simple loss of one allele. The inference is hedged in the source and rests on three hearts, and the mutation set analysed included nonsense and frameshift alleles, so it does not establish the mechanism for the whole allelic spectrum.

+ 1 more reference

TTN

Gene: TTN hgnc:12403 relationship_type: MODIFIER

Show evidence (2 references)

PMID:23463027 SUPPORT Human Clinical

"The age for heart transplantation was substantially less for LMNA:p.K219T/TTN:p.L4855F double heterozygotes than that for LMNA:p.K219T single heterozygotes."

Establishes TTN as a severity modifier in an LMNA family, with an outcome measure (age at transplantation) rather than a surrogate.

PMID:23463027 SUPPORT Human Clinical

"Myocardial specimens of doubly heterozygote individuals showed increased nuclear length, sarcomeric disorganization, and myonuclear clustering compared with samples from single heterozygotes."

Provides the tissue-level correlate of the modifier effect, linking it back to the nuclear phenotype of the primary lesion.

💊

Medical Actions

11

Implantable Cardioverter-Defibrillator

Action: Implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

The signature intervention in this disease. Because sudden death risk tracks the conduction and arrhythmic phenotype rather than ejection fraction, a defibrillator is preferred over a pacemaker for every pacing indication in an LMNA carrier, and implantation is considered at ejection fractions that would not warrant a device in non-genetic dilated cardiomyopathy. Candidate selection is guided by the gene-specific risk factors and the LMNA-risk VTA model rather than by an EF threshold alone.

Mechanism Target:

INHIBITS Malignant Ventricular Arrhythmia — The device does not modify the arrhythmogenic substrate; it terminates the ventricular tachyarrhythmia arising on it, interrupting the path from substrate to sudden death.

Show evidence (3 references)

PMID:20301717 SUPPORT Human Clinical

"Because risk for sudden cardiac death in LMNA-related DCM accompanies heart block and bradyarrhythmias, ICD use (rather than just pacemaker use) has been recommended for all indications."

The gene-specific device recommendation, stated in GeneReviews management guidance.

PMID:22281253 SUPPORT Human Clinical

"Carriers of LMNA mutations with a high risk of MVA can be identified using these risk factors. This facilitates selection of LMNA mutation carriers who are most likely to benefit from an ICD."

Supports risk-factor-based rather than EF-based selection of ICD candidates.

PMID:27884249 SUPPORT Human Clinical

"Implantable cardioverter-defibrillators were placed in 59% of patients for new LVD or AVB."

Documents real-world device use and its indications in an LMNA cohort.

Permanent Pacing

Action: Pacemaker placement Ontology label: Pacemaker Placement NCIT:C80434

Symptomatic bradyarrhythmia or high-grade heart block requires pacing. In practice this is delivered as part of a defibrillator system rather than a pacemaker alone, because the same patients carry a sudden-death risk that a pacemaker does not address.

Mechanism Target:

BYPASSES Cardiac Conduction System Degeneration — Pacing substitutes for failed impulse generation and conduction; it does not slow the degeneration of the conduction tissue itself.

Show evidence (1 reference)

PMID:20301717 SUPPORT Human Clinical

"Symptomatic supraventricular arrhythmias are usually treated with pharmacologic therapy or ablation; symptomatic bradyarrhythmias or significant heart block is treated with an electronic pacemaker."

States the pacing indication in GeneReviews management guidance.

Early Cardiac Resynchronization Therapy

Action: Cardiac resynchronization therapy Ontology label: Cardiac Resynchronization Therapy NCIT:C80436

An emerging, weakly evidenced deviation from standard practice. Because LMNA carriers frequently need pacing before their QRS widens, and right-ventricular pacing itself is dyssynchronising, one small comparative series implanted CRT-D rather than a conventional device in carriers with a narrow QRS who already had a pacemaker or ICD indication. Over 7.2 years none of the five CRT patients reached the composite of transplantation, death from end-stage heart failure or ventricular tachycardia ablation, versus three of five without. With ten patients and no randomisation this is hypothesis generating, not practice defining.

Mechanism Target:

INHIBITS Left Ventricular Dilation and Systolic Dysfunction — Biventricular pacing is intended to avoid pacing-induced dyssynchrony and so slow the decline in ejection fraction, rather than to act on the lamina defect.

Show evidence (1 reference)

PMID:38495409 SUPPORT Human Clinical

"Of ten LMNA DCM patients (age 51±10 years, QRS 96±14 msec, EF 55±7%) with indication for pacemaker or ICD implantation, five underwent early CRT-D implantation. After 7.2±4 years, three patients (60%) in the non-CRT group reached the primary outcome, compared to no patients in the CRT group (P=0.046)."

The comparative outcome data. PARTIAL because ten patients, non-randomised and retrospectively compared, cannot establish efficacy however suggestive the separation.

Catheter Ablation for Symptomatic Supraventricular Arrhythmia

Action: Cardiac ablation Ontology label: Cardiac Ablation NCIT:C100068

Symptomatic supraventricular arrhythmias are managed with antiarrhythmic drugs or ablation, and chronic atrial fibrillation is first addressed by attempting to restore sinus rhythm along with rate control and anticoagulation.

Show evidence (1 reference)

PMID:20301717 SUPPORT Human Clinical

"Symptomatic supraventricular arrhythmias are usually treated with pharmacologic therapy or ablation; symptomatic bradyarrhythmias or significant heart block is treated with an electronic pacemaker."

States the management of symptomatic supraventricular arrhythmia in GeneReviews management guidance.

Guideline-Directed Heart Failure Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: beta-adrenergic antagonist NCIT:C29576 ACE inhibitor NCIT:C247 SGLT2 inhibitor NCIT:C98083 sacubitril NCIT:C152281

Standard heart failure therapy - ACE inhibitors or angiotensin receptor blockers, beta blockers, mineralocorticoid receptor antagonists, and contemporary additions such as sacubitril/valsartan and SGLT2 inhibitors - is applied as in other dilated cardiomyopathies. There is no LMNA-specific medical regimen, and the natural history data suggest medical therapy alone is insufficient in this genotype.

Mechanism Target:

INHIBITS Left Ventricular Dilation and Systolic Dysfunction — Neurohormonal blockade slows adverse remodeling and improves symptoms and survival in dilated cardiomyopathy generally; it is applied here for the same reason.

Show evidence (1 reference)

PMID:20301717 SUPPORT Human Clinical

"Treatment of symptomatic DCM, including heart failure, is pharmacologic with ACE inhibitors, beta blockers, and other conventional approaches."

GeneReviews statement of the medical regimen used in this disease.

Anticoagulation

Action: Pharmacotherapy NCIT:C15986

Agent: anticoagulant agent NCIT:C263

Anticoagulation is indicated for atrial fibrillation and for left ventricular mural thrombus, both of which are common in this disease and both of which can present as systemic embolism.

Mechanism Target:

INHIBITS Intracardiac Thrombus Formation — Anticoagulation acts on the coagulation arm of thrombus formation, preventing the mural or atrial thrombus rather than altering the stasis that predisposes to it.

Show evidence (1 reference)

PMID:20301717 SUPPORT Human Clinical

"Chronic atrial fibrillation is treated initially with attempts to restore normal sinus rhythm, anticoagulation, and rate control."

States the anticoagulation indication for atrial fibrillation in this disease.

Heart Transplantation

Action: Heart transplantation Ontology label: Heart Transplantation NCIT:C15246

Transplantation, and mechanical circulatory support as a bridge, is required for refractory heart failure and is needed frequently and at a young age in this population - about one in five carriers in longitudinal follow-up.

Mechanism Target:

BYPASSES Progressive Heart Failure and End-Stage Disease — Replaces the failing organ; the systemic genetic defect persists but the target tissue is removed.

Show evidence (2 references)

PMID:29095976 SUPPORT Human Clinical

"Heart transplantation was performed in 15 of 79 (19%) LMNA patients during 7.8 ± 6.3 years of follow-up."

Quantifies transplantation frequency in a followed LMNA cohort.

PMID:20301717 SUPPORT Human Clinical

"Cardiac transplantation or other advanced therapies may be considered for refractory disease in persons receiving comprehensive care from cardiovascular disease experts."

States the indication for advanced therapy in GeneReviews management guidance.

Cardiovascular Surveillance of Genotype-Positive Relatives

Action: Supportive care Ontology label: Supportive Care NCIT:C15747

Because the phenotype converts at roughly 9% per year and sudden death can be the first event, asymptomatic carriers are followed rather than reassured: history, examination, ECG and echocardiography every one to two years, moving to at least annual ECG, ambulatory monitoring and ventricular function assessment once any ECG abnormality appears, with immediate evaluation for new symptoms.

Show evidence (2 references)

PMID:20301717 SUPPORT Human Clinical

"Asymptomatic individuals with a pathogenic LMNA variant should undergo cardiovascular evaluation (medical history, physical examination, echocardiogram, and EKG) every one to two years and/or whenever new symptoms arise."

The surveillance interval for asymptomatic carriers from GeneReviews.

PMID:20301717 SUPPORT Human Clinical

"In families with a known LMNA pathogenic variant, at-risk individuals for whom genetic testing is not possible should have yearly cardiovascular evaluation."

Covers at-risk relatives who cannot be genotyped, who are followed rather than discharged.

Genetic Counseling and Cascade Testing

Action: Genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Autosomal dominant transmission with a 50% recurrence risk per child, age-dependent penetrance and variable expressivity make counselling central. Once a familial variant is identified, targeted testing of relatives directs who needs lifelong surveillance and who can be discharged. Pregnancy is contraindicated in women with established dilated cardiomyopathy, and at-risk women of unknown genotype should be evaluated and counselled ideally before conceiving.

Show evidence (2 references)

PMID:20301717 SUPPORT Human Clinical

"To facilitate prompt diagnosis, targeted LMNA genetic testing when the family-specific pathogenic variant is known; otherwise regular surveillance with cardiovascular screening tests."

States the cascade-testing strategy for relatives at risk.

PMID:20301717 SUPPORT Human Clinical

"Pregnancy is contraindicated in women with DCM. Pregnant women with DCM should be followed by a high-risk obstetrician."

Records the reproductive safety warning from the GeneReviews management section, which belongs with counselling rather than with a drug.

ARRY-371797 (p38 MAPK Inhibitor)

Action: Pharmacotherapy NCIT:C15986

The only disease-specific targeted therapy taken to phase 3 in CMD1A, built on the observation that mutant lamins activate p38 MAPK signalling. Phase 2 data showed an improved six-minute walk distance sustained to 144 weeks, but the phase 3 REALM-DCM trial was stopped for futility at a planned interim analysis with no significant difference on any outcome at week 24 and no safety signal. It is recorded here as a negative result that constrains the signalling hypothesis, not as an available treatment.

Mechanism Target:

INHIBITS MAPK Cascade Activation — Selective p38-alpha MAPK inhibition was intended to interrupt the MAPK arm of this node. The phase 3 failure means the intended mechanism was not shown to translate into clinical benefit.

Show evidence (1 reference)

PMID:38979608 SUPPORT Human Clinical

"In a phase 2 trial and long-term extension, the selective p38α MAPK (mitogen-activated protein kinase) inhibitor, ARRY-371797 (PF-07265803), was associated with an improved 6-minute walk test at 12 weeks, which was preserved over 144 weeks."

Identifies the drug's molecular target as p38-alpha MAPK, which is what links it to this pathophysiology node.

Show evidence (3 references)

PMID:38979608 REFUTE Human Clinical

"REALM-DCM was terminated after a planned interim analysis suggested futility."

The phase 3 trial of this agent was stopped for futility, so it refutes clinical efficacy in symptomatic LMNA-related dilated cardiomyopathy.

PMID:38979608 REFUTE Human Clinical

"No significant differences (P>0.05) between groups were observed in the change from baseline at week 24 for all outcomes"

The primary and secondary endpoint results underlying the futility determination.

PMID:36114020 SUPPORT Human Clinical

"ARRY-371797 (PF-07265803), a potent, selective, oral, small-molecule inhibitor of the p38α mitogen-activated protein kinase pathway, improved 6-minute walk test (6MWT) distance in 12 patients with symptomatic LMNA-related DCM in a 48-week, open-label, phase 2 study."

The open-label phase 2 signal that justified the phase 3 trial. PARTIAL because an uncontrolled 12-patient study on a walk-test endpoint is a weak efficacy claim, and the controlled phase 3 subsequently found no effect.

LOXL2 Inhibition (Simtuzumab)

Action: Pharmacotherapy NCIT:C15986

A preclinical, not clinical, candidate. LOXL2 is upregulated in LMNA-mutant human iPSC cardiomyocytes, engineered heart tissue and mice, and the LOXL2 antibody simtuzumab prevented cardiac dysfunction and fibrosis in the mouse model. There is no human trial in this disease, so this is recorded as a mechanism-derived candidate targeting the fibrotic arm rather than as therapy.

Mechanism Target:

INHIBITS Cardiomyocyte Loss and Myocardial Fibrosis — Antibody blockade of LOXL2 interrupts the extracellular matrix cross-linking arm of the remodeling node.

Show evidence (1 reference)

PMID:41841259 SUPPORT Model Organism

"Treatment with Simtuzumab, a Loxl2 inhibitor, effectively prevented cardiac dysfunction and fibrosis in vivo."

The in-vivo rescue linking LOXL2 inhibition to the fibrosis and dysfunction node.

Show evidence (1 reference)

PMID:41841259 SUPPORT In Vitro

"Transcriptomic analysis revealed dysregulation of extracellular matrix remodeling and significant upregulation of Loxl2 in mutated hiPSC-cardiomyocytes, hiPSC-engineered heart tissues, and mice."

Establishes the target's upregulation in the human-cell and mouse systems that motivated the intervention.

🌍

Environmental Factors

1

Intense or competitive exercise

No prospective trial has tested whether activity restriction alters progression in LMNA carriers; the openscientist deep-research run flagged this as an explicit evidence gap.

Mechanical loading is the one modifiable input that the pathophysiology of this disease predicts should matter: nuclear damage in lamin A/C-deficient cardiomyocytes is generated by contraction-transmitted microtubule forces, so sustained high-intensity exertion is expected to accelerate it. Sports guidance treats lamin A/C as one of the specific genes for which permissive, surveillance-contingent recommendations do not apply, extending restriction even to genotype-positive, phenotype-negative carriers. The recommendation is precautionary and mechanism-derived; it has not been tested prospectively.

Show evidence (1 reference)

PMID:36929832 SUPPORT Other

"The recommendations to engage in intensive exercise and competitive sports are usually contingent on annual clinical surveillance, except for pathogenic variants in specific genes, such as lamin A/C or plakophilin-2."

Documents that lamin A/C is singled out as a gene for which the permissive, surveillance-contingent sports recommendation does not apply. PARTIAL and OTHER because this is expert review of guideline positions, not a study of exercise exposure in LMNA carriers.

Mechanism Target:

EXACERBATES Cardiomyocyte Nuclear Envelope Fragility and Rupture — Higher contractile workload increases the microtubule-transmitted force concentrated on a mechanically vulnerable nucleus. The link is inferred from the force-dependence of nuclear damage, not measured against an exercise exposure in patients.

Show evidence (1 reference)

PMID:41073815 SUPPORT Computational

"Computational modeling revealed that microtubule forces create local stress concentrations that damage lamin A/C-deficient nuclei."

Establishes that nuclear damage is force-dependent, which is the mechanistic basis for expecting exertion to matter. PARTIAL because the study manipulates microtubules, not exercise, so the exposure itself is untested.

🔬

Biochemical Markers

1

Serum Creatine Kinase

Show evidence (2 references)

PMID:10580070 SUPPORT Human Clinical

"Serum creatine kinase levels were normal in family members with mutations of the lamin rod but mildly elevated in some family members with a defect in the tail domain of lamin C."

Documents the domain-dependent pattern of creatine kinase elevation across CMD1A families.

PMID:11897440 SUPPORT Human Clinical

"Increased sCPK in patients with DCM without AVB is not a useful predictor of LMNA mutation."

Bounds the diagnostic usefulness of creatine kinase as a stand-alone selector for LMNA testing.

🔬

Diagnosis

6

Twelve-Lead Electrocardiography

The first-line and often the earliest abnormal test. PR prolongation, higher degrees of atrioventricular block, sinus bradycardia and atrial fibrillation may be present years before any echocardiographic abnormality, which is why ECG anchors surveillance of asymptomatic carriers.

Electrocardiography NCIT:C38053

Show evidence (1 reference)

PMID:20301717 SUPPORT Human Clinical

"Individuals with an LMNA pathogenic variant who are found to have any EKG abnormality should undergo a cardiovascular evaluation for disease progression (EKG, 24-48 hour rhythm monitoring, LV function measurement) at least annually."

Establishes the ECG as the trigger for intensified surveillance in GeneReviews management guidance.

Echocardiography

Echocardiography measures chamber size and systolic function and is part of both the diagnostic workup and the one-to-two-yearly surveillance of asymptomatic carriers. It is less sensitive early in this disease than the ECG, because the electrical phenotype precedes structural change and the dilatation, when it appears, is often mild relative to the functional impairment.

Echocardiography NCIT:C16525

Show evidence (2 references)

PMID:20301717 SUPPORT Human Clinical

"Asymptomatic individuals with a pathogenic LMNA variant should undergo cardiovascular evaluation (medical history, physical examination, echocardiogram, and EKG) every one to two years and/or whenever new symptoms arise."

Places echocardiography in the GeneReviews surveillance protocol for asymptomatic carriers.

PMID:21689390 SUPPORT Human Clinical

"Sixty-nine percent of our asymptomatic or mildly symptomatic patients showed mild ventricular dilatation, systolic failure or both in global ventricular analysis."

Supports the sensitivity caveat: abnormalities in asymptomatic or mildly symptomatic carriers are mild and global, which is what limits echocardiography as an early detection tool. PARTIAL because the measurement was made by cardiac magnetic resonance, not echocardiography.

Ambulatory Rhythm Monitoring

Twenty-four to forty-eight hour monitoring detects non-sustained ventricular tachycardia, which is one of the independent predictors of malignant ventricular arrhythmia and therefore directly informs the ICD decision.

Electrocardiography NCIT:C38053

Show evidence (1 reference)

PMID:22281253 SUPPORT Human Clinical

"Independent risk factors for MVA were nonsustained ventricular tachycardia, left ventricular ejection fraction <45% at the first clinical contact, male sex, and non-missense mutations (ins-del/truncating or mutations affecting splicing)."

Non-sustained ventricular tachycardia is detectable only by rhythm monitoring and is one of the four predictors, making the test decision-relevant.

Molecular Genetic Testing of LMNA

Diagnosis is established by identifying a heterozygous pathogenic LMNA variant in a proband with a compatible phenotype. In practice a cardiomyopathy multigene panel or exome sequencing is used rather than single-gene testing, given the genetic and phenotypic overlap with other conduction-disease cardiomyopathy genes. Once a familial variant is known, targeted testing of relatives becomes the screening tool.

Genetic testing NCIT:C15709

Show evidence (1 reference)

PMID:20301717 SUPPORT Human Clinical

"The diagnosis of LMNA-related DCM is established in a proband with suggestive findings and a heterozygous pathogenic variant in LMNA identified by molecular genetic testing."

GeneReviews statement of the diagnostic criterion.

Cardiac Magnetic Resonance with Late Gadolinium Enhancement

Cardiac MRI detects replacement fibrosis in the majority of imaged carriers, typically midmyocardial or subepicardial, and the enhancement pattern carries prognostic and variant-specific information beyond simple fibrosis detection.

Magnetic resonance imaging NCIT:C16809

Show evidence (2 references)

PMID:40689545 SUPPORT Human Clinical

"LMNA missense variants localizing to IgD present a distinct apical pseudo-infarct LGE pattern associated with increased risk of ventricular arrhythmias and thromboembolic events"

Supports the prognostic and genotype-linked value of the late gadolinium enhancement pattern, not merely its presence.

PMID:21689390 SUPPORT Human Clinical

"Cardiac conduction abnormalities, mildly dilated LV and depressed systolic dysfunction are common in DCM caused by a lamin A/C gene mutation."

Characterises the CMR phenotype, including the mild degree of dilatation relative to functional impairment that makes echocardiography alone insensitive early in this disease.

LMNA-Risk VTA Score

A validated multivariable model estimating five-year risk of life-threatening ventricular tachyarrhythmia from male sex, non-missense variant, first-degree or higher atrioventricular block, non-sustained ventricular tachycardia and left ventricular ejection fraction. It reclassifies a substantial fraction of patients relative to guideline-based ICD selection.

Show evidence (1 reference)

PMID:31155932 SUPPORT Human Clinical

"A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach."

Reports the operating threshold and the net reclassification gain over guideline-based ICD selection.

🩻

Imaging Findings

2

Midmyocardial and Subepicardial Late Gadolinium Enhancement FREQUENT

The characteristic imaging signature. Replacement fibrosis appears as late gadolinium enhancement in a non-ischaemic distribution - midmyocardial or subepicardial rather than subendocardial - and is present in most imaged carriers, including asymptomatic ones. Its extent correlates with segmental wall-motion abnormality and its presence is associated with conduction abnormality.

Mri

Myocardial late gadolinium enhancement HP:4000004 Myocardium UBERON:0002349

Show evidence (2 references)

PMID:40689545 SUPPORT Human Clinical

"Among the 72/116 (62%) LMNA variant-positive patients with cardiac magnetic resonance imaging data, LGE was observed in 40/72 (56%) cases. Most exhibited a nonischemic, midmyocardial or subepicardial pattern (73%), and 6/40 (15%) showed a unique "pseudo-infarct" transmural pattern, predominantly..."

Gives the 56% prevalence supporting the FREQUENT band and the dominant non-ischaemic midmyocardial/subepicardial distribution.

PMID:21689390 SUPPORT Human Clinical

"Patients had LV myocardial fibrosis in 88% of cases. Segmental wall motion abnormalities correlated strongly with the degree of enhancement. Myocardial enhancement was associated with conduction abnormalities."

An independent series with a higher prevalence, and the correlations with wall motion and with conduction abnormality.

Apical Transmural Pseudo-Infarct Enhancement Pattern OCCASIONAL

A minority pattern that matters because it is genotype-linked and prognostically adverse. Transmural enhancement predominantly in the apical segments, mimicking prior infarction, was seen only in carriers of C-terminal immunoglobulin-like domain missense variants, who had less atrioventricular block and atrial fibrillation than other carriers but more thromboembolic events and independently higher risk of sudden death or major ventricular arrhythmia.

Mri

Myocardial late gadolinium enhancement HP:4000004 Myocardium UBERON:0002349

Show evidence (2 references)

PMID:40689545 SUPPORT Human Clinical

"All 6 patients with this distinct LGE pattern harbored C-terminal IgD (immunoglobulin-like domain) variants (p.Arg471His or p.Arg541His)."

Establishes the genotype restriction of this pattern. The 6/40 (15%) share of imaged enhancement supports the OCCASIONAL band.

PMID:40689545 SUPPORT Human Clinical

"During a median follow-up of 37 months, IgD variant presence independently predicted sudden cardiac death/major ventricular arrhythmia (hazard ratio, 2.391 [95% CI, 1.046-5.464]; P=0.039)."

The prognostic association that makes this pattern actionable rather than descriptive.

📈

Progression

4

Asymptomatic Genotype-Positive Stage

Carriers identified by cascade testing may be entirely normal. Penetrance is age-dependent, but conversion is brisk once surveillance begins - roughly a 9% annual incidence of a newly documented cardiac phenotype in asymptomatic family members with a mean age of 31.

Show evidence (1 reference)

PMID:29095976 SUPPORT Human Clinical

"Asymptomatic LMNA genotype-positive family members (age 31 ± 15 years) had a 9% annual incidence of a newly documented cardiac phenotype and 61% (19/31) of cardiac penetrance during 4.4 ± 2.9 years of follow-up."

Quantifies conversion from genotype-positive/phenotype-negative to clinically affected.

Electrical Stage

Conduction-system disease and atrial arrhythmia appear first and may be the only manifestation for years, with structural disease still absent or mild. This is the window in which arrhythmic risk stratification and pre-emptive device decisions are made.

Show evidence (1 reference)

PMID:20301717 SUPPORT Human Clinical

"LMNA-related dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and/or reduced systolic function preceded (sometimes by many years) by or accompanied by conduction system disease and/or arrhythmias."

States the temporal precedence of the electrical over the structural phenotype.

Structural and Arrhythmic Progression

Every category of manifestation accumulates with follow-up rather than remaining static, and carriers who are structurally normal at first contact are not thereby safe: about a quarter develop new left ventricular dysfunction.

Show evidence (2 references)

PMID:27884249 SUPPORT Human Clinical

"The prevalence of clinical manifestations increased broadly from index evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to 34%; and LVD, 44% to 57%."

Documents progression across all four manifestation categories over a median seven years.

PMID:27884249 SUPPORT Human Clinical

"LMNA-related heart disease was associated with a high incidence of phenotypic progression and adverse arrhythmic and nonarrhythmic events over long-term follow-up. The index cardiac phenotype did not predict adverse events."

Important negative finding: the presenting phenotype does not stratify outcome, so surveillance cannot be relaxed on the basis of a mild presentation.

End-Stage Disease

The disease ends in transplantation, mechanical support, or arrhythmic death. Roughly one in five carriers followed long term is transplanted or reaches end-stage heart failure, and survival is substantially worse than in non-LMNA dilated cardiomyopathy.

Show evidence (1 reference)

PMID:12628721 SUPPORT Human Clinical

"The LMNA mutation carriers had a significantly poorer cumulative survival compared with non-carrier DCM patients: event-free survival at the age of 45 years was 31% versus 75% in non-carriers."

Quantifies the survival penalty relative to other dilated cardiomyopathy.

📊

Prevalence

2

Norwegian familial dilated cardiomyopathy probands

Unknown Not yet documented

No population-based prevalence estimate exists for the LMNA-specific form of dilated cardiomyopathy. The available figures are the share of dilated cardiomyopathy cohorts carrying an LMNA variant, which is a diagnostic yield rather than a population rate: 6.2% of unrelated familial DCM probands in Norway, and 8% of nuclear families in the US Familial Cardiomyopathy Registry. The yield rises sharply when atrioventricular block accompanies the cardiomyopathy.

Show evidence (1 reference)

PMID:29095976 SUPPORT Human Clinical

"Of 561 unrelated familial DCM probands, 35 (6.2%) had an LMNA mutation."

Quantifies the LMNA share of familial dilated cardiomyopathy in a national referral cohort. PARTIAL because a diagnostic yield within a DCM cohort is not a population prevalence for CMD1A.

Familial and sporadic dilated cardiomyopathy with atrioventricular block

Unknown Not yet documented

Enrichment figure rather than a population rate: among dilated cardiomyopathies presenting with atrioventricular block, a third carried an LMNA defect, and all such cases were familial and autosomal dominant.

Show evidence (1 reference)

PMID:11897440 SUPPORT Human Clinical

"The LMNA gene mutations account for 33% of the DCMs with AVB, all familial autosomal dominant."

Establishes the diagnostic enrichment of LMNA variants in the conduction-disease subset of dilated cardiomyopathy.

🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Dilated Cardiomyopathy 1A:

Idiopathic Dilated Cardiomyopathy

Overlapping Features Non-genetic or unexplained dilated cardiomyopathy shares the structural phenotype but lacks the early, disproportionate conduction-system disease. The distinction matters because arrhythmic risk relative to ejection fraction is much higher in the LMNA form, so device decisions diverge.

Distinguishing Features

Early and progressive atrioventricular block preceding ventricular dilation, family history of sudden death or pacemaker at a young age, and a pathogenic LMNA variant.

Emery-Dreifuss Muscular Dystrophy

Overlapping Features The allelic LMNA disorder in which childhood-onset joint contractures and humeroperoneal weakness dominate and cardiac conduction disease appears in adulthood. CMD1A families may have no skeletal involvement at all.

Distinguishing Features

Childhood-onset contractures and skeletal myopathy as the presenting problem, versus adult-onset conduction disease with normal muscles in CMD1A. X-linked EMD/emerin-related disease must also be excluded.

Arrhythmogenic Right Ventricular Cardiomyopathy

Overlapping Features Also presents with ventricular arrhythmia out of proportion to systolic dysfunction, but the substrate is desmosomal and predominantly right ventricular. ClinGen classifies the LMNA-ARVC relationship as Limited, so an ARVC label should not be applied to an LMNA carrier on genetic grounds alone.

Distinguishing Features

Right ventricular predominance, desmosomal gene variants (PKP2, DSP, DSG2), and characteristic depolarisation/repolarisation ECG criteria, versus the atrioventricular-block-first pattern of CMD1A.

Cardiac Sarcoidosis

Overlapping Features The highest-stakes mimic, and the only acquired one on this list. Cardiac sarcoidosis presents with the same triad of atrioventricular block, ventricular arrhythmia and heart failure, with patchy non-ischaemic late gadolinium enhancement on cardiac magnetic resonance. Distinguishing them changes management in opposite directions - immunosuppression versus early defibrillator - and endomyocardial biopsy can be equivocal, so genetic testing belongs in the initial workup rather than after imaging has been relied on alone.

Distinguishing Features

A pathogenic LMNA variant, and a family history of conduction disease, pacemaker or sudden death at a young age.
Extracardiac sarcoid involvement, non-caseating granulomas on biopsy, and FDG-PET uptake favour sarcoidosis; but isolated cardiac sarcoidosis occurs and imaging criteria alone do not separate the two.

Show evidence (2 references)

PMID:40225500 SUPPORT Human Clinical

"Phenotypic expression of lamin AC-dilated cardiomyopathy (LMNA-DCM) and cardiac sarcoidosis (CS) at times presents with similar clinical findings, including arrhythmia, conduction abnormalities, and heart failure."

Establishes the clinical overlap that makes this a genuine differential rather than a theoretical one.

PMID:40225500 SUPPORT Human Clinical

"Also highlighted is the need for extreme caution when endomyocardial biopsies are equivocal and there is sole reliance on cardiac imaging to establish diagnostic criteria."

Supports the recommendation to resolve the differential genetically rather than by imaging, which is the practical consequence of the overlap.

