Dilated Cardiomyopathy 1HH

Genetic MONDO:0013479 Pathograph 6 Show in embeddings browser Dilated Cardiomyopathy Genetic Disorder

Dilated cardiomyopathy 1HH (CMD1HH) is the BAG3-related form of familial isolated dilated cardiomyopathy. BAG3 encodes Bcl2-associated athanogene 3, a co-chaperone that is not a component of the contractile apparatus at all: it is the organizing hub of protein quality control at the sarcomeric Z-disc. Working with Hsc70 and the small heat shock protein HSPB8, BAG3 initiates chaperone-assisted selective autophagy (CASA), the pathway that recognizes and disposes of mechanically damaged Z-disc proteins - notably force-unfolded filamin - and replaces them. CMD1HH is therefore mechanistically distinct from the sarcomeric dilated cardiomyopathies: the primary lesion is a failure of proteostasis and structural turnover in a myocyte under continuous mechanical load, not a defect of force generation. BAG3 was established as a dilated cardiomyopathy gene by Norton and colleagues in 2011 through combined genome-wide copy-number and exome analysis in a multigenerational family, with loss-of-function alleles (a whole-exon deletion, frameshift, nonsense, and missense variants) segregating with disease and bag3 knockdown recapitulating dilated cardiomyopathy and heart failure in zebrafish. ClinGen classifies the BAG3-DCM relationship as Definitive with autosomal dominant inheritance; the operative mechanism for truncating alleles is haploinsufficiency.

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🏷

Classifications

Harrison's Part

👪

Inheritance

Autosomal dominant HP:0000006

CMD1HH is inherited as an autosomal dominant trait, with loss-of-function BAG3 alleles - exon deletion, frameshift, nonsense, and missense variants - segregating with disease in affected families. Penetrance is incomplete and age-related, as in the sarcomeric dilated cardiomyopathies.

Autosomal dominant inheritance Penetrance: INCOMPLETE

Show evidence (2 references)

CGGV:assertion_1bec07e1-0186-4f45-bd8e-7d8a0f2547a9-2025-05-30T160000.000Z SUPPORT Other

ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies the BAG3-dilated cardiomyopathy relationship as Definitive with autosomal dominant inheritance.

PMID:21353195 SUPPORT Human Clinical

"In a multigenerational family with autosomal dominant transmission, we employed whole-exome sequencing in a proband and three of his affected family members"

Documents the autosomal dominant multigenerational family in which BAG3 was established as a dilated cardiomyopathy gene.

⚙

Pathophysiology

BAG3 Loss-of-Function Variant

The initiating lesion in CMD1HH is a loss-of-function variant in BAG3, encoding the heat shock protein co-chaperone Bcl2-associated athanogene 3. The founding allele was an 8733 bp deletion removing exon 4, and the disease allele class also includes frameshift, nonsense, and missense variants. Unlike the sarcomeric dilated cardiomyopathies, the affected protein is not part of the contractile machinery: BAG3 is a quality-control co-chaperone, so the lesion removes maintenance capacity rather than force-generating capacity.

Cardiomyocyte CL:0000746

BAG3 hgnc:939

Heat shock protein binding GO:0031072 ↓ DECREASED

Z disc GO:0030018

Downstream

Impaired Chaperone-Assisted Selective Autophagy at the Z-Disc Reduced BAG3 co-chaperone function degrades the CASA pathway that disposes of mechanically damaged Z-disc proteins.

Show evidence (2 references)

PMID:21353195 SUPPORT Human Clinical

"a 8733 bp deletion, encompassing exon 4 of the heat shock protein cochaperone BCL2-associated athanogene 3 (BAG3), was found in seven affected family members and was absent in 355 controls"

Identifies the founding BAG3 loss-of-function allele and its segregation with disease, establishing the trigger lesion of this entity.

PMID:21353195 SUPPORT Human Clinical

"We conclude that new comprehensive genomic approaches have identified rare variants in BAG3 as causative of DCM."

States the causal conclusion linking rare BAG3 variants to dilated cardiomyopathy.

