CMD1OO (OMIM 620247; MONDO:0859381) is a historically proposed VEZF1-associated form of familial dilated cardiomyopathy. The current ClinGen report also records the OMIM designation with a provisional question mark (?Cardiomyopathy, dilated, 1OO). ClinGen classifies the autosomal dominant gene-disease relationship as No Known Disease Relationship. Its expert panel excluded the genetic evidence in the defining Shi et al. report (PMID:36657711) because of concerns about suspect data. The reported heterozygous c.490A>T p.(Lys164*) allele and its promoter-reporter results are therefore historical observations from an excluded study, not an established molecular diagnosis. Independent zebrafish and rat cardiomyocyte experiments support roles for Vezf1 in contractile-gene transcription, cardiomyocyte growth and contractile reserve, but do not demonstrate that human VEZF1 variants cause DCM. Clinical evaluation, surveillance and treatment should follow the observed DCM phenotype and family history; the VEZF1 attribution does not establish variant-specific prognosis or predictive testing.
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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 (OMIM 620247; MONDO:0859381) is a historically proposed VEZF1-associated form
of familial dilated cardiomyopathy. The current ClinGen report also records the OMIM
designation with a provisional question mark (?Cardiomyopathy, dilated, 1OO). ClinGen
classifies the autosomal dominant gene-disease relationship as No Known Disease Relationship.
Its expert panel excluded the genetic evidence in the defining Shi et al. report (PMID:36657711)
because of concerns about suspect data. The reported heterozygous c.490A>T p.(Lys164*)
allele and its promoter-reporter results are therefore historical observations from an
excluded study, not an established molecular diagnosis. Independent zebrafish and rat
cardiomyocyte experiments support roles for Vezf1 in contractile-gene transcription,
cardiomyocyte growth and contractile reserve, but do not demonstrate that human VEZF1
variants cause DCM. Clinical evaluation, surveillance and treatment should follow the
observed DCM phenotype and family history; the VEZF1 attribution does not establish variant-specific
prognosis or predictive testing.
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: Reported autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Shi et al. reported dominant segregation with complete penetrance in one pedigree.
ClinGen excluded this genetic evidence. Neither a causal inheritance model nor a penetrance
estimate for VEZF1-associated human DCM is established.
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: >-
Historical segregation claim from the study excluded by ClinGen; it does not establish
recurrence risk or penetrance for clinical counseling.
- reference: CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2025-01-10T170000.000Z
reference_title: VEZF1 / dilated cardiomyopathy (No Known Disease Relationship)
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Publications that presented genetic evidence were excluded due to DCM GCEP concerns
of suspect data in accordance with other publications from this author group as described
in the DCM GCEP Specification Document (Shi et al., 2023, PMID: 36657711).
explanation: Explains why the reported pedigree cannot establish VEZF1 disease inheritance.
quote_role: REVIEW_SYNTHESIS
references:
- reference: CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2025-01-10T170000.000Z
title: VEZF1 / dilated cardiomyopathy (No Known Disease Relationship)
- reference: >-
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2026-03-04T17:00:00.000Z
title: curation results for Gene-Disease Validity
- 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: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/
title: Dilated Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
tags:
- GeneReviews
- reference: PMID:20301486
title: Dilated Cardiomyopathy Overview.
tags:
- GeneReviews
- reference: PMID:28912180
title: 'Dilated Cardiomyopathy: Genetic Determinants and Mechanisms.'
- reference: >-
url:https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2022/03/29/19/53/2022-aha-acc-hfsa-heart-failure-guideline-gl-hf
title: '2022 AHA/ACC/HFSA Heart Failure Guideline: Key Perspectives - American College of Cardiology'
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
tags:
- GeneReviews
- reference: PMID:36385324
title: Contemporary Data on the Status and Medical Management of Acute Heart Failure.
pathophysiology:
- name: Reported VEZF1 p.Lys164Ter Allele
biological_scale: MOLECULAR
role: trigger
mechanism_confidence: HYPOTHETICAL
description: >-
The historical candidate initiating alteration is the heterozygous nonsense allele
p.Lys164Ter. Its relationship to human DCM is unestablished because ClinGen excluded
the defining genetic study. This node records the reported physical alteration, separately
from the reported functional assay.
genes:
- preferred_term: VEZF1 (vascular endothelial zinc finger 1)
term:
id: hgnc:12949
label: VEZF1
genetic_context:
gene:
preferred_term: VEZF1
term:
id: hgnc:12949
label: VEZF1
variant_origin: GERMLINE
zygosity: HETEROZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Reported heterozygous germline nonsense allele from the excluded family study; human
disease causality is unestablished.
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: Historical allele identification; not accepted human causal evidence.
- reference: CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2025-01-10T170000.000Z
reference_title: VEZF1 / dilated cardiomyopathy (No Known Disease Relationship)
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Publications that presented genetic evidence were excluded due to DCM GCEP concerns
of suspect data in accordance with other publications from this author group as described
in the DCM GCEP Specification Document (Shi et al., 2023, PMID: 36657711).
explanation: Limits interpretation of the proposed initiating alteration.
quote_role: REVIEW_SYNTHESIS
downstream:
- target: Reported Loss of VEZF1 Promoter Transactivation
causal_link_type: DIRECT
description: >-
Shi et al. reported loss of promoter transactivation for the mutant protein. This
is an assay result from the same excluded publication, without independent validation
of this allele.
evidence:
- 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: Reported variant-to-reporter effect; does not establish human disease causality.
- name: Reported Loss of VEZF1 Promoter Transactivation
biological_scale: MOLECULAR
role: effector
mechanism_confidence: HYPOTHETICAL
description: >-
Shi et al. reported that mutant VEZF1 failed to activate MYH7 and ET1 (EDN1) promoter
reporters. The reporter system is distinct from endogenous transcription in human myocardium.
