Cardiomyopathy Dilated 2F

Mendelian MONDO:0030680 Pathograph 22 Show in embeddings browser Dilated Cardiomyopathy Genetic Disorder

Cardiomyopathy, dilated, 2F (CMD2F) is an autosomal recessive dilated cardiomyopathy caused by biallelic truncating variants in BAG5, which encodes a five-BAG-domain co-chaperone that acts as a nucleotide exchange factor for HSC70/Hsp70. Affected individuals present in adolescence or young adulthood with left ventricular dilatation, reduced ejection fraction, advanced heart failure and ventricular arrhythmias that can be refractory. The clinical evidence base is small: five patients from four Japanese families in the founding report, two further compound-heterozygous patients known here only through a later summary, and three affected siblings from one consanguineous Middle Eastern family. Two mechanisms have been proposed, both from stress-provoked mouse models: disruption of junctional membrane complexes with abnormal calcium handling under catecholamine stimulation, and an impaired endoplasmic reticulum stress response with excess cardiomyocyte apoptosis. Wild-type BAG5 delivered by AAV9 rescued one mouse model; this is not a human treatment. BAG5 is distinct from BAG3, a separate autosomal dominant dilated cardiomyopathy gene.

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1
Inheritance
8
Pathophys.
8
Phenotypes
3
Gaps
22
Pathograph
1
Genes
7
Medical Actions
2
Models
8
References
1
Deep Research
🏷

Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic truncating BAG5 variants (homozygous, or compound heterozygous in a later report) segregate with disease. The founding report describes complete penetrance in five biallelic patients; this is a small-sample observation, not a population penetrance estimate. Heterozygous parents were clinically unaffected, although minor ECG changes were noted in two of three female carriers in one family.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:35044787 SUPPORT DIRECT Human Clinical
"we identified that homozygous truncating mutations in the gene encoding Bcl-2–associated athanogene (BAG) co-chaperone 5 (BAG5) caused inherited DCM in five patients among four unrelated families with complete penetrance."
Homozygous truncating variants in four unrelated families support recessive inheritance.
PMID:38796549 SUPPORT DIRECT Human Clinical
"Exome and Sanger sequencing identified a novel BAG5 variant, c.444_445delGA (p.Lys149AsnfsTer6), homozygous in affected siblings and heterozygous in parents and unaffected siblings."
Segregation in an independent consanguineous family is consistent with recessive inheritance.
CGGV:assertion_97fe83b7-fe12-4014-9706-6847446fa9bd-2024-06-14T160000.000Z SUPPORT INDIRECT Other
"BAG5 | HGNC:941 | dilated cardiomyopathy | MONDO:0005021 | AR | Moderate"
ClinGen records an autosomal recessive mode for BAG5; the record is for the parent dilated cardiomyopathy term, not CMD2F itself.
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Discussions and Knowledge Gaps

3
How representative is the reported CMD2F phenotype, given that it rests on about seven families, two of them known here only secondhand?
KNOWLEDGE GAP OPEN cmd2f_small_evidence_base
Attached to
genetic#BAG5
Five founding patients, two compound-heterozygous patients summarized by a later paper, and three genotyped siblings in one consanguineous family make up the clinical record. The case report of refractory arrhythmia and the compound-heterozygous report could not be retrieved, and patient counts may overlap. Phenotype frequencies, penetrance and prognosis cannot be estimated from these data.
Show evidence (1 reference)
PMID:38796549 SUPPORT DIRECT BACKGROUND Human Clinical
"Notably, all individuals carrying homozygous or compound heterozygous BAG5 variants developed DCM, highlighting a strong genotype–phenotype correlation."
The penetrance claim rests on a handful of patients.
Patients develop DCM without a known trigger, but both knock-in mice need an exogenous stressor; which mechanism, if either, operates in human myocardium?