Impaired Chaperone-Assisted Selective Autophagy at the Z-Disc

BAG3 initiates chaperone-assisted selective autophagy (CASA), the pathway that disposes of misfolded and mechanically damaged proteins. In striated muscle, BAG3 coordinates Hsc70 and the small heat shock protein HSPB8, with the chaperone-associated ubiquitin ligase CHIP and the autophagic adaptor p62, to degrade force-unfolded Z-disc components such as filamin so that they can be replaced. This machinery is required continuously because the Z-disc is under mechanical, thermal, and oxidative stress with every contraction. A BAG3 loss-of-function allele reduces the capacity of this disposal pathway; CASA is mechanistically distinct from chaperone-mediated autophagy.

Cardiomyocyte CL:0000746

Autophagy GO:0006914 ↓ DECREASED

Z disc GO:0030018

Downstream

Z-Disc Disintegration and Sarcomere Structural Failure Without CASA-mediated turnover, damaged Z-disc components accumulate and the Z-disc loses structural integrity.

Show evidence (3 references)

PMID:20060297 SUPPORT Model Organism

"Stv and its mammalian ortholog BAG-3 coordinate the activity of Hsc70 and the small heat shock protein HspB8 during disposal that is initiated by the chaperone-associated ubiquitin ligase CHIP and the autophagic ubiquitin adaptor p62."

Defines the BAG3-organized CASA machinery - Hsc70, HspB8, CHIP, p62 - that this node represents.

PMID:20060297 SUPPORT Model Organism

"Instead of keeping Z disk proteins in a folded conformation, this machinery facilitates the degradation of damaged components, such as filamin, through chaperone-assisted selective autophagy (CASA)."

States that the BAG3 machinery works by degrading damaged Z-disc components rather than refolding them - the distinguishing feature of this mechanism.

PMID:31326538 SUPPORT In Vitro

"Under mechanical stress, the cochaperone cooperates with the small heat shock protein HSPB8 and the cytoskeleton-associated protein SYNPO2 to degrade force-unfolded forms of the actin-crosslinking protein filamin."

Specifies the mechanical-stress trigger and the filamin substrate of BAG3-initiated CASA.

Z-Disc Disintegration and Sarcomere Structural Failure

The Z-disc is the anchor for actin thin filaments and the mechanical node of the sarcomere. When CASA cannot clear force-damaged components, they accumulate and the Z-disc disintegrates, producing progressive structural failure of the contractile apparatus. This has been shown across species - impaired CASA causes Z-disc disintegration and progressive muscle weakness in flies, mice, and humans - and in the heart it converts a maintenance defect into a contractile one.

Cardiomyocyte CL:0000746

Sarcomere Organization GO:0045214 ⚠ ABNORMAL Muscle Contraction GO:0006936 ↓ DECREASED

Z disc GO:0030018

Downstream

Ventricular Dilation and Systolic Dysfunction Progressive structural failure of the contractile apparatus produces chamber dilation and falling systolic performance.

Show evidence (2 references)

PMID:20060297 SUPPORT Model Organism

"Impaired CASA results in Z disk disintegration and progressive muscle weakness in flies, mice, and men."

States the direct structural consequence of impaired BAG3-dependent CASA - Z-disc disintegration and progressive weakness - across species including humans.

PMID:20060297 SUPPORT Model Organism

"the Z disk, a protein assembly essential for actin anchoring in striated muscles, which is subjected to mechanical, thermal, and oxidative stress during contraction"

Establishes why the Z-disc requires continuous quality control - it is the actin anchor and bears the mechanical stress of every contraction.

Ventricular Dilation and Systolic Dysfunction

Cumulative Z-disc and sarcomere degradation produces the defining structural remodeling of dilated cardiomyopathy: left ventricular chamber enlargement with wall thinning, myocyte loss, and interstitial fibrosis, with falling ejection fraction. Knockdown of bag3 in zebrafish reproduces this dilated phenotype and heart failure, confirming that loss of the co-chaperone is sufficient to generate the remodeling.