The result belongs to the publication whose genetic evidence ClinGen excluded; no independent
variant-specific functional replication is established by the sources here.
genes:
- preferred_term: VEZF1 (vascular endothelial zinc finger 1)
term:
id: hgnc:12949
label: VEZF1
molecular_functions:
- preferred_term: DNA-binding transcription factor activity of VEZF1
term:
id: GO:0003700
label: DNA-binding transcription factor activity
modifier: DECREASED
evidence:
- 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: Historical reporter observation from the excluded publication.
downstream:
- target: Reduced Transcription of Cardiomyocyte Contractile and Growth Targets
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Extension from the reported allele-specific reporter defect to endogenous contractile-gene
expression is hypothetical. Independent Vezf1 depletion experiments support the general
transcriptional role but did not test p.Lys164Ter.
evidence:
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
qPCR analysis of RNA samples from NRVMs confirmed that transcription of Myh7 and
Atp1a2 were decreased and Ska mRNA levels were increased in response to Vezf1 knockdown
explanation: Independent depletion model supports this inference, not the human allele-specific step.
directness: INDIRECT
- name: Reduced Transcription of Cardiomyocyte Contractile and Growth Targets
biological_scale: MOLECULAR
role: amplifier
mechanism_confidence: HYPOTHETICAL
description: >-
In neonatal rat ventricular cardiomyocytes, Vezf1 depletion reduces Myh7/beta-MHC and
Atp1a2 expression while increasing Acta1/skeletal alpha-actin, lowering the beta-MHC/Ska
ratio at RNA and protein levels. Reporter mutagenesis implicates an MCAT element in
the Myh7 promoter; Vezf1 co-immunoprecipitates with TEAD-1 from rat left ventricular
tissue. The study supports a transcriptional mechanism in experimental systems, not
a demonstrated pathway from the reported human allele to DCM.
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: IN_VITRO
snippet: >-
qPCR analysis of RNA samples from NRVMs confirmed that transcription of Myh7 and
Atp1a2 were decreased and Ska mRNA levels were increased in response to Vezf1 knockdown
explanation: Endogenous transcript changes in neonatal rat cardiomyocytes.
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Similar to mRNA data, Vezf1 silencing resulted in a significant reduction in β-MHC/Ska
ratio at protein level
explanation: Protein-level confirmation of the contractile-protein imbalance.
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
However, unlike control siRNA treated cells, the mutation of an MCAT binding site
at −211 to −189 (Δβe3) has no effect in Vezf1 silenced cells.
explanation: >-
Reporter mutagenesis supports an MCAT-dependent response; it does not demonstrate
direct VEZF1 binding to the MCAT motif.
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: We found that Vezf1 binds TEAD-1 in hearts in vivo
explanation: Co-immunoprecipitation from rat left ventricular lysates identifies a protein partner.
downstream:
- target: Impaired Cardiomyocyte Contractile Function
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The altered contractile-gene program is a proposed contributor to impaired shortening.
Knockdown perturbs both, but selective correction of Myh7/Acta1 imbalance was not
shown to rescue function.
evidence:
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: However, Vezf1 knockdown significantly attenuated cardiomyocyte shortening
explanation: >-
Independent depletion links Vezf1 function to cellular shortening, indirectly supporting
the proposed transcription-to-function connection.
directness: INDIRECT
- target: Reduced Cardiomyocyte Growth
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Transcriptional changes are a candidate contributor to reduced cardiomyocyte growth,
inferred from the shared perturbation. The responsible target genes and intermediates
have not been resolved.
evidence:
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Microscopy analysis of cardiomyocyte size shows that depletion of Vezf1 by two
different siRNAs significantly attenuates isoprenaline-induced increase in cardiomyocyte
size
explanation: Adult rat cardiomyocyte growth response measured independently of shortening.
directness: INDIRECT
- name: Impaired Cardiomyocyte Contractile Function
biological_scale: CELLULAR
role: effector
mechanism_confidence: HYPOTHETICAL
description: >-
Vezf1-depleted zebrafish show impaired adrenergic augmentation of ventricular systolic
function, despite preserved baseline systolic function in the larval measurements.
Adult rat cardiomyocyte knockdown reduces cellular shortening. Calcium-transient measurements
were unchanged in isolated zebrafish hearts and adult rat cardiomyocytes under the
tested conditions; these negative assays do not exclude every excitation-contraction
defect. Neither model carries the reported human allele.
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
evidence:
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Vezf1 knockdown does not affect cardiac systolic function analyzed at 2 dpf and 4
dpf, but abrogates the isoprenaline-induced enhancement of cardiac contractile function
at 4 dpf
explanation: Larval baseline and stress-response results are distinct.
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: However, Vezf1 knockdown significantly attenuated cardiomyocyte shortening
explanation: Functional deficit measured directly in adult rat cardiomyocytes.
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Similar to findings in zebrafish in vivo, Vezf1 knockdown in adult rat cardiomyocytes
has no effect on Ca2+ transient kinetics
explanation: Negative adult-cell calcium result, limited to the tested readouts.
downstream:
- target: Left Ventricular Dilation and Systolic Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Progression from experimental Vezf1 loss to human ventricular dilation remains hypothetical.
The larval model did not establish adult human DCM, and ClinGen found no accepted
human genetic evidence.
evidence:
- reference: CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2025-01-10T170000.000Z
reference_title: VEZF1 / dilated cardiomyopathy (No Known Disease Relationship)
supports: NO_EVIDENCE
evidence_source: OTHER
snippet: No convincing evidence for a causal role for VEZF1 for AD DCM has been reported.
explanation: Limits the proposed model-to-human disease link.
quote_role: REVIEW_SYNTHESIS
- name: Reduced Cardiomyocyte Growth
biological_scale: CELLULAR
role: effector
mechanism_confidence: HYPOTHETICAL
description: >-
Vezf1 depletion reduces larval zebrafish cardiomyocyte size and number and blunts the
growth response to isoprenaline. Vezf1 depletion also attenuates adrenergic enlargement
of adult rat cardiomyocytes. These model findings concern cell growth separately from
contractile function and do not establish a human VEZF1 disease mechanism.
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
biological_processes:
- 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: >-
Vezf1 knockdown also results in reduced cardiomyocyte size, or atrophy, at baseline
and suppresses isoprenaline-induced increase in the size of cardiomyocytes
explanation: Growth defect in zebrafish.
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Microscopy analysis of cardiomyocyte size shows that depletion of Vezf1 by two different
siRNAs significantly attenuates isoprenaline-induced increase in cardiomyocyte size
explanation: Adult rat cardiomyocyte growth response measured independently of shortening.
- 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: >-
Ventricular enlargement with reduced systolic function defines the DCM phenotype. This
common clinical endpoint is established for DCM generally; attributing it to VEZF1
variants is unestablished. Heart failure and sudden cardiac death are recognized general
DCM complications, not demonstrated penetrance or outcome estimates for this proposed
subtype.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/
reference_title: Dilated Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: An ejection fraction of less than 50% is considered systolic dysfunction.
explanation: General DCM systolic-function criterion.
quote_role: REVIEW_SYNTHESIS
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/
reference_title: Dilated Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Enlargement is most commonly assessed in adults by either echocardiography or cardiac MRI.
explanation: General DCM structural criterion.
quote_role: REVIEW_SYNTHESIS
downstream:
- target: Dilated Cardiomyopathy
description: The ventricular enlargement and systolic dysfunction comprise the clinical DCM phenotype.
causal_link_type: DIRECT
phenotypes:
- category: Cardiovascular
name: Dilated Cardiomyopathy
description: >-
DCM was the phenotype reported in the historical family study. The proposed VEZF1 etiology
is not established. No genotype-specific frequency, age of onset, heart-failure rate
or sudden-death risk can be assigned from the accepted evidence.
phenotype_term:
preferred_term: Dilated cardiomyopathy
term:
id: HP:0001644
label: Dilated cardiomyopathy
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: >-
Historical phenotype ascertainment from the excluded study; this is not validation
of VEZF1 causality.
- reference: CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2025-01-10T170000.000Z
reference_title: VEZF1 / dilated cardiomyopathy (No Known Disease Relationship)
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Publications that presented genetic evidence were excluded due to DCM GCEP concerns
of suspect data in accordance with other publications from this author group as described
in the DCM GCEP Specification Document (Shi et al., 2023, PMID: 36657711).
explanation: Explains the evidentiary limitation on the proposed subtype.
quote_role: REVIEW_SYNTHESIS
genetic:
- name: VEZF1
association: Historically proposed; ClinGen No Known Disease Relationship
relationship_type: UNKNOWN
variant_origin: GERMLINE
gene_term:
preferred_term: VEZF1 (vascular endothelial zinc finger 1)
term:
id: hgnc:12949
label: VEZF1
notes: >-
The classification is No Known Disease Relationship, not Disputed, Refuted, Limited
or an absence of assessment. ClinGen scored no human genetic evidence after excluding
the Shi et al. report. Experimental cardiovascular biology does not by itself establish
a Mendelian relationship. The current online report explicitly includes CMD1OO (OMIM
620247; MONDO:0859381).
evidence:
- reference: CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2025-01-10T170000.000Z
reference_title: VEZF1 / dilated cardiomyopathy (No Known Disease Relationship)
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Publications that presented genetic evidence were excluded due to DCM GCEP concerns
of suspect data in accordance with other publications from this author group as described
in the DCM GCEP Specification Document (Shi et al., 2023, PMID: 36657711).
explanation: The defining genetic study was excluded from the expert gene-disease evaluation.
quote_role: REVIEW_SYNTHESIS
- reference: CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2025-01-10T170000.000Z
reference_title: VEZF1 / dilated cardiomyopathy (No Known Disease Relationship)
supports: SUPPORT
evidence_source: OTHER
snippet: No convincing evidence for a causal role for VEZF1 for AD DCM has been reported.
explanation: Lack of accepted evidence for the proposed causal relationship.
quote_role: REVIEW_SYNTHESIS
variants:
- name: VEZF1 c.490A>T p.(Lys164*)
description: >-
Historically reported heterozygous NM_007146.3:c.490A>T p.(Lys164*) nonsense allele
in Shi et al. The gene-disease panel excluded this study; the report does not establish
a clinically actionable VEZF1 diagnosis. No independent ACMG/AMP classification is
assigned here.
gene:
preferred_term: VEZF1
term:
id: hgnc:12949
label: VEZF1
type: nonsense
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: Records the published allele nomenclature only; the genetic report was excluded by ClinGen.
- reference: CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2025-01-10T170000.000Z
reference_title: VEZF1 / dilated cardiomyopathy (No Known Disease Relationship)
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Publications that presented genetic evidence were excluded due to DCM GCEP concerns
of suspect data in accordance with other publications from this author group as
described in the DCM GCEP Specification Document (Shi et al., 2023, PMID: 36657711).
explanation: Explains the limitation of using this report as pathogenicity evidence.
quote_role: REVIEW_SYNTHESIS
gene_disease_validity:
- validity_classification: NO_KNOWN_DISEASE_RELATIONSHIP
classified_by: CLINGEN
external_id: CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2025-01-10T170000.000Z
notes: >-
The pinned ClinGen CSV records the January 10, 2025 assertion under dilated cardiomyopathy.