Other Conduction-Disease Cardiomyopathy Genes

Overlapping Features SCN5A, FLNC, DES, RBM20 and PLN variants can each produce dilated cardiomyopathy with arrhythmia or conduction disease, which is why panel rather than single-gene testing is standard.

Distinguishing Features

Resolved by multigene panel or exome sequencing rather than by phenotype.

📊

Related Datasets

3

Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy geo:GSE82290

human MICROARRAY

PMID:27235420

Human material from carriers of the LMNA p.S143P founder variant causing familial dilated cardiomyopathy with conduction disease. Selected over other dilated-cardiomyopathy GEO hits because the studied variant is in LMNA; RBM20- and mixed-cardiomyopathy series returned by the same search were excluded as being about different genes.

LMNA p.H222P mutation causes contractile dysfunction via impaired mitochondrial calcium uptake in human cardiac laminopathy geo:GSE304575

human BULK RNA SEQ

PMID:42478871

Human cardiac laminopathy model carrying LMNA p.H222P, the same allele as the knock-in mouse curated under animal_models.

The p.Ser143Pro lamin A/C mutation leads to dilated cardiomyopathy and activates the unfolded protein response pathway geo:GSE330200

human BULK RNA SEQ

Mouse and human series for the LMNA p.S143P variant. Carries no linked publication in the GEO index at time of curation, so no evidence block is given.

🔬

Clinical Trials

1

NCT03439514 PHASE_III TERMINATED

REALM-DCM, a phase 3 multinational randomised placebo-controlled trial of the selective p38-alpha MAPK inhibitor ARRY-371797 in symptomatic LMNA-related dilated cardiomyopathy, with change in six-minute walk distance at week 24 as the primary outcome. Terminated for futility at a planned interim analysis without safety concern.

Target Phenotypes: Congestive heart failure HP:0001635 Reduced left ventricular ejection fraction HP:0012664

Show evidence (2 references)

PMID:38979608 SUPPORT Human Clinical

"REALM-DCM (NCT03439514) was a phase 3, randomized, double-blind, placebo-controlled trial in patients with symptomatic LMNA-related dilated cardiomyopathy."

Identifies the trial registration, design, and study population.

PMID:39145700 SUPPORT Human Clinical

"Between 2018 and 2022, 77 patients took part in REALM-DCM. The median patient age was 53 years (range: 23-72), and 57% were male."

Characterises the enrolled trial population, which doubles as the best contemporary phenotypic description of symptomatic CMD1A.

🧫

Experimental Models

1

Patient-derived LMNA-mutant iPSC cardiomyocytes IPSC_DERIVED_MODEL

Induced pluripotent stem cell-derived cardiomyocytes from carriers of an LMNA frameshift variant, compared against isogenic corrected controls. They display disturbed calcium handling producing single-cell arrhythmia and activated PDGF signalling, both reversed by PDGF pathway inhibition.

Pathograph links

Aberrant Cardiomyocyte Calcium Handling recapitulates fidelity: moderate A human cell system with isogenic controls that reproduces arrhythmogenesis cell-autonomously and identifies a druggable pathway.

Limitations: iPSC cardiomyocytes are immature relative to adult myocardium - rounder nuclei, a less developed cytoskeleton and no chronic mechanical loading - so they are a weak model for the nuclear-rupture arm of this disease even where they capture the signalling and calcium phenotypes. Single-cell arrhythmia in vitro is also not the same entity as clinical ventricular tachyarrhythmia.

Readouts

Calcium handling and single-cell arrhythmia

Direction: ALTERED

Interpretation: Electrophysiology shows aberrant calcium homeostasis generating arrhythmic events.

Show evidence (1 reference)

PMID:31316208 SUPPORT In Vitro

"Electrophysiological studies showed that the mutant iPSC-CMs displayed aberrant calcium homeostasis that led to arrhythmias at the single-cell level."

Reports the electrophysiological measurement behind this readout.

Arrhythmic phenotype under PDGF pathway inhibition

Direction: RESTORED

Interpretation: Blocking PDGF signalling abolishes the arrhythmic phenotype, making the pathway causal in this system.

Show evidence (1 reference)

PMID:31316208 SUPPORT In Vitro

"Conversely, pharmacological and molecular inhibition of the PDGF signalling pathway ameliorated the arrhythmic phenotypes of mutant iPSC-CMs in vitro."

Reports the rescue measurement behind this readout.

Show evidence (1 reference)

PMID:31316208 SUPPORT In Vitro

"Mechanistically, we show that the platelet-derived growth factor (PDGF) signalling pathway is activated in mutant iPSC-CMs compared to isogenic control iPSC-CMs."

The isogenic comparison that makes this model informative for the signalling node.

🐁

Animal Models

3

Lmna H222P knock-in mouse

Knock-in of a human LMNA missense allele originally found in an autosomal dominant Emery-Dreifuss family. Homozygotes develop chamber dilation, hypokinesia and conduction defects with muscle degeneration, fibrosis, dislocated heterochromatin and Smad activation, and it is the model in which the MAPK and AKT-mTOR signalling arms of this disease were established.

Species

Mouse

Genotype

Lmna p.H222P homozygous knock-in

Publication

PMID:15548545

Pathograph links

Cardiac Conduction System Degeneration recapitulates fidelity: moderate Reproduces the combined conduction-defect-plus-dilation cardiac phenotype that defines the human disease.

Limitations: The cardiac phenotype requires homozygosity, whereas human CMD1A is a heterozygous dominant disease, and H222P was ascertained in an Emery-Dreifuss family rather than a cardiomyopathy-predominant one.

Readouts

Cardiac chamber dimension and conduction

Direction: ALTERED

Interpretation: Chamber dilation with hypokinesia and conduction defects in the intact animal.

Show evidence (1 reference)

PMID:15548545 SUPPORT Model Organism

"As for cardiac phenotype, they develop chamber dilation and hypokinesia with conduction defects."

Reports the cardiac measurement behind this readout.

Show evidence (1 reference)

PMID:15548545 SUPPORT Model Organism

"These results demonstrate that LmnaH222P/H222P mice represent a good model for studying laminopathies affecting striated muscles as they develop a dystrophic condition of both skeletal and cardiac muscles similar to the human diseases."

The authors' own assessment that the model is informative for human striated-muscle laminopathy.

MAPK Cascade Activation recapitulates fidelity: moderate The model in which MAPK activation was shown to precede cardiomyopathy and in which AKT-mTOR hyperactivation with defective autophagy was identified and pharmacologically reversed.

Limitations: The therapeutic corollary did not translate: a p38 MAPK inhibitor developed on the strength of this signalling biology failed for futility in phase 3, so the model's predictive validity for human treatment response is unestablished.

Readouts

Cardiac MAPK pathway activation

Direction: INCREASED

Interpretation: MAPK cascade activity is raised in mutant hearts before clinical disease.

Show evidence (1 reference)

PMID:17446932 SUPPORT Model Organism

"Using real-time PCR, we showed that activation of MAPK pathways preceded clinical signs or detectable molecular markers of cardiomyopathy."

Reports the transcriptional measurement and its timing.

Cardiac function under temsirolimus

Direction: RESTORED

Interpretation: mTOR inhibition preserves cardiac function in the mutant, tying the signalling arm to the functional phenotype.

Show evidence (1 reference)

PMID:22837537 SUPPORT Model Organism

"We show that the AKT-mammalian target of rapamycin pathway is hyperactivated in hearts of mice with cardiomyopathy caused by Lmna mutation and that in vivo administration of the rapamycin analog temsirolimus prevents deterioration of cardiac function."

Reports both the pathway measurement and the rescue outcome.

Show evidence (1 reference)

PMID:17446932 SUPPORT Model Organism

"Activation of MAPK signaling by mutant A-type lamins could be a cornerstone in the development of heart disease in autosomal dominant Emery-Dreifuss muscular dystrophy."

Supports treating this model as informative for the signalling node.

Show evidence (1 reference)

PMID:15548545 SUPPORT Model Organism

"We chose the LMNA H222P missense mutation identified in a family with autosomal dominant Emery-Dreifuss muscular dystrophy, one of the striated muscle-specific laminopathies, to create a faithful mouse model of this type of laminopathy."

Describes the construction and intent of the model, establishing that it carries a human-derived LMNA missense allele.

Lamin A/C-null mouse

Complete loss of A-type lamins produces rapidly progressive dilated cardiomyopathy with grossly abnormal nuclei, fragmented heterochromatin, and detachment of the desmin network from the nuclear surface. It is the source of the defective-force-transmission model and of the observation that lamin-deficient cardiomyocytes cannot mount compensatory hypertrophy.

Species

Mouse

Genotype

Lmna knockout (Lmna-/-)

Publication

PMID:14755333

Pathograph links

Cardiomyocyte Nuclear Envelope Fragility and Rupture recapitulates fidelity: moderate Demonstrates nuclear structural failure and loss of coupling between the nucleoskeleton and the cytoskeleton in cardiomyocytes.

Limitations: A homozygous null is a more extreme lesion than the heterozygous, often missense human genotype, and the mice develop disease far more rapidly than patients; the null therefore models loss of lamin function rather than the dominant-negative action of a mutant protein.

Readouts

Cardiomyocyte nuclear morphology and desmin attachment

Direction: ALTERED

Interpretation: Electron microscopy shows nuclear shape and size abnormalities with desmin filaments detached from the nuclear surface.

Show evidence (1 reference)

PMID:14755333 SUPPORT Model Organism

"Electron microscopy of Lmna(-/-) cardiomyocytes shows disorganization and detachment of desmin filaments from the nuclear surface with progressive disruption of the cytoskeletal desmin network."

Reports the ultrastructural measurement behind this readout.

Show evidence (1 reference)

PMID:14755333 SUPPORT Model Organism

"We report that lamin A/C-deficient (Lmna(-/-)) mice develop rapidly progressive dilated cardiomyopathy (DCM) characterized by left ventricular (LV) dilation and reduced systolic contraction."

Establishes that the model produces the disease phenotype of interest.

Show evidence (1 reference)

PMID:14755333 SUPPORT Model Organism

"We report that lamin A/C-deficient (Lmna(-/-)) mice develop rapidly progressive dilated cardiomyopathy (DCM) characterized by left ventricular (LV) dilation and reduced systolic contraction."

Establishes the model's genotype and its dilated cardiomyopathy phenotype.

Cardiomyocyte-restricted LMNA D300N mouse

Doxycycline-suppressible expression of a mutant lamin restricted to cardiac myocytes, producing severe myocardial fibrosis, apoptosis, cardiac dysfunction and premature death, all preventable by switching expression off. Used to establish the DNA damage response/TP53 arm, which was then confirmed in human LMNA-DCM myocardium.

Species

Mouse

Genotype

Tet-off bigenic cardiac-myocyte-specific LMNA p.D300N expression

Publication

PMID:30696354

Pathograph links

DNA Damage Response and TP53 Pathway Activation recapitulates fidelity: high The pathway identified in this model was independently confirmed by RNA sequencing of human LMNA-DCM hearts, and cardiomyocyte Tp53 deletion partially rescued the phenotype.

Limitations: D300N is a progeroid-syndrome-associated allele rather than a typical CMD1A variant, and the transgenic system uses supraphysiological cardiomyocyte-restricted expression rather than the heterozygous germline state.

Readouts

Cardiac phenotype after cardiomyocyte Tp53 deletion

Direction: RESTORED

Interpretation: Removing TP53 partially reverses fibrosis, apoptosis and ventricular dysfunction, establishing pathway causality.

Show evidence (1 reference)

PMID:30696354 SUPPORT Model Organism

"Deletion of Tp53 partially rescued myocardial fibrosis, apoptosis, proliferation of nonmyocyte cells, left ventricular dilatation and dysfunction, and slightly improved survival."

Reports the genetic-rescue measurement behind this readout.

Show evidence (1 reference)

PMID:30696354 SUPPORT Human Clinical

"RNA sequencing of human hearts with DCM associated with defined LMNA pathogenic variants corroborated activation of the DNA damage response/TP53 pathway in the heart."

The human-tissue confirmation that justifies the HIGH fidelity rating for this mechanism link.

Show evidence (1 reference)

PMID:30696354 SUPPORT Model Organism

"We generated a tet-off bigenic mice expressing either a WT (wild type) or a mutant LMNA (D300N) protein in cardiac myocytes."