Cardiomyocyte CL:0000746 Cardiac Fibroblast CL:0002548

Heart Contraction GO:0060047 ↓ DECREASED Extracellular Matrix Organization GO:0030198 ↑ INCREASED

Left ventricle UBERON:0002084

Downstream

Heart Failure

Show evidence (1 reference)

PMID:21353195 SUPPORT Model Organism

"Knockdown of bag3 in a zebrafish model recapitulated DCM and heart failure."

Demonstrates that loss of bag3 is sufficient to produce the dilated cardiomyopathy and heart failure phenotype in vivo.

Heart Failure

The dilated, poorly contracting ventricle produces progressive systolic heart failure, the clinical endpoint of CMD1HH. Dilated cardiomyopathy is the most frequent precipitating cause of heart transplantation, and advanced BAG3-related disease follows the same course.

Cardiomyocyte CL:0000746

Heart Contraction GO:0060047 ⚠ ABNORMAL

Show evidence (1 reference)

PMID:21353195 SUPPORT Human Clinical

"Dilated cardiomyopathy commonly causes heart failure and is the most frequent precipitating cause of heart transplantation."

States the heart-failure and transplantation burden that constitutes the clinical endpoint of this disease.

⬡

Pathograph

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

●

Phenotypes

Dilated Cardiomyopathy OBLIGATE Cardiovascular HP:0001644

Show evidence (1 reference)

PMID:21353195 SUPPORT Model Organism

"Knockdown of bag3 in a zebrafish model recapitulated DCM and heart failure."

Confirms the dilated cardiomyopathy phenotype as the consequence of bag3 loss.

Congestive Heart Failure Cardiovascular HP:0001635

Show evidence (1 reference)

PMID:21353195 SUPPORT Human Clinical

"Dilated cardiomyopathy commonly causes heart failure and is the most frequent precipitating cause of heart transplantation."

Documents heart failure as the dominant clinical consequence of dilated cardiomyopathy.

🧬

Genetic Associations

BAG3

Gene: BAG3 hgnc:939 relationship_type: CAUSATIVE

Show evidence (2 references)

CGGV:assertion_1bec07e1-0186-4f45-bd8e-7d8a0f2547a9-2025-05-30T160000.000Z SUPPORT Other

ClinGen's Gene Curation Expert Panel classifies this gene-disease relationship as Definitive, which is the authority for curating the gene as CAUSATIVE rather than a candidate.

PMID:21353195 SUPPORT Human Clinical

"In a multigenerational family with autosomal dominant transmission, we employed whole-exome sequencing in a proband and three of his affected family members"

Establishes the gene-disease relationship by exome sequencing in a multigenerational dominant family, which is the ascertainment behind the autosomal dominant mode recorded above.

💊

Medical Actions

Heart Failure Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Standard guideline-directed heart-failure therapy targeting the neurohormonal drive of adverse remodeling.

Heart Transplantation

Action: organ transplantation Ontology label: Organ Transplantation NCIT:C15289

Advanced, refractory disease is an indication for transplantation.

📊

Prevalence

Unrelated dilated cardiomyopathy probands

Unknown Unknown

BAG3 is a definitive but numerically minor dilated cardiomyopathy gene. In the founding study, seven rare BAG3 variants absent from 355 control DNAs were identified among 311 additional unrelated DCM probands.

Show evidence (1 reference)

PMID:21353195 SUPPORT Human Clinical

"we sequenced the coding exons in BAG3 in 311 other unrelated DCM probands and identified one frameshift, two nonsense, and four missense rare variants absent in 355 control DNAs, four of which were familial and segregated with disease"

Gives the yield of rare BAG3 variants among unrelated dilated cardiomyopathy probands and their segregation with disease.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy 1HH
creation_date: "2026-08-22T00:00:00Z"
synonyms:
- CMD1HH
- BAG3 familial isolated dilated cardiomyopathy
- dilated cardiomyopathy type 1HH
- cardiomyopathy, dilated, 1HH
- BAG3-related dilated cardiomyopathy
description: >-
  Dilated cardiomyopathy 1HH (CMD1HH) is the BAG3-related form of familial
  isolated dilated cardiomyopathy. BAG3 encodes Bcl2-associated athanogene 3, a
  co-chaperone that is not a component of the contractile apparatus at all: it is
  the organizing hub of protein quality control at the sarcomeric Z-disc. Working
  with Hsc70 and the small heat shock protein HSPB8, BAG3 initiates
  chaperone-assisted selective autophagy (CASA), the pathway that recognizes and
  disposes of mechanically damaged Z-disc proteins - notably force-unfolded
  filamin - and replaces them. CMD1HH is therefore mechanistically distinct from
  the sarcomeric dilated cardiomyopathies: the primary lesion is a failure of
  proteostasis and structural turnover in a myocyte under continuous mechanical
  load, not a defect of force generation. BAG3 was established as a dilated
  cardiomyopathy gene by Norton and colleagues in 2011 through combined
  genome-wide copy-number and exome analysis in a multigenerational family, with
  loss-of-function alleles (a whole-exon deletion, frameshift, nonsense, and
  missense variants) segregating with disease and bag3 knockdown recapitulating
  dilated cardiomyopathy and heart failure in zebrafish. ClinGen classifies the
  BAG3-DCM relationship as Definitive with autosomal dominant inheritance; the
  operative mechanism for truncating alleles is haploinsufficiency.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: dilated cardiomyopathy 1HH
  term:
    id: MONDO:0013479
    label: dilated cardiomyopathy 1HH
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant
  description: >-
    CMD1HH is inherited as an autosomal dominant trait, with loss-of-function BAG3
    alleles - exon deletion, frameshift, nonsense, and missense variants -
    segregating with disease in affected families. Penetrance is incomplete and
    age-related, as in the sarcomeric dilated cardiomyopathies.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  evidence:
  - reference: CGGV:assertion_1bec07e1-0186-4f45-bd8e-7d8a0f2547a9-2025-05-30T160000.000Z
    reference_title: "BAG3 / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BAG3 | HGNC:939 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: >-
      ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies the
      BAG3-dilated cardiomyopathy relationship as Definitive with autosomal
      dominant inheritance.
  - reference: PMID:21353195
    reference_title: "Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a multigenerational family with autosomal dominant transmission, we
      employed whole-exome sequencing in a proband and three of his affected family
      members
    explanation: >-
      Documents the autosomal dominant multigenerational family in which BAG3 was
      established as a dilated cardiomyopathy gene.
prevalence:
- population: Unrelated dilated cardiomyopathy probands
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    BAG3 is a definitive but numerically minor dilated cardiomyopathy gene. In the
    founding study, seven rare BAG3 variants absent from 355 control DNAs were
    identified among 311 additional unrelated DCM probands.
  evidence:
  - reference: PMID:21353195
    reference_title: "Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we sequenced the coding exons in BAG3 in 311 other unrelated DCM probands and
      identified one frameshift, two nonsense, and four missense rare variants
      absent in 355 control DNAs, four of which were familial and segregated with
      disease
    explanation: >-
      Gives the yield of rare BAG3 variants among unrelated dilated cardiomyopathy
      probands and their segregation with disease.
pathophysiology:
- name: BAG3 Loss-of-Function Variant
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The initiating lesion in CMD1HH is a loss-of-function variant in BAG3,
    encoding the heat shock protein co-chaperone Bcl2-associated athanogene 3. The
    founding allele was an 8733 bp deletion removing exon 4, and the disease allele
    class also includes frameshift, nonsense, and missense variants. Unlike the
    sarcomeric dilated cardiomyopathies, the affected protein is not part of the
    contractile machinery: BAG3 is a quality-control co-chaperone, so the lesion
    removes maintenance capacity rather than force-generating capacity.
  genes:
  - preferred_term: BAG3
    term:
      id: hgnc:939
      label: BAG3
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: Heat shock protein binding
    term:
      id: GO:0031072
      label: heat shock protein binding
    modifier: DECREASED
  cellular_components:
  - preferred_term: Z disc
    term:
      id: GO:0030018
      label: Z disc
  evidence:
  - reference: PMID:21353195
    reference_title: "Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a 8733 bp deletion, encompassing exon 4 of the heat shock protein cochaperone
      BCL2-associated athanogene 3 (BAG3), was found in seven affected family
      members and was absent in 355 controls
    explanation: >-
      Identifies the founding BAG3 loss-of-function allele and its segregation with
      disease, establishing the trigger lesion of this entity.
  - reference: PMID:21353195
    reference_title: "Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that new comprehensive genomic approaches have identified rare variants in BAG3 as causative of DCM."
    explanation: >-
      States the causal conclusion linking rare BAG3 variants to dilated
      cardiomyopathy.