The current report displays March 4, 2026 and the specific MONDO:0859381 entity,
with the same classification and summary; its summary retains the January 2025 working-group
approval date.
evidence:
- reference: CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2025-01-10T170000.000Z
reference_title: VEZF1 / dilated cardiomyopathy (No Known Disease Relationship)
supports: SUPPORT
evidence_source: OTHER
snippet: No convincing evidence for a causal role for VEZF1 for AD DCM has been reported.
explanation: ClinGen conclusion for autosomal dominant VEZF1-associated DCM.
quote_role: REVIEW_SYNTHESIS
experimental_models:
- name: Neonatal rat primary cardiomyocytes with Vezf1 silencing
experimental_model_type: PRIMARY_CELL_CULTURE
publication: PMID:31911272
description: >-
Neonatal rat ventricular cardiomyocyte Vezf1 siRNA experiments measured RNA sequencing,
endogenous Myh7/Atp1a2/Acta1 expression, beta-MHC/Ska protein ratios and beta-MHC promoter
activity. MCAT-site mutagenesis tested promoter dependence.
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: PERTURBS
description: Manipulates Vezf1 abundance and measures the contractile-gene response.
limitations: >-
Rat neonatal cells with depletion of wild-type Vezf1; no human p.Lys164Ter allele,
patient-derived cells or demonstration of human DCM causality.
evidence:
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
qPCR analysis of RNA samples from NRVMs confirmed that transcription of Myh7 and
Atp1a2 were decreased and Ska mRNA levels were increased in response to Vezf1 knockdown
explanation: Endogenous transcript changes in neonatal rat cardiomyocytes.
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Similar to mRNA data, Vezf1 silencing resulted in a significant reduction in β-MHC/Ska
ratio at protein level
explanation: Protein-level confirmation of the contractile-protein imbalance.
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
However, unlike control siRNA treated cells, the mutation of an MCAT binding site
at −211 to −189 (Δβe3) has no effect in Vezf1 silenced cells.
explanation: >-
Reporter mutagenesis supports an MCAT-dependent response; it does not demonstrate
direct VEZF1 binding to the MCAT motif.
- name: Adult rat ventricular cardiomyocytes with Vezf1 silencing
experimental_model_type: PRIMARY_CELL_CULTURE
publication: PMID:31911272
description: >-
Isolated adult rat cardiomyocytes provide direct measurements of shortening, adrenergic
cell growth, sarcomere length and calcium transients after Vezf1 depletion.
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
modeled_mechanisms:
- target: Impaired Cardiomyocyte Contractile Function
relationship: PERTURBS
description: Vezf1 depletion reduces shortening.
limitations: Depletion in cultured rat cells does not model the human allele or establish a Mendelian diagnosis.
evidence:
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: However, Vezf1 knockdown significantly attenuated cardiomyocyte shortening
explanation: Functional deficit measured directly in adult rat cardiomyocytes.
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Similar to findings in zebrafish in vivo, Vezf1 knockdown in adult rat cardiomyocytes
has no effect on Ca2+ transient kinetics
explanation: Negative adult-cell calcium result, limited to the tested readouts.
- target: Reduced Cardiomyocyte Growth
relationship: PERTURBS
description: Depletes Vezf1 and measures the resulting cardiomyocyte growth defect.
limitations: >-
Experimental gene depletion does not establish human variant causality or a genotype-specific
growth phenotype.
evidence:
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Microscopy analysis of cardiomyocyte size shows that depletion of Vezf1 by two
different siRNAs significantly attenuates isoprenaline-induced increase in cardiomyocyte
size
explanation: Adult rat cardiomyocyte growth response measured independently of shortening.
animal_models:
- name: vezf1 knockdown zebrafish
species: Zebrafish
genotype: vezf1 morpholino knockdown
publication: PMID:31911272
description: >-
Larval zebrafish morpholino depletion of vezf1 tests cardiac growth and beta-adrenergic
reserve. Capped Vezf1 RNA provides a rescue arm. This is a gene-function experiment,
not a variant-specific model of established human DCM.
modeled_mechanisms:
- target: Impaired Cardiomyocyte Contractile Function
relationship: PERTURBS
description: Tests Vezf1-dependent contractile reserve in larvae.
limitations: >-
Whole-organism, transient depletion without the human allele. Reduced ventricular
size and preserved baseline systolic function differ from the defining human DCM
phenotype. Vascular effects may contribute.
readouts:
- name: Ventricular contractile response to beta-adrenergic stimulation
target: Impaired Cardiomyocyte Contractile Function
direction: DECREASED
interpretation: >-
Stress-response impairment; it does not establish a human disease trigger or imply
absence of baseline structural changes.
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
direction: UNCHANGED
interpretation: >-
No change in the tested calcium measurements; this does not exclude all excitation-contraction
abnormalities.
evidence:
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We found Vezf1 KD and control MO ventricles to show similar resting Ca2+ concentration,
Ca2+ transient amplitude, and Ca2+ transient decay time
explanation: Direct measurements in isolated zebrafish hearts.
evidence:
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Vezf1 knockdown does not affect cardiac systolic function analyzed at 2 dpf and
4 dpf, but abrogates the isoprenaline-induced enhancement of cardiac contractile
function at 4 dpf
explanation: Larval baseline and stress-response results are distinct.
- target: Impaired Cardiomyocyte Contractile Function
relationship: RESCUES
description: Capped Vezf1 RNA restores several cardiac functional readouts after morpholino depletion.
limitations: >-
Rescue of gene depletion in larvae, not correction of the human p.Lys164Ter variant
or evidence of clinical therapeutic efficacy.
evidence:
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Injection of capped Vezf1 RNA results in full or partial rescue of the phenotype
induced by Vezf1 knockdown
explanation: Cardiac phenotype rescue supports the specificity of the perturbation.
- target: Reduced Cardiomyocyte Growth
relationship: PERTURBS
description: Depletes Vezf1 and measures the resulting cardiomyocyte growth defect.
limitations: >-
Experimental gene depletion does not establish human variant causality or a genotype-specific
growth phenotype.
evidence:
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Vezf1 knockdown also results in reduced cardiomyocyte size, or atrophy, at baseline
and suppresses isoprenaline-induced increase in the size of cardiomyocytes
explanation: Growth defect in zebrafish.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: NOT_YET_DOCUMENTED
notes: >-
There is no established prevalence or penetrance estimate for a VEZF1-caused DCM entity.
The historical family report was excluded by ClinGen; its reported absence of the allele
in comparison cohorts is not a population frequency estimate.
evidence:
- reference: CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2025-01-10T170000.000Z
reference_title: VEZF1 / dilated cardiomyopathy (No Known Disease Relationship)
supports: SUPPORT
evidence_source: OTHER
snippet: No convincing evidence for a causal role for VEZF1 for AD DCM has been reported.
explanation: >-
Without accepted human causality, the literature does not define the prevalence of
a confirmed VEZF1 subtype.
quote_role: REVIEW_SYNTHESIS
diagnosis:
- name: Echocardiography and cardiac magnetic resonance imaging
description: >-
Establish ventricular enlargement and systolic dysfunction independently of genotype.
Imaging diagnoses the DCM phenotype and does not establish a VEZF1 cause.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/
reference_title: Dilated Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: An ejection fraction of less than 50% is considered systolic dysfunction.
explanation: General DCM systolic-function criterion.
quote_role: REVIEW_SYNTHESIS
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/
reference_title: Dilated Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Enlargement is most commonly assessed in adults by either echocardiography or cardiac MRI.
explanation: General DCM structural criterion.
quote_role: REVIEW_SYNTHESIS
- name: Cardiovascular genetics evaluation
description: >-
Use family history, phenotyping and molecular testing focused on validated DCM genes.
Exome sequencing was the discovery method in the historical report; a VEZF1 finding
alone does not establish a molecular diagnosis.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A cardiomyopathy multigene panel that includes the genes with a ClinGen classification
of definitive, strong, or moderate (as listed in Table 2) is most likely to identify
the genetic cause of the condition while also limiting identification of variants
of uncertain significance and pathogenic variants in genes that do not explain the
underlying phenotype.
explanation: >-
GeneReviews recommends diagnostic panels focused on genes with established disease validity.
quote_role: REVIEW_SYNTHESIS
- reference: CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2025-01-10T170000.000Z
reference_title: VEZF1 / dilated cardiomyopathy (No Known Disease Relationship)
supports: SUPPORT
evidence_source: OTHER
snippet: No convincing evidence for a causal role for VEZF1 for AD DCM has been reported.
explanation: VEZF1 does not meet an established causal relationship in this assessment.
quote_role: REVIEW_SYNTHESIS
- name: Clinical surveillance of at-risk relatives
description: >-
When no validated familial molecular cause is established, relatives require cardiovascular
screening based on age and family history. Absence of the reported VEZF1 allele is
not sufficient to release a relative from surveillance. A validated finding in another
DCM gene may independently inform family assessment.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/
reference_title: Dilated Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Perform cardiovascular screening on asymptomatic at-risk family members at intervals
based on the individual's age
explanation: Screening continues when the molecular cause is unknown.
quote_role: REVIEW_SYNTHESIS
- reference: CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2025-01-10T170000.000Z
reference_title: VEZF1 / dilated cardiomyopathy (No Known Disease Relationship)
supports: SUPPORT
evidence_source: OTHER
snippet: No convincing evidence for a causal role for VEZF1 for AD DCM has been reported.
explanation: The VEZF1 attribution does not provide a validated familial cause.
quote_role: REVIEW_SYNTHESIS
- name: Electrocardiography and ambulatory rhythm monitoring
description: >-
General DCM evaluation includes assessment for conduction disease and arrhythmia; rhythm
findings and family history guide risk assessment rather than the unvalidated VEZF1
attribution.
evidence:
- reference: PMID:28912180
reference_title: 'Dilated Cardiomyopathy: Genetic Determinants and Mechanisms.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Holter monitoring, for its ease, remains a mainstay using 24–48 hour sampling.
explanation: General DCM rhythm assessment, not a VEZF1-specific protocol.
quote_role: REVIEW_SYNTHESIS
treatments:
- name: Genetic counseling
description: >-
Explain the uncertainty of the reported VEZF1 association and the distinction between
a research finding and a validated familial molecular diagnosis. Counseling and clinical
family surveillance remain appropriate even when genetic testing is inconclusive.
treatment_term:
preferred_term: Genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
target_phenotypes:
- preferred_term: Dilated cardiomyopathy
term:
id: HP:0001644
label: Dilated cardiomyopathy
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/
reference_title: Dilated Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Given the complexity of interpreting genetic test results and their implications
for surveillance and management, health care providers should consider referral to
a cardiovascular genetics center or a genetic counselor specializing in cardiac genetics
explanation: General DCM genetics referral guidance.
quote_role: REVIEW_SYNTHESIS
- reference: CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2025-01-10T170000.000Z
reference_title: VEZF1 / dilated cardiomyopathy (No Known Disease Relationship)
supports: SUPPORT
evidence_source: OTHER
snippet: No convincing evidence for a causal role for VEZF1 for AD DCM has been reported.
explanation: Explains why VEZF1-based predictive counseling is unsupported.
quote_role: REVIEW_SYNTHESIS
- name: Guideline-Directed Heart Failure Pharmacotherapy
description: >-
Treat symptomatic DCM with reduced ejection fraction according to general heart-failure
guidance: renin-angiotensin system inhibition (ARNI, or ACE inhibitor/ARB when appropriate),
beta blocker, mineralocorticoid receptor antagonist and SGLT2 inhibitor in eligible
patients. This is phenotype-directed care extrapolated from HFrEF, without demonstrated
VEZF1-specific efficacy.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
target_phenotypes:
- preferred_term: Dilated cardiomyopathy
term:
id: HP:0001644
label: Dilated cardiomyopathy
evidence:
- reference: PMID:36385324
reference_title: Contemporary Data on the Status and Medical Management of Acute Heart Failure.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The use of four foundational heart failure treatments including ACEi/ARNIs, b-blockers,
MRAs, and SGLT2 inhibitors is supported by recent guidelines.
explanation: >-
Complete statement of the four foundational classes in a published heart-failure
review; general HFrEF care, not a VEZF1-specific treatment study.
quote_role: REVIEW_SYNTHESIS
- name: Implantable cardioverter-defibrillator
description: >-
Consider under standard DCM/HFrEF sudden-death prevention indications after individualized
risk assessment. The VEZF1 label alone is not an indication.
treatment_term:
preferred_term: Implantable Cardioverter-Defibrillator Placement
term:
id: NCIT:C80435
label: Implantable Cardioverter-Defibrillator Placement
evidence:
- reference: PMID:28912180
reference_title: 'Dilated Cardiomyopathy: Genetic Determinants and Mechanisms.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The improvement of survival with ICDs in patients with LVEF less than 35% is also well established
explanation: General DCM management; no VEZF1-specific response is established.
quote_role: REVIEW_SYNTHESIS
- name: Cardiac resynchronization therapy
description: >-
Consider for patients meeting standard ventricular dysfunction and electrical dyssynchrony
criteria despite appropriate medical therapy; this is general DCM care.
treatment_term:
preferred_term: Cardiac Resynchronization Therapy
term:
id: NCIT:C80436
label: Cardiac Resynchronization Therapy
evidence:
- reference: PMID:28912180
reference_title: 'Dilated Cardiomyopathy: Genetic Determinants and Mechanisms.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
DCM patients on optimal therapy with complete left bundle branch block (LBBB) may
benefit from cardiac resynchronization
explanation: General DCM management; no VEZF1-specific response is established.
quote_role: REVIEW_SYNTHESIS
- name: Left ventricular assist device
description: >-
Advanced support for selected patients with refractory heart failure after specialist
assessment, extrapolated from general DCM management.
treatment_term:
preferred_term: Left Ventricular Assist Device Insertion
term:
id: NCIT:C172327
label: Left Ventricular Assist Device Insertion
evidence:
- reference: PMID:28912180
reference_title: 'Dilated Cardiomyopathy: Genetic Determinants and Mechanisms.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with refractory heart failure may require advanced therapies including left
ventricular assist devices or cardiac transplant
explanation: General DCM management; no VEZF1-specific response is established.
quote_role: REVIEW_SYNTHESIS
- name: Cardiac transplantation
description: >-
An option for selected patients with refractory advanced heart failure under standard
eligibility assessment; no VEZF1-specific outcome data are established.
treatment_term:
preferred_term: Heart Transplantation
term:
id: NCIT:C15246
label: Heart Transplantation
evidence:
- reference: PMID:28912180
reference_title: 'Dilated Cardiomyopathy: Genetic Determinants and Mechanisms.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with refractory heart failure may require advanced therapies including left
ventricular assist devices or cardiac transplant
explanation: General DCM management; no VEZF1-specific response is established.
quote_role: REVIEW_SYNTHESIS
discussions:
- discussion_id: vezf1_dcm_gene_validity
kind: OPEN_QUESTION
status: OPEN
prompt: What independent human genetic evidence would establish or reject a causal VEZF1-DCM relationship?
attaches_to:
- pathophysiology#Reported VEZF1 p.Lys164Ter Allele
rationale: >-
ClinGen has assessed the relationship and classified it as No Known Disease Relationship
after excluding the defining genetic publication. Independent experimental biology
provides plausibility but does not establish human causation. Independent ascertainment,
segregation and variant-specific functional studies are needed.
proposed_experiments:
- experiment_id: vezf1_dcm_cohort_replication
name: Look for further VEZF1 loss-of-function alleles in DCM cohorts
description: >-
Independently ascertain sequenced DCM families, assess rare VEZF1 variants and segregation
with appropriate controls, and test specific variants in isogenic human cardiomyocytes.
Candidate discovery should be separated from clinical pathogenicity interpretation.
evidence:
- reference: CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2025-01-10T170000.000Z
reference_title: VEZF1 / dilated cardiomyopathy (No Known Disease Relationship)
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Publications that presented genetic evidence were excluded due to DCM GCEP concerns
of suspect data in accordance with other publications from this author group as described
in the DCM GCEP Specification Document (Shi et al., 2023, PMID: 36657711).
explanation: Reason the founding genetic evidence was excluded.
quote_role: REVIEW_SYNTHESIS
- reference: CGGV:assertion_17572620-69e6-4e55-9d4f-bc4ff78f452b-2025-01-10T170000.000Z
reference_title: VEZF1 / dilated cardiomyopathy (No Known Disease Relationship)
supports: SUPPORT
evidence_source: OTHER
snippet: No convincing evidence for a causal role for VEZF1 for AD DCM has been reported.
explanation: Current expert conclusion.
quote_role: REVIEW_SYNTHESIS
- 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
- pathophysiology#Reduced Cardiomyocyte Growth
rationale: >-
Experimental Vezf1 depletion affects cardiomyocyte gene expression and function, but
whole-larva knockdown also changes vascular development. Mouse embryonic stem-cell
differentiation experiments link Vezf1 loss to elevated Cited2, reduced proangiogenic
gene activation and impaired tube formation; Cited2 reduction partly rescues this defect.
These data describe potential cell-type contributions, not an established vascular
mechanism in human CMD1OO.
proposed_experiments:
- experiment_id: vezf1_conditional_knockout_lineage
name: Compare cardiomyocyte-restricted and endothelial-restricted Vezf1 loss
description: >-
Compare cardiomyocyte-restricted and endothelial-restricted Vezf1 perturbations,
with lineage-specific rescue and cardiac functional readouts. Such experiments would
separate contributions in models; human gene-disease validation would remain a separate
requirement.
evidence:
- reference: PMID:31911272
reference_title: Vezf1 regulates cardiac structure and contractile function.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We cannot thus rule out that Vezf1-mediated regulation of endothelial cell -derived
factors, such as ET-1, may have had effect on the observed cardiac phenotype, such
as reduced cardiac growth in the zebrafish
explanation: Authors explicitly retain an endothelial contribution.
- 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: The repression of Cited2 in Vezf1−/sh ECs largely rescued the defective tube formation on Matrigel
explanation: Cited2 reduction rescues an endothelial differentiation phenotype in vitro, not human DCM.
- 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: >-
These data confirm that expression of Cited2 is not regulated by Dnmt3b or changes
in DNA methylation at its CpGi and support the direct role of Vezf1 in regulating
Cited2 expression.
explanation: The full text does not support a Dnmt3b-mediated explanation for this Cited2 effect.
notes: >-
CMD1OO and Cardiomyopathy Dilated 100 identify the same historical catalog entry. Retention
of its identifier does not endorse VEZF1 as an established DCM gene. Reduced VEZF1 expression
in acquired human heart disease is observational evidence, not proof of inherited VEZF1
disease. No VEZF1-specific clinical trial, validated natural-history estimate or targeted
treatment is established by the sources reviewed here.
datasets:
- accession: geo:GSE5406
description: >-
Human failing-heart and donor myocardial expression data reanalyzed for VEZF1 expression
in Paavola et al.; not a cohort of VEZF1 variant carriers.
data_type: MICROARRAY
publication: PMID:31911272
title: Human ischemic cardiomyopathy, idiopathic cardiomyopathy, and nonfailing controls
- accession: geo:GSE1145
description: >-
Human heart-failure expression data reanalyzed in Paavola et al.; expression association
does not establish genetic causality.
data_type: MICROARRAY
publication: PMID:31911272
title: changes in cardiac transcription profiles brought about by heart failure
- accession: arrayexpress:E-MTAB-7124
description: >-
RNA sequencing of neonatal rat ventricular cardiomyocytes after Vezf1 siRNA depletion
versus control; an experimental gene-function dataset.
data_type: BULK_RNA_SEQ
publication: PMID:31911272
title: >-
RNA sequencing analysis for differentially expressed genes in neonatal rat cardiomyocytes
following knockdown of transcription factor Vezf1
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Review VEZF1-associated DCM against ClinGen and full-text experimental evidence · 2026-10-04T10:50:20Z · View source
Reviewed the existing entry, Falcon deep-research narrative and citations, primary abstracts, newly fetched full text of PMID:31911272 and PMID:29794136, the full GeneReviews DCM chapter, and ClinGen CCID:008937. Main was rebased before starting; preflight returned SKIP because MONDO records no causal gene, so identity was checked manually: the live ClinGen report explicitly identifies VEZF1, MONDO:0859381 and OMIM 620247. The disease remains a historical catalog entry with unestablished etiology, not an endorsed molecular diagnosis. The major correction is external gene validity. The original entry and CREATE record incorrectly stated that no ClinGen assessment existed. ClinGen's pinned CSV records No Known Disease Relationship in January 2025; the current public report displays March 4, 2026 with the same conclusion and retains the January 2025 approval date in its summary. The panel excluded Shi et al. 2023 because of concerns of suspect data. This review attributes that judgment precisely to ClinGen and does not claim a retraction or independently adjudicate research misconduct. The historical allele and reporter observation remain explicitly qualified; unsupported CAUSATIVE and curator-assigned LIKELY_PATHOGENIC labels are removed. The previous history is left unchanged. Full-text use: Paavola et al. distinguishes neonatal rat RNA-seq/promoter/protein experiments, adult rat shortening/growth/calcium experiments, isolated zebrafish-heart calcium measurements, and rat tissue co-immunoprecipitation. Both fish and adult rat calcium kinetics were measured; the negative result does not exclude every excitation-contraction abnormality. Added MYH7/ATP1A2/ACTA1 changes, beta-MHC/Ska protein imbalance, MCAT reporter interpretation, adult-cell model, capped-RNA rescue and datasets. No direct VEZF1-MCAT DNA binding or selective MYH7 rescue is inferred. Human heart-failure expression results are observational and do not establish inherited VEZF1 disease. AlAbdi et al. supports Cited2 rescue and specifically does not support a Dnmt3b-mediated explanation of the Cited2 effect. Vascular findings remain a model-level open question. Eight-dimension research completeness assessment: 1. Phenotypes: adequate for the accepted evidence. Retained the historically reported DCM phenotype with an exclusion caveat; removed generic introductory heart-failure and sudden-death statements masquerading as subtype observations. No penetrance, onset or outcome rates inferred. 2. Subtypes: N/A; no verified subtype division surfaced. 3. Pathophysiology: adequate with confidence limits. Split reported physical allele from reported promoter effect; endogenous transcription, cell function and generic DCM endpoint are separate. Human causal steps are hypothetical and unsupported transitions are explicit. Preserved the established general DCM endpoint and its phenotype edge. 4. Treatments/trials: adequate as explicit general-DCM extrapolation. Added source-backed four-class HFrEF pharmacotherapy and ICD, CRT, LVAD and transplant options; no genotype-specific efficacy or trial is asserted. Detailed dosing, anticoagulation and emerging therapies are not inferred from the research report. 5. Genetics: substantive correction to ClinGen No Known Disease Relationship, UNKNOWN relationship type, historical allele nomenclature and uncertainty. No independently assigned ACMG tier or clinical penetrance estimate. 6. Diagnostics: mined the full GeneReviews chapter for imaging, validated gene panels, genetics referral and age-based family surveillance when no molecular cause is established. Removed the unsupported claim that a negative VEZF1 test allows discharge from surveillance. Clinical surveillance is under diagnosis; counseling remains under treatments. 7. References: full-text mechanisms and clinical guidance consumed; all evidence uses cached exact passages. The Shi paper remains abstract-only on this fetch, and its excluded status prevents treating the inaccessible patient details as accepted evidence. Structured ClinGen cache generated with the repository clingen-rebuild recipe after fetch-reference did not route CGGV. URL caches generated only through fetch-reference. No reference cache hand-authored. 8. Overall: the research is used but its provisional human-causality framing is superseded by the expert assessment it missed. Model findings and clinical extrapolation are clearly distinguished from human gene validity. Dataset accessions GSE5406, GSE1145 and E-MTAB-7124 were verified with just verify-datasets. GEO source caches are included; the retired shared accession JSON was not read or recreated. Retained original identifiers and synonyms. Removed process-oriented KB notes; provenance belongs here. Full-text source limitations and rationale are explicit rather than replaced with unsupported prose.
Create: Cardiomyopathy Dilated 100 (CMD1OO, VEZF1, MONDO:0859381) · 2026-08-27T17:50:27Z · View source
De-novo creation of the VEZF1-attributed leaf entity CMD1OO (MONDO:0859381, OMIM 620247), with module conformance rather than a re-derived remodeling chain. Entry-type decision: DISEASE. MONDO:0859381 is a leaf with no descendants. IDENTITY RESOLUTION WITHOUT A GENE IN THE STUB. This stub is unusual: it carries no genes: block, because MONDO records no causal-gene relationship (RO:0004003) for the 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; the MedGen record supplied the gene (VEZF1, 17q22), the OMIM designation, the disease definition and the source citation (Shi et al. 2023 = PMID:36657711), from which the primary literature was located directly on PubMed. THE NAME IS A TRAP, and it is recorded in the entry description, synonyms and notes. The OMIM designation is CMD1OO with two capital letter Os, continuing the alphabetical suffix series; MONDO and MedGen render it "cardiomyopathy, dilated, 100", reading the letters as digits. This is not the hundredth numbered DCM locus. Both spellings are in synonyms so a search on either finds the entry; disease_term keeps the MONDO label unchanged. NEC preflight returned SKIP as expected, since MONDO records no causal gene. The manual check specified for SKIP was performed: the MONDO term's OMIM xref (620247) matches the OMIM identifier in the MedGen record, and the gene named there (VEZF1) is the report's dominant gene (VEZF1=49 mentions, then MYH7=10 and TEAD1=8, which are the mechanism partners curated here rather than rival disease genes). Deep research: falcon. Its reference_validation reported 4/4 resolved, 0 unresolved, 0 unverifiable, 0 off topic. Notably the report reached the same causal chain independently but could NOT recover the variant details, listing HGVS nomenclature, variant class and functional effect as fields to leave null pending inspection of the original article. Those are curated here because they are in the abstract of PMID:36657711, fetched directly. Recorded in the entry notes because it is the opposite of the usual DR failure mode. Pathophysiology: 4 atomic nodes, 3 edges, single root, all reachable. VEZF1 nonsense variant abolishes transcriptional transactivation (MOLECULAR) -> reduced transcription of cardiomyocyte contractile and growth targets (MOLECULAR) -> impaired cardiomyocyte contractile function and compensatory growth (CELLULAR) -> left ventricular dilation and systolic dysfunction (ORGANISM). 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. Confidence: the trigger and its two downstream nodes carry mechanism_confidence: PROVISIONAL, because the whole entity rests on one family with one nonsense allele plus one reporter assay, and there is no ClinGen gene-disease validity assertion for VEZF1 in any cardiomyopathy (checked against the 494 CGGV records in references_cache: zero mention VEZF1). The final structural node is generic dilated cardiomyopathy and is ESTABLISHED. The variant is recorded LIKELY_PATHOGENIC rather than PATHOGENIC for the same reason, with the reasoning in its evidence explanation. The zebrafish model carries two readouts including a genuine negative one: calcium transient kinetics are UNCHANGED, which is what localizes the lesion downstream of excitation-contraction coupling. Two discussions: gene-disease validity (one family, no ClinGen assertion, with a replication experiment proposed and the observation that VEZF1 is absent from most cardiomyopathy panels so absence of further reports may mean nobody looked); and whether the cardiac phenotype is cardiomyocyte-autonomous or partly vascular, since VEZF1 is better characterized as a vascular-development factor and the zebrafish experiment is a global knockdown. Scope note: OMIM's clinical synopsis, via MedGen, additionally lists atrial septal defect, second-degree atrioventricular block, premature ventricular contraction and reduced left ventricular ejection fraction. None is curated as a phenotype, because the only primary source is abstract-only and does not mention them, and MedGen/OMIM are not citable reference prefixes here. Recorded in notes so a curator with full-text access knows what to look for. No frequency values are asserted anywhere; the entity is one family. Validation actually run and read, on this file: just validate (passed); just count-verified-snippets (Snippets checked: 26/26 verified against cached references); just validate-terms (Validation passed); just validate-disorders (batched sweep); just check-duplicate-keys, check_folded_hyphens, check_snippet_length --against-ref origin/main, just check-title-snippets, just check-reference-titles, just check-snippet-grading, just check-cache-order, just check-term-cache-integrity all OK. All 3 distinct evidence reference_title values checked programmatically against cached frontmatter titles; 0 mismatches. One snippet drafted from memory of a paper's framing rather than its text failed validation and was replaced with the cached sentence. Known tooling gap: just refresh-orphadata fails on a drifted sha256 in this checkout. Orphanet has no entry for this concept and none is cited.
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.
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)
The evidence is an aggregated disease-level synthesis based on a published family, experimental studies, and databases—not individual EHR data.
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)
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)
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:
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.
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)
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:
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.
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.
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)
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.
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.
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:
Spontaneous or treatment-associated reverse remodeling occurs in generic DCM, but no remission rate or critical intervention window is known for DCM100.
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)
The phenotype should be established independently of genotype through:
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.
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.
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.
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.
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:
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.
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.
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.
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.
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)
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)
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)
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)
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
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 4 |
| Resolved | 4 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 4 |
| On topic | 2 |
| Off topic | 0 |
All extracted references resolved successfully.