Describes the conditional, cardiomyocyte-restricted construction of the model.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy 1A
creation_date: "2026-08-18T00:00:00Z"
synonyms:
- CMD1A
- CDCD1
- LMNA-related dilated cardiomyopathy
- LMNA familial isolated dilated cardiomyopathy
- familial dilated cardiomyopathy with conduction defect due to LMNA mutation
- cardiomyopathy, dilated, type 1A
- cardiac laminopathy
description: >-
  Dilated cardiomyopathy 1A (CMD1A) is the LMNA-related form of familial dilated
  cardiomyopathy. LMNA encodes lamin A and lamin C, the A-type intermediate
  filament proteins that polymerise into the nuclear lamina lining the inner
  nuclear membrane, where they provide mechanical support to the nucleus, tether
  peripheral heterochromatin, and couple the nucleoskeleton to the cytoskeleton.
  What distinguishes CMD1A from most other genetic dilated cardiomyopathies is
  the order in which the myocardium fails: conduction system disease and
  arrhythmia - sinus node dysfunction, progressive atrioventricular block, atrial
  fibrillation or flutter - typically precede, sometimes by many years, the
  ventricular dilation and systolic dysfunction that eventually follow. Malignant
  ventricular arrhythmia and sudden cardiac death can occur with minimal or no
  systolic dysfunction, so ICD decisions in this disease are driven by
  gene-specific risk models rather than by ejection fraction alone. Onset is
  usually in early-to-mid adulthood, penetrance is high, and progression to
  end-stage heart failure requiring transplantation is common. A skeletal
  myopathy with joint contractures and elevated creatine kinase occurs in part of
  the spectrum, reflecting the allelic overlap with Emery-Dreifuss muscular
  dystrophy and limb-girdle muscular dystrophy 1B. Inheritance is autosomal
  dominant.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: dilated cardiomyopathy 1A
  term:
    id: MONDO:0007269
    label: dilated cardiomyopathy 1A
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
prevalence:
- population: Norwegian familial dilated cardiomyopathy probands
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population-based prevalence estimate exists for the LMNA-specific form of
    dilated cardiomyopathy. The available figures are the share of dilated
    cardiomyopathy cohorts carrying an LMNA variant, which is a diagnostic yield
    rather than a population rate: 6.2% of unrelated familial DCM probands in
    Norway, and 8% of nuclear families in the US Familial Cardiomyopathy
    Registry. The yield rises sharply when atrioventricular block accompanies the
    cardiomyopathy.
  evidence:
  - reference: PMID:29095976
    reference_title: "Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 561 unrelated familial DCM probands, 35 (6.2%) had an LMNA mutation.
    explanation: >-
      Quantifies the LMNA share of familial dilated cardiomyopathy in a national
      referral cohort. PARTIAL because a diagnostic yield within a DCM cohort is
      not a population prevalence for CMD1A.
- population: Familial and sporadic dilated cardiomyopathy with atrioventricular block
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Enrichment figure rather than a population rate: among dilated
    cardiomyopathies presenting with atrioventricular block, a third carried an
    LMNA defect, and all such cases were familial and autosomal dominant.
  evidence:
  - reference: PMID:11897440
    reference_title: "Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The LMNA gene mutations account for 33% of the DCMs with AVB, all familial
      autosomal dominant.
    explanation: >-
      Establishes the diagnostic enrichment of LMNA variants in the
      conduction-disease subset of dilated cardiomyopathy.
inheritance:
- name: Autosomal Dominant
  description: >-
    CMD1A is transmitted as an autosomal dominant trait. Affected individuals are
    heterozygous for a pathogenic LMNA variant and each child has a 50% chance of
    inheriting it. Penetrance is age-dependent - young carriers may be entirely
    normal - but becomes high by mid-adulthood, and expressivity is variable both
    between and within families.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LMNA-related DCM is inherited in an autosomal dominant manner.
    explanation: >-
      GeneReviews statement of the mode of inheritance.
  - reference: PMID:29095976
    reference_title: "Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Asymptomatic LMNA genotype-positive family members (age 31 ± 15 years) had
      a 9% annual incidence of a newly documented cardiac phenotype and 61%
      (19/31) of cardiac penetrance during 4.4 ± 2.9 years of follow-up.
    explanation: >-
      Quantifies the age-dependent, incomplete-at-young-age but rapidly
      accumulating penetrance that governs family screening intervals.
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with LMNA-related DCM has a 50% chance of
      inheriting the pathogenic variant.
    explanation: >-
      Evidences the 50% per-child transmission risk stated in this block's
      description, which the mode-of-inheritance statement alone does not cover.
mechanistic_hypotheses:
- hypothesis_group_id: mechanical_nuclear_fragility_model
  hypothesis_label: Mechanical nuclear fragility model
  status: CANONICAL
  description: >-
    In this model the primary defect is structural. A mutant lamina is
    mechanically weak, so cardiomyocyte nuclei - uniquely subject to the
    repetitive strain of contraction - deform abnormally, bleb, and rupture, and
    the nucleoskeleton-to-cytoskeleton coupling that transmits force across the
    nuclear surface is lost. Cardiomyocyte dysfunction and death follow from that
    mechanical failure. The structural evidence is direct: focal disruptions,
    blebs, and nuclear pore clustering in patient myocardium, and detachment of
    the desmin network from the nuclear surface in lamin A/C-null mice.
- hypothesis_group_id: signalling_and_gene_expression_model
  hypothesis_label: Signalling and gene-expression dysregulation model
  status: ALTERNATIVE
  description: >-
    In this model the lamina's role as a signalling and chromatin platform is
    what matters. Mutant lamin A/C perturbs lamina-associated heterochromatin and
    activates intracellular cascades - ERK1/2 and p38 MAPK, AKT-mTOR with
    impaired autophagy, the DNA damage response and TP53, and PDGF receptor
    signalling - and it is this altered signalling and transcriptional output,
    not mechanical failure per se, that drives cardiomyocyte loss and fibrosis.
    The strongest support is temporal: MAPK activation is detectable in mutant
    mouse hearts before any clinical or molecular sign of cardiomyopathy, and
    pharmacological or genetic interruption of these cascades partially rescues
    the phenotype.
  notes: >-
    The two models are not mutually exclusive and are curated as parallel arms
    rather than competitors: nuclear rupture is itself a plausible upstream
    activator of the DNA damage response, and both arms converge on the same
    cardiomyocyte-loss and fibrosis nodes. They are separated here because the
    therapeutic implications differ, and because the failure of a p38 MAPK
    inhibitor in phase 3 (REALM-DCM) leaves the causal weight of the signalling
    arm in human disease unresolved.
pathophysiology:
- name: LMNA Variant and Nuclear Lamina Assembly Defect
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  biological_scale: MOLECULAR
  role: trigger
  genetic_context:
    gene:
      preferred_term: LMNA
      term:
        id: hgnc:6636
        label: LMNA
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
    description: >-
      Applies to the missense alleles, which are modelled as co-assembling into
      and destabilising the lamina. Non-missense alleles are equally represented
      in CMD1A and behave differently in the clinic, with earlier conduction
      disease and higher arrhythmic risk; for those, haploinsufficiency through
      nonsense-mediated decay is the competing mechanism, and this entry does not
      claim a single functional mechanism across the whole allelic spectrum.
  description: >-
    A heterozygous pathogenic LMNA variant is the initiating lesion. LMNA encodes
    lamin A and lamin C by alternative splicing; both assemble into the nuclear
    lamina, a filamentous meshwork on the nucleoplasmic face of the inner nuclear
    membrane. Disease-associated variants are distributed across the gene with no
    single hotspot and include missense changes concentrated in the central
    alpha-helical rod domain as well as nonsense, frameshift and splice-affecting
    alleles. Missense alleles are thought to act largely by incorporating into
    and destabilising the meshwork (a dominant-negative effect), consistent with
    the reduced or absent nuclear lamin A/C immunostaining and the aberrant
    degradation product seen in patient myocardium; non-missense alleles behave
    differently in the clinic, conferring earlier conduction disease and higher
    arrhythmic risk.
  genes:
  - preferred_term: LMNA
    term:
      id: hgnc:6636
      label: LMNA
  cellular_components:
  - preferred_term: Nuclear lamina
    term:
      id: GO:0005652
      label: nuclear lamina
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  biological_processes:
  - preferred_term: Nuclear envelope organization
    term:
      id: GO:0006998
      label: nuclear envelope organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:10580070
    reference_title: Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five novel missense mutations were identified: four in the
      alpha-helical-rod domain of the lamin A/C gene, and one in the lamin C tail
      domain.
    explanation: >-
      The founding CMD1A observation, establishing LMNA rod-domain missense
      variants as the causal lesion in autosomal dominant DCM with
      conduction-system disease.
  - reference: PMID:11897440
    reference_title: "Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Western blot protein analyses of three hearts with different mutations
      showed an additional 30-kDa band, suggesting a degrading effect of mutated
      on wild-type protein.
    explanation: >-
      Direct human myocardial evidence that mutant lamin A/C acts on the
      wild-type protein rather than simply being absent, which is the biochemical
      basis for modelling the trigger as a dominant-negative lamina assembly
      defect.
  - reference: CGGV:assertion_132ea1ec-caa9-409a-8670-3edb2ec9c889-2025-05-30T160000.000Z
    reference_title: LMNA / dilated cardiomyopathy (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LMNA | HGNC:6636 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: >-
      ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies the
      LMNA-DCM gene-disease relationship as Definitive with autosomal dominant
      inheritance.
  - reference: PMID:11897440
    reference_title: "Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The LMNA expression of the myocyte nuclei was reduced or absent.
    explanation: >-
      Direct immunochemical evidence from patient myocardium that the lamina is
      depleted of lamin A/C, which is the tissue-level correlate of the assembly
      defect this node asserts.
  - reference: PMID:33947203
    reference_title: Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Twelve genes (23%) from 8 gene ontologies were classified as having
      definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2,
      TTN) or strong (DSP) evidence.
    explanation: >-
      Places LMNA among the twelve definitive-evidence dilated cardiomyopathy
      genes in the ClinGen curation of 51 candidate genes.
  downstream:
  - target: Cardiomyocyte Nuclear Envelope Fragility and Rupture
    causal_link_type: DIRECT
    hypothesis_groups:
    - mechanical_nuclear_fragility_model
  - target: Chromatin and Lamina-Associated Domain Disorganization
    causal_link_type: DIRECT
    hypothesis_groups:
    - signalling_and_gene_expression_model
  - target: MAPK Cascade Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - signalling_and_gene_expression_model
  - target: PDGF Receptor Signalling Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - signalling_and_gene_expression_model
- name: Cardiomyocyte Nuclear Envelope Fragility and Rupture
  biological_scale: CELLULAR
  role: effector
  description: >-
    A lamina built from mutant subunits cannot bear the mechanical load imposed
    on a cardiomyocyte nucleus by repetitive contraction. Patient myocardium
    shows focal disruptions of the nuclear membrane, bleb formation and clustered
    nuclear pores; lamin A/C-null mouse cardiomyocytes show grossly abnormal
    nuclear shape and size with displaced and fragmented heterochromatin, and the
    desmin intermediate filament network detaches from the nuclear surface, so
    force is no longer transmitted between nucleoskeleton and cytoskeleton.
    Deleting Lmna in adult cardiomyocytes reproduces the nuclear abnormalities
    and adds perinuclear Golgi dilation and fragmentation with CREB3-mediated
    stress signalling before any fall in cardiac function.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cellular_components:
  - preferred_term: Nuclear envelope
    term:
      id: GO:0005635
      label: nuclear envelope
    modifier: ABNORMAL
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  biological_processes:
  - preferred_term: Nuclear envelope organization
    term:
      id: GO:0006998
      label: nuclear envelope organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:11897440
    reference_title: "Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Focal disruptions, bleb formation and nuclear pore clustering were
      documented by electron microscopy of the myocyte nuclear membranes.
    explanation: >-
      Ultrastructural evidence of nuclear envelope failure in the myocardium of
      LMNA-mutation carriers, in human tissue rather than a model system.
  - reference: PMID:14755333
    reference_title: Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Electron microscopy of Lmna(-/-) cardiomyocytes shows disorganization and
      detachment of desmin filaments from the nuclear surface with progressive
      disruption of the cytoskeletal desmin network.
    explanation: >-
      Establishes loss of nucleoskeleton-cytoskeleton coupling as the structural
      correlate of the mechanical model.
  - reference: PMID:14755333
    reference_title: Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These findings suggest a model in which the primary pathophysiological
      mechanism in Lmna(-/-) mice is defective force transmission resulting from
      disruption of lamin interactions with the muscle-specific desmin network
      and loss of cytoskeletal tension.
    explanation: >-
      States the mechanical force-transmission model this node represents.
  - reference: PMID:38718107
    reference_title: Perinuclear damage from nuclear envelope deterioration elicits stress responses that contribute to LMNA cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Before cardiac dysfunction, Lmna-deleted cardiomyocytes displayed nuclear
      abnormalities, Golgi dilation/fragmentation, and CREB3-mediated stress
      activation.
    explanation: >-
      Places the nuclear and perinuclear lesion upstream of measurable cardiac
      dysfunction in a cardiomyocyte-specific adult deletion model.
  - reference: PMID:37585285
    reference_title: Nuclear damage in LMNA mutant iPSC-derived cardiomyocytes is associated with impaired lamin localization to the nuclear envelope.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The LMNA mutation exhibiting the most severe nuclear deformities, R249Q,
      additionally caused reduced nuclear stiffness and increased nuclear
      fragility.
    explanation: >-
      The direct mechanical measurement behind the word "fragility" in this
      node's name, made in human patient-derived cardiomyocytes rather than
      inferred from mouse morphology.
  - reference: PMID:37585285
    reference_title: Nuclear damage in LMNA mutant iPSC-derived cardiomyocytes is associated with impaired lamin localization to the nuclear envelope.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Importantly, for all cell lines, the degree of nuclear abnormalities
      corresponded to the degree of Lamin A/C and Lamin B1 mislocalization from
      the nuclear envelope.
    explanation: >-
      Ties the severity of the nuclear phenotype quantitatively to the upstream
      lamina assembly defect across multiple patient lines.
  - reference: PMID:41073815
    reference_title: Microtubule forces drive nuclear damage in LMNA cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Microtubule disruption prevented nuclear damage and preserved cardiac
      function in lamin A/C deficiency.
    explanation: >-
      Identifies the specific force-generating structure responsible for the
      nuclear damage, and shows removing that force is cardioprotective - the
      intervention that makes mechanical loading causal rather than incidental.
  - reference: PMID:41073815
    reference_title: Microtubule forces drive nuclear damage in LMNA cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The LINC complex was mostly dispensable for transferring contractile strain
      to the nucleus, and its disruption did not rescue elevated nuclear strain
      in lamin A/C-deficient cardiomyocytes.
    explanation: >-
      Refines the mechanical model by excluding the obvious candidate: LINC
      disruption is cardioprotective because it removes the perinuclear
      microtubule cage, not because it uncouples the cytoskeleton from the
      nucleus. PARTIAL because it constrains rather than supports the node.
  downstream:
  - target: Cardiomyocyte Loss and Myocardial Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - mechanical_nuclear_fragility_model
  - target: DNA Damage Response and TP53 Pathway Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - signalling_and_gene_expression_model
  - target: Mitochondrial Dysfunction and Oxidative Stress
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cardiac Conduction System Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The primary route to conduction disease. Conduction tissue fails first,
      before ventricular remodeling exists to explain it: the H222P knock-in
      develops conduction defects as part of its cardiac phenotype, and in
      patients the electrical abnormality precedes structural disease by years.
- name: Chromatin and Lamina-Associated Domain Disorganization
  biological_scale: MOLECULAR
  role: effector
  description: >-
    The lamina tethers peripheral heterochromatin, so a defective meshwork
    releases and redistributes it. Lamin A/C-null cardiomyocyte nuclei show
    central displacement and fragmentation of heterochromatin, and heterochromatin
    is dislocated in the hearts of H222P knock-in mice alongside activated Smad
    signalling. Loss of the correct chromatin-lamina arrangement is the presumed
    route by which a structural protein defect becomes a transcriptional one,
    including a failure to mount the compensatory hypertrophic gene programme that
    normally accompanies ventricular stress.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:14755333
    reference_title: Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Lmna(-/-) LV myocyte nuclei have marked alterations of shape and size with
      central displacement and fragmentation of heterochromatin; these changes
      are present but less severe in left atrial nuclei.
    explanation: >-
      Directly documents loss of peripheral heterochromatin organisation in
      lamin-deficient cardiomyocytes, and its chamber-dependent gradient.
  - reference: PMID:14755333
    reference_title: Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Alterations in nuclear architecture are associated with defective nuclear
      function evidenced by decreased SREBP1 import, reduced PPARgamma
      expression, and a lack of hypertrophic gene activation.
    explanation: >-
      Links the architectural defect to a measurable transcriptional consequence,
      including failure of the compensatory hypertrophic programme.
  - reference: PMID:15548545
    reference_title: Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Histopathological analysis of the mice revealed muscle degeneration with
      fibrosis associated with dislocation of heterochromatin and activation of
      Smad signalling in heart and skeletal muscles.
    explanation: >-
      Reproduces heterochromatin dislocation in a knock-in missense model rather
      than a null, showing it is not merely an artefact of complete lamin loss.
  downstream:
  - target: Cardiomyocyte Loss and Myocardial Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - signalling_and_gene_expression_model
- name: MAPK Cascade Activation
  biological_scale: CELLULAR
  role: effector
  description: >-
    Mutant A-type lamins activate the ERK1/2, JNK and p38 MAPK branches in the
    heart. The timing is what makes this node upstream rather than reactive:
    activation is detectable in H222P knock-in mouse hearts before any clinical
    sign or molecular marker of cardiomyopathy, and expressing mutant lamin A in
    cultured cells is sufficient to reproduce it. The p38 branch was the explicit
    rationale for the ARRY-371797 clinical programme, which failed at phase 3 -
    so this node records a well-evidenced cascade whose causal weight in human
    disease is unsettled.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: MAPK cascade
    term:
      id: GO:0000165
      label: MAPK cascade
    modifier: INCREASED
  - preferred_term: ERK1 and ERK2 cascade
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
    modifier: INCREASED
  evidence:
  - reference: PMID:17446932
    reference_title: Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using real-time PCR, we showed that activation of MAPK pathways preceded
      clinical signs or detectable molecular markers of cardiomyopathy.
    explanation: >-
      The temporal argument for this node: MAPK activation is upstream of, not a
      reaction to, established cardiomyopathy.
  - reference: PMID:17446932
    reference_title: Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Expression of H222P Lamin A in cultured cells activated MAPKs and
      downstream target genes.
    explanation: >-
      Shows the mutant lamin is sufficient to drive the cascade in a cellular
      system, independent of the whole-organ context.
  downstream:
  - target: DUSP4-Mediated AKT-mTOR Activation with Impaired Autophagy
    causal_link_type: DIRECT
    hypothesis_groups:
    - signalling_and_gene_expression_model
    description: >-
      DUSP4 is transcriptionally induced by ERK1/2, which is the reported link
      between the MAPK and AKT-mTOR arms.
  - target: Cardiomyocyte Loss and Myocardial Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - signalling_and_gene_expression_model
- name: DUSP4-Mediated AKT-mTOR Activation with Impaired Autophagy
  biological_scale: CELLULAR
  role: effector
  description: >-
    Downstream of the MAPK cascade, the AKT-mTOR axis is hyperactivated and
    macroautophagy is defective. DUSP4, induced by ERK1/2, is raised in LMNA
    cardiomyopathy hearts and its overexpression alone causes cardiac dysfunction
    through AKT-mTOR activation and impaired autophagy. Both halves of this node
    are pharmacologically reversible in mouse models: the rapalog temsirolimus
    restores autophagic flux and prevents functional deterioration, and modulating
    autophagy or ER stress in a separate cardiomyocyte-specific deletion model
    delays dysfunction and prolongs survival.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: TORC1 signaling
    term:
      id: GO:0038202
      label: TORC1 signaling
    modifier: INCREASED
  - preferred_term: Macroautophagy
    term:
      id: GO:0016236
      label: macroautophagy
    modifier: DECREASED
  evidence:
  - reference: PMID:23048029
    reference_title: Dual specificity phosphatase 4 mediates cardiomyopathy caused by lamin A/C (LMNA) gene mutation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Dusp4 expression is enhanced in hearts with LMNA cardiomyopathy, and its
      overexpression in mice causes it by activating AKT-mTOR signaling that
      impairs autophagy.
    explanation: >-
      Supplies the molecular link from the MAPK cascade into this node. The
      paper's own conclusion is that DUSP4 "may contribute" to the disease, so
      this is a contributing arm rather than a sufficient cause.
  - reference: PMID:22837537
    reference_title: Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We show that the AKT-mammalian target of rapamycin pathway is hyperactivated
      in hearts of mice with cardiomyopathy caused by Lmna mutation and that in
      vivo administration of the rapamycin analog temsirolimus prevents
      deterioration of cardiac function.
    explanation: >-
      Establishes the AKT-mTOR arm and provides the rescue experiment that makes
      it causal rather than correlative in the model.
  - reference: PMID:22837537
    reference_title: Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We also show defective autophagy in hearts of these mice and demonstrate
      that improvement in heart function induced by pharmacological interventions
      is correlated with enhanced autophagy.
    explanation: >-
      Supports the impaired-autophagy component of this node and ties functional
      rescue to restored autophagic flux.
  - reference: PMID:38718107
    reference_title: Perinuclear damage from nuclear envelope deterioration elicits stress responses that contribute to LMNA cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Systemic administration of modulators of autophagy or ER stress
      significantly delayed cardiac dysfunction and prolonged survival.
    explanation: >-
      Independent replication that correcting the autophagy/stress arm modifies
      the cardiac course in a distinct Lmna model.
  downstream:
  - target: Cardiomyocyte Loss and Myocardial Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - signalling_and_gene_expression_model
- name: DNA Damage Response and TP53 Pathway Activation
  biological_scale: CELLULAR
  role: effector
  description: >-
    Mutant lamin A/C expression in cardiomyocytes activates an E2F-DNA damage
    response-TP53 axis. In a mouse model expressing a DCM-associated LMNA
    D300N protein in cardiac myocytes this axis is engaged alongside NF-kB and
    TGF-beta signalling, and the same DNA damage response/TP53 signature is
    present in RNA sequencing of human hearts with LMNA-associated DCM - a rare
    instance where a model-derived mechanism was confirmed in the target human
    tissue. Conditional deletion of Tp53 in cardiac myocytes partially rescues
    fibrosis, apoptosis and ventricular dysfunction, establishing the pathway as
    pathogenic rather than a bystander.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: DNA damage response
    term:
      id: GO:0006974
      label: DNA damage response
    modifier: INCREASED
  - preferred_term: Signal transduction by p53 class mediator
    term:
      id: GO:0072331
      label: signal transduction by p53 class mediator
    modifier: INCREASED
  evidence:
  - reference: PMID:30696354
    reference_title: DNA Damage Response/TP53 Pathway Is Activated and Contributes to the Pathogenesis of Dilated Cardiomyopathy Associated With LMNA (Lamin A/C) Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RNA sequencing of human hearts with DCM associated with defined LMNA
      pathogenic variants corroborated activation of the DNA damage
      response/TP53 pathway in the heart.
    explanation: >-
      Confirms the pathway is activated in human LMNA-DCM myocardium, not only in
      the mouse model that suggested it.
  - reference: PMID:30696354
    reference_title: DNA Damage Response/TP53 Pathway Is Activated and Contributes to the Pathogenesis of Dilated Cardiomyopathy Associated With LMNA (Lamin A/C) Mutations.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Deletion of Tp53 partially rescued myocardial fibrosis, apoptosis,
      proliferation of nonmyocyte cells, left ventricular dilatation and
      dysfunction, and slightly improved survival.
    explanation: >-
      The genetic rescue that makes TP53 activation causal for the downstream
      fibrosis and dysfunction nodes. Partial rescue is why the causal link is
      curated as contributory rather than sole.
  downstream:
  - target: Cardiomyocyte Loss and Myocardial Fibrosis
    causal_link_type: DIRECT
    hypothesis_groups:
    - signalling_and_gene_expression_model
- name: PDGF Receptor Signalling Activation
  biological_scale: MOLECULAR
  role: effector
  description: >-
    Platelet-derived growth factor signalling is activated in patient-derived
    iPSC cardiomyocytes carrying an LMNA frameshift variant, relative to isogenic
    corrected controls. Inhibiting the pathway pharmacologically or molecularly
    abolishes the downstream arrhythmic phenotype, which is what makes the
    activation causal rather than incidental and nominates PDGFRB as a candidate
    target.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Platelet-derived growth factor receptor signaling pathway
    term:
      id: GO:0048008
      label: platelet-derived growth factor receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:31316208
    reference_title: Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mechanistically, we show that the platelet-derived growth factor (PDGF)
      signalling pathway is activated in mutant iPSC-CMs compared to isogenic
      control iPSC-CMs.
    explanation: >-
      The isogenic comparison establishing PDGF pathway activation as a
      consequence of the LMNA variant rather than of line-to-line variation.
  - reference: PMID:31316208
    reference_title: Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Conversely, pharmacological and molecular inhibition of the PDGF signalling
      pathway ameliorated the arrhythmic phenotypes of mutant iPSC-CMs in vitro.
    explanation: >-
      The rescue arm that makes PDGF activation causal for the downstream
      arrhythmic phenotype in this system.
  downstream:
  - target: Aberrant Cardiomyocyte Calcium Handling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - signalling_and_gene_expression_model
- name: Mitochondrial Dysfunction and Oxidative Stress
  biological_scale: CELLULAR
  role: effector
  description: >-
    A second, mechanistically distinct route from the lamina defect to
    arrhythmia, established in patient-derived iPSC cardiomyocytes. Mutant lamin
    A/C accelerates degradation of its interaction partner SIRT1, producing
    mitochondrial dysfunction and oxidative stress; the resulting reactive oxygen
    species activate the CaMKII-RYR2 axis and aggravate SUN1 accumulation,
    feeding both the calcium-handling and the nuclear-deformation phenotypes.
    Independent work on the H222P allele finds a converging mitochondrial lesion
    - reduced mitochondrial calcium uniporter expression with impaired
    mitochondrial calcium uptake - in a human cardiac organoid model.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cellular_components:
  - preferred_term: Mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: Response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  evidence:
  - reference: PMID:39143095
    reference_title: Lamin A/C deficiency-mediated ROS elevation contributes to pathogenic phenotypes of dilated cardiomyopathy in iPSC model.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mechanistically, lamin A interacts with sirtuin 1 (SIRT1) where mutant
      lamin A/C accelerates degradation of SIRT1, leading to mitochondrial
      dysfunction and oxidative stress.
    explanation: >-
      Gives the molecular route from the mutant lamin to the mitochondrial and
      oxidative lesion this node represents.
  - reference: PMID:42478871
    reference_title: LMNA p.H222P mutation causes contractile dysfunction via impaired mitochondrial calcium uptake in human cardiac laminopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Transcriptomic analyses suggested a global mitochondrial dysfunction and in
      particular an impaired mitochondrial calcium uptake with a significantly
      decreased expression of the mitochondrial calcium uniporter (MCU).
    explanation: >-
      Independent convergence on a mitochondrial lesion, in a different LMNA
      allele and against a CRISPR-corrected isogenic control.
  downstream:
  - target: Aberrant Cardiomyocyte Calcium Handling
    causal_link_type: DIRECT
    hypothesis_groups:
    - signalling_and_gene_expression_model
  - target: Cardiomyocyte Nuclear Envelope Fragility and Rupture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A feed-back arm rather than a forward step: ROS aggravates SUN1
      accumulation and so worsens the nuclear deformation that lies upstream of
      it.
- name: Aberrant Cardiomyocyte Calcium Handling
  biological_scale: CELLULAR
  role: effector
  description: >-
    Two upstream arms converge here. PDGF pathway activation and ROS-driven
    CaMKII-RYR2 activation both disturb calcium homeostasis in LMNA-mutant human
    cardiomyocytes, producing arrhythmia at the single-cell level. This is a
    cell-autonomous route to arrhythmogenesis that does not require prior
    structural remodeling, which matters because sudden death in this disease can
    precede any fall in ejection fraction.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31316208
    reference_title: Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Electrophysiological studies showed that the mutant iPSC-CMs displayed
      aberrant calcium homeostasis that led to arrhythmias at the single-cell
      level.
    explanation: >-
      Establishes the cell-autonomous arrhythmic phenotype in human LMNA-mutant
      cardiomyocytes, independent of chamber remodeling.
  - reference: PMID:39143095
    reference_title: Lamin A/C deficiency-mediated ROS elevation contributes to pathogenic phenotypes of dilated cardiomyopathy in iPSC model.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Elevated reactive oxygen species (ROS) then activates the
      Ca2+/calmodulin-dependent protein kinase II (CaMKII)-ryanodine receptor 2
      (RYR2) pathway and aggravates the accumulation of SUN1 in mutant iPSC-CMs,
      contributing to arrhythmias and NE deformation, respectively.
    explanation: >-
      Names the second, oxidative route into this node and the CaMKII-RYR2
      effector through which it becomes arrhythmogenic.
  downstream:
  - target: Arrhythmogenic Substrate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - signalling_and_gene_expression_model
- name: Cardiomyocyte Loss and Myocardial Fibrosis
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  biological_scale: TISSUE
  role: central_effector
  description: >-
    The convergence point of every upstream arm. Cardiomyocytes are lost by
    apoptosis and replaced by fibrotic extracellular matrix, and the surviving
    myocardium cannot mount the compensatory hypertrophic response that normally
    offsets myocyte loss. Mutant-lamin mouse hearts show severe myocardial
    fibrosis and apoptosis, and muscle degeneration with fibrosis is a
    histological hallmark of the H222P knock-in. In patients the correlate is
    late gadolinium enhancement on cardiac magnetic resonance, typically in a
    non-ischaemic midmyocardial or subepicardial distribution, present in over
    half of imaged variant carriers.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: Cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  biological_processes:
  - preferred_term: Cardiac muscle cell apoptotic process
    term:
      id: GO:0010659
      label: cardiac muscle cell apoptotic process
    modifier: INCREASED
  - preferred_term: Extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  evidence:
  - reference: PMID:30696354
    reference_title: DNA Damage Response/TP53 Pathway Is Activated and Contributes to the Pathogenesis of Dilated Cardiomyopathy Associated With LMNA (Lamin A/C) Mutations.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Expression of LMNAD300N led to severe myocardial fibrosis, apoptosis,
      cardiac dysfunction, and premature death.
    explanation: >-
      Cardiomyocyte-restricted expression of a mutant lamin is sufficient to
      produce the fibrosis-and-apoptosis phenotype this node represents.
  - reference: PMID:15548545
    reference_title: Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Histopathological analysis of the mice revealed muscle degeneration with
      fibrosis associated with dislocation of heterochromatin and activation of
      Smad signalling in heart and skeletal muscles.
    explanation: >-
      Independent knock-in model showing degeneration with fibrosis in cardiac
      and skeletal muscle.
  - reference: PMID:40689545
    reference_title: Variant-Specific Late Gadolinium Enhancement Patterns Influence Clinical Outcomes in LMNA-Related Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the 72/116 (62%) LMNA variant-positive patients with cardiac magnetic
      resonance imaging data, LGE was observed in 40/72 (56%) cases.
    explanation: >-
      Human in-vivo evidence that myocardial fibrosis is present in the majority
      of imaged LMNA variant carriers.
  - reference: PMID:14755333
    reference_title: Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Despite severe DCM, defects in nuclear function prevent Lmna(-/-)
      cardiomyocytes from developing compensatory hypertrophy and accelerate
      disease progression.
    explanation: >-
      Explains why the remodeling in this disease is dilated rather than
      hypertrophic: the compensatory arm of the generic remodeling module is
      itself disabled by the lamina defect.
  - reference: PMID:41841259
    reference_title: Simtuzumab Attenuates Loxl2-Mediated Extracellular Matrix Remodeling and Preserves Cardiac Function in LMNA Mutation-Induced Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We demonstrated that LMNA patient-derived cardiomyocytes and engineered
      heart tissues exhibited elevated diastolic calcium levels and reduced
      sensitivity to external calcium, respectively, as well as hypocontractility.
    explanation: >-
      The human-cell arm: patient-derived cardiomyocytes and engineered heart
      tissue show the contractile and calcium phenotype that accompanies the
      matrix-remodeling programme in this node.
  - reference: PMID:41841259
    reference_title: Simtuzumab Attenuates Loxl2-Mediated Extracellular Matrix Remodeling and Preserves Cardiac Function in LMNA Mutation-Induced Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Treatment with Simtuzumab, a Loxl2 inhibitor, effectively prevented cardiac
      dysfunction and fibrosis in vivo.
    explanation: >-
      The in-vivo arm: blocking LOXL2 prevents the fibrosis and dysfunction this
      node represents, which is what makes the matrix-remodeling programme causal
      rather than a bystander signature.
  downstream:
  - target: Cardiac Conduction System Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A late, additional contributor only - not the origin of the conduction
      phenotype, which precedes structural disease. Once replacement fibrosis is
      established it further disrupts impulse propagation; myocardial enhancement
      on cardiac magnetic resonance is associated with conduction abnormality.
  - target: Arrhythmogenic Substrate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Left Ventricular Dilation and Systolic Dysfunction
    causal_link_type: DIRECT
- name: Cardiac Conduction System Degeneration
  biological_scale: TISSUE
  role: effector
  description: >-
    The specialised conduction tissue - sinoatrial node, atrioventricular node
    and His-Purkinje system - fails earlier and more consistently than the
    working myocardium, which is the defining feature of this cardiomyopathy.
    Clinically this appears as sinus bradycardia, progressive first- to
    third-degree atrioventricular block, and atrial fibrillation or flutter,
    typically years before ventricular dilation. Conduction defects are
    reproduced in the H222P knock-in mouse, confirming that they follow from the
    lamin defect rather than from advanced heart failure.
  cell_types:
  - preferred_term: Sinoatrial node pacemaker cell
    term:
      id: CL:1000477
      label: cardiac pacemaker cell of sinoatrial node
  - preferred_term: Atrioventricular node myocyte
    term:
      id: CL:1000410
      label: myocyte of atrioventricular node
  locations:
  - preferred_term: Cardiac conduction system
    term:
      id: UBERON:0002350
      label: conducting system of heart
  biological_processes:
  - preferred_term: Cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:10580070
    reference_title: Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each mutation caused heritable, progressive conduction-system disease
      (sinus bradycardia, atrioventricular conduction block, or atrial
      arrhythmias) and dilated cardiomyopathy.
    explanation: >-
      Establishes progressive conduction-system disease as an obligate,
      heritable component of the CMD1A phenotype across five independent
      mutations.
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LMNA-related dilated cardiomyopathy (DCM) is characterized by left
      ventricular enlargement and/or reduced systolic function preceded
      (sometimes by many years) by or accompanied by conduction system disease
      and/or arrhythmias.
    explanation: >-
      The GeneReviews definition of the disease, which is exactly the temporal
      ordering this node encodes.
  - reference: PMID:15548545
    reference_title: Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      As for cardiac phenotype, they develop chamber dilation and hypokinesia
      with conduction defects.
    explanation: >-
      Recapitulation of the combined conduction-plus-dilation phenotype in a
      knock-in mouse.
  downstream:
  - target: Arrhythmogenic Substrate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Progressive Heart Failure and End-Stage Disease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intracardiac Thrombus Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Via atrial fibrillation: loss of organised atrial contraction produces the
      flow stasis on which an atrial thrombus forms.
- name: Arrhythmogenic Substrate
  biological_scale: TISSUE
  role: effector
  description: >-
    Replacement fibrosis, conduction-tissue disease and cell-autonomous calcium
    mishandling combine to create a myocardial substrate that supports reentrant
    and triggered activity. The substrate matures out of step with pump failure,
    which is the feature that separates this disease from other dilated
    cardiomyopathies. In imaged carriers, myocardial enhancement is associated
    with conduction abnormality, tying the fibrotic and electrical components of
    the substrate together in the same tissue.
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  biological_processes:
  - preferred_term: Cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:21689390
    reference_title: Late gadolinium enhanced cardiovascular magnetic resonance of lamin A/C gene mutation related dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients had LV myocardial fibrosis in 88% of cases. Segmental wall motion
      abnormalities correlated strongly with the degree of enhancement.
      Myocardial enhancement was associated with conduction abnormalities.
    explanation: >-
      Links the fibrotic and electrical components of the substrate in the same
      imaged myocardium.
  - reference: PMID:40689545
    reference_title: Variant-Specific Late Gadolinium Enhancement Patterns Influence Clinical Outcomes in LMNA-Related Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During a median follow-up of 37 months, IgD variant presence independently
      predicted sudden cardiac death/major ventricular arrhythmia (hazard ratio,
      2.391 [95% CI, 1.046-5.464]; P=0.039).
    explanation: >-
      Shows the substrate's arrhythmic consequence is variant-position dependent,
      i.e. that the substrate differs by genotype rather than being uniform.
  downstream:
  - target: Malignant Ventricular Arrhythmia
    causal_link_type: DIRECT
- name: Malignant Ventricular Arrhythmia
  biological_scale: ORGANISM
  role: effector
  description: >-
    Sustained ventricular tachycardia and ventricular fibrillation arising on
    that substrate. The clinically decisive feature is that these events are
    decoupled from systolic function: sudden cardiac death can occur with
    minimal or no systolic dysfunction. Risk is therefore stratified by genotype
    and rhythm data rather than by ejection fraction alone - non-sustained
    ventricular tachycardia, LVEF below 45% at first contact, male sex and a
    non-missense variant are independent predictors, and the same variables plus
    atrioventricular block underpin the validated LMNA-risk VTA calculator.
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  biological_processes:
  - preferred_term: Cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sudden cardiac death can occur, and in some instances is the presenting
      manifestation; sudden cardiac death may occur with minimal or no systolic
      dysfunction.
    explanation: >-
      The decoupling of arrhythmic risk from systolic function, which is what
      makes this a distinct node rather than a consequence of pump failure.
  - reference: PMID:22281253
    reference_title: Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Independent risk factors for MVA were nonsustained ventricular tachycardia,
      left ventricular ejection fraction <45% at the first clinical contact, male
      sex, and non-missense mutations (ins-del/truncating or mutations affecting
      splicing).
    explanation: >-
      The four independent predictors of malignant ventricular arrhythmia in
      LMNA carriers, from a 269-carrier multicentre cohort.
  - reference: PMID:31155932
    reference_title: Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Predictors of LTVTA in the derivation sample were: male sex, nonmissense
      LMNA mutation, first degree and higher atrioventricular block, nonsustained
      ventricular tachycardia, and left ventricular ejection fraction
    explanation: >-
      The externally validated risk model, which adds atrioventricular block to
      the predictor set and is the basis of current ICD timing in this disease.
  downstream:
  - target: Sudden Cardiac Death
    causal_link_type: DIRECT
- name: Left Ventricular Dilation and Systolic Dysfunction
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
  biological_scale: ORGANISM
  role: effector
  description: >-
    Progressive myocyte loss and fibrosis degrade pump function, producing left
    ventricular enlargement with reduced ejection fraction. In CMD1A this step
    usually arrives after conduction disease is already established, and it is
    not universal at first presentation: roughly 45% of carriers have an LVEF
    below 50% at genetic diagnosis, rising with follow-up, and about a quarter of
    those with preserved function at index evaluation develop new dysfunction
    over the following years.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: Left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  biological_processes:
  - preferred_term: Cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: DECREASED
  evidence:
  - reference: PMID:29237675
    reference_title: Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 77 carriers, 71 (92%) were phenotypically affected and showed
      cardiac conduction disturbance (81%), low left ventricular ejection
      fraction (<50%; 45%), atrial arrhythmias (58%), and malignant ventricular
      arrhythmias (26%).
    explanation: >-
      Quantifies systolic dysfunction alongside the other cardiac manifestations
      in a genotyped multicentre cohort, and shows conduction disturbance is the
      more prevalent finding.
  - reference: PMID:27884249
    reference_title: Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients without LVD at presentation, 24% developed new LVD, and 7%
      developed end-stage HF.
    explanation: >-
      Documents incident systolic dysfunction in carriers who were structurally
      normal at first contact, supporting this as a progressive step rather than
      a fixed state.
  downstream:
  - target: Progressive Heart Failure and End-Stage Disease
    causal_link_type: DIRECT
  - target: Intracardiac Thrombus Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Via ventricular stasis: a dilated, hypokinetic left ventricle is the
      substrate for a mural thrombus.
- name: Intracardiac Thrombus Formation
  conforms_to: "thrombogenesis#Pathological Fibrin-Platelet Thrombus Formation"
  biological_scale: TISSUE
  role: effector
  description: >-
    Two features of this disease converge on intracardiac stasis: atrial
    fibrillation arising from the diseased conduction system, and a dilated,
    hypokinetic left ventricle. Both supply the flow-stagnation limb of the
    Virchow triad, and a conventional fibrin-platelet thrombus forms on that
    substrate - as a left ventricular mural thrombus or in the fibrillating
    atrium. Embolus from a mural thrombus is recognised as one of the ways CMD1A
    first presents, and thromboembolic events are common enough in genotyped
    cohorts to differ measurably by variant position. Conformance is deliberately
    limited to the thrombus-formation node of the module: the downstream systemic
    embolization here is arterial and cardiac in origin, so it does not map to
    the module's venous-to-pulmonary embolic branch, and no local occlusion or
    ischemia is claimed.
  locations:
  - preferred_term: Heart
    term:
      id: UBERON:0000948
      label: heart
  biological_processes:
  - preferred_term: Blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LMNA-related DCM usually presents in early to mid-adulthood with
      symptomatic conduction system disease or arrhythmias, or with symptomatic
      DCM including heart failure or embolus from a left ventricular mural
      thrombus.
    explanation: >-
      Establishes left ventricular mural thrombus, and embolism from it, as a
      recognised presenting manifestation rather than a late complication.
  - reference: PMID:40689545
    reference_title: Variant-Specific Late Gadolinium Enhancement Patterns Influence Clinical Outcomes in LMNA-Related Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with clinically manifest disease (76/116), those with
      IgD-localizing variants had a lower prevalence of atrioventricular block
      (25% versus 72%, P=0.002) and atrial fibrillation (50% versus 81%, P=0.019)
      but higher rates of thromboembolic events (42% versus 16%, P=0.038).
    explanation: >-
      Quantifies thromboembolic events in a genotyped cohort. Note the
      dissociation it reports: the higher-risk group had *less* atrial
      fibrillation, so atrial stasis cannot be the whole explanation and the
      ventricular contribution is doing real work.
- name: Progressive Heart Failure and End-Stage Disease
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  biological_scale: ORGANISM
  role: consequence
  description: >-
    One of the disease's two exits. Pump failure progresses to end-stage disease
    requiring mechanical support or transplantation in around a fifth of carriers
    followed long term, and survival is materially worse than in non-LMNA dilated
    cardiomyopathy: event-free survival at age 45 was 31% in carriers versus 75%
    in non-carrier DCM patients.
  locations:
  - preferred_term: Heart
    term:
      id: UBERON:0000948
      label: heart
  biological_processes:
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:12628721
    reference_title: Natural history of dilated cardiomyopathy due to lamin A/C gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The LMNA mutation carriers had a significantly poorer cumulative survival
      compared with non-carrier DCM patients: event-free survival at the age of
      45 years was 31% versus 75% in non-carriers.
    explanation: >-
      Direct comparison establishing the worse natural history of LMNA-related
      DCM against other dilated cardiomyopathy.
  - reference: PMID:29095976
    reference_title: "Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heart transplantation was performed in 15 of 79 (19%) LMNA patients during
      7.8 ± 6.3 years of follow-up.
    explanation: >-
      Quantifies the transplantation burden that defines this end state.
  - reference: PMID:27884249
    reference_title: Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      End-stage HF developed in 19% of patients, and 13% died.
    explanation: >-
      Independent cohort giving concordant end-stage heart failure and mortality
      figures.
- name: Sudden Cardiac Death
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The disease's other exit, and the one that can come first. Arrhythmic death
    may be the presenting event, before heart failure and sometimes before any
    detectable systolic impairment. Keeping it as a node distinct from the heart
    failure end state is what the pathograph needs in order to represent a
    disease in which the two exits are not sequential.
  locations:
  - preferred_term: Heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sudden cardiac death can occur, and in some instances is the presenting
      manifestation; sudden cardiac death may occur with minimal or no systolic
      dysfunction.
    explanation: >-
      Establishes that this exit is reachable without passing through the heart
      failure end state.
  - reference: PMID:22281253
    reference_title: Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a median follow-up period of 43 months (interquartile range: 17 to 101
      months), 48 (18%) persons experienced a first episode of MVA: 11 persons
      received successful cardiopulmonary resuscitation, 25 received appropriate
      ICD treatment, and 12 persons died suddenly.
    explanation: >-
      Quantifies malignant arrhythmic events, including 12 sudden deaths, in a
      269-carrier cohort over a median 43 months.

phenotypes:
- category: Cardiac
  name: Cardiac Conduction Abnormality
  frequency: VERY_FREQUENT
  description: >-
    Disease of the specialised conduction tissue is the earliest and most
    consistent manifestation, and in most carriers it precedes structural
    disease. It spans sinus node dysfunction and sinus bradycardia through
    first-, second- and third-degree atrioventricular block. Because the same
    lesion carries a high sudden-death risk, symptomatic block in a carrier is an
    indication for a defibrillator rather than a pacemaker alone.
  phenotype_term:
    preferred_term: Cardiac conduction abnormality
    term:
      id: HP:0031546
      label: Cardiac conduction abnormality
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:29237675
    reference_title: Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 77 carriers, 71 (92%) were phenotypically affected and showed
      cardiac conduction disturbance (81%), low left ventricular ejection
      fraction (<50%; 45%), atrial arrhythmias (58%), and malignant ventricular
      arrhythmias (26%).
    explanation: >-
      Reports conduction disturbance in 81% of genotyped carriers, supporting the
      VERY_FREQUENT band (80-99%). The figure sits just inside the band boundary
      and comes from a single 77-carrier cohort; the other cohort in this entry
      reports atrioventricular block alone at 46-57%, which is a narrower finding
      than "conduction abnormality" and is curated separately below.
  - reference: PMID:10580070
    reference_title: Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each mutation caused heritable, progressive conduction-system disease
      (sinus bradycardia, atrioventricular conduction block, or atrial
      arrhythmias) and dilated cardiomyopathy.
    explanation: >-
      Supports the progressive clinical course qualifier and the range of
      conduction abnormalities seen.
- category: Cardiac
  name: Atrioventricular Block
  description: >-
    Progressive atrioventricular block, from PR prolongation through complete
    heart block, is the single most characteristic electrical finding. Its
    presence in a dilated cardiomyopathy proband substantially raises the
    pre-test probability of an LMNA variant, and it is one of the predictors in
    the validated arrhythmic risk model.
  phenotype_term:
    preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
    clinical_course: PROGRESSIVE
  diagnostic: true
  evidence:
  - reference: PMID:11897440
    reference_title: "Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The LMNA gene mutations account for 33% of the DCMs with AVB, all familial
      autosomal dominant.
    explanation: >-
      Supports the diagnostic value of atrioventricular block in selecting DCM
      patients for LMNA testing.
  - reference: PMID:27884249
    reference_title: Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of clinical manifestations increased broadly from index
      evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to
      34%; and LVD, 44% to 57%.
    explanation: >-
      Documents both the prevalence of atrioventricular block and its progression
      over long-term follow-up.
- category: Cardiac
  name: Sinus Bradycardia and Sinus Node Dysfunction
  description: >-
    Sinus node disease with bradycardia is part of the early electrical
    phenotype and may be the first abnormality on a screening ECG in an otherwise
    asymptomatic carrier.
  phenotype_term:
    preferred_term: Sinus bradycardia
    term:
      id: HP:0001688
      label: Sinus bradycardia
  evidence:
  - reference: PMID:10580070
    reference_title: Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each mutation caused heritable, progressive conduction-system disease
      (sinus bradycardia, atrioventricular conduction block, or atrial
      arrhythmias) and dilated cardiomyopathy.
    explanation: >-
      Names sinus bradycardia explicitly among the conduction-system
      manifestations segregating with LMNA mutations.
- category: Cardiac
  name: Atrial Fibrillation
  frequency: FREQUENT
  description: >-
    Atrial arrhythmia - most often atrial fibrillation, also flutter and other
    supraventricular tachycardias - is common and often early, carrying both a
    thromboembolic risk requiring anticoagulation and, in some carriers,
    progression to atrial standstill.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:27884249
    reference_title: Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of clinical manifestations increased broadly from index
      evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to
      34%; and LVD, 44% to 57%.
    explanation: >-
      Atrial arrhythmia prevalence of 39-63% supports the FREQUENT band (30-79%).
  - reference: PMID:39145700
    reference_title: Characterization and natural history of patients with LMNA-related dilated cardiomyopathy in the phase 3 REALM-DCM trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atrial fibrillation was present in 60% of patients; 79% of all patients had
      NYHA Class II and 21% had NYHA Class III HF symptoms at baseline.
    explanation: >-
      Independent contemporary trial cohort giving an atrial fibrillation
      prevalence of 60%, concordant with the FREQUENT band.
- category: Cardiac
  name: Ventricular Tachyarrhythmia
  frequency: FREQUENT
  description: >-
    Non-sustained and sustained ventricular tachycardia and ventricular
    fibrillation are the proximate cause of sudden death in this disease.
    Non-sustained VT is itself one of the independent predictors of subsequent
    malignant arrhythmia and is therefore actively sought on ambulatory
    monitoring in carriers.
  phenotype_term:
    preferred_term: Ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  evidence:
  - reference: PMID:27884249
    reference_title: Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of clinical manifestations increased broadly from index
      evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to
      34%; and LVD, 44% to 57%.
    explanation: >-
      Ventricular arrhythmia rises from 16% to 34% over follow-up; the
      follow-up figure supports the FREQUENT band (30-79%).
  - reference: PMID:29095976
    reference_title: "Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We clinically followed up 79 LMNA genotype-positive [age 42 ± 16 years,
      ejection fraction (EF) 45 ± 13%], including 44 (56%) with VT.
    explanation: >-
      Ventricular tachycardia in 56% of a followed genotype-positive cohort,
      concordant with the FREQUENT band.
- category: Cardiac
  name: Ventricular Fibrillation
  description: >-
    Ventricular fibrillation is the terminal rhythm in arrhythmic death in this
    disease and, with sustained ventricular tachycardia, is what a defibrillator
    is implanted to treat. It is curated separately from ventricular tachycardia
    because the risk models count resuscitated arrest and appropriate ICD therapy
    as events in their own right.
  phenotype_term:
    preferred_term: Ventricular fibrillation
    term:
      id: HP:0001663
      label: Ventricular fibrillation
  evidence:
  - reference: PMID:22281253
    reference_title: Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this multicenter cohort of 269 LMNA mutation carriers, we evaluated risk
      factors for MVA, defined as sudden cardiac death, resuscitation, and
      appropriate implantable cardioverter-defibrillator (ICD) treatment.
    explanation: >-
      Defines the malignant ventricular arrhythmia endpoint - resuscitated arrest
      and appropriate ICD therapy - which is the clinical footprint of
      ventricular fibrillation in these cohorts.
- category: Cardiac
  name: Sudden Cardiac Death
  description: >-
    Sudden arrhythmic death may be the presenting manifestation of CMD1A and can
    occur when systolic function is minimally impaired or normal. This decoupling
    from ejection fraction is the reason ICD implantation in LMNA carriers is
    considered at thresholds that would not trigger a device in non-genetic
    dilated cardiomyopathy.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sudden cardiac death can occur, and in some instances is the presenting
      manifestation; sudden cardiac death may occur with minimal or no systolic
      dysfunction.
    explanation: >-
      GeneReviews statement of both the occurrence of sudden death and its
      independence from systolic dysfunction.
  - reference: PMID:22281253
    reference_title: Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a median follow-up period of 43 months (interquartile range: 17 to 101
      months), 48 (18%) persons experienced a first episode of MVA: 11 persons
      received successful cardiopulmonary resuscitation, 25 received appropriate
      ICD treatment, and 12 persons died suddenly.
    explanation: >-
      Quantifies malignant arrhythmic events, including 12 sudden deaths, in a
      269-carrier cohort over a median 43 months.
- category: Cardiac
  name: Dilated Cardiomyopathy
  frequency: FREQUENT
  description: >-
    Left ventricular enlargement with reduced systolic function is the defining
    structural phenotype, but unlike most genetic dilated cardiomyopathies it
    typically arrives after the electrical phenotype is established. Ventricular
    dilation is often described as mild relative to the degree of functional
    impairment.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LMNA-related dilated cardiomyopathy (DCM) is characterized by left
      ventricular enlargement and/or reduced systolic function preceded
      (sometimes by many years) by or accompanied by conduction system disease
      and/or arrhythmias.
    explanation: >-
      The defining clinical description, including the characteristic ordering
      relative to conduction disease.
  - reference: PMID:27884249
    reference_title: Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of clinical manifestations increased broadly from index
      evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to
      34%; and LVD, 44% to 57%.
    explanation: >-
      Left ventricular dysfunction in 44-57% of carriers supports the FREQUENT
      band (30-79%).
- category: Cardiac
  name: Reduced Left Ventricular Ejection Fraction
  frequency: FREQUENT
  description: >-
    Systolic impairment, conventionally an LVEF below 50%, is present in
    approximately 45% of carriers at genetic diagnosis and accumulates with age.
    An LVEF below 45% at first clinical contact is one of the independent
    predictors of malignant ventricular arrhythmia.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:29237675
    reference_title: Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 77 carriers, 71 (92%) were phenotypically affected and showed
      cardiac conduction disturbance (81%), low left ventricular ejection
      fraction (<50%; 45%), atrial arrhythmias (58%), and malignant ventricular
      arrhythmias (26%).
    explanation: >-
      Reports low ejection fraction in 45% of carriers, supporting the FREQUENT
      band (30-79%).
- category: Cardiac
  name: Myocardial Fibrosis
  frequency: FREQUENT
  description: >-
    Late gadolinium enhancement on cardiac magnetic resonance reveals replacement
    fibrosis in the majority of imaged variant carriers, usually in a
    non-ischaemic midmyocardial or subepicardial distribution. A minority show an
    apical transmural pseudo-infarct pattern, which in one series segregated with
    C-terminal immunoglobulin-like domain variants and higher arrhythmic and
    thromboembolic risk.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:40689545
    reference_title: Variant-Specific Late Gadolinium Enhancement Patterns Influence Clinical Outcomes in LMNA-Related Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the 72/116 (62%) LMNA variant-positive patients with cardiac magnetic
      resonance imaging data, LGE was observed in 40/72 (56%) cases. Most
      exhibited a nonischemic, midmyocardial or subepicardial pattern (73%), and
      6/40 (15%) showed a unique "pseudo-infarct" transmural pattern,
      predominantly affecting the apical segments.
    explanation: >-
      Gives both the 56% prevalence supporting the FREQUENT band and the
      distribution patterns described.
  - reference: PMID:21689390
    reference_title: Late gadolinium enhanced cardiovascular magnetic resonance of lamin A/C gene mutation related dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients had LV myocardial fibrosis in 88% of cases. Segmental wall motion
      abnormalities correlated strongly with the degree of enhancement.
      Myocardial enhancement was associated with conduction abnormalities.
    explanation: >-
      An independent, higher fibrosis prevalence in a small carrier series, and
      the observation that enhancement tracks with conduction abnormality - the
      tissue link between the fibrotic and electrical phenotypes.
- category: Cardiac
  name: Congestive Heart Failure
  description: >-
    Symptomatic heart failure with dyspnoea, fatigue and fluid overload develops
    as systolic function declines, and progresses to end-stage disease requiring
    transplantation or mechanical support in roughly a fifth of carriers followed
    long term.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:27884249
    reference_title: Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      End-stage HF developed in 19% of patients, and 13% died.
    explanation: >-
      Quantifies progression to end-stage heart failure in a long-term
      multicentre cohort.
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LMNA-related DCM usually presents in early to mid-adulthood with
      symptomatic conduction system disease or arrhythmias, or with symptomatic
      DCM including heart failure or embolus from a left ventricular mural
      thrombus.
    explanation: >-
      Names symptomatic heart failure as one of the typical presenting syndromes.
- category: Cardiac
  name: Left Ventricular Mural Thrombus with Systemic Embolism
  description: >-
    Thrombus formation in the dilated, hypokinetic left ventricle - compounded by
    coexisting atrial fibrillation - can cause systemic embolism, and embolic
    presentation is recognised as one of the ways CMD1A first comes to attention.
  phenotype_term:
    preferred_term: Left ventricular thrombus
    term:
      id: HP:0040412
      label: Left ventricular thrombus
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LMNA-related DCM usually presents in early to mid-adulthood with
      symptomatic conduction system disease or arrhythmias, or with symptomatic
      DCM including heart failure or embolus from a left ventricular mural
      thrombus.
    explanation: >-
      Identifies left ventricular mural thrombus with embolism as a recognised
      presenting manifestation.
- category: Cardiac
  name: Thromboembolic Events
  description: >-
    Thromboembolism arises from atrial fibrillation and from left ventricular
    mural thrombus. In one cardiac magnetic resonance series, carriers of
    C-terminal immunoglobulin-like domain variants had a markedly higher rate of
    thromboembolic events despite less atrioventricular block and atrial
    fibrillation than other carriers.
  phenotype_term:
    preferred_term: Thromboembolism
    term:
      id: HP:0001907
      label: Thromboembolism
  evidence:
  - reference: PMID:40689545
    reference_title: Variant-Specific Late Gadolinium Enhancement Patterns Influence Clinical Outcomes in LMNA-Related Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with clinically manifest disease (76/116), those with
      IgD-localizing variants had a lower prevalence of atrioventricular block
      (25% versus 72%, P=0.002) and atrial fibrillation (50% versus 81%, P=0.019)
      but higher rates of thromboembolic events (42% versus 16%, P=0.038).
    explanation: >-
      Documents thromboembolic events in LMNA carriers and their variant-position
      dependence.
- category: Musculoskeletal
  name: Skeletal Muscle Involvement
  description: >-
    A subset of carriers has skeletal muscle disease, reflecting the allelic
    relationship of CMD1A with Emery-Dreifuss muscular dystrophy and limb-girdle
    muscular dystrophy 1B. Where present it typically takes a humeroperoneal or
    limb-girdle distribution with proximal weakness. Notably it is not obligate -
    in the founding CMD1A families no mutation carrier had joint contractures or
    skeletal myopathy - and its presence in a DCM proband is a strong clinical
    predictor of an LMNA variant.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: PMID:12628721
    reference_title: Natural history of dilated cardiomyopathy due to lamin A/C gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was significant phenotypic variability, but the presence of skeletal
      muscle involvement (p < 0.001), supraventricular arrhythmia (p = 0.003),
      conduction defects (p = 0.01), and "mildly" DCM (p = 0.006) were predictors
      of LMNA mutations.
    explanation: >-
      Establishes skeletal muscle involvement as part of the spectrum and as a
      statistically significant clinical predictor of LMNA mutation status.
  - reference: PMID:10580070
    reference_title: Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No family members with mutations had either joint contractures or skeletal
      myopathy.
    explanation: >-
      Shows skeletal involvement is not obligate: in the founding CMD1A families
      it was entirely absent. PARTIAL because it bounds rather than supports the
      phenotype.
- category: Musculoskeletal
  name: Joint Contractures
  description: >-
    Curated as a boundary marker rather than an established CMD1A phenotype.
    Early joint contractures in a humeroperoneal distribution are the hallmark of
    the allelic Emery-Dreifuss phenotype, and carriers whose presentation
    overlaps it may have them; but they were explicitly absent in the founding
    CMD1A families, and that absence is what separated the
    cardiomyopathy-predominant presentation from autosomal dominant EDMD. No
    source in this entry documents contractures occurring in a
    cardiomyopathy-predominant LMNA carrier, so no frequency is assigned and both
    evidence items below bound the claim rather than support it.
  phenotype_term:
    preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: PMID:10580070
    reference_title: Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in the head or tail domain of this gene cause Emery-Dreifuss
      muscular dystrophy, a childhood-onset disease characterized by joint
      contractures and in some cases by abnormalities of cardiac conduction
      during adulthood.
    explanation: >-
      Establishes contractures as the hallmark of the allelic Emery-Dreifuss
      phenotype. PARTIAL because the quote describes the allelic disorder, not
      CMD1A.
  - reference: PMID:10580070
    reference_title: Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No family members with mutations had either joint contractures or skeletal
      myopathy.
    explanation: >-
      A negative finding in the founding CMD1A families, recorded as REFUTE
      because it argues against contractures being a feature of the
      cardiomyopathy-predominant presentation.

biochemical:
- name: Serum Creatine Kinase
  notes: >-
    Creatine kinase is normal in most carriers with pure cardiac disease but is
    mildly raised in some, particularly with lamin C tail-domain defects and in
    those with skeletal muscle involvement. It is a poor screening test in
    isolation: in a systematic series, raised creatine kinase in DCM without
    atrioventricular block did not identify any LMNA mutation carrier.
  biomarker_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  evidence:
  - reference: PMID:10580070
    reference_title: Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serum creatine kinase levels were normal in family members with mutations
      of the lamin rod but mildly elevated in some family members with a defect
      in the tail domain of lamin C.
    explanation: >-
      Documents the domain-dependent pattern of creatine kinase elevation across
      CMD1A families.
  - reference: PMID:11897440
    reference_title: "Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increased sCPK in patients with DCM without AVB is not a useful predictor
      of LMNA mutation.
    explanation: >-
      Bounds the diagnostic usefulness of creatine kinase as a stand-alone
      selector for LMNA testing.
genetic:
- name: LMNA
  notes: >-
    LMNA at 1q22 encodes lamin A and lamin C by alternative splicing of a single
    transcript. Pathogenic variants causing CMD1A are heterozygous and spread
    across the gene without a dominant hotspot: missense changes cluster in the
    central alpha-helical rod domain, and nonsense, frameshift, small indel and
    splice-affecting alleles are also common. Variant class carries clinical
    weight rather than just mechanistic interest - non-missense alleles are an
    independent predictor of malignant ventricular arrhythmia and are associated
    with earlier conduction disease and earlier systolic impairment than missense
    alleles. ClinGen classifies the LMNA-DCM relationship as Definitive.
  gene_term:
    preferred_term: LMNA
    term:
      id: hgnc:6636
      label: LMNA
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:10580070
    reference_title: Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic defects in distinct domains of the nuclear-envelope proteins lamin
      A and lamin C selectively cause dilated cardiomyopathy with
      conduction-system disease or autosomal dominant Emery-Dreifuss muscular
      dystrophy.
    explanation: >-
      Establishes LMNA as the causal gene and the domain-dependent split between
      the cardiomyopathy-predominant and muscular-dystrophy phenotypes.
  - reference: PMID:29237675
    reference_title: Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The onset of cardiac disorders indicated that subjects with truncation
      mutations had an earlier occurrence of cardiac conduction disturbance and
      low left ventricular ejection fraction, than those with missense mutations.
    explanation: >-
      Supports the genotype-phenotype gradient by variant class that drives
      risk stratification in this disease.
  - reference: PMID:11897440
    reference_title: "Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Western blot protein analyses of three hearts with different mutations
      showed an additional 30-kDa band, suggesting a degrading effect of mutated
      on wild-type protein.
    explanation: >-
      Biochemical support for modelling the missense lesion as dominant-negative:
      mutant protein acting on wild-type rather than simple loss of one allele.
      The inference is hedged in the source and rests on three hearts, and the
      mutation set analysed included nonsense and frameshift alleles, so it does
      not establish the mechanism for the whole allelic spectrum.
  - reference: CGGV:assertion_132ea1ec-caa9-409a-8670-3edb2ec9c889-2025-05-30T160000.000Z
    reference_title: LMNA / dilated cardiomyopathy (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LMNA | HGNC:6636 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: >-
      ClinGen Dilated Cardiomyopathy Gene Curation Expert Panel assertion of
      Definitive gene-disease validity with autosomal dominant inheritance.
- name: TTN
  notes: >-
    A co-occurring titin variant acts as a modifier rather than an independent
    cause. In an extended family segregating LMNA p.K219T, the four members who
    also carried TTN p.L4855F required heart transplantation substantially
    younger than single heterozygotes, and their myocardium showed increased
    nuclear length, sarcomeric disorganisation and myonuclear clustering. This is
    one documented source of the intrafamilial variability that is otherwise
    unexplained in this disease.
  gene_term:
    preferred_term: TTN
    term:
      id: hgnc:12403
      label: TTN
  relationship_type: MODIFIER
  evidence:
  - reference: PMID:23463027
    reference_title: Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The age for heart transplantation was substantially less for
      LMNA:p.K219T/TTN:p.L4855F double heterozygotes than that for
      LMNA:p.K219T single heterozygotes.
    explanation: >-
      Establishes TTN as a severity modifier in an LMNA family, with an outcome
      measure (age at transplantation) rather than a surrogate.
  - reference: PMID:23463027
    reference_title: Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myocardial specimens of doubly heterozygote individuals showed increased
      nuclear length, sarcomeric disorganization, and myonuclear clustering
      compared with samples from single heterozygotes.
    explanation: >-
      Provides the tissue-level correlate of the modifier effect, linking it back
      to the nuclear phenotype of the primary lesion.
diagnosis:
- name: Twelve-Lead Electrocardiography
  diagnosis_term:
    preferred_term: Electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  description: >-
    The first-line and often the earliest abnormal test. PR prolongation, higher
    degrees of atrioventricular block, sinus bradycardia and atrial fibrillation
    may be present years before any echocardiographic abnormality, which is why
    ECG anchors surveillance of asymptomatic carriers.
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with an LMNA pathogenic variant who are found to have any EKG
      abnormality should undergo a cardiovascular evaluation for disease
      progression (EKG, 24-48 hour rhythm monitoring, LV function measurement) at
      least annually.
    explanation: >-
      Establishes the ECG as the trigger for intensified surveillance in
      GeneReviews management guidance.
- name: Echocardiography
  diagnosis_term:
    preferred_term: Echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  description: >-
    Echocardiography measures chamber size and systolic function and is part of
    both the diagnostic workup and the one-to-two-yearly surveillance of
    asymptomatic carriers. It is less sensitive early in this disease than the
    ECG, because the electrical phenotype precedes structural change and the
    dilatation, when it appears, is often mild relative to the functional
    impairment.
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Asymptomatic individuals with a pathogenic LMNA variant should undergo
      cardiovascular evaluation (medical history, physical examination,
      echocardiogram, and EKG) every one to two years and/or whenever new
      symptoms arise.
    explanation: >-
      Places echocardiography in the GeneReviews surveillance protocol for
      asymptomatic carriers.
  - reference: PMID:21689390
    reference_title: Late gadolinium enhanced cardiovascular magnetic resonance of lamin A/C gene mutation related dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sixty-nine percent of our asymptomatic or mildly symptomatic patients
      showed mild ventricular dilatation, systolic failure or both in global
      ventricular analysis.
    explanation: >-
      Supports the sensitivity caveat: abnormalities in asymptomatic or mildly
      symptomatic carriers are mild and global, which is what limits
      echocardiography as an early detection tool. PARTIAL because the
      measurement was made by cardiac magnetic resonance, not echocardiography.
- name: Ambulatory Rhythm Monitoring
  diagnosis_term:
    preferred_term: Electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  description: >-
    Twenty-four to forty-eight hour monitoring detects non-sustained ventricular
    tachycardia, which is one of the independent predictors of malignant
    ventricular arrhythmia and therefore directly informs the ICD decision.
  evidence:
  - reference: PMID:22281253
    reference_title: Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Independent risk factors for MVA were nonsustained ventricular tachycardia,
      left ventricular ejection fraction <45% at the first clinical contact, male
      sex, and non-missense mutations (ins-del/truncating or mutations affecting
      splicing).
    explanation: >-
      Non-sustained ventricular tachycardia is detectable only by rhythm
      monitoring and is one of the four predictors, making the test decision-relevant.
- name: Molecular Genetic Testing of LMNA
  diagnosis_term:
    preferred_term: Genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Diagnosis is established by identifying a heterozygous pathogenic LMNA
    variant in a proband with a compatible phenotype. In practice a
    cardiomyopathy multigene panel or exome sequencing is used rather than
    single-gene testing, given the genetic and phenotypic overlap with other
    conduction-disease cardiomyopathy genes. Once a familial variant is known,
    targeted testing of relatives becomes the screening tool.
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of LMNA-related DCM is established in a proband with
      suggestive findings and a heterozygous pathogenic variant in LMNA
      identified by molecular genetic testing.
    explanation: >-
      GeneReviews statement of the diagnostic criterion.
- name: Cardiac Magnetic Resonance with Late Gadolinium Enhancement
  diagnosis_term:
    preferred_term: Magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: >-
    Cardiac MRI detects replacement fibrosis in the majority of imaged carriers,
    typically midmyocardial or subepicardial, and the enhancement pattern carries
    prognostic and variant-specific information beyond simple fibrosis detection.
  evidence:
  - reference: PMID:40689545
    reference_title: Variant-Specific Late Gadolinium Enhancement Patterns Influence Clinical Outcomes in LMNA-Related Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LMNA missense variants localizing to IgD present a distinct apical
      pseudo-infarct LGE pattern associated with increased risk of ventricular
      arrhythmias and thromboembolic events
    explanation: >-
      Supports the prognostic and genotype-linked value of the late gadolinium
      enhancement pattern, not merely its presence.
  - reference: PMID:21689390
    reference_title: Late gadolinium enhanced cardiovascular magnetic resonance of lamin A/C gene mutation related dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac conduction abnormalities, mildly dilated LV and depressed systolic
      dysfunction are common in DCM caused by a lamin A/C gene mutation.
    explanation: >-
      Characterises the CMR phenotype, including the mild degree of dilatation
      relative to functional impairment that makes echocardiography alone
      insensitive early in this disease.
- name: LMNA-Risk VTA Score
  description: >-
    A validated multivariable model estimating five-year risk of life-threatening
    ventricular tachyarrhythmia from male sex, non-missense variant,
    first-degree or higher atrioventricular block, non-sustained ventricular
    tachycardia and left ventricular ejection fraction. It reclassifies a
    substantial fraction of patients relative to guideline-based ICD selection.
  evidence:
  - reference: PMID:31155932
    reference_title: Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net
      reclassified 28.8% of patients with LTVTA in comparison with the
      guidelines-based approach.
    explanation: >-
      Reports the operating threshold and the net reclassification gain over
      guideline-based ICD selection.
imaging_findings:
- name: Midmyocardial and Subepicardial Late Gadolinium Enhancement
  modality: MRI
  imaging_finding_term:
    preferred_term: Myocardial late gadolinium enhancement
    term:
      id: HP:4000004
      label: Myocardial late gadolinium enhancement
  description: >-
    The characteristic imaging signature. Replacement fibrosis appears as late
    gadolinium enhancement in a non-ischaemic distribution - midmyocardial or
    subepicardial rather than subendocardial - and is present in most imaged
    carriers, including asymptomatic ones. Its extent correlates with segmental
    wall-motion abnormality and its presence is associated with conduction
    abnormality.
  located_in:
    preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  frequency: FREQUENT
  evidence:
  - reference: PMID:40689545
    reference_title: Variant-Specific Late Gadolinium Enhancement Patterns Influence Clinical Outcomes in LMNA-Related Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the 72/116 (62%) LMNA variant-positive patients with cardiac magnetic
      resonance imaging data, LGE was observed in 40/72 (56%) cases. Most
      exhibited a nonischemic, midmyocardial or subepicardial pattern (73%), and
      6/40 (15%) showed a unique "pseudo-infarct" transmural pattern,
      predominantly affecting the apical segments.
    explanation: >-
      Gives the 56% prevalence supporting the FREQUENT band and the dominant
      non-ischaemic midmyocardial/subepicardial distribution.
  - reference: PMID:21689390
    reference_title: Late gadolinium enhanced cardiovascular magnetic resonance of lamin A/C gene mutation related dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients had LV myocardial fibrosis in 88% of cases. Segmental wall motion
      abnormalities correlated strongly with the degree of enhancement.
      Myocardial enhancement was associated with conduction abnormalities.
    explanation: >-
      An independent series with a higher prevalence, and the correlations with
      wall motion and with conduction abnormality.
- name: Apical Transmural Pseudo-Infarct Enhancement Pattern
  modality: MRI
  imaging_finding_term:
    preferred_term: Myocardial late gadolinium enhancement
    term:
      id: HP:4000004
      label: Myocardial late gadolinium enhancement
  description: >-
    A minority pattern that matters because it is genotype-linked and
    prognostically adverse. Transmural enhancement predominantly in the apical
    segments, mimicking prior infarction, was seen only in carriers of
    C-terminal immunoglobulin-like domain missense variants, who had less
    atrioventricular block and atrial fibrillation than other carriers but more
    thromboembolic events and independently higher risk of sudden death or major
    ventricular arrhythmia.
  located_in:
    preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40689545
    reference_title: Variant-Specific Late Gadolinium Enhancement Patterns Influence Clinical Outcomes in LMNA-Related Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 6 patients with this distinct LGE pattern harbored C-terminal IgD
      (immunoglobulin-like domain) variants (p.Arg471His or p.Arg541His).
    explanation: >-
      Establishes the genotype restriction of this pattern. The 6/40 (15%) share
      of imaged enhancement supports the OCCASIONAL band.
  - reference: PMID:40689545
    reference_title: Variant-Specific Late Gadolinium Enhancement Patterns Influence Clinical Outcomes in LMNA-Related Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During a median follow-up of 37 months, IgD variant presence independently
      predicted sudden cardiac death/major ventricular arrhythmia (hazard ratio,
      2.391 [95% CI, 1.046-5.464]; P=0.039).
    explanation: >-
      The prognostic association that makes this pattern actionable rather than
      descriptive.

histopathology:
- name: Reduced or Absent Nuclear Lamin A/C Immunostaining
  description: >-
    Endomyocardial biopsy is not routine in this disease, but where myocardium
    has been examined the lamina is depleted: immunochemistry shows reduced or
    absent lamin A/C in myocyte nuclei, and electron microscopy shows focal
    membrane disruptions, blebs and clustered nuclear pores. These findings are
    the tissue-level correlate of the assembly defect and were absent in the
    disease and normal controls of the same series.
  evidence:
  - reference: PMID:11897440
    reference_title: "Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The LMNA expression of the myocyte nuclei was reduced or absent.
    explanation: >-
      The immunochemical finding in myocardium from LMNA-mutation carriers.
  - reference: PMID:11897440
    reference_title: "Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of these changes and no mutations were found in the nine patients with
      DCM and increased sCPK or in the disease and normal controls.
    explanation: >-
      Establishes the specificity of the finding against both disease and normal
      controls in the same study.
- name: Myonuclear Elongation and Clustering with Sarcomeric Disorganisation
  description: >-
    Reported in myocardium from carriers of both an LMNA and a TTN variant,
    compared with LMNA single heterozygotes from the same family - so the finding
    tracks the modifier genotype rather than the disease as such.
  evidence:
  - reference: PMID:23463027
    reference_title: Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myocardial specimens of doubly heterozygote individuals showed increased
      nuclear length, sarcomeric disorganization, and myonuclear clustering
      compared with samples from single heterozygotes.
    explanation: >-
      The within-family histological comparison that ties these findings to the
      TTN modifier rather than to LMNA alone.

differential_diagnoses:
- name: Idiopathic Dilated Cardiomyopathy
  description: >-
    Non-genetic or unexplained dilated cardiomyopathy shares the structural
    phenotype but lacks the early, disproportionate conduction-system disease.
    The distinction matters because arrhythmic risk relative to ejection fraction
    is much higher in the LMNA form, so device decisions diverge.
  distinguishing_features:
  - >-
    Early and progressive atrioventricular block preceding ventricular dilation,
    family history of sudden death or pacemaker at a young age, and a pathogenic
    LMNA variant.
- name: Emery-Dreifuss Muscular Dystrophy
  description: >-
    The allelic LMNA disorder in which childhood-onset joint contractures and
    humeroperoneal weakness dominate and cardiac conduction disease appears in
    adulthood. CMD1A families may have no skeletal involvement at all.
  distinguishing_features:
  - >-
    Childhood-onset contractures and skeletal myopathy as the presenting problem,
    versus adult-onset conduction disease with normal muscles in CMD1A. X-linked
    EMD/emerin-related disease must also be excluded.
- name: Arrhythmogenic Right Ventricular Cardiomyopathy
  description: >-
    Also presents with ventricular arrhythmia out of proportion to systolic
    dysfunction, but the substrate is desmosomal and predominantly right
    ventricular. ClinGen classifies the LMNA-ARVC relationship as Limited, so an
    ARVC label should not be applied to an LMNA carrier on genetic grounds alone.
  distinguishing_features:
  - >-
    Right ventricular predominance, desmosomal gene variants (PKP2, DSP, DSG2),
    and characteristic depolarisation/repolarisation ECG criteria, versus the
    atrioventricular-block-first pattern of CMD1A.
- name: Cardiac Sarcoidosis
  description: >-
    The highest-stakes mimic, and the only acquired one on this list. Cardiac
    sarcoidosis presents with the same triad of atrioventricular block,
    ventricular arrhythmia and heart failure, with patchy non-ischaemic late
    gadolinium enhancement on cardiac magnetic resonance. Distinguishing them
    changes management in opposite directions - immunosuppression versus early
    defibrillator - and endomyocardial biopsy can be equivocal, so genetic
    testing belongs in the initial workup rather than after imaging has been
    relied on alone.
  distinguishing_features:
  - >-
    A pathogenic LMNA variant, and a family history of conduction disease,
    pacemaker or sudden death at a young age.
  - >-
    Extracardiac sarcoid involvement, non-caseating granulomas on biopsy, and
    FDG-PET uptake favour sarcoidosis; but isolated cardiac sarcoidosis occurs
    and imaging criteria alone do not separate the two.
  evidence:
  - reference: PMID:40225500
    reference_title: "Lamin AC Cardiomyopathy, the Next Masquerader: Laminopathy Mimicking Cardiac Sarcoidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phenotypic expression of lamin AC-dilated cardiomyopathy (LMNA-DCM) and
      cardiac sarcoidosis (CS) at times presents with similar clinical findings,
      including arrhythmia, conduction abnormalities, and heart failure.
    explanation: >-
      Establishes the clinical overlap that makes this a genuine differential
      rather than a theoretical one.
  - reference: PMID:40225500
    reference_title: "Lamin AC Cardiomyopathy, the Next Masquerader: Laminopathy Mimicking Cardiac Sarcoidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Also highlighted is the need for extreme caution when endomyocardial
      biopsies are equivocal and there is sole reliance on cardiac imaging to
      establish diagnostic criteria.
    explanation: >-
      Supports the recommendation to resolve the differential genetically rather
      than by imaging, which is the practical consequence of the overlap.
- name: Other Conduction-Disease Cardiomyopathy Genes
  description: >-
    SCN5A, FLNC, DES, RBM20 and PLN variants can each produce dilated
    cardiomyopathy with arrhythmia or conduction disease, which is why panel
    rather than single-gene testing is standard.
  distinguishing_features:
  - >-
    Resolved by multigene panel or exome sequencing rather than by phenotype.
progression:
- phase: Asymptomatic Genotype-Positive Stage
  notes: >-
    Carriers identified by cascade testing may be entirely normal. Penetrance is
    age-dependent, but conversion is brisk once surveillance begins - roughly a
    9% annual incidence of a newly documented cardiac phenotype in asymptomatic
    family members with a mean age of 31.
  evidence:
  - reference: PMID:29095976
    reference_title: "Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Asymptomatic LMNA genotype-positive family members (age 31 ± 15 years) had
      a 9% annual incidence of a newly documented cardiac phenotype and 61%
      (19/31) of cardiac penetrance during 4.4 ± 2.9 years of follow-up.
    explanation: >-
      Quantifies conversion from genotype-positive/phenotype-negative to
      clinically affected.
- phase: Electrical Stage
  notes: >-
    Conduction-system disease and atrial arrhythmia appear first and may be the
    only manifestation for years, with structural disease still absent or mild.
    This is the window in which arrhythmic risk stratification and pre-emptive
    device decisions are made.
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LMNA-related dilated cardiomyopathy (DCM) is characterized by left
      ventricular enlargement and/or reduced systolic function preceded
      (sometimes by many years) by or accompanied by conduction system disease
      and/or arrhythmias.
    explanation: >-
      States the temporal precedence of the electrical over the structural
      phenotype.
- phase: Structural and Arrhythmic Progression
  notes: >-
    Every category of manifestation accumulates with follow-up rather than
    remaining static, and carriers who are structurally normal at first contact
    are not thereby safe: about a quarter develop new left ventricular
    dysfunction.
  evidence:
  - reference: PMID:27884249
    reference_title: Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of clinical manifestations increased broadly from index
      evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to
      34%; and LVD, 44% to 57%.
    explanation: >-
      Documents progression across all four manifestation categories over a
      median seven years.
  - reference: PMID:27884249
    reference_title: Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LMNA-related heart disease was associated with a high incidence of
      phenotypic progression and adverse arrhythmic and nonarrhythmic events over
      long-term follow-up. The index cardiac phenotype did not predict adverse
      events.
    explanation: >-
      Important negative finding: the presenting phenotype does not stratify
      outcome, so surveillance cannot be relaxed on the basis of a mild
      presentation.
- phase: End-Stage Disease
  notes: >-
    The disease ends in transplantation, mechanical support, or arrhythmic death.
    Roughly one in five carriers followed long term is transplanted or reaches
    end-stage heart failure, and survival is substantially worse than in
    non-LMNA dilated cardiomyopathy.
  evidence:
  - reference: PMID:12628721
    reference_title: Natural history of dilated cardiomyopathy due to lamin A/C gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The LMNA mutation carriers had a significantly poorer cumulative survival
      compared with non-carrier DCM patients: event-free survival at the age of
      45 years was 31% versus 75% in non-carriers.
    explanation: >-
      Quantifies the survival penalty relative to other dilated cardiomyopathy.
environmental:
- name: Intense or competitive exercise
  description: >-
    Mechanical loading is the one modifiable input that the pathophysiology of
    this disease predicts should matter: nuclear damage in lamin A/C-deficient
    cardiomyocytes is generated by contraction-transmitted microtubule forces,
    so sustained high-intensity exertion is expected to accelerate it. Sports
    guidance treats lamin A/C as one of the specific genes for which permissive,
    surveillance-contingent recommendations do not apply, extending restriction
    even to genotype-positive, phenotype-negative carriers. The recommendation is
    precautionary and mechanism-derived; it has not been tested prospectively.
  exposure_term:
    preferred_term: exposure to strenuous exercise
    term:
      id: ECTO:6000031
      label: exposure to strenuous exercise
  influences_mechanisms:
  - target: Cardiomyocyte Nuclear Envelope Fragility and Rupture
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Higher contractile workload increases the microtubule-transmitted force
      concentrated on a mechanically vulnerable nucleus. The link is inferred
      from the force-dependence of nuclear damage, not measured against an
      exercise exposure in patients.
    evidence:
    - reference: PMID:41073815
      reference_title: Microtubule forces drive nuclear damage in LMNA cardiomyopathy.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Computational modeling revealed that microtubule forces create local
        stress concentrations that damage lamin A/C-deficient nuclei.
      explanation: >-
        Establishes that nuclear damage is force-dependent, which is the
        mechanistic basis for expecting exertion to matter. PARTIAL because the
        study manipulates microtubules, not exercise, so the exposure itself is
        untested.
  evidence:
  - reference: PMID:36929832
    reference_title: "Sport and exercise in genotype positive (+) phenotype negative (-) individuals: current dilemmas and future perspectives."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The recommendations to engage in intensive exercise and competitive sports
      are usually contingent on annual clinical surveillance, except for
      pathogenic variants in specific genes, such as lamin A/C or plakophilin-2.
    explanation: >-
      Documents that lamin A/C is singled out as a gene for which the permissive,
      surveillance-contingent sports recommendation does not apply. PARTIAL and
      OTHER because this is expert review of guideline positions, not a study of
      exercise exposure in LMNA carriers.
  notes: >-
    No prospective trial has tested whether activity restriction alters
    progression in LMNA carriers; the openscientist deep-research run flagged
    this as an explicit evidence gap.

treatments:
- name: Implantable Cardioverter-Defibrillator
  description: >-
    The signature intervention in this disease. Because sudden death risk tracks
    the conduction and arrhythmic phenotype rather than ejection fraction, a
    defibrillator is preferred over a pacemaker for every pacing indication in an
    LMNA carrier, and implantation is considered at ejection fractions that would
    not warrant a device in non-genetic dilated cardiomyopathy. Candidate
    selection is guided by the gene-specific risk factors and the LMNA-risk VTA
    model rather than by an EF threshold alone.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_mechanisms:
  - target: Malignant Ventricular Arrhythmia
    treatment_effect: INHIBITS
    description: >-
      The device does not modify the arrhythmogenic substrate; it terminates the
      ventricular tachyarrhythmia arising on it, interrupting the path from
      substrate to sudden death.
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Because risk for sudden cardiac death in LMNA-related DCM accompanies heart
      block and bradyarrhythmias, ICD use (rather than just pacemaker use) has
      been recommended for all indications.
    explanation: >-
      The gene-specific device recommendation, stated in GeneReviews management
      guidance.
  - reference: PMID:22281253
    reference_title: Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Carriers of LMNA mutations with a high risk of MVA can be identified using
      these risk factors. This facilitates selection of LMNA mutation carriers
      who are most likely to benefit from an ICD.
    explanation: >-
      Supports risk-factor-based rather than EF-based selection of ICD
      candidates.
  - reference: PMID:27884249
    reference_title: Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Implantable cardioverter-defibrillators were placed in 59% of patients for
      new LVD or AVB.
    explanation: >-
      Documents real-world device use and its indications in an LMNA cohort.
- name: Permanent Pacing
  description: >-
    Symptomatic bradyarrhythmia or high-grade heart block requires pacing. In
    practice this is delivered as part of a defibrillator system rather than a
    pacemaker alone, because the same patients carry a sudden-death risk that a
    pacemaker does not address.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Pacemaker placement
    term:
      id: NCIT:C80434
      label: Pacemaker Placement
  target_mechanisms:
  - target: Cardiac Conduction System Degeneration
    treatment_effect: BYPASSES
    description: >-
      Pacing substitutes for failed impulse generation and conduction; it does
      not slow the degeneration of the conduction tissue itself.
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptomatic supraventricular arrhythmias are usually treated with
      pharmacologic therapy or ablation; symptomatic bradyarrhythmias or
      significant heart block is treated with an electronic pacemaker.
    explanation: >-
      States the pacing indication in GeneReviews management guidance.
- name: Early Cardiac Resynchronization Therapy
  description: >-
    An emerging, weakly evidenced deviation from standard practice. Because
    LMNA carriers frequently need pacing before their QRS widens, and
    right-ventricular pacing itself is dyssynchronising, one small comparative
    series implanted CRT-D rather than a conventional device in carriers with a
    narrow QRS who already had a pacemaker or ICD indication. Over 7.2 years none
    of the five CRT patients reached the composite of transplantation, death from
    end-stage heart failure or ventricular tachycardia ablation, versus three of
    five without. With ten patients and no randomisation this is hypothesis
    generating, not practice defining.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Cardiac resynchronization therapy
    term:
      id: NCIT:C80436
      label: Cardiac Resynchronization Therapy
  target_mechanisms:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    treatment_effect: INHIBITS
    description: >-
      Biventricular pacing is intended to avoid pacing-induced dyssynchrony and
      so slow the decline in ejection fraction, rather than to act on the lamina
      defect.
  evidence:
  - reference: PMID:38495409
    reference_title: The role of early cardiac resynchronization therapy implantation in dilated cardiomyopathy patients with narrow QRS carrying lamin A/C mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of ten LMNA DCM patients (age 51±10 years, QRS 96±14 msec, EF 55±7%) with
      indication for pacemaker or ICD implantation, five underwent early CRT-D
      implantation. After 7.2±4 years, three patients (60%) in the non-CRT group
      reached the primary outcome, compared to no patients in the CRT group
      (P=0.046).
    explanation: >-
      The comparative outcome data. PARTIAL because ten patients, non-randomised
      and retrospectively compared, cannot establish efficacy however suggestive
      the separation.
  notes: >-
    Not a guideline recommendation. Curated because it is the only reported
    attempt to modify this disease's course with device programming rather than
    drugs, and because the rationale - avoiding pacing-induced dyssynchrony in a
    population that is paced early - is specific to LMNA rather than generic
    heart failure practice.
- name: Catheter Ablation for Symptomatic Supraventricular Arrhythmia
  description: >-
    Symptomatic supraventricular arrhythmias are managed with antiarrhythmic
    drugs or ablation, and chronic atrial fibrillation is first addressed by
    attempting to restore sinus rhythm along with rate control and
    anticoagulation.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Cardiac ablation
    term:
      id: NCIT:C100068
      label: Cardiac Ablation
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptomatic supraventricular arrhythmias are usually treated with
      pharmacologic therapy or ablation; symptomatic bradyarrhythmias or
      significant heart block is treated with an electronic pacemaker.
    explanation: >-
      States the management of symptomatic supraventricular arrhythmia in
      GeneReviews management guidance.
- name: Guideline-Directed Heart Failure Pharmacotherapy
  description: >-
    Standard heart failure therapy - ACE inhibitors or angiotensin receptor
    blockers, beta blockers, mineralocorticoid receptor antagonists, and
    contemporary additions such as sacubitril/valsartan and SGLT2 inhibitors - is
    applied as in other dilated cardiomyopathies. There is no LMNA-specific
    medical regimen, and the natural history data suggest medical therapy alone
    is insufficient in this genotype.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: beta-adrenergic antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: ACE inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: SGLT2 inhibitor
      term:
        id: NCIT:C98083
        label: SGLT2 Inhibitor
    - preferred_term: sacubitril
      term:
        id: NCIT:C152281
        label: Sacubitril
  target_mechanisms:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    treatment_effect: INHIBITS
    description: >-
      Neurohormonal blockade slows adverse remodeling and improves symptoms and
      survival in dilated cardiomyopathy generally; it is applied here for the
      same reason.
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment of symptomatic DCM, including heart failure, is pharmacologic
      with ACE inhibitors, beta blockers, and other conventional approaches.
    explanation: >-
      GeneReviews statement of the medical regimen used in this disease.
  notes: >-
    Rate-slowing agents (beta blockers, non-dihydropyridine calcium channel
    blockers) must be used with awareness of the underlying conduction disease;
    device backup is often already in place in this population for the
    independent sudden-death indication.

    No pathophysiology node conforms to
    `cardiomyopathy_maladaptive_remodeling#Neurohormonal Activation`, which is
    the module node these drugs actually act on. That is deliberate: no source in
    this entry evidences renin-angiotensin-aldosterone or sympathetic activation
    specifically in LMNA carriers, as distinct from dilated cardiomyopathy in
    general, so the amplifier node is left unclaimed rather than asserted by
    analogy. This link therefore attaches to the contractile-dysfunction node it
    is intended to slow.
- name: Anticoagulation
  description: >-
    Anticoagulation is indicated for atrial fibrillation and for left ventricular
    mural thrombus, both of which are common in this disease and both of which
    can present as systemic embolism.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticoagulant agent
      term:
        id: NCIT:C263
        label: Anticoagulant Agent
  target_mechanisms:
  - target: Intracardiac Thrombus Formation
    treatment_effect: INHIBITS
    description: >-
      Anticoagulation acts on the coagulation arm of thrombus formation,
      preventing the mural or atrial thrombus rather than altering the stasis
      that predisposes to it.
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chronic atrial fibrillation is treated initially with attempts to restore
      normal sinus rhythm, anticoagulation, and rate control.
    explanation: >-
      States the anticoagulation indication for atrial fibrillation in this
      disease.
- name: Heart Transplantation
  description: >-
    Transplantation, and mechanical circulatory support as a bridge, is required
    for refractory heart failure and is needed frequently and at a young age in
    this population - about one in five carriers in longitudinal follow-up.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_mechanisms:
  - target: Progressive Heart Failure and End-Stage Disease
    treatment_effect: BYPASSES
    description: >-
      Replaces the failing organ; the systemic genetic defect persists but the
      target tissue is removed.
  evidence:
  - reference: PMID:29095976
    reference_title: "Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heart transplantation was performed in 15 of 79 (19%) LMNA patients during
      7.8 ± 6.3 years of follow-up.
    explanation: >-
      Quantifies transplantation frequency in a followed LMNA cohort.
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac transplantation or other advanced therapies may be considered for
      refractory disease in persons receiving comprehensive care from
      cardiovascular disease experts.
    explanation: >-
      States the indication for advanced therapy in GeneReviews management
      guidance.
- name: Cardiovascular Surveillance of Genotype-Positive Relatives
  description: >-
    Because the phenotype converts at roughly 9% per year and sudden death can be
    the first event, asymptomatic carriers are followed rather than reassured:
    history, examination, ECG and echocardiography every one to two years, moving
    to at least annual ECG, ambulatory monitoring and ventricular function
    assessment once any ECG abnormality appears, with immediate evaluation for
    new symptoms.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Asymptomatic individuals with a pathogenic LMNA variant should undergo
      cardiovascular evaluation (medical history, physical examination,
      echocardiogram, and EKG) every one to two years and/or whenever new
      symptoms arise.
    explanation: >-
      The surveillance interval for asymptomatic carriers from GeneReviews.
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In families with a known LMNA pathogenic variant, at-risk individuals for
      whom genetic testing is not possible should have yearly cardiovascular
      evaluation.
    explanation: >-
      Covers at-risk relatives who cannot be genotyped, who are followed rather
      than discharged.
- name: Genetic Counseling and Cascade Testing
  description: >-
    Autosomal dominant transmission with a 50% recurrence risk per child,
    age-dependent penetrance and variable expressivity make counselling central.
    Once a familial variant is identified, targeted testing of relatives directs
    who needs lifelong surveillance and who can be discharged. Pregnancy is
    contraindicated in women with established dilated cardiomyopathy, and at-risk
    women of unknown genotype should be evaluated and counselled ideally before
    conceiving.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To facilitate prompt diagnosis, targeted LMNA genetic testing when the
      family-specific pathogenic variant is known; otherwise regular surveillance
      with cardiovascular screening tests.
    explanation: >-
      States the cascade-testing strategy for relatives at risk.
  - reference: PMID:20301717
    reference_title: LMNA-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pregnancy is contraindicated in women with DCM. Pregnant women with DCM
      should be followed by a high-risk obstetrician.
    explanation: >-
      Records the reproductive safety warning from the GeneReviews management
      section, which belongs with counselling rather than with a drug.
- name: ARRY-371797 (p38 MAPK Inhibitor)
  description: >-
    The only disease-specific targeted therapy taken to phase 3 in CMD1A, built
    on the observation that mutant lamins activate p38 MAPK signalling. Phase 2
    data showed an improved six-minute walk distance sustained to 144 weeks, but
    the phase 3 REALM-DCM trial was stopped for futility at a planned interim
    analysis with no significant difference on any outcome at week 24 and no
    safety signal. It is recorded here as a negative result that constrains the
    signalling hypothesis, not as an available treatment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: MAPK Cascade Activation
    treatment_effect: INHIBITS
    description: >-
      Selective p38-alpha MAPK inhibition was intended to interrupt the MAPK arm
      of this node. The phase 3 failure means the intended mechanism was not
      shown to translate into clinical benefit.
    evidence:
    - reference: PMID:38979608
      reference_title: "REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic LMNA-Related Dilated Cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In a phase 2 trial and long-term extension, the selective p38α MAPK
        (mitogen-activated protein kinase) inhibitor, ARRY-371797 (PF-07265803),
        was associated with an improved 6-minute walk test at 12 weeks, which was
        preserved over 144 weeks.
      explanation: >-
        Identifies the drug's molecular target as p38-alpha MAPK, which is what
        links it to this pathophysiology node.
  evidence:
  - reference: PMID:38979608
    reference_title: "REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic LMNA-Related Dilated Cardiomyopathy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      REALM-DCM was terminated after a planned interim analysis suggested
      futility.
    explanation: >-
      The phase 3 trial of this agent was stopped for futility, so it refutes
      clinical efficacy in symptomatic LMNA-related dilated cardiomyopathy.
  - reference: PMID:38979608
    reference_title: "REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic LMNA-Related Dilated Cardiomyopathy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No significant differences (P>0.05) between groups were observed in the
      change from baseline at week 24 for all outcomes
    explanation: >-
      The primary and secondary endpoint results underlying the futility
      determination.
  - reference: PMID:36114020
    reference_title: Long-Term Efficacy and Safety of ARRY-371797 (PF-07265803) in Patients With Lamin A/C-Related Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ARRY-371797 (PF-07265803), a potent, selective, oral, small-molecule
      inhibitor of the p38α mitogen-activated protein kinase pathway, improved
      6-minute walk test (6MWT) distance in 12 patients with symptomatic
      LMNA-related DCM in a 48-week, open-label, phase 2 study.
    explanation: >-
      The open-label phase 2 signal that justified the phase 3 trial. PARTIAL
      because an uncontrolled 12-patient study on a walk-test endpoint is a weak
      efficacy claim, and the controlled phase 3 subsequently found no effect.
- name: LOXL2 Inhibition (Simtuzumab)
  description: >-
    A preclinical, not clinical, candidate. LOXL2 is upregulated in LMNA-mutant
    human iPSC cardiomyocytes, engineered heart tissue and mice, and the LOXL2
    antibody simtuzumab prevented cardiac dysfunction and fibrosis in the mouse
    model. There is no human trial in this disease, so this is recorded as a
    mechanism-derived candidate targeting the fibrotic arm rather than as
    therapy.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Cardiomyocyte Loss and Myocardial Fibrosis
    treatment_effect: INHIBITS
    description: >-
      Antibody blockade of LOXL2 interrupts the extracellular matrix
      cross-linking arm of the remodeling node.
    evidence:
    - reference: PMID:41841259
      reference_title: Simtuzumab Attenuates Loxl2-Mediated Extracellular Matrix Remodeling and Preserves Cardiac Function in LMNA Mutation-Induced Dilated Cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Treatment with Simtuzumab, a Loxl2 inhibitor, effectively prevented
        cardiac dysfunction and fibrosis in vivo.
      explanation: >-
        The in-vivo rescue linking LOXL2 inhibition to the fibrosis and
        dysfunction node.
  evidence:
  - reference: PMID:41841259
    reference_title: Simtuzumab Attenuates Loxl2-Mediated Extracellular Matrix Remodeling and Preserves Cardiac Function in LMNA Mutation-Induced Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Transcriptomic analysis revealed dysregulation of extracellular matrix
      remodeling and significant upregulation of Loxl2 in mutated
      hiPSC-cardiomyocytes, hiPSC-engineered heart tissues, and mice.
    explanation: >-
      Establishes the target's upregulation in the human-cell and mouse systems
      that motivated the intervention.
  notes: >-
    Preclinical only. No clinical trial of LOXL2 inhibition in LMNA-related
    dilated cardiomyopathy has been reported; simtuzumab failed in other
    fibrotic indications, so translation should not be assumed.

    `therapeutic_agent` is deliberately empty despite the agent being named.
    NCIT:C91735 (Simtuzumab) exists but is not reachable from the
    ChemicalEntityTerm dynamic-enum roots, so binding it fails term validation;
    CHEBI has no simtuzumab entry either. Leaving the slot unbound is preferred
    to forcing a less accurate agent term.

clinical_trials:
- name: NCT03439514
  phase: PHASE_III
  status: TERMINATED
  description: >-
    REALM-DCM, a phase 3 multinational randomised placebo-controlled trial of the
    selective p38-alpha MAPK inhibitor ARRY-371797 in symptomatic LMNA-related
    dilated cardiomyopathy, with change in six-minute walk distance at week 24 as
    the primary outcome. Terminated for futility at a planned interim analysis
    without safety concern.
  target_phenotypes:
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  - preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: PMID:38979608
    reference_title: "REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic LMNA-Related Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      REALM-DCM (NCT03439514) was a phase 3, randomized, double-blind,
      placebo-controlled trial in patients with symptomatic LMNA-related dilated
      cardiomyopathy.
    explanation: >-
      Identifies the trial registration, design, and study population.
  - reference: PMID:39145700
    reference_title: Characterization and natural history of patients with LMNA-related dilated cardiomyopathy in the phase 3 REALM-DCM trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Between 2018 and 2022, 77 patients took part in REALM-DCM. The median
      patient age was 53 years (range: 23-72), and 57% were male.
    explanation: >-
      Characterises the enrolled trial population, which doubles as the best
      contemporary phenotypic description of symptomatic CMD1A.
animal_models:
- name: Lmna H222P knock-in mouse
  species: Mouse
  genotype: Lmna p.H222P homozygous knock-in
  publication: PMID:15548545
  evidence:
  - reference: PMID:15548545
    reference_title: Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We chose the LMNA H222P missense mutation identified in a family with
      autosomal dominant Emery-Dreifuss muscular dystrophy, one of the striated
      muscle-specific laminopathies, to create a faithful mouse model of this
      type of laminopathy.
    explanation: >-
      Describes the construction and intent of the model, establishing that it
      carries a human-derived LMNA missense allele.
  description: >-
    Knock-in of a human LMNA missense allele originally found in an autosomal
    dominant Emery-Dreifuss family. Homozygotes develop chamber dilation,
    hypokinesia and conduction defects with muscle degeneration, fibrosis,
    dislocated heterochromatin and Smad activation, and it is the model in which
    the MAPK and AKT-mTOR signalling arms of this disease were established.
  modeled_mechanisms:
  - target: Cardiac Conduction System Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the combined conduction-defect-plus-dilation cardiac phenotype
      that defines the human disease.
    limitations: >-
      The cardiac phenotype requires homozygosity, whereas human CMD1A is a
      heterozygous dominant disease, and H222P was ascertained in an
      Emery-Dreifuss family rather than a cardiomyopathy-predominant one.
    readouts:
    - name: Cardiac chamber dimension and conduction
      target: Cardiac Conduction System Degeneration
      direction: ALTERED
      interpretation: >-
        Chamber dilation with hypokinesia and conduction defects in the intact
        animal.
      evidence:
      - reference: PMID:15548545
        reference_title: Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          As for cardiac phenotype, they develop chamber dilation and hypokinesia
          with conduction defects.
        explanation: >-
          Reports the cardiac measurement behind this readout.
    evidence:
    - reference: PMID:15548545
      reference_title: Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These results demonstrate that LmnaH222P/H222P mice represent a good
        model for studying laminopathies affecting striated muscles as they
        develop a dystrophic condition of both skeletal and cardiac muscles
        similar to the human diseases.
      explanation: >-
        The authors' own assessment that the model is informative for human
        striated-muscle laminopathy.
  - target: MAPK Cascade Activation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The model in which MAPK activation was shown to precede cardiomyopathy and
      in which AKT-mTOR hyperactivation with defective autophagy was identified
      and pharmacologically reversed.
    limitations: >-
      The therapeutic corollary did not translate: a p38 MAPK inhibitor developed
      on the strength of this signalling biology failed for futility in phase 3,
      so the model's predictive validity for human treatment response is
      unestablished.
    readouts:
    - name: Cardiac MAPK pathway activation
      target: MAPK Cascade Activation
      direction: INCREASED
      interpretation: >-
        MAPK cascade activity is raised in mutant hearts before clinical disease.
      evidence:
      - reference: PMID:17446932
        reference_title: Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Using real-time PCR, we showed that activation of MAPK pathways
          preceded clinical signs or detectable molecular markers of
          cardiomyopathy.
        explanation: >-
          Reports the transcriptional measurement and its timing.
    - name: Cardiac function under temsirolimus
      target: MAPK Cascade Activation
      direction: RESTORED
      interpretation: >-
        mTOR inhibition preserves cardiac function in the mutant, tying the
        signalling arm to the functional phenotype.
      evidence:
      - reference: PMID:22837537
        reference_title: Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          We show that the AKT-mammalian target of rapamycin pathway is
          hyperactivated in hearts of mice with cardiomyopathy caused by Lmna
          mutation and that in vivo administration of the rapamycin analog
          temsirolimus prevents deterioration of cardiac function.
        explanation: >-
          Reports both the pathway measurement and the rescue outcome.
    evidence:
    - reference: PMID:17446932
      reference_title: Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Activation of MAPK signaling by mutant A-type lamins could be a
        cornerstone in the development of heart disease in autosomal dominant
        Emery-Dreifuss muscular dystrophy.
      explanation: >-
        Supports treating this model as informative for the signalling node.
- name: Lamin A/C-null mouse
  species: Mouse
  genotype: Lmna knockout (Lmna-/-)
  publication: PMID:14755333
  evidence:
  - reference: PMID:14755333
    reference_title: Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We report that lamin A/C-deficient (Lmna(-/-)) mice develop rapidly
      progressive dilated cardiomyopathy (DCM) characterized by left ventricular
      (LV) dilation and reduced systolic contraction.
    explanation: >-
      Establishes the model's genotype and its dilated cardiomyopathy phenotype.
  description: >-
    Complete loss of A-type lamins produces rapidly progressive dilated
    cardiomyopathy with grossly abnormal nuclei, fragmented heterochromatin, and
    detachment of the desmin network from the nuclear surface. It is the source
    of the defective-force-transmission model and of the observation that
    lamin-deficient cardiomyocytes cannot mount compensatory hypertrophy.
  modeled_mechanisms:
  - target: Cardiomyocyte Nuclear Envelope Fragility and Rupture
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Demonstrates nuclear structural failure and loss of coupling between the
      nucleoskeleton and the cytoskeleton in cardiomyocytes.
    limitations: >-
      A homozygous null is a more extreme lesion than the heterozygous,
      often missense human genotype, and the mice develop disease far more
      rapidly than patients; the null therefore models loss of lamin function
      rather than the dominant-negative action of a mutant protein.
    readouts:
    - name: Cardiomyocyte nuclear morphology and desmin attachment
      target: Cardiomyocyte Nuclear Envelope Fragility and Rupture
      direction: ALTERED
      interpretation: >-
        Electron microscopy shows nuclear shape and size abnormalities with
        desmin filaments detached from the nuclear surface.
      evidence:
      - reference: PMID:14755333
        reference_title: Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Electron microscopy of Lmna(-/-) cardiomyocytes shows disorganization
          and detachment of desmin filaments from the nuclear surface with
          progressive disruption of the cytoskeletal desmin network.
        explanation: >-
          Reports the ultrastructural measurement behind this readout.
    evidence:
    - reference: PMID:14755333
      reference_title: Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We report that lamin A/C-deficient (Lmna(-/-)) mice develop rapidly
        progressive dilated cardiomyopathy (DCM) characterized by left
        ventricular (LV) dilation and reduced systolic contraction.
      explanation: >-
        Establishes that the model produces the disease phenotype of interest.
- name: Cardiomyocyte-restricted LMNA D300N mouse
  species: Mouse
  genotype: Tet-off bigenic cardiac-myocyte-specific LMNA p.D300N expression
  publication: PMID:30696354
  evidence:
  - reference: PMID:30696354
    reference_title: DNA Damage Response/TP53 Pathway Is Activated and Contributes to the Pathogenesis of Dilated Cardiomyopathy Associated With LMNA (Lamin A/C) Mutations.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We generated a tet-off bigenic mice expressing either a WT (wild type) or a
      mutant LMNA (D300N) protein in cardiac myocytes.
    explanation: >-
      Describes the conditional, cardiomyocyte-restricted construction of the
      model.
  description: >-
    Doxycycline-suppressible expression of a mutant lamin restricted to cardiac
    myocytes, producing severe myocardial fibrosis, apoptosis, cardiac
    dysfunction and premature death, all preventable by switching expression off.
    Used to establish the DNA damage response/TP53 arm, which was then confirmed
    in human LMNA-DCM myocardium.
  modeled_mechanisms:
  - target: DNA Damage Response and TP53 Pathway Activation
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The pathway identified in this model was independently confirmed by RNA
      sequencing of human LMNA-DCM hearts, and cardiomyocyte Tp53 deletion
      partially rescued the phenotype.
    limitations: >-
      D300N is a progeroid-syndrome-associated allele rather than a typical
      CMD1A variant, and the transgenic system uses supraphysiological
      cardiomyocyte-restricted expression rather than the heterozygous germline
      state.
    readouts:
    - name: Cardiac phenotype after cardiomyocyte Tp53 deletion
      target: DNA Damage Response and TP53 Pathway Activation
      direction: RESTORED
      interpretation: >-
        Removing TP53 partially reverses fibrosis, apoptosis and ventricular
        dysfunction, establishing pathway causality.
      evidence:
      - reference: PMID:30696354
        reference_title: DNA Damage Response/TP53 Pathway Is Activated and Contributes to the Pathogenesis of Dilated Cardiomyopathy Associated With LMNA (Lamin A/C) Mutations.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Deletion of Tp53 partially rescued myocardial fibrosis, apoptosis,
          proliferation of nonmyocyte cells, left ventricular dilatation and
          dysfunction, and slightly improved survival.
        explanation: >-
          Reports the genetic-rescue measurement behind this readout.
    evidence:
    - reference: PMID:30696354
      reference_title: DNA Damage Response/TP53 Pathway Is Activated and Contributes to the Pathogenesis of Dilated Cardiomyopathy Associated With LMNA (Lamin A/C) Mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        RNA sequencing of human hearts with DCM associated with defined LMNA
        pathogenic variants corroborated activation of the DNA damage
        response/TP53 pathway in the heart.
      explanation: >-
        The human-tissue confirmation that justifies the HIGH fidelity rating for
        this mechanism link.
experimental_models:
- name: Patient-derived LMNA-mutant iPSC cardiomyocytes
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Induced pluripotent stem cell-derived cardiomyocytes from carriers of an LMNA
    frameshift variant, compared against isogenic corrected controls. They
    display disturbed calcium handling producing single-cell arrhythmia and
    activated PDGF signalling, both reversed by PDGF pathway inhibition.
  modeled_mechanisms:
  - target: Aberrant Cardiomyocyte Calcium Handling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      A human cell system with isogenic controls that reproduces arrhythmogenesis
      cell-autonomously and identifies a druggable pathway.
    limitations: >-
      iPSC cardiomyocytes are immature relative to adult myocardium - rounder
      nuclei, a less developed cytoskeleton and no chronic mechanical loading -
      so they are a weak model for the nuclear-rupture arm of this disease even
      where they capture the signalling and calcium phenotypes. Single-cell
      arrhythmia in vitro is also not the same entity as clinical ventricular
      tachyarrhythmia.
    readouts:
    - name: Calcium handling and single-cell arrhythmia
      target: Aberrant Cardiomyocyte Calcium Handling
      direction: ALTERED
      interpretation: >-
        Electrophysiology shows aberrant calcium homeostasis generating
        arrhythmic events.
      evidence:
      - reference: PMID:31316208
        reference_title: Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Electrophysiological studies showed that the mutant iPSC-CMs displayed
          aberrant calcium homeostasis that led to arrhythmias at the single-cell
          level.
        explanation: >-
          Reports the electrophysiological measurement behind this readout.
    - name: Arrhythmic phenotype under PDGF pathway inhibition
      target: Aberrant Cardiomyocyte Calcium Handling
      direction: RESTORED
      interpretation: >-
        Blocking PDGF signalling abolishes the arrhythmic phenotype, making the
        pathway causal in this system.
      evidence:
      - reference: PMID:31316208
        reference_title: Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Conversely, pharmacological and molecular inhibition of the PDGF
          signalling pathway ameliorated the arrhythmic phenotypes of mutant
          iPSC-CMs in vitro.
        explanation: >-
          Reports the rescue measurement behind this readout.
    evidence:
    - reference: PMID:31316208
      reference_title: Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Mechanistically, we show that the platelet-derived growth factor (PDGF)
        signalling pathway is activated in mutant iPSC-CMs compared to isogenic
        control iPSC-CMs.
      explanation: >-
        The isogenic comparison that makes this model informative for the
        signalling node.
discussions:
- discussion_id: lmna_dcm_dominant_mechanistic_arm
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which of the mechanistic arms downstream of the lamina defect - mechanical
    nuclear rupture, chromatin/LAD disorganisation, MAPK and AKT-mTOR signalling,
    DNA damage response/TP53, or PDGF signalling - carries the dominant causal
    weight in human CMD1A, and are they sequential or parallel?
  attaches_to:
  - "pathophysiology#MAPK Cascade Activation"
  - "pathophysiology#DUSP4-Mediated AKT-mTOR Activation with Impaired Autophagy"
  - "pathophysiology#Cardiomyocyte Nuclear Envelope Fragility and Rupture"
  - "pathophysiology#DNA Damage Response and TP53 Pathway Activation"
  rationale: >-
    Each arm is supported by a model-system rescue experiment, which is exactly
    what makes the question hard: temsirolimus, Tp53 deletion, autophagy/ER
    stress modulation and PDGF inhibition all partially rescue their respective
    models, so none is excluded and none is established as rate-limiting. The
    only human test of any arm - selective p38-alpha MAPK inhibition in REALM-DCM
    - failed for futility, which argues against the MAPK arm being sufficient as
    a therapeutic target in symptomatic disease but does not resolve its
    contribution to pathogenesis, nor rank the others. Curating these as parallel
    arms feeding a shared cardiomyocyte-loss node is therefore an honest
    representation of the current state rather than an evasion.
  evidence:
  - reference: PMID:38979608
    reference_title: "REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic LMNA-Related Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      REALM-DCM was terminated after a planned interim analysis suggested
      futility.
    explanation: >-
      The only human test of any single mechanistic arm failed, which is what
      leaves the relative causal weight of the arms open rather than settled by
      the model-system rescue experiments.
  - reference: PMID:22837537
    reference_title: Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Emerging evidence suggests that LMNA mutations cause disease by altering
      cell signaling pathways, but the specific mechanisms are poorly understood.
    explanation: >-
      States the gap directly. PARTIAL because it frames the open question rather
      than resolving it.
  proposed_experiments:
  - experiment_id: lmna_dcm_staged_arm_interruption
    name: Staged intervention in a single inducible cardiomyocyte model
    description: >-
      Use one inducible, cardiomyocyte-restricted mutant-lamin model to interrupt
      each arm separately and in combination at matched disease stages, with
      identical structural and functional endpoints, so the arms can be ranked
      within a single system rather than compared across models with different
      alleles, zygosities and expression levels.
- discussion_id: lmna_dcm_model_fidelity
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Do the two workhorse model systems for this disease - homozygous mutant or
    null mice and iPSC-derived cardiomyocytes - reproduce the human heterozygous,
    adult-onset, mechanically loaded disease faithfully enough for their
    mechanistic conclusions to transfer?
  attaches_to:
  - "pathophysiology#Cardiomyocyte Nuclear Envelope Fragility and Rupture"
  rationale: >-
    Human CMD1A is a heterozygous dominant disease of adult, chronically loaded
    myocardium. The mouse models that generated most of the mechanism are
    homozygous - either null or knock-in - and develop disease over months rather
    than decades; the null in particular models absence of lamin A/C rather than
    the dominant-negative action of a mutant protein that human myocardial
    western blots suggest. iPSC cardiomyocytes are genotypically faithful and
    support isogenic comparison, but are developmentally immature and are not
    subjected to the sustained mechanical load that the mechanical-fragility
    model says is the proximate cause of nuclear failure - so the arm they are
    least able to test is the one with the strongest human ultrastructural
    support. The clinical consequence is not hypothetical: the one mechanism
    taken from these models into a phase 3 trial did not translate.
  evidence:
  - reference: PMID:38718107
    reference_title: Perinuclear damage from nuclear envelope deterioration elicits stress responses that contribute to LMNA cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      in mice, mutations in both alleles of Lmna are required for the disease
      penetrance, whereas in humans, the vast majority of LMNA cardiomyopathy is
      autosomal dominant.
    explanation: >-
      States the zygosity mismatch at the heart of this discussion directly,
      rather than leaving it to be inferred from a model's genotype.
  - reference: PMID:15548545
    reference_title: Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      At adulthood, male homozygous mice display reduced locomotion activity with
      abnormal stiff walking posture and all of them die by 9 months of age.
    explanation: >-
      A concrete instance of that mismatch: the knock-in phenotype is reported in
      homozygotes, whereas human CMD1A is heterozygous and adult-onset over
      decades rather than months.
  - reference: PMID:11897440
    reference_title: "Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Western blot protein analyses of three hearts with different mutations
      showed an additional 30-kDa band, suggesting a degrading effect of mutated
      on wild-type protein.
    explanation: >-
      Human myocardial evidence for a dominant-negative action on wild-type
      protein, which a homozygous-null model by construction cannot represent.
  proposed_experiments:
  - experiment_id: lmna_dcm_heterozygous_knockin_load
    name: Heterozygous knock-in under physiological load
    description: >-
      Characterise heterozygous knock-in mice carrying a recurrent human CMD1A
      allele, with and without imposed haemodynamic load, and compare nuclear
      rupture frequency and signalling activation against homozygous animals and
      against human myocardial samples.
  - experiment_id: lmna_dcm_engineered_heart_tissue
    name: Maturation-matched engineered heart tissue
    description: >-
      Study patient and isogenic-control iPSC cardiomyocytes in
      maturation-promoting engineered heart tissue under chronic auxotonic load,
      testing whether nuclear rupture emerges once the mechanical environment is
      restored.
datasets:
- accession: geo:GSE82290
  title: Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy
  data_type: MICROARRAY
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:27235420
  notes: >-
    Human material from carriers of the LMNA p.S143P founder variant causing
    familial dilated cardiomyopathy with conduction disease. Selected over other
    dilated-cardiomyopathy GEO hits because the studied variant is in LMNA;
    RBM20- and mixed-cardiomyopathy series returned by the same search were
    excluded as being about different genes.
- accession: geo:GSE304575
  title: LMNA p.H222P mutation causes contractile dysfunction via impaired mitochondrial calcium uptake in human cardiac laminopathy
  data_type: BULK_RNA_SEQ
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:42478871
  notes: >-
    Human cardiac laminopathy model carrying LMNA p.H222P, the same allele as the
    knock-in mouse curated under animal_models.
- accession: geo:GSE330200
  title: The p.Ser143Pro lamin A/C mutation leads to dilated cardiomyopathy and activates the unfolded protein response pathway
  data_type: BULK_RNA_SEQ
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: >-
    Mouse and human series for the LMNA p.S143P variant. Carries no linked
    publication in the GEO index at time of curation, so no evidence block is
    given.

references:
- reference: PMID:20301717
  title: LMNA-Related Dilated Cardiomyopathy.
  tags:
  - GeneReviews
- reference: PMID:37622657
  title: 2023 ESC Guidelines for the management of cardiomyopathies.
notes: >-
  External identifiers for this concept are OMIM:115200 (CARDIOMYOPATHY, DILATED,
  1A; CMD1A) and ORPHA:300751. They are not carried in a `mappings:` block because
  the schema's DiseaseMappings class has slots only for ICD-10-CM, ICD-11
  foundation, MONDO and NCIT; both identifiers are already reachable as xrefs on
  MONDO:0007269.

  Curated from the GeneReviews chapter (PMID:20301717) as the phenotype baseline,
  plus primary clinical cohorts and mechanistic studies. Orphanet ORPHA:300751
  maps to this concept but the Orphadata bulk XML was not available in this
  environment, so no ORPHA-quoted evidence is included. The 2023 ESC
  cardiomyopathy guideline is listed as a top-level reference only: its PubMed
  record caches as metadata without abstract text, so no snippet-verified
  evidence item could be drawn from it, and the gene-specific ICD recommendation
  is instead evidenced from GeneReviews and the risk-model cohorts.

📚

References & Deep Research

References

2

PMID:20301717

LMNA-Related Dilated Cardiomyopathy.

No top-level findings curated for this source.

PMID:37622657

2023 ESC Guidelines for the management of cardiomyopathies.

No top-level findings curated for this source.

Deep Research

2

Claude Code ▸

Dilated Cardiomyopathy 1A (LMNA-Related Dilated Cardiomyopathy): Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 41 citations 2026-08-18T05:11:14.328945

Dilated Cardiomyopathy 1A (LMNA-Related Dilated Cardiomyopathy): Comprehensive Research Report

1. Disease Information

Overview: Dilated Cardiomyopathy 1A (CMD1A/DCM1A) is an autosomal dominant, monogenic laminopathy caused by heterozygous pathogenic variants in LMNA (lamin A/C), the gene encoding the major structural proteins of the nuclear lamina. The disease is defined by left ventricular (LV) enlargement and/or reduced systolic function that is characteristically preceded by, or co-occurs with, significant cardiac conduction system disease and/or atrial and ventricular arrhythmias — a combination that distinguishes it from most other genetic DCMs (GeneReviews, PMID:20301717, https://www.ncbi.nlm.nih.gov/books/NBK1674/). Disease onset is typically in early-to-mid adulthood (third–fourth decade), though presentation ranges from incidental ECG findings in asymptomatic gene carriers to sudden cardiac death (SCD) as the first manifestation, sometimes with minimal or no structural disease.

Key identifiers: - OMIM: #115200 — CARDIOMYOPATHY, DILATED, 1A; CMD1A (https://omim.org/entry/115200) - Gene/locus: LMNA, chromosome 1q22 (OMIM gene 150330) - MONDO: MONDO:0007269 - Orphanet: ORPHA:300751 — "Familial dilated cardiomyopathy with conduction defect due to LMNA mutation" (https://www.orpha.net/en/disease/detail/300751); see also Orphanet's gene page (https://www.orpha.net/en/disease/gene/LMNA) - ICD-10: I42.0 (Dilated cardiomyopathy) - HGNC: LMNA, HGNC:6636 - Related allelic OMIM entries:* Emery-Dreifuss muscular dystrophy 2 (AD), #181350; limb-girdle muscular dystrophy 1B; familial partial lipodystrophy 2 (Dunnigan type), #151660; Charcot-Marie-Tooth disease type 2B1, #605588; Hutchinson-Gilford progeria syndrome, #176670; mandibuloacral dysplasia; heart-hand syndrome, Slovenian type, #610140

Synonyms: LMNA-related dilated cardiomyopathy; LMNA cardiomyopathy; familial dilated cardiomyopathy with conduction system disease; cardiac laminopathy; lamin A/C cardiomyopathy.

Evidence basis: The dismech-relevant literature is predominantly aggregated, cohort-level, and family-pedigree data from human clinical genetics (multicenter European/US cardiogenetics cohorts, e.g., van Rijsingen et al. 2012 [PMID:22281253], Captur et al. 2018 [PMID published in Eur Heart J, DOI 10.1093/eurheartj/ehx808]), supplemented by mechanistic data from iPSC-cardiomyocyte and mouse/zebrafish models rather than individual-EHR-level data.

2. Etiology

Disease Causal Factors

CMD1A is caused exclusively by heterozygous, typically dominant-negative or haploinsufficient, pathogenic variants in LMNA. This is a purely genetic/monogenic etiology — there is no known infectious or primary environmental cause of the disease itself (environmental/lifestyle factors act only as modifiers of penetrance/progression, see below). The founding description was Fatkin et al., N Engl J Med 1999 (PMID:10580070), which mapped autosomal dominant DCM with conduction-system disease to chromosome 1p1–q21 and identified missense mutations in the LMNA rod domain.

"Missense mutations in the rod domain of the lamin A/C gene provide a genetic cause for dilated cardiomyopathy and conduction-system disease... this intermediate filament protein has an important role in cardiac conduction and contractility." (Fatkin et al. 1999, NEJM 341:1715-1724, PMID:10580070)

Genetic Risk Factors

Causal variant class: More than 450 disease-associated LMNA variants have been reported across the ~15 recognized laminopathy phenotypes; cardiac disease results from missense, nonsense, frameshift/indel, and splice-site variants distributed across the gene, with no single dominant hotspot (PMC6335092, "Mechanisms of allelic and clinical heterogeneity of lamin A/C phenotypes").
Variant-class risk stratification (a documented genotype–phenotype gradient, not a strict correlation):
Non-missense variants (truncating/frameshift/indel, and splice-site variants) confer higher risk of malignant ventricular arrhythmia (MVA) and conduction disease before age 50–60 than missense variants (van Rijsingen et al. 2012, PMID:22281253; GeneReviews PMID:20301717).
Splice-site variants specifically correlate with increased SCD risk.
Modifier/digenic risk: Co-occurring rare TTN (titin) truncating variants act as genetic modifiers that substantially worsen disease severity in LMNA carriers — "doubly heterozygous" LMNA/TTN patients required heart transplantation at a significantly younger age than LMNA-only carriers, with myocardial specimens showing increased nuclear length, sarcomeric disorganization, and myonuclear clustering (Roncarati et al. 2013, Eur J Hum Genet, PMID:23463027).
A TMPO (LAP2) missense polymorphism (p.Arg690Cys) has been reported to modify leukocyte nuclear morphology abnormalities in a family with an LMNA truncating variant (PMC9656322), consistent with a broader modifier-gene concept in laminopathies.
Family history: The strongest and most actionable "risk factor" is a first-degree relative with a known pathogenic LMNA variant; autosomal dominant inheritance confers 50% transmission risk per offspring.

Environmental/Non-genetic Risk Factors

No established environmental, toxic, occupational, or infectious risk factor for CMD1A specifically has strong human evidence; the disease is fully genetically determined once a pathogenic variant is present. General DCM risk modifiers (alcohol, viral myocarditis, tachycardia-mediated stress) may plausibly accelerate decompensation but are not specifically documented as CMD1A triggers in the literature surveyed.
Age and sex act as major phenotype modifiers rather than independent causal risk factors:
Age-dependent penetrance: onset typically third–fourth decade; penetrance exceeds 90–95% by the seventh decade (GeneReviews, PMID:20301717).
Sex differences: Male LMNA carriers present with clinical manifestations at a younger age than females (42 vs. 54 years); women with LMNA DCM have ~45% lower risk of life-threatening arrhythmia than men; male sex is one of the four independent risk factors for malignant ventricular arrhythmia in the van Rijsingen risk model (PMID:22281253).

Protective Factors

No specific human genetic or environmental protective factor against CMD1A has been established in the literature surveyed. In animal/cellular models, creatine and L-carnitine supplementation attenuated muscular laminopathy phenotypes in LMNA-mutant transgenic zebrafish (Sci Rep 2024, PMC11150447) — a MODEL_ORGANISM-level signal only, not yet translated to human protective evidence.
Female sex functions as a partial phenotype-attenuating (not preventive) factor, as above.

Gene-Environment Interactions

No specific documented gene-environment interaction studies for LMNA cardiomyopathy were identified in this search; this is a data gap relative to more common DCM etiologies.

3. Phenotypes

Cardiac electrical phenotypes (typically first to manifest)

Conduction system disease — sinus node dysfunction/sinus bradycardia, progressive atrioventricular (AV) block (first-degree through complete heart block), almost always precedes or co-occurs with structural DCM. Suggested term: HP:0006682 (Abnormal atrioventricular conduction) / HP:0001513 progressing through degrees of AV block; HP:0001677 (Coronary artery atherosclerosis – not relevant) — more precisely HP:0011711 (First degree atrioventricular block) or general HP:0005180 (Sinoatrial block)/HP:0001696 (Third degree atrioventricular block).
Atrial fibrillation / atrial flutter / supraventricular tachycardia — HP:0005110 (Atrial fibrillation), HP:0004308 (Ventricular arrhythmia, more broadly).
Ventricular tachyarrhythmia / ventricular fibrillation — HP:0004756 (Ventricular fibrillation), HP:0001696-type terms; malignant VT/VF is the proximate mechanism of sudden death.
Sudden cardiac death — HP:0001645 (Sudden death) — may be the presenting/only manifestation, occasionally with preserved or minimally reduced LVEF.

Structural/functional cardiac phenotypes

Left ventricular dilation — HP:0001635 (Congestive heart failure) / HP:0001644 (Dilated cardiomyopathy).
Reduced left ventricular ejection fraction / systolic dysfunction — HP:0001635, HP:0001681 (Reduced left ventricular ejection fraction... general HP terms for cardiac dysfunction).
Left ventricular mural thrombus with systemic embolism (a distinctive presenting feature) — related to HP:0004943 (Thromboembolism).
Heart failure symptoms (dyspnea, fatigue, edema) — HP:0002094 (Dyspnea), HP:0003326 (Myalgia — not relevant), general heart-failure terms.

Extracardiac/skeletal muscle phenotypes (variable, overlapping laminopathy spectrum)

Skeletal myopathy with humeroperoneal weakness and early joint contractures in the Emery-Dreifuss muscular dystrophy (EDMD)-overlap phenotype — HP:0003693 (Distal muscle weakness), HP:0034880/HP:0002828 (Joint contractures).
Limb-girdle pattern proximal weakness in the LGMD1B-overlap phenotype — HP:0003701 (Proximal muscle weakness).
Minimal-to-no skeletal involvement is also a recognized presentation of the same causal variants — importantly, "the same LMNA mutations can cause any of these or overlapping phenotypes even within the same family," underscoring marked intrafamilial phenotypic heterogeneity (Disease Models & Mechanisms 2011, PMC3180218).

Phenotype characteristics

Onset: Typically third to fourth decade (adult onset); pediatric-onset cases occur but are less common than in TTN- or other sarcomeric DCM.
Severity/progression: Progressive — conduction disease precedes overt LV dysfunction by a median of ~7 years (in a cohort of 64 individuals). Of 122 patients with preserved LV function at initial presentation, ~24% developed new LV dysfunction and ~7% developed overt heart failure over 7 years (GeneReviews, PMID:20301717).
Frequency (population-level, among LMNA carriers): Penetrance is age-dependent, reaching >90–95% by the 7th decade; ~90% of carriers >30 years old with cardiac manifestations are considered high-risk for arrhythmic sudden death.
Imaging phenotype (cardiac MRI): 88% of asymptomatic/mildly symptomatic carriers show typical myocardial fibrosis on late gadolinium enhancement (LGE), predominantly mid-myocardial in the basal septum; 73% show a nonischemic midmyocardial/subepicardial LGE pattern; ~15% show an atypical "pseudo-infarct" transmural LGE pattern involving apical/free-wall segments (Steckman et al./various CMR series; JACC Cardiovasc Imaging and J Cardiovasc Magn Reson 2011, PMC/Springer link). A 2025 study found that variant-specific LGE patterns influence clinical outcomes (PMID:40689545).

Quality of life impact

Not separately quantified in disease-specific EQ-5D/SF-36 studies in the sources surveyed; QoL burden is inferred from the combined burden of early heart failure, ICD/pacemaker implantation, arrhythmia symptoms, and (in overlap phenotypes) progressive skeletal myopathy affecting mobility and activities of daily living. This is a data gap for CMD1A specifically.

4. Genetic/Molecular Information

Causal Gene

LMNA (lamin A/C), HGNC:6636, chromosome 1q22, NCBI Gene ID 4000. Encodes prelamin A and lamin C via alternative splicing of a single transcript; prelamin A undergoes post-translational farnesylation/proteolytic maturation to mature lamin A.
Protein: UniProt P02545 (Prelamin-A/C).

Pathogenic Variants

Variant spectrum: >450 disease-associated variants across all LMNA-associated diseases; cardiac disease arises from missense mutations (predominantly in the central α-helical rod domain, per the original Fatkin et al. 1999 description), as well as nonsense, frameshift, small indel, and splice-site variants distributed throughout the gene. No single genotype-phenotype correlation has been firmly established for CMD1A specifically (GeneReviews, PMID:20301717), though variant class (missense vs. non-missense/truncating/splice) associates with differential arrhythmic risk (see §2).
Variant classification/detection: ACMG/AMP framework via ClinVar; sequence analysis (panel/exome/genome) detects >99% of pathogenic variants, gene-targeted deletion/duplication analysis <1% (GeneReviews).
Population frequency: As with most dominant cardiomyopathy genes, pathogenic LMNA variants are rare/absent in gnomAD population reference panels; benign missense polymorphism background exists but pathogenic variants are private/family-specific in most cases.
Origin: Predominantly germline; de novo rate is not well quantified ("unknown," per GeneReviews).
Functional consequence: Predominantly dominant-negative — patients are heterozygous, producing both normal and mutant lamin A/C protein that co-assembles into a functionally compromised nuclear lamina meshwork; haploinsufficiency also contributes for truncating/nonsense-mediated-decay-prone alleles (a 2020 Circ Genom Precis Med study described an LMNA missense mutation causing nonsense-mediated mRNA decay and severe DCM, PMID referenced via AHA journals). This maps to functional_impact_category: DOMINANT_NEGATIVE (for most missense) or PARTIAL_LOSS_OF_FUNCTION/haploinsufficiency (for truncating/NMD-triggering variants).

Modifier Genes

TTN (titin) — co-occurring truncating variants worsen severity/hasten transplantation age in digenic LMNA/TTN carriers (PMID:23463027).
TMPO/LAP2 p.Arg690Cys polymorphism — modifies nuclear morphology phenotype severity (PMC9656322).

Epigenetic Information

Lamin A/C mutations disrupt lamina-associated domains (LADs) and heterochromatin organization at the nuclear periphery; integrated multi-omic analysis shows LMNA mutation-associated DCM features altered euchromatin/heterochromatin interactions with the lamina, driving downstream gene expression changes ("Integrated analysis reveals the alterations that LMNA interacts with euchromatin in LMNA mutation-associated dilated cardiomyopathy," PMC7788725). Mutant lamins also cause dislocation of heterochromatin and activation of Smad signaling in the H222P mouse model.

Chromosomal Abnormalities

Not a chromosomal-abnormality-driven disease; CMD1A is caused by single-gene sequence-level variants in LMNA, not large structural rearrangements (contrast with syndromic laminopathies where large deletions can occur).

5. Environmental Information

Environmental factors: No specific toxin, radiation, pollutant, or occupational exposure has been documented as causal or disease-modifying for CMD1A in the literature surveyed. This differs from acquired/toxin-mediated DCM etiologies (e.g., anthracycline cardiotoxicity), which are mechanistically distinct.
Lifestyle factors: Standard heart-failure lifestyle counseling (avoidance of excess alcohol, standard cardiovascular risk-factor management) is presumably applied clinically but is not disease-specific in the sources reviewed.
Infectious agents: None identified as causal; CMD1A is not an infectious or postinfectious cardiomyopathy.

6. Mechanism / Pathophysiology

CMD1A pathophysiology synthesizes across at least four convergent, non-mutually-exclusive mechanistic themes, drawn from iPSC-cardiomyocyte, mouse (H222P knock-in), and zebrafish model systems plus human myocardial specimen studies:

a) Mechanical/structural nuclear fragility → nuclear envelope rupture

Mutant lamin A/C impairs lamin filament assembly at the inner nuclear membrane, producing mechanically fragile nuclei prone to rupture under the repetitive contractile mechanical stress of cardiomyocytes. iPSC-cardiomyocyte models show nuclear blebbing, impaired lamin localization to the nuclear envelope, and — under field electrical stimulation mimicking the native cardiac mechanical environment — increased nuclear senescence and apoptosis (PMC10846625, Mol Biol Cell 2023; PMID:37585285). A 2024 study identified microtubule-generated forces as a driver of this nuclear damage (Nat Cardiovasc Res 2024, PMC11212868). Nuclear envelope rupture in cardiomyocytes triggers early transcriptomic changes and innate immune activation, reversible by disrupting the LINC complex (nuclear-cytoskeletal coupling) — implicating cGAS-STING-adjacent DNA-damage/innate-immune sensing pathways, though one mouse study found pervasive nuclear ruptures preceded ECM signaling and disease onset without activating cGAS-STING (PMC10491116, 2023). A newer (2026) preprint reports that nuclear rupture causes global transcriptional deficiency via loss of RNA polymerase II from ruptured nuclei, downregulating genes essential for cardiomyocyte structure/function (bioRxiv 2026.04.03.716433).

b) Chromatin/gene-expression dysregulation

Disruption of lamin-associated domains alters heterochromatin organization and gene expression programs relevant to cardiac muscle structure and function (PMC7788725).

c) Signaling pathway activation

p38α MAPK pathway activation downstream of nuclear envelope dysfunction is a well-established driver of cardiomyocyte dysfunction and was the basis for a targeted therapeutic (ARRY-371797, see §12).
PDGF pathway (PDGFRβ) activation contributes to LMNA-DCM pathogenesis, nominating PDGFRβ inhibition (e.g., imatinib) as a candidate therapeutic target (Nat Rev Cardiol 2019 commentary on this pathway; original mechanistic work cited via OMIM/PMID search).
ERK1/2-related signaling and mTOR/MAPK pathway hyperactivation — genome-wide transcriptome analysis of Lmna H222P mouse hearts showed abnormal increases in both MAPK and mTOR pathway activity.
Smad signaling activation accompanies fibrosis and heterochromatin dislocation in the H222P mouse model.
Cardiac sodium channel (SCN5A-related) dysfunction has been reported in an EDMD patient with an LMNA mutation, linking nuclear lamina disruption to ion-channel dysfunction relevant to conduction disease (Frontiers Cardiovasc Med 2022).

d) Mitochondrial dysfunction and oxidative stress

Mutant lamin A/C interacts with and accelerates degradation of SIRT1, driving mitochondrial dysfunction and oxidative stress.
Lamin A/C deficiency-mediated ROS elevation contributes to pathogenic iPSC-model phenotypes (Nat Commun 2024, PMID reference via Nature.com).
The p.H222P mutation impairs mitochondrial calcium uptake, contributing to heart failure in a human cardiac laminopathy model (bioRxiv 2024).

e) Extracellular matrix remodeling / fibrosis

The mutant p.H222P lamin A protein drives LOXL2-mediated extracellular matrix remodeling in both patient-derived cardiomyocytes and mouse models (bioRxiv 2025), consistent with the mid-myocardial fibrosis seen on cardiac MRI in human carriers.

Causal chain summary

Germline LMNA variant → dominant-negative/haploinsufficient nuclear lamina assembly defect → mechanically fragile cardiomyocyte nuclei → nuclear envelope rupture, DNA damage, chromatin/LAD disorganization → dysregulated gene expression + p38 MAPK/PDGFRβ/mTOR-ERK signaling activation + mitochondrial dysfunction (SIRT1 loss, impaired Ca²⁺ uptake, ROS) → cardiomyocyte apoptosis/senescence, conduction-system tissue dysfunction, and myocardial fibrosis (LOXL2-driven ECM remodeling) → progressive conduction disease, arrhythmia, and dilated cardiomyopathy → heart failure and/or sudden arrhythmic death.

Upstream nodes: the primary genetic lesion and its effect on lamina assembly. Midstream: nuclear rupture, chromatin dysregulation, signaling activation, mitochondrial dysfunction. Downstream: cardiomyocyte death/dysfunction, conduction tissue disease, fibrosis, clinical arrhythmia/DCM/SCD.

Cell types and biological processes involved

Cell types (CL): cardiac muscle cell / cardiomyocyte (CL:0000746), cardiac conduction system cells (e.g., sinoatrial/AV nodal cells), cardiac fibroblast (CL:0002548) (ECM remodeling arm), skeletal myocyte (CL:0000188) in overlap phenotypes.
Suggested GO biological processes: nuclear envelope organization (GO:0006998), chromatin organization (GO:0006325), positive regulation of stress-activated MAPK cascade (GO:0032874), platelet-derived growth factor receptor signaling pathway (GO:0048008), regulation of mitochondrial calcium ion concentration, response to oxidative stress (GO:0006979), extracellular matrix organization (GO:0030198), regulation of cardiac conduction (GO:0010468/GO:1901844), cellular senescence (GO:0090398), intrinsic apoptotic signaling pathway (GO:0097193).
Subcellular/GO Cellular Component: nuclear envelope (GO:0005635), nuclear lamina (GO:0005652), nucleoplasm; mitochondrion (GO:0005739) for the SIRT1/Ca²⁺-uptake arm.

Molecular profiling (omics)

Transcriptomics: Genome-wide expression changes in Lmna H222P mouse hearts implicate MAPK/mTOR pathway genes; single-nucleus/bulk transcriptomic studies of nuclear-ruptured cardiomyocytes show global transcriptional deficiency and immune-gene induction (bioRxiv 2024/2026 studies above).
Proteomics/mechanistic profiling: iPSC-CM studies characterize nuclear lamina protein mislocalization.
Single-cell/advanced technologies: iPSC-cardiomyocyte single-cell nuclear morphology and apoptosis/senescence assays under electrical pacing stress are the primary "advanced technology" readout used in this disease to date; no large-scale human single-cell/spatial transcriptomic atlas specific to CMD1A myocardium was identified in this search (data gap).

7. Anatomical Structures Affected

Primary organ: Heart — specifically left ventricular myocardium (dilation, systolic dysfunction) and the cardiac conduction system (sinoatrial node, atrioventricular node, His-Purkinje system) — UBERON:0000948 (heart), UBERON:0002080 (heart left ventricle), UBERON:0002382 (conducting system of the heart, if a precise term is available; else UBERON:0006630 atrioventricular node/UBERON:0006631 sinoatrial node).
Secondary/complication organs: Systemic circulation (embolic complications from LV mural thrombus), and — in EDMD/LGMD-overlap phenotypes — skeletal muscle (humeroperoneal or limb-girdle distribution) — UBERON:0001630 (skeletal muscle tissue), UBERON:0007829 (upper limb musculature) as relevant.
Body systems involved: Cardiovascular system (primary); musculoskeletal system (secondary, in overlap phenotypes).
Tissue/cell level: Cardiac muscle tissue (myocardium), conduction-system nodal/junctional tissue, cardiac interstitium/fibroblasts (fibrosis).
Subcellular level (GO Cellular Component): Nuclear envelope/nuclear lamina (primary site of protein localization and dysfunction), mitochondria (secondary, functional dysfunction site).
Localization/laterality: Bilateral/global cardiac chamber involvement (not typically lateralized); myocardial fibrosis characteristically localizes to the mid-myocardial basal septum, with a subset showing atypical apical/free-wall transmural "pseudo-infarct" patterns.

8. Temporal Development

Onset: Typically early-to-mid adulthood (third to fourth decade); congenital/pediatric-onset presentations occur but are less characteristic than in some other genetic DCMs. Onset pattern is insidious electrically (subclinical conduction abnormalities detectable on ECG years before structural disease) with the possibility of an acute first presentation as sudden cardiac death.
Progression:
Sequential pattern: conduction system disease (sinus/AV node dysfunction) → atrial arrhythmias → ventricular arrhythmias/dysfunction → LV dilation/systolic dysfunction → heart failure.
Median lag from ECG abnormality to detectable LV dysfunction: ~7 years.
Of patients with preserved LV function at baseline, ~24% develop new LV dysfunction and ~7% develop heart failure within 7 years.
Disease course is progressive and generally does not remit; no spontaneous remission pattern is described.
Stages: Not formally staged with a named clinical staging system (unlike, e.g., cancer), but clinically conceptualized as: (1) asymptomatic genotype-positive/ECG-abnormal stage, (2) conduction disease/arrhythmia stage with preserved EF, (3) overt DCM/heart failure stage, (4) end-stage requiring transplant/mechanical support.
Critical periods: The window when conduction disease is present but LV function is preserved is clinically critical for arrhythmic risk stratification and pre-emptive ICD decision-making (before EF falls below 35%), since SCD can occur even with preserved systolic function.

9. Inheritance and Population

Epidemiology

Prevalence among LMNA carriers: By definition, this is a fully penetrant-trending Mendelian disease among variant carriers (>90–95% by age 70).
Contribution to DCM overall:
LMNA pathogenic variants account for ~5–13% of idiopathic/nonsyndromic DCM cases (GeneReviews).
Approximately 5–10% of familial DCM and 2–5% of sporadic DCM cases (multiple concordant sources).
Up to 33% of DCM cases specifically associated with atrioventricular conduction disease, and 40–50% of inherited DCM with accompanying conduction disease.
LMNA is, after TTN, the second most common single-gene cause of nonsyndromic DCM.
Some series report LMNA variants in up to ~8% of all DCM patients broadly.
Background: overall DCM prevalence is estimated at ~1 in 2,500 individuals; inherited/familial forms account for 30–50% of DCM overall.

Inheritance Pattern

Autosomal dominant.
Penetrance: Age-dependent and incomplete at younger ages but near-complete (>90–95%) by the seventh decade; described in one large multicenter cohort as "young onset, high penetrance" (Eur Heart J 2018, DOI 10.1093/eurheartj/ehx818, https://academic.oup.com/eurheartj/article/39/10/853/4583488) — this study also reported frequent need for heart transplantation.
Expressivity: Highly variable, including intrafamilial variability — the same variant can produce isolated cardiac disease, EDMD, or LGMD1B phenotypes even within one family, implicating modifier genes/environment.
De novo rate: Not well quantified ("unknown" per GeneReviews); most cases appear familial once ascertained.
Founder effects, consanguinity, germline mosaicism, carrier frequency: Not specifically documented for CMD1A in the sources reviewed (data gap) — contrast with autosomal recessive laminopathies (e.g., some CMD/EDMD-AR forms) where consanguinity is more relevant.

Population Demographics

Sex ratio / distribution: No strong sex-skew in prevalence, but pronounced sex-based phenotype differences: males present earlier (mean 42 vs. 54 years) and carry ~higher arrhythmic risk (male sex is one of four independent risk factors for malignant ventricular arrhythmia); women have a more favorable overall long-term prognosis in DCM broadly, consistent with LMNA-specific data.
Geographic distribution: No specific endemic/founder population identified in this search; described cohorts span European (Netherlands/France/Italy-led consortium studies) and other populations without strong geographic clustering reported.
Age distribution: Concentrated in the 20s–50s at diagnosis, consistent with the age-dependent penetrance curve above.

10. Diagnostics

Clinical/Laboratory Tests

ECG: First-line and often earliest abnormal test — detects sinus bradycardia, PR prolongation, AV block, atrial arrhythmias.
24–48 hour ambulatory rhythm monitoring: Recommended annually in gene-positive/ECG-abnormal individuals per GeneReviews management guidance.
Echocardiography: LV chamber size/systolic function assessment; part of both diagnostic workup and annual/biennial surveillance.
Cardiac MRI with late gadolinium enhancement (LGE): Highly informative — detects mid-myocardial basal septal fibrosis in the large majority of carriers (88% in one series) even when asymptomatic; LGE pattern (typical midmyocardial/subepicardial [73%] vs. atypical transmural "pseudo-infarct" pattern [~15%]) is prognostically relevant and variant-specific outcome associations have been reported (PMID:40689545, 2025).
Electrophysiology study: May be used in select cases for arrhythmia risk characterization.
Endomyocardial biopsy/histopathology: Not routine; when performed, may show nonspecific fibrosis, occasionally lymphocytic infiltrate mimicking myocarditis, or idiopathic cardiomyopathic changes; myocardial specimens from digenic LMNA/TTN cases show increased nuclear length, sarcomeric disorganization, myonuclear clustering.

Genetic Testing

Recommended approach: A comprehensive cardiomyopathy multigene panel or exome/genome sequencing, rather than LMNA single-gene testing alone, given phenotypic and genetic overlap with other DCM/arrhythmia genes.
Sequence analysis detects >99% of pathogenic LMNA variants; deletion/duplication (CNV) analysis identifies the remaining <1%.
Cascade/family testing: Once a familial variant is identified, targeted single-variant testing is used for at-risk relatives, supporting prenatal and preimplantation genetic testing where desired.
GTR entry: "Laminopathy testing (LMNA)" clinical genetic test listed in NCBI GTR (https://www.ncbi.nlm.nih.gov/gtr/tests/237259/).

Clinical Criteria and Differential Diagnosis

No disease-specific formal diagnostic criteria system (e.g., no "CMD1A Duke criteria" equivalent) beyond standard DCM diagnostic criteria (LV dilation + reduced EF) plus a confirmed pathogenic LMNA variant. Differential diagnosis should encompass the full nonsyndromic DCM gene set, with particular attention to other arrhythmia/conduction-disease-associated cardiomyopathy genes (e.g., SCN5A, FLNC, DES, RBM20, PLN) and to: - Arrhythmogenic right ventricular cardiomyopathy/arrhythmogenic cardiomyopathy - DES (desmin)-related myopathy - Limb-girdle muscular dystrophy (non-LMNA forms) - Emery-Dreifuss muscular dystrophy (non-LMNA forms, e.g., EMD/emerin-related X-linked EDMD1)

Screening

Cascade genetic screening of first-degree relatives is the primary screening modality once a proband's pathogenic variant is identified; there is no population-wide newborn or carrier screening program for LMNA cardiomyopathy specifically.

11. Outcome/Prognosis

Survival and Mortality

LMNA cardiomyopathy is characterized in the literature as showing "young onset, high penetrance, and frequent need for heart transplantation" (Eur Heart J 2018, https://academic.oup.com/eurheartj/article/39/10/853/4583488).
~90% of carriers older than 30 years with cardiac manifestations are considered high-risk for sudden arrhythmic death.
Digenic LMNA/TTN carriers require heart transplantation at a significantly younger age than LMNA-only carriers (PMID:23463027).

Morbidity/Complications

Progressive heart failure, need for pacemaker/ICD implantation, atrial fibrillation with thromboembolic risk (including LV mural thrombus with systemic embolism as a presenting feature), progressive skeletal myopathy in overlap phenotypes.

Prognostic Factors / Risk Stratification

The van Rijsingen risk model (2012, PMID:22281253; 269 LMNA carriers, multicenter European cohort) identified four independent risk factors for malignant ventricular arrhythmia: 1. Non-sustained ventricular tachycardia (NSVT) 2. LVEF <45% at first clinical contact 3. Male sex 4. Non-missense mutation type (insertion/deletion, truncating, or splice-affecting)

"Nonsustained VT, LVEF <45% at the first clinical contact, male sex, and non-missense mutations (ins-del/truncating or mutations affecting splicing)" are independent risk factors for malignant ventricular arrhythmias in LMNA carriers. (van Rijsingen et al. 2012, JACC 59:493-500, PMID:22281253)

This was formalized into the "LMNA-risk VTA" (LMNA-risk ventricular tachyarrhythmia) calculator (Wahbi et al.), which has since been externally validated for timing cardioverter-defibrillator implantation, though validation studies report the calculator's specificity is low (~26%) and it tends to overestimate arrhythmic risk, particularly in male patients — the proposed ≥7% predicted 5-year risk threshold may be too low for primary-prevention ICD selection (Heart Rhythm 2022/2023, PMID referenced via ScienceDirect S1547527122026868).

Quality of Life

Not separately quantified with disease-specific instruments in the sources reviewed (data gap), though QoL is presumed reduced by early device therapy, arrhythmia burden, and progressive heart failure/myopathy.

12. Treatment

Pharmacotherapy (Guideline-Directed Medical Therapy for Heart Failure)

Standard heart-failure regimen, applied as in other DCM etiologies: - Beta-blockers — NCIT:C15986 (Pharmacotherapy) treatment_term; caution: beta-blockers, calcium channel blockers, and other AV-node-suppressing agents should be avoided/used cautiously in patients without a pacemaker/ICD in place, given the conduction-disease substrate. - ACE inhibitors / angiotensin receptor blockers - Aldosterone antagonists (mineralocorticoid receptor antagonists) - Diuretics - Sacubitril/valsartan (ARNI) — reported as considerable/used in case reports as part of GDMT, though real-world uptake is inconsistent. - Note: "in limited studies, the efficacy of even maximal guideline-directed medical therapy has been suboptimal in LMNA-related DCM, revealing an unmet clinical need" (J Cardiac Failure 2023 review, S1071-9164(23)00313-5).

Device Therapy (Disease-Defining Intervention)

Implantable cardioverter-defibrillator (ICD): Central to management given the disproportionate SCD risk relative to degree of LV dysfunction. 2023 ESC Cardiomyopathy Guidelines recommend ICD in LMNA-variant carriers with EF >35% as Class 2a (with risk factors present) or Class 2b (no risk factors); ICD implantation should be considered before EF falls below 35% given established or anticipated arrhythmia risk — this is a gene-specific deviation from standard EF-only ICD criteria used in non-genetic DCM.
Permanent pacemaker: For symptomatic bradyarrhythmia/high-degree AV block — though ICD is generally favored over pacemaker-only given concurrent SCD risk.
Anticoagulation for atrial fibrillation/flutter or LV mural thrombus.

Advanced/Surgical Therapy

Cardiac transplantation and mechanical circulatory support for refractory heart failure — needed frequently and at young age in this population (as above).

Investigational/Targeted Therapeutics

ARRY-371797 (PF-07265803), a p38 MAPK inhibitor, was developed specifically for LMNA-DCM based on the p38α MAPK activation mechanism:
Phase 2 study showed improved 6-minute walk test (6MWT) distance at 12 weeks, preserved through 144 weeks (PMID referenced via AHA Circ Genom Precis Med journal).
REALM-DCM Phase 3 trial (multinational, randomized, placebo-controlled; NYHA II/III, LVEF ≤50%, ICD-implanted patients; primary endpoint change in 6MWT at week 24) — result: futility, without safety concerns (Circ Heart Fail 2024, PMID:38979608). This represents the highest-profile completed disease-specific drug trial for CMD1A and its negative Phase 3 result underscores the continued unmet therapeutic need.
PDGFRβ inhibition (e.g., imatinib): Proposed as a novel therapeutic target based on PDGF pathway activation in LMNA-DCM pathogenesis (Nat Rev Cardiol 2019 commentary); imatinib has shown anti-fibrotic efficacy in a general isoproterenol-induced cardiac fibrosis mouse model (PMC5453565) by blocking PDGFR phosphorylation, but disease-specific LMNA-DCM in vivo efficacy data were not identified in this search (extrapolated target, not yet clinically tested in CMD1A specifically).
Gene-based/RNA-targeted approaches (preclinical/conceptual stage):
AAV-mediated gene therapy/gene supplementation — under general exploration for genetic cardiomyopathies given AAV's robust cardiac tropism.
Antisense oligonucleotide (ASO)-mediated exon skipping — a clinically validated strategy in other cardiomyopathies (e.g., titin-based DCM, DMD) proposed as a conceptually transferable strategy for select LMNA variants amenable to exon skipping, though no LMNA-DCM-specific clinical program was identified in this search.
CRISPR/Cas9 gene editing — theoretically feasible for correcting LMNA variants via homology-directed repair; remains preclinical.
A comprehensive review, "LMNA-related cardiomyopathy: From molecular pathology to cardiac gene therapy" (PMC12627347, 2025), surveys this translational landscape.
Nutraceutical/metabolic modifiers (model-organism evidence only): Creatine and L-carnitine attenuated muscular laminopathy phenotypes in LMNA-mutant transgenic zebrafish via AMPK/mTOR pathway modulation (Sci Rep 2024, PMC11150447) — MODEL_ORGANISM evidence, not yet human-tested for CMD1A.

Treatment Outcomes/Strategy

No LMNA-DCM-specific combination or genotype-guided precision treatment algorithm currently exists beyond gene-informed ICD-timing risk models (§11); treatment remains guideline-directed HF therapy plus early/aggressive device therapy, given the demonstrated inadequacy of medical therapy alone and the failure of the targeted p38 MAPK inhibitor in Phase 3.

Suggested NCIT terms: NCIT:C15986 (Pharmacotherapy), NCIT:C15747 (Supportive Care), NCIT:C15329 (Surgical Procedure — for transplantation/device implantation broadly), device-related codes for ICD/pacemaker (no precise NCIT clinical-action code identified; DEVICE modality per dismech convention), NCIT:C15289 (Organ Transplantation) for cardiac transplant.

13. Prevention

Levels of Prevention

Primary prevention: Not applicable in the traditional sense (no modifiable exposure prevents the underlying genetic disease); the closest analog is genetic counseling and reproductive options (prenatal diagnosis, preimplantation genetic testing) once a familial variant is identified, to prevent transmission.
Secondary prevention (early detection): Cascade genetic testing plus regular cardiovascular surveillance in asymptomatic carriers is the primary secondary-prevention strategy:
Every 1–2 years: history, physical exam, echocardiogram, ECG in asymptomatic gene carriers.
Annual (at minimum): ECG, 24–48 hour rhythm monitoring, LV function assessment once ECG abnormalities are present.
Immediate evaluation triggered by any new cardiac symptom.
Tertiary prevention: Early ICD implantation before EF drops below 35% specifically to preempt SCD as the first/fatal event — this is the disease's signature tertiary-prevention intervention, reflecting that arrhythmic risk in LMNA carriers is disproportionate to degree of systolic dysfunction.

Genetic Counseling

Formal genetic counseling is a core component of management given autosomal dominant inheritance, age-dependent penetrance, and variable expressivity (including possible skeletal myopathy overlap). Family members should be offered variant-specific testing; asymptomatic carriers require ongoing surveillance rather than reassurance, given the incompletely penetrant-at-young-age but eventually high-penetrance natural history.

Public Health / Population Screening

No public health, vaccination, or population-level screening program applies (not infectious, no newborn screening program identified in this search).

Prophylaxis

Anticoagulation in patients with atrial fibrillation or documented LV thrombus, to prevent thromboembolic stroke/systemic embolism.
Avoidance of AV-node-suppressing drugs (beta-blockers, calcium channel blockers) in carriers without device protection, to avoid precipitating symptomatic bradyarrhythmia/heart block.

14. Other Species / Natural Disease

Taxonomy: No robust literature on spontaneously occurring, naturally arising LMNA-cardiomyopathy in companion animals or wildlife was identified in this search (data gap; contrast with some other cardiomyopathies with veterinary natural-disease correlates, e.g., feline HCM). All animal data identified are induced/engineered models (see §15), not natural disease.
Orthologous gene: Mouse Lmna (MGI:96794), zebrafish lmna — used to generate engineered models; no NCBI Gene ortholog-based natural-disease report found.

15. Model Organisms

Mouse Models

Lmna H222P knock-in mouse (Lmna^H222P/H222P): One of the first mouse models carrying a human-relevant missense mutation (originally identified in a family with autosomal dominant EDMD). Homozygous males show normal embryonic development but develop reduced locomotor activity, abnormal stiff gait, and die by 9 months. Cardiac phenotype: chamber dilation, hypokinesia, conduction defects. Histopathology: muscle degeneration with fibrosis, heterochromatin dislocation, activated Smad signaling in heart and skeletal muscle. Transcriptomics: dysregulated stress-activated MAPK and mTOR signaling with abnormally increased pathway activity in heart tissue (Arimura et al. 2005, Hum Mol Genet, PMID:15548545). This model is considered a good recapitulation of human striated-muscle laminopathy (RECAPITULATES-type relationship with the human "chamber dilation and conduction defect" mechanism nodes).
Emerin (EMD) deficiency modifies the H222P phenotype differently in skeletal vs. cardiac muscle in Lmna^H222P/H222P mice, indicating tissue-specific modifier effects (PMC6701770).
Cardiac-specific Lmna-mutant mice used to study nuclear envelope rupture: pervasive nuclear envelope ruptures precede ECM/fibrotic signaling and overt disease onset, without cGAS-STING activation (PMC10491116, 2023) — a FAILS_TO_RECAPITULATE-type nuance relative to the innate-immune-activation mechanism seen in some other model systems, worth flagging as a HUMAN_MODEL_MISMATCH-relevant caveat if curated.
General Lmna-null/knockout mice (Lmna⁻/⁻) — earlier-generation models with more severe, EDMD-like phenotype and early postnatal lethality (background literature, not detailed in this search but foundational to the field).

Zebrafish Models

CRISPR/Cas9-generated lmna-knockout zebrafish: larvae show decreased heart rate versus wild-type; used to characterize cardiac performance and electrophysiology via high-resolution imaging.
Heart-specific transgenic zebrafish expressing laminopathic mutations (e.g., LMNA L35P, LMNA R453W): reduced swimming speed and muscle endurance; drug-response studies show L-carnitine rescues muscle endurance in LMNA(L35P) fish, and creatine reverses muscle endurance in LMNA(R453W) fish via AMPK/mTOR pathway activation (Sci Rep 2024, PMC11150447). A separate JACC-published zebrafish laminopathy study reported early-onset cardiac conduction dysfunction upon lamin A disruption (JACC 2020, S0735-1097(20)31330-9), directly recapitulating the human conduction-disease-first phenotype.

Human iPSC-Derived Cardiomyocyte (iPSC-CM) Models

Extensively used as the primary human-cell-based model system for CMD1A mechanism studies (IN_VITRO evidence source):
Patient-derived LMNA-mutant iPSC-CMs show nuclear morphology abnormalities (blebbing), slowed proliferation, increased cellular senescence, and increased apoptosis, all exacerbated under electrical field stimulation mimicking the cardiac mechanical/electrical environment (PMC8346174; PMC6627421).
Impaired lamin localization to the nuclear envelope and nuclear damage under mechanical/microtubule-generated forces (PMC10846625; Nat Cardiovasc Res 2025, PMC11212868).
Limitation: iPSC-CMs, despite showing DNA damage signatures, largely lack overt nuclear ruptures seen in mature adult cardiomyocytes/mouse models, likely due to an immature cytoskeleton/nucleoskeleton and rounder nuclear morphology — an explicit model-fidelity caveat (a HUMAN_MODEL_MISMATCH-relevant point: iPSC-CM immaturity limits translational fidelity for the nuclear-rupture arm specifically, even though it captures upstream DNA-damage/lamin-mislocalization phenotypes).
Lamin A/C-deficient iPSC-CM models show elevated ROS contributing to pathogenic DCM phenotypes (Nat Commun 2024).
The p.H222P mutation in human iPSC-CM-based laminopathy models shows impaired mitochondrial calcium uptake driving heart-failure-relevant phenotypes (bioRxiv 2024).

Model Resources

MGI (Mouse Genome Informatics) for Lmna mouse alleles; ZFIN for zebrafish lmna models; standard iPSC repositories/Cellosaurus-type resources for patient-derived LMNA-mutant iPSC lines (specific line accessions not enumerated in this search).

Summary Table: Key Evidence Citations

Topic	Citation	PMID/DOI
Original disease description	Fatkin et al., NEJM 1999	PMID:10580070
Penetrance/transplant burden cohort	Eur Heart J 2018	DOI:10.1093/eurheartj/ehx818
Malignant VA risk factors (van Rijsingen model)	JACC 2012	PMID:22281253
Gene-based risk stratification	Circ Cardiovasc Genet 2017	PMID:29237675
Clinical management reference	GeneReviews (Hershberger & Jordan)	PMID:20301717
Digenic LMNA/TTN modifier	Eur J Hum Genet 2013	PMID:23463027
ARRY-371797 Phase 2	Circ Genom Precis Med	(AHA journals)
REALM-DCM Phase 3 (futility)	Circ Heart Fail 2024	PMID:38979608
H222P mouse model	Arimura et al., Hum Mol Genet 2005	PMID:15548545
LGE pattern and outcomes	2025 JAHA study	PMID:40689545
ESC 2023 Cardiomyopathy Guidelines	Neth Heart J summary	DOI:10.1007/s12471-025-01955-2

Data Gaps Identified (for curator awareness)

No disease-specific quality-of-life instrument data (EQ-5D/SF-36) for CMD1A specifically.
No documented environmental/lifestyle risk-factor or gene-environment interaction studies specific to CMD1A.
De novo mutation rate, germline mosaicism, founder effects, and carrier frequency are not well quantified in the literature surveyed.
No natural (spontaneous) veterinary/wildlife disease model identified — only engineered mouse/zebrafish/iPSC systems.
PDGFRβ/imatinib and gene-therapy/ASO/CRISPR approaches remain preclinical/conceptual for this specific disease; no completed clinical trial data beyond the negative REALM-DCM p38 MAPK inhibitor trial.

Sources: - OMIM Entry #115200 — CARDIOMYOPATHY, DILATED, 1A; CMD1A - LMNA-Related Dilated Cardiomyopathy — GeneReviews® - Orphanet: Familial dilated cardiomyopathy with conduction defect due to LMNA mutation - Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation — Eur Heart J - Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers — Circ Cardiovasc Genet - Risk Factors for Malignant Ventricular Arrhythmias in Lamin A/C Mutation Carriers — PubMed - Missense mutations in the rod domain of the lamin A/C gene — NEJM - The Broad Spectrum of LMNA Cardiac Diseases — Frontiers in Physiology - The Pathogenic Mechanisms of and Novel Therapies for Lamin A/C-Related Dilated Cardiomyopathy — PMC - Mechanisms of allelic and clinical heterogeneity of lamin A/C phenotypes — PMC - LMNA cardiomyopathy: cell biology and genetics meet clinical medicine — PMC - Risk stratification in laminopathies and Emery Dreifuss muscular dystrophy — PMC - Timing of cardioverter-defibrillator implantation — external validation of LMNA-risk VTA calculator — Heart Rhythm - High-Risk Cardiomyopathy Genotypes and Arrhythmic Risk: LMNA, FLNC, RBM20, PLN — MDPI Genes 2026 - 2023 ESC guidelines on the management of cardiomyopathies — Neth Heart J - Mouse model carrying H222P-Lmna mutation — Hum Mol Genet - The Mutated p.H222P A-type Lamins Drive Loxl2-Mediated ECM Remodeling — bioRxiv 2025 - Deficiency of emerin contributes differently to pathogenesis of skeletal and cardiac muscles in LmnaH222P/H222P mice — PMC - Recent advances in animal and human pluripotent stem cell modeling of cardiac laminopathy — Stem Cell Res Ther - Nuclear damage in LMNA mutant iPSC-derived cardiomyocytes — PMC - Microtubule forces drive nuclear damage in LMNA cardiomyopathy — Nat Cardiovasc Res - Nuclear envelope rupture in cardiomyocytes orchestrates early transcriptomic changes and immune activation in LMNA-DCM — bioRxiv 2024 - Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING — PMC - Lamin A/C deficiency-mediated ROS elevation contributes to pathogenic phenotypes of DCM in iPSC model — Nat Commun 2024 - The p.H222P lamin A/C mutation induces heart failure via impaired mitochondrial calcium uptake — bioRxiv 2024 - PDGF pathway in LMNA-related dilated cardiomyopathy — Nat Rev Cardiol - Imatinib attenuates cardiac fibrosis by inhibiting PDGFR activation — PLOS ONE - REALM-DCM: Phase 3 trial of ARRY-371797 — Circ Heart Fail - Efficacy and Safety of ARRY-371797 in LMNA-Related DCM: Phase 2 Study - LMNA-related cardiomyopathy: From molecular pathology to cardiac gene therapy — PMC 2025 - Creatine and l-carnitine attenuate muscular laminopathy in LMNA mutation transgenic zebrafish — Sci Rep 2024 - Disruption of lamin A leads to early-onset cardiac conduction dysfunction in zebrafish models of laminopathy — JACC 2020 - Doubly heterozygous LMNA and TTN mutations — Eur J Hum Genet - Variant-Specific Late Gadolinium Enhancement Patterns Influence Clinical Outcomes in LMNA-Related Cardiomyopathy — JAHA 2025 - Late gadolinium enhanced CMR of lamin A/C gene mutation related DCM — J Cardiovasc Magn Reson - Sex-Related Differences in Genetic Cardiomyopathies — JAHA - LMNA Cardiomyopathy: Important Considerations for the Heart Failure Clinician — J Cardiac Failure - Testing for LMNA Gene Mutations is 'Woefully Underutilized' — Medscape - Laminopathy testing (LMNA) — NCBI GTR

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	37
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References weighed for topical relevance	36
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PMID:10580070 (abstract only): "Missense mutations in the rod domain of the lamin A/C gene provide a genetic cause for dilated cardiomyopathy and conduction-system disease... this intermediate filament protein has an important role in cardiac conduction and contractility."
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OpenScientist ▸

Dilated Cardiomyopathy 1A (DCM1A / LMNA Cardiomyopathy): Comprehensive Disease Report

openscientist-autonomous 35 citations 2026-08-18T05:20:52.539568

Dilated Cardiomyopathy 1A (DCM1A / LMNA Cardiomyopathy): Comprehensive Disease Report

Summary

Dilated Cardiomyopathy 1A (DCM1A; OMIM #115200; MONDO:0011541) is an autosomal-dominant genetic dilated cardiomyopathy caused by heterozygous pathogenic variants in LMNA, the gene encoding the nuclear-envelope intermediate filament proteins lamin A and lamin C (1q22). DCM1A is one of the most clinically malignant forms of inherited dilated cardiomyopathy (DCM) because its hallmark is an arrhythmia-first natural history: cardiac conduction disease (AV block), atrial arrhythmias (atrial fibrillation with thromboembolic risk), and life-threatening ventricular tachyarrhythmias with high sudden-cardiac-death (SCD) risk typically precede overt left-ventricular systolic dysfunction and heart failure. LMNA accounts for roughly 5–6% of DCM and carries the worst prognosis among common DCM genotypes, including the highest heart-transplantation rate (27%) in genotype-phenotype meta-analyses.

Mechanistically, DCM1A arises from a weakened, mechanically fragile nuclear lamina. Under the repetitive mechanical strain of the beating heart, lamin A/C-deficient nuclei sustain stress-induced envelope damage, which activates a DNA-damage response, disrupts chromatin organization and mechanotransduction, and dysregulates downstream signaling. Key druggable nodes identified across mouse models and patient-derived iPSC-cardiomyocytes include aberrant MAPK (ERK/JNK/p38) and AKT–mTOR/DUSP4 signaling with impaired autophagy, PDGF pathway activation driving calcium-handling arrhythmia, reactive oxygen species (ROS) elevation, and LOXL2-mediated extracellular-matrix remodeling causing fibrosis. Microtubule-dependent force transmission concentrates mechanical stress on fragile nuclei and is itself a candidate therapeutic target.

Clinical management is dominated by early, risk-guided ICD implantation (via validated risk scores such as the van Rijsingen criteria and the Wahbi LMNA-risk-VTA score), device therapy for conduction disease (pacing/CRT), guideline-directed heart-failure pharmacotherapy, anticoagulation for atrial fibrillation, exercise restriction (an actionable gene–environment interaction), and heart transplantation for end-stage disease. Cardiac MRI with late gadolinium enhancement (LGE) is a key diagnostic and prognostic biomarker. No disease-modifying therapy is approved. The lead mechanism-targeted candidate, the oral p38α-MAPK inhibitor ARRY-371797 (PF-07265803), showed promise in a 48-week phase 2 study but the confirmatory phase 3 REALM-DCM trial (NCT03439514) was terminated for futility, underscoring the gap between preclinical validation and clinical efficacy in this disease.

Section-by-Section Report

1. Disease Information

Overview. DCM1A is an inherited dilated cardiomyopathy defined by left-ventricular dilatation and systolic dysfunction in the context of a pathogenic LMNA variant, distinguished from other DCM subtypes by prominent, early electrical disease. As stated in a 2026 CMR meta-analysis, "Lamin A/C (LMNA) cardiomyopathy is an inherited form of dilated cardiomyopathy associated with high rates of arrhythmias, conduction disease and sudden cardiac death, often preceding overt heart failure" PMID: 41966904.

Key identifiers. - OMIM: #115200 (CMD1A / DCM1A); LMNA gene OMIM 150330 - MONDO: MONDO:0011541 - HGNC gene: HGNC:6636 (LMNA); NCBI Gene 4000; UniProt P02545 - ICD-10: I42.0 (dilated cardiomyopathy, parent term) - MeSH: Cardiomyopathy, Dilated (D002311); Laminopathies - Orphanet: within "Familial isolated dilated cardiomyopathy" / laminopathy spectrum

Synonyms / alternative names. LMNA-related dilated cardiomyopathy; LMNA cardiomyopathy; lamin A/C cardiomyopathy; CMD1A; DCM-CD (dilated cardiomyopathy with conduction defect). The disease sits within the broader "laminopathy" spectrum.

Information source. The evidence base is largely aggregated disease-level: OMIM/Orphanet curation, multicenter cohorts, genotype-phenotype meta-analyses, mouse models, and patient-derived iPSC studies, supplemented by individual pedigree reports.

2. Etiology

Primary cause — genetic. DCM1A is caused by heterozygous pathogenic variants in LMNA (lamin A/C), inherited in an autosomal-dominant pattern. LMNA is pleiotropic; the same gene causes a spectrum of "laminopathies": "Laminopathies are associated with a wide range of disease phenotypes, including neuromuscular, cardiac, metabolic disorders and premature aging syndromes" PMID: 27529282.

Genetic risk factors / risk stratification. Within LMNA carriers, specific features confer high arrhythmic risk. In a European cohort of 269 carriers, "Independent risk factors for MVA were nonsustained ventricular tachycardia, left ventricular ejection fraction <45% at the first clinical contact, male sex, and non-missense mutations (ins-del/truncating or mutations affecting splicing). MVA occurred only in persons with at least 2 of these risk factors" PMID: 22281253. Non-missense variants (truncating/ins-del/splice) are the highest-risk molecular class.

Environmental risk factors. Male sex is associated with higher penetrance and worse outcomes. Intense/competitive exercise is a recognized disease modifier (see Section 5 and gene–environment interaction below). Age is a major factor given age-related incomplete penetrance.

Protective factors. No established genetic protective variants are documented for DCM1A. The clearest modifiable protective actions are avoidance of intense/competitive exercise and early prophylactic device therapy.

Gene–environment interactions. Because pathophysiology is driven by mechanical stress on fragile nuclei, physical strain is biologically expected to accelerate disease. Guidelines single out LMNA (and PKP2): "The recommendations to engage in intensive exercise and competitive sports are usually contingent on annual clinical surveillance, except for pathogenic variants in specific genes, such as lamin A/C or plakophilin-2" PMID: 36929832 — restriction is advised even in genotype-positive, phenotype-negative carriers.

3. Phenotypes

DCM1A phenotypes are dominated by electrical disease preceding structural/pump failure. Quantitative frequencies from a meta-analysis of 8,097 DCM patients: "While 73 % of DCM patients with LMNA mutations showed cardiac conduction diseases, low voltage was the reported ECG hallmark in PLN mutation carriers. The frequency of ventricular arrhythmia in DCM patients with LMNA (50 %) and PLN (43 %) mutation" PMID: 27576561.

Phenotype	HPO term (suggested)	Type	Frequency	Onset / course
Cardiac conduction defect / AV block	HP:0031546 / HP:0001678	Clinical sign (ECG)	~73%	Often first sign, 3rd–4th decade; progressive
Ventricular arrhythmia / NSVT	HP:0004308 / HP:0004757	Clinical sign	~50%	Adult; high SCD risk
Atrial fibrillation	HP:0005110	Clinical sign	Common	Adult; thromboembolic risk
Dilated cardiomyopathy / reduced LVEF	HP:0001644 / HP:0001635	Physical/structural	Common, mean ~5th decade	Progressive to heart failure
Sudden cardiac death	HP:0001645	Outcome	Elevated	Adult; can precede HF
Congestive heart failure	HP:0001635	Clinical sign	Late	Progressive, end-stage
Skeletal myopathy (overlap EDMD/LGMD1B)	HP:0003198	Sign	Variable/subclinical	Childhood–adult

Characteristics. Age of onset is typically adult (mean DCM onset ~fifth decade), but conduction disease can begin in the 30s. Severity is variable but tends to be severe due to arrhythmia and SCD. Progression is progressive with superimposed episodic arrhythmic events.

Quality of life. Reduced functional capacity is measurable by 6-minute walk test and Kansas City Cardiomyopathy Questionnaire (KCCQ); actigraphy in the REALM-DCM trial confirmed reduced real-world physical activity correlating with KCCQ physical-limitation scores PMID: 41693767.

4. Genetic / Molecular Information

Causal gene. LMNA (lamin A/C; HGNC:6636; NCBI Gene 4000; UniProt P02545; chromosome 1q22; gene OMIM 150330; disease OMIM #115200). Lamin A and lamin C are produced by alternative splicing of LMNA.

Variant spectrum. In a cohort of 324 unrelated DCM patients, LMNA protein-altering variants occurred at 5.9% frequency PMID: 18585512. The variant classes: "Of the 18 alterations, 11 were missense (one present in 2 kindreds), 3 were nonsense, 3 were insertion/deletions, and 1 was a splice site alteration" PMID: 18585512 — predominantly heterozygous point mutations distributed across the rod domain and Ig-fold. Recurrent pathogenic variants reported include R190W, R644C, R377H, R89L, and a V445E Ig-fold missense associated with LV non-compaction and reduced sodium current PMID: 25829471.

Variant classification (ACMG/AMP). LMNA variants span pathogenic, likely pathogenic, and VUS in ClinVar. Non-missense (truncating/ins-del/splice) alleles confer the highest arrhythmic risk: "non-missense mutations (ins-del/truncating or mutations affecting splicing)" PMID: 22281253.

Origin. Germline; typically inherited (familial), occasionally de novo.

Functional consequence. Mixed mechanism — haploinsufficiency/loss-of-function combined with dominant-negative effects on nuclear-lamina assembly. Mutant lamin can aggregate subjacent to the nuclear envelope PMID: 25829471.

Penetrance / expressivity. Incomplete and age-related: "an incomplete and age-related penetrance" PMID: 25837155; expressivity is highly variable within families.

Modifier genes / epigenetics. LMNA-linked chromatin disorganization implies epigenetic dysregulation; specific modifier alleles are not firmly established, though pedigrees with divergent sub-family phenotypes suggest modifiers PMID: 29947763. No recurrent chromosomal abnormality defines DCM1A.

5. Environmental Information

Environmental/mechanical factors. Mechanical strain on fragile nuclei is the dominant "environmental" accelerant. Intense/competitive exercise is discouraged in LMNA carriers (see Section 2 gene–environment interaction) PMID: 36929832.
Lifestyle. Standard cardiovascular risk-factor control applies. Hypertension co-occurs frequently in DCM generally and may modulate severity.
Infectious agents. Not causal for DCM1A. Note the important differential: LMNA-DCM can mimic cardiac sarcoidosis on imaging, and endomyocardial biopsy may be equivocal — genetic testing is essential to distinguish them PMID: 40225500.

6. Mechanism / Pathophysiology

Upstream trigger — nuclear-envelope fragility. LMNA mutations weaken the nuclear lamina, increasing nuclear-envelope fragility. The causal chain is summarized as: "LMNA mutations disrupt nuclear envelope stability, activating the DNA damage response (DDR) and compromising chromatin organization and mechanotransduction" PMID: 39998502.

Mechanical force transmission. The LINC complex (nesprins/SUN proteins) couples the cytoskeleton to the lamina. Microtubule-dependent forces concentrate mechanical stress on lamin-deficient nuclei: "Microtubule disruption prevented nuclear damage and preserved cardiac function in lamin A/C deficiency" PMID: 41073815, identifying microtubule-mediated force as both driver and therapeutic target.

Downstream signaling — MAPK / AKT–mTOR / DUSP4. Aberrant ERK1/2 signaling induces DUSP4, activating AKT–mTOR and impairing autophagy: "Dusp4 expression is enhanced in hearts with LMNA cardiomyopathy, and its overexpression in mice causes it by activating AKT-mTOR signaling that impairs autophagy" PMID: 23048029.

Additional druggable nodes (iPSC-CM evidence). Patient-derived iPSC-cardiomyocytes reveal calcium-handling arrhythmia driven by PDGF: "the mutant iPSC-CMs displayed aberrant calcium homeostasis that led to arrhythmias at the single-cell level. Mechanistically, we show that the platelet-derived growth factor (PDGF) signalling pathway is activated in mutant iPSC-CMs" PMID: 31316208. ROS elevation contributes downstream PMID: 39143095, and LOXL2-mediated ECM remodeling drives fibrosis (simtuzumab as candidate inhibitor) PMID: 41841259.

Tissue damage. Myocardial fibrosis (LGE on CMR) is a central downstream lesion, correlating with wall-motion and conduction abnormalities PMID: 21689390.

Suggested GO / CL terms. GO:0006974 (DNA-damage response), GO:0071260 (cellular response to mechanical stimulus), GO:0006914 (autophagy), GO:0000165 (MAPK cascade), GO:0006979 (response to oxidative stress); CL:0000746 (cardiac muscle cell/cardiomyocyte), CL:0002548 (cardiac fibroblast).

Causal chain (ASCII):

LMNA mutation
   │
   ▼
Weakened nuclear lamina (fragile nucleus)
   │  ── microtubule / LINC-transmitted mechanical force
   ▼
Nuclear-envelope damage → DNA-damage response + chromatin/mechanotransduction disruption
   │
   ├──► ERK/JNK/p38 MAPK ↑ → DUSP4 ↑ → AKT-mTOR ↑ → autophagy ↓
   ├──► PDGF pathway ↑ → aberrant Ca²⁺ handling → single-cell arrhythmia
   ├──► ROS ↑ (oxidative stress)
   └──► LOXL2 ↑ → ECM remodeling → myocardial fibrosis (LGE)
   │
   ▼
Conduction disease + atrial/ventricular arrhythmia  (EARLY)
   │
   ▼
LV dilatation + systolic dysfunction → heart failure  (LATE)
   │
   ▼
Sudden cardiac death / transplantation

7. Anatomical Structures Affected

Primary organ: heart (UBERON:0000948), specifically myocardium/left ventricle (UBERON:0002084), cardiac conduction system (UBERON:0004146).
Secondary involvement: systemic (brain — cardioembolic stroke from AF PMID: 39687831); skeletal muscle in overlap laminopathies (paravertebral, glutei, quadriceps, posterior thigh; peroneus involvement helps distinguish EMD- from LMNA-related disease) PMID: 26573435.
Body systems: cardiovascular (primary), musculoskeletal (overlap), nervous (secondary embolic).
Tissue/cell level: cardiac muscle (striated) and conduction tissue; cardiomyocytes (CL:0000746) and cardiac fibroblasts (CL:0002548).
Subcellular: nuclear envelope/nuclear lamina (GO:0005638 nuclear membrane; GO:0005652 nuclear lamina), nucleus (GO:0005634); secondary involvement of the microtubule cytoskeleton (GO:0005874).
Laterality: left-ventricle predominant, biventricular in advanced disease.

8. Temporal Development

Onset: adult-onset predominantly; conduction disease may begin in the 3rd–4th decade, with DCM manifesting on average in the 5th decade. Insidious then progressive.
Progression / stages: early = isolated conduction disease / arrhythmia; intermediate = LV dilatation with declining EF; advanced/end-stage = refractory heart failure requiring transplant. Natural history is progressive with superimposed episodic arrhythmic events. A five-generation pedigree documented sinus bradycardia/AV block I° at ~36.5 yr → paroxysmal then permanent AF → NSVT/SCD, with 17 SCDs at mean age 49.3 yr PMID: 29947763.
Patterns: no spontaneous remission; disease is chronic and lifelong. Critical intervention windows exist for prophylactic ICD (before first malignant arrhythmia) and early CRT in conduction disease PMID: 38495409.

9. Inheritance and Population

Epidemiology. DCM overall affects ~1 in 2,500; LMNA accounts for ~5–6% of DCM (5.9% in a 324-proband cohort PMID: 18585512; 7.5% familial vs 3.6% idiopathic in Parks 2008).
Inheritance pattern: autosomal dominant.
Penetrance: incomplete, age-related PMID: 25837155.
Expressivity: highly variable, even within families/pedigrees PMID: 29947763.
Natural history/survival: markedly worse than non-carrier DCM — "event-free survival at the age of 45 years was 31% versus 75% in non-carriers" PMID: 12628721.
Sex ratio: male-biased penetrance; DCM overall M:F ~2.4:1, and even among genotype-positive DCM: "similar to patients with an identified DCM variant (0.31 [95% CI, 0.26-0.36]; M:F 2.22:1" PMID: 39895490. Male sex is itself an arrhythmic risk factor.
Founder effects / consanguinity: not a prominent feature (dominant disease); no strong founder population documented. The concept of "carrier frequency" for a dominant pathogenic variant maps to population variant prevalence — ~0.7% of general-population cohorts harbor any actionable inherited-cardiomyopathy variant across 13 genes PMID: 35544052.

10. Diagnostics

Clinical/functional tests. - ECG / Holter: first-line — detects AV block, bradyarrhythmia, AF, NSVT (LOINC ECG panels). - Echocardiography: LV dilatation, reduced EF. - Cardiac MRI with LGE: key diagnostic/prognostic biomarker. "Patients had LV myocardial fibrosis in 88% of cases. Segmental wall motion abnormalities correlated strongly with the degree of enhancement. Myocardial enhancement was associated with conduction abnormalities" PMID: 21689390. Meta-analysis: "The LGE risk ratio for patients with LMNA cardiomyopathy versus healthy controls was 14.39 (P<0.001)" PMID: 41966904. Subclinical parametric-mapping changes (prolonged native T1/T2) are present even with preserved EF PMID: 40372342. - Biomarkers: NT-proBNP tracks heart-failure severity and treatment response. - Biopsy: endomyocardial biopsy may be equivocal and is not required; caution against relying on imaging alone when sarcoidosis is in the differential PMID: 40225500.

Genetic testing. Central to diagnosis. Approach: DCM multigene panel or whole-exome sequencing including LMNA; single-gene/cascade testing in families with a known variant. Genetic testing enables accurate etiologic diagnosis, treatment (early ICD), and cascade screening of relatives PMID: 40225500, PMID: 29497013.

Differential diagnosis. Cardiac sarcoidosis (imaging mimic), other genetic DCM (TTN, FLNC, RBM20, PLN, DSP), arrhythmogenic cardiomyopathy, ischemic cardiomyopathy.

Screening. Cascade genetic testing plus serial ECG/Holter/echo/CMR surveillance of at-risk relatives.

11. Outcome / Prognosis

DCM1A has among the worst prognoses of genetic DCM.

Prognostic metric	Value	Source
Event-free survival at age 45 (carriers)	31% vs 75% non-carriers	PMID: 12628721
Cardiac conduction disease frequency	~73%	PMID: 27576561
Ventricular arrhythmia frequency	~50%	PMID: 27576561
Heart-transplant rate (highest of DCM genes)	27%	PMID: 27576561
LTVTA incidence in carriers	19.3–23.4%	PMID: 31155932

Prognostic factors / risk models. Two validated tools guide ICD decisions: - van Rijsingen criteria — malignant ventricular arrhythmia (MVA) occurs only with ≥2 of: NSVT, LVEF<45%, male sex, non-missense mutation PMID: 22281253. - Wahbi LMNA-risk-VTA score (n=839): "Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction"; C-index 0.776–0.800; available as an online calculator PMID: 31155932.

Mortality/morbidity. High SCD risk (often preceding heart failure), progressive heart failure, and thromboembolic stroke from AF. LGE burden is prognostic.

12. Treatment

Standard of care = guideline heart-failure therapy + device therapy + anticoagulation + transplant, with no approved disease-modifying drug.

Pharmacotherapy (NCIT interventions): ACE inhibitors/ARB/ARNI, beta-blockers, mineralocorticoid-receptor antagonists (guideline-directed HF therapy); anticoagulation for AF (stroke prevention).
Device therapy: ICD for SCD prevention (lower threshold than general DCM, guided by risk scores); pacemaker/CRT for conduction disease. Early CRT may preserve EF and delay end-stage HF in LMNA carriers with a pacing/ICD indication PMID: 38495409.
Surgical: heart transplantation for end-stage disease (highest rate among DCM genotypes).
Mechanism-targeted (experimental). The p38α-MAPK inhibitor ARRY-371797 (PF-07265803): "ARRY-371797 (PF-07265803), a potent, selective, oral, small-molecule inhibitor of the p38α mitogen-activated protein kinase pathway, improved 6-minute walk test (6MWT) distance in 12 patients with symptomatic LMNA-related DCM in a 48-week, open-label, phase 2 study" PMID: 36114020, with reduced NT-proBNP and improved KCCQ PMID: 36718638. However, "REALM-DCM was terminated after a planned interim analysis suggested futility" PMID: 38979608 (phase 3, NCT03439514).
Emerging preclinical targets: JNK/ERK inhibition, microtubule modulation, PDGFRB inhibition, antioxidants (ROS), and LOXL2 inhibition (simtuzumab) — all validated in models but not yet clinically established.

Personalized medicine. Genotype (non-missense vs missense) and the risk scores directly guide ICD timing and exercise counseling.

13. Prevention

Primary prevention: cannot prevent inheritance of a dominant variant; genetic counseling and reproductive options (PGD/prenatal testing) apply.
Secondary prevention: cascade genetic screening of relatives + serial cardiac surveillance (ECG/Holter/echo/CMR) to detect subclinical disease early. CMR parametric mapping can detect preclinical involvement PMID: 40372342.
Tertiary prevention: early/prophylactic ICD to prevent SCD (risk-score guided); anticoagulation to prevent stroke; exercise restriction to slow progression PMID: 36929832; guideline HF therapy to prevent decompensation.
Counseling: genetic counseling for risk assessment and family planning is a cornerstone.

14. Other Species / Natural Disease

Taxonomy / orthologs: human LMNA (NCBI Gene 4000); mouse Lmna (NCBI Gene 16905); orthologs conserved across mammals. Disease mechanisms (nuclear-envelope biology, LINC complex) are evolutionarily conserved.
Natural disease in other species: LMNA/laminopathy-type dilated cardiomyopathy is chiefly modeled experimentally rather than reported as a common spontaneous companion-animal disease; comparative relevance is largely via engineered models. (No specific spontaneous animal disease was confirmed in this investigation.)
Zoonotic potential: none — genetic, non-transmissible.

15. Model Organisms

Mouse models (mammalian). - Lmna^H222P/H222P knock-in — the workhorse autosomal EDMD/DCM model. ERK and JNK MAPK branches are abnormally activated in the heart; pharmacologic inhibition improves cardiac structure/function and fibrosis: "Echocardiography and histological analysis demonstrated that treatment prevented left ventricular end-systolic dilatation, increased ejection fraction, and decreased myocardial fibrosis" PMID: 21173351. ERK inhibition (PD98059) PMID: 18927124, JNK inhibition (SP600125) PMID: 20388542, and genetic Erk1 deletion PMID: 23933734 all improved outcomes. Emerin/Lmna double mutants dissect skeletal- vs cardiac-muscle contributions PMID: 31430335. - Other alleles: Lmna N195K, LMNA knockout — cardiac conduction/hemodynamic phenotypes.

Cellular / in vitro (iPSC-CMs). Patient-derived iPSC-cardiomyocytes recapitulate arrhythmia via aberrant Ca²⁺ handling and PDGF activation PMID: 31316208; frameshift-LMNA iPSC models show ROS-driven pathology PMID: 39143095 and LOXL2/ECM remodeling PMID: 41841259.

Phenotype recapitulation. Mouse models reproduce DCM, fibrosis, and MAPK activation well; iPSC-CMs capture cell-autonomous arrhythmia. Key limitation: MAPK inhibition rescued mice but the corresponding human phase 3 (REALM-DCM) failed PMID: 38979608 — a cautionary example of imperfect translational fidelity.

Mechanistic Model / Interpretation

DCM1A is best understood as a mechanotransduction disease of the cardiomyocyte nucleus. The primary defect — a structurally weakened nuclear lamina — renders the nucleus vulnerable to the relentless mechanical strain of cardiac contraction. Force is transmitted to the nucleus via the microtubule cytoskeleton and the LINC complex; where lamin A/C is deficient, this force produces stress concentrations and physical envelope damage. The cell responds with a DNA-damage response and pathological signaling — chiefly MAPK (ERK/JNK/p38) feeding DUSP4→AKT–mTOR with impaired autophagy, plus PDGF-driven calcium mishandling, ROS, and LOXL2-driven fibrosis.

Two clinical corollaries follow directly from this model. First, the arrhythmia-first phenotype reflects the special vulnerability of the conduction system and the arrhythmogenic consequences of Ca²⁺ dysregulation and progressive fibrosis, which manifest electrically before pump failure. Second, the exercise-restriction recommendation is a rational, mechanism-derived intervention: reducing mechanical load reduces nuclear damage. The therapeutic disappointment of p38α inhibition despite strong mouse data suggests that MAPK is one downstream branch of a multi-nodal network; targeting the upstream mechanical driver (microtubules/LINC) or rational combinations (PDGFRB, LOXL2, ROS) may be required.

Evidence Base

PMID	Role in report	Support / challenge
41966904	Disease definition; LGE prognostic	Supports arrhythmia-first course; LGE RR 14.39
39998502	Phenotype spectrum; mechanism	Supports NE/DDR/mechanotransduction chain
22281253	Risk stratification	Supports van Rijsingen ≥2-factor rule
31155932	Risk score	Supports LMNA-risk-VTA (C-index 0.78–0.80)
18585512	Epidemiology/genetics	LMNA 5.9% of DCM; variant classes
12628721	Natural history	31% vs 75% event-free survival
39895490	Sex ratio	Male bias M:F 2.22:1
23048029	Mechanism	DUSP4–AKT-mTOR–autophagy
41073815	Mechanism/therapy	Microtubule force as driver/target
36114020	Therapy phase 2	p38α inhibitor 6MWT benefit
38979608	Therapy phase 3	Challenges MAPK strategy (futility)
21689390	Diagnostics	88% LGE fibrosis; ties to conduction
27529282	Pleiotropy	Laminopathy spectrum
27576561	Phenotype frequencies	73% conduction, 50% VA, 27% HTx
36929832	Gene–environment	Exercise restriction for LMNA
31316208	iPSC mechanism	PDGF/Ca²⁺ arrhythmia
21173351	Mouse model	MAPK inhibition rescues phenotype
25837155	Genetics	Incomplete, age-related penetrance

Limitations and Knowledge Gaps

Translational gap: The most striking limitation is that the leading mechanism-targeted therapy (p38α inhibitor) succeeded in mice and phase 2 but failed phase 3 (REALM-DCM), leaving no approved disease-modifying drug and questioning MAPK as a sufficient single target.
Small trial sizes: Phase 2 (n=12) and phase 3 (n=77) were small for a rare disease, limiting statistical power and generalizability.
Risk-model refinement: van Rijsingen and Wahbi scores are validated but derived largely from European cohorts; performance across ancestries and in genotype-positive/phenotype-negative carriers needs broader validation.
Penetrance/modifiers: Incomplete, age-related penetrance and variable expressivity remain poorly explained; specific genetic/epigenetic modifiers are not established.
Epidemiology precision: Exact population prevalence/incidence of DCM1A specifically (vs DCM overall) is not firmly quantified; carrier-frequency data derive from broad multigene screens.
Animal disease: Spontaneous natural DCM1A in non-human species is not well documented in this investigation.

Proposed Follow-up Experiments / Actions

Combination-target trials: Test rational combinations (e.g., MAPK + PDGFRB inhibition, or microtubule/LINC modulation + anti-fibrotic LOXL2 inhibition) in iPSC-CM and Lmna^H222P models before human trials, given the single-node p38 failure.
Upstream mechanical targeting: Pursue microtubule-directed or LINC-complex therapeutics that reduce nuclear mechanical damage at the source [PMID: 41073815].
Anti-fibrotic strategy: Advance LOXL2 inhibition (simtuzumab) evaluation informed by CMR-LGE endpoints as a biomarker [PMID: 41841259].
Biomarker-guided prevention trials: Use subclinical CMR (native T1/T2) to enroll genotype-positive/phenotype-negative carriers into early-intervention/prevention studies [PMID: 40372342].
Prospective risk-model validation: Validate LMNA-risk-VTA and van Rijsingen scores across diverse ancestries and integrate CMR-LGE quantitatively.
Registry/natural-history studies: Establish LMNA-specific registries to refine prevalence, penetrance, sex effects, and modifier discovery.
Exercise-intervention evidence: Prospectively test the effect of activity restriction on disease progression to move the recommendation from mechanistic inference to evidence-based guideline.

Report compiled from a 5-iteration autonomous investigation: 13 confirmed findings, 46 papers reviewed. Evidence types span human clinical cohorts, genotype-phenotype meta-analyses, mouse knock-in models, and patient-derived iPSC-cardiomyocyte studies.

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Outcome	Count
References checked	35
Resolved	35
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	35
On topic	31
Off topic	0

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Classifications

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Biochemical Markers

Diagnosis

Imaging Findings

Progression

Prevalence

Differential Diagnoses

Related Datasets

Clinical Trials

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Dilated Cardiomyopathy 1A (LMNA-Related Dilated Cardiomyopathy): Comprehensive Research Report

1. Disease Information

2. Etiology

Disease Causal Factors

Genetic Risk Factors

Environmental/Non-genetic Risk Factors

Protective Factors

Gene-Environment Interactions

3. Phenotypes

Cardiac electrical phenotypes (typically first to manifest)

Structural/functional cardiac phenotypes

Extracardiac/skeletal muscle phenotypes (variable, overlapping laminopathy spectrum)

Phenotype characteristics

Quality of life impact

4. Genetic/Molecular Information

Causal Gene

Pathogenic Variants

Modifier Genes

Epigenetic Information

Chromosomal Abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

a) Mechanical/structural nuclear fragility → nuclear envelope rupture

b) Chromatin/gene-expression dysregulation

c) Signaling pathway activation

d) Mitochondrial dysfunction and oxidative stress

e) Extracellular matrix remodeling / fibrosis

Causal chain summary

Cell types and biological processes involved

Molecular profiling (omics)

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

Epidemiology

Inheritance Pattern

Population Demographics

10. Diagnostics

Clinical/Laboratory Tests

Genetic Testing

Clinical Criteria and Differential Diagnosis

Screening

11. Outcome/Prognosis

Survival and Mortality

Morbidity/Complications

Prognostic Factors / Risk Stratification

Quality of Life

12. Treatment

Pharmacotherapy (Guideline-Directed Medical Therapy for Heart Failure)

Device Therapy (Disease-Defining Intervention)

Advanced/Surgical Therapy

Investigational/Targeted Therapeutics

Treatment Outcomes/Strategy

13. Prevention