  downstream:
  - target: Impaired Chaperone-Assisted Selective Autophagy at the Z-Disc
    causal_link_type: DIRECT
    description: >-
      Reduced BAG3 co-chaperone function degrades the CASA pathway that disposes of
      mechanically damaged Z-disc proteins.
- name: Impaired Chaperone-Assisted Selective Autophagy at the Z-Disc
  biological_scale: MOLECULAR
  role: effector
  description: >-
    BAG3 initiates chaperone-assisted selective autophagy (CASA), the pathway that
    disposes of misfolded and mechanically damaged proteins. In striated muscle,
    BAG3 coordinates Hsc70 and the small heat shock protein HSPB8, with the
    chaperone-associated ubiquitin ligase CHIP and the autophagic adaptor p62, to
    degrade force-unfolded Z-disc components such as filamin so that they can be
    replaced. This machinery is required continuously because the Z-disc is under
    mechanical, thermal, and oxidative stress with every contraction. A BAG3
    loss-of-function allele reduces the capacity of this disposal pathway; CASA is
    mechanistically distinct from chaperone-mediated autophagy.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: DECREASED
  cellular_components:
  - preferred_term: Z disc
    term:
      id: GO:0030018
      label: Z disc
  evidence:
  - reference: PMID:20060297
    reference_title: "Chaperone-assisted selective autophagy is essential for muscle maintenance."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Stv and its mammalian ortholog BAG-3 coordinate the activity of Hsc70 and the
      small heat shock protein HspB8 during disposal that is initiated by the
      chaperone-associated ubiquitin ligase CHIP and the autophagic ubiquitin
      adaptor p62.
    explanation: >-
      Defines the BAG3-organized CASA machinery - Hsc70, HspB8, CHIP, p62 - that
      this node represents.
  - reference: PMID:20060297
    reference_title: "Chaperone-assisted selective autophagy is essential for muscle maintenance."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Instead of keeping Z disk proteins in a folded conformation, this machinery
      facilitates the degradation of damaged components, such as filamin, through
      chaperone-assisted selective autophagy (CASA).
    explanation: >-
      States that the BAG3 machinery works by degrading damaged Z-disc components
      rather than refolding them - the distinguishing feature of this mechanism.
  - reference: PMID:31326538
    reference_title: "The Hippo network kinase STK38 contributes to protein homeostasis by inhibiting BAG3-mediated autophagy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Under mechanical stress, the cochaperone cooperates with the small heat shock
      protein HSPB8 and the cytoskeleton-associated protein SYNPO2 to degrade
      force-unfolded forms of the actin-crosslinking protein filamin.
    explanation: >-
      Specifies the mechanical-stress trigger and the filamin substrate of
      BAG3-initiated CASA.
  downstream:
  - target: Z-Disc Disintegration and Sarcomere Structural Failure
    causal_link_type: DIRECT
    description: >-
      Without CASA-mediated turnover, damaged Z-disc components accumulate and the
      Z-disc loses structural integrity.
- name: Z-Disc Disintegration and Sarcomere Structural Failure
  biological_scale: CELLULAR
  role: effector
  description: >-
    The Z-disc is the anchor for actin thin filaments and the mechanical node of
    the sarcomere. When CASA cannot clear force-damaged components, they accumulate
    and the Z-disc disintegrates, producing progressive structural failure of the
    contractile apparatus. This has been shown across species - impaired CASA
    causes Z-disc disintegration and progressive muscle weakness in flies, mice,
    and humans - and in the heart it converts a maintenance defect into a
    contractile one.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Sarcomere Organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  - preferred_term: Muscle Contraction
    term:
      id: GO:0006936
      label: muscle contraction
    modifier: DECREASED
  cellular_components:
  - preferred_term: Z disc
    term:
      id: GO:0030018
      label: Z disc
  evidence:
  - reference: PMID:20060297
    reference_title: "Chaperone-assisted selective autophagy is essential for muscle maintenance."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Impaired CASA results in Z disk disintegration and progressive muscle weakness in flies, mice, and men."
    explanation: >-
      States the direct structural consequence of impaired BAG3-dependent CASA -
      Z-disc disintegration and progressive weakness - across species including
      humans.
  - reference: PMID:20060297
    reference_title: "Chaperone-assisted selective autophagy is essential for muscle maintenance."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the Z disk, a protein assembly essential for actin anchoring in striated
      muscles, which is subjected to mechanical, thermal, and oxidative stress
      during contraction
    explanation: >-
      Establishes why the Z-disc requires continuous quality control - it is the
      actin anchor and bears the mechanical stress of every contraction.
  downstream:
  - target: Ventricular Dilation and Systolic Dysfunction
    causal_link_type: DIRECT
    description: >-
      Progressive structural failure of the contractile apparatus produces chamber
      dilation and falling systolic performance.
- name: Ventricular Dilation and Systolic Dysfunction
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    Cumulative Z-disc and sarcomere degradation produces the defining structural
    remodeling of dilated cardiomyopathy: left ventricular chamber enlargement with
    wall thinning, myocyte loss, and interstitial fibrosis, with falling ejection
    fraction. Knockdown of bag3 in zebrafish reproduces this dilated phenotype and
    heart failure, confirming that loss of the co-chaperone is sufficient to
    generate the remodeling.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: Cardiac Fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: Heart Contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: DECREASED
  - preferred_term: Extracellular Matrix Organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  locations:
  - preferred_term: Left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:21353195
    reference_title: "Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Knockdown of bag3 in a zebrafish model recapitulated DCM and heart failure."
    explanation: >-
      Demonstrates that loss of bag3 is sufficient to produce the dilated
      cardiomyopathy and heart failure phenotype in vivo.
  downstream:
  - target: Heart Failure
    causal_link_type: DIRECT
- name: Heart Failure
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    The dilated, poorly contracting ventricle produces progressive systolic heart
    failure, the clinical endpoint of CMD1HH. Dilated cardiomyopathy is the most
    frequent precipitating cause of heart transplantation, and advanced BAG3-related
    disease follows the same course.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Heart Contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:21353195
    reference_title: "Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dilated cardiomyopathy commonly causes heart failure and is the most frequent
      precipitating cause of heart transplantation.
    explanation: >-
      States the heart-failure and transplantation burden that constitutes the
      clinical endpoint of this disease.
phenotypes:
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: >-
    Left ventricular dilation with systolic dysfunction is the defining feature of
    CMD1HH.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  frequency: OBLIGATE
  evidence:
  - reference: PMID:21353195
    reference_title: "Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Knockdown of bag3 in a zebrafish model recapitulated DCM and heart failure."
    explanation: >-
      Confirms the dilated cardiomyopathy phenotype as the consequence of bag3
      loss.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    Progressive systolic dysfunction produces heart failure, frequently
    transplantation-requiring in advanced disease.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:21353195
    reference_title: "Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dilated cardiomyopathy commonly causes heart failure and is the most frequent
      precipitating cause of heart transplantation.
    explanation: >-
      Documents heart failure as the dominant clinical consequence of dilated
      cardiomyopathy.
genetic:
- name: BAG3
  gene_term:
    preferred_term: BAG3
    term:
      id: hgnc:939
      label: BAG3
  relationship_type: CAUSATIVE
  frequency: >-
    Definitive but numerically minor cause of familial dilated cardiomyopathy.
    Seven rare variants were found among 311 unrelated probands in the
    founding study, four of them familial and segregating with disease.
  case_fractions:
  - population: Unrelated dilated cardiomyopathy probands (founding cohort)
    cohort_size: 311
    notes: >-
      No percentage is recorded. The founding study reports seven rare BAG3
      variants absent from 355 controls among 311 probands, of which four were
      familial and segregated with disease; the pathogenic subset is therefore
      between four and seven and a single case fraction would have to be
      derived rather than quoted.
    evidence:
    - reference: PMID:21353195
      reference_title: "Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we sequenced the coding exons in BAG3 in 311 other unrelated DCM
        probands and identified one frameshift, two nonsense, and four
        missense rare variants absent in 355 control DNAs, four of which were
        familial and segregated with disease
      explanation: >-
        Gives the cohort size and the variant yield, including the segregation
        subset, which is the basis for recording a cohort denominator without
        a derived percentage.
  evidence:
  - reference: CGGV:assertion_1bec07e1-0186-4f45-bd8e-7d8a0f2547a9-2025-05-30T160000.000Z
    reference_title: "BAG3 / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      BAG3 | HGNC:939 | dilated cardiomyopathy | MONDO:0005021 | AD |
      Definitive
    explanation: >-
      ClinGen's Gene Curation Expert Panel classifies this gene-disease
      relationship as Definitive, which is the authority for curating the gene
      as CAUSATIVE rather than a candidate.
  - reference: PMID:21353195
    reference_title: "Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a multigenerational family with autosomal dominant transmission, we
      employed whole-exome sequencing in a proband and three of his affected
      family members
    explanation: >-
      Establishes the gene-disease relationship by exome sequencing in a
      multigenerational dominant family, which is the ascertainment behind the
      autosomal dominant mode recorded above.
treatments:
- name: Heart Failure Pharmacotherapy
  description: >-
    Standard guideline-directed heart-failure therapy targeting the neurohormonal
    drive of adverse remodeling.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Heart Transplantation
  description: >-
    Advanced, refractory disease is an indication for transplantation.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
references:
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
notes: >-
  CMD1HH is the BAG3 member of the numbered dilated cardiomyopathy series and
  carries ClinGen Definitive gene-disease validity. It conforms to the shared
  cardiomyopathy_maladaptive_remodeling module.