HUMAN MODEL MISMATCH OPEN cmd2f_stress_dependent_mouse_models
Attached to
pathophysiology#Junctional Membrane Complex Disruption pathophysiology#Impaired Cardiomyocyte ER Stress Response pathophysiology#Cardiomyocyte Apoptosis
One mouse needs catecholamine stimulation and the other tunicamycin to show cardiac dysfunction; the unstressed p.Lys149fs-equivalent mouse is normal to 12 months. The ER-stress study found no genotype difference in CHOP or GRP78 and used one heart per group for apoptosis. Arrhythmia appeared only in male mice, whereas ECG changes among human carriers appeared only in females. Patient-derived cardiomyocytes or explanted myocardium would be needed to tell the branches apart.
Proposed experiments
Compare JMC integrity, calcium transients and ER-stress apoptosis in BAG5-null iPSC cardiomyocytes
exp_cmd2f_ipsc_cardiomyocytes
Derive iPSC cardiomyocytes from a biallelic BAG5 patient with isogenic corrected controls. Measure junctional membrane complex protein abundance and calcium transients with and without isoproterenol, and apoptosis and UPR branch activation (ATF6, XBP1 splicing) with and without tunicamycin, to test which branch is present without in vivo stress.
Show evidence (3 references)
PMID:38796549 SUPPORT DIRECT Model Organism
"Bag5-/- mice displayed no abnormalities up to 12 months old and showed no anomalies during an exercise stress test."
The unstressed model lacks the human phenotype.
PMID:38796549 SUPPORT DIRECT Model Organism
"Interestingly, only Bag5 KI male mice demonstrated arrhythmia, which was more pronounced in Bag5-/- than in Bag5+/-males."
Sex pattern opposite to that seen in human carriers.
PMID:38796549 SUPPORT INDIRECT Model Organism
"These findings suggest that BAG5 might potentially exert a protective role in mitigating ER stress-induced cardiomyocyte apoptosis through alternative pathways, possibly involving ATF6 or XBP1, warranting further exploration."
The ER-stress effector pathway is unresolved.
Do heterozygous BAG5 truncating variants carry any cardiac risk?
KNOWLEDGE GAP OPEN cmd2f_heterozygous_carriers
Attached to
genetic#BAG5
Heterozygous truncations were reported in three patients with tachycardia-induced cardiomyopathy, and two of three female heterozygous relatives in one family had borderline ECG changes. Both observations are small and unconfirmed, and they are not part of the recessive CMD2F phenotype.
Show evidence (2 references)
PMID:35044787 SUPPORT INDIRECT Human Clinical
"We also identified heterozygous truncating mutations in three patients with tachycardia-induced cardiomyopathy, a reversible DCM subtype associated with abnormal calcium homeostasis."
Possible heterozygous susceptibility in a different phenotype.
PMID:38796549 SUPPORT INDIRECT Human Clinical
"suggesting a potential predisposition to arrhythmia in female carriers of the BAG5 variant."
Based on two female carriers with borderline ECG changes.
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Pathophysiology

8
Biallelic BAG5 Truncating Variants
Mechanism confidence: Provisional
Reported pathogenic alleles are nonsense or frameshift variants (p.Arg197Ter, p.Arg390Ter and p.His7ThrfsTer5 in Japanese families; p.Lys149AsnfsTer6 in a Middle Eastern family), carried homozygously or in compound heterozygosity. The gene-disease link rests on about seven families, so the trigger is graded provisional rather than established.
BAG5 hgnc:941 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BAG5 (hgnc:941). hgnc:941 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context allele_type: nonsense and frameshift variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Most reported patients are homozygous; two Japanese patients are reported, secondhand, as compound heterozygous for p.Arg197Ter and p.Arg390Ter. Loss of function is inferred from the truncating allele class, absent Bag5 protein in a knock-in mouse, and reduced BAG5 immunostaining in patient myocardium.
Downstream
Loss of BAG5 Protein Truncating alleles are expected to abolish or markedly reduce BAG5 protein.
Show evidence (3 references)
PMID:35044787 SUPPORT DIRECT Human Clinical
"we identified that homozygous truncating mutations in the gene encoding Bcl-2–associated athanogene (BAG) co-chaperone 5 (BAG5) caused inherited DCM in five patients among four unrelated families with complete penetrance."
The founding gene-disease report.
PMID:38796549 SUPPORT DIRECT Human Clinical
"Exome and Sanger sequencing identified a novel BAG5 variant, c.444_445delGA (p.Lys149AsnfsTer6), homozygous in affected siblings and heterozygous in parents and unaffected siblings."
An independent family with a different truncating allele.
PMID:38796549 SUPPORT DIRECT BACKGROUND Human Clinical
"Subsequently, Inoue et al. reported two unrelated cases of DCM caused by compound heterozygous truncating variants in BAG5."
Secondhand summary of the 2023 compound-heterozygous report, whose own text could not be retrieved.
Loss of BAG5 Protein
Mechanism confidence: Provisional
BAG5 is a co-chaperone with five BAG domains. Its fifth BAG domain binds the Hsp70 nucleotide-binding domain and promotes ADP release. Absence of BAG5 protein is shown in the knock-in mouse heart and reduced BAG5 is reported in patient myocardium.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
BAG5 hgnc:941 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BAG5 (hgnc:941). hgnc:941 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired HSC70 Nucleotide Exchange and Protein Refolding Without BAG5, its nucleotide-exchange activity on HSC70/Hsp70 is lost. The biochemistry is in vitro; that this deficit operates in patient cardiomyocytes is inferred.
Impaired Cardiomyocyte ER Stress Response In cultured rat cardiomyocytes Bag5 rises in the ER during ER stress and stabilizes GRP78; loss of this buffer is proposed to leave cardiomyocytes vulnerable to ER stress.
Show evidence (1 reference)
PMID:38796549 SUPPORT DIRECT Model Organism
"Western blot analysis revealed that the expression of Bag5 protein in cardiac tissue was completely absent in Bag5−/− mice and decreased in Bag5+/− mice, when compared to that in Bag5+/+ mice"
Protein loss measured in mouse heart.
Impaired HSC70 Nucleotide Exchange and Protein Refolding
Mechanism confidence: Hypothetical
BAG5 accelerates ADP release from HSC70/Hsp70 and enhances chaperone-mediated refolding in vitro. Loss of this co-chaperone activity is the presumed proximal molecular lesion, but no assay has measured HSC70 cycling or client folding in BAG5-deficient cardiomyocytes.
BAG5 hgnc:941 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BAG5 (hgnc:941). hgnc:941 is a gene from the HUGO Gene Nomenclature Committee.
protein refolding GO:0042026 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein refolding (GO:0042026). GO:0042026 is a biological process from the Gene Ontology.
adenyl-nucleotide exchange factor activity GO:0000774 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased adenyl-nucleotide exchange factor activity (GO:0000774). GO:0000774 is a molecular function from the Gene Ontology.
Downstream
Junctional Membrane Complex Disruption The founding study proposes that BAG5 maintains functional junctional membrane complex proteins; which HSC70 clients are involved is not established in the available abstract.
Show evidence (2 references)
PMID:35044787 SUPPORT INDIRECT BACKGROUND In Vitro
"BAG5 acts as a nucleotide exchange factor for heat shock cognate 71 kDa protein (HSC70), promoting adenosine diphosphate release and activating HSC70-mediated protein folding."
States the normal co-chaperone function whose loss is proposed.
PMID:20223214 SUPPORT INDIRECT BACKGROUND In Vitro
"In fact, BD5 reduced the affinity of the NBD for ADP."
Biochemical basis of the nucleotide-exchange activity.
Junctional Membrane Complex Disruption
Mechanism confidence: Provisional
Under catecholamine stimulation, Bag5-mutant mouse cardiomyocytes lose functional junctional membrane complex proteins and the complex structure is disrupted. Shown in mice; not measured in patient tissue.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
junctional membrane complex GO:0030314 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves abnormal junctional membrane complex (GO:0030314). GO:0030314 is a cellular component from the Gene Ontology.
Animal models
Bag5 truncating knock-in mouse (catecholamine stress) Mouse partially recapitulates Mutant cardiomyocytes lose functional JMC proteins and JMC structure under catecholamine stimulation.
Downstream
Abnormal Cardiomyocyte Calcium Handling Junctional membrane complexes couple sarcolemmal calcium entry to sarcoplasmic reticulum release; their disruption accompanies calcium-handling abnormalities in mutant cardiomyocytes.
Show evidence (1 reference)
PMID:35044787 SUPPORT DIRECT Model Organism
"Bag5-mutant mouse cardiomyocytes exhibited decreased abundance of functional JMC proteins under catecholamine stimulation, disrupted JMC structure, and calcium handling abnormalities."
Mouse cardiomyocyte data under catecholamine stress.
Abnormal Cardiomyocyte Calcium Handling
Mechanism confidence: Provisional
Calcium-handling abnormalities in Bag5-mutant mouse cardiomyocytes are proposed to drive both arrhythmia and contractile failure. Human support is indirect: reduced SERCA2 immunostaining was reported in compound-heterozygous patient myocardium.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
intracellular calcium ion homeostasis GO:0006874 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal intracellular calcium ion homeostasis (GO:0006874). GO:0006874 is a biological process from the Gene Ontology.
Downstream
Ventricular Arrhythmia Mutant mice became arrhythmogenic under catecholamine stimulation, alongside the calcium-handling defect; the arrhythmia mechanism (triggered activity or re-entry) was not resolved in the abstract.
Left Ventricular Dilatation and Systolic Dysfunction Calcium mishandling is proposed to impair contraction and lead to dilatation under adrenergic stress in mice.
Show evidence (2 references)
PMID:35044787 SUPPORT DIRECT Model Organism
"Bag5-mutant mouse cardiomyocytes exhibited decreased abundance of functional JMC proteins under catecholamine stimulation, disrupted JMC structure, and calcium handling abnormalities."
Calcium-handling abnormalities in mutant mouse cardiomyocytes.
PMID:38796549 SUPPORT INDIRECT BACKGROUND Human Clinical
"Immunohistochemical analysis of heart tissue from these patients revealed a significant reduction in BAG5 and SERCA2 protein expression."
Reduced SERCA2 in patient tissue is compatible with, but does not demonstrate, a calcium-handling defect.
Impaired Cardiomyocyte ER Stress Response
Mechanism confidence: Hypothetical
A second proposed branch. In neonatal rat cardiomyocytes Bag5 protects against ER stress-induced death, and Bag5 knock-in mice develop systolic dysfunction only after tunicamycin-induced ER stress. GRP78 and CHOP did not differ by genotype in mouse hearts (n = 1 per genotype), so the effector pathway is unresolved. The two branches are not mutually exclusive.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
response to endoplasmic reticulum stress GO:0034976 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal response to endoplasmic reticulum stress (GO:0034976). GO:0034976 is a biological process from the Gene Ontology.
Downstream
Cardiomyocyte Apoptosis ER stress produced more apoptotic cells in Bag5-deficient mouse hearts, independent of measurable differences in CHOP or GRP78.
Show evidence (2 references)
PMID:26729625 SUPPORT INDIRECT In Vitro
"Adenoviral mediated expression of Bag5 significantly decreased cell death as well as improved cellular viability in ER stress."
Gain-of-function evidence for a protective role in cultured rat cardiomyocytes.
PMID:38796549 SUPPORT DIRECT Model Organism
"To develop DCM in Bag5 point mutant KI mice, ER stress is required."
The knock-in phenotype is stress dependent.
Cardiomyocyte Apoptosis
Mechanism confidence: Hypothetical
Excess cardiomyocyte apoptosis was seen in ER-stressed Bag5 knock-in mouse hearts. Sample sizes were minimal and apoptosis has not been examined in patient myocardium.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
cardiac muscle cell apoptotic process GO:0010659 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cardiac muscle cell apoptotic process (GO:0010659). GO:0010659 is a biological process from the Gene Ontology.
Animal models
Bag5 p.Lys149fs-equivalent knock-in mouse (ER stress) Mouse partially recapitulates More TUNEL-positive cells in tunicamycin-treated homozygous hearts.
Downstream
Left Ventricular Dilatation and Systolic Dysfunction Loss of cardiomyocytes is proposed to reduce systolic function; in mice, tunicamycin lowered ejection fraction in knock-ins without overt histological change.
Show evidence (2 references)
PMID:38796549 SUPPORT DIRECT Model Organism
"Their cardiac tissues exhibited a notable increase in apoptotic cells, despite non-distinctive changes in CHOP and GRