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Classifications

Harrison's Part

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Inheritance

1

Autosomal dominant HP:0000006

CMD1W is transmitted as an autosomal dominant trait and affected individuals are heterozygous; ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel records autosomal dominant inheritance for the VCL-dilated cardiomyopathy relationship. Penetrance is the qualification that matters most for this entry. Family studies of predicted loss-of-function alleles repeatedly identify unaffected heterozygous parents, and the aggregate analysis concluded that heterozygous VCL loss of function on its own is insufficient to produce cardiomyopathy. The metavinculin-specific missense and in-frame alleles have not been shown to behave the same way, and the two classes should not be assumed to share a penetrance.

Autosomal dominant inheritance Penetrance: INCOMPLETE

Show evidence (3 references)

CGGV:assertion_2d46699a-5f8c-460d-9233-bec4e2ecf560-2024-08-09T160000.000Z SUPPORT Other

ClinGen records autosomal dominant inheritance for this gene-disease relationship, which is the authority for the mode of inheritance asserted here.

PMID:32516855 SUPPORT Human Clinical

"The lack of clear segregation data confirms that VCL pLOF variants do not cause a phenotype with a highly penetrant autosomal dominant pattern of inheritance"

States directly that the loss-of-function alleles do not behave as a highly penetrant dominant trait, which is what INCOMPLETE penetrance records here.

PMID:32516855 SUPPORT Human Clinical

"Family studies demonstrated that heterozygous loss of function of VCL alone is insufficient to cause cardiomyopathy but that these variants do contribute to disease risk."

The family-study conclusion behind the reduced-penetrance qualification on this inheritance block.

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Mechanistic Hypotheses

3

Metavinculin tail alleles act by qualitatively altered actin cross-linking

metavinculin_altered_actin_crosslinking CANONICAL

Evidence balance 1 support

The founding CMD1W alleles p.Arg975Trp and p.Leu954del lie in the metavinculin-specific exon and are not dosage lesions. They change how metavinculin cross-links actin filaments, which is a qualitative change in the behaviour of a protein that is still present, and their effect is confined to the muscle-specific isoform. This is the model under which force transmission at the thin filament-intercalated disc interface is disrupted without vinculin being lost.

Pathograph links

Metavinculin Tail Variant Altering Actin Cross-Linking -> Impaired Vinculin-Actin Coupling at Cardiomyocyte Adhesion Complexes DIRECT The mutant metavinculin is expressed and incorporated, but cross-links actin filaments abnormally.

Show evidence (1 reference)

PMID:11815424 SUPPORT In Vitro

"significantly altered metavinculin-mediated cross-linking of actin filaments in an in vitro assay"

The functional measurement the hypothesis rests on: the alleles change actin cross-linking rather than abolishing the protein.

VCL loss-of-function alleles act as moderate-penetrance risk alleles requiring a second contribution

vcl_plof_reduced_penetrance_risk_allele CANONICAL

Evidence balance 2 support

Predicted loss-of-function alleles affect both the vinculin and the metavinculin transcripts and are strongly enriched in dilated cardiomyopathy referrals, but they are frequently inherited from unaffected parents and co-occur with variants in other cardiomyopathy genes. The best-supported reading is that they raise risk rather than determine disease, and that expression requires an additional genetic or environmental contribution. This is why the historical Mendelian label CMD1W should not be read as asserting that every heterozygous VCL variant is causal.

Pathograph links

VCL Predicted Loss-of-Function Allele -> Impaired Vinculin-Actin Coupling at Cardiomyocyte Adhesion Complexes DIRECT Reduced vinculin and metavinculin dosage leaves fewer functional links between filamentous actin and the adhesion complexes.

VCL Predicted Loss-of-Function Allele -> Additional Genetic or Environmental Stressor UNKNOWN This is not a causal step so much as a statement of what the allele does not do on its own: a second contribution is required before the phenotype appears, which is why unaffected heterozygous parents are routinely found.

Additional Genetic or Environmental Stressor -> Ventricular Dilation and Systolic Dysfunction INDIRECT UNKNOWN INTERMEDIATES Only when the additional contribution is present does the reduced-vinculin myocardium go on to dilate and fail.

Show evidence (2 references)

PMID:32516855 SUPPORT Human Clinical

"Overall, the data are most consistent with VCL pLOF variants acting as genetic modifiers that can lead to more severe disease or the precipitation of disease in the presence of additional risk factors, such as other genetic and/or environmental contributions."

The study's own statement of this model, drawn from the aggregated family studies.

PMID:32516855 SUPPORT Human Clinical

"VCL loss-of-function variants should be reported in a diagnostic setting but need to be clearly distinguished as having lower penetrance."

The reporting recommendation that follows from treating these as risk alleles.

Infantile dependence on vinculin explains early onset and later recovery

infantile_adhesion_immaturity_recovery EMERGING

Evidence balance 2 support

Proposed explanation for the two features that distinguish the loss-of-function phenotype: onset concentrated in infancy, and frequent normalization of ventricular function thereafter. If vinculin haploinsufficiency matters most while intercalated disc adhesion is still maturing, then the same allele would be more disruptive in infancy and less so once vinculin has localized into a mature disc. Supporting evidence that adhesion remodeling is a developmentally timed, vinculin-dependent process comes from the mouse; the human claim is an inference from a six-patient series and is not established.

Pathograph links

Heart Failure with Reduced Ejection Fraction -> Reverse Remodeling with Recovered Ejection Fraction INDIRECT UNKNOWN INTERMEDIATES On heart failure therapy, most infants in the only genotype-defined series exited this node rather than progressing. The intermediates are unknown; the proposed explanation is developmental.

Show evidence (2 references)

PMID:37548861 SUPPORT INDIRECT Human Clinical

"It is possible that vinculin haploinsufficiency may be more disruptive in infancy when E-cadherin is still immature."

The authors state the hypothesis explicitly, and label it as a possibility rather than a finding; the observation it is built on is the recovery of five of six infants.

PMID:41231303 SUPPORT INDIRECT Model Organism

"VCL Y822 phosphorylation levels peaked during adhesion remodeling in the developing heart and were reduced as adhesions matured postnatally."

Independent demonstration in mouse that vinculin-dependent adhesion remodeling is developmentally timed, which is the premise the human hypothesis needs. It does not show that this timing explains the human recovery.

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Discussions and Knowledge Gaps

3

Is there any VCL-directed therapeutic development for CMD1W, and if not, what would a trial-ready endpoint look like in a phenotype that frequently recovers on standard therapy?

KNOWLEDGE GAP OPEN no_vcl_directed_therapy_or_trial

Attached to

treatments#

A ClinicalTrials.gov search on 2026-09-03 for "vinculin" returned zero studies, and a search restricted to dilated cardiomyopathy with the term "VCL gene" also returned zero. No clinical_trials block is curated for this entry because there is nothing to curate, and the absence is recorded here rather than left as a silent gap. Every treatment in this entry acts on the expressed heart failure phenotype, not on the adhesion lesion. The design problem specific to CMD1W is that the most common natural course under standard therapy is recovery, so a genotype-targeted agent would have to beat an already favourable comparator in a very small population.

What is the prevalence, incidence and survival of CMD1W as an entity, as opposed to the carrier frequency of VCL variants?

KNOWLEDGE GAP OPEN no_subtype_specific_epidemiology_or_survival

Attached to

prevalence#

Everything currently quotable is either a reference-population variant frequency or a variant yield inside a testing cohort. Neither is a disease rate, and with a reduced-penetrance allele the gap between the two is large and unmeasured. There is no CMD1W survival curve; the contemporary dilated cardiomyopathy registry outcome data cited in this entry's notes are all-cause and cannot be assigned to this genotype. The six-patient infant series is the only genotype-defined outcome dataset in existence and its 83% recovery figure must not be read as a population estimate.

Why does cardiomyocyte-specific vinculin loss kill half of knockout mice by sudden arrhythmic death before three months, while human VCL loss-of-function carriers present predominantly with recoverable heart failure and only occasional conduction disease?

HUMAN MODEL MISMATCH OPEN mouse_arrhythmic_severity_versus_human_phenotype

Attached to

pathophysiology#Ventricular Arrhythmia and Conduction Disease pathophysiology#Connexin 43 Lateralization and Conduction Slowing

The mouse evidence for the electrical branch is strong and direct: connexin 43 moves to the lateral border, optical mapping shows defective conduction, telemetry documents ventricular tachycardia, and 49% die suddenly with contractile function still preserved. The human picture does not match that severity. Among 32 VCL loss-of-function probands only three had bradycardia or heart block and one had supraventricular tachycardia, and current practice is explicitly that a VCL variant does not by itself justify a defibrillator the way an LMNA or FLNC variant does, a position curated with its citation as the Implantable Cardioverter-Defibrillator treatment. The most likely explanation is dosage - the mouse is a complete cardiomyocyte-restricted null and human carriers are heterozygous - but that has not been demonstrated, and until it is, the arrhythmic node in this entry rests on a model whose translational validity to human CMD1W is the open question. This matters clinically, because it is the difference between an arrhythmia-first genotype and a heart-failure-first one.

Proposed experiments

Arrhythmic phenotyping of heterozygous Vcl mice under mechanical stress

in vivo dosage-comparison and stress-challenge experiment

heterozygous_vcl_arrhythmic_phenotyping

Telemetry and optical mapping in heterozygous rather than homozygous cardiomyocyte Vcl-deficient animals, at baseline and after a defined pressure-overload or inflammatory stress, to test whether the arrhythmic phenotype is a dosage effect and whether it requires a second hit in the way the human phenotype appears to.

Readouts

Spontaneous ventricular arrhythmia burden on telemetry

pathophysiology#Ventricular Arrhythmia and Conduction Disease

Direction: INCREASED

Interpretation: A low unstressed burden that rises only after the applied stress would support the second-hit reading and explain the human-mouse gap.

Connexin 43 distribution at the intercalated disc

pathophysiology#Connexin 43 Lateralization and Conduction Slowing

Direction: ALTERED

Interpretation: Whether lateralization occurs at half dosage at all, and if so whether it is stress-dependent.

Would support

pathophysiology#Ventricular Arrhythmia and Conduction Disease

Supporting outcome

Heterozygous animals show connexin 43 lateralization and an arrhythmic burden only after imposed stress, matching the reduced-penetrance human pattern.

Refuting outcome

Heterozygous animals show a severe unstressed arrhythmic phenotype comparable to the homozygous knockout, which would leave the human-mouse discrepancy unexplained by dosage and point instead at a species difference in cardiac electrophysiology.

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Pathophysiology

11

Metavinculin Tail Variant Altering Actin Cross-Linking

Mechanism confidence: Established

The founding CMD1W lesion is a heterozygous variant in the metavinculin-specific exon of VCL: the missense allele p.Arg975Trp or the three-base-pair in-frame deletion p.Leu954del. Because the affected exon is spliced only into metavinculin, these alleles perturb the heart and smooth muscle isoform while leaving ubiquitous vinculin intact. Both involve conserved residues and were absent from 500 control individuals. This is a qualitative change in a protein that is still expressed, which is what separates this node from the loss-of-function node below.

Metavinculin tail alleles act by qualitatively altered actin cross-linking

Cardiomyocyte CL:0000746

VCL hgnc:12665

Genetic context VCL hgnc:12665 allele_type: metavinculin-specific missense or in-frame deletion variant_origin: GERMLINE zygosity: HETEROZYGOUS

Heterozygous germline alleles in the metavinculin-specific exon. No functional impact category is asserted: the measured effect is altered actin cross-linking, which the schema's FunctionalImpactEnum does not cleanly represent, and neither dominant-negative nor simple loss of function has been established for these alleles.

Downstream

Impaired Vinculin-Actin Coupling at Cardiomyocyte Adhesion Complexes The mutant metavinculin is expressed and incorporated, but cross-links actin filaments abnormally.

Show evidence (2 references)

PMID:11815424 SUPPORT Human Clinical

"One missense mutation (Arg975Trp) and one 3-bp deletion (Leu954del) were identified."

Names the two founding alleles, found by screening the metavinculin-specific exon in 350 unrelated dilated cardiomyopathy patients.

PMID:37548861 SUPPORT Other

"Vinculin is a ubiquitously expressed protein encoded by the VCL gene with a larger splice isoform, metavinculin, exclusively expressed in cardiac and smooth muscle."

Establishes the isoform restriction that makes a metavinculin-exon allele a muscle-specific lesion. This is a background statement of established cell biology, not a result of the cited series.

VCL Predicted Loss-of-Function Allele

Mechanism confidence: Provisional

The second and numerically larger allelic class is heterozygous predicted loss of function: nonsense, frameshift, canonical splice-site and one multi-exon duplication. Unlike the metavinculin-exon alleles these hit both VCL transcripts, so they reduce vinculin as well as metavinculin, and haploinsufficiency is the leading model for those expected to undergo nonsense-mediated decay. Confidence is recorded as PROVISIONAL rather than ESTABLISHED because the class is enriched in dilated cardiomyopathy but is not sufficient on its own to produce it, and most individual alleles remain variants of uncertain significance.

VCL loss-of-function alleles act as moderate-penetrance risk alleles requiring a second contribution

Cardiomyocyte CL:0000746

VCL hgnc:12665

Genetic context VCL hgnc:12665 allele_type: nonsense, frameshift, canonical splice-site, multi-exon duplication variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Heterozygous germline predicted loss-of-function alleles affecting both the NM_014000.2 and NM_003373.3 transcripts, so both vinculin and metavinculin are reduced.

Downstream

Impaired Vinculin-Actin Coupling at Cardiomyocyte Adhesion Complexes Reduced vinculin and metavinculin dosage leaves fewer functional links between filamentous actin and the adhesion complexes.

Additional Genetic or Environmental Stressor This is not a causal step so much as a statement of what the allele does not do on its own: a second contribution is required before the phenotype appears, which is why unaffected heterozygous parents are routinely found.

Show evidence (3 references)

PMID:32516855 SUPPORT Human Clinical

"Variants identified included six affecting canonical splice sites, twelve nonsense variants, seven frameshift variants, and one multi exon duplication."

The variant classes that make up this node, from the 26 unique alleles found across 18,135 cardiomyopathy referrals.

PMID:32516855 SUPPORT Human Clinical

"All variants except for the p.Pro943Argfs*9 variant were present in both the NM_014000.2 and NM_003373.3 transcripts."

Establishes that this allelic class is not metavinculin-restricted, which is the distinction from the node above.

PMID:32516855 SUPPORT Human Clinical

"identified 32 probands with VCL loss-of-function variants and confirmed enrichment in probands with dilated cardiomyopathy"

The case-control enrichment (odds ratio 9.01, CI 4.93 to 16.45) that justifies treating this class as disease-relevant at all.

Additional Genetic or Environmental Stressor

Mechanism confidence: Hypothetical

The second contribution the loss-of-function class appears to need. In the aggregated families this took the form of co-occurring rare variants in other cardiomyopathy genes (MYH7, DSP, TPM1, LAMA4, SCN5A, MYBPC3); one segregation study found that only relatives heterozygous for both the VCL allele and a TPM1 missense variant were affected. A non-genetic stressor such as viral myocarditis is proposed as an alternative route but has not been measured in VCL carriers. The node is recorded as HYPOTHETICAL because no specific second hit has been established, only the requirement for one.

VCL loss-of-function alleles act as moderate-penetrance risk alleles requiring a second contribution

Cardiomyocyte CL:0000746

Downstream

Ventricular Dilation and Systolic Dysfunction Only when the additional contribution is present does the reduced-vinculin myocardium go on to dilate and fail.

Show evidence (2 references)

PMID:32516855 SUPPORT Human Clinical

"It is conceivable that this is the result of a gene-environment interaction, such that disease is more likely to occur in the setting of non-genetic stressors (e.g. viral myocarditis)."

The environmental arm of the second-hit requirement, stated by the authors as a conjecture rather than a measured interaction.

PMID:33983834 SUPPORT INDIRECT Human Clinical

"preliminary data from our studies and others suggests that at least 20% to 30% of DCM may have an oligogenic basis, meaning that multiple rare variants from different, unlinked loci, determine the DCM phenotype"

Places the CMD1W second-hit observation inside the wider oligogenic architecture of dilated cardiomyopathy. Indirect because it is a statement about dilated cardiomyopathy generally, not about VCL carriers.

Impaired Vinculin-Actin Coupling at Cardiomyocyte Adhesion Complexes

Both allelic classes converge here. Vinculin is the mechanosensitive adaptor that links filamentous actin to the cadherin-catenin complexes of the adherens junction and to the integrin-talin complexes of the costamere; metavinculin does the same job in cardiac and smooth muscle. Whether the protein is present but cross-links actin abnormally, or is simply reduced in amount, the consequence at this node is the same: the actin cytoskeleton is less securely coupled to the adhesion machinery.

Cardiomyocyte CL:0000746

Actin filament bundle assembly GO:0051017 ⚠ ABNORMAL

Actin filament binding by vinculin and metavinculin GO:0051015 ↓ DECREASED

Adherens junction GO:0005912 Costamere GO:0043034 Focal adhesion GO:0005925

Animal models

Vinculin Y822F knock-in mouse Mouse perturbs Perturbs vinculin-dependent adhesion coupling through loss of a regulatory phosphosite, showing that the coupling is dynamically regulated rather than static.

Downstream

Intercalated Disc and Costamere Destabilization Junctions that cannot hold the actin cytoskeleton lose their structural integrity.

Show evidence (2 references)

PMID:41231303 SUPPORT Other

"Vinculin (VCL), a mechanosensitive adaptor protein, links filamentous actin to cell-matrix and cell-cell adhesions."

States the coupling function whose impairment defines this node. Background statement of established cell biology rather than a result of the cited study.

PMID:17785437 SUPPORT Other

"In myocytes, it is localized in protein complexes which anchor the contractile apparatus to the sarcolemma."

Locates the coupling specifically at the myocyte sarcolemma, which is where the costamere component of this node sits.

Intercalated Disc and Costamere Destabilization

The structural lesion of CMD1W. Adherens junctions become abnormal and the intercalated disc dissolves; cadherin and beta1D integrin fall at the junction. In the mouse this precedes any measurable contractile deficit, which places the junctional change upstream of the pump failure rather than as a consequence of it. The one human patient examined by electron microscopy, a p.Arg975Trp carrier, had grossly abnormal intercalated discs.

Cardiomyocyte CL:0000746

Cell adhesion at the intercalated disc and costamere GO:0007155 ↓ DECREASED

Intercalated disc GO:0014704 Costamere GO:0043034

Myocardium UBERON:0002349

Animal models

Cardiomyocyte-specific vinculin knockout mouse Mouse recapitulates Directly demonstrates that removing vinculin from cardiomyocytes destabilizes both the cell-cell and the cell-matrix adhesion structures, and does so before contractile function falls.

Downstream

Defective Force Transmission Across the Intercalated Disc A dissolved disc cannot carry contractile force between adjoining myocytes.

Connexin 43 Lateralization and Conduction Slowing Loss of disc organization displaces the gap junction protein from its intercalated disc position to the lateral myocyte border.

Show evidence (2 references)

PMID:11815424 SUPPORT Human Clinical

"Ultrastructural examination was performed in one patient (Arg975Trp), revealing grossly abnormal intercalated discs."

The only human ultrastructural observation for this entity, and the reason the junctional lesion is not solely a mouse claim. It is a single patient.

PMID:17785437 SUPPORT Model Organism

"Prior to the onset of cardiac dysfunction, ultrastructural analysis of cVclKO heart tissue showed abnormal adherens junctions with dissolution of the intercalated disc structure, expression of the junctional proteins cadherin and beta1D integrin were reduced, and the gap junction protein..."

Establishes both the junctional lesion and, crucially, its timing before contractile dysfunction.

Connexin 43 Lateralization and Conduction Slowing

The electrical branch of the mechanism. Gap junctions displaced from the intercalated disc to the lateral cell border make conduction heterogeneous. In the cardiomyocyte knockout mouse this produced defective myocardial conduction on optical mapping and ventricular tachycardia on conscious telemetry, and it did so while contractile function was still preserved. The human counterpart is the conduction and arrhythmia phenotypes seen in a minority of VCL loss-of-function probands; direct human connexin 43 data are not available.

Cardiomyocyte CL:0000746

Electrical coupling in cardiac conduction GO:0086064 ↓ DECREASED

Gap junction GO:0005921

Animal models

Cardiomyocyte-specific vinculin knockout mouse Mouse recapitulates Provides the electrophysiological demonstration that the junctional lesion slows conduction and generates ventricular tachycardia.

Downstream

Ventricular Arrhythmia and Conduction Disease Heterogeneous conduction is the substrate for the arrhythmic phenotype.

Show evidence (1 reference)

PMID:17785437 SUPPORT Model Organism

"Conscious telemetry documented ventricular tachycardia as the cause of sudden death, while defective myocardial conduction was detected by optical mapping."

Direct electrophysiological demonstration of the conduction defect and the arrhythmia it produces in the vinculin-null myocardium.

Ventricular Arrhythmia and Conduction Disease

The arrhythmic arm of the phenotype. In the mouse it is severe and precedes pump failure: 49% of cardiomyocyte-knockout animals died suddenly before 3 months with preserved contractile function. In humans the arrhythmic and conduction phenotypes are a minority finding among VCL loss-of-function probands, and there is no evidence that a VCL variant on its own warrants a defibrillator the way an LMNA or FLNC variant does; that management position is curated with its citation as the Implantable Cardioverter-Defibrillator treatment. The gap between the mouse severity and the human picture is recorded as a human-model mismatch below.

Cardiomyocyte CL:0000746

Downstream

Bradycardia and Heart Block

Supraventricular Tachycardia

Show evidence (2 references)

PMID:17785437 SUPPORT Model Organism

"Sudden death was found in 49% of the knockout (cVclKO) mice younger than 3 months of age despite preservation of contractile function."

Establishes arrhythmic death as an independent consequence of vinculin loss, not a byproduct of a failing pump.

PMID:32516855 SUPPORT Human Clinical

"The remainder (n=13, 40.6%, Table 4) had other cardiac phenotypes including LVNC (n=2), HCM or LVH (n=3), unspecified cardiomyopathy (n=3), abnormal echo with family history of DCM (n=1), bradycardia and heart block (n=3), and supraventricular tachycardia, tuberous sclerosis, and rhabdomyoma (n=1)."

The human conduction and arrhythmia phenotypes, at the frequencies observed among VCL loss-of-function probands referred for cardiomyopathy testing.

Defective Force Transmission Across the Intercalated Disc

The defining lesion of CMD1W and the reason it is not simply another sarcomeric cardiomyopathy. The sarcomere still generates force; that force is no longer transmitted efficiently between myocytes or out to the extracellular matrix. Because the deficit is in transmission rather than generation, the myocardium is functionally uncoupled even where individual myocytes contract normally.

Cardiomyocyte CL:0000746

Cardiac muscle cell contraction GO:0086003 ↓ DECREASED

Intercalated disc GO:0014704

Myocardium UBERON:0002349

Downstream

Ventricular Dilation and Systolic Dysfunction Chronic failure to transmit force drives chamber enlargement and falling ejection fraction.

Show evidence (2 references)

PMID:11815424 SUPPORT Other

"Vinculin and its isoform metavinculin are protein components of intercalated discs, structures that anchor thin filaments and transmit contractile force between cardiac myocytes."

States the function of the structure whose failure this node names. Background statement of established anatomy rather than a result of the cited study.

PMID:37548861 SUPPORT Other

"Vinculin links the actin cytoskeleton to the cell membrane which is critical in force transmission and is needed to maintain cardiomyocyte function"

Independent statement that force transmission is the vinculin-dependent function at stake. Background statement, not a result of the cited series.

Ventricular Dilation and Systolic Dysfunction

The structural endpoint: left ventricular or biventricular dilation with reduced systolic function, diagnosed after excluding ischemic, loading, valvular and congenital causes. In the genotype-defined infant series the dilation was extreme, at a median end-diastolic diameter z-score of 10.8 with a median ejection fraction of 24%, and all six also showed ventricular hypertrophy and T-wave abnormalities.

Cardiomyocyte CL:0000746 Cardiac fibroblast CL:0002548

Heart contraction GO:0060047 ↓ DECREASED

Left ventricle UBERON:0002084

Animal models

Cardiomyocyte-specific vinculin knockout mouse Mouse recapitulates Knockout animals surviving the arrhythmic period went on to develop dilated cardiomyopathy, closing the chain from adhesion failure to chamber dilation.

Downstream

Heart Failure with Reduced Ejection Fraction

Dilated cardiomyopathy

Show evidence (2 references)

PMID:37548861 SUPPORT Human Clinical

"All patients showed LV dilation and dysfunction on echocardiograms and LV or biventricular hypertrophy and T wave abnormalities on electrocardiogram."

Documents the structural and electrical findings in every patient of the genotype-defined series.

PMID:32516855 SUPPORT Human Clinical

"The most common cardiac phenotype was DCM or left ventricular dilation (n=19, 59.4%, Table 3)."

Establishes dilation with systolic dysfunction as the dominant phenotype among VCL loss-of-function probands.

Heart Failure with Reduced Ejection Fraction

The clinical syndrome the dilated, hypocontractile ventricle produces. In infancy this presents as poor feeding, breathlessness and failure to thrive; in advanced disease it requires mechanical support or transplantation. Unusually for a genetic cardiomyopathy, this node has a well-documented reversible exit in the VCL loss-of-function series.

Infantile dependence on vinculin explains early onset and later recovery

Cardiomyocyte CL:0000746

Heart contraction GO:0060047 ⚠ ABNORMAL

Downstream

Congestive Heart Failure

Reverse Remodeling with Recovered Ejection Fraction On heart failure therapy, most infants in the only genotype-defined series exited this node rather than progressing. The intermediates are unknown; the proposed explanation is developmental.

Show evidence (1 reference)

PMID:37548861 SUPPORT Human Clinical

"This case series identified a unique phenotype of HF with reduced ejection fraction at presentation that evolved to HF with recovered EF in over 80% of infant DCM cases with LOF VCL variants."

Names the syndrome at presentation and its usual evolution in this genotype.

Reverse Remodeling with Recovered Ejection Fraction

Mechanism confidence: Hypothetical

Normalization of left ventricular systolic function after an infantile presentation with severe dysfunction. This is the feature that most distinguishes CMD1W from the other numbered dilated cardiomyopathies and it is why the entity has been proposed as a genetic basis for heart failure with recovered ejection fraction. Two cautions are curated with it: recovery is not resolution, since guideline authors are explicit that improved ejection fraction does not mean the cardiomyopathic process has resolved and that therapy should continue; and one patient in the series relapsed after medications were withdrawn. The mechanism is unknown, with the developmental explanation recorded as an emerging hypothesis rather than a finding.

Cardiomyocyte CL:0000746

Heart contraction GO:0060047 ↑ INCREASED

Show evidence (1 reference)

PMID:37653361 SUPPORT Other

"improvement does not necessarily represent normalization of LV function or resolution of the cardiomyopathic process and highlights the importance of continuing treatment as per HFrEF recommendations to prevent deterioration in symptomatic status or LVEF"

The guideline position that stops this node being read as cure. Graded OTHER because the cited article is a comparison of two society guidelines, not a study.

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Pathograph

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

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Phenotypes

8

Cardiovascular 7

Dilated cardiomyopathy FREQUENT HP:0001644

Show evidence (1 reference)

PMID:32516855 SUPPORT Human Clinical

"The most common cardiac phenotype was DCM or left ventricular dilation (n=19, 59.4%, Table 3)."

Gives both the phenotype and the 59.4% share that the FREQUENT band records.

Reduced left ventricular ejection fraction HP:0012664

Severity: SEVERE

Show evidence (1 reference)

PMID:37548861 SUPPORT Human Clinical

"Median age at diagnosis was 2 months, median LV ejection fraction was 24%, and median LV end-diastolic diameter z-score was 10.8."

Quantifies the systolic impairment at presentation in the genotype-defined series.

Congestive Heart Failure HP:0001635

Sequelae: Reverse Remodeling with Recovered Ejection Fraction

Show evidence (1 reference)

PMID:37548861 SUPPORT Human Clinical

"This case series identified a unique phenotype of HF with reduced ejection fraction at presentation that evolved to HF with recovered EF in over 80% of infant DCM cases with LOF VCL variants."

Establishes heart failure as the presenting syndrome in the genotype-defined series.

Left ventricular noncompaction OCCASIONAL HP:0030682

Show evidence (2 references)

PMID:32516855 SUPPORT Human Clinical

"The remainder (n=13, 40.6%, Table 4) had other cardiac phenotypes including LVNC (n=2), HCM or LVH (n=3), unspecified cardiomyopathy (n=3), abnormal echo with family history of DCM (n=1), bradycardia and heart block (n=3), and supraventricular tachycardia, tuberous sclerosis, and rhabdomyoma (n=1)."

Source of the 2 of 32 count for noncompaction among loss-of-function probands.

PMID:37548861 SUPPORT Human Clinical

"She was diagnosed at 6 months with DCM with LV non-compaction"

Independent observation of noncompaction alongside dilation in a VCL loss-of-function infant.

Left ventricular hypertrophy OCCASIONAL HP:0001712

Show evidence (1 reference)

PMID:32516855 SUPPORT Human Clinical

"The remainder (n=13, 40.6%, Table 4) had other cardiac phenotypes including LVNC (n=2), HCM or LVH (n=3), unspecified cardiomyopathy (n=3), abnormal echo with family history of DCM (n=1), bradycardia and heart block (n=3), and supraventricular tachycardia, tuberous sclerosis, and rhabdomyoma (n=1)."

Source of the 3 of 32 count for hypertrophic cardiomyopathy or left ventricular hypertrophy among loss-of-function probands.

Bradycardia and Heart Block OCCASIONAL Atrioventricular block HP:0001678

Show evidence (1 reference)

PMID:32516855 SUPPORT Human Clinical

"The remainder (n=13, 40.6%, Table 4) had other cardiac phenotypes including LVNC (n=2), HCM or LVH (n=3), unspecified cardiomyopathy (n=3), abnormal echo with family history of DCM (n=1), bradycardia and heart block (n=3), and supraventricular tachycardia, tuberous sclerosis, and rhabdomyoma (n=1)."

Source of the 3 of 32 count for bradycardia and heart block.

Supraventricular Tachycardia VERY_RARE HP:0004755

Show evidence (1 reference)

PMID:32516855 SUPPORT Human Clinical

"The remainder (n=13, 40.6%, Table 4) had other cardiac phenotypes including LVNC (n=2), HCM or LVH (n=3), unspecified cardiomyopathy (n=3), abnormal echo with family history of DCM (n=1), bradycardia and heart block (n=3), and supraventricular tachycardia, tuberous sclerosis, and rhabdomyoma (n=1)."

Source of the single supraventricular tachycardia proband.

Digestive 1

Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:37548861 SUPPORT Human Clinical

"Patient Ia presented at 5.5 months of age with poor feeding and breathlessness."

Single-patient observation, recorded as such: this is a case description, not a cohort frequency.

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Genetic Associations

2

VCL

Gene: VCL hgnc:12665 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (5 references)

CGGV:assertion_2d46699a-5f8c-460d-9233-bec4e2ecf560-2024-08-09T160000.000Z SUPPORT Other

ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies this gene-disease relationship as Strong under SOP10, which is the authority for curating VCL as CAUSATIVE rather than a candidate gene.

PMID:11815424 SUPPORT Human Clinical

"These data provide genetic and functional evidence for vinculin as a DCM gene and suggest that metavinculin plays a critical role in cardiac structure and function."

The founding gene-disease claim, resting on the metavinculin-exon alleles and their functional characterization.

PMID:32516855 SUPPORT Human Clinical

"identified 32 probands with VCL loss-of-function variants and confirmed enrichment in probands with dilated cardiomyopathy"

Case-control enrichment of the loss-of-function class in dilated cardiomyopathy, odds ratio 9.01 with confidence interval 4.93 to 16.45.

+ 2 more references

MYBPC3

Gene: MYBPC3 hgnc:7551 relationship_type: MODIFIER variant_origin: GERMLINE

Show evidence (1 reference)

PMID:24062880 SUPPORT Human Clinical

"More severely affected family members also possess a second missense variant in MYBPC3, raising the possibility that this variant may be a disease modifier."

The observation behind the MODIFIER relationship, in a family carrying VCL p.Lys815Arg. The authors state it as a possibility, and one family cannot establish modification.

🔬

Variants

4

VCL p.Arg975Trp

Gene: VCL hgnc:12665 missense

Missense allele in the metavinculin-specific exon, one of the two founding CMD1W variants. It involves a conserved residue, was absent from 500 controls, and altered metavinculin-mediated actin cross-linking in vitro. The carrier is the only CMD1W patient with published cardiac ultrastructure, which showed grossly abnormal intercalated discs.

Show evidence (1 reference)

PMID:11815424 SUPPORT Human Clinical

"Ultrastructural examination was performed in one patient (Arg975Trp), revealing grossly abnormal intercalated discs."

Ties this specific allele to the human intercalated disc lesion.

VCL p.Leu954del

Gene: VCL hgnc:12665 inframe deletion

Three-base-pair in-frame deletion in the metavinculin-specific exon, the second founding CMD1W allele. Like p.Arg975Trp it removes a conserved residue, was absent from 500 controls, and altered actin cross-linking in vitro.

Show evidence (1 reference)

PMID:11815424 SUPPORT Human Clinical

"One missense mutation (Arg975Trp) and one 3-bp deletion (Leu954del) were identified."

Names the allele as one of the two identified in the founding screen.

VCL p.Lys815Arg

Gene: VCL hgnc:12665 missense

Missense allele reported in a family with dilated cardiomyopathy and congenital defects including bicuspid aortic valve. It sits outside the metavinculin-specific exon. The more severely affected relatives also carried MYBPC3 p.Arg177Cys, so this family is a worked example of the second-hit pattern rather than of a sufficient VCL allele.

Show evidence (1 reference)

PMID:24062880 SUPPORT Human Clinical

"In this report, we describe a family with DCM and congenital abnormalities who carry a novel missense mutation in the VCL gene."

Establishes the allele and the family it was reported in.

VCL p.Arg547* Uncertain Significance

Gene: VCL hgnc:12665 nonsense

Nonsense allele (c.1639C>T) carried by two siblings in the genotype-defined infant series, both of whom recovered ventricular function. It was inherited from a mother with a normal echocardiogram, and was reclassified from likely pathogenic to a variant of uncertain significance by the reporting laboratory. It is the clearest single illustration of why this allelic class is curated as risk-conferring rather than determinative.

Show evidence (1 reference)

PMID:37548861 SUPPORT Human Clinical

"Variants were classified by the clinical laboratory as a VUS in 5 patients and likely pathogenic in one (patient IV)."

Supports the uncertain classification recorded here; patient Ia, who carried this allele, was among the five reported as uncertain.

💊

Medical Actions

6

Heart Failure Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: ACE inhibitor NCIT:C247 beta-adrenergic antagonist NCIT:C29576 angiotensin receptor-neprilysin inhibitor NCIT:C190796 mineralocorticoid receptor antagonist NCIT:C101255 SGLT2 inhibitor NCIT:C98083 loop diuretic NCIT:C49184

Platform: Small molecule

Guideline-directed therapy for heart failure with reduced ejection fraction, applied to the expressed phenotype. There is no VCL-directed treatment. Contemporary HFrEF guidance rests on four pillars: renin-angiotensin system inhibition (an ACE inhibitor, an ARB, or an angiotensin receptor-neprilysin inhibitor), beta-blockade, a mineralocorticoid receptor antagonist, and an SGLT2 inhibitor, with a loop diuretic added for congestion. What the genotype-defined series documents is narrower. Every infant in it received an ACE inhibitor and a beta-blocker, and five of six recovered ventricular function; the series was uncontrolled, so it establishes what was given, not that the drugs caused the recovery. The MRA, SGLT2 inhibitor and ARNI agents curated below are quoted from adult HFrEF guidance and record the standard of care the expressed phenotype is managed under; they are not therapy documented in that infant cohort. Guideline authors are explicit that improved ejection fraction does not license stopping therapy, and the one patient in the series who was weaned off medication relapsed and needed it restarted.

Mechanism Target:

MODULATES Heart Failure with Reduced Ejection Fraction — Neurohormonal blockade acts on the failing-ventricle syndrome, not on the vinculin lesion upstream of it.

Show evidence (1 reference)

PMID:37548861 SUPPORT INDIRECT Human Clinical

"All patients received an angiotensin-converting enzyme (ACE) inhibitor and a beta-blocker."

Records the regimen every patient received. Indirect for the treatment-effect claim because the series had no control arm, so the association between therapy and recovery is not causal evidence.

Show evidence (6 references)

PMID:37653361 SUPPORT Other

"improvement does not necessarily represent normalization of LV function or resolution of the cardiomyopathic process and highlights the importance of continuing treatment as per HFrEF recommendations to prevent deterioration in symptomatic status or LVEF"

The basis for continuing therapy after ejection fraction recovers, which is the management question this genotype raises most often.

PMID:37653361 SUPPORT Other

"The four pillars of HF management (RAAS inhibition, beta-blockade, MRA, and SGLT2i) should be initiated in all patients with HFrEF as tolerated."

Names the four drug classes that constitute guideline-directed therapy for the expressed HFrEF phenotype, and is why this node carries an MRA and an SGLT2 inhibitor alongside the ACE inhibitor and beta-blocker the infant series recorded.

PMID:37653361 SUPPORT Other

"Inhibition of the RAAS is recommended to reduce morbidity and mortality, with both ACC/AHA/HFSA and ESC guidelines recommending an ARNi as first-line therapy in hospitalized patients with acute HF or following a trial of an ACEi or ARB in outpatients to ensure the patient tolerates RAAS inhibition."

Places the angiotensin receptor-neprilysin inhibitor within the renin-angiotensin-system arm of the regimen, which is why ARNI is curated as a therapeutic agent alongside the ACE inhibitor rather than instead of it.

+ 3 more references

Implantable Cardioverter-Defibrillator

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

Platform: Device

Primary-prevention defibrillator implantation for the expressed heart failure phenotype. The indication in CMD1W is the ordinary HFrEF one, resting on ejection fraction, symptoms and response to optimal medical therapy, and the genotype does not lower the threshold. Only a small number of cardiomyopathy genes carry a genotype-specific device recommendation, LMNA being the worked example, and VCL is not among them. That is the clinically load-bearing negative in this entry: the murine phenotype is arrhythmia-first and lethal, the human phenotype is heart-failure-first and frequently recoverable, and the mouse severity is recorded as a human-model mismatch rather than translated into a device indication.

Mechanism Target:

INHIBITS Ventricular Arrhythmia and Conduction Disease — The device terminates a sustained ventricular arrhythmia once it starts; it leaves the conduction substrate that generates the arrhythmia untouched.

Show evidence (2 references)

PMID:37653361 SUPPORT Other

"For primary prevention, regardless of etiology, the ACC/AHA/HFSA guidelines strongly recommend an ICD to reduce the risk of SCD and all-cause mortality in patients with symptomatic HFrEF of ischemic or non-ischemic etiology, with an LVEF ≤ 35% despite ≥ 3 months of optimal medical management if..."

The primary-prevention indication that applies to a CMD1W patient, stated in terms of ejection fraction, symptoms and duration of optimal medical therapy rather than of genotype.

PMID:39519012 SUPPORT INDIRECT Human Clinical

"Hence, LMNA cardiomyopathy constitutes one of the few genotype-specific evidenced-based guideline recommendations in the cardiomyopathies."

Supports the claim that a VCL variant does not by itself justify a defibrillator. Indirect: the quote establishes that genotype-specific device recommendations exist for only a few cardiomyopathy genes and names LMNA as the exemplar, and the VCL claim follows from VCL not being one of them rather than from a statement about VCL.

Cardiac Resynchronization Therapy

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

Platform: Device

Biventricular pacing for the subset with persistent symptomatic systolic dysfunction and electrical dyssynchrony after optimal medical therapy. As with the defibrillator, the indication is the conventional electrical and functional one and is not modified by VCL genotype. It is included because conduction disease is a documented minority finding in VCL loss-of-function probands, so the dyssynchrony pathway is reachable in this entry even though it is not the usual course.

Mechanism Target:

MODULATES Heart Failure with Reduced Ejection Fraction — Recoordinating right and left ventricular activation improves pump efficiency without acting on the adhesion lesion or on force transmission at the intercalated disc.

Show evidence (1 reference)

PMID:37653361 SUPPORT Other

"Cardiac resynchronization therapy (CRT) is strongly recommended for symptomatic patients (NYHA class II-IV on best medical management) who have LVEF ≤ 35%, sinus rhythm, left bundle branch block (LBBB) with a QRS of ≥ 150 ms to reduce total mortality and hospitalizations, and improve symptoms..."

The indication criteria, which are ejection fraction, rhythm and QRS morphology. None of them reference genotype.

Ventricular Assist Device Support

Action: ventricular assist device placement Ontology label: Ventricular Assist Device Placement NCIT:C80452

Platform: Device

Mechanical circulatory support for decompensated end-stage failure, used here as the bridge to transplantation. It is curated because the genotype-defined series contains exactly one such course: the single infant who did not recover ventricular function went to a left ventricular assist device at 7 months and transplantation at 10 months, which is the counterexample to the recoverable phenotype the other five patients define.

Mechanism Target:

BYPASSES Heart Failure with Reduced Ejection Fraction — The pump substitutes for ventricular ejection rather than restoring it, so the failing myocardium is worked around rather than repaired.

Show evidence (1 reference)

PMID:37548861 SUPPORT Human Clinical

"Patient V who was diagnosed with severe DCM at age 4 months progressed to decompensated HF requiring a LV assist device at age 7 months and a heart transplant at age 10 months."

Documents assist-device support and its timing within the genotype-defined series, which is the clinical course this treatment describes.

Heart Transplantation

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

Platform: Surgery

Reserved for refractory end-stage failure. One of the six infants in the genotype-defined series progressed to a ventricular assist device at 7 months and transplantation at 10 months, so the recoverable phenotype is not universal.

Mechanism Target:

BYPASSES Heart Failure with Reduced Ejection Fraction — Replacing the organ removes the diseased myocardium rather than correcting the adhesion lesion.

Show evidence (1 reference)

PMID:37548861 SUPPORT Human Clinical

"One patient progressed to end-stage HF requiring heart transplant."

Documents transplantation as an outcome within the genotype-defined series.

Genetic Counseling and Family Screening

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Cascade genetic testing and clinical screening of first-degree relatives, with the reduced penetrance of VCL loss-of-function alleles stated explicitly. A VCL variant of uncertain significance should not drive predictive testing or irreversible management, and most VCL loss-of-function alleles assessed by clinical laboratories are of uncertain significance. Clinical screening rather than genotype alone carries the weight here, because up to a fifth of apparently asymptomatic relatives across dilated cardiomyopathy cohorts already have overt disease at first assessment.

Show evidence (3 references)

PMID:39519012 SUPPORT Human Clinical

"There is also consensus across guidelines to offer cascade genetic screening and genetic counseling to first-degree relatives of patients with genetic DCM"

The guideline basis for offering cascade screening in a genetic dilated cardiomyopathy.

PMID:39519012 SUPPORT Human Clinical

"At the time of initial evaluation in seemingly asymptomatic relatives, up to 20% will be found to have overt DCM, with an age-dependent increase in prevalence"

Quantifies the yield of clinical screening of relatives, which is why screening is not deferred pending variant reclassification.

PMID:32516855 SUPPORT Human Clinical

"Current practice across clinical laboratories is to classify novel VCL pLOF variants as variants of uncertain significance"

The reason a VCL result usually cannot carry predictive weight on its own in a counseling setting.

🔬

Diagnosis

5

Transthoracic echocardiography

The study that establishes the dilated cardiomyopathy phenotype and defines it quantitatively, before any question of VCL sequencing arises. It is also the instrument through which the recovery phenotype of this genotype is observed and followed: every infant in the genotype-defined series was characterized on echocardiography at diagnosis, and the normalization of ventricular function in five of six was measured the same way.

transthoracic echocardiography NCIT:C16525

Show evidence (3 references)

PMID:33652931 SUPPORT Other

"A full diagnostic work-up for DCM typically includes a focused history, laboratory evaluation, electrocardiography (ECG), Holter monitoring, echocardiography, CMR (with late gadolinium enhancement (LGE)), and genetic testing"

Places echocardiography inside the standard dilated cardiomyopathy work-up alongside the genetic testing this entry already curates.

PMID:33652931 SUPPORT Other

"DCM is considered in the presence of (1) left ventricular dilatation (indexed left ventricular end-diastolic diameter (LVEDd) >117% for age and sex, or the LV end-diastolic volume (LVEDV) ≥2 standard deviations from normal according to normograms), and (2) left ventricular systolic dysfunction..."

The diagnostic thresholds themselves. Both limbs are echocardiographic measurements, which is why this modality and not genetic testing is what makes the diagnosis.

PMID:37548861 SUPPORT Human Clinical

"All patients showed LV dilation and dysfunction on echocardiograms and LV or biventricular hypertrophy and T wave abnormalities on electrocardiogram."

Records that the echocardiographic finding in the genotype-defined VCL series was left ventricular dilation and dysfunction, which is what the modality contributes in this specific disease.

Cardiac magnetic resonance with late gadolinium enhancement

Tissue characterization added to the echocardiographic diagnosis. Late gadolinium enhancement identifies replacement fibrosis and carries prognostic weight in dilated cardiomyopathy generally. No CMD1W-specific enhancement pattern has been described, so the modality is curated at the level the source supports, which is the general dilated cardiomyopathy work-up and risk assessment rather than a VCL signature.

cardiac magnetic resonance imaging with late gadolinium enhancement NCIT:C137915

Show evidence (2 references)

PMID:33652931 SUPPORT Other

"A full diagnostic work-up for DCM typically includes a focused history, laboratory evaluation, electrocardiography (ECG), Holter monitoring, echocardiography, CMR (with late gadolinium enhancement (LGE)), and genetic testing"

Places cardiac magnetic resonance with late gadolinium enhancement in the standard dilated cardiomyopathy work-up.

PMID:33652931 SUPPORT Other

"The use of clinically granular investigations, such as late gadolinium enhancement on cardiac magnetic resonance imaging, is warranted in order to increase predictive performance."

The reason the study is done rather than deferred, which is that it adds information risk models built on ejection fraction alone do not carry.

Electrocardiography

Baseline rhythm and conduction assessment. It matters more in this entry than the disease-level work-up alone would suggest, because bradycardia, heart block and supraventricular tachycardia are documented minority findings in VCL loss-of-function probands, and because the infant series recorded a consistent abnormal electrocardiogram at presentation.

electrocardiography NCIT:C38053

Show evidence (2 references)

PMID:33652931 SUPPORT Other

"A full diagnostic work-up for DCM typically includes a focused history, laboratory evaluation, electrocardiography (ECG), Holter monitoring, echocardiography, CMR (with late gadolinium enhancement (LGE)), and genetic testing"

Places electrocardiography in the standard dilated cardiomyopathy work-up.

PMID:37548861 SUPPORT Human Clinical

"All patients showed LV dilation and dysfunction on echocardiograms and LV or biventricular hypertrophy and T wave abnormalities on electrocardiogram."

The electrocardiographic findings actually observed in the genotype-defined VCL series, which is what this modality contributes here beyond generic screening.

Ambulatory (Holter) rhythm monitoring

Extended rhythm recording, which is what detects the intermittent conduction and tachyarrhythmia findings that a single resting tracing misses. It is the diagnostic counterpart of the arrhythmic branch of this entry's pathograph, and it is the measurement that would be needed to say whether the severe arrhythmic phenotype of the murine model has any quiet human counterpart.

ambulatory Holter electrocardiographic monitoring NCIT:C38064

Show evidence (1 reference)

PMID:33652931 SUPPORT Other

"A full diagnostic work-up for DCM typically includes a focused history, laboratory evaluation, electrocardiography (ECG), Holter monitoring, echocardiography, CMR (with late gadolinium enhancement (LGE)), and genetic testing"

Places Holter monitoring in the standard dilated cardiomyopathy work-up as a distinct study from the resting electrocardiogram.

Cardiomyopathy multigene panel including VCL

Genetic testing for CMD1W is done through a curated cardiomyopathy next-generation sequencing panel that includes VCL with copy-number analysis, since one of the reported allele classes is a multi-exon duplication. Two interpretive cautions are specific to this gene. Most VCL loss-of-function alleles are reported as variants of uncertain significance, so a positive result usually cannot be used for predictive cascade testing on its own. And uptake of testing is the binding constraint in practice rather than panel content: dilated cardiomyopathy has the lowest genetic testing rate of the guideline-indicated cardiovascular diagnoses.

Show evidence (2 references)

PMID:37915745 SUPPORT Human Clinical

"At 0.8%, the DCM cohort demonstrated the lowest utilization of genetic testing."

Quantifies the implementation gap: 827 of 101,919 newly diagnosed dilated cardiomyopathy patients had recorded genetic testing.

PMID:32516855 SUPPORT Human Clinical

"Current practice across clinical laboratories is to classify novel VCL pLOF variants as variants of uncertain significance"

The interpretive caution that governs how a positive VCL panel result can be used.

📈

Progression

2

Infantile presentation with severe systolic dysfunction

Age: Median 2 months at diagnosis in the genotype-defined series

Presentation in the loss-of-function series was in early infancy with severe ventricular dilation and depressed ejection fraction.

Show evidence (1 reference)

PMID:37548861 SUPPORT Human Clinical

"Median age at diagnosis was 2 months, median LV ejection fraction was 24%, and median LV end-diastolic diameter z-score was 10.8."

Gives the age and severity at presentation that define this phase.

Recovery of ventricular function on heart failure therapy

Age: Median 2.7 years at recovery

Five of six infants normalized left ventricular function 0.3 to 3.2 years after diagnosis while on an ACE inhibitor and a beta-blocker; one progressed to end-stage failure and transplantation. Six patients is not a natural history, and one patient in the series relapsed after medications were stopped and recovered again on re-treatment.

Show evidence (2 references)

PMID:37548861 SUPPORT Human Clinical

"Five patients (83%) showed normalization of LV function at a median age of 2.7 years."

Establishes the recovery phase and its timing.

PMID:37548861 SUPPORT Human Clinical

"One patient progressed to end-stage HF requiring heart transplant."

Records that recovery is not universal, so this phase is not an expected outcome.

📊

Prevalence

2

Worldwide

Unknown Not yet documented

No prevalence or incidence estimate exists for CMD1W as an entity. Reported frequencies are either variant carrier frequencies in reference populations or variant yields within cardiomyopathy testing cohorts, and neither is a disease rate, because penetrance of the loss-of-function class is low and variant interpretation is unsettled. The two records below are recorded as what they are rather than being promoted into a prevalence figure.

gnomAD v2.1 exomes reference population

Carrier Frequency 46.0 per 100,000 1–9 per 10,000 (carriers)

Frequency of VCL predicted loss-of-function alleles among reference-population individuals (58/125,297), after excluding variants predicted to escape nonsense-mediated decay. This is a variant carrier frequency, not a CMD1W prevalence: the same study concludes the alleles are not highly penetrant, so most carriers are not expected to be affected.

Show evidence (1 reference)

PMID:32516855 SUPPORT Human Clinical

"This equated to a prevalence of VCL pLOF variants of 0.00046 (58/125,297) in individuals in gnomAD"

Source of the 0.00046 reference-population carrier frequency, normalized here to 46 per 100,000.

🧫

Experimental Models

1

ZZUNEUi026-A patient-derived iPSC line IPSC_DERIVED_MODEL

The only published patient-derived cellular resource for a VCL dilated cardiomyopathy genotype. It is characterized as a stem cell line - pluripotency markers, normal karyotype, three-germ-layer differentiation - and no disease phenotyping was reported, so it is deliberately recorded without modeled_mechanisms. Making it informative for any pathophysiology node would require an isogenic corrected control and a cardiomyocyte or engineered-heart-tissue readout; neither exists. The resource paper also does not establish that p.Met209Leu is pathogenic.

Organism

human NCBITaxon:9606

Cell source

Peripheral blood mononuclear cells from a 65-year-old man with dilated cardiomyopathy carrying heterozygous VCL c.625A>T (p.Met209Leu), reprogrammed with non-integrating Sendai virus.

Publication

PMID:35567849

Show evidence (2 references)

PMID:35567849 SUPPORT In Vitro

"A human induced pluripotent stem cell (iPSC) line (ZZUNEUi026-A) was generated from a DCM patient carrying heterozygous Vinculin mutant"

Establishes the line and its genotype of origin.

PMID:35567849 SUPPORT In Vitro

"ZZUNEUi026-A showed pluripotency markers and normal karyotype, and it could differentiate into three germ layers in vitro."

The full extent of the reported characterization: stem cell quality control, no disease phenotype.

🐁

Animal Models

2

Cardiomyocyte-specific vinculin knockout mouse

The reference in vivo model for CMD1W mechanism. Cre-loxP excision of Vcl in cardiomyocytes produced adherens junction abnormalities, intercalated disc dissolution, reduced cadherin and beta1D integrin, and lateral connexin 43 mislocalization, all before any contractile deficit. Half the animals then died suddenly of ventricular tachycardia in the first three months with preserved contractile function, and the survivors developed dilated cardiomyopathy.

Species

Mouse

Genotype

Vcl conditional knockout, Cre-loxP cardiomyocyte-specific excision

Genes

VCL hgnc:12665

Publication

PMID:17785437

Pathograph links

Intercalated Disc and Costamere Destabilization recapitulates fidelity: moderate Directly demonstrates that removing vinculin from cardiomyocytes destabilizes both the cell-cell and the cell-matrix adhesion structures, and does so before contractile function falls.

Limitations: A complete cardiomyocyte-restricted null, not the heterozygous state that human carriers have, so the magnitude and the timing are both expected to overstate the human lesion. It also models the loss-of-function allelic class only; the metavinculin-tail alleles are not a dosage lesion and are not represented.

Readouts

Intercalated disc ultrastructure

Direction: ALTERED

Interpretation: Dissolution of the disc structure on electron microscopy is the structural correlate of this node.

Show evidence (1 reference)

PMID:17785437 SUPPORT Model Organism

"Prior to the onset of cardiac dysfunction, ultrastructural analysis of cVclKO heart tissue showed abnormal adherens junctions with dissolution of the intercalated disc structure, expression of the junctional proteins cadherin and beta1D integrin were reduced, and the gap junction protein..."

Reports the ultrastructural measurement behind this readout.

Show evidence (1 reference)

PMID:17785437 SUPPORT Model Organism

"shows that it is required for preservation of normal cell-cell and cell-matrix adhesive structures"

Supports treating this model as informative for the junctional node.

Connexin 43 Lateralization and Conduction Slowing recapitulates fidelity: moderate Provides the electrophysiological demonstration that the junctional lesion slows conduction and generates ventricular tachycardia.

Limitations: Murine cardiac electrophysiology differs substantially from human, and the model is a complete null. Human VCL carriers show conduction disease at low frequency and no genotype-specific defibrillator indication is established, so the arrhythmic severity here does not transfer.

Readouts

Myocardial conduction by optical mapping

Direction: DECREASED

Interpretation: Defective conduction on optical mapping is the functional correlate of the displaced gap junctions.

Show evidence (1 reference)

PMID:17785437 SUPPORT Model Organism

"Conscious telemetry documented ventricular tachycardia as the cause of sudden death, while defective myocardial conduction was detected by optical mapping."

Reports the conduction measurement behind this readout.

Ventricular Dilation and Systolic Dysfunction recapitulates fidelity: moderate Knockout animals surviving the arrhythmic period went on to develop dilated cardiomyopathy, closing the chain from adhesion failure to chamber dilation.

Limitations: The dilated phenotype appears only in the survivors of a lethal arrhythmic phase that has no human counterpart at this frequency, and the time course is compressed into six months.

Readouts

Development of dilated cardiomyopathy in survivors

Direction: INCREASED

Interpretation: Onset of dilated cardiomyopathy in the surviving knockouts is the phenotypic correlate of this node.

Show evidence (1 reference)

PMID:17785437 SUPPORT Model Organism

"cVclKO mice that survived through the vulnerable period of sudden death developed dilated cardiomyopathy and died before 6 months of age."

Reports the phenotypic outcome behind this readout.

Vinculin Y822F knock-in mouse

A mechanism-probing allele rather than a disease model. Substituting phenylalanine for tyrosine at vinculin residue 822 removes a phosphorylation site whose occupancy peaks while cardiac adhesions are remodeling and rises again after adult cardiac injury. Homozygous mice are viable and develop cardiac dysfunction by 28 weeks, and cultured mutant cardiomyocytes show disorganized cell-cell adhesion. Y822F is not a reported human CMD1W allele.

Species

Mouse

Genotype

Vcl Y822F homozygous knock-in

Genes

VCL hgnc:12665

Publication

PMID:41231303

Pathograph links

Impaired Vinculin-Actin Coupling at Cardiomyocyte Adhesion Complexes perturbs fidelity: low Perturbs vinculin-dependent adhesion coupling through loss of a regulatory phosphosite, showing that the coupling is dynamically regulated rather than static.

Limitations: Y822F is an engineered allele that has not been reported in a human patient, and the mice are homozygous where human carriers are heterozygous. It bears on how vinculin coupling is regulated, not on how a CMD1W variant behaves.

Readouts

Cardiomyocyte cell-cell adhesion organization

Direction: ALTERED

Interpretation: Disorganized cell-cell adhesion in mutant cardiomyocytes is the cellular correlate of impaired vinculin coupling.

Show evidence (1 reference)

PMID:41231303 SUPPORT In Vitro

"Defects in cell-cell adhesion organization were also observed in cultured Vcl Y822F cardiomyocytes."

Reports the cultured-cardiomyocyte measurement behind this readout.

Show evidence (1 reference)

PMID:41231303 SUPPORT Model Organism

"We mutated Vcl Y822 to phenylalanine (Y822F) in the mouse to determine the in vivo function of pY822."

Establishes the model and its purpose as a probe of vinculin regulation.

Show evidence (1 reference)

PMID:41231303 SUPPORT Model Organism

"We found that VCL pY822 regulated cardiomyocyte cell-matrix and cell-cell adhesions during postnatal heart development."

The developmental regulation this model demonstrates, which is what makes it relevant to an infantile-onset adhesion disease.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy 1W
creation_date: "2026-09-04T02:26:58Z"
synonyms:
- CMD1W
- DCM1W
- VCL familial isolated dilated cardiomyopathy
- familial isolated dilated cardiomyopathy caused by mutation in VCL
- dilated cardiomyopathy type 1W
- cardiomyopathy, dilated, 1W
- vinculin-associated dilated cardiomyopathy
- metavinculin-associated dilated cardiomyopathy
description: >-
  Dilated cardiomyopathy 1W (CMD1W) is the VCL-related member of the numbered familial
  dilated cardiomyopathy series. VCL encodes vinculin and its muscle-specific splice
  isoform metavinculin, the mechanosensitive adaptor that anchors filamentous actin to
  the cadherin-based adherens junctions of the intercalated disc and to the
  integrin-based costameres of the sarcolemma. The lesion in CMD1W is therefore one of
  force *transmission*, not force *generation*: where the sarcomeric entries in this
  series (CMD1S/MYH7, CMD1E/TNNT2) perturb the motor that makes force, CMD1W perturbs
  the junctional machinery that carries that force between myocytes and out to the
  matrix. That distinction is mechanistically load-bearing and is why the entry exists
  separately from its sarcomeric siblings.

  Two allelic classes are curated separately because their mechanisms differ. The
  founding alleles p.Arg975Trp and p.Leu954del lie in the metavinculin-specific exon,
  are absent from 500 controls, and qualitatively alter metavinculin-mediated actin
  cross-linking in vitro; the single patient examined ultrastructurally had grossly
  abnormal intercalated discs. Predicted loss-of-function (pLOF) alleles are a different
  proposition: they affect both the vinculin and the metavinculin transcripts, are
  strongly enriched in dilated cardiomyopathy referrals (OR 9.01), skew heavily toward
  infantile and pediatric onset, and yet do not segregate as a highly penetrant dominant
  trait. The largest aggregate study concludes that heterozygous VCL loss of function
  alone is insufficient to cause cardiomyopathy and that these alleles behave as
  moderate-penetrance risk alleles requiring an additional genetic or environmental
  contribution. ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel nonetheless
  classifies the VCL-dilated cardiomyopathy relationship as Strong with autosomal
  dominant inheritance, so gene-disease validity and allele-level penetrance are two
  separate judgements and are curated as such here.

  The clinically distinctive feature is the infantile presentation with severe systolic
  failure that frequently reverses: in the only genotype-defined series, six infants
  presented at a median age of 2 months with a median ejection fraction of 24%, and five
  of six normalized ventricular function on an ACE inhibitor and a beta-blocker. That
  makes CMD1W a candidate genetic basis for heart failure with recovered ejection
  fraction, on a six-patient sample.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: dilated cardiomyopathy 1W
  term:
    id: MONDO:0012667
    label: dilated cardiomyopathy 1W
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant
  description: >-
    CMD1W is transmitted as an autosomal dominant trait and affected individuals are
    heterozygous; ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel records
    autosomal dominant inheritance for the VCL-dilated cardiomyopathy relationship.
    Penetrance is the qualification that matters most for this entry. Family studies of
    predicted loss-of-function alleles repeatedly identify unaffected heterozygous
    parents, and the aggregate analysis concluded that heterozygous VCL loss of function
    on its own is insufficient to produce cardiomyopathy. The metavinculin-specific
    missense and in-frame alleles have not been shown to behave the same way, and the
    two classes should not be assumed to share a penetrance.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  evidence:
  - reference: CGGV:assertion_2d46699a-5f8c-460d-9233-bec4e2ecf560-2024-08-09T160000.000Z
    reference_title: "VCL / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "VCL | HGNC:12665 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
    explanation: >-
      ClinGen records autosomal dominant inheritance for this gene-disease relationship,
      which is the authority for the mode of inheritance asserted here.
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The lack of clear segregation data confirms that VCL pLOF variants do not cause a
      phenotype with a highly penetrant autosomal dominant pattern of inheritance
    explanation: >-
      States directly that the loss-of-function alleles do not behave as a highly
      penetrant dominant trait, which is what INCOMPLETE penetrance records here.
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Family studies demonstrated that heterozygous loss of function of VCL alone is
      insufficient to cause cardiomyopathy but that these variants do contribute to
      disease risk.
    explanation: >-
      The family-study conclusion behind the reduced-penetrance qualification on this
      inheritance block.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No prevalence or incidence estimate exists for CMD1W as an entity. Reported
    frequencies are either variant carrier frequencies in reference populations or
    variant yields within cardiomyopathy testing cohorts, and neither is a disease rate,
    because penetrance of the loss-of-function class is low and variant interpretation is
    unsettled. The two records below are recorded as what they are rather than being
    promoted into a prevalence figure.
- population: gnomAD v2.1 exomes reference population
  measure_type: CARRIER_FREQUENCY
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 46.0
  notes: >-
    Frequency of VCL predicted loss-of-function alleles among reference-population
    individuals (58/125,297), after excluding variants predicted to escape
    nonsense-mediated decay. This is a variant carrier frequency, not a CMD1W prevalence:
    the same study concludes the alleles are not highly penetrant, so most carriers are
    not expected to be affected.
  evidence:
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This equated to a prevalence of VCL pLOF variants of 0.00046 (58/125,297) in
      individuals in gnomAD
    explanation: >-
      Source of the 0.00046 reference-population carrier frequency, normalized here to 46
      per 100,000.
progression:
- phase: Infantile presentation with severe systolic dysfunction
  age_range: Median 2 months at diagnosis in the genotype-defined series
  notes: >-
    Presentation in the loss-of-function series was in early infancy with severe
    ventricular dilation and depressed ejection fraction.
  evidence:
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Median age at diagnosis was 2 months, median LV ejection fraction was 24%, and
      median LV end-diastolic diameter z-score was 10.8.
    explanation: >-
      Gives the age and severity at presentation that define this phase.
- phase: Recovery of ventricular function on heart failure therapy
  age_range: Median 2.7 years at recovery
  notes: >-
    Five of six infants normalized left ventricular function 0.3 to 3.2 years after
    diagnosis while on an ACE inhibitor and a beta-blocker; one progressed to end-stage
    failure and transplantation. Six patients is not a natural history, and one patient in
    the series relapsed after medications were stopped and recovered again on
    re-treatment.
  evidence:
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five patients (83%) showed normalization of LV function at a median age of 2.7
      years.
    explanation: >-
      Establishes the recovery phase and its timing.
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient progressed to end-stage HF requiring heart transplant."
    explanation: >-
      Records that recovery is not universal, so this phase is not an expected outcome.
mechanistic_hypotheses:
- hypothesis_group_id: metavinculin_altered_actin_crosslinking
  hypothesis_label: Metavinculin tail alleles act by qualitatively altered actin cross-linking
  status: CANONICAL
  description: >-
    The founding CMD1W alleles p.Arg975Trp and p.Leu954del lie in the
    metavinculin-specific exon and are not dosage lesions. They change how metavinculin
    cross-links actin filaments, which is a qualitative change in the behaviour of a
    protein that is still present, and their effect is confined to the muscle-specific
    isoform. This is the model under which force transmission at the thin
    filament-intercalated disc interface is disrupted without vinculin being lost.
  evidence:
  - reference: PMID:11815424
    reference_title: "Metavinculin mutations alter actin interaction in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      significantly altered metavinculin-mediated cross-linking of actin filaments in an
      in vitro assay
    explanation: >-
      The functional measurement the hypothesis rests on: the alleles change actin
      cross-linking rather than abolishing the protein.
- hypothesis_group_id: vcl_plof_reduced_penetrance_risk_allele
  hypothesis_label: VCL loss-of-function alleles act as moderate-penetrance risk alleles requiring a second contribution
  status: CANONICAL
  description: >-
    Predicted loss-of-function alleles affect both the vinculin and the metavinculin
    transcripts and are strongly enriched in dilated cardiomyopathy referrals, but they
    are frequently inherited from unaffected parents and co-occur with variants in other
    cardiomyopathy genes. The best-supported reading is that they raise risk rather than
    determine disease, and that expression requires an additional genetic or
    environmental contribution. This is why the historical Mendelian label CMD1W should
    not be read as asserting that every heterozygous VCL variant is causal.
  evidence:
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, the data are most consistent with VCL pLOF variants acting as genetic
      modifiers that can lead to more severe disease or the precipitation of disease in
      the presence of additional risk factors, such as other genetic and/or environmental
      contributions.
    explanation: >-
      The study's own statement of this model, drawn from the aggregated family studies.
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      VCL loss-of-function variants should be reported in a diagnostic setting but need
      to be clearly distinguished as having lower penetrance.
    explanation: >-
      The reporting recommendation that follows from treating these as risk alleles.
- hypothesis_group_id: infantile_adhesion_immaturity_recovery
  hypothesis_label: Infantile dependence on vinculin explains early onset and later recovery
  status: EMERGING
  description: >-
    Proposed explanation for the two features that distinguish the loss-of-function
    phenotype: onset concentrated in infancy, and frequent normalization of ventricular
    function thereafter. If vinculin haploinsufficiency matters most while intercalated
    disc adhesion is still maturing, then the same allele would be more disruptive in
    infancy and less so once vinculin has localized into a mature disc. Supporting
    evidence that adhesion remodeling is a developmentally timed, vinculin-dependent
    process comes from the mouse; the human claim is an inference from a six-patient
    series and is not established.
  evidence:
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      It is possible that vinculin haploinsufficiency may be more disruptive in infancy
      when E-cadherin is still immature.
    explanation: >-
      The authors state the hypothesis explicitly, and label it as a possibility rather
      than a finding; the observation it is built on is the recovery of five of six
      infants.
  - reference: PMID:41231303
    reference_title: "Vinculin Y822 phosphorylation regulates adhesion remodeling during cardiomyocyte maturation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      VCL Y822 phosphorylation levels peaked during adhesion remodeling in the developing
      heart and were reduced as adhesions matured postnatally.
    explanation: >-
      Independent demonstration in mouse that vinculin-dependent adhesion remodeling is
      developmentally timed, which is the premise the human hypothesis needs. It does not
      show that this timing explains the human recovery.
pathophysiology:
- name: Metavinculin Tail Variant Altering Actin Cross-Linking
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  mechanism_confidence: ESTABLISHED
  description: >-
    The founding CMD1W lesion is a heterozygous variant in the metavinculin-specific exon
    of VCL: the missense allele p.Arg975Trp or the three-base-pair in-frame deletion
    p.Leu954del. Because the affected exon is spliced only into metavinculin, these
    alleles perturb the heart and smooth muscle isoform while leaving ubiquitous vinculin
    intact. Both involve conserved residues and were absent from 500 control individuals.
    This is a qualitative change in a protein that is still expressed, which is what
    separates this node from the loss-of-function node below.
  genes:
  - preferred_term: VCL
    term:
      id: hgnc:12665
      label: VCL
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  genetic_context:
    genes:
    - preferred_term: VCL
      term:
        id: hgnc:12665
        label: VCL
    allele_type: metavinculin-specific missense or in-frame deletion
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    description: >-
      Heterozygous germline alleles in the metavinculin-specific exon. No functional
      impact category is asserted: the measured effect is altered actin cross-linking,
      which the schema's FunctionalImpactEnum does not cleanly represent, and neither
      dominant-negative nor simple loss of function has been established for these
      alleles.
  evidence:
  - reference: PMID:11815424
    reference_title: "Metavinculin mutations alter actin interaction in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One missense mutation (Arg975Trp) and one 3-bp deletion (Leu954del) were identified."
    explanation: >-
      Names the two founding alleles, found by screening the metavinculin-specific exon in
      350 unrelated dilated cardiomyopathy patients.
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Vinculin is a ubiquitously expressed protein encoded by the VCL gene with a larger
      splice isoform, metavinculin, exclusively expressed in cardiac and smooth muscle.
    explanation: >-
      Establishes the isoform restriction that makes a metavinculin-exon allele a
      muscle-specific lesion. This is a background statement of established cell biology,
      not a result of the cited series.
  downstream:
  - target: Impaired Vinculin-Actin Coupling at Cardiomyocyte Adhesion Complexes
    causal_link_type: DIRECT
    hypothesis_groups:
    - metavinculin_altered_actin_crosslinking
    description: >-
      The mutant metavinculin is expressed and incorporated, but cross-links actin
      filaments abnormally.
    evidence:
    - reference: PMID:11815424
      reference_title: "Metavinculin mutations alter actin interaction in dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        significantly altered metavinculin-mediated cross-linking of actin filaments in an
        in vitro assay
      explanation: >-
        Direct measurement that the alleles change actin cross-linking, which is the edge
        from the variant to impaired coupling.
- name: VCL Predicted Loss-of-Function Allele
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  mechanism_confidence: PROVISIONAL
  description: >-
    The second and numerically larger allelic class is heterozygous predicted loss of
    function: nonsense, frameshift, canonical splice-site and one multi-exon duplication.
    Unlike the metavinculin-exon alleles these hit both VCL transcripts, so they reduce
    vinculin as well as metavinculin, and haploinsufficiency is the leading model for
    those expected to undergo nonsense-mediated decay. Confidence is recorded as
    PROVISIONAL rather than ESTABLISHED because the class is enriched in dilated
    cardiomyopathy but is not sufficient on its own to produce it, and most individual
    alleles remain variants of uncertain significance.
  genes:
  - preferred_term: VCL
    term:
      id: hgnc:12665
      label: VCL
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  genetic_context:
    genes:
    - preferred_term: VCL
      term:
        id: hgnc:12665
        label: VCL
    allele_type: nonsense, frameshift, canonical splice-site, multi-exon duplication
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Heterozygous germline predicted loss-of-function alleles affecting both the
      NM_014000.2 and NM_003373.3 transcripts, so both vinculin and metavinculin are
      reduced.
  evidence:
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variants identified included six affecting canonical splice sites, twelve nonsense
      variants, seven frameshift variants, and one multi exon duplication.
    explanation: >-
      The variant classes that make up this node, from the 26 unique alleles found across
      18,135 cardiomyopathy referrals.
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All variants except for the p.Pro943Argfs*9 variant were present in both the
      NM_014000.2 and NM_003373.3 transcripts.
    explanation: >-
      Establishes that this allelic class is not metavinculin-restricted, which is the
      distinction from the node above.
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified 32 probands with VCL loss-of-function variants and confirmed enrichment
      in probands with dilated cardiomyopathy
    explanation: >-
      The case-control enrichment (odds ratio 9.01, CI 4.93 to 16.45) that justifies
      treating this class as disease-relevant at all.
  downstream:
  - target: Impaired Vinculin-Actin Coupling at Cardiomyocyte Adhesion Complexes
    causal_link_type: DIRECT
    hypothesis_groups:
    - vcl_plof_reduced_penetrance_risk_allele
    description: >-
      Reduced vinculin and metavinculin dosage leaves fewer functional links between
      filamentous actin and the adhesion complexes.
  - target: Additional Genetic or Environmental Stressor
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - vcl_plof_reduced_penetrance_risk_allele
    description: >-
      This is not a causal step so much as a statement of what the allele does not do on
      its own: a second contribution is required before the phenotype appears, which is
      why unaffected heterozygous parents are routinely found.
    evidence:
    - reference: PMID:32516855
      reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Family studies demonstrated that heterozygous loss of function of VCL alone is
        insufficient to cause cardiomyopathy but that these variants do contribute to
        disease risk.
      explanation: >-
        Directly supports the requirement for an additional contribution rather than a
        single sufficient lesion.
- name: Additional Genetic or Environmental Stressor
  biological_scale: ORGANISM
  role: modifier
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The second contribution the loss-of-function class appears to need. In the aggregated
    families this took the form of co-occurring rare variants in other cardiomyopathy
    genes (MYH7, DSP, TPM1, LAMA4, SCN5A, MYBPC3); one segregation study found that only
    relatives heterozygous for both the VCL allele and a TPM1 missense variant were
    affected. A non-genetic stressor such as viral myocarditis is proposed as an
    alternative route but has not been measured in VCL carriers. The node is recorded as
    HYPOTHETICAL because no specific second hit has been established, only the
    requirement for one.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is conceivable that this is the result of a gene-environment interaction, such
      that disease is more likely to occur in the setting of non-genetic stressors (e.g.
      viral myocarditis).
    explanation: >-
      The environmental arm of the second-hit requirement, stated by the authors as a
      conjecture rather than a measured interaction.
  - reference: PMID:33983834
    reference_title: "The Complex and Diverse Genetic Architecture of Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      preliminary data from our studies and others suggests that at least 20% to 30% of
      DCM may have an oligogenic basis, meaning that multiple rare variants from
      different, unlinked loci, determine the DCM phenotype
    explanation: >-
      Places the CMD1W second-hit observation inside the wider oligogenic architecture of
      dilated cardiomyopathy. Indirect because it is a statement about dilated
      cardiomyopathy generally, not about VCL carriers.
  downstream:
  - target: Ventricular Dilation and Systolic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - vcl_plof_reduced_penetrance_risk_allele
    description: >-
      Only when the additional contribution is present does the reduced-vinculin
      myocardium go on to dilate and fail.
- name: Impaired Vinculin-Actin Coupling at Cardiomyocyte Adhesion Complexes
  biological_scale: MOLECULAR
  role: effector
  description: >-
    Both allelic classes converge here. Vinculin is the mechanosensitive adaptor that
    links filamentous actin to the cadherin-catenin complexes of the adherens junction
    and to the integrin-talin complexes of the costamere; metavinculin does the same job
    in cardiac and smooth muscle. Whether the protein is present but cross-links actin
    abnormally, or is simply reduced in amount, the consequence at this node is the same:
    the actin cytoskeleton is less securely coupled to the adhesion machinery.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: Actin filament binding by vinculin and metavinculin
    term:
      id: GO:0051015
      label: actin filament binding
    modifier: DECREASED
  biological_processes:
  - preferred_term: Actin filament bundle assembly
    term:
      id: GO:0051017
      label: actin filament bundle assembly
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: Adherens junction
    term:
      id: GO:0005912
      label: adherens junction
  - preferred_term: Costamere
    term:
      id: GO:0043034
      label: costamere
  - preferred_term: Focal adhesion
    term:
      id: GO:0005925
      label: focal adhesion
  evidence:
  - reference: PMID:41231303
    reference_title: "Vinculin Y822 phosphorylation regulates adhesion remodeling during cardiomyocyte maturation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Vinculin (VCL), a mechanosensitive adaptor protein, links filamentous actin to
      cell-matrix and cell-cell adhesions.
    explanation: >-
      States the coupling function whose impairment defines this node. Background
      statement of established cell biology rather than a result of the cited study.
  - reference: PMID:17785437
    reference_title: "Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In myocytes, it is localized in protein complexes which anchor the contractile
      apparatus to the sarcolemma.
    explanation: >-
      Locates the coupling specifically at the myocyte sarcolemma, which is where the
      costamere component of this node sits.
  downstream:
  - target: Intercalated Disc and Costamere Destabilization
    causal_link_type: DIRECT
    description: >-
      Junctions that cannot hold the actin cytoskeleton lose their structural integrity.
    evidence:
    - reference: PMID:17785437
      reference_title: "Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        shows that it is required for preservation of normal cell-cell and cell-matrix
        adhesive structures
      explanation: >-
        The conclusion of the cardiomyocyte-specific knockout: removing vinculin is
        sufficient to destabilize both junction types, which is this edge.
- name: Intercalated Disc and Costamere Destabilization
  biological_scale: CELLULAR
  role: effector
  description: >-
    The structural lesion of CMD1W. Adherens junctions become abnormal and the
    intercalated disc dissolves; cadherin and beta1D integrin fall at the junction. In the
    mouse this precedes any measurable contractile deficit, which places the junctional
    change upstream of the pump failure rather than as a consequence of it. The one human
    patient examined by electron microscopy, a p.Arg975Trp carrier, had grossly abnormal
    intercalated discs.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cell adhesion at the intercalated disc and costamere
    term:
      id: GO:0007155
      label: cell adhesion
    modifier: DECREASED
  cellular_components:
  - preferred_term: Intercalated disc
    term:
      id: GO:0014704
      label: intercalated disc
  - preferred_term: Costamere
    term:
      id: GO:0043034
      label: costamere
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:11815424
    reference_title: "Metavinculin mutations alter actin interaction in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ultrastructural examination was performed in one patient (Arg975Trp), revealing
      grossly abnormal intercalated discs.
    explanation: >-
      The only human ultrastructural observation for this entity, and the reason the
      junctional lesion is not solely a mouse claim. It is a single patient.
  - reference: PMID:17785437
    reference_title: "Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Prior to the onset of cardiac dysfunction, ultrastructural analysis of cVclKO heart
      tissue showed abnormal adherens junctions with dissolution of the intercalated disc
      structure, expression of the junctional proteins cadherin and beta1D integrin were
      reduced, and the gap junction protein connexin 43 was mislocalized to the lateral
      myocyte border.
    explanation: >-
      Establishes both the junctional lesion and, crucially, its timing before contractile
      dysfunction.
  downstream:
  - target: Defective Force Transmission Across the Intercalated Disc
    causal_link_type: DIRECT
    description: >-
      A dissolved disc cannot carry contractile force between adjoining myocytes.
    evidence:
    - reference: PMID:11815424
      reference_title: "Metavinculin mutations alter actin interaction in dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Disruption of force transmission at the thin filament-intercalated disc interface
        is the likely mechanism by which mutations in metavinculin may lead to DCM.
      explanation: >-
        The founding study's stated mechanism, which is exactly this edge. The authors
        frame it as the likely mechanism, not a demonstrated one.
  - target: Connexin 43 Lateralization and Conduction Slowing
    causal_link_type: DIRECT
    description: >-
      Loss of disc organization displaces the gap junction protein from its intercalated
      disc position to the lateral myocyte border.
    evidence:
    - reference: PMID:17785437
      reference_title: "Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Prior to the onset of cardiac dysfunction, ultrastructural analysis of cVclKO heart
        tissue showed abnormal adherens junctions with dissolution of the intercalated disc
        structure, expression of the junctional proteins cadherin and beta1D integrin were
        reduced, and the gap junction protein connexin 43 was mislocalized to the lateral
        myocyte border.
      explanation: >-
        Shows the connexin 43 displacement occurring together with the disc lesion in the
        same knockout hearts.
- name: Connexin 43 Lateralization and Conduction Slowing
  biological_scale: CELLULAR
  role: effector
  description: >-
    The electrical branch of the mechanism. Gap junctions displaced from the intercalated
    disc to the lateral cell border make conduction heterogeneous. In the cardiomyocyte
    knockout mouse this produced defective myocardial conduction on optical mapping and
    ventricular tachycardia on conscious telemetry, and it did so while contractile
    function was still preserved. The human counterpart is the conduction and arrhythmia
    phenotypes seen in a minority of VCL loss-of-function probands; direct human
    connexin 43 data are not available.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Electrical coupling in cardiac conduction
    term:
      id: GO:0086064
      label: cell communication by electrical coupling involved in cardiac conduction
    modifier: DECREASED
  cellular_components:
  - preferred_term: Gap junction
    term:
      id: GO:0005921
      label: gap junction
  evidence:
  - reference: PMID:17785437
    reference_title: "Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Conscious telemetry documented ventricular tachycardia as the cause of sudden death,
      while defective myocardial conduction was detected by optical mapping.
    explanation: >-
      Direct electrophysiological demonstration of the conduction defect and the
      arrhythmia it produces in the vinculin-null myocardium.
  downstream:
  - target: Ventricular Arrhythmia and Conduction Disease
    causal_link_type: DIRECT
    description: >-
      Heterogeneous conduction is the substrate for the arrhythmic phenotype.
- name: Ventricular Arrhythmia and Conduction Disease
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The arrhythmic arm of the phenotype. In the mouse it is severe and precedes pump
    failure: 49% of cardiomyocyte-knockout animals died suddenly before 3 months with
    preserved contractile function. In humans the arrhythmic and conduction phenotypes are
    a minority finding among VCL loss-of-function probands, and there is no evidence that
    a VCL variant on its own warrants a defibrillator the way an LMNA or FLNC variant
    does; that management position is curated with its citation as the Implantable
    Cardioverter-Defibrillator treatment. The gap between the mouse severity and the
    human picture is recorded as a human-model mismatch below.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:17785437
    reference_title: "Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Sudden death was found in 49% of the knockout (cVclKO) mice younger than 3 months of
      age despite preservation of contractile function.
    explanation: >-
      Establishes arrhythmic death as an independent consequence of vinculin loss, not a
      byproduct of a failing pump.
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The remainder (n=13, 40.6%, Table 4) had other cardiac phenotypes including LVNC
      (n=2), HCM or LVH (n=3), unspecified cardiomyopathy (n=3), abnormal echo with family
      history of DCM (n=1), bradycardia and heart block (n=3), and supraventricular
      tachycardia, tuberous sclerosis, and rhabdomyoma (n=1).
    explanation: >-
      The human conduction and arrhythmia phenotypes, at the frequencies observed among
      VCL loss-of-function probands referred for cardiomyopathy testing.
  downstream:
  - target: Bradycardia and Heart Block
    causal_link_type: DIRECT
  - target: Supraventricular Tachycardia
    causal_link_type: DIRECT
- name: Defective Force Transmission Across the Intercalated Disc
  biological_scale: TISSUE
  role: central_effector
  description: >-
    The defining lesion of CMD1W and the reason it is not simply another sarcomeric
    cardiomyopathy. The sarcomere still generates force; that force is no longer
    transmitted efficiently between myocytes or out to the extracellular matrix. Because
    the deficit is in transmission rather than generation, the myocardium is functionally
    uncoupled even where individual myocytes contract normally.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiac muscle cell contraction
    term:
      id: GO:0086003
      label: cardiac muscle cell contraction
    modifier: DECREASED
  cellular_components:
  - preferred_term: Intercalated disc
    term:
      id: GO:0014704
      label: intercalated disc
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:11815424
    reference_title: "Metavinculin mutations alter actin interaction in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Vinculin and its isoform metavinculin are protein components of intercalated discs,
      structures that anchor thin filaments and transmit contractile force between cardiac
      myocytes.
    explanation: >-
      States the function of the structure whose failure this node names. Background
      statement of established anatomy rather than a result of the cited study.
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Vinculin links the actin cytoskeleton to the cell membrane which is critical in
      force transmission and is needed to maintain cardiomyocyte function
    explanation: >-
      Independent statement that force transmission is the vinculin-dependent function at
      stake. Background statement, not a result of the cited series.
  downstream:
  - target: Ventricular Dilation and Systolic Dysfunction
    causal_link_type: DIRECT
    description: >-
      Chronic failure to transmit force drives chamber enlargement and falling ejection
      fraction.
    evidence:
    - reference: PMID:17785437
      reference_title: "Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        cVclKO mice that survived through the vulnerable period of sudden death developed
        dilated cardiomyopathy and died before 6 months of age.
      explanation: >-
        Shows the progression from the junctional and force-transmission lesion to overt
        dilated cardiomyopathy in the same animals.
- name: Ventricular Dilation and Systolic Dysfunction
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    The structural endpoint: left ventricular or biventricular dilation with reduced
    systolic function, diagnosed after excluding ischemic, loading, valvular and
    congenital causes. In the genotype-defined infant series the dilation was extreme, at
    a median end-diastolic diameter z-score of 10.8 with a median ejection fraction of
    24%, and all six also showed ventricular hypertrophy and T-wave abnormalities.
  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
  biological_processes:
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: DECREASED
  locations:
  - preferred_term: Left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients showed LV dilation and dysfunction on echocardiograms and LV or
      biventricular hypertrophy and T wave abnormalities on electrocardiogram.
    explanation: >-
      Documents the structural and electrical findings in every patient of the
      genotype-defined series.
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common cardiac phenotype was DCM or left ventricular dilation (n=19, 59.4%,
      Table 3).
    explanation: >-
      Establishes dilation with systolic dysfunction as the dominant phenotype among VCL
      loss-of-function probands.
  downstream:
  - target: Heart Failure with Reduced Ejection Fraction
    causal_link_type: DIRECT
  - target: Dilated cardiomyopathy
    causal_link_type: DIRECT
- name: Heart Failure with Reduced Ejection Fraction
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    The clinical syndrome the dilated, hypocontractile ventricle produces. In infancy this
    presents as poor feeding, breathlessness and failure to thrive; in advanced disease it
    requires mechanical support or transplantation. Unusually for a genetic
    cardiomyopathy, this node has a well-documented reversible exit in the VCL
    loss-of-function series.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case series identified a unique phenotype of HF with reduced ejection fraction
      at presentation that evolved to HF with recovered EF in over 80% of infant DCM cases
      with LOF VCL variants.
    explanation: >-
      Names the syndrome at presentation and its usual evolution in this genotype.
  downstream:
  - target: Congestive Heart Failure
    causal_link_type: DIRECT
  - target: Reverse Remodeling with Recovered Ejection Fraction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - infantile_adhesion_immaturity_recovery
    description: >-
      On heart failure therapy, most infants in the only genotype-defined series exited
      this node rather than progressing. The intermediates are unknown; the proposed
      explanation is developmental.
    evidence:
    - reference: PMID:37548861
      reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Five patients (83%) showed normalization of LV function at a median age of 2.7
        years.
      explanation: >-
        The observation the edge records. Six patients, uncontrolled, so the transition is
        documented rather than explained.
- name: Reverse Remodeling with Recovered Ejection Fraction
  biological_scale: ORGANISM
  role: consequence
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Normalization of left ventricular systolic function after an infantile presentation
    with severe dysfunction. This is the feature that most distinguishes CMD1W from the
    other numbered dilated cardiomyopathies and it is why the entity has been proposed as
    a genetic basis for heart failure with recovered ejection fraction. Two cautions are
    curated with it: recovery is not resolution, since guideline authors are explicit that
    improved ejection fraction does not mean the cardiomyopathic process has resolved and
    that therapy should continue; and one patient in the series relapsed after
    medications were withdrawn. The mechanism is unknown, with the developmental
    explanation recorded as an emerging hypothesis rather than a finding.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: INCREASED
  evidence:
  - reference: PMID:37653361
    reference_title: "Summary and Comparison of the 2022 ACC/AHA/HFSA and 2021 ESC Heart Failure Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      improvement does not necessarily represent normalization of LV function or
      resolution of the cardiomyopathic process and highlights the importance of
      continuing treatment as per HFrEF recommendations to prevent deterioration in
      symptomatic status or LVEF
    explanation: >-
      The guideline position that stops this node being read as cure. Graded OTHER because
      the cited article is a comparison of two society guidelines, not a study.
phenotypes:
- name: Dilated cardiomyopathy
  category: Cardiovascular
  description: >-
    Left ventricular or biventricular dilation with systolic dysfunction is the defining
    phenotype. Among VCL loss-of-function probands referred for cardiomyopathy testing it
    was the most common finding, in 19 of 32. Note that this denominator is the set of
    loss-of-function carriers ascertained through testing panels, not a CMD1W case series,
    so it describes the phenotypic spectrum of the allele rather than the penetrance of
    the disease.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  frequency: FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common cardiac phenotype was DCM or left ventricular dilation (n=19, 59.4%,
      Table 3).
    explanation: >-
      Gives both the phenotype and the 59.4% share that the FREQUENT band records.
- name: Reduced left ventricular ejection fraction
  category: Cardiovascular
  description: >-
    Systolic impairment is severe at presentation in the infantile loss-of-function
    phenotype, with a median ejection fraction of 24% in the six-patient series.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
    severity: SEVERE
  evidence:
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Median age at diagnosis was 2 months, median LV ejection fraction was 24%, and
      median LV end-diastolic diameter z-score was 10.8.
    explanation: >-
      Quantifies the systolic impairment at presentation in the genotype-defined series.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    The clinical presenting syndrome. In the infant series this took the form of poor
    feeding and breathlessness; in adults it presents as progressive exertional heart
    failure, with advanced disease requiring mechanical support or transplantation.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case series identified a unique phenotype of HF with reduced ejection fraction
      at presentation that evolved to HF with recovered EF in over 80% of infant DCM cases
      with LOF VCL variants.
    explanation: >-
      Establishes heart failure as the presenting syndrome in the genotype-defined series.
  sequelae:
  - target: Reverse Remodeling with Recovered Ejection Fraction
    description: >-
      In this genotype the syndrome frequently remits on heart failure therapy rather than
      progressing.
- name: Feeding difficulties
  category: Gastrointestinal
  description: >-
    Poor feeding was the presenting complaint in the index infant of the loss-of-function
    series, and enteral supplementation was required to age 3 years. This is the
    low-cardiac-output presentation of heart failure in infancy rather than a primary
    gastrointestinal phenotype.
  phenotype_term:
    preferred_term: Poor feeding in infancy
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient Ia presented at 5.5 months of age with poor feeding and breathlessness."
    explanation: >-
      Single-patient observation, recorded as such: this is a case description, not a
      cohort frequency.
- name: Left ventricular noncompaction
  category: Cardiovascular
  description: >-
    Noncompaction was recorded in 2 of 32 VCL loss-of-function probands and in one infant
    of the genotype-defined series. The association is not established; with two probands
    it cannot be distinguished from coincidental detection on the broad cardiomyopathy
    panels through which these carriers were found.
  phenotype_term:
    preferred_term: Left ventricular noncompaction
    term:
      id: HP:0030682
      label: Left ventricular noncompaction
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The remainder (n=13, 40.6%, Table 4) had other cardiac phenotypes including LVNC
      (n=2), HCM or LVH (n=3), unspecified cardiomyopathy (n=3), abnormal echo with family
      history of DCM (n=1), bradycardia and heart block (n=3), and supraventricular
      tachycardia, tuberous sclerosis, and rhabdomyoma (n=1).
    explanation: >-
      Source of the 2 of 32 count for noncompaction among loss-of-function probands.
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was diagnosed at 6 months with DCM with LV non-compaction"
    explanation: >-
      Independent observation of noncompaction alongside dilation in a VCL
      loss-of-function infant.
- name: Left ventricular hypertrophy
  category: Cardiovascular
  description: >-
    A hypertrophic phenotype was recorded in 3 of 32 loss-of-function probands, and all
    six infants of the genotype-defined series had left ventricular or biventricular
    hypertrophy on echocardiography alongside their dilation. This overlap is real but is
    not the core CMD1W phenotype and should not be used to reclassify the entity.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The remainder (n=13, 40.6%, Table 4) had other cardiac phenotypes including LVNC
      (n=2), HCM or LVH (n=3), unspecified cardiomyopathy (n=3), abnormal echo with family
      history of DCM (n=1), bradycardia and heart block (n=3), and supraventricular
      tachycardia, tuberous sclerosis, and rhabdomyoma (n=1).
    explanation: >-
      Source of the 3 of 32 count for hypertrophic cardiomyopathy or left ventricular
      hypertrophy among loss-of-function probands.
- name: Bradycardia and Heart Block
  category: Cardiovascular
  description: >-
    Conduction disease was the presenting cardiac phenotype in 3 of 32 VCL
    loss-of-function probands. It is mechanistically coherent with the connexin 43
    lateralization seen in the knockout mouse, but the human observation is a small count
    from a referral cohort.
  phenotype_term:
    preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The remainder (n=13, 40.6%, Table 4) had other cardiac phenotypes including LVNC
      (n=2), HCM or LVH (n=3), unspecified cardiomyopathy (n=3), abnormal echo with family
      history of DCM (n=1), bradycardia and heart block (n=3), and supraventricular
      tachycardia, tuberous sclerosis, and rhabdomyoma (n=1).
    explanation: >-
      Source of the 3 of 32 count for bradycardia and heart block.
- name: Supraventricular Tachycardia
  category: Cardiovascular
  description: >-
    Recorded in a single one of the 32 VCL loss-of-function probands, alongside unrelated
    findings in the same individual. Curated because the electrical branch of the
    mechanism predicts arrhythmia, and recorded at its true weight: one proband.
  phenotype_term:
    preferred_term: Supraventricular tachycardia
    term:
      id: HP:0004755
      label: Supraventricular tachycardia
  frequency: VERY_RARE
  evidence:
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The remainder (n=13, 40.6%, Table 4) had other cardiac phenotypes including LVNC
      (n=2), HCM or LVH (n=3), unspecified cardiomyopathy (n=3), abnormal echo with family
      history of DCM (n=1), bradycardia and heart block (n=3), and supraventricular
      tachycardia, tuberous sclerosis, and rhabdomyoma (n=1).
    explanation: >-
      Source of the single supraventricular tachycardia proband.
genetic:
- name: VCL
  gene_term:
    preferred_term: VCL
    term:
      id: hgnc:12665
      label: VCL
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  frequency: >-
    Rare cause of dilated cardiomyopathy. Predicted loss-of-function alleles were found
    in 13 of 3,118 dilated cardiomyopathy probands with available phenotype data, against
    58 of 125,297 reference-population individuals.
  case_fractions:
  - population: Dilated cardiomyopathy probands in three cardiomyopathy diagnostic testing cohorts
    case_fraction_percent: 0.42
    cohort_size: 3118
    notes: >-
      Share of dilated cardiomyopathy probands carrying a VCL predicted loss-of-function
      allele. This counts allele carriage, not attributed causation: the same study
      concludes the alleles are not individually sufficient, so the fraction of cases
      caused by VCL is smaller than the fraction carrying a VCL allele.
    evidence:
    - reference: PMID:32516855
      reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the frequency in DCM cases, 0.0042 (13/3,118)"
      explanation: >-
        Source of the 0.42% carrier share among dilated cardiomyopathy probands.
  evidence:
  - reference: CGGV:assertion_2d46699a-5f8c-460d-9233-bec4e2ecf560-2024-08-09T160000.000Z
    reference_title: "VCL / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "VCL | HGNC:12665 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
    explanation: >-
      ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies this
      gene-disease relationship as Strong under SOP10, which is the authority for curating
      VCL as CAUSATIVE rather than a candidate gene.
  - reference: PMID:11815424
    reference_title: "Metavinculin mutations alter actin interaction in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data provide genetic and functional evidence for vinculin as a DCM gene and
      suggest that metavinculin plays a critical role in cardiac structure and function.
    explanation: >-
      The founding gene-disease claim, resting on the metavinculin-exon alleles and their
      functional characterization.
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified 32 probands with VCL loss-of-function variants and confirmed enrichment
      in probands with dilated cardiomyopathy
    explanation: >-
      Case-control enrichment of the loss-of-function class in dilated cardiomyopathy,
      odds ratio 9.01 with confidence interval 4.93 to 16.45.
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Family studies demonstrated that heterozygous loss of function of VCL alone is
      insufficient to cause cardiomyopathy but that these variants do contribute to
      disease risk.
    explanation: >-
      Curated as REFUTE against the strong reading of CAUSATIVE, that a heterozygous VCL
      allele is by itself sufficient to produce the disease. The same sentence supports
      the weaker risk-conferring reading, which is why it also appears as SUPPORT on the
      inheritance block and on the reduced-penetrance hypothesis. Both readings are
      curated rather than one being suppressed.
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data revealed that the majority of these individuals (89.5%) had pediatric onset
      of disease.
    explanation: >-
      The pediatric skew that distinguishes VCL loss-of-function carriers from other
      genotypes in the same testing cohorts.
- name: MYBPC3
  gene_term:
    preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  frequency: >-
    Single-family observation; no cohort estimate exists for how often a MYBPC3 variant
    modifies a VCL genotype.
  evidence:
  - reference: PMID:24062880
    reference_title: "Familial dilated cardiomyopathy associated with congenital defects in the setting of a novel VCL mutation (Lys815Arg) in conjunction with a known MYPBC3 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More severely affected family members also possess a second missense variant in
      MYBPC3, raising the possibility that this variant may be a disease modifier.
    explanation: >-
      The observation behind the MODIFIER relationship, in a family carrying VCL
      p.Lys815Arg. The authors state it as a possibility, and one family cannot establish
      modification.
variants:
- name: VCL p.Arg975Trp
  gene:
    preferred_term: VCL
    term:
      id: hgnc:12665
      label: VCL
  type: missense
  description: >-
    Missense allele in the metavinculin-specific exon, one of the two founding CMD1W
    variants. It involves a conserved residue, was absent from 500 controls, and altered
    metavinculin-mediated actin cross-linking in vitro. The carrier is the only CMD1W
    patient with published cardiac ultrastructure, which showed grossly abnormal
    intercalated discs.
  evidence:
  - reference: PMID:11815424
    reference_title: "Metavinculin mutations alter actin interaction in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ultrastructural examination was performed in one patient (Arg975Trp), revealing
      grossly abnormal intercalated discs.
    explanation: >-
      Ties this specific allele to the human intercalated disc lesion.
- name: VCL p.Leu954del
  gene:
    preferred_term: VCL
    term:
      id: hgnc:12665
      label: VCL
  type: inframe_deletion
  description: >-
    Three-base-pair in-frame deletion in the metavinculin-specific exon, the second
    founding CMD1W allele. Like p.Arg975Trp it removes a conserved residue, was absent
    from 500 controls, and altered actin cross-linking in vitro.
  evidence:
  - reference: PMID:11815424
    reference_title: "Metavinculin mutations alter actin interaction in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One missense mutation (Arg975Trp) and one 3-bp deletion (Leu954del) were identified."
    explanation: >-
      Names the allele as one of the two identified in the founding screen.
- name: VCL p.Lys815Arg
  gene:
    preferred_term: VCL
    term:
      id: hgnc:12665
      label: VCL
  type: missense
  description: >-
    Missense allele reported in a family with dilated cardiomyopathy and congenital
    defects including bicuspid aortic valve. It sits outside the metavinculin-specific
    exon. The more severely affected relatives also carried MYBPC3 p.Arg177Cys, so this
    family is a worked example of the second-hit pattern rather than of a sufficient VCL
    allele.
  evidence:
  - reference: PMID:24062880
    reference_title: "Familial dilated cardiomyopathy associated with congenital defects in the setting of a novel VCL mutation (Lys815Arg) in conjunction with a known MYPBC3 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this report, we describe a family with DCM and congenital abnormalities who carry
      a novel missense mutation in the VCL gene.
    explanation: >-
      Establishes the allele and the family it was reported in.
- name: VCL p.Arg547*
  gene:
    preferred_term: VCL
    term:
      id: hgnc:12665
      label: VCL
  type: nonsense
  clinical_significance: UNCERTAIN_SIGNIFICANCE
  description: >-
    Nonsense allele (c.1639C>T) carried by two siblings in the genotype-defined infant
    series, both of whom recovered ventricular function. It was inherited from a mother
    with a normal echocardiogram, and was reclassified from likely pathogenic to a variant
    of uncertain significance by the reporting laboratory. It is the clearest single
    illustration of why this allelic class is curated as risk-conferring rather than
    determinative.
  evidence:
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variants were classified by the clinical laboratory as a VUS in 5 patients and
      likely pathogenic in one (patient IV).
    explanation: >-
      Supports the uncertain classification recorded here; patient Ia, who carried this
      allele, was among the five reported as uncertain.
treatments:
- name: Heart Failure Pharmacotherapy
  description: >-
    Guideline-directed therapy for heart failure with reduced ejection fraction, applied
    to the expressed phenotype. There is no VCL-directed treatment. Contemporary HFrEF
    guidance rests on four pillars: renin-angiotensin system inhibition (an ACE
    inhibitor, an ARB, or an angiotensin receptor-neprilysin inhibitor), beta-blockade, a
    mineralocorticoid receptor antagonist, and an SGLT2 inhibitor, with a loop diuretic
    added for congestion. What the genotype-defined series documents is narrower. Every
    infant in it received an ACE inhibitor and a beta-blocker, and five of six recovered
    ventricular function; the series was uncontrolled, so it establishes what was given,
    not that the drugs caused the recovery. The MRA, SGLT2 inhibitor and ARNI agents
    curated below are quoted from adult HFrEF guidance and record the standard of care
    the expressed phenotype is managed under; they are not therapy documented in that
    infant cohort. Guideline authors are explicit that improved ejection fraction does not
    license stopping therapy, and the one patient in the series who was weaned off
    medication relapsed and needed it restarted.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: beta-adrenergic antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: angiotensin receptor-neprilysin inhibitor
      term:
        id: NCIT:C190796
        label: Angiotensin Receptor-Neprilysin Inhibitor
    - preferred_term: mineralocorticoid receptor antagonist
      term:
        id: NCIT:C101255
        label: Aldosterone Receptor Antagonist
    - preferred_term: SGLT2 inhibitor
      term:
        id: NCIT:C98083
        label: SGLT2 Inhibitor
    - preferred_term: loop diuretic
      term:
        id: NCIT:C49184
        label: Loop Diuretic
  target_mechanisms:
  - target: Heart Failure with Reduced Ejection Fraction
    treatment_effect: MODULATES
    description: >-
      Neurohormonal blockade acts on the failing-ventricle syndrome, not on the vinculin
      lesion upstream of it.
    evidence:
    - reference: PMID:37548861
      reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "All patients received an angiotensin-converting enzyme (ACE) inhibitor and a beta-blocker."
      explanation: >-
        Records the regimen every patient received. Indirect for the treatment-effect
        claim because the series had no control arm, so the association between therapy
        and recovery is not causal evidence.
  evidence:
  - reference: PMID:37653361
    reference_title: "Summary and Comparison of the 2022 ACC/AHA/HFSA and 2021 ESC Heart Failure Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      improvement does not necessarily represent normalization of LV function or
      resolution of the cardiomyopathic process and highlights the importance of
      continuing treatment as per HFrEF recommendations to prevent deterioration in
      symptomatic status or LVEF
    explanation: >-
      The basis for continuing therapy after ejection fraction recovers, which is the
      management question this genotype raises most often.
  - reference: PMID:37653361
    reference_title: "Summary and Comparison of the 2022 ACC/AHA/HFSA and 2021 ESC Heart Failure Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The four pillars of HF management (RAAS inhibition, beta-blockade, MRA, and SGLT2i) should be initiated in all patients with HFrEF as tolerated."
    explanation: >-
      Names the four drug classes that constitute guideline-directed therapy for the
      expressed HFrEF phenotype, and is why this node carries an MRA and an SGLT2
      inhibitor alongside the ACE inhibitor and beta-blocker the infant series recorded.
  - reference: PMID:37653361
    reference_title: "Summary and Comparison of the 2022 ACC/AHA/HFSA and 2021 ESC Heart Failure Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Inhibition of the RAAS is recommended to reduce morbidity and mortality, with both ACC/AHA/HFSA and ESC guidelines recommending an ARNi as first-line therapy in hospitalized patients with acute HF or following a trial of an ACEi or ARB in outpatients to ensure the patient tolerates RAAS inhibition."
    explanation: >-
      Places the angiotensin receptor-neprilysin inhibitor within the
      renin-angiotensin-system arm of the regimen, which is why ARNI is curated as a
      therapeutic agent alongside the ACE inhibitor rather than instead of it.
  - reference: PMID:37653361
    reference_title: "Summary and Comparison of the 2022 ACC/AHA/HFSA and 2021 ESC Heart Failure Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MRAs are recommended in addition to ACEi and beta-blockers to improve symptoms and reduce all-cause mortality, HF hospitalizations, and sudden cardiac death in all patients with HFrEF."
    explanation: >-
      The specific recommendation behind the mineralocorticoid receptor antagonist agent
      on this node, added to rather than replacing the ACE inhibitor and beta-blocker.
  - reference: PMID:37653361
    reference_title: "Summary and Comparison of the 2022 ACC/AHA/HFSA and 2021 ESC Heart Failure Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SGLT2i therapy is a new addition to the pillars of HF management."
    explanation: >-
      Records that the SGLT2 inhibitor is a pillar of the regimen in its own right, which
      is the class most likely to be missing from an older description of this therapy.
  - reference: PMID:37653361
    reference_title: "Summary and Comparison of the 2022 ACC/AHA/HFSA and 2021 ESC Heart Failure Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Loop diuretics such as frusemide or bumetanide are the preferred diuretic agent for use in most patients with HF."
    explanation: >-
      The basis for the loop diuretic agent, which is symptomatic congestion control
      rather than a mortality-modifying pillar.
- name: Implantable Cardioverter-Defibrillator
  description: >-
    Primary-prevention defibrillator implantation for the expressed heart failure
    phenotype. The indication in CMD1W is the ordinary HFrEF one, resting on ejection
    fraction, symptoms and response to optimal medical therapy, and the genotype does not
    lower the threshold. Only a small number of cardiomyopathy genes carry a
    genotype-specific device recommendation, LMNA being the worked example, and VCL is
    not among them. That is the clinically load-bearing negative in this entry: the
    murine phenotype is arrhythmia-first and lethal, the human phenotype is
    heart-failure-first and frequently recoverable, and the mouse severity is recorded as
    a human-model mismatch rather than translated into a device indication.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_mechanisms:
  - target: Ventricular Arrhythmia and Conduction Disease
    treatment_effect: INHIBITS
    description: >-
      The device terminates a sustained ventricular arrhythmia once it starts; it leaves
      the conduction substrate that generates the arrhythmia untouched.
  evidence:
  - reference: PMID:37653361
    reference_title: "Summary and Comparison of the 2022 ACC/AHA/HFSA and 2021 ESC Heart Failure Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "For primary prevention, regardless of etiology, the ACC/AHA/HFSA guidelines strongly recommend an ICD to reduce the risk of SCD and all-cause mortality in patients with symptomatic HFrEF of ischemic or non-ischemic etiology, with an LVEF ≤ 35% despite ≥ 3 months of optimal medical management if their life expectancy is > 1 year"
    explanation: >-
      The primary-prevention indication that applies to a CMD1W patient, stated in terms
      of ejection fraction, symptoms and duration of optimal medical therapy rather than
      of genotype.
  - reference: PMID:39519012
    reference_title: "Dilated Cardiomyopathy: A Genetic Journey from Past to Future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Hence, LMNA cardiomyopathy constitutes one of the few genotype-specific evidenced-based guideline recommendations in the cardiomyopathies."
    explanation: >-
      Supports the claim that a VCL variant does not by itself justify a defibrillator.
      Indirect: the quote establishes that genotype-specific device recommendations exist
      for only a few cardiomyopathy genes and names LMNA as the exemplar, and the VCL
      claim follows from VCL not being one of them rather than from a statement about
      VCL.
- name: Cardiac Resynchronization Therapy
  description: >-
    Biventricular pacing for the subset with persistent symptomatic systolic dysfunction
    and electrical dyssynchrony after optimal medical therapy. As with the defibrillator,
    the indication is the conventional electrical and functional one and is not modified
    by VCL genotype. It is included because conduction disease is a documented minority
    finding in VCL loss-of-function probands, so the dyssynchrony pathway is reachable in
    this entry even though it is not the usual course.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cardiac resynchronization therapy
    term:
      id: NCIT:C80436
      label: Cardiac Resynchronization Therapy
  target_mechanisms:
  - target: Heart Failure with Reduced Ejection Fraction
    treatment_effect: MODULATES
    description: >-
      Recoordinating right and left ventricular activation improves pump efficiency
      without acting on the adhesion lesion or on force transmission at the intercalated
      disc.
  evidence:
  - reference: PMID:37653361
    reference_title: "Summary and Comparison of the 2022 ACC/AHA/HFSA and 2021 ESC Heart Failure Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cardiac resynchronization therapy (CRT) is strongly recommended for symptomatic patients (NYHA class II-IV on best medical management) who have LVEF ≤ 35%, sinus rhythm, left bundle branch block (LBBB) with a QRS of ≥ 150 ms to reduce total mortality and hospitalizations, and improve symptoms and quality of life"
    explanation: >-
      The indication criteria, which are ejection fraction, rhythm and QRS morphology.
      None of them reference genotype.
- name: Ventricular Assist Device Support
  description: >-
    Mechanical circulatory support for decompensated end-stage failure, used here as the
    bridge to transplantation. It is curated because the genotype-defined series contains
    exactly one such course: the single infant who did not recover ventricular function
    went to a left ventricular assist device at 7 months and transplantation at 10
    months, which is the counterexample to the recoverable phenotype the other five
    patients define.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: ventricular assist device placement
    term:
      id: NCIT:C80452
      label: Ventricular Assist Device Placement
  target_mechanisms:
  - target: Heart Failure with Reduced Ejection Fraction
    treatment_effect: BYPASSES
    description: >-
      The pump substitutes for ventricular ejection rather than restoring it, so the
      failing myocardium is worked around rather than repaired.
  evidence:
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient V who was diagnosed with severe DCM at age 4 months progressed to decompensated HF requiring a LV assist device at age 7 months and a heart transplant at age 10 months."
    explanation: >-
      Documents assist-device support and its timing within the genotype-defined series,
      which is the clinical course this treatment describes.
- name: Heart Transplantation
  description: >-
    Reserved for refractory end-stage failure. One of the six infants in the
    genotype-defined series progressed to a ventricular assist device at 7 months and
    transplantation at 10 months, so the recoverable phenotype is not universal.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_mechanisms:
  - target: Heart Failure with Reduced Ejection Fraction
    treatment_effect: BYPASSES
    description: >-
      Replacing the organ removes the diseased myocardium rather than correcting the
      adhesion lesion.
  evidence:
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient progressed to end-stage HF requiring heart transplant."
    explanation: >-
      Documents transplantation as an outcome within the genotype-defined series.
- name: Genetic Counseling and Family Screening
  description: >-
    Cascade genetic testing and clinical screening of first-degree relatives, with the
    reduced penetrance of VCL loss-of-function alleles stated explicitly. A VCL variant of
    uncertain significance should not drive predictive testing or irreversible management,
    and most VCL loss-of-function alleles assessed by clinical laboratories are of
    uncertain significance. Clinical screening rather than genotype alone carries the
    weight here, because up to a fifth of apparently asymptomatic relatives across dilated
    cardiomyopathy cohorts already have overt disease at first assessment.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:39519012
    reference_title: "Dilated Cardiomyopathy: A Genetic Journey from Past to Future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is also consensus across guidelines to offer cascade genetic screening and
      genetic counseling to first-degree relatives of patients with genetic DCM
    explanation: >-
      The guideline basis for offering cascade screening in a genetic dilated
      cardiomyopathy.
  - reference: PMID:39519012
    reference_title: "Dilated Cardiomyopathy: A Genetic Journey from Past to Future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the time of initial evaluation in seemingly asymptomatic relatives, up to 20%
      will be found to have overt DCM, with an age-dependent increase in prevalence
    explanation: >-
      Quantifies the yield of clinical screening of relatives, which is why screening is
      not deferred pending variant reclassification.
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Current practice across clinical laboratories is to classify novel VCL pLOF variants
      as variants of uncertain significance
    explanation: >-
      The reason a VCL result usually cannot carry predictive weight on its own in a
      counseling setting.
animal_models:
- name: Cardiomyocyte-specific vinculin knockout mouse
  species: Mouse
  genotype: Vcl conditional knockout, Cre-loxP cardiomyocyte-specific excision
  publication: PMID:17785437
  description: >-
    The reference in vivo model for CMD1W mechanism. Cre-loxP excision of Vcl in
    cardiomyocytes produced adherens junction abnormalities, intercalated disc dissolution,
    reduced cadherin and beta1D integrin, and lateral connexin 43 mislocalization, all
    before any contractile deficit. Half the animals then died suddenly of ventricular
    tachycardia in the first three months with preserved contractile function, and the
    survivors developed dilated cardiomyopathy.
  genes:
  - preferred_term: VCL
    term:
      id: hgnc:12665
      label: VCL
  modeled_mechanisms:
  - target: Intercalated Disc and Costamere Destabilization
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Directly demonstrates that removing vinculin from cardiomyocytes destabilizes both
      the cell-cell and the cell-matrix adhesion structures, and does so before contractile
      function falls.
    limitations: >-
      A complete cardiomyocyte-restricted null, not the heterozygous state that human
      carriers have, so the magnitude and the timing are both expected to overstate the
      human lesion. It also models the loss-of-function allelic class only; the
      metavinculin-tail alleles are not a dosage lesion and are not represented.
    readouts:
    - name: Intercalated disc ultrastructure
      target: Intercalated Disc and Costamere Destabilization
      direction: ALTERED
      interpretation: >-
        Dissolution of the disc structure on electron microscopy is the structural
        correlate of this node.
      evidence:
      - reference: PMID:17785437
        reference_title: "Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Prior to the onset of cardiac dysfunction, ultrastructural analysis of cVclKO
          heart tissue showed abnormal adherens junctions with dissolution of the
          intercalated disc structure, expression of the junctional proteins cadherin and
          beta1D integrin were reduced, and the gap junction protein connexin 43 was
          mislocalized to the lateral myocyte border.
        explanation: Reports the ultrastructural measurement behind this readout.
    evidence:
    - reference: PMID:17785437
      reference_title: "Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        shows that it is required for preservation of normal cell-cell and cell-matrix
        adhesive structures
      explanation: >-
        Supports treating this model as informative for the junctional node.
  - target: Connexin 43 Lateralization and Conduction Slowing
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Provides the electrophysiological demonstration that the junctional lesion slows
      conduction and generates ventricular tachycardia.
    limitations: >-
      Murine cardiac electrophysiology differs substantially from human, and the model is a
      complete null. Human VCL carriers show conduction disease at low frequency and no
      genotype-specific defibrillator indication is established, so the arrhythmic severity
      here does not transfer.
    readouts:
    - name: Myocardial conduction by optical mapping
      target: Connexin 43 Lateralization and Conduction Slowing
      direction: DECREASED
      interpretation: >-
        Defective conduction on optical mapping is the functional correlate of the
        displaced gap junctions.
      evidence:
      - reference: PMID:17785437
        reference_title: "Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Conscious telemetry documented ventricular tachycardia as the cause of sudden
          death, while defective myocardial conduction was detected by optical mapping.
        explanation: Reports the conduction measurement behind this readout.
  - target: Ventricular Dilation and Systolic Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Knockout animals surviving the arrhythmic period went on to develop dilated
      cardiomyopathy, closing the chain from adhesion failure to chamber dilation.
    limitations: >-
      The dilated phenotype appears only in the survivors of a lethal arrhythmic phase that
      has no human counterpart at this frequency, and the time course is compressed into
      six months.
    readouts:
    - name: Development of dilated cardiomyopathy in survivors
      target: Ventricular Dilation and Systolic Dysfunction
      direction: INCREASED
      interpretation: >-
        Onset of dilated cardiomyopathy in the surviving knockouts is the phenotypic
        correlate of this node.
      evidence:
      - reference: PMID:17785437
        reference_title: "Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          cVclKO mice that survived through the vulnerable period of sudden death developed
          dilated cardiomyopathy and died before 6 months of age.
        explanation: Reports the phenotypic outcome behind this readout.
- name: Vinculin Y822F knock-in mouse
  species: Mouse
  genotype: Vcl Y822F homozygous knock-in
  publication: PMID:41231303
  description: >-
    A mechanism-probing allele rather than a disease model. Substituting phenylalanine for
    tyrosine at vinculin residue 822 removes a phosphorylation site whose occupancy peaks
    while cardiac adhesions are remodeling and rises again after adult cardiac injury.
    Homozygous mice are viable and develop cardiac dysfunction by 28 weeks, and cultured
    mutant cardiomyocytes show disorganized cell-cell adhesion. Y822F is not a reported
    human CMD1W allele.
  genes:
  - preferred_term: VCL
    term:
      id: hgnc:12665
      label: VCL
  modeled_mechanisms:
  - target: Impaired Vinculin-Actin Coupling at Cardiomyocyte Adhesion Complexes
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      Perturbs vinculin-dependent adhesion coupling through loss of a regulatory
      phosphosite, showing that the coupling is dynamically regulated rather than static.
    limitations: >-
      Y822F is an engineered allele that has not been reported in a human patient, and the
      mice are homozygous where human carriers are heterozygous. It bears on how vinculin
      coupling is regulated, not on how a CMD1W variant behaves.
    readouts:
    - name: Cardiomyocyte cell-cell adhesion organization
      target: Impaired Vinculin-Actin Coupling at Cardiomyocyte Adhesion Complexes
      direction: ALTERED
      interpretation: >-
        Disorganized cell-cell adhesion in mutant cardiomyocytes is the cellular correlate
        of impaired vinculin coupling.
      evidence:
      - reference: PMID:41231303
        reference_title: "Vinculin Y822 phosphorylation regulates adhesion remodeling during cardiomyocyte maturation."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Defects in cell-cell adhesion organization were also observed in cultured Vcl
          Y822F cardiomyocytes.
        explanation: >-
          Reports the cultured-cardiomyocyte measurement behind this readout.
    evidence:
    - reference: PMID:41231303
      reference_title: "Vinculin Y822 phosphorylation regulates adhesion remodeling during cardiomyocyte maturation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We mutated Vcl Y822 to phenylalanine (Y822F) in the mouse to determine the in vivo
        function of pY822.
      explanation: >-
        Establishes the model and its purpose as a probe of vinculin regulation.
  evidence:
  - reference: PMID:41231303
    reference_title: "Vinculin Y822 phosphorylation regulates adhesion remodeling during cardiomyocyte maturation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found that VCL pY822 regulated cardiomyocyte cell-matrix and cell-cell adhesions
      during postnatal heart development.
    explanation: >-
      The developmental regulation this model demonstrates, which is what makes it relevant
      to an infantile-onset adhesion disease.
experimental_models:
- name: ZZUNEUi026-A patient-derived iPSC line
  experimental_model_type: IPSC_DERIVED_MODEL
  publication: PMID:35567849
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: >-
    Peripheral blood mononuclear cells from a 65-year-old man with dilated cardiomyopathy
    carrying heterozygous VCL c.625A>T (p.Met209Leu), reprogrammed with non-integrating
    Sendai virus.
  description: >-
    The only published patient-derived cellular resource for a VCL dilated cardiomyopathy
    genotype. It is characterized as a stem cell line - pluripotency markers, normal
    karyotype, three-germ-layer differentiation - and no disease phenotyping was reported,
    so it is deliberately recorded without modeled_mechanisms. Making it informative for
    any pathophysiology node would require an isogenic corrected control and a
    cardiomyocyte or engineered-heart-tissue readout; neither exists. The resource paper
    also does not establish that p.Met209Leu is pathogenic.
  evidence:
  - reference: PMID:35567849
    reference_title: "Establishment of a human iPSC (ZZUNEUi026-A) from a dilated cardiomyopathy patient carrying heterozygous Vinculin (c. 625A > T) mutant."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A human induced pluripotent stem cell (iPSC) line (ZZUNEUi026-A) was generated from a
      DCM patient carrying heterozygous Vinculin mutant
    explanation: >-
      Establishes the line and its genotype of origin.
  - reference: PMID:35567849
    reference_title: "Establishment of a human iPSC (ZZUNEUi026-A) from a dilated cardiomyopathy patient carrying heterozygous Vinculin (c. 625A > T) mutant."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ZZUNEUi026-A showed pluripotency markers and normal karyotype, and it could
      differentiate into three germ layers in vitro.
    explanation: >-
      The full extent of the reported characterization: stem cell quality control, no
      disease phenotype.
discussions:
- discussion_id: no_vcl_directed_therapy_or_trial
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is there any VCL-directed therapeutic development for CMD1W, and if not, what would a
    trial-ready endpoint look like in a phenotype that frequently recovers on standard
    therapy?
  attaches_to:
  - treatments#
  rationale: >-
    A ClinicalTrials.gov search on 2026-09-03 for "vinculin" returned zero studies, and a
    search restricted to dilated cardiomyopathy with the term "VCL gene" also returned
    zero. No clinical_trials block is curated for this entry because there is nothing to
    curate, and the absence is recorded here rather than left as a silent gap. Every
    treatment in this entry acts on the expressed heart failure phenotype, not on the
    adhesion lesion. The design problem specific to CMD1W is that the most common natural
    course under standard therapy is recovery, so a genotype-targeted agent would have to
    beat an already favourable comparator in a very small population.
- discussion_id: no_subtype_specific_epidemiology_or_survival
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the prevalence, incidence and survival of CMD1W as an entity, as opposed to
    the carrier frequency of VCL variants?
  attaches_to:
  - prevalence#
  rationale: >-
    Everything currently quotable is either a reference-population variant frequency or a
    variant yield inside a testing cohort. Neither is a disease rate, and with a
    reduced-penetrance allele the gap between the two is large and unmeasured. There is no
    CMD1W survival curve; the contemporary dilated cardiomyopathy registry outcome data
    cited in this entry's notes are all-cause and cannot be assigned to this genotype. The
    six-patient infant series is the only genotype-defined outcome dataset in existence and
    its 83% recovery figure must not be read as a population estimate.
- discussion_id: mouse_arrhythmic_severity_versus_human_phenotype
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why does cardiomyocyte-specific vinculin loss kill half of knockout mice by sudden
    arrhythmic death before three months, while human VCL loss-of-function carriers present
    predominantly with recoverable heart failure and only occasional conduction disease?
  attaches_to:
  - pathophysiology#Ventricular Arrhythmia and Conduction Disease
  - pathophysiology#Connexin 43 Lateralization and Conduction Slowing
  rationale: >-
    The mouse evidence for the electrical branch is strong and direct: connexin 43 moves to
    the lateral border, optical mapping shows defective conduction, telemetry documents
    ventricular tachycardia, and 49% die suddenly with contractile function still
    preserved. The human picture does not match that severity. Among 32 VCL
    loss-of-function probands only three had bradycardia or heart block and one had
    supraventricular tachycardia, and current practice is explicitly that a VCL variant does
    not by itself justify a defibrillator the way an LMNA or FLNC variant does, a position
    curated with its citation as the Implantable Cardioverter-Defibrillator treatment. The most
    likely explanation is dosage - the mouse is a complete cardiomyocyte-restricted null and
    human carriers are heterozygous - but that has not been demonstrated, and until it is,
    the arrhythmic node in this entry rests on a model whose translational validity to human
    CMD1W is the open question. This matters clinically, because it is the difference
    between an arrhythmia-first genotype and a heart-failure-first one.
  proposed_experiments:
  - experiment_id: heterozygous_vcl_arrhythmic_phenotyping
    name: Arrhythmic phenotyping of heterozygous Vcl mice under mechanical stress
    description: >-
      Telemetry and optical mapping in heterozygous rather than homozygous cardiomyocyte
      Vcl-deficient animals, at baseline and after a defined pressure-overload or
      inflammatory stress, to test whether the arrhythmic phenotype is a dosage effect and
      whether it requires a second hit in the way the human phenotype appears to.
    experiment_type:
      preferred_term: in vivo dosage-comparison and stress-challenge experiment
    readouts:
    - name: Spontaneous ventricular arrhythmia burden on telemetry
      target: pathophysiology#Ventricular Arrhythmia and Conduction Disease
      direction: INCREASED
      interpretation: >-
        A low unstressed burden that rises only after the applied stress would support the
        second-hit reading and explain the human-mouse gap.
    - name: Connexin 43 distribution at the intercalated disc
      target: pathophysiology#Connexin 43 Lateralization and Conduction Slowing
      direction: ALTERED
      interpretation: >-
        Whether lateralization occurs at half dosage at all, and if so whether it is
        stress-dependent.
    would_support:
    - pathophysiology#Ventricular Arrhythmia and Conduction Disease
    supporting_outcome:
    - >-
      Heterozygous animals show connexin 43 lateralization and an arrhythmic burden only
      after imposed stress, matching the reduced-penetrance human pattern.
    refuting_outcome:
    - >-
      Heterozygous animals show a severe unstressed arrhythmic phenotype comparable to the
      homozygous knockout, which would leave the human-mouse discrepancy unexplained by
      dosage and point instead at a species difference in cardiac electrophysiology.
diagnosis:
- name: Transthoracic echocardiography
  description: >-
    The study that establishes the dilated cardiomyopathy phenotype and defines it
    quantitatively, before any question of VCL sequencing arises. It is also the
    instrument through which the recovery phenotype of this genotype is observed and
    followed: every infant in the genotype-defined series was characterized on
    echocardiography at diagnosis, and the normalization of ventricular function in five
    of six was measured the same way.
  diagnosis_term:
    preferred_term: transthoracic echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:33652931
    reference_title: "Diagnosis and Risk Prediction of Dilated Cardiomyopathy in the Era of Big Data and Genomics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A full diagnostic work-up for DCM typically includes a focused history, laboratory evaluation, electrocardiography (ECG), Holter monitoring, echocardiography, CMR (with late gadolinium enhancement (LGE)), and genetic testing"
    explanation: >-
      Places echocardiography inside the standard dilated cardiomyopathy work-up
      alongside the genetic testing this entry already curates.
  - reference: PMID:33652931
    reference_title: "Diagnosis and Risk Prediction of Dilated Cardiomyopathy in the Era of Big Data and Genomics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DCM is considered in the presence of (1) left ventricular dilatation (indexed left ventricular end-diastolic diameter (LVEDd) >117% for age and sex, or the LV end-diastolic volume (LVEDV) ≥2 standard deviations from normal according to normograms), and (2) left ventricular systolic dysfunction (LV ejection fraction (LVEF) <45% and/or LV fractional shortening <25%)."
    explanation: >-
      The diagnostic thresholds themselves. Both limbs are echocardiographic
      measurements, which is why this modality and not genetic testing is what makes the
      diagnosis.
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients showed LV dilation and dysfunction on echocardiograms and LV or biventricular hypertrophy and T wave abnormalities on electrocardiogram."
    explanation: >-
      Records that the echocardiographic finding in the genotype-defined VCL series was
      left ventricular dilation and dysfunction, which is what the modality contributes
      in this specific disease.
- name: Cardiac magnetic resonance with late gadolinium enhancement
  description: >-
    Tissue characterization added to the echocardiographic diagnosis. Late gadolinium
    enhancement identifies replacement fibrosis and carries prognostic weight in dilated
    cardiomyopathy generally. No CMD1W-specific enhancement pattern has been described,
    so the modality is curated at the level the source supports, which is the general
    dilated cardiomyopathy work-up and risk assessment rather than a VCL signature.
  diagnosis_term:
    preferred_term: cardiac magnetic resonance imaging with late gadolinium enhancement
    term:
      id: NCIT:C137915
      label: Magnetic Resonance Imaging of the Heart
  evidence:
  - reference: PMID:33652931
    reference_title: "Diagnosis and Risk Prediction of Dilated Cardiomyopathy in the Era of Big Data and Genomics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A full diagnostic work-up for DCM typically includes a focused history, laboratory evaluation, electrocardiography (ECG), Holter monitoring, echocardiography, CMR (with late gadolinium enhancement (LGE)), and genetic testing"
    explanation: >-
      Places cardiac magnetic resonance with late gadolinium enhancement in the standard
      dilated cardiomyopathy work-up.
  - reference: PMID:33652931
    reference_title: "Diagnosis and Risk Prediction of Dilated Cardiomyopathy in the Era of Big Data and Genomics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The use of clinically granular investigations, such as late gadolinium enhancement on cardiac magnetic resonance imaging, is warranted in order to increase predictive performance."
    explanation: >-
      The reason the study is done rather than deferred, which is that it adds
      information risk models built on ejection fraction alone do not carry.
- name: Electrocardiography
  description: >-
    Baseline rhythm and conduction assessment. It matters more in this entry than the
    disease-level work-up alone would suggest, because bradycardia, heart block and
    supraventricular tachycardia are documented minority findings in VCL
    loss-of-function probands, and because the infant series recorded a consistent
    abnormal electrocardiogram at presentation.
  diagnosis_term:
    preferred_term: electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  evidence:
  - reference: PMID:33652931
    reference_title: "Diagnosis and Risk Prediction of Dilated Cardiomyopathy in the Era of Big Data and Genomics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A full diagnostic work-up for DCM typically includes a focused history, laboratory evaluation, electrocardiography (ECG), Holter monitoring, echocardiography, CMR (with late gadolinium enhancement (LGE)), and genetic testing"
    explanation: >-
      Places electrocardiography in the standard dilated cardiomyopathy work-up.
  - reference: PMID:37548861
    reference_title: "Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients showed LV dilation and dysfunction on echocardiograms and LV or biventricular hypertrophy and T wave abnormalities on electrocardiogram."
    explanation: >-
      The electrocardiographic findings actually observed in the genotype-defined VCL
      series, which is what this modality contributes here beyond generic screening.
- name: Ambulatory (Holter) rhythm monitoring
  description: >-
    Extended rhythm recording, which is what detects the intermittent conduction and
    tachyarrhythmia findings that a single resting tracing misses. It is the diagnostic
    counterpart of the arrhythmic branch of this entry's pathograph, and it is the
    measurement that would be needed to say whether the severe arrhythmic phenotype of
    the murine model has any quiet human counterpart.
  diagnosis_term:
    preferred_term: ambulatory Holter electrocardiographic monitoring
    term:
      id: NCIT:C38064
      label: Holter Monitoring
  evidence:
  - reference: PMID:33652931
    reference_title: "Diagnosis and Risk Prediction of Dilated Cardiomyopathy in the Era of Big Data and Genomics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A full diagnostic work-up for DCM typically includes a focused history, laboratory evaluation, electrocardiography (ECG), Holter monitoring, echocardiography, CMR (with late gadolinium enhancement (LGE)), and genetic testing"
    explanation: >-
      Places Holter monitoring in the standard dilated cardiomyopathy work-up as a
      distinct study from the resting electrocardiogram.
- name: Cardiomyopathy multigene panel including VCL
  description: >-
    Genetic testing for CMD1W is done through a curated cardiomyopathy next-generation
    sequencing panel that includes VCL with copy-number analysis, since one of the reported
    allele classes is a multi-exon duplication. Two interpretive cautions are specific to
    this gene. Most VCL loss-of-function alleles are reported as variants of uncertain
    significance, so a positive result usually cannot be used for predictive cascade
    testing on its own. And uptake of testing is the binding constraint in practice rather
    than panel content: dilated cardiomyopathy has the lowest genetic testing rate of the
    guideline-indicated cardiovascular diagnoses.
  evidence:
  - reference: PMID:37915745
    reference_title: "Real-world utilization of guideline-directed genetic testing in inherited cardiovascular diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 0.8%, the DCM cohort demonstrated the lowest utilization of genetic testing."
    explanation: >-
      Quantifies the implementation gap: 827 of 101,919 newly diagnosed dilated
      cardiomyopathy patients had recorded genetic testing.
  - reference: PMID:32516855
    reference_title: "An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Current practice across clinical laboratories is to classify novel VCL pLOF variants
      as variants of uncertain significance
    explanation: >-
      The interpretive caution that governs how a positive VCL panel result can be used.
references:
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
notes: >-
  CMD1W is the VCL member of the numbered dilated cardiomyopathy series. The reason it
  earns a separate entry rather than folding into the parent is mechanistic and is curated
  explicitly: its lesion is in force transmission at the intercalated disc and costamere,
  not in force generation by the sarcomere. Its sarcomeric siblings in this series
  (CMD1S/MYH7, CMD1E/TNNT2) perturb the motor; CMD1W perturbs the junction that motor
  pushes against. That difference shows up clinically as an infantile, frequently
  recoverable phenotype rather than the progressive adult course typical of the sarcomeric
  entries, and it is why the entry conforms to the shared
  cardiomyopathy_maladaptive_remodeling module only from the Primary Cardiomyocyte Insult
  node onward, with three intervening adhesion nodes of its own.

  Two allelic classes, curated apart. The metavinculin-specific exon alleles
  (p.Arg975Trp, p.Leu954del) are qualitative: the protein is present and cross-links actin
  abnormally, and the effect is restricted to the muscle isoform. The predicted
  loss-of-function alleles hit both transcripts and reduce dosage. Keeping them as separate
  trigger nodes is not bookkeeping - the founding entity was defined on the first class,
  and almost all modern evidence, including the epidemiology, the pediatric skew and the
  recovery phenotype, comes from the second. Conflating them would attribute the infant
  recovery data to the metavinculin alleles, where no such data exist.

  Gene-disease validity and penetrance are separate judgements. ClinGen classified
  VCL-dilated cardiomyopathy as Strong in August 2024, which is a statement about whether
  the gene causes the disease. The largest aggregate study concluded that a heterozygous
  loss-of-function allele is insufficient on its own, which is a statement about individual
  alleles. Both are curated: the ClinGen row supports the CAUSATIVE relationship, and the
  same Hawley sentence appears as SUPPORT on the inheritance and hypothesis blocks and as
  REFUTE against the strong reading of CAUSATIVE in the genetic block, because it genuinely
  cuts both ways depending on the claim.

  What was checked and not curated.
  ClinicalTrials.gov was searched directly on 2026-09-03 rather than relying on the
  deep-research report: "vinculin" returned zero studies and a dilated cardiomyopathy search
  with "VCL gene" returned zero. No clinical_trials block is present and the absence is
  recorded as a knowledge gap.
  No environmental block is curated. The deep-research report lists alcohol, cardiotoxic
  chemotherapy, hypertension and viral myocarditis as plausible second hits, but none has
  been measured in VCL carriers; the only citable statement is the Hawley conjecture, which
  is curated on the Additional Genetic or Environmental Stressor pathophysiology node
  instead, where its status as a conjecture is visible.
  No ORPHA record is cited. The Orphanet concept for familial isolated dilated
  cardiomyopathy (ORPHA:154) is not VCL-specific and is not in this repository's reference
  cache.
  Two references fetched during curation are deliberately not cited. PMID:38867869, the
  commentary on the 2023 ESC cardiomyopathy guidelines, was read for the device and
  risk-stratification question but its only genotype-specific statement lists the genes
  associated with an arrhythmogenic non-dilated phenotype (FLNC, DSP, DES, PLN, TMEM43,
  RBM20); VCL is absent from that list, and quoting a list to assert something about a
  gene it does not name would be an argument from silence, so the defibrillator caveat is
  cited to a source that states the genotype-specific principle positively instead.
  PMID:19952892 (Zemljic-Harpf, vinculin and talin in the myocardium) is a review whose
  mechanistic content here is carried by the primary sources already cited on the same
  nodes, principally the cardiomyocyte-specific knockout, so it would add a citation
  without adding a claim.
  GO:0060047 heart contraction is retained on the two nodes that carry it. It is an
  organ-level process where the convention prefers HP or UBERON, but the term is used the
  same way across the numbered dilated cardiomyopathy series and in the shared
  cardiomyopathy entries, and dropping it here alone would make this entry inconsistent
  with its siblings for no gain.
  Contemporary dilated cardiomyopathy registry outcomes (PMID:32452075, 1.46 combined
  death/transplant/assist-device events per 100 patient-years in the most recent enrolment
  era) were read but not curated as evidence, because they are all-cause and cannot be
  assigned to this genotype. No CMD1W survival estimate exists.

  GeneReviews scope. The applicable GeneReviews resource is the disease-level "Dilated
  Cardiomyopathy Overview" (PMID:20301486), tagged in `references`. Its indexed PubMed
  record is content_type abstract_only and carries only the chapter's purpose statement,
  with no Clinical Characteristics or Management sections, so no snippet is quoted from it
  and the phenotype baseline for this entry is built from the primary VCL cohort, case
  series and pedigree literature.

  Source provenance. The Edison/falcon deep-research report
  (research/Dilated_Cardiomyopathy_1W-deep-research-falcon.md) was used as a lead list
  only. It cites by author-year key with DOIs and carries no PMIDs, so every DOI was
  resolved to a PMID through the PMC ID converter or a PubMed title search and the PMID is
  what is cited here, keeping every evidence item on the snippet-checked path. The report's
  own term-validation section flags five HP identifiers as "named something else"; those
  are false alarms caused by the validator reading a frequency column as a label, and each
  identifier was re-verified independently against OLS before use. The report also declines
  to name a MONDO identifier for the entity and suggests using the parent term instead;
  MONDO:0012667 does exist and is used here.

📚

References & Deep Research

References

1

PMID:20301486

Dilated Cardiomyopathy Overview.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

CMD1W is the VCL member of the numbered dilated cardiomyopathy series. The reason it earns a separate entry rather than folding into the parent is mechanistic and is curated explicitly: its lesion is in force transmission at the intercalated disc and costamere, not in force generation by the sarcomere. Its sarcomeric siblings in this series (CMD1S/MYH7, CMD1E/TNNT2) perturb the motor; CMD1W perturbs the junction that motor pushes against. That difference shows up clinically as an infantile, frequently recoverable phenotype rather than the progressive adult course typical of the sarcomeric entries, and it is why the entry conforms to the shared cardiomyopathy_maladaptive_remodeling module only from the Primary Cardiomyocyte Insult node onward, with three intervening adhesion nodes of its own. Two allelic classes, curated apart. The metavinculin-specific exon alleles (p.Arg975Trp, p.Leu954del) are qualitative: the protein is present and cross-links actin abnormally, and the effect is restricted to the muscle isoform. The predicted loss-of-function alleles hit both transcripts and reduce dosage. Keeping them as separate trigger nodes is not bookkeeping - the founding entity was defined on the first class, and almost all modern evidence, including the epidemiology, the pediatric skew and the recovery phenotype, comes from the second. Conflating them would attribute the infant recovery data to the metavinculin alleles, where no such data exist. Gene-disease validity and penetrance are separate judgements. ClinGen classified VCL-dilated cardiomyopathy as Strong in August 2024, which is a statement about whether the gene causes the disease. The largest aggregate study concluded that a heterozygous loss-of-function allele is insufficient on its own, which is a statement about individual alleles. Both are curated: the ClinGen row supports the CAUSATIVE relationship, and the same Hawley sentence appears as SUPPORT on the inheritance and hypothesis blocks and as REFUTE against the strong reading of CAUSATIVE in the genetic block, because it genuinely cuts both ways depending on the claim. What was checked and not curated. ClinicalTrials.gov was searched directly on 2026-09-03 rather than relying on the deep-research report: "vinculin" returned zero studies and a dilated cardiomyopathy search with "VCL gene" returned zero. No clinical_trials block is present and the absence is recorded as a knowledge gap. No environmental block is curated. The deep-research report lists alcohol, cardiotoxic chemotherapy, hypertension and viral myocarditis as plausible second hits, but none has been measured in VCL carriers; the only citable statement is the Hawley conjecture, which is curated on the Additional Genetic or Environmental Stressor pathophysiology node instead, where its status as a conjecture is visible. No ORPHA record is cited. The Orphanet concept for familial isolated dilated cardiomyopathy (ORPHA:154) is not VCL-specific and is not in this repository's reference cache. Two references fetched during curation are deliberately not cited. PMID:38867869, the commentary on the 2023 ESC cardiomyopathy guidelines, was read for the device and risk-stratification question but its only genotype-specific statement lists the genes associated with an arrhythmogenic non-dilated phenotype (FLNC, DSP, DES, PLN, TMEM43, RBM20); VCL is absent from that list, and quoting a list to assert something about a gene it does not name would be an argument from silence, so the defibrillator caveat is cited to a source that states the genotype-specific principle positively instead. PMID:19952892 (Zemljic-Harpf, vinculin and talin in the myocardium) is a review whose mechanistic content here is carried by the primary sources already cited on the same nodes, principally the cardiomyocyte-specific knockout, so it would add a citation without adding a claim. GO:0060047 heart contraction is retained on the two nodes that carry it. It is an organ-level process where the convention prefers HP or UBERON, but the term is used the same way across the numbered dilated cardiomyopathy series and in the shared cardiomyopathy entries, and dropping it here alone would make this entry inconsistent with its siblings for no gain. Contemporary dilated cardiomyopathy registry outcomes (PMID:32452075, 1.46 combined death/transplant/assist-device events per 100 patient-years in the most recent enrolment era) were read but not curated as evidence, because they are all-cause and cannot be assigned to this genotype. No CMD1W survival estimate exists. GeneReviews scope. The applicable GeneReviews resource is the disease-level "Dilated Cardiomyopathy Overview" (PMID:20301486), tagged in `references`. Its indexed PubMed record is content_type abstract_only and carries only the chapter's purpose statement, with no Clinical Characteristics or Management sections, so no snippet is quoted from it and the phenotype baseline for this entry is built from the primary VCL cohort, case series and pedigree literature. Source provenance. The Edison/falcon deep-research report (research/Dilated_Cardiomyopathy_1W-deep-research-falcon.md) was used as a lead list only. It cites by author-year key with DOIs and carries no PMIDs, so every DOI was resolved to a PMID through the PMC ID converter or a PubMed title search and the PMID is what is cited here, keeping every evidence item on the snippet-checked path. The report's own term-validation section flags five HP identifiers as "named something else"; those are false alarms caused by the validator reading a frequency column as a label, and each identifier was re-verified independently against OLS before use. The report also declines to name a MONDO identifier for the entity and suggests using the parent term instead; MONDO:0012667 does exist and is used here.

Address review on PR #10877 · 2026-09-04T16:43:30Z · View source

Addressed the three IMPORTANT findings on PR #10877, all of the same shape: references this PR fetched into references_cache/ and then never cited. No new literature was fetched and no deep research was run. Finding 1 (treatments named only two of the four HFrEF pillars). Heart Failure Pharmacotherapy now carries five therapeutic_agent entries beyond the original ACE inhibitor and beta-adrenergic antagonist: angiotensin receptor-neprilysin inhibitor (NCIT:C190796), mineralocorticoid receptor antagonist (NCIT:C101255 Aldosterone Receptor Antagonist), SGLT2 inhibitor (NCIT:C98083) and loop diuretic (NCIT:C448 Diuretic). Five new evidence items from PMID:37653361 back them: the four-pillars sentence, the RAAS/ARNi first-line sentence, the MRA recommendation, the SGLT2i pillar sentence and the loop-diuretic preference sentence. The node description was rewritten to name the four pillars and, importantly, to keep the adult guideline regimen separate from what the six-infant genotype-defined series actually received (an ACE inhibitor and a beta-blocker only), so the entry does not imply infants were given SGLT2 inhibitors. Finding 2 (no device or advanced-care therapy despite an uncited device-indication claim in prose twice). Three new DEVICE treatments were added rather than one: Implantable Cardioverter-Defibrillator (NCIT:C80435 Implantable Cardioverter-Defibrillator Placement, INHIBITS Ventricular Arrhythmia and Conduction Disease), Cardiac Resynchronization Therapy (NCIT:C80436, MODULATES Heart Failure with Reduced Ejection Fraction) and Ventricular Assist Device Support (NCIT:C80452 Ventricular Assist Device Placement, BYPASSES the same node). The ICD entry carries the ACC/AHA/HFSA primary-prevention indication from PMID:37653361 and, for the VCL-specific caveat, the PMID:39519012 sentence that LMNA cardiomyopathy is one of the few genotype-specific evidence-based guideline recommendations in the cardiomyopathies, marked directness: INDIRECT with an explanation that states the inference step explicitly (the VCL claim follows from VCL not being on that short list, not from any statement about VCL). The VAD entry quotes the Zahavich sentence describing the one infant who went to an assist device at 7 months and transplantation at 10 months. The two prose device claims were kept, not deleted, and each now points at the curated ICD treatment. Finding 3 (diagnosis covered only the genetic panel). Four diagnosis entries were added ahead of the multigene panel, all grounded in the previously uncited PMID:33652931: transthoracic echocardiography (NCIT:C16525), cardiac magnetic resonance with late gadolinium enhancement (NCIT:C137915), electrocardiography (NCIT:C38053) and ambulatory Holter rhythm monitoring (NCIT:C38064). Evidence is the full diagnostic work-up sentence, the DCM diagnostic-criteria sentence, the LGE predictive-performance sentence, and the Zahavich sentence recording the echocardiographic and electrocardiographic findings in the VCL series. Suggestions taken and declined. reference_title capitalization was matched to the cache frontmatter for PMID:37548861 (16 occurrences) and PMID:24062880 (2 occurrences). GO:0060047 heart contraction was retained on the two nodes that carry it, with the reason recorded in notes: the term is used the same way across the numbered dilated cardiomyopathy series and the shared cardiomyopathy entries, so dropping it here alone would create a sibling inconsistency for no gain. The two remaining references cached by this PR and still uncited, PMID:38867869 and PMID:19952892, were added to the What was checked and not curated section of notes with reasons; PMID:38867869 was specifically declined because its only genotype-specific statement is a gene list that does not name VCL, and quoting it for the defibrillator caveat would have been an argument from silence. Term derivation. Every NCIT CURIE added was re-derived rather than recalled: each was confirmed present in cache/ncit/terms.csv with the label used, confirmed a member of cache/enums/treatmentactionterm or chemicalentityterm as appropriate, and its OLS definition read to confirm it names the right concept. NCIT:C80435 is the procedure Implantable Cardioverter-Defibrillator Placement, not a device term, and NCIT:C101255 Aldosterone Receptor Antagonist carries the synonym Aldosterone inhibitor (mineralocorticoid receptor antagonist), which is why it is the correct binding for the MRA class. No new cache rows were needed. Snippet handling. All 15 new snippets were extracted programmatically from the cache files rather than transcribed, preserving the thin-space and non-breaking-space characters the guideline text uses around the LVEF and QRS thresholds, and each is written as a single-line double-quoted scalar so no folded-scalar join can alter it. evidence_source follows how this file already grades each publication: OTHER for PMID:37653361 and for the newly cited review PMID:33652931, HUMAN_CLINICAL for PMID:39519012 and PMID:37548861. Validation. just validate (93/93 snippets verified, up from 76/76), validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence, check-not4curation and the batched validate-disorders all pass. git status shows only the disorder YAML modified: no references_cache upgrades and no cache CSV churn.

Create: Dilated_Cardiomyopathy_1W · 2026-09-04T03:35:55Z · View source

De novo creation of the VCL/metavinculin dilated cardiomyopathy entry (MONDO:0012667), curating the mechanism as a failure of force transmission at the intercalated disc and costamere rather than a failure of sarcomeric force generation. This is what distinguishes it from its sarcomeric siblings in the numbered series (CMD1S/MYH7, CMD1E/TNNT2) and is the stated reason for a separate entry. Modelling decisions. - Two trigger nodes, not one. Metavinculin-exon alleles (p.Arg975Trp, p.Leu954del) are isoform-restricted and act by qualitatively altered actin cross-linking; predicted loss-of-function alleles affect both the NM_014000.2 and NM_003373.3 transcripts and act by dosage reduction. Almost all modern evidence (case-control enrichment, pediatric skew, infantile recovery) comes from the second class alone, so merging the classes would have attributed outcome data to alleles that have none. - A third pathophysiology node, "Additional Genetic or Environmental Stressor", carries the second-hit requirement that Hawley 2020 (PMID:32516855) establishes, with mechanism_confidence HYPOTHETICAL because the requirement is demonstrated but no specific second hit is. - Three mechanistic_hypotheses with edges opting in: metavinculin altered cross-linking (CANONICAL), pLOF reduced-penetrance risk allele (CANONICAL), and infantile adhesion immaturity explaining onset and recovery (EMERGING). - Conformance to cardiomyopathy_maladaptive_remodeling is declared at Primary Cardiomyocyte Insult, Ventricular Remodeling and Structural Cardiac Impairment and Heart Failure, with three adhesion-specific nodes in between that the module does not cover. Gene-disease validity versus allele penetrance. ClinGen classifies VCL-dilated cardiomyopathy as Strong (CGGV assertion 2d46699a, 2024-08-09, SOP10), which supports relationship_type CAUSATIVE. Hawley 2020 concludes a heterozygous loss-of-function allele is insufficient on its own. Both are curated: that Hawley sentence appears as SUPPORT on the inheritance block and the reduced-penetrance hypothesis, and as REFUTE against the strong reading of CAUSATIVE in the genetic block, with the reasoning stated in the explanation. HUMAN_MODEL_MISMATCH recorded. The cardiomyocyte-specific Vcl knockout mouse (PMID:17785437) kills 49% of animals by sudden arrhythmic death before three months with preserved contractile function; among 32 human VCL loss-of-function probands only three had bradycardia or heart block and one had supraventricular tachycardia. Recorded as a discussion attached to the two arrhythmia nodes, with a proposed heterozygous-dosage plus stress-challenge experiment, rather than letting the mouse severity stand as the human claim. Sourcing and defect handling. The Edison/falcon report (research/Dilated_Cardiomyopathy_1W-deep-research-falcon.md) was used as a lead list only. Three known defects were handled explicitly: - Its frontmatter carries mondo_id: '' (dismech#10335), so `just preflight-dr` was run by hand against MONDO:0012667. PASS, VCL mentioned 71 times. - The report carries no PMIDs, only DOIs. Every DOI intended for use was resolved to a PMID via the PMC ID converter or a PubMed title search, and the PMID is what is cited, so no evidence item depends on the unchecked DOI: skip-prefix path. Four DOIs had no PMC record and were resolved by title search: 10.1161/hc0402.102930 -> PMID:11815424, 10.2310/jim.0b013e3181c5e074 -> PMID:19952892, 10.1016/j.scr.2022.102812 -> PMID:35567849, 10.1002/ejhf.1914 -> PMID:32452075. - hgnc:12665 was verified independently against OAK (sqlite:obo:hgnc) rather than taken from the report, since HGNC is in the report validator's unresolvable_prefixes and a clean validation table cannot vouch for a gene CURIE. The report's term-validation section flags five HP identifiers as "named something else" (HP:0001644, HP:0001635, HP:0001711, HP:0030682, HP:0001653). These are false alarms: the validator read the frequency column of a markdown table as the label. Each identifier used was re-verified against OLS before binding. The report also declines to name a MONDO identifier and recommends the parent term; MONDO:0012667 exists and is used. Two HP identifiers the report suggested were not used as suggested: HP:0001711 (which HPO calls "Abnormal left ventricle morphology") was replaced with HP:0012664 "Reduced left ventricular ejection fraction" for the systolic dysfunction phenotype, and HP:0001653 (Mitral regurgitation) was dropped because the report itself records it as DCM-general with no subtype frequency and no citable VCL-specific observation exists. Checked and deliberately not curated. - ClinicalTrials.gov was searched directly (2026-09-03) rather than trusting the report: query "vinculin" returns 0 studies; dilated cardiomyopathy with "VCL gene" returns 0. No clinical_trials block; the absence is a KNOWLEDGE_GAP discussion attached to treatments#. - No environmental block. Alcohol, cardiotoxic chemotherapy, hypertension and viral myocarditis are named in the report as plausible second hits but none is measured in VCL carriers. The only citable statement is the Hawley conjecture, curated on the second-hit pathophysiology node where its status is visible. Adding speculative environmental entries would have needed evidence the literature does not supply. - No survival or prognosis figures. Merlo 2020 (PMID:32452075) registry outcomes were read but not curated, being all-cause and not assignable to this genotype. Recorded as a second KNOWLEDGE_GAP. - No ORPHA citation. ORPHA:154 (familial isolated DCM) is not VCL-specific and is not in this repository's reference cache. - GeneReviews: the applicable chapter is the disease-level "Dilated Cardiomyopathy Overview" (PMID:20301486). Its indexed PubMed record is content_type abstract_only and carries only the chapter purpose statement, so it is tagged in `references` and nothing is quoted from it; the phenotype baseline comes from the primary VCL cohort and case-series literature. - The iPSC line ZZUNEUi026-A (PMID:35567849) is curated in experimental_models without modeled_mechanisms, on purpose: the resource paper reports stem-cell quality control only and no disease phenotyping, so no mechanism link would be honest. The reason is stated in the model's description. Phenotype frequency caveat. The 59.4%, 6.3% and 9.4% figures are denominated over 32 VCL loss-of-function probands ascertained through cardiomyopathy testing panels, not over a CMD1W case series. They describe the phenotypic spectrum of the allele, not the penetrance of the disease, and each phenotype description says so. Validation, all run to completion on this branch: just validate (No issues found); just validate-terms (passed); just count-verified-snippets (76/76 verified); just check-entity-refs (OK); just check-causal-targets (OK, no new broken targets); just check-duplicate-keys (OK); just check-qualifier-terms (OK); just check-qualifier-terms-online (OK, 326 labels match, 97 resolved online); just check-enum-values (OK); just check-folded-hyphens (OK); just check-snippet-length (OK); just check-title-snippets (OK); just check-snippet-grading (OK); just check-environmental-evidence (OK); just validate-disorders (all passed); just check-stubs after stub deletion (OK, no errors); pytest tests/test_data.py filtered to entity-ref, subtype-FK, model-readout, causal-target and unique-name selections (21241 passed). Cache changes are derived, produced by validate-terms: GO:0005925, GO:0014704 and GO:0043034 added to the cellularcomponentterm enum cache and to cache/go/terms.csv, MONDO:0012667 added to the diseaseterm enum cache and cache/mondo/terms.csv. No cache row was hand-written. Lump/split disposition, as evidence for issue #9865: entry_type DISEASE, curated as a per-gene entry. dashboard/priority.json scores MONDO:0012667 at 48.5 with recommended_action LUMP_INTO_PARENT on specificity_bucket subtype_series. One of the features behind that score is wrong: clingen_strong_count is 0, but ClinGen does hold a Strong assertion for this gene-disease pair, filed against MONDO:0005021 rather than the numbered term, so the counter keyed on MONDO:0012667 sees nothing. Every numbered stub whose gene carries a ClinGen assertion against the parent term will mis-score the same way. The grouping file kb/groupings/Familial_Dilated_Cardiomyopathy.yaml was deliberately not edited, since several sibling curation PRs are open and would all conflict on its members: list; adding CMD1W is left for a batched maintainer pass.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 41 citations 2026-09-03T20:39:19.523737

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Dilated Cardiomyopathy 1W
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Dilated Cardiomyopathy 1W covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Dilated Cardiomyopathy 1W (VCL-associated DCM): comprehensive disease-characteristics report

Executive summary and evidence caveat

Dilated cardiomyopathy 1W (DCM1W) is the historical OMIM-style designation for dilated cardiomyopathy associated with heterozygous variation in VCL, encoding vinculin and its muscle-specific splice isoform metavinculin. The defining phenotype is left-ventricular or biventricular dilation with systolic dysfunction, after excluding coronary disease and abnormal loading conditions sufficient to explain the phenotype. Contemporary evidence requires an important qualification: some metavinculin missense/in-frame variants have functional evidence consistent with disease causation, whereas heterozygous VCL predicted loss-of-function (pLOF) variants appear more often to confer reduced-penetrance susceptibility or a modifier effect than fully penetrant monogenic disease. Thus, “Mendelian DCM1W” should not be interpreted as implying that every heterozygous VCL variant is causal. (hawley2020anassessmentof pages 12-15, hawley2020anassessmentof pages 8-12, olson2002metavinculinmutationsalter pages 1-2)

The strongest recent subtype-specific clinical study is a 2023 series of six infants: median age at diagnosis was 2 months, median LVEF 24%, and five of six recovered normal ventricular function, although one required transplantation. This suggests a potentially recoverable infantile phenotype, but the sample is far too small to provide population-level prognosis. (zahavich2023heartfailurewith pages 1-2)

The following compact table is suitable for a knowledge-base record; the narrative thereafter expands and qualifies its contents.

Knowledge-base field	DCM1W essential annotation	Evidence / ontology suggestions
Disease identity and identifiers	Dilated cardiomyopathy 1W (DCM1W) is the historical Mendelian label for VCL-associated dilated cardiomyopathy, characterized by ventricular dilation and systolic dysfunction after exclusion of sufficient ischemic, loading, valvular, or congenital causes. A subtype-specific MONDO identifier was not verified; use broader MONDO:0005021 (dilated cardiomyopathy) or MONDO:0016333 (familial dilated cardiomyopathy) with a VCL qualifier rather than inventing an identifier.	Open Targets maps VCL to dilated and familial dilated cardiomyopathy (OpenTargets Search: dilated cardiomyopathy-VCL). Suggested phenotype ontology: HP:0001644 Dilated cardiomyopathy.
Gene, protein, and locus	VCL encodes vinculin, a 117-kDa, 1,066-aa mechanosensitive actin-binding adaptor. The muscle-specific splice isoform metavinculin contains an additional 68 aa. Locus: 10q22.1–q23 in the foundational report; a later iPSC resource specifies 10q22.2. Vinculin/metavinculin localize to cardiomyocyte costameres and intercalated-disc adherens junctions.	Vinculin links F-actin to integrin- and cadherin-associated adhesion complexes (zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2, olson2002metavinculinmutationsalter pages 1-2, li2024vinculiny822phosphorylation pages 1-3). Suggested GO: GO:0005925 focal adhesion, GO:0005912 adherens junction, GO:0051015 actin filament binding; CL: CL:0000746 cardiac muscle cell.
Foundational metavinculin variants	p.Leu954del (in-frame 3-bp deletion) and p.Arg975Trp (missense) were identified among 350 unrelated DCM patients, absent from 500 controls, and significantly altered metavinculin-mediated actin-filament cross-linking in vitro. The p.Arg975Trp carrier had grossly abnormal intercalated discs.	Human genetic plus in-vitro functional evidence supports impaired force transmission at the thin-filament/intercalated-disc interface (olson2002metavinculinmutationsalter pages 1-2).
VCL predicted loss-of-function variants	In 18,135 cardiomyopathy-test referrals, 30 heterozygous probands carried 26 unique pLOF variants: 12 nonsense, seven frameshift, six canonical splice-site, and one multi-exon duplication. Rare pLOF variants were enriched in DCM: OR 9.01 (95% CI 4.93–16.45), rising to 11.33 (5.80–22.15) under stricter filtering. Population prevalence was approximately 0.0003–0.00046 in gnomAD, depending on filtering.	Human case-control evidence (hawley2020anassessmentof pages 4-8, hawley2020anassessmentof pages 18-20, hawley2020anassessmentof pages 8-12). Individual variants must be classified under ACMG/AMP criteria; many remain VUS.
Inheritance and penetrance	Usually modeled as heterozygous/autosomal-dominant susceptibility, but family data do not support uniformly sufficient, highly penetrant monogenic causation. Current evidence favors reduced/incomplete penetrance, variable expressivity, and a moderate-risk or modifier effect involving other genetic or environmental stressors. No convincing biallelic human series, anticipation, founder effect, or carrier-frequency estimate specific to DCM1W is established.	Family studies found no clear dominant segregation; possible modifiers include MYH7, DSP, TPM1, LAMA4, SCN5A, and MYBPC3 (hawley2020anassessmentof pages 12-15, hawley2020anassessmentof pages 8-12, wells2011familialdilatedcardiomyopathy pages 3-4).
Hallmark phenotype and onset	Hallmark disease is left-ventricular or biventricular dilation with reduced systolic function, often presenting as heart failure or arrhythmia. Among 32 VCL-pLOF probands, DCM/LV dilation occurred in 19/32 (59.4%); 22/32 (68.8%) had onset before 20 years, 16/32 (50%) by 10 years, and 13/32 (40.6%) in infancy. In the DCM subgroup, 17/19 (89.5%) had pediatric onset. Less-certain associated findings include LV noncompaction, hypertrophy, bradycardia, heart block, and ventricular tachycardia.	Human cohort evidence (hawley2020anassessmentof pages 8-12). Suggested HPO: HP:0001644 Dilated cardiomyopathy, HP:0001635 Congestive heart failure, HP:0001711 Abnormality of left ventricular function, HP:0004756 Ventricular tachycardia, HP:0001678 Atrioventricular block.
2023 infant outcomes	Six infants with VCL LOF variants had median diagnosis age 2 months, median LVEF 24%, and median LV end-diastolic-diameter z-score 10.8. With heart-failure medication, 5/6 (83%) normalized LV function after 0.3–3.2 years (median recovery age 2.7 years); 1/6 progressed to end-stage failure and transplantation. Five variants were VUS and one likely pathogenic, and four infants had additional cardiomyopathy-gene VUS.	Small human case series; estimates are not population-level rates and require replication (zahavich2023heartfailurewith pages 1-2).
Core mechanism	Pathogenic or risk-conferring VCL dysfunction leads to impaired vinculin/metavinculin binding and actin cross-linking; this weakens cadherin-based cell–cell and integrin-based cell–matrix anchorage; junctional instability results in defective force transmission and conduction; chronic mechanical stress is inferred to cause cardiomyocyte injury, adverse remodeling, ventricular dilation, systolic failure, and arrhythmia. Mouse knockout directly demonstrates reduced cadherin/β1-integrin, lateral connexin-43 redistribution, adherens-junction dissolution, intercalated-disc disruption, and disorganized mitochondria before dysfunction.	Human in-vitro and mouse evidence (zemljicharpf2009vinculinandtalin pages 4-5, zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2, olson2002metavinculinmutationsalter pages 1-2). Suggested GO: GO:0007155 cell adhesion, GO:0007015 actin filament organization, GO:0072659 protein localization to plasma membrane, GO:0003012 muscle system process.
Diagnostic approach	Establish the DCM phenotype with history and three-generation pedigree, examination, ECG/Holter, echocardiography, and CMR with late gadolinium enhancement; measure natriuretic peptides/troponin and exclude coronary disease, abnormal loading, valvular/congenital disease, toxins, infection, endocrine/metabolic disease, and sustained tachyarrhythmia. Use a curated cardiomyopathy multigene NGS panel including VCL with deletion/duplication analysis; WES/WGS or RNA studies may follow unresolved cases. Confirm candidate variants and perform segregation/cascade testing, but do not use a VCL VUS for predictive testing. Biopsy is reserved for selected suspected myocarditis, infiltrative, or inflammatory disease.	Contemporary DCM criteria and work-up (sammani2021diagnosisandrisk pages 2-4, newman2024dilatedcardiomyopathya pages 2-4, grasso2024thenew2023 pages 1-2). Genetic testing remains markedly underused: only 827/101,919 (0.8%) newly diagnosed US DCM patients had recorded testing within six months (longoni2023realworldutilizationof pages 1-2).
Treatment and surveillance	No approved VCL-specific therapy exists. Treat the expressed phenotype according to DCM/HFrEF guidance: ARNI or ACE inhibitor/ARB, evidence-based β-blocker, mineralocorticoid-receptor antagonist, SGLT2 inhibitor, and diuretics for congestion; continue guideline-directed therapy after EF recovery because recovery may not represent resolution. Consider ICD/CRT according to LVEF, conduction, arrhythmia, CMR, and overall risk—not VCL genotype alone. Advanced disease may require LV assist support or transplantation. Genotype-positive relatives need longitudinal ECG/imaging surveillance.	The infant series used ACE inhibitors and β-blockers (zahavich2023heartfailurewith pages 1-2); contemporary HF guidance supports continued therapy in improved EF (badger2023summaryandcomparison pages 6-7). Suggested NCIT concepts: Angiotensin-Converting Enzyme Inhibitor, Beta-Adrenergic Blocker, Implantable Cardioverter Defibrillator, Cardiac Resynchronization Therapy, Heart Transplantation.
Experimental and comparative models	Mouse: cardiac-specific Vcl knockout caused ventricular tachycardia/sudden death in 49% before 3 months; survivors developed DCM and died before 6 months. Heterozygous mice showed conduction/junction abnormalities and stress-induced vulnerability. Zebrafish: vinculin knockdown produced impaired contractility, pericardial edema, and blood congestion. Human iPSC: line ZZUNEUi026-A, from a 65-year-old man with heterozygous c.625A>T (p.Met209Leu), has a normal karyotype and can generate cardiomyocytes, but disease phenotyping was not reported. Y822F mouse: defective adhesion organization and cardiac dysfunction at 28 weeks implicate post-translational regulation.	Animal and cellular-resource evidence (zemljicharpf2009vinculinandtalin pages 4-5, wells2011familialdilatedcardiomyopathy pages 3-4, zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2, liu2022establishmentofa pages 1-2, li2024vinculiny822phosphorylation pages 1-3). Species: Mus musculus NCBI Taxon 10090; Danio rerio 7955; Homo sapiens 9606.
Major evidence limitations	DCM1W is ultra-rare and genetically heterogeneous; no reliable subtype-specific prevalence, incidence, sex ratio, penetrance percentage, survival curve, founder effect, protective allele, epigenetic signature, single-cell/spatial/multi-omics profile, or validated prognostic biomarker exists. Foundational missense/in-frame variants and modern pLOF observations may represent different allelic mechanisms. Many reported variants are VUS, unaffected heterozygotes occur, pedigrees are small, oligogenic findings are common, and the favorable infant recovery estimate derives from only six patients. No VCL-directed clinical trial was identified.	Modern authors explicitly recommend distinguishing VCL pLOF alleles from conventional highly penetrant Mendelian variants (zahavich2023heartfailurewith pages 1-2, hawley2020anassessmentof pages 12-15, hawley2020anassessmentof pages 15-18).

Table: Compact evidence-based summary of VCL-associated dilated cardiomyopathy, including disease identity, variants, penetrance, phenotype, mechanism, diagnosis, management, models, ontology suggestions, and key uncertainties.

1. Disease information

Definition

DCM is a myocardial disorder with ventricular dilation and impaired systolic function not adequately explained by coronary artery disease, hypertension, valvular disease, or congenital heart disease. One quantitative formulation requires LV end-diastolic dimension above 117% of the age- and sex-predicted value, or LV end-diastolic volume ≥2 SD above normal, together with LVEF <45% and/or fractional shortening <25%. Definitions vary across cohorts; a contemporary registry used LVEF <50% after exclusion of significant coronary disease and abnormal loading. (sammani2021diagnosisandrisk pages 2-4, grasso2024thenew2023 pages 1-2, merlo2020contemporarysurvivaltrends pages 1-4)

Identifiers and synonyms

Preferred name: Dilated cardiomyopathy 1W.
Synonyms: DCM1W; VCL-related dilated cardiomyopathy; vinculin-associated DCM; metavinculin-associated DCM; familial dilated cardiomyopathy due to VCL.
OMIM phenotype: 611407, commonly indexed as DCM1W. VCL gene OMIM: 193065. These identifiers should be checked against the current OMIM release before production ingestion.
MONDO: no subtype-specific MONDO identifier was verified in the retrieved evidence. Use MONDO:0005021, dilated cardiomyopathy, or MONDO:0016333, familial dilated cardiomyopathy, qualified by VCL, rather than inventing a subtype identifier. Open Targets links VCL to both records. (OpenTargets Search: dilated cardiomyopathy-VCL)
Orphanet: the broader familial isolated DCM concept is commonly represented by ORPHA:154; this is not VCL-specific.
ICD-10-CM: I42.0, dilated cardiomyopathy. ICD coding does not resolve DCM1W.
ICD-11: use the dilated-cardiomyopathy entity under cardiomyopathies; no VCL-specific code was identified.
MeSH: Dilated Cardiomyopathy; no gene-specific MeSH descriptor.
Suggested HPO anchor: HP:0001644, Dilated cardiomyopathy.

Data provenance

The disease description is an aggregated disease-level synthesis, not an individual EHR record. Evidence includes human case reports and pedigrees, a cohort assembled from >18,000 diagnostic/research referrals, a six-infant registry series with whole-genome sequencing, population controls, biochemical assays, and animal models. The 2023 real-world implementation statistic below derives from de-identified EHR/claims data rather than DCM1W-specific patients. (hawley2020anassessmentof pages 4-8, zahavich2023heartfailurewith pages 1-2, longoni2023realworldutilizationof pages 1-2)

2. Etiology

Causal and susceptibility factors

The implicated gene is VCL. Vinculin is a mechanosensitive adaptor coupling F-actin to cadherin-associated cell–cell adhesions and integrin-associated cell–matrix adhesions. Metavinculin is generated by muscle-specific alternative splicing and contains an additional 68 amino acids. Both isoforms occur at cardiomyocyte intercalated discs and costameres, major sites of contractile-force transmission. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2, olson2002metavinculinmutationsalter pages 1-2, li2024vinculiny822phosphorylation pages 1-3)

The foundational human study screened 350 unrelated DCM patients and found p.Arg975Trp and p.Leu954del in the metavinculin-specific region. Both affected conserved residues, were absent in 500 controls, and significantly altered actin-filament cross-linking in vitro. Its conclusion stated: “Disruption of force transmission at the thin filament-intercalated disc interface is the likely mechanism.” PMID 11815424; published 29 January 2002; DOI/URL: https://doi.org/10.1161/hc0402.102930. (olson2002metavinculinmutationsalter pages 1-2)

Modern pLOF evidence is statistically strong but penetrance is low. In 18,135 cardiomyopathy-test referrals, 30 heterozygous probands carried 26 unique pLOF variants: 12 nonsense, seven frameshift, six canonical splice variants, and one multi-exon duplication. Rare VCL pLOF variants were enriched in DCM, with OR 9.01 (95% CI 4.93–16.45), or 11.33 (5.80–22.15) under stricter filtering. Published June 2020; DOI/URL: https://doi.org/10.1002/humu.24061. (hawley2020anassessmentof pages 4-8, hawley2020anassessmentof pages 18-20, hawley2020anassessmentof pages 8-12)

Genetic risk and modifiers

Family data do not show uniformly convincing autosomal-dominant segregation. Unaffected heterozygotes and co-occurring variants support incomplete penetrance and possible oligogenic inheritance. Candidate co-contributors reported in VCL-positive cases include MYH7, DSP, TPM1, LAMA4, SCN5A, and MYBPC3. In one pedigree, VCL c.2444A>G (p.Lys815Arg) co-occurred with MYBPC3 p.Arg177Cys in more severely affected relatives, but modification was suggested rather than proved. (hawley2020anassessmentof pages 12-15, hawley2020anassessmentof pages 8-12, wells2011familialdilatedcardiomyopathy pages 3-4)

Environmental and gene–environment risk

No exposure is established specifically for DCM1W. Plausible “second hits” derive from DCM generally: viral myocarditis/inflammation, alcohol, anthracyclines and other cardiotoxic drugs, radiation, sustained tachyarrhythmia, hypertension, pregnancy, endocrine/metabolic disease, and heavy-metal exposure. VCL pLOF has been proposed to sensitize myocardium to such stress, but direct human VCL-by-exposure interaction estimates are unavailable. Mouse Vcl haploinsufficiency is comparatively mild at baseline but markedly worsens after pressure overload, supporting a stress-dependent model. (zemljicharpf2009vinculinandtalin pages 4-5, hershberger2021thecomplexand pages 3-4, hawley2020anassessmentof pages 12-15)

Protective factors

No validated protective VCL allele, modifier gene, diet, drug, or exposure has been identified. Avoidance of cardiotoxic exposures and early treatment are prudent risk reduction, not demonstrated primary prevention of DCM1W.

3. Phenotypes

Phenotype	Type and characteristics	Frequency/evidence	Suggested HPO
Dilated cardiomyopathy/LV dilation	Imaging sign; often progressive, but recovery can occur	19/32 (59.4%) VCL-pLOF probands	HP:0001644
LV systolic dysfunction	Imaging/functional abnormality; variable from asymptomatic to severe	Median LVEF 24% in six infants	HP:0001711
Congestive heart failure	Clinical syndrome: dyspnea, feeding difficulty, fatigue, edema, poor exercise tolerance	Presenting syndrome in the infant series; exact broader frequency unavailable	HP:0001635
Cardiomegaly/ventricular enlargement	Imaging/physical manifestation	Infant median LVEDD z-score 10.8	HP:0001640 / HP:0001712
Ventricular tachycardia/sudden-death susceptibility	Electrical phenotype	Human cases include VT; exact frequency unknown	HP:0004756; HP:0001645
Conduction disease/bradycardia	ECG sign	Three of 32 pLOF probands had bradycardia/heart block phenotypes	HP:0001662; HP:0001678
LV noncompaction	Imaging trait; association uncertain	2/32 pLOF probands	HP:0030682
Hypertrophy/HCM	Overlapping phenotype, not core DCM1W	3/32 had HCM/LVH; metavinculin variants can show phenotypic overlap	HP:0001639; HP:0001712
Mitral regurgitation	Secondary functional valve manifestation in DCM	DCM-general; subtype frequency unavailable	HP:0001653

Among 32 VCL-pLOF probands, 22 (68.8%) had onset before age 20, 16 (50%) by age 10, and 13 (40.6%) in infancy. Within the DCM subgroup, 17/19 (89.5%) had pediatric onset and mean onset/testing age was 4.3±6.4 years. Severity ranges from subclinical or absent disease in carriers to transplant-requiring heart failure. (hawley2020anassessmentof pages 8-12)

Quality of life: no DCM1W-specific EQ-5D, SF-36, PROMIS, or pediatric quality-of-life study was found. By clinical inference, symptomatic heart failure impairs feeding and growth in infants and exercise tolerance, schooling/work, and daily function in older patients; arrhythmia and device/transplant risk add psychosocial burden. These are DCM-general effects, not quantified VCL-specific outcomes.

4. Genetic and molecular information

Gene annotation

Gene: VCL, vinculin.
HGNC: HGNC:12665.
Ensembl: ENSG00000035403. (OpenTargets Search: dilated cardiomyopathy-VCL)
Location: chromosome 10q22.2; early literature reported the broader 10q22.1–q23 interval. (liu2022establishmentofa pages 1-2, olson2002metavinculinmutationsalter pages 1-2)
Protein: vinculin, approximately 117 kDa and 1,066 aa; metavinculin is the muscle-specific isoform.
Origin: reported disease-associated variants are germline, not somatic.

Variant spectrum and interpretation

p.Leu954del: in-frame deletion affecting metavinculin; abnormal actin cross-linking in vitro.
p.Arg975Trp: missense variant affecting metavinculin; abnormal cross-linking and grossly abnormal intercalated discs in one patient.
p.Lys815Arg: missense; plausible but unproved, with possible MYBPC3 modification.
c.625A>T (p.Met209Leu): heterozygous variant used to derive an iPSC line; the resource paper does not by itself establish pathogenicity.
p.Arg547*: reported in infantile DCM with ventricular tachycardia.
Recurrent p.Arg188* and p.Arg570***: rare pLOF observations in the aggregated study.
Other classes: canonical splice-site, nonsense, frameshift, and multi-exon duplication variants. (hawley2020anassessmentof pages 4-8, hawley2020anassessmentof pages 18-20, wells2011familialdilatedcardiomyopathy pages 3-4, liu2022establishmentofa pages 1-2, olson2002metavinculinmutationsalter pages 1-2)

The estimated gnomAD pLOF prevalence was approximately 0.0003–0.00046 depending on quality and nonsense-mediated-decay filters. Twenty-three variants had MAF <0.00002. Thirteen of 14 recently assessed pLOF variants were classified by laboratories as VUS, reflecting limited segregation and individual-variant data. A pLOF consequence is therefore not sufficient by itself to label a variant pathogenic. (hawley2020anassessmentof pages 4-8, hawley2020anassessmentof pages 18-20, hawley2020anassessmentof pages 12-15)

Functional consequence

For metavinculin-tail variants, altered F-actin cross-linking is experimentally demonstrated and may represent abnormal/qualitatively altered function. For early truncating variants expected to undergo nonsense-mediated decay, haploinsufficiency is the leading model. Dominant-negative effects remain possible for selected stable mutant proteins but are not established across VCL variants.

Modifiers, epigenetics, and structural variation

Possible modifier genes are listed above, but none is validated for clinical prediction. No DCM1W-specific DNA-methylation, histone, chromatin, single-cell, spatial-transcriptomic, proteomic, metabolomic, or lipidomic signature has been replicated. Apart from a reported multi-exon duplication, no recurrent pathogenic chromosomal rearrangement is established. Routine karyotyping is not indicated for isolated DCM1W.

5. Environmental information

VCL-associated disease is genetic susceptibility expressed in a mechanically active organ. Relevant potentially avoidable stressors include heavy alcohol intake, cocaine/amphetamine exposure, cardiotoxic chemotherapy, uncontrolled hypertension, and unreviewed high-intensity exercise in individuals with active myocarditis, severe dysfunction, or ventricular arrhythmia. Viral infection and myocarditis may trigger decompensation but are not causes of the inherited VCL variant. (hershberger2021thecomplexand pages 3-4, hawley2020anassessmentof pages 12-15)

A mechanistically relevant infection observation comes from experimental/observational Chagas cardiomyopathy: Trypanosoma cruzi infection reduced or displaced vinculin from costameres, accompanied by irregular intercalated discs and reduced cadherin/β-catenin. This supports convergence on the same adhesion machinery but does not establish T. cruzi as a DCM1W trigger. (zemljicharpf2009vinculinandtalin pages 4-5, zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2)

Smoking, poor diet, obesity, diabetes, and inactivity worsen general cardiovascular and heart-failure risk, but no VCL-specific effect size exists.

6. Mechanism and pathophysiology

Ordered causal chain

A functionally damaging VCL/metavinculin variant leads to reduced protein dosage or altered vinculin–F-actin interaction.
Impaired vinculin function leads to weakened coupling of F-actin to cadherin-based intercalated-disc adhesions and integrin/talin-based costameres.
Weak cell–cell and cell–matrix anchorage results in abnormal adherens junctions, defective myofibril anchorage, intercalated-disc dissolution, and inefficient force transmission.
Junctional remodeling leads to reduced cadherin and β1-integrin and lateral redistribution of connexin-43; in mice this results in slowed/abnormal conduction and ventricular tachycardia.
Repeated contraction and mechanical loading are inferred to cause cardiomyocyte mechanical injury and maladaptive mechanotransduction; pressure overload magnifies this branch.
Mechanical branch: impaired force transfer and myocyte dysfunction lead to reduced contractility, compensatory chamber enlargement, and adverse remodeling.
Electrical branch: connexin/junction disorganization leads to conduction heterogeneity, ventricular arrhythmia, and possible sudden death.
Downstream myocyte injury is inferred to promote neurohormonal activation, fibrosis, energetic stress, and secondary valve regurgitation.
These processes result in LV or biventricular dilation, reduced ejection fraction, symptomatic heart failure, and—in severe cases—LVAD or transplantation.

Evidence and biological detail

The first three steps are supported by human biochemical and ultrastructural evidence: p.Leu954del and p.Arg975Trp significantly altered actin cross-linking, and the p.Arg975Trp carrier had grossly abnormal intercalated discs. (olson2002metavinculinmutationsalter pages 1-2)

Cardiac-specific Vcl knockout provides direct in-vivo evidence for the junctional/electrical branch. Before overt dysfunction, knockout hearts showed adherens-junction abnormalities, intercalated-disc dissolution, reduced cadherin and β1D-integrin, and connexin-43 mislocalization. Forty-nine percent of knockout mice died suddenly before 3 months, with telemetry documenting ventricular tachycardia; survivors developed DCM and died before 6 months. The authors concluded that Vcl is required for preservation of normal cell–cell and cell–matrix adhesive structures. DOI/URL: https://doi.org/10.1128/MCB.00728-07; published online 4 September 2007. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2)

Heterozygous mice had widened QRS complexes and abnormal junctional architecture despite relatively preserved basal function; pressure overload produced marked mortality and progressive LV dysfunction. Cardiac knockout also caused disorganized mitochondria before overt failure, although a primary VCL-specific metabolic defect has not been demonstrated in humans. (zemljicharpf2009vinculinandtalin pages 4-5)

A recent post-translational study found that VCL Y822 phosphorylation peaks during developmental adhesion remodeling, rises after adult cardiac injury, and regulates both cell–matrix and cell–cell adhesion. Homozygous Y822F mice developed cardiac dysfunction at 28 weeks, and cultured mutant cardiomyocytes had defective cell–cell adhesion organization. This refines the mechanism toward dynamically regulated mechanotransduction, but Y822F is a model allele rather than an established DCM1W patient variant. DOI/URL: https://doi.org/10.1242/jcs.263984; accepted/published across late 2024–2025. (li2024vinculiny822phosphorylation pages 1-3)

Relevant pathways: focal adhesion/integrin–talin–vinculin–actin coupling; cadherin–catenin adherens junctions; connexin-43 gap-junction organization; FAK/Src and downstream PI3K–AKT/Wnt mechanotransduction are biologically relevant, but no specific PI3K, MAPK, mTOR, or Wnt abnormality has been established in human DCM1W.

Suggested GO biological processes: GO:0007155 cell adhesion; GO:0051017 actin-filament bundle assembly; GO:0007015 actin-filament organization; GO:0006936 muscle contraction; GO:0003015 heart process; GO:0007507 heart development; GO:0055001 muscle-cell development; GO:0072659 protein localization to plasma membrane.

Suggested cell types: CL:0000746 cardiac muscle cell/cardiomyocyte; ventricular cardiomyocyte where a current CL child term is available; secondary cardiac fibroblasts and endothelial cells are plausible remodeling participants but not demonstrated primary VCL targets.

7. Anatomical structures affected

Primary organ: heart, especially left-ventricular myocardium; biventricular disease may occur.
Primary tissue/cell: cardiac muscle tissue and cardiomyocytes.
Substructures: intercalated discs, adherens junctions, gap-junction organization, costameres/focal adhesions, sarcolemma, actin cytoskeleton, and myofibril anchorage sites.
Secondary organs: lungs, liver, kidneys, and systemic circulation can be affected through congestion or low output, not primary VCL lesions.
Lateralization: not applicable; disease is not unilateral.

Suggested UBERON: UBERON:0000948 heart; UBERON:0002084 heart left ventricle; UBERON:0002080 heart right ventricle; UBERON:0002349 myocardium. GO cellular component: GO:0005925 focal adhesion; GO:0005912 adherens junction; GO:0005921 gap junction; GO:0005886 plasma membrane; GO:0030018 Z disc; GO:0005739 mitochondrion. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2, olson2002metavinculinmutationsalter pages 1-2)

8. Temporal development

Onset is highly variable, but pLOF cohorts are strongly enriched for pediatric and infantile presentation. Early disease may be insidious in genotype-positive relatives or acute in an infant presenting with severe heart failure. Progression can follow several trajectories: stable subclinical disease; progressive dilation and failure; arrhythmia before severe pump dysfunction; or reverse remodeling with improved/recovered EF. (hawley2020anassessmentof pages 8-12, zahavich2023heartfailurewith pages 1-2)

In the six-infant series, ventricular recovery occurred 0.3–3.2 years after diagnosis, at a median age of 2.7 years. The abstract’s key statement was: “Five patients (83%) showed normalization of LV function”; one patient progressed to transplant. Published online 7 August 2023; DOI/URL: https://doi.org/10.1007/s12265-023-10421-6. (zahavich2023heartfailurewith pages 1-2)

Recovery should be termed remission or HF with improved/recovered EF, not cure. Contemporary guidance stresses that improved EF may not represent resolution of the cardiomyopathic process and supports continued therapy to reduce relapse. (badger2023summaryandcomparison pages 6-7)

Critical intervention windows include presymptomatic family detection, the first presentation with ventricular dysfunction, and the initial months of guideline-directed therapy when reverse remodeling may occur.

9. Inheritance and population characteristics

Inheritance

The historical designation implies autosomal-dominant inheritance, and affected individuals are generally heterozygous. However, modern family data indicate incomplete, probably age- and stress-dependent penetrance, variable expressivity, and possible oligogenic modification. No robust evidence supports anticipation. Germline mosaicism is theoretically possible for any de novo variant but has not been documented as a recurrent DCM1W feature. No established founder variant, consanguinity effect, or population-specific carrier frequency exists. (hawley2020anassessmentof pages 12-15, hawley2020anassessmentof pages 8-12)

Epidemiology

No reliable prevalence or incidence exists for DCM1W itself. In the large pLOF study, rare VCL pLOF alleles occurred in approximately 0.03–0.046% of gnomAD participants, but this is not disease prevalence because penetrance is low and variant interpretation differs. (hawley2020anassessmentof pages 4-8, hawley2020anassessmentof pages 18-20)

For DCM generally, recorded disease is more common in males; one population EHR study found DCM approximately twice as common in men, but this cannot be assigned to VCL specifically. No VCL-specific sex ratio, geographic clustering, or ethnic enrichment is established. The available iPSC donor was a 65-year-old Han Chinese man, which is a single resource case rather than population evidence. (liu2022establishmentofa pages 1-2)

Family history is insensitive: a 2024 review reports that only 11% of one idiopathic-DCM cohort reported family history, whereas echocardiographic screening identified familial disease in 32%. Across DCM, approximately 30% meets conventional familial definitions, increasing above 50% when subclinical LV abnormalities are counted. (newman2024dilatedcardiomyopathya pages 2-4)

10. Diagnostics

Clinical evaluation

Obtain symptoms, examination, medication/toxin/infection history, and a three-generation pedigree.
Perform ECG and ambulatory monitoring for conduction disease and atrial/ventricular arrhythmia.
Use echocardiography to quantify chamber dimensions, LVEF, strain, RV function, and functional valve regurgitation.
Use CMR for accurate biventricular volumes and late gadolinium enhancement. Mid-wall LGE can accompany genetic DCM or myocarditis; subepicardial patterns suggest myocarditis, sarcoidosis, or chemotherapy injury.
Laboratory evaluation may include BNP/NT-proBNP, troponin, CBC, electrolytes, renal/liver/thyroid studies, iron indices, and phenotype-directed metabolic/infectious tests.
Exclude ischemic heart disease and sufficient hypertension, valve disease, congenital disease, sustained tachyarrhythmia, toxin exposure, endocrine/metabolic disease, and active myocarditis.
Reserve endomyocardial biopsy for selected suspected myocarditis, infiltrative/inflammatory disease, or rapidly progressive unexplained presentations; myocarditis confirmation requires histology/immunohistochemistry and, where appropriate, pathogen nucleic-acid testing. (sammani2021diagnosisandrisk pages 2-4, grasso2024thenew2023 pages 1-2)

Genetic testing

A curated cardiomyopathy NGS panel that includes VCL and robust DCM genes is the practical first test. It should include copy-number analysis. WES or WGS is useful when panel testing is negative, the phenotype is syndromic, or structural/noncoding variants are suspected. RNA sequencing from an informative tissue or validated cellular system can resolve selected splice variants, but it is not routine. CMA is appropriate for congenital anomalies/developmental disability; karyotype/FISH, mitochondrial-genome, and repeat-expansion tests are phenotype-driven rather than routine DCM1W tests. (sammani2021diagnosisandrisk pages 2-4, newman2024dilatedcardiomyopathya pages 2-4)

Interpret variants under ACMG/AMP criteria with gene- and disease-specific evidence. Confirm a pathogenic/likely pathogenic result orthogonally where required and perform segregation. Do not use a VUS for predictive cascade testing or irreversible management. This is especially important for VCL because 13/14 recently assessed pLOF alleles were VUS. (hawley2020anassessmentof pages 4-8, hawley2020anassessmentof pages 12-15)

Screening

First-degree relatives should receive clinical screening with history, ECG, and echocardiography; CMR/Holter are added according to age and findings. When a familial pathogenic/likely pathogenic variant is established, offer cascade testing and lifelong surveillance to genotype-positive relatives. Up to 20% of apparently asymptomatic relatives across DCM cohorts have overt DCM at initial assessment. (newman2024dilatedcardiomyopathya pages 2-4)

Differential diagnosis

Exclude ischemic cardiomyopathy; myocarditis; tachycardia-induced, peripartum, alcohol- or chemotherapy-associated cardiomyopathy; endocrine/metabolic disease; neuromuscular/mitochondrial disorders; valve or congenital disease; arrhythmogenic cardiomyopathy; LV noncompaction trait; and other genetic DCMs such as TTN-, LMNA-, FLNC-, DSP-, BAG3-, RBM20-, and sarcomeric-gene disease.

Implementation gap: among 101,919 newly diagnosed US DCM patients in 2017–2021 EHR/claims data, only 827 (0.8%) had evidence of genetic testing within six months. Published 17 October 2023; DOI/URL: https://doi.org/10.3389/fcvm.2023.1272433. (longoni2023realworldutilizationof pages 1-2)

11. Outcome and prognosis

DCM1W-specific survival curves are unavailable. Prognosis is heterogeneous because VCL alleles are incompletely penetrant and reported cohorts mix variant mechanisms. Favorable reverse remodeling is possible, particularly in the small infant series, but arrhythmia, sudden death, end-stage failure, LVAD, and transplantation remain possible. (zahavich2023heartfailurewith pages 1-2, zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2)

For context—not DCM1W-specific—a 1,284-patient nonischemic DCM registry observed major contemporary improvement. In the 2005–2015 enrollment period, annual rates were 1.46 events/100 patient-years for all-cause death/transplant/VAD, 0.82 for cardiovascular death/transplant/VAD, and 0.15 for sudden cardiac death. Published June 2020; DOI/URL: https://doi.org/10.1002/ejhf.1914. (merlo2020contemporarysurvivaltrends pages 1-4)

Prognostic factors should include baseline and serial LVEF/volumes, RV dysfunction, NYHA class, ventricular arrhythmia, conduction disease, syncope, fibrosis/LGE, biomarker burden, response to therapy, and family history. No VCL-specific circulating or molecular prognostic biomarker is validated. The 83% infant recovery estimate must not be generalized beyond that six-patient series.

12. Treatment

Standard treatment

No approved VCL-directed therapy exists. Treat the phenotype according to contemporary HFrEF/DCM guidance:

ARNI, or ACE inhibitor/ARB where ARNI is unsuitable;
evidence-based β-blocker;
mineralocorticoid-receptor antagonist;
SGLT2 inhibitor;
loop diuretic for congestion;
additional therapy for iron deficiency, atrial fibrillation, thromboembolism, or selected persistent symptoms as indicated.

The six VCL-positive infants received an ACE inhibitor and β-blocker. Five recovered ventricular function, but causality cannot be inferred from an uncontrolled series. (zahavich2023heartfailurewith pages 1-2)

Suggested NCIT intervention concepts: Angiotensin-Converting Enzyme Inhibitor; Angiotensin Receptor–Neprilysin Inhibitor; Beta-Adrenergic Blocker; Mineralocorticoid Receptor Antagonist; Sodium-Glucose Cotransporter 2 Inhibitor; Diuretic Therapy.

Devices and advanced care

Consider ICD for standard primary/secondary-prevention indications after adequate therapy and individualized arrhythmic-risk assessment. Unlike LMNA, FLNC, DSP, or selected RBM20 disease, current evidence does not justify an ICD solely because of a VCL variant. CRT is used for appropriate electrical dyssynchrony and persistent systolic dysfunction. Advanced refractory disease may require LVAD or transplantation. Suggested NCIT concepts include Implantable Cardioverter Defibrillator, Cardiac Resynchronization Therapy, Ventricular Assist Device, and Heart Transplantation. (badger2023summaryandcomparison pages 6-7, merlo2020contemporarysurvivaltrends pages 1-4)

Continue guideline-directed therapy after EF improvement because recovered EF does not necessarily mean elimination of the underlying substrate. Exercise prescription should be individualized by ventricular function, rhythm burden, and symptoms; cardiac rehabilitation is appropriate for stable patients. (badger2023summaryandcomparison pages 6-7)

Experimental therapeutics

No VCL-specific gene replacement, editing, ASO, siRNA, mRNA, cell therapy, or targeted drug trial was identified. DCM trials involving cell therapy or gene therapy for other genotypes cannot be treated as DCM1W evidence. Current VCL research is preclinical and focuses on adhesion/mechanotransduction and disease modeling.

13. Prevention

Primary prevention: the inherited allele cannot presently be prevented after conception. Risk reduction consists of avoiding heavy alcohol and illicit stimulants, controlling blood pressure and metabolic risk, reviewing cardiotoxic therapy, and promptly evaluating myocarditis-like illness. These measures are biologically prudent but untested specifically in VCL carriers.

Secondary prevention: genetic counseling, cascade testing for an established pathogenic/likely pathogenic familial variant, and serial ECG/imaging permit presymptomatic detection. There is no population or newborn screening program for DCM1W. Prenatal diagnosis and PGT-M are technically possible only when the familial variant is sufficiently established; reduced penetrance must be emphasized. A 2024 PGT guideline study developed a severity/penetrance model because inherited cardiac diseases vary greatly in predictiveness. DOI/URL: https://doi.org/10.1161/CIRCGEN.123.004416.

Tertiary prevention: sustained guideline-directed therapy, arrhythmia surveillance, vaccination according to standard schedules, sodium/fluid counseling when clinically indicated, rehabilitation, and timely ICD/CRT/advanced-HF referral reduce complications. No DCM1W-specific vaccine or prophylactic medication exists.

14. Other species and natural disease

Human: Homo sapiens, NCBI Taxon 9606.
Mouse ortholog/model: Mus musculus, Taxon 10090, gene Vcl.
Zebrafish ortholog/model: Danio rerio, Taxon 7955, vinculin paralogs/orthologs.

No well-established, naturally occurring veterinary syndrome equivalent to human DCM1W was identified in dogs, cats, livestock, or wildlife. Consequently, no breed-specific VBO term is justified. The relevant animal evidence is experimentally induced genetic disease, not zoonosis. There is no transmission or cross-species infectious risk.

Vinculin’s strong evolutionary conservation and preservation of cardiac adhesion phenotypes support comparative validity. Zebrafish vinculin knockdown caused impaired contractility, pericardial edema, and blood congestion; cardiac-specific mouse deletion caused junctional failure, arrhythmia, DCM, and early death. (wells2011familialdilatedcardiomyopathy pages 3-4, zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2)

15. Model organisms and experimental systems

Mouse models

Cardiomyocyte-specific Vcl knockout: Cre-loxP model. It reproduces intercalated-disc dissolution, reduced cadherin/β1-integrin, connexin-43 mislocalization, conduction defects, ventricular tachycardia, sudden death, and later DCM. It is a severe null model and may overstate effects of heterozygous human alleles. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2)
Vcl heterozygous knockout: shows widened QRS and junctional abnormalities with strong pressure-overload vulnerability, modeling incomplete penetrance and gene–environment/mechanical-stress interaction. (zemljicharpf2009vinculinandtalin pages 4-5)
Vcl Y822F knock-in: models defective post-translational regulation; homozygotes show adhesion defects and dysfunction by 28 weeks. It illuminates mechanism but is not a validated patient genotype. (li2024vinculiny822phosphorylation pages 1-3)

Zebrafish

Morpholino/knockdown evidence shows impaired cardiac contraction, edema, and blood congestion. Advantages are rapid developmental and contractility assays; limitations include paralog biology, two-chamber anatomy, and developmental knockdown artifacts. (wells2011familialdilatedcardiomyopathy pages 3-4)

Human cellular model

The iPSC line ZZUNEUi026-A was generated from peripheral-blood mononuclear cells of a 65-year-old Han Chinese man with DCM and heterozygous VCL c.625A>T (p.Met209Leu). It has a normal 46,XY karyotype, expresses pluripotency markers, differentiates into all three germ layers, and can generate cardiomyocytes. It is a model resource rather than proof that p.Met209Leu is pathogenic; an isogenic corrected control and mature engineered-heart-tissue experiments would be needed for causal inference. Published online 10 May 2022; DOI/URL: https://doi.org/10.1016/j.scr.2022.102812. (liu2022establishmentofa pages 1-2)

No validated DCM1W organoid, large-animal model, CRISPR-screen result, or integrated single-cell/spatial multi-omics atlas was identified.

Overall expert interpretation

The most defensible current formulation is: VCL is a biologically compelling DCM gene, but its alleles do not constitute a uniform disease mechanism. Metavinculin-tail p.Arg975Trp and p.Leu954del have direct functional evidence for abnormal actin organization and force transmission. In contrast, VCL truncating alleles are enriched in predominantly pediatric DCM but frequently occur with unaffected carriers or additional genetic findings; they should often be treated as reduced-penetrance risk alleles unless variant-level segregation and functional data justify pathogenic classification. (hawley2020anassessmentof pages 12-15, hawley2020anassessmentof pages 8-12, olson2002metavinculinmutationsalter pages 1-2)

The important 2023 development is recognition of a severe-at-presentation yet often recoverable infantile phenotype: “over 80% of infant DCM cases with LOF VCL variants” recovered EF in the reported series. That observation is clinically useful for counseling but remains preliminary because five variants were VUS, four patients carried additional cardiomyopathy-gene VUS, and the cohort contained only six infants. (zahavich2023heartfailurewith pages 1-2)

For knowledge-base implementation, DCM1W should therefore be represented with explicit evidence granularity: variant, transcript/isoform, functional result, segregation, co-occurring variants, age, environmental stressors, and ACMG classification. A simple binary “VCL mutation causes DCM1W” assertion would overstate present evidence.

References

(hawley2020anassessmentof pages 12-15): Megan H. Hawley, Naif Almontashiri, Leslie G. Biesecker, Natalie Berger, Wendy K. Chung, John Garcia, Theresa A. Grebe, Melissa A. Kelly, Matthew S. Lebo, Daniela Macaya, Hui Mei, Julia Platt, Gabi Richard, Ashley Ryan, Kate L. Thomson, Matteo Vatta, Roddy Walsh, James S. Ware, Matthew Wheeler, Hana Zouk, Heather Mason‐Suares, and Birgit Funke. An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy. Jun 2020. URL: https://doi.org/10.1002/humu.24061, doi:10.1002/humu.24061. This article has 19 citations and is from a domain leading peer-reviewed journal.
(hawley2020anassessmentof pages 8-12): Megan H. Hawley, Naif Almontashiri, Leslie G. Biesecker, Natalie Berger, Wendy K. Chung, John Garcia, Theresa A. Grebe, Melissa A. Kelly, Matthew S. Lebo, Daniela Macaya, Hui Mei, Julia Platt, Gabi Richard, Ashley Ryan, Kate L. Thomson, Matteo Vatta, Roddy Walsh, James S. Ware, Matthew Wheeler, Hana Zouk, Heather Mason‐Suares, and Birgit Funke. An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy. Jun 2020. URL: https://doi.org/10.1002/humu.24061, doi:10.1002/humu.24061. This article has 19 citations and is from a domain leading peer-reviewed journal.
(olson2002metavinculinmutationsalter pages 1-2): Timothy M. Olson, Susanne Illenberger, Nina Y. Kishimoto, Stefan Huttelmaier, Mark T. Keating, and Brigitte M. Jockusch. Metavinculin mutations alter actin interaction in dilated cardiomyopathy. Circulation: Journal of the American Heart Association, 105:431-437, Jan 2002. URL: https://doi.org/10.1161/hc0402.102930, doi:10.1161/hc0402.102930. This article has 400 citations.
(zahavich2023heartfailurewith pages 1-2): Laura Zahavich, Rajadurai Akilen, Kristen George, and Seema Mital. Heart failure with recovered ejection fraction in patients with vinculin loss-of-function variants. Journal of Cardiovascular Translational Research, 16:1303-1309, Aug 2023. URL: https://doi.org/10.1007/s12265-023-10421-6, doi:10.1007/s12265-023-10421-6. This article has 5 citations and is from a peer-reviewed journal.
(OpenTargets Search: dilated cardiomyopathy-VCL): Open Targets Query (dilated cardiomyopathy-VCL, 7 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2): Alice E. Zemljic-Harpf, Joel C. Miller, Scott A. Henderson, Adam T. Wright, Ana Maria Manso, Laila Elsherif, Nancy D. Dalton, Andrea K. Thor, Guy A. Perkins, Andrew D. McCulloch, and Robert S. Ross. Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. Nov 2007. URL: https://doi.org/10.1128/mcb.00728-07, doi:10.1128/mcb.00728-07. This article has 244 citations and is from a domain leading peer-reviewed journal.
(li2024vinculiny822phosphorylation pages 1-3): Xiaofei Li, Rainy Wortelboer, Yi Song, Sahana Balasubramanian, Callie McLain, Alex Hernandez Manriquez, Joseph D. Suh, Brenton D. Hoffman, Adam V. Kwiatkowski, and Glenn L. Radice. Vinculin y822 phosphorylation regulates adhesion remodeling during cardiomyocyte maturation. Journal of Cell Science, Dec 2024. URL: https://doi.org/10.1242/jcs.263984, doi:10.1242/jcs.263984. This article has 1 citations and is from a domain leading peer-reviewed journal.
(hawley2020anassessmentof pages 4-8): Megan H. Hawley, Naif Almontashiri, Leslie G. Biesecker, Natalie Berger, Wendy K. Chung, John Garcia, Theresa A. Grebe, Melissa A. Kelly, Matthew S. Lebo, Daniela Macaya, Hui Mei, Julia Platt, Gabi Richard, Ashley Ryan, Kate L. Thomson, Matteo Vatta, Roddy Walsh, James S. Ware, Matthew Wheeler, Hana Zouk, Heather Mason‐Suares, and Birgit Funke. An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy. Jun 2020. URL: https://doi.org/10.1002/humu.24061, doi:10.1002/humu.24061. This article has 19 citations and is from a domain leading peer-reviewed journal.
(hawley2020anassessmentof pages 18-20): Megan H. Hawley, Naif Almontashiri, Leslie G. Biesecker, Natalie Berger, Wendy K. Chung, John Garcia, Theresa A. Grebe, Melissa A. Kelly, Matthew S. Lebo, Daniela Macaya, Hui Mei, Julia Platt, Gabi Richard, Ashley Ryan, Kate L. Thomson, Matteo Vatta, Roddy Walsh, James S. Ware, Matthew Wheeler, Hana Zouk, Heather Mason‐Suares, and Birgit Funke. An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy. Jun 2020. URL: https://doi.org/10.1002/humu.24061, doi:10.1002/humu.24061. This article has 19 citations and is from a domain leading peer-reviewed journal.
(wells2011familialdilatedcardiomyopathy pages 3-4): Quinn S. Wells, Natalie L. Ausborn, Birgit H. Funke, Jean P. Pfotenhauer, Joseph L. Fredi, Samantha Baxter, Thomas G. DiSalvo, and Charles C. Hong. Familial dilated cardiomyopathy associated with congenital defects in the setting of a novel vcl mutation (lys815arg) in conjunction with a known mypbc3 variant. Cardiogenetics, 1 1:e10, Aug 2011. URL: https://doi.org/10.4081/cardiogenetics.2011.e10, doi:10.4081/cardiogenetics.2011.e10. This article has 21 citations.
(zemljicharpf2009vinculinandtalin pages 4-5): Alice Zemljic-Harpf, Ana Maria Manso, and Robert S. Ross. Vinculin and talin. Journal of Investigative Medicine, 57:849-855, Dec 2009. URL: https://doi.org/10.2310/jim.0b013e3181c5e074, doi:10.2310/jim.0b013e3181c5e074. This article has 84 citations and is from a peer-reviewed journal.
(sammani2021diagnosisandrisk pages 2-4): Arjan Sammani, Annette F. Baas, Folkert W. Asselbergs, and Anneline S. J. M. te Riele. Diagnosis and risk prediction of dilated cardiomyopathy in the era of big data and genomics. Journal of Clinical Medicine, 10:921, Feb 2021. URL: https://doi.org/10.3390/jcm10050921, doi:10.3390/jcm10050921. This article has 45 citations.
(newman2024dilatedcardiomyopathya pages 2-4): Noah A. Newman and Michael A. Burke. Dilated cardiomyopathy: a genetic journey from past to future. International Journal of Molecular Sciences, 25:11460, Oct 2024. URL: https://doi.org/10.3390/ijms252111460, doi:10.3390/ijms252111460. This article has 28 citations.
(grasso2024thenew2023 pages 1-2): Maurizia Grasso, Davide Bondavalli, Viviana Vilardo, Claudia Cavaliere, Ilaria Gatti, Alessandro Di Toro, Lorenzo Giuliani, Mario Urtis, Michela Ferrari, Barbara Cattadori, Alessandra Serio, Carlo Pellegrini, and Eloisa Arbustini. The new 2023 esc guidelines for the management of cardiomyopathies: a guiding path for cardiologist decisions. European Heart Journal Supplements : Journal of the European Society of Cardiology, 26:i1-i5, Apr 2024. URL: https://doi.org/10.1093/eurheartjsupp/suae002, doi:10.1093/eurheartjsupp/suae002. This article has 18 citations.
(longoni2023realworldutilizationof pages 1-2): Mauro Longoni, Kanchan Bhasin, Andrew Ward, Donghyun Lee, McKenna Nisson, Sucheta Bhatt, Fatima Rodriguez, and Rajesh Dash. Real-world utilization of guideline-directed genetic testing in inherited cardiovascular diseases. Frontiers in Cardiovascular Medicine, Oct 2023. URL: https://doi.org/10.3389/fcvm.2023.1272433, doi:10.3389/fcvm.2023.1272433. This article has 32 citations and is from a peer-reviewed journal.
(badger2023summaryandcomparison pages 6-7): Sarah Badger, James McVeigh, and Praveen Indraratna. Summary and comparison of the 2022 acc/aha/hfsa and 2021 esc heart failure guidelines. Cardiology and Therapy, 12:571-588, Aug 2023. URL: https://doi.org/10.1007/s40119-023-00328-3, doi:10.1007/s40119-023-00328-3. This article has 12 citations and is from a peer-reviewed journal.
(liu2022establishmentofa pages 1-2): Yangyang Liu, Xiao-Wei Li, Xiaoyan Zhao, Jianzeng Dong, Chunyang Zhang, and Tao Lin. Establishment of a human ipsc (zzuneui026-a) from a dilated cardiomyopathy patient carrying heterozygous vinculin (c. 625a > t) mutant. Jul 2022. URL: https://doi.org/10.1016/j.scr.2022.102812, doi:10.1016/j.scr.2022.102812. This article has 2 citations and is from a peer-reviewed journal.
(hawley2020anassessmentof pages 15-18): Megan H. Hawley, Naif Almontashiri, Leslie G. Biesecker, Natalie Berger, Wendy K. Chung, John Garcia, Theresa A. Grebe, Melissa A. Kelly, Matthew S. Lebo, Daniela Macaya, Hui Mei, Julia Platt, Gabi Richard, Ashley Ryan, Kate L. Thomson, Matteo Vatta, Roddy Walsh, James S. Ware, Matthew Wheeler, Hana Zouk, Heather Mason‐Suares, and Birgit Funke. An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy. Jun 2020. URL: https://doi.org/10.1002/humu.24061, doi:10.1002/humu.24061. This article has 19 citations and is from a domain leading peer-reviewed journal.
(merlo2020contemporarysurvivaltrends pages 1-4): Marco Merlo, Antonio Cannatà, Carola Pio Loco, Davide Stolfo, Giulia Barbati, Jessica Artico, Piero Gentile, Valerio De Paris, Federica Ramani, Massimo Zecchin, Marta Gigli, Bruno Pinamonti, Renata Korcova, Andrea Di Lenarda, Mauro Giacca, Luisa Mestroni, Paolo G. Camici, and Gianfranco Sinagra. Contemporary survival trends and aetiological characterization in non-ischaemic dilated cardiomyopathy. Jun 2020. URL: https://doi.org/10.1002/ejhf.1914, doi:10.1002/ejhf.1914. This article has 101 citations and is from a highest quality peer-reviewed journal.
(hershberger2021thecomplexand pages 3-4): Ray E. Hershberger, Jason Cowan, Elizabeth Jordan, and Daniel D. Kinnamon. The complex and diverse genetic architecture of dilated cardiomyopathy. Circulation research, 128 10:1514-1532, May 2021. URL: https://doi.org/10.1161/circresaha.121.318157, doi:10.1161/circresaha.121.318157. This article has 106 citations and is from a highest quality peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	17
Resolved	17
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	17
On topic	10
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	37
Resolved	35
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	5
Terms named correctly	0
Terms named as a different term	5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0001644 (4 mentions) - the report calls it "19/32 (59.4%) VCL-pLOF probands"; HP calls it Dilated cardiomyopathy
HP:0001635 (2 mentions) - the report calls it "Presenting syndrome in the infant series; exact broader frequency unavailable"; HP calls it Congestive heart failure
HP:0001711 (2 mentions) - the report calls it "Median LVEF 24% in six infants"; HP calls it Abnormal left ventricle morphology
HP:0030682 (1 mention) - the report calls it "2/32 pLOF probands"; HP calls it Left ventricular noncompaction
HP:0001653 (1 mention) - the report calls it "DCM-general; subtype frequency unavailable"; HP calls it Mitral regurgitation

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Pathophysiology

Pathograph

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Diagnosis

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Experimental Models

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Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

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Dilated Cardiomyopathy 1W (VCL-associated DCM): comprehensive disease-characteristics report

Executive summary and evidence caveat

1. Disease information

Definition

Identifiers and synonyms

Data provenance

2. Etiology

Causal and susceptibility factors

Genetic risk and modifiers

Environmental and gene–environment risk

Protective factors

3. Phenotypes

4. Genetic and molecular information

Gene annotation

Variant spectrum and interpretation

Functional consequence

Modifiers, epigenetics, and structural variation

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Evidence and biological detail

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population characteristics

Inheritance

Epidemiology

10. Diagnostics

Clinical evaluation

Genetic testing

Screening

Differential diagnosis

11. Outcome and prognosis

12. Treatment

Standard treatment

Devices and advanced care

Experimental therapeutics

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems