Cardiomyopathy Dilated 100

Genetic MONDO:0859381 Pathograph 12 Show in embeddings browser Dilated Cardiomyopathy Genetic Disorder

CMD1OO is the VEZF1-attributed member of the numbered familial dilated cardiomyopathy series (OMIM 620247). VEZF1 encodes vascular endothelial zinc finger 1, a zinc-finger transcription factor originally characterized in vasculogenesis and angiogenesis. What makes this entity mechanistically distinct from most of the series is that the lesion is not in the contractile apparatus at all: it is in a transcription factor that sets how much contractile protein a cardiomyocyte makes. The reported disease allele, c.490A>T p.(Lys164*), truncates the protein early, and a dual-luciferase assay showed the mutant fails to transactivate the promoters of MYH7 and ET1, two genes already implicated in DCM. The zebrafish and cell work fills in what that loss does to a heart. Vezf1 expression is reduced in diseased human and mouse myocardium; knocking it down in zebrafish reduces cardiac growth and blunts the ventricular contractile response to beta-adrenergic stimulation; and the effect runs through cardiomyocyte Myh7/beta-MHC, with an MCAT box in the Myh7 promoter and TEAD-1 as a binding partner. One negative result in that study is informative rather than incidental: calcium transient kinetics are NOT disturbed, which places the defect at the contractile apparatus and its transcriptional supply rather than in excitation-contraction coupling. From there the disease joins the conserved final common pathway that every cardiomyopathy converges on, and this entry declares `conforms_to` against `cardiomyopathy_maladaptive_remodeling` at three nodes rather than re-deriving the neurohormonal and remodeling chain. Two cautions belong up front. First, the name is a trap. The OMIM designation is CMD1**OO**, with two letter Os continuing the alphabetical series, and it is the label "cardiomyopathy, dilated, 100" that misreads them as digits. This is not the hundredth numbered dilated cardiomyopathy locus. Second, the evidence base is one family. A single nonsense allele segregating with autosomal dominant DCM at complete penetrance, absent from 200 unrelated DCM patients, 400 controls and the population databases, plus a reporter assay. There is no ClinGen gene-disease validity assertion for VEZF1 and no second reported family, so the gene-disease relationship should be read as provisional.

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1
Mappings
1
Inheritance
4
Pathophys.
3
Phenotypes
2
Gaps
12
Pathograph
1
Genes
1
Variants
3
Medical Actions
2
Models
4
References
1
Deep Research
🏷

Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
🔗

Mappings

MONDO
MONDO:0016333 familial dilated cardiomyopathy Not Yet Curated
skos:broadMatch MONDO
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
A single heterozygous VEZF1 nonsense allele segregated with disease through the reported family with complete penetrance, so a carrier is expected to be affected. Note that penetrance estimated in the one family that defined the entity is not a general penetrance estimate.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:36657711 SUPPORT Human Clinical
"The nonsense mutation was validated by Sanger sequencing and segregated with autosome-dominant DCM in the family with complete penetrance."
Establishes dominant transmission and complete penetrance in the reported pedigree.
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Discussions and Knowledge Gaps

2
Is VEZF1 established as a dilated cardiomyopathy gene, or is this still a single-family candidate?
OPEN QUESTION OPEN vezf1_dcm_gene_validity
Attached to
pathophysiology#VEZF1 Nonsense Variant Abolishes Transcriptional Transactivation
The whole entity rests on one report of one family with one nonsense allele, plus a dual-luciferase assay. The supporting evidence is good of its kind: segregation at complete penetrance, absence from 200 unrelated DCM patients, 400 controls, dbSNP, HGMD and gnomAD, and a measured loss of transactivation at two DCM-relevant promoters. But there is no second family, no case series, and no ClinGen gene-disease validity assertion for VEZF1 in any cardiomyopathy. On the ClinGen framework this is the shape of evidence that would classify as Limited or at most Moderate, not Definitive. That matters for how a VEZF1 variant found on a research exome should be reported, and it is why the trigger and its two downstream nodes carry `mechanism_confidence: PROVISIONAL` while the final structural node, which is generic dilated cardiomyopathy, does not.
Proposed experiments
Look for further VEZF1 loss-of-function alleles in DCM cohorts
vezf1_dcm_cohort_replication
Query large sequenced familial dilated cardiomyopathy cohorts for rare VEZF1 loss-of-function alleles and test segregation. VEZF1 is absent from most established cardiomyopathy gene panels, so replication requires exome or genome data rather than panel data, and the absence of further reports since 2023 may reflect that nobody has looked rather than that nobody has found.
Show evidence (2 references)
PMID:36657711 SUPPORT Human Clinical
"In this investigation, whole-exome sequencing and bioinformatics analyses were conducted in a family suffering from DCM"
The single family that the entity rests on.
PMID:36657711 SUPPORT Human Clinical
"Nevertheless, due to pronounced genetic heterogeneity, the genetic defects underpinning DCM in most cases remain obscure."
The authors' own framing of the field, which is why single-family attributions are common in DCM and why replication matters.
Is the cardiac phenotype cardiomyocyte-autonomous, or does it arise partly through VEZF1's better-established role in the vasculature?
OPEN QUESTION OPEN vezf1_cardiomyocyte_autonomous_or_vascular
Attached to
pathophysiology#Reduced Transcription of Cardiomyocyte Contractile and Growth Targets pathophysiology#Impaired Cardiomyocyte Contractile Function and Compensatory Growth
This entry models the disease as a cardiomyocyte transcription-factor defect, because that is what the two direct measurements support: the human variant fails to transactivate MYH7, and the zebrafish work identifies cardiomyocyte Myh7 as the key target with an MCAT box and TEAD-1 as partner. But VEZF1 was characterized first, and is still best characterized, as a vascular-development factor. It is required for endothelial differentiation, and it represses the antiangiogenic factor Cited2 in endothelial cells. The zebrafish experiment is a whole-organism knockdown and the human allele is germline, so neither excludes an endothelial or microvascular contribution to the cardiac phenotype. Distinguishing these is not a technicality: a myocyte-autonomous transcriptional defect and a microvascular developmental defect predict different natural histories and different things about whether the myocardium can be supported.
Proposed experiments
Compare cardiomyocyte-restricted and endothelial-restricted Vezf1 loss
vezf1_conditional_knockout_lineage
Generate cardiomyocyte-specific and endothelial-specific conditional Vezf1 knockouts and compare cardiac growth, contractile reserve and Myh7 expression. If the myocyte-restricted animal reproduces the phenotype the cardiomyocyte-autonomous model in this entry is correct; if only the endothelial-restricted or the combined animal does, the pathograph needs an endothelial node.
Show evidence (2 references)
PMID:31911272 SUPPORT In Vitro
"We further identify a key role for an MCAT binding site in the Myh7 promoter regulating the response to Vezf1 knockdown and show that TEAD-1 is a binding partner of Vezf1."
The cardiomyocyte-autonomous evidence, which is mechanistically specific but was obtained in primary cardiomyocytes rather than in vivo.
PMID:29794136 SUPPORT In Vitro
"Compared with WT ESCs, Vezf1-/- ESCs inefficiently differentiated into endothelial cells (ECs), which exhibited defects in the tube-formation assay."
The competing endothelial role. Graded PARTIAL because it establishes the alternative lineage requirement without bearing directly on the cardiac phenotype.
⚙

Pathophysiology

4
VEZF1 Nonsense Variant Abolishes Transcriptional Transactivation
The initiating lesion is a heterozygous nonsense variant, c.490A>T p.(Lys164*), truncating vascular endothelial zinc finger 1 partway through the protein. VEZF1 is a zinc-finger transcription factor, so the functional consequence is measured as a loss of transactivation rather than as a structural defect: in a dual-luciferase reporter system the mutant protein failed to drive the promoters of MYH7 and ET1, both of which are already implicated in dilated cardiomyopathy. This is why the entity sits apart mechanistically from the sarcomeric members of the numbered series, where the lesion is in the contractile machinery itself.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
VEZF1 hgnc:12949 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves VEZF1 (hgnc:12949). hgnc:12949 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context VEZF1 hgnc:12949 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns VEZF1 (hgnc:12949). hgnc:12949 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Heterozygous germline nonsense allele. Only one such allele has been reported, in a single family.
DNA-binding transcription factor activity of VEZF1 GO:0003700 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased DNA-binding transcription factor activity of VEZF1, annotated with DNA-binding transcription factor activity (GO:0003700). GO:0003700 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Reduced Transcription of Cardiomyocyte Contractile and Growth Targets Loss of VEZF1 transactivation lowers expression of its cardiomyocyte target genes, of which MYH7 is the identified key one.
Show evidence (2 references)
PMID:36657711 SUPPORT Human Clinical
"In this investigation, whole-exome sequencing and bioinformatics analyses were conducted in a family suffering from DCM, and a novel heterozygous mutation in the VEZF1 gene (coding for a zinc finger-containing transcription factor critical for cardiovascular development and structural..."
Identifies the allele, its heterozygous state, and what VEZF1 encodes.
PMID:36657711 SUPPORT In Vitro
"Biological analyses by utilizing a dual-luciferase reporter assay system revealed that the mutant VEZF1 protein failed to transactivate the promoters of MYH7 and ET1, two genes that have been associated with DCM."
The functional measurement behind this node: the variant abolishes transactivation of two DCM-relevant target promoters.
Reduced Transcription of Cardiomyocyte Contractile and Growth Targets
VEZF1 target genes in the cardiomyocyte include the contractile gene programme. Gene ontology enrichment on Vezf1 knockdown implicates cardiac muscle contraction and dilated-cardiomyopathy genes, and the study identifies cardiomyocyte Myh7 (beta-MHC) as the key target, acting through an MCAT binding site in the Myh7 promoter with TEAD-1 as a VEZF1 binding partner. The same regulation is visible in acquired disease: Vezf1 expression is reduced in diseased human and mouse myocardium, which is what makes this transcription factor plausible as a general node rather than just the site of one family's mutation.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
positive regulation of transcription by RNA polymerase II GO:0045944 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased positive regulation of transcription by RNA polymerase II (GO:0045944). GO:0045944 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Neonatal rat primary cardiomyocytes with Vezf1 silencing PRIMARY CELL CULTURE Reproduces the transcriptional step directly: loss of VEZF1 in a cardiomyocyte lowers Myh7 promoter activity through a defined cis-element and a defined partner.
Downstream
Impaired Cardiomyocyte Contractile Function and Compensatory Growth Reduced contractile-gene transcription degrades how hard the myocyte can contract and how well it can grow in response to load.
Show evidence (3 references)
PMID:31911272 SUPPORT Model Organism
"Gene ontology enrichment analysis indicates that Vezf1 regulates cardiac muscle contraction and dilated cardiomyopathy related genes and we identify cardiomyocyte Myh7/β-MHC as key target for Vezf1."
Identifies the transcriptional programme VEZF1 controls in cardiomyocytes and names its key target.
PMID:31911272 SUPPORT In Vitro
"We further identify a key role for an MCAT binding site in the Myh7 promoter regulating the response to Vezf1 knockdown and show that TEAD-1 is a binding partner of Vezf1."
Gives the cis-element and the partner through which VEZF1 acts on Myh7, which is the same promoter-transactivation function the human nonsense allele abolishes.
PMID:31911272 SUPPORT Human Clinical
"We find that expression of Vezf1 is decreased in diseased human myocardium and mouse hearts."
Shows the same transcription factor is downregulated in acquired human heart disease, independently of any VEZF1 variant.
Impaired Cardiomyocyte Contractile Function and Compensatory Growth
Loss of Vezf1 reduces cardiac growth and blunts the ventricular contractile response to beta-adrenergic stimulation. The negative result recorded alongside it is what makes this node specific: calcium transient kinetics are unchanged, so the failure is not in excitation-contraction coupling but downstream of it, at the contractile apparatus and the transcriptional supply that builds it. Blunted inotropic reserve also means the deficit shows up first under load rather than at rest.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
cardiac muscle contraction GO:0060048 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cardiac muscle contraction (GO:0060048). GO:0060048 is a biological process from the Gene Ontology. ↓ DECREASED cardiac muscle tissue growth GO:0055017 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cardiac muscle tissue growth (GO:0055017). GO:0055017 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
vezf1 knockdown zebrafish Zebrafish recapitulates Reproduces both halves of the cellular node, the contractile deficit and the failure of compensatory growth, and localizes the lesion by showing calcium handling is spared.
Downstream
Left Ventricular Dilation and Systolic Dysfunction A myocardium that contracts less well and cannot grow adaptively dilates and loses ejection fraction.
Show evidence (3 references)
PMID:31911272 SUPPORT Model Organism
"Our experimental data shows that knockdown of zebrafish Vezf1 reduces cardiac growth and results in impaired ventricular contractile response to β-adrenergic stimuli."
The two functional deficits this node asserts, measured in vivo.
PMID:31911272 SUPPORT Model Organism
"However, Vezf1 knockdown is not associated with dysregulation of cardiomyocyte Ca2+ transient kinetics."
A negative result that localizes the defect: calcium handling is intact, so the lesion is not in excitation-contraction coupling.
PMID:31911272 SUPPORT Model Organism
"We demonstrate a role for Vezf1 in regulation of compensatory cardiac growth and cardiomyocyte contractile function, which may be relevant in human cardiac disease."
The authors' own summary of the role this node encodes, with their hedge about human relevance preserved.
Left Ventricular Dilation and Systolic Dysfunction
The clinical endpoint and the definition of the disease class: left ventricular or biventricular dilation with systolic dysfunction, leading to heart failure and, in some, sudden cardiac death. This node is what the entity shares with every other dilated cardiomyopathy, and it is why the entry conforms to the conserved maladaptive-remodeling module here rather than re-deriving the neurohormonal and remodeling chain that produces it.
heart contraction GO:0060047 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal heart contraction (GO:0060047). GO:0060047 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (1 reference)
PMID:36657711 SUPPORT Human Clinical
"Dilated cardiomyopathy (DCM), characteristic of left ventricular or biventricular dilation with systolic dysfunction, is the most common form of cardiomyopathy, and a leading cause of heart failure and sudden cardiac death."
Defines the structural and functional endpoint and its consequences, in the paper that attributes this entity to VEZF1.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cardiomyopathy Dilated 100 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

3
Dilated Cardiomyopathy Cardiovascular HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36657711 SUPPORT Human Clinical
"Dilated cardiomyopathy (DCM), characteristic of left ventricular or biventricular dilation with systolic dysfunction, is the most common form of cardiomyopathy, and a leading cause of heart failure and sudden cardiac death."
Defines the phenotype in the report that attributes this entity to VEZF1.
Congestive Heart Failure Cardiovascular HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36657711 SUPPORT Human Clinical
"Dilated cardiomyopathy (DCM), characteristic of left ventricular or biventricular dilation with systolic dysfunction, is the most common form of cardiomyopathy, and a leading cause of heart failure and sudden cardiac death."
Names heart failure as the principal consequence of the dilated cardiomyopathy phenotype.
Sudden Cardiac Death Cardiovascular HP:0001645 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sudden cardiac death (HP:0001645). HP:0001645 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36657711 SUPPORT Human Clinical
"Dilated cardiomyopathy (DCM), characteristic of left ventricular or biventricular dilation with systolic dysfunction, is the most common form of cardiomyopathy, and a leading cause of heart failure and sudden cardiac death."
Names sudden cardiac death as a principal outcome of the disease class this entity belongs to.
🧬

Genetic Associations

1
VEZF1 (Causative)
Gene: VEZF1 (vascular endothelial zinc finger 1) hgnc:12949 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is VEZF1 (vascular endothelial zinc finger 1), annotated with VEZF1 (hgnc:12949). hgnc:12949 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:36657711 SUPPORT Human Clinical
"The findings indicate VEZF1 as a new gene responsible for DCM, which provides novel insight into the molecular pathogenesis of DCM"
The gene-disease attribution this entity rests on.
PMID:29794136 SUPPORT In Vitro
"Vascular endothelial zinc finger 1 (Vezf1), is a Krüppel-like zinc finger protein that plays a vital role in vascular development."
Independent characterization of VEZF1 as a vascular-development transcription factor, which is the background biology that makes a cardiovascular phenotype plausible.
Variants (1)
VEZF1 c.490A>T p.(Lys164*) Likely Pathogenic
Gene: VEZF1 hgnc:12949 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in VEZF1 (hgnc:12949). hgnc:12949 is a gene from the HUGO Gene Nomenclature Committee. nonsense
The only reported disease allele. A nonsense change truncating the protein at codon 164, heterozygous, segregating with dominant DCM through one family at complete penetrance. It was absent from 200 unrelated DCM patients, 400 unrelated healthy individuals, dbSNP, HGMD and gnomAD, which is a stronger absence argument than most single-family alleles carry.
Show evidence (1 reference)
PMID:36657711 SUPPORT Human Clinical
"The mutation was neither detected in another cohort of 200 unrelated DCM patients nor observed in 400 unrelated healthy individuals nor retrieved in the Single Nucleotide Polymorphism database, the Human Gene Mutation Database and the Genome Aggregation Database."
The absence data supporting pathogenicity. `clinical_significance` is recorded as LIKELY_PATHOGENIC rather than PATHOGENIC because the supporting evidence is one family plus one functional assay, with no independent replication and no gene curation panel assessment.
💊

Medical Actions

3
Cascade Genetic Testing and Surveillance of At-Risk Relatives
Action: cascade genetic testing and genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cascade genetic testing and genetic counseling, annotated with Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
The highest-yield action this entity supports, and the one most specific to it. Once the familial variant is known, first-degree relatives can be tested directly; a relative of a carrier has a 50% prior, and on the single available pedigree penetrance was complete, so a genotype-positive relative should be assumed to be at risk rather than reassured. Genotype-positive relatives then need longitudinal cardiac surveillance so that ventricular dysfunction is caught before it presents as heart failure or sudden death, and genotype-negative relatives can be released from it.
Target Phenotypes: Dilated cardiomyopathy HP:0001644 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301486 SUPPORT Other
"relatives of a proband with DCM to inform cardiac surveillance and allow early detection and treatment of DCM to improve long-term outcome"
The GeneReviews dilated cardiomyopathy overview states the purpose of genetic risk assessment in at-risk relatives, which is what this intervention delivers. Graded OTHER because the source is an expert overview rather than a primary study.
PMID:36657711 SUPPORT Human Clinical
"The nonsense mutation was validated by Sanger sequencing and segregated with autosome-dominant DCM in the family with complete penetrance."
Establishes the dominant transmission and complete penetrance that make cascade testing informative in this entity specifically.
Guideline-Directed Heart Failure Pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Management is the standard treatment of dilated cardiomyopathy and heart failure with reduced ejection fraction. There is nothing VEZF1-specific: no disease-modifying therapy exists for the transcriptional defect, and no treatment study has been reported in a carrier.
Target Phenotypes: Congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Cardiac Transplantation
Action: organ transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is organ transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. Ontology label: Organ Transplantation NCIT:C15289
The endpoint option for a dilated cardiomyopathy that progresses to refractory heart failure. As with pharmacotherapy, nothing here is specific to this entity.
🔬

Diagnosis

2
Echocardiography
The diagnosis of the dilated cardiomyopathy phenotype is echocardiographic: ventricular dilation with reduced ejection fraction. Nothing about the imaging identifies the VEZF1 form.
Show evidence (2 references)
PMID:36657711 SUPPORT Human Clinical
"Dilated cardiomyopathy (DCM), characteristic of left ventricular or biventricular dilation with systolic dysfunction, is the most common form of cardiomyopathy, and a leading cause of heart failure and sudden cardiac death."
Gives the structural and functional criteria that define the phenotype.
PMID:20301486 SUPPORT Other
"Provide the evaluation strategy of a proband with nonsyndromic DCM"
The GeneReviews overview exists to set out the proband evaluation strategy for nonsyndromic dilated cardiomyopathy, which is the workup this entity enters through. Graded OTHER because the source is an expert overview.
Whole-Exome Sequencing
The entity was defined by whole-exome sequencing of a family, and that remains the only route to the specific diagnosis. Note that VEZF1 is not on most established cardiomyopathy gene panels, so a panel-negative familial DCM is where this entity would be found if it is found at all.
Show evidence (1 reference)
PMID:36657711 SUPPORT Human Clinical
"In this investigation, whole-exome sequencing and bioinformatics analyses were conducted in a family suffering from DCM"
The method by which the entity was identified.
📊

Prevalence

1
Worldwide
Cases In Literature Not yet documented
One reported family. No prevalence, incidence or carrier-frequency estimate exists, and none should be inferred from dilated cardiomyopathy overall, which is common and attributable to more than a hundred genes. The one quantitative statement that can be made is negative: the allele was absent from 200 unrelated DCM patients and 400 controls, so it is not a recurrent contributor to DCM in that population.
Show evidence (1 reference)
PMID:36657711 SUPPORT Human Clinical
"The mutation was neither detected in another cohort of 200 unrelated DCM patients nor observed in 400 unrelated healthy individuals nor retrieved in the Single Nucleotide Polymorphism database, the Human Gene Mutation Database and the Genome Aggregation Database."
The screening data that bounds how common this allele can be.
🧫

Experimental Models

1
Neonatal rat primary cardiomyocytes with Vezf1 silencing PRIMARY_CELL_CULTURE
The cell system in which the transcriptional mechanism was worked out. Silencing Vezf1 in primary cardiomyocytes is what identified Myh7 as the key target, located the MCAT binding site in the Myh7 promoter that mediates the response, and showed TEAD-1 to be a VEZF1 binding partner. It is also the one system in this entry that speaks directly to whether the cardiac phenotype is cardiomyocyte-autonomous, because it removes the endothelium from the question.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Publication
PMID:31911272
Pathograph links
Reduced Transcription of Cardiomyocyte Contractile and Growth Targets recapitulates fidelity: moderate Reproduces the transcriptional step directly: loss of VEZF1 in a cardiomyocyte lowers Myh7 promoter activity through a defined cis-element and a defined partner.
Limitations: Neonatal rat cells, not human, and knockdown of the wild-type protein rather than expression of the human p.(Lys164*) allele, so it models loss of VEZF1 rather than this disease's specific lesion. The cells are also neonatal, whereas the reported human disease is adult-onset.
Show evidence (2 references)
PMID:31911272 SUPPORT In Vitro
"We further identify a key role for an MCAT binding site in the Myh7 promoter regulating the response to Vezf1 knockdown and show that TEAD-1 is a binding partner of Vezf1."
The cis-element and binding partner identified in this system, which is the mechanism the transcriptional node asserts.
+ 1 more reference
🐁

Animal Models

1
vezf1 knockdown zebrafish
The only in vivo model bearing on the cardiac phenotype. Knocking down the zebrafish ortholog reduces cardiac growth and blunts the ventricular contractile response to beta-adrenergic stimulation, while leaving cardiomyocyte calcium transient kinetics intact.
Species
Zebrafish
Genotype
vezf1 morpholino knockdown
Publication
PMID:31911272
Pathograph links
Impaired Cardiomyocyte Contractile Function and Compensatory Growth recapitulates fidelity: moderate Reproduces both halves of the cellular node, the contractile deficit and the failure of compensatory growth, and localizes the lesion by showing calcium handling is spared.
Limitations: A knockdown in a fish, not the human nonsense allele in a mammal, and the readout is larval cardiac function rather than the adult-onset dilated cardiomyopathy of the reported family. Morpholino knockdown also depletes the protein globally, so a cardiomyocyte-autonomous interpretation is not established: VEZF1 is primarily a vascular-development factor and an endothelial contribution to the cardiac phenotype has not been excluded.
Readouts
Ventricular contractile response to beta-adrenergic stimulation
Direction: DECREASED
Interpretation: Blunted inotropic reserve is the functional signature of the contractile deficit and indicates the defect emerges under load.
Show evidence (1 reference)
PMID:31911272 SUPPORT Model Organism
"Our experimental data shows that knockdown of zebrafish Vezf1 reduces cardiac growth and results in impaired ventricular contractile response to β-adrenergic stimuli."
Reports the measured contractile and growth deficits.
Cardiomyocyte calcium transient kinetics
Direction: UNCHANGED
Interpretation: A genuine negative result. Intact calcium handling excludes excitation-contraction coupling as the site of the lesion and places it downstream, at the contractile apparatus.
Show evidence (1 reference)
PMID:31911272 SUPPORT Model Organism
"However, Vezf1 knockdown is not associated with dysregulation of cardiomyocyte Ca2+ transient kinetics."
Records the negative calcium-handling result.
Show evidence (1 reference)
PMID:31911272 SUPPORT Model Organism
"We demonstrate a role for Vezf1 in regulation of compensatory cardiac growth and cardiomyocyte contractile function, which may be relevant in human cardiac disease."
Supports treating this model as informative for the contractile node, with the authors' own hedge about human relevance retained.
{ }

Source YAML

click to show 
name: Cardiomyopathy Dilated 100
creation_date: "2026-08-27T00:00:00Z"
category: Genetic
synonyms:
- CMD1OO
- cardiomyopathy, dilated, 1OO
- CMD100
- VEZF1-related dilated cardiomyopathy
- VEZF1 familial dilated cardiomyopathy
disease_term:
  preferred_term: cardiomyopathy, dilated, 100
  term:
    id: MONDO:0859381
    label: cardiomyopathy, dilated, 100
description: >-
  CMD1OO is the VEZF1-attributed member of the numbered familial dilated
  cardiomyopathy series (OMIM 620247). VEZF1 encodes vascular endothelial zinc
  finger 1, a zinc-finger transcription factor originally characterized in
  vasculogenesis and angiogenesis. What makes this entity mechanistically
  distinct from most of the series is that the lesion is not in the contractile
  apparatus at all: it is in a transcription factor that sets how much
  contractile protein a cardiomyocyte makes. The reported disease allele,
  c.490A>T p.(Lys164*), truncates the protein early, and a dual-luciferase
  assay showed the mutant fails to transactivate the promoters of MYH7 and ET1,
  two genes already implicated in DCM.


  The zebrafish and cell work fills in what that loss does to a heart. Vezf1
  expression is reduced in diseased human and mouse myocardium; knocking it
  down in zebrafish reduces cardiac growth and blunts the ventricular
  contractile response to beta-adrenergic stimulation; and the effect runs
  through cardiomyocyte Myh7/beta-MHC, with an MCAT box in the Myh7 promoter
  and TEAD-1 as a binding partner. One negative result in that study is
  informative rather than incidental: calcium transient kinetics are NOT
  disturbed, which places the defect at the contractile apparatus and its
  transcriptional supply rather than in excitation-contraction coupling.


  From there the disease joins the conserved final common pathway that every
  cardiomyopathy converges on, and this entry declares `conforms_to` against
  `cardiomyopathy_maladaptive_remodeling` at three nodes rather than
  re-deriving the neurohormonal and remodeling chain.


  Two cautions belong up front. First, the name is a trap. The OMIM designation
  is CMD1**OO**, with two letter Os continuing the alphabetical series, and it
  is the label "cardiomyopathy, dilated, 100" that misreads them as digits.
  This is not the hundredth numbered dilated cardiomyopathy locus. Second, the
  evidence base is one family. A single nonsense allele segregating with
  autosomal dominant DCM at complete penetrance, absent from 200 unrelated DCM
  patients, 400 controls and the population databases, plus a reporter assay.
  There is no ClinGen gene-disease validity assertion for VEZF1 and no second
  reported family, so the gene-disease relationship should be read as provisional.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0016333
      label: familial dilated cardiomyopathy
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A single heterozygous VEZF1 nonsense allele segregated with disease through
    the reported family with complete penetrance, so a carrier is expected to be
    affected. Note that penetrance estimated in the one family that defined the
    entity is not a general penetrance estimate.
  evidence:
  - reference: PMID:36657711
    reference_title: VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The nonsense mutation was validated by Sanger sequencing and segregated
      with autosome-dominant DCM in the family with complete penetrance.
    explanation: >-
      Establishes dominant transmission and complete penetrance in the reported
      pedigree.
references:
- reference: PMID:36657711
  title: VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
- reference: PMID:31911272
  title: Vezf1 regulates cardiac structure and contractile function.
- reference: PMID:29794136
  title: The transcription factor Vezf1 represses the expression of the antiangiogenic factor Cited2 in endothelial cells.
- reference: PMID:20301486
  title: "Dilated Cardiomyopathy Overview."
  tags:
  - GeneReviews
pathophysiology:
- name: VEZF1 Nonsense Variant Abolishes Transcriptional Transactivation
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: PROVISIONAL
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The initiating lesion is a heterozygous nonsense variant, c.490A>T
    p.(Lys164*), truncating vascular endothelial zinc finger 1 partway through
    the protein. VEZF1 is a zinc-finger transcription factor, so the functional
    consequence is measured as a loss of transactivation rather than as a
    structural defect: in a dual-luciferase reporter system the mutant protein
    failed to drive the promoters of MYH7 and ET1, both of which are already
    implicated in dilated cardiomyopathy. This is why the entity sits apart
    mechanistically from the sarcomeric members of the numbered series, where
    the lesion is in the contractile machinery itself.
  genes:
  - preferred_term: VEZF1
    term:
      id: hgnc:12949
      label: VEZF1
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity of VEZF1
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    modifier: DECREASED
  genetic_context:
    gene:
      preferred_term: VEZF1
      term:
        id: hgnc:12949
        label: VEZF1
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Heterozygous germline nonsense allele. Only one such allele has been
      reported, in a single family.
  evidence:
  - reference: PMID:36657711
    reference_title: VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this investigation, whole-exome sequencing and bioinformatics analyses
      were conducted in a family suffering from DCM, and a novel heterozygous
      mutation in the VEZF1 gene (coding for a zinc finger-containing
      transcription factor critical for cardiovascular development and
      structural remodeling), NM_007146.3: c.490A > T; p.(Lys164*), was
      identified.
    explanation: >-
      Identifies the allele, its heterozygous state, and what VEZF1 encodes.
  - reference: PMID:36657711
    reference_title: VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Biological analyses by utilizing a dual-luciferase reporter assay system
      revealed that the mutant VEZF1 protein failed to transactivate the
      promoters of MYH7 and ET1, two genes that have been associated with DCM.
    explanation: >-
      The functional measurement behind this node: the variant abolishes
      transactivation of two DCM-relevant target promoters.
  downstream:
  - target: Reduced Transcription of Cardiomyocyte Contractile and Growth Targets
    description: >-
      Loss of VEZF1 transactivation lowers expression of its cardiomyocyte
      target genes, of which MYH7 is the identified key one.
- name: Reduced Transcription of Cardiomyocyte Contractile and Growth Targets
  biological_scale: MOLECULAR
  role: amplifier
  mechanism_confidence: PROVISIONAL
  description: >-
    VEZF1 target genes in the cardiomyocyte include the contractile gene
    programme. Gene ontology enrichment on Vezf1 knockdown implicates cardiac
    muscle contraction and dilated-cardiomyopathy genes, and the study
    identifies cardiomyocyte Myh7 (beta-MHC) as the key target, acting through
    an MCAT binding site in the Myh7 promoter with TEAD-1 as a VEZF1 binding
    partner. The same regulation is visible in acquired disease: Vezf1
    expression is reduced in diseased human and mouse myocardium, which is what
    makes this transcription factor plausible as a general node rather than
    just the site of one family's mutation.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: positive regulation of transcription by RNA polymerase II
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    modifier: DECREASED
  evidence:
  - reference: PMID:31911272
    reference_title: Vezf1 regulates cardiac structure and contractile function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Gene ontology enrichment analysis indicates that Vezf1 regulates cardiac
      muscle contraction and dilated cardiomyopathy related genes and we
      identify cardiomyocyte Myh7/β-MHC as key target for Vezf1.
    explanation: >-
      Identifies the transcriptional programme VEZF1 controls in cardiomyocytes
      and names its key target.
  - reference: PMID:31911272
    reference_title: Vezf1 regulates cardiac structure and contractile function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We further identify a key role for an MCAT binding site in the Myh7
      promoter regulating the response to Vezf1 knockdown and show that TEAD-1
      is a binding partner of Vezf1.
    explanation: >-
      Gives the cis-element and the partner through which VEZF1 acts on Myh7,
      which is the same promoter-transactivation function the human nonsense
      allele abolishes.
  - reference: PMID:31911272
    reference_title: Vezf1 regulates cardiac structure and contractile function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We find that expression of Vezf1 is decreased in diseased human myocardium
      and mouse hearts.
    explanation: >-
      Shows the same transcription factor is downregulated in acquired human
      heart disease, independently of any VEZF1 variant.
  downstream:
  - target: Impaired Cardiomyocyte Contractile Function and Compensatory Growth
    description: >-
      Reduced contractile-gene transcription degrades how hard the myocyte can
      contract and how well it can grow in response to load.
- name: Impaired Cardiomyocyte Contractile Function and Compensatory Growth
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
  description: >-
    Loss of Vezf1 reduces cardiac growth and blunts the ventricular contractile
    response to beta-adrenergic stimulation. The negative result recorded
    alongside it is what makes this node specific: calcium transient kinetics
    are unchanged, so the failure is not in excitation-contraction coupling but
    downstream of it, at the contractile apparatus and the transcriptional
    supply that builds it. Blunted inotropic reserve also means the deficit
    shows up first under load rather than at rest.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: DECREASED
  - preferred_term: cardiac muscle tissue growth
    term:
      id: GO:0055017
      label: cardiac muscle tissue growth
    modifier: DECREASED
  evidence:
  - reference: PMID:31911272
    reference_title: Vezf1 regulates cardiac structure and contractile function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our experimental data shows that knockdown of zebrafish Vezf1 reduces
      cardiac growth and results in impaired ventricular contractile response to
      β-adrenergic stimuli.
    explanation: >-
      The two functional deficits this node asserts, measured in vivo.
  - reference: PMID:31911272
    reference_title: Vezf1 regulates cardiac structure and contractile function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, Vezf1 knockdown is not associated with dysregulation of
      cardiomyocyte Ca2+ transient kinetics.
    explanation: >-
      A negative result that localizes the defect: calcium handling is intact,
      so the lesion is not in excitation-contraction coupling.
  - reference: PMID:31911272
    reference_title: Vezf1 regulates cardiac structure and contractile function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We demonstrate a role for Vezf1 in regulation of compensatory cardiac
      growth and cardiomyocyte contractile function, which may be relevant in
      human cardiac disease.
    explanation: >-
      The authors' own summary of the role this node encodes, with their hedge
      about human relevance preserved.
  downstream:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    description: >-
      A myocardium that contracts less well and cannot grow adaptively dilates
      and loses ejection fraction.
- name: Left Ventricular Dilation and Systolic Dysfunction
  biological_scale: ORGANISM
  role: consequence
  mechanism_confidence: ESTABLISHED
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    The clinical endpoint and the definition of the disease class: left
    ventricular or biventricular dilation with systolic dysfunction, leading to
    heart failure and, in some, sudden cardiac death. This node is what the
    entity shares with every other dilated cardiomyopathy, and it is why the
    entry conforms to the conserved maladaptive-remodeling module here rather
    than re-deriving the neurohormonal and remodeling chain that produces it.
  biological_processes:
  - preferred_term: heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36657711
    reference_title: VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dilated cardiomyopathy (DCM), characteristic of left ventricular or
      biventricular dilation with systolic dysfunction, is the most common form
      of cardiomyopathy, and a leading cause of heart failure and sudden cardiac
      death.
    explanation: >-
      Defines the structural and functional endpoint and its consequences, in
      the paper that attributes this entity to VEZF1.
phenotypes:
- category: Cardiovascular
  name: Dilated Cardiomyopathy
  description: >-
    The defining feature: enlargement of the left or both ventricles with
    impaired systolic function. It is what puts the entity in the numbered
    familial dilated cardiomyopathy series, and there is nothing about the
    echocardiographic picture that distinguishes the VEZF1 form from the rest.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  diagnostic: true
  evidence:
  - reference: PMID:36657711
    reference_title: VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dilated cardiomyopathy (DCM), characteristic of left ventricular or
      biventricular dilation with systolic dysfunction, is the most common form
      of cardiomyopathy, and a leading cause of heart failure and sudden cardiac
      death.
    explanation: >-
      Defines the phenotype in the report that attributes this entity to VEZF1.
- category: Cardiovascular
  name: Congestive Heart Failure
  description: >-
    The clinical syndrome the ventricular dysfunction produces, and the usual
    reason a family with this entity comes to attention.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:36657711
    reference_title: VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dilated cardiomyopathy (DCM), characteristic of left ventricular or
      biventricular dilation with systolic dysfunction, is the most common form
      of cardiomyopathy, and a leading cause of heart failure and sudden cardiac
      death.
    explanation: >-
      Names heart failure as the principal consequence of the dilated
      cardiomyopathy phenotype.
- category: Cardiovascular
  name: Sudden Cardiac Death
  description: >-
    The other principal outcome of dilated cardiomyopathy, and the reason
    arrhythmia surveillance matters in a family carrying a dominant allele at
    complete penetrance.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:36657711
    reference_title: VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dilated cardiomyopathy (DCM), characteristic of left ventricular or
      biventricular dilation with systolic dysfunction, is the most common form
      of cardiomyopathy, and a leading cause of heart failure and sudden cardiac
      death.
    explanation: >-
      Names sudden cardiac death as a principal outcome of the disease class
      this entity belongs to.
genetic:
- name: VEZF1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: VEZF1 (vascular endothelial zinc finger 1)
    term:
      id: hgnc:12949
      label: VEZF1
  notes: >-
    The only gene attributed to this entity, and the attribution rests on one
    family. There is no ClinGen gene-disease validity assertion for VEZF1 in
    any cardiomyopathy, no second reported family, and no case series. The
    supporting evidence is strong for a single-family report (segregation at
    complete penetrance, absence from 200 unrelated DCM patients, 400 controls,
    dbSNP, HGMD and gnomAD, plus a reporter assay showing loss of
    transactivation) but it is exactly the shape of evidence that a gene
    curation panel would classify as Limited or Moderate rather than
    Definitive. Treat the gene-disease relationship as provisional.


    VEZF1 has substantial independent cardiovascular biology that makes the
    attribution biologically plausible rather than merely statistical: it was
    characterized first as a regulator of vasculogenesis and angiogenesis, it
    represses the antiangiogenic factor Cited2 in endothelial cells, and its
    expression falls in diseased human myocardium.
  evidence:
  - reference: PMID:36657711
    reference_title: VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The findings indicate VEZF1 as a new gene responsible for DCM, which
      provides novel insight into the molecular pathogenesis of DCM
    explanation: >-
      The gene-disease attribution this entity rests on.
  - reference: PMID:29794136
    reference_title: The transcription factor Vezf1 represses the expression of the antiangiogenic factor Cited2 in endothelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Vascular endothelial zinc finger 1 (Vezf1), is a Krüppel-like zinc finger
      protein that plays a vital role in vascular development.
    explanation: >-
      Independent characterization of VEZF1 as a vascular-development
      transcription factor, which is the background biology that makes a
      cardiovascular phenotype plausible.
  variants:
  - name: VEZF1 c.490A>T p.(Lys164*)
    description: >-
      The only reported disease allele. A nonsense change truncating the protein
      at codon 164, heterozygous, segregating with dominant DCM through one
      family at complete penetrance. It was absent from 200 unrelated DCM
      patients, 400 unrelated healthy individuals, dbSNP, HGMD and gnomAD, which
      is a stronger absence argument than most single-family alleles carry.
    gene:
      preferred_term: VEZF1
      term:
        id: hgnc:12949
        label: VEZF1
    clinical_significance: LIKELY_PATHOGENIC
    type: nonsense
    evidence:
    - reference: PMID:36657711
      reference_title: VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The mutation was neither detected in another cohort of 200 unrelated DCM
        patients nor observed in 400 unrelated healthy individuals nor retrieved
        in the Single Nucleotide Polymorphism database, the Human Gene Mutation
        Database and the Genome Aggregation Database.
      explanation: >-
        The absence data supporting pathogenicity. `clinical_significance` is
        recorded as LIKELY_PATHOGENIC rather than PATHOGENIC because the
        supporting evidence is one family plus one functional assay, with no
        independent replication and no gene curation panel assessment.
experimental_models:
- name: Neonatal rat primary cardiomyocytes with Vezf1 silencing
  experimental_model_type: PRIMARY_CELL_CULTURE
  publication: PMID:31911272
  description: >-
    The cell system in which the transcriptional mechanism was worked out.
    Silencing Vezf1 in primary cardiomyocytes is what identified Myh7 as the key
    target, located the MCAT binding site in the Myh7 promoter that mediates the
    response, and showed TEAD-1 to be a VEZF1 binding partner. It is also the
    one system in this entry that speaks directly to whether the cardiac
    phenotype is cardiomyocyte-autonomous, because it removes the endothelium
    from the question.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  modeled_mechanisms:
  - target: Reduced Transcription of Cardiomyocyte Contractile and Growth Targets
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the transcriptional step directly: loss of VEZF1 in a
      cardiomyocyte lowers Myh7 promoter activity through a defined cis-element
      and a defined partner.
    limitations: >-
      Neonatal rat cells, not human, and knockdown of the wild-type protein
      rather than expression of the human p.(Lys164*) allele, so it models loss
      of VEZF1 rather than this disease's specific lesion. The cells are also
      neonatal, whereas the reported human disease is adult-onset.
    evidence:
    - reference: PMID:31911272
      reference_title: Vezf1 regulates cardiac structure and contractile function.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We further identify a key role for an MCAT binding site in the Myh7
        promoter regulating the response to Vezf1 knockdown and show that TEAD-1
        is a binding partner of Vezf1.
      explanation: >-
        The cis-element and binding partner identified in this system, which is
        the mechanism the transcriptional node asserts.
    - reference: PMID:31911272
      reference_title: Vezf1 regulates cardiac structure and contractile function.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The role of Vezf1 in regulating cardiac growth and contractile function
        was studied in zebrafish and in primary cardiomyocytes.
      explanation: >-
        Establishes primary cardiomyocytes as one of the two systems used,
        alongside the zebrafish curated under `animal_models`.
animal_models:
- name: vezf1 knockdown zebrafish
  species: Zebrafish
  genotype: vezf1 morpholino knockdown
  publication: PMID:31911272
  description: >-
    The only in vivo model bearing on the cardiac phenotype. Knocking down the
    zebrafish ortholog reduces cardiac growth and blunts the ventricular
    contractile response to beta-adrenergic stimulation, while leaving
    cardiomyocyte calcium transient kinetics intact.
  modeled_mechanisms:
  - target: Impaired Cardiomyocyte Contractile Function and Compensatory Growth
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces both halves of the cellular node, the contractile deficit and
      the failure of compensatory growth, and localizes the lesion by showing
      calcium handling is spared.
    limitations: >-
      A knockdown in a fish, not the human nonsense allele in a mammal, and the
      readout is larval cardiac function rather than the adult-onset dilated
      cardiomyopathy of the reported family. Morpholino knockdown also depletes
      the protein globally, so a cardiomyocyte-autonomous interpretation is not
      established: VEZF1 is primarily a vascular-development factor and an
      endothelial contribution to the cardiac phenotype has not been excluded.
    readouts:
    - name: Ventricular contractile response to beta-adrenergic stimulation
      target: Impaired Cardiomyocyte Contractile Function and Compensatory Growth
      direction: DECREASED
      interpretation: >-
        Blunted inotropic reserve is the functional signature of the contractile
        deficit and indicates the defect emerges under load.
      evidence:
      - reference: PMID:31911272
        reference_title: Vezf1 regulates cardiac structure and contractile function.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Our experimental data shows that knockdown of zebrafish Vezf1 reduces
          cardiac growth and results in impaired ventricular contractile
          response to β-adrenergic stimuli.
        explanation: >-
          Reports the measured contractile and growth deficits.
    - name: Cardiomyocyte calcium transient kinetics
      target: Impaired Cardiomyocyte Contractile Function and Compensatory Growth
      direction: UNCHANGED
      interpretation: >-
        A genuine negative result. Intact calcium handling excludes
        excitation-contraction coupling as the site of the lesion and places it
        downstream, at the contractile apparatus.
      evidence:
      - reference: PMID:31911272
        reference_title: Vezf1 regulates cardiac structure and contractile function.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          However, Vezf1 knockdown is not associated with dysregulation of
          cardiomyocyte Ca2+ transient kinetics.
        explanation: >-
          Records the negative calcium-handling result.
    evidence:
    - reference: PMID:31911272
      reference_title: Vezf1 regulates cardiac structure and contractile function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We demonstrate a role for Vezf1 in regulation of compensatory cardiac
        growth and cardiomyocyte contractile function, which may be relevant in
        human cardiac disease.
      explanation: >-
        Supports treating this model as informative for the contractile node,
        with the authors' own hedge about human relevance retained.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    One reported family. No prevalence, incidence or carrier-frequency estimate
    exists, and none should be inferred from dilated cardiomyopathy overall,
    which is common and attributable to more than a hundred genes. The one
    quantitative statement that can be made is negative: the allele was absent
    from 200 unrelated DCM patients and 400 controls, so it is not a
    recurrent contributor to DCM in that population.
  evidence:
  - reference: PMID:36657711
    reference_title: VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation was neither detected in another cohort of 200 unrelated DCM
      patients nor observed in 400 unrelated healthy individuals nor retrieved
      in the Single Nucleotide Polymorphism database, the Human Gene Mutation
      Database and the Genome Aggregation Database.
    explanation: >-
      The screening data that bounds how common this allele can be.
diagnosis:
- name: Echocardiography
  description: >-
    The diagnosis of the dilated cardiomyopathy phenotype is echocardiographic:
    ventricular dilation with reduced ejection fraction. Nothing about the
    imaging identifies the VEZF1 form.
  evidence:
  - reference: PMID:36657711
    reference_title: VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dilated cardiomyopathy (DCM), characteristic of left ventricular or
      biventricular dilation with systolic dysfunction, is the most common form
      of cardiomyopathy, and a leading cause of heart failure and sudden cardiac
      death.
    explanation: >-
      Gives the structural and functional criteria that define the phenotype.
  - reference: PMID:20301486
    reference_title: "Dilated Cardiomyopathy Overview."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Provide the evaluation strategy of a proband with nonsyndromic DCM
    explanation: >-
      The GeneReviews overview exists to set out the proband evaluation strategy
      for nonsyndromic dilated cardiomyopathy, which is the workup this entity
      enters through. Graded OTHER because the source is an expert overview.
- name: Whole-Exome Sequencing
  description: >-
    The entity was defined by whole-exome sequencing of a family, and that
    remains the only route to the specific diagnosis. Note that VEZF1 is not on
    most established cardiomyopathy gene panels, so a panel-negative familial
    DCM is where this entity would be found if it is found at all.
  evidence:
  - reference: PMID:36657711
    reference_title: VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this investigation, whole-exome sequencing and bioinformatics analyses
      were conducted in a family suffering from DCM
    explanation: >-
      The method by which the entity was identified.
treatments:
- name: Cascade Genetic Testing and Surveillance of At-Risk Relatives
  description: >-
    The highest-yield action this entity supports, and the one most specific to
    it. Once the familial variant is known, first-degree relatives can be tested
    directly; a relative of a carrier has a 50% prior, and on the single
    available pedigree penetrance was complete, so a genotype-positive relative
    should be assumed to be at risk rather than reassured. Genotype-positive
    relatives then need longitudinal cardiac surveillance so that ventricular
    dysfunction is caught before it presents as heart failure or sudden death,
    and genotype-negative relatives can be released from it.
  treatment_term:
    preferred_term: cascade genetic testing and genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  target_phenotypes:
  - preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:20301486
    reference_title: "Dilated Cardiomyopathy Overview."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      relatives of a proband with DCM to inform cardiac surveillance and allow
      early detection and treatment of DCM to improve long-term outcome
    explanation: >-
      The GeneReviews dilated cardiomyopathy overview states the purpose of
      genetic risk assessment in at-risk relatives, which is what this
      intervention delivers. Graded OTHER because the source is an expert
      overview rather than a primary study.
  - reference: PMID:36657711
    reference_title: VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The nonsense mutation was validated by Sanger sequencing and segregated
      with autosome-dominant DCM in the family with complete penetrance.
    explanation: >-
      Establishes the dominant transmission and complete penetrance that make
      cascade testing informative in this entity specifically.
  notes: >-
    Carries no `target_mechanisms`. Testing and surveillance are diagnostic and
    monitoring actions, not therapeutic ones acting on a pathograph node. Note
    also that the complete penetrance figure comes from one pedigree and should
    not be quoted to a family as a general penetrance estimate.
- name: Guideline-Directed Heart Failure Pharmacotherapy
  description: >-
    Management is the standard treatment of dilated cardiomyopathy and heart
    failure with reduced ejection fraction. There is nothing VEZF1-specific: no
    disease-modifying therapy exists for the transcriptional defect, and no
    treatment study has been reported in a carrier.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  notes: >-
    No evidence block and no `target_mechanisms`. Neither the founding report
    nor the model-organism study addresses treatment, and citing a general
    heart-failure guideline here would present it as though it were about this
    entity. Recorded because it is what a carrier actually receives.
- name: Cardiac Transplantation
  description: >-
    The endpoint option for a dilated cardiomyopathy that progresses to
    refractory heart failure. As with pharmacotherapy, nothing here is specific
    to this entity.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  notes: >-
    No evidence block, for the same reason as the pharmacotherapy entry.
discussions:
- discussion_id: vezf1_dcm_gene_validity
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Is VEZF1 established as a dilated cardiomyopathy gene, or is this still a
    single-family candidate?
  attaches_to:
  - pathophysiology#VEZF1 Nonsense Variant Abolishes Transcriptional Transactivation
  rationale: >-
    The whole entity rests on one report of one family with one nonsense allele,
    plus a dual-luciferase assay. The supporting evidence is good of its kind:
    segregation at complete penetrance, absence from 200 unrelated DCM patients,
    400 controls, dbSNP, HGMD and gnomAD, and a measured loss of transactivation
    at two DCM-relevant promoters. But there is no second family, no case
    series, and no ClinGen gene-disease validity assertion for VEZF1 in any
    cardiomyopathy. On the ClinGen framework this is the shape of evidence that
    would classify as Limited or at most Moderate, not Definitive. That matters
    for how a VEZF1 variant found on a research exome should be reported, and it
    is why the trigger and its two downstream nodes carry
    `mechanism_confidence: PROVISIONAL` while the final structural node, which
    is generic dilated cardiomyopathy, does not.
  proposed_experiments:
  - experiment_id: vezf1_dcm_cohort_replication
    name: Look for further VEZF1 loss-of-function alleles in DCM cohorts
    description: >-
      Query large sequenced familial dilated cardiomyopathy cohorts for rare
      VEZF1 loss-of-function alleles and test segregation. VEZF1 is absent from
      most established cardiomyopathy gene panels, so replication requires
      exome or genome data rather than panel data, and the absence of further
      reports since 2023 may reflect that nobody has looked rather than that
      nobody has found.
  evidence:
  - reference: PMID:36657711
    reference_title: VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this investigation, whole-exome sequencing and bioinformatics analyses
      were conducted in a family suffering from DCM
    explanation: >-
      The single family that the entity rests on.
  - reference: PMID:36657711
    reference_title: VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nevertheless, due to pronounced genetic heterogeneity, the genetic defects
      underpinning DCM in most cases remain obscure.
    explanation: >-
      The authors' own framing of the field, which is why single-family
      attributions are common in DCM and why replication matters.
- discussion_id: vezf1_cardiomyocyte_autonomous_or_vascular
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Is the cardiac phenotype cardiomyocyte-autonomous, or does it arise partly
    through VEZF1's better-established role in the vasculature?
  attaches_to:
  - pathophysiology#Reduced Transcription of Cardiomyocyte Contractile and Growth Targets
  - pathophysiology#Impaired Cardiomyocyte Contractile Function and Compensatory Growth
  rationale: >-
    This entry models the disease as a cardiomyocyte transcription-factor
    defect, because that is what the two direct measurements support: the human
    variant fails to transactivate MYH7, and the zebrafish work identifies
    cardiomyocyte Myh7 as the key target with an MCAT box and TEAD-1 as partner.
    But VEZF1 was characterized first, and is still best characterized, as a
    vascular-development factor. It is required for endothelial differentiation,
    and it represses the antiangiogenic factor Cited2 in endothelial cells. The
    zebrafish experiment is a whole-organism knockdown and the human allele is
    germline, so neither excludes an endothelial or microvascular contribution
    to the cardiac phenotype. Distinguishing these is not a technicality: a
    myocyte-autonomous transcriptional defect and a microvascular
    developmental defect predict different natural histories and different
    things about whether the myocardium can be supported.
  proposed_experiments:
  - experiment_id: vezf1_conditional_knockout_lineage
    name: Compare cardiomyocyte-restricted and endothelial-restricted Vezf1 loss
    description: >-
      Generate cardiomyocyte-specific and endothelial-specific conditional Vezf1
      knockouts and compare cardiac growth, contractile reserve and Myh7
      expression. If the myocyte-restricted animal reproduces the phenotype the
      cardiomyocyte-autonomous model in this entry is correct; if only the
      endothelial-restricted or the combined animal does, the pathograph needs
      an endothelial node.
  evidence:
  - reference: PMID:31911272
    reference_title: Vezf1 regulates cardiac structure and contractile function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We further identify a key role for an MCAT binding site in the Myh7
      promoter regulating the response to Vezf1 knockdown and show that TEAD-1
      is a binding partner of Vezf1.
    explanation: >-
      The cardiomyocyte-autonomous evidence, which is mechanistically specific
      but was obtained in primary cardiomyocytes rather than in vivo.
  - reference: PMID:29794136
    reference_title: The transcription factor Vezf1 represses the expression of the antiangiogenic factor Cited2 in endothelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Compared with WT ESCs, Vezf1-/- ESCs inefficiently differentiated into
      endothelial cells (ECs), which exhibited defects in the tube-formation
      assay.
    explanation: >-
      The competing endothelial role. Graded PARTIAL because it establishes the
      alternative lineage requirement without bearing directly on the cardiac
      phenotype.
notes: >-
  Entry-type decision: DISEASE. MONDO:0859381 is a leaf with no descendants.
  Unusually for this queue, the stub carries NO `genes:` block, because MONDO
  records no causal-gene relationship for this term. Identity was therefore
  resolved through the stub's MONDO xrefs rather than by asking MONDO for a
  gene: MONDO:0859381 carries `OMIM:620247` and `MEDGEN:1840927`, and the
  MedGen record supplies the gene (VEZF1, 17q22), the OMIM designation, the
  disease definition and the source citation (Shi et al., 2023, PMID:36657711).


  THE NAME IS A TRAP. The OMIM designation is CMD1OO, with two capital letter
  Os continuing the alphabetical suffix series (CMD1A, CMD1B, ... CMD1NN,
  CMD1OO). The MONDO and MedGen labels render it "cardiomyopathy, dilated, 100",
  reading the letters as digits. This is NOT the hundredth numbered dilated
  cardiomyopathy locus. Both spellings are recorded in `synonyms` so a search
  on either finds this entry, and the disease_term keeps the MONDO label
  unchanged.


  Named-entity check: `just preflight-dr` returns SKIP for this MONDO term
  because MONDO records no causal gene, so the automated gene-frequency check
  cannot discriminate. The manual check specified for a SKIP verdict was
  performed instead: the OMIM xref on the MONDO term (620247) matches the OMIM
  identifier in the MedGen record, and the gene named there (VEZF1) is the gene
  of the deep-research report and of every reference cited here. The report's
  own gene tally, which the SKIP verdict still prints, is consistent
  (VEZF1=49, then MYH7=10 and TEAD1=8, which are the two mechanism partners
  curated here rather than rival disease genes).


  Deep research provenance: the falcon report reached the same causal chain
  independently but could NOT recover the variant details, listing HGVS
  nomenclature, variant class and functional effect of the human allele as
  fields to leave null pending inspection of the original article. Those
  details are curated here because they are in the abstract of PMID:36657711,
  which was fetched directly. This is worth recording because it is the
  opposite of the usual failure mode: the report under-claimed rather than
  over-claimed.


  OMIM's clinical synopsis, as surfaced through MedGen, additionally lists
  atrial septal defect, second-degree atrioventricular block, premature
  ventricular contraction and reduced left ventricular ejection fraction. None
  of these is curated as a phenotype here, because the only primary source is
  abstract-only and its abstract does not mention them, and MedGen and OMIM are
  not citable reference prefixes in this repository. They are recorded here so
  a later curator with full-text access knows what to look for rather than
  re-deriving the gap.


  Module conformance: three nodes declare `conforms_to` against
  `cardiomyopathy_maladaptive_remodeling` (Primary Cardiomyocyte Insult,
  Progressive Contractile Dysfunction, Structural Cardiac Impairment and Heart
  Failure). Conformance is not inheritance, so the disease-specific content is
  duplicated in full. The module's Neurohormonal Activation and Ventricular
  Remodeling nodes are deliberately NOT conformed to: nothing in the VEZF1
  literature measures either in this disease, and asserting conformance on the
  strength of the general DCM pathway would be inheriting the module rather
  than declaring agreement with it.


  No frequency values are asserted on any phenotype. The entity is one family
  and no denominator exists.


  GeneReviews has no VEZF1-specific chapter, but the disease-level "Dilated
  Cardiomyopathy Overview" (PMID:20301486) does apply and is tagged and mined
  here, on both the cascade-testing treatment and the echocardiography
  diagnosis entry. This follows the precedent set by the numbered-series peers
  `Dilated_Cardiomyopathy_1AA` and `Dilated_Cardiomyopathy_1EE`, which are in
  the same position of having no gene-specific chapter. An earlier draft of
  this entry asserted that no GeneReviews baseline existed at all, which was
  true only of a gene-specific chapter and is corrected here. Orphanet has no
  entry keyed to this concept, so no ORPHA reference is cited. `just refresh-orphadata` is currently failing on a drifted sha256 in
  this repository and was not run.
datasets: []
📚

References & Deep Research

References

4
PMID:36657711
VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
No top-level findings curated for this source.
PMID:31911272
Vezf1 regulates cardiac structure and contractile function.
No top-level findings curated for this source.
PMID:29794136
The transcription factor Vezf1 represses the expression of the antiangiogenic factor Cited2 in endothelial cells.
No top-level findings curated for this source.
PMID:20301486
Dilated Cardiomyopathy Overview.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Cardiomyopathy, Dilated, 100 (DCM100): Research Report
Edison Scientific Literature 5 citations 2026-08-27T10:45:29.824458

Cardiomyopathy, Dilated, 100 (DCM100): Research Report

Executive summary and evidence limits

Cardiomyopathy, dilated, 100 (DCM100) is an exceptionally rare Mendelian form of familial dilated cardiomyopathy associated with VEZF1 (vascular endothelial zinc finger 1). The exact disease is indexed as MONDO:0859381; OpenTargets links it to VEZF1 through the 2023 defining report, PMID 36657711. It must not be confused with the distinct, autosomal-recessive RPL3L-associated neonatal DCM. (OpenTargets Search: Cardiomyopathy Dilated 100)

The disease-specific evidence base is currently very small. One family report establishes the association, while most mechanistic information comes from human myocardial-expression datasets, zebrafish knockdown, and cultured rodent cardiomyocytes. Accordingly, claims below are labeled DCM100-specific, supportive experimental evidence, or generic-DCM extrapolation. Exact pedigree details, the reported HGVS variant, patient-level phenotype, OMIM number, penetrance, and variant frequency could not be verified from the accessible full text and are therefore not invented.

The following table provides the most compact knowledge-base representation.

Field Finding Evidence scope Suggested ontology terms Key citation
Exact disease name / synonyms Cardiomyopathy, dilated, 100; shorthand DCM100. Distinct from generic dilated cardiomyopathy and distinct from recessive RPL3L-associated neonatal DCM. DCM100-specific for exact name; comparison to RPL3L based on separate literature mapping. MONDO:0859381 (OpenTargets Search: Cardiomyopathy Dilated 100)
MONDO ID MONDO:0859381 for “cardiomyopathy, dilated, 100”. DCM100-specific MONDO:0859381 (OpenTargets Search: Cardiomyopathy Dilated 100)
Causal gene VEZF1 (vascular endothelial zinc finger 1). OpenTargets maps VEZF1 as the associated target for this disease with literature support from PMID 36657711. DCM100-specific Gene symbol: VEZF1 (OpenTargets Search: Cardiomyopathy Dilated 100)
Protein role VEZF1 is a zinc-finger transcription factor implicated in regulation of cardiac structure/function and angiogenic programs; in cardiomyocytes it regulates expression of contraction/cardiomyopathy-related genes including MYH7 and interacts with TEAD1. Gene/mechanism evidence relevant to DCM100; mostly experimental, not all from human DCM100 patients. GO:0006355 regulation of DNA-templated transcription; GO:0060048 cardiac muscle contraction; GO:0001525 angiogenesis (paavola2020vezf1regulatescardiac pages 1-2, paavola2020vezf1regulatescardiac pages 5-7, paavola2020vezf1regulatescardiac pages 7-8, paavola2020vezf1regulatescardiac pages 11-12)
Inheritance Autosomal dominant pattern is most likely for DCM100 because the defining publication is titled “VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy” and describes a familial DCM gene-disease relationship; exact pedigree details were not recoverable here. DCM100-specific but partially inferred from defining publication metadata HP:0000006 Autosomal dominant inheritance (OpenTargets Search: Cardiomyopathy Dilated 100)
Defining human evidence Defining report: Shi HY, Xie MS, Guo YH, et al. “VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.” European Journal of Medical Genetics. 2023; DOI: 10.1016/j.ejmg.2023.104705; PMID: 36657711. Exact variant HGVS, family size, and frequencies were not available in recovered context and should not be invented. DCM100-specific NCIT: C16612 Genetic Finding (OpenTargets Search: Cardiomyopathy Dilated 100)
Core phenotype Dilated cardiomyopathy phenotype is expected: left ventricular dilatation and systolic dysfunction, progressing to heart failure/arrhythmic risk as in familial DCM. Direct DCM100-specific phenotypic granularity beyond this was not recoverable in current context. Mixed: DCM100-specific at disease label; generic DCM for detailed phenotype framing HP:0001644 Dilated cardiomyopathy; HP:0001670 Abnormal cardiac ventricle morphology; HP:0001638 Cardiomyopathy; HP:0005162 Reduced ejection fraction (OpenTargets Search: Cardiomyopathy Dilated 100, mcnally2017dilatedcardiomyopathygenetic pages 2-3)
Mechanistic chain Proposed chain: VEZF1 loss-of-function → altered transcriptional control in cardiomyocytes → reduced MYH7/β-MHC and dysregulation of other contraction-related genes → impaired compensatory growth and reduced contractile reserve → ventricular dysfunction / DCM phenotype. Vezf1 also binds TEAD1 and affects an MCAT site in the Myh7 promoter. Mechanism is experimental and supportive, not direct proof from all DCM100 patients GO:0006357 regulation of transcription by RNA polymerase II; GO:0060048 cardiac muscle contraction; GO:0003015 heart process (paavola2020vezf1regulatescardiac pages 5-7, paavola2020vezf1regulatescardiac pages 7-8, paavola2020vezf1regulatescardiac pages 8-9, paavola2020vezf1regulatescardiac pages 11-12)
Primary anatomy / cell type / subcellular localization Primary organ/tissue: heart / myocardium, especially left ventricle. Key cell types: cardiomyocytes and likely endothelial cells. VEZF1 is described as a nuclear protein. Mostly mechanism/model evidence; anatomy aligns with DCM100 disease concept UBERON:0000948 heart; UBERON:0002084 myocardium; UBERON:0002082 cardiac ventricle; UBERON:0002080 left ventricle; CL:0002494 cardiomyocyte; CL:0000115 endothelial cell; GO:0005634 nucleus (paavola2020vezf1regulatescardiac pages 1-2, paavola2020vezf1regulatescardiac pages 4-5, paavola2020vezf1regulatescardiac pages 9-11)
Diagnostic approach No DCM100-specific diagnostic guideline was recovered. Practical approach is generic hereditary DCM workup plus molecular confirmation: clinical exam/family history, ECG, echocardiography, CMR, natriuretic peptides/heart-failure biomarkers, and multigene cardiomyopathy testing including VEZF1 if available. Generic DCM criteria cited include LVEF <45% or FS <25% with increased LV size. Mostly extrapolated from generic DCM NCIT: C38043 Electrocardiography; NCIT: C16576 Echocardiography; NCIT: C16809 Magnetic Resonance Imaging; NCIT: C47809 Genetic Testing (mcnally2017dilatedcardiomyopathygenetic pages 2-3)
Treatment status No DCM100-specific targeted therapy was identified. Management should follow guideline-directed therapy for dilated cardiomyopathy/heart failure, with consideration of arrhythmia prevention, ICD/CRT when indicated, advanced HF therapies, and transplantation in end-stage disease. Extrapolated from generic DCM; not DCM100-specific NCIT: C101526 Heart Failure Management; NCIT: C173520 Implantable Cardioverter Defibrillator Placement; NCIT: C80450 Cardiac Resynchronization Therapy; NCIT: C15202 Heart Transplantation (mcnally2017dilatedcardiomyopathygenetic pages 2-3)
Epidemiology Ultra-rare / not established for DCM100 specifically. No prevalence, incidence, sex ratio, or carrier frequency for DCM100 were recoverable. Familial DCM more broadly accounts for roughly 30–50% of DCM, with identifiable genetic causes in about 40% of familial cases in the cited review. DCM100-specific data unavailable; generic DCM/familial DCM figures extrapolated NCIT: C25190 Prevalence (mcnally2017dilatedcardiomyopathygenetic pages 2-3)
Model systems Zebrafish Vezf1 knockdown reduces cardiac growth and blunts β-adrenergic stress-induced contractile response; rat cardiomyocytes with Vezf1 silencing show reduced shortening, reduced β-MHC/MYH7, increased skeletal α-actin, and TEAD1 interaction; expression is decreased in diseased human myocardium and post-MI mouse hearts. Mechanistic/model evidence supportive of DCM100 biology CL:0002494 cardiomyocyte; GO:0060048 cardiac muscle contraction; GO:0001525 angiogenesis (paavola2020vezf1regulatescardiac pages 1-2, paavola2020vezf1regulatescardiac pages 4-5, paavola2020vezf1regulatescardiac pages 5-7, paavola2020vezf1regulatescardiac pages 7-8, paavola2020vezf1regulatescardiac pages 8-9, paavola2020vezf1regulatescardiac pages 9-11, paavola2020vezf1regulatescardiac pages 11-12)

Table: This table summarizes the highest-confidence facts currently recoverable for Cardiomyopathy, Dilated, 100, clearly separating disease-specific findings from broader DCM extrapolations. It is designed for direct knowledge-base ingestion with ontology suggestions and context-ID citations.

1. Disease information

Definition

DCM is a myocardial disorder characterized by ventricular—usually left-ventricular—dilatation and systolic dysfunction not adequately explained by abnormal loading conditions or coronary disease. Historical research criteria include fractional shortening <25% or left-ventricular ejection fraction <45%, together with LV end-diastolic diameter >117% of the value predicted for age and body-surface area. DCM100 denotes the VEZF1-associated familial subtype, rather than all DCM. (mcnally2017dilatedcardiomyopathygenetic pages 2-3)

Identifiers and synonyms

  • Preferred name: Cardiomyopathy, dilated, 100
  • Synonyms: Dilated cardiomyopathy 100; DCM100; VEZF1-related dilated cardiomyopathy
  • MONDO: MONDO:0859381
  • Causal gene: VEZF1, Ensembl ENSG00000136451
  • Defining publication: Shi HY et al., VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy, European Journal of Medical Genetics, 2023; DOI: https://doi.org/10.1016/j.ejmg.2023.104705; PMID: https://pubmed.ncbi.nlm.nih.gov/36657711/ (OpenTargets Search: Cardiomyopathy Dilated 100)
  • OMIM/Orphanet: an exact disease-level number was not independently recoverable from the available evidence.
  • ICD-10: DCM generally maps to I42.0, but this is not specific to DCM100.
  • ICD-11/MeSH: use the broader dilated-cardiomyopathy concepts; no subtype-specific code was verified.

The evidence is an aggregated disease-level synthesis based on a published family, experimental studies, and databases—not individual EHR data.

2. Etiology and risk factors

Causal factor

The defining human report attributes familial DCM to a VEZF1 loss-of-function mutation. The familial title and disease classification support autosomal-dominant transmission, but exact segregation counts and the variant’s HGVS description require confirmation from the original article before clinical use. OpenTargets records one disease–target evidence item tied to PMID 36657711. (OpenTargets Search: Cardiomyopathy Dilated 100)

Genetic and environmental risk

The principal established DCM100 risk is carriage of the familial VEZF1 variant. No independently replicated susceptibility loci, modifier genes, founder allele, carrier frequency, germline mosaicism, anticipation, or population-specific enrichment have been reported for this subtype in the retrieved evidence.

No DCM100-specific environmental risk or protective factor has been established. For DCM generally, myocardial stressors—viral myocarditis, alcohol, cardiotoxic drugs, pregnancy, endocrine/metabolic disease, sustained tachyarrhythmia, and hemodynamic overload—may precipitate or worsen ventricular dysfunction. Applying these as VEZF1 gene–environment interactions is biologically plausible but unproven.

Experimental data provide one candidate interaction: Vezf1-deficient zebrafish had a disproportionately impaired response to β-adrenergic stress, suggesting that reduced VEZF1 limits cardiac contractile reserve under increased demand. This is a model-organism observation, not demonstrated penetrance modification in human carriers. (paavola2020vezf1regulatescardiac pages 2-3, paavola2020vezf1regulatescardiac pages 8-9)

3. Phenotypes

The confidently assignable phenotype is dilated cardiomyopathy with ventricular systolic dysfunction. The accessible evidence does not support reliable DCM100-specific frequencies, onset ages, sex differences, or extracardiac manifestations.

Suggested terms include:

  • Dilated cardiomyopathy — HP:0001644: defining structural/functional phenotype.
  • Reduced left-ventricular ejection fraction — HP:0012664 or the current HPO equivalent used by the target database.
  • Left-ventricular dilatation — HP:0001711.
  • Congestive heart failure — HP:0001635: possible advanced manifestation.
  • Cardiomegaly — HP:0001640, dyspnea — HP:0002094, exercise intolerance — HP:0003546, fatigue — HP:0012378, peripheral edema — HP:0012398, and cardiac arrhythmia — HP:0011675: clinically plausible generic DCM manifestations, but not confirmed as frequencies in DCM100.

DCM can impair exercise capacity, schooling or employment, sleep, independence, and psychosocial well-being. No DCM100-specific EQ-5D, SF-36, KCCQ, or pediatric quality-of-life data exist in the retrieved literature.

4. Genetic and molecular information

Gene and protein

VEZF1 encodes a highly conserved nuclear C2H2 zinc-finger transcription factor with six zinc-finger motifs and a proline-rich transactivation domain. It is expressed in endothelial cells and adult cardiomyocytes and participates in angiogenesis, cardiac growth, and transcriptional control of contractile genes. (paavola2020vezf1regulatescardiac pages 1-2, paavola2020vezf1regulatescardiac pages 11-12)

Variant evidence

The defining publication reports a loss-of-function mutation segregating with familial DCM. However, the following could not be independently recovered and should remain null fields pending inspection of the original article:

  • HGVS genomic/cDNA/protein nomenclature;
  • missense, nonsense, frameshift, or splice class;
  • ClinVar classification and accession;
  • gnomAD/TOPMed frequency;
  • ACMG/AMP criteria;
  • number of carriers and affected relatives;
  • functional effect of the specific human allele.

The presumed origin is germline, given familial Mendelian transmission. There is no evidence that DCM100 is somatic. No validated modifier gene, pathogenic copy-number change, methylation signature, or disease-specific chromosomal abnormality is established.

5. Environmental information

No toxin, infection, radiation, occupational exposure, diet, smoking behavior, alcohol exposure, or pathogen has been shown to cause DCM100. These should be captured only as general DCM differential etiologies or possible secondary stressors—not as causes of the VEZF1 subtype.

Reasonable risk-reduction practice is avoidance of cardiotoxic exposures, recreational stimulants, heavy alcohol consumption, and unsupervised extreme exercise after cardiomyopathy is recognized. This is generic cardiomyopathy care rather than evidence for primary prevention of VEZF1 disease.

6. Mechanism and pathophysiology

Proposed causal chain

  1. Upstream genetic event: reduced VEZF1 function.
  2. Transcriptional dysregulation: altered VEZF1–TEAD1 regulation of muscle genes, including MYH7/β-myosin heavy chain, ATP1A2, TCAP, ACTA1, MYH11, and troponin genes.
  3. Contractile-unit imbalance: reduced MYH7/β-MHC with increased skeletal α-actin lowers the myosin/actin ratio.
  4. Cellular phenotype: reduced cardiomyocyte growth and shortening with impaired compensatory response to adrenergic/hemodynamic stress.
  5. Organ phenotype: reduced contractile reserve, ventricular systolic dysfunction, remodeling, and DCM/heart failure. (paavola2020vezf1regulatescardiac pages 5-7, paavola2020vezf1regulatescardiac pages 7-8, paavola2020vezf1regulatescardiac pages 8-9, paavola2020vezf1regulatescardiac pages 9-11)

In neonatal rat cardiomyocytes, VEZF1 silencing significantly altered 1,144 transcripts at FDR <0.05; 28 were increased and 53 decreased by more than twofold. Enrichment implicated muscle contraction and DCM pathways. Zebrafish Vezf1 knockdown reduced ventricular-myosin-heavy-chain expression by 92% and impaired the stress-induced increase in ejection performance without changing calcium-transient kinetics. These findings argue for altered contractile-gene transcription rather than a primary calcium-handling defect. (paavola2020vezf1regulatescardiac pages 5-7, paavola2020vezf1regulatescardiac pages 7-8, paavola2020vezf1regulatescardiac pages 8-9)

Promoter experiments showed that VEZF1 knockdown reduced β-MHC reporter activity by 52–80%. VEZF1 co-immunoprecipitated with TEAD1, and an MCAT element in the MYH7 promoter partly mediated the response. (paavola2020vezf1regulatescardiac pages 7-8, paavola2020vezf1regulatescardiac pages 9-11, paavola2020vezf1regulatescardiac pages 11-12)

Vascular and epigenetic dimensions

VEZF1 also regulates vasculogenesis and angiogenesis. Zebrafish knockdown altered axial-vessel geometry and stress-induced intersegmental-vessel formation. Endothelial signaling may therefore contribute, but cardiomyocyte-autonomous effects are supported by isolated-cell experiments. (paavola2020vezf1regulatescardiac pages 4-5, paavola2020vezf1regulatescardiac pages 11-12)

VEZF1 has previously been implicated in regulation of DNMT3B and DNA methylation, but no DCM100-specific epigenomic signature has been demonstrated. Likewise, no disease-specific proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or CRISPR-screen dataset was found.

Suggested ontology annotations

  • GO biological process: regulation of DNA-templated transcription; cardiac muscle contraction; regulation of heart contraction; cardiac muscle-cell development; angiogenesis; response to adrenergic stimulus.
  • GO cellular component: nucleus (GO:0005634), transcription-regulator complex, sarcomere (GO:0030017) downstream.
  • Cell Ontology: cardiomyocyte (CL:0002494), ventricular cardiomyocyte, endothelial cell (CL:0000115), cardiac fibroblast as a downstream remodeling cell.

7. Anatomical structures affected

The primary organ is the heart (UBERON:0000948), particularly myocardium (UBERON:0002084) and left ventricle (UBERON:0002080). Cardiomyocytes are the principal effector cells; cardiac endothelial cells may contribute through vascular and paracrine regulation. VEZF1 acts in the nucleus, while downstream damage involves sarcomeres and the contractile apparatus. (paavola2020vezf1regulatescardiac pages 1-2, paavola2020vezf1regulatescardiac pages 9-11, paavola2020vezf1regulatescardiac pages 11-12)

Secondary involvement in advanced DCM can include lungs, liver, kidneys, and systemic venous tissues through low cardiac output and congestion. These are complications of heart failure, not primary VEZF1 target organs. Lateralization is not applicable.

8. Temporal development

The DCM100-specific onset distribution is unknown. Generic inherited DCM may be clinically silent before progressive LV enlargement, reduced systolic function, symptomatic heart failure, arrhythmia, or sudden death. In genetic DCM, ventricular enlargement may precede measurable functional decline, and strain abnormalities may precede dimensional changes in relatives. (mcnally2017dilatedcardiomyopathygenetic pages 2-3)

A practical course model is:

  1. genotype-positive/phenotype-negative;
  2. subtle strain or ECG abnormality;
  3. LV enlargement with mild systolic dysfunction;
  4. symptomatic DCM/HFrEF;
  5. advanced heart failure, malignant arrhythmia, mechanical support, or transplantation.

Spontaneous or treatment-associated reverse remodeling occurs in generic DCM, but no remission rate or critical intervention window is known for DCM100.

9. Inheritance and population

The available human evidence supports familial autosomal-dominant inheritance. Each child of a heterozygous carrier would therefore have a theoretical 50% transmission probability, although disease penetrance may be incomplete or age-dependent. Actual DCM100 penetrance and expressivity have not been quantified.

No subtype-specific prevalence, incidence, carrier frequency, founder effect, ethnic enrichment, geographic distribution, sex ratio, or age distribution is known. DCM100 should presently be considered ultra-rare. In DCM overall, familial disease is estimated in approximately 30–50% of cases, and an identifiable genetic cause is found in roughly 40% of familial cases; these values must not be assigned to VEZF1 specifically. (mcnally2017dilatedcardiomyopathygenetic pages 2-3)

10. Diagnostics

Clinical evaluation

The phenotype should be established independently of genotype through:

  • history, three-generation pedigree, physical examination, and exclusion of ischemic/loading causes;
  • 12-lead ECG and ambulatory monitoring for conduction disease and atrial/ventricular arrhythmia;
  • transthoracic echocardiography for LV dimensions, ejection fraction, fractional shortening, valve regurgitation, and strain;
  • cardiac MRI for chamber volumes, function, edema, and fibrosis/late gadolinium enhancement;
  • BNP or NT-proBNP and troponin as severity/injury markers;
  • laboratory exclusion of thyroid, metabolic, infectious, inflammatory, toxic, and nutritional causes where clinically indicated. CMR fibrosis has prognostic value in broader DCM. (mcnally2017dilatedcardiomyopathygenetic pages 2-3)

Endomyocardial biopsy is not routine for genetic DCM but may be appropriate when myocarditis, infiltrative disease, storage disease, or a treatment-changing inflammatory diagnosis is suspected.

Genetic testing

A contemporary strategy is a validated cardiomyopathy panel with deletion/duplication analysis, ensuring VEZF1 coverage if the laboratory recognizes the gene–disease relationship. Exome or genome sequencing is appropriate when panel testing is negative, especially in multiplex families; RNA studies may clarify splice variants. A VUS must not be used for predictive testing or irreversible management decisions.

Once a pathogenic familial variant is confirmed, offer targeted cascade testing to first-degree relatives. Genotype-positive relatives require longitudinal ECG and imaging surveillance. If the causal variant remains uncertain, first-degree relatives should still receive phenotype screening because familial DCM may be clinically silent. (mcnally2017dilatedcardiomyopathygenetic pages 2-3)

CMA, karyotyping, FISH, mitochondrial-genome testing, and repeat-expansion testing are not first-line for isolated DCM100 unless syndromic findings suggest another diagnosis.

Differential diagnosis

Exclude ischemic cardiomyopathy, myocarditis, tachycardia-induced cardiomyopathy, toxic/alcohol-related disease, peripartum cardiomyopathy, endocrine/nutritional disease, mitochondrial/metabolic cardiomyopathy, neuromuscular disease, congenital heart disease, and other genetic DCM genes such as TTN, LMNA, FLNC, DSP, RBM20, BAG3, and PLN.

11. Outcome and prognosis

No DCM100-specific survival, transplant-free survival, sudden-death rate, recovery rate, or validated prognostic biomarker is available. Prognosis should therefore be based on the observed phenotype rather than the VEZF1 label alone.

Generic adverse markers include severe LV dysfunction or dilatation, persistent symptoms, ventricular arrhythmia, conduction disease, syncope, fibrosis on CMR, severe mitral regurgitation, rising natriuretic peptides, and failure to reverse remodel. DCM can lead to chronic disability, recurrent hospitalization, thromboembolism, progressive pump failure, ventricular arrhythmia, sudden cardiac death, ventricular-assist-device implantation, or transplantation. Disease-specific quality-of-life statistics are unavailable.

12. Treatment

There is no approved VEZF1-targeted therapy, gene therapy, RNA therapy, or DCM100-specific clinical trial. Treatment is phenotype-directed and extrapolated from DCM/HFrEF practice:

  • neurohormonal heart-failure therapy appropriate to age and physiology: ACE inhibitor/ARB or ARNI, evidence-based β-blocker, mineralocorticoid-receptor antagonist, and an SGLT2 inhibitor in eligible patients;
  • loop diuretic for congestion;
  • anticoagulation only for standard indications such as atrial fibrillation, intracardiac thrombus, or embolism—not solely for the genotype;
  • antiarrhythmic therapy, catheter ablation, or pacing where indicated;
  • ICD for guideline-defined sudden-death prevention and CRT for qualifying ventricular dysfunction/electrical dyssynchrony;
  • temporary or durable mechanical circulatory support and heart transplantation for refractory advanced failure.

Pediatric prescribing requires specialist dosing and recognition that much evidence is extrapolated from adults. No pharmacogenomic interaction with VEZF1 is known.

Suggested NCIt concepts include heart-failure therapy, beta-adrenergic blocking agent therapy, angiotensin-receptor/neprilysin inhibitor therapy, diuretic therapy, implantable cardioverter-defibrillator placement, cardiac resynchronization therapy, ventricular-assist-device therapy, and heart transplantation.

Experimental cell therapies investigated in generic nonischemic DCM cannot be considered DCM100 treatment. ClinicalTrials.gov searches identified broad pediatric/DCM studies, but none selected patients by VEZF1 genotype.

13. Prevention

Primary prevention

The inherited variant itself cannot currently be prevented after conception. Avoidance of cardiotoxins and treatment of hypertension, arrhythmia, infection, endocrine disease, and other myocardial stressors are prudent but unproven as VEZF1-specific preventive measures.

Secondary prevention

The most actionable intervention is family identification and surveillance: genetic counseling, cascade testing for a confirmed pathogenic variant, periodic ECG/ambulatory monitoring and echocardiography or CMR, and early treatment of ventricular dysfunction. Reproductive options may include prenatal diagnosis or preimplantation genetic testing once a clearly pathogenic familial variant is established.

Tertiary prevention

Guideline-directed heart-failure therapy, rhythm surveillance, vaccination according to routine schedules, exercise counseling, prompt management of decompensation, and devices when indicated aim to prevent hospitalization, embolism, sudden death, and end-stage failure. There is no DCM100-specific immunization or chemoprophylaxis.

14. Other species and natural disease

No naturally occurring VEZF1-related DCM100 has been established in companion animals, livestock, or wildlife, and no breed-specific VBO annotation is justified. The disorder is not infectious and has no zoonotic or cross-species transmission.

Relevant experimental taxa are Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), Rattus norvegicus (10116), and Danio rerio (7955). VEZF1 function is evolutionarily conserved across vertebrates. (paavola2020vezf1regulatescardiac pages 1-2)

15. Model organisms and advanced research

Zebrafish

Morpholino-mediated Vezf1 depletion produced reduced cardiomyocyte growth, pericardial enlargement, vascular abnormalities, and impaired β-adrenergic augmentation of contractility. Co-injection of Vezf1 mRNA rescued vascular phenotypes, supporting knockdown specificity. Calcium-transient kinetics were preserved, while ventricular MHC expression fell markedly. Limitations include transient morpholino knockdown, embryonic physiology, and absence of the exact human allele. (paavola2020vezf1regulatescardiac pages 4-5, paavola2020vezf1regulatescardiac pages 5-7, paavola2020vezf1regulatescardiac pages 8-9)

Rodent cardiomyocytes and mice

VEZF1 knockdown in neonatal and adult rat ventricular cardiomyocytes reduced cell growth, shortening, MYH7/β-MHC expression, and β-MHC promoter activity; it increased skeletal α-actin and altered the contractile transcriptome. These experiments support a cardiomyocyte-autonomous transcriptional mechanism. (paavola2020vezf1regulatescardiac pages 5-7, paavola2020vezf1regulatescardiac pages 7-8, paavola2020vezf1regulatescardiac pages 9-11)

Vezf1-null mice are embryonically lethal with major vascular defects, making a conventional null model unsuitable for adult DCM natural history. A conditional cardiomyocyte-specific knock-in of the human DCM100 variant would be more informative. (paavola2020vezf1regulatescardiac pages 2-3)

Human tissues

Across two human heart-failure expression datasets, VEZF1 expression was approximately 20–25% lower in idiopathic cardiomyopathy and 16–25% lower in ischemic cardiomyopathy than controls. In a separate autopsy series, expression was 43% lower in ischemic-heart-disease sudden-death hearts. These observations show association with diseased myocardium but do not prove that acquired reduction causes DCM100. (paavola2020vezf1regulatescardiac pages 4-5)

Priority research needs

  1. Independent VEZF1 families and rigorous ClinGen-level replication.
  2. Public deposition and expert classification of the defining variant.
  3. Longitudinal penetrance and genotype–phenotype studies.
  4. Patient-derived iPSC cardiomyocytes and isogenic correction.
  5. Variant-specific knock-in mouse or zebrafish models.
  6. Single-cell and spatial transcriptomics separating cardiomyocyte from endothelial effects.
  7. ChIP-seq/CUT&RUN mapping of VEZF1–TEAD1 targets.
  8. Rescue studies testing whether restoration of VEZF1 or MYH7 normalizes contractility.

Key abstract quotations and source appraisal

  • The 2020 mechanistic paper states: “We demonstrate a role for Vezf1 in regulation of compensatory cardiac growth and cardiomyocyte contractile function.” This is supported by zebrafish and cultured-cell experiments, not by a DCM100 clinical cohort. (paavola2020vezf1regulatescardiac pages 1-2)
  • Its principal mechanistic finding was that VEZF1 knockdown regulates contraction/DCM-related genes and identifies MYH7/β-MHC as a key target, with TEAD1 as a binding partner. (paavola2020vezf1regulatescardiac pages 1-2, paavola2020vezf1regulatescardiac pages 7-8)
  • The defining 2023 human paper is titled “VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.” Its PMID and disease–gene linkage are verified, but exact abstract wording and patient-level data were not recoverable in the accessible corpus. (OpenTargets Search: Cardiomyopathy Dilated 100)

Overall interpretation

DCM100 is best regarded as a provisional-to-emerging, ultra-rare VEZF1-associated autosomal-dominant DCM subtype supported by one familial report and biologically coherent experimental evidence. VEZF1 connects endothelial biology with cardiomyocyte transcription, particularly the TEAD1–MYH7 contractile program. Nevertheless, the present evidence does not justify subtype-specific estimates of penetrance, prognosis, variant frequency, or treatment response. Clinical care should therefore combine confirmation of the familial molecular finding with standard hereditary-DCM phenotyping, cascade screening, longitudinal surveillance, and guideline-directed heart-failure and arrhythmia management. (OpenTargets Search: Cardiomyopathy Dilated 100, paavola2020vezf1regulatescardiac pages 1-2, mcnally2017dilatedcardiomyopathygenetic pages 2-3)

References

  1. (OpenTargets Search: Cardiomyopathy Dilated 100): Open Targets Query (Cardiomyopathy Dilated 100, 6 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (paavola2020vezf1regulatescardiac pages 1-2): Jere Paavola, Tarja Alakoski, Johanna Ulvila, Teemu Kilpiö, Juuso Sirén, Sanni Perttunen, Suneeta Narumanchi, Hong Wang, Ruizhu Lin, Katja Porvari, Juhani Junttila, Heikki Huikuri, Katariina Immonen, Päivi Lakkisto, Johanna Magga, Ilkka Tikkanen, and Risto Kerkelä. Vezf1 regulates cardiac structure and contractile function. EBioMedicine, 51:102608, Jan 2020. URL: https://doi.org/10.1016/j.ebiom.2019.102608, doi:10.1016/j.ebiom.2019.102608. This article has 22 citations and is from a peer-reviewed journal.

  3. (paavola2020vezf1regulatescardiac pages 5-7): Jere Paavola, Tarja Alakoski, Johanna Ulvila, Teemu Kilpiö, Juuso Sirén, Sanni Perttunen, Suneeta Narumanchi, Hong Wang, Ruizhu Lin, Katja Porvari, Juhani Junttila, Heikki Huikuri, Katariina Immonen, Päivi Lakkisto, Johanna Magga, Ilkka Tikkanen, and Risto Kerkelä. Vezf1 regulates cardiac structure and contractile function. EBioMedicine, 51:102608, Jan 2020. URL: https://doi.org/10.1016/j.ebiom.2019.102608, doi:10.1016/j.ebiom.2019.102608. This article has 22 citations and is from a peer-reviewed journal.

  4. (paavola2020vezf1regulatescardiac pages 7-8): Jere Paavola, Tarja Alakoski, Johanna Ulvila, Teemu Kilpiö, Juuso Sirén, Sanni Perttunen, Suneeta Narumanchi, Hong Wang, Ruizhu Lin, Katja Porvari, Juhani Junttila, Heikki Huikuri, Katariina Immonen, Päivi Lakkisto, Johanna Magga, Ilkka Tikkanen, and Risto Kerkelä. Vezf1 regulates cardiac structure and contractile function. EBioMedicine, 51:102608, Jan 2020. URL: https://doi.org/10.1016/j.ebiom.2019.102608, doi:10.1016/j.ebiom.2019.102608. This article has 22 citations and is from a peer-reviewed journal.

  5. (paavola2020vezf1regulatescardiac pages 11-12): Jere Paavola, Tarja Alakoski, Johanna Ulvila, Teemu Kilpiö, Juuso Sirén, Sanni Perttunen, Suneeta Narumanchi, Hong Wang, Ruizhu Lin, Katja Porvari, Juhani Junttila, Heikki Huikuri, Katariina Immonen, Päivi Lakkisto, Johanna Magga, Ilkka Tikkanen, and Risto Kerkelä. Vezf1 regulates cardiac structure and contractile function. EBioMedicine, 51:102608, Jan 2020. URL: https://doi.org/10.1016/j.ebiom.2019.102608, doi:10.1016/j.ebiom.2019.102608. This article has 22 citations and is from a peer-reviewed journal.

  6. (mcnally2017dilatedcardiomyopathygenetic pages 2-3): Elizabeth M. McNally and Luisa Mestroni. Dilated cardiomyopathy: genetic determinants and mechanisms. Circulation Research, 121:731–748, Sep 2017. URL: https://doi.org/10.1161/circresaha.116.309396, doi:10.1161/circresaha.116.309396. This article has 995 citations and is from a highest quality peer-reviewed journal.

  7. (paavola2020vezf1regulatescardiac pages 8-9): Jere Paavola, Tarja Alakoski, Johanna Ulvila, Teemu Kilpiö, Juuso Sirén, Sanni Perttunen, Suneeta Narumanchi, Hong Wang, Ruizhu Lin, Katja Porvari, Juhani Junttila, Heikki Huikuri, Katariina Immonen, Päivi Lakkisto, Johanna Magga, Ilkka Tikkanen, and Risto Kerkelä. Vezf1 regulates cardiac structure and contractile function. EBioMedicine, 51:102608, Jan 2020. URL: https://doi.org/10.1016/j.ebiom.2019.102608, doi:10.1016/j.ebiom.2019.102608. This article has 22 citations and is from a peer-reviewed journal.

  8. (paavola2020vezf1regulatescardiac pages 4-5): Jere Paavola, Tarja Alakoski, Johanna Ulvila, Teemu Kilpiö, Juuso Sirén, Sanni Perttunen, Suneeta Narumanchi, Hong Wang, Ruizhu Lin, Katja Porvari, Juhani Junttila, Heikki Huikuri, Katariina Immonen, Päivi Lakkisto, Johanna Magga, Ilkka Tikkanen, and Risto Kerkelä. Vezf1 regulates cardiac structure and contractile function. EBioMedicine, 51:102608, Jan 2020. URL: https://doi.org/10.1016/j.ebiom.2019.102608, doi:10.1016/j.ebiom.2019.102608. This article has 22 citations and is from a peer-reviewed journal.

  9. (paavola2020vezf1regulatescardiac pages 9-11): Jere Paavola, Tarja Alakoski, Johanna Ulvila, Teemu Kilpiö, Juuso Sirén, Sanni Perttunen, Suneeta Narumanchi, Hong Wang, Ruizhu Lin, Katja Porvari, Juhani Junttila, Heikki Huikuri, Katariina Immonen, Päivi Lakkisto, Johanna Magga, Ilkka Tikkanen, and Risto Kerkelä. Vezf1 regulates cardiac structure and contractile function. EBioMedicine, 51:102608, Jan 2020. URL: https://doi.org/10.1016/j.ebiom.2019.102608, doi:10.1016/j.ebiom.2019.102608. This article has 22 citations and is from a peer-reviewed journal.

  10. (paavola2020vezf1regulatescardiac pages 2-3): Jere Paavola, Tarja Alakoski, Johanna Ulvila, Teemu Kilpiö, Juuso Sirén, Sanni Perttunen, Suneeta Narumanchi, Hong Wang, Ruizhu Lin, Katja Porvari, Juhani Junttila, Heikki Huikuri, Katariina Immonen, Päivi Lakkisto, Johanna Magga, Ilkka Tikkanen, and Risto Kerkelä. Vezf1 regulates cardiac structure and contractile function. EBioMedicine, 51:102608, Jan 2020. URL: https://doi.org/10.1016/j.ebiom.2019.102608, doi:10.1016/j.ebiom.2019.102608. This article has 22 citations and is from a peer-reviewed journal.

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