  Mechanistic distinctiveness is the point of this entry. BAG3 is not a component
  of the contractile apparatus: it is the organizing co-chaperone of
  chaperone-assisted selective autophagy (CASA) at the Z-disc. The disease is
  therefore a failure of protein quality control and structural turnover in a
  continuously load-bearing myocyte, not a defect of force generation - the
  counterpart, within dilated cardiomyopathy, of what KLHL24/CMH29 is within the
  hypertrophic series. This is why it is curated with a proteostasis chain
  (impaired CASA -> Z-disc disintegration) upstream of the shared remodeling nodes
  rather than with a sarcomeric contractile lesion.

  Evidence scope caveat: the CASA mechanism nodes rest on Drosophila/mouse and
  cell-based work (PMID:20060297, PMID:31326538) plus the zebrafish bag3 knockdown,
  with the human evidence being genetic (segregation and case-control variant
  burden) rather than direct demonstration of impaired CASA in patient myocardium.

  GeneReviews scope. The GeneReviews resource applicable to this entry is the
  disease-level "Dilated Cardiomyopathy Overview" (PMID:20301486), tagged
  accordingly in `references`. Its indexed PubMed record is content_type
  abstract_only and carries only the chapter's purpose statement, not the
  Clinical Characteristics, Management, or Genetic Counseling sections, so
  section-by-section GeneReviews mining is not possible from the cache and no
  snippet is quoted from it. The clinical-characteristics baseline for this
  entry is therefore built from the primary BAG3 cohort and pedigree literature
  cited throughout, principally PMID:21353195.

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PMID:20301486

Dilated Cardiomyopathy Overview.

No top-level findings curated for this source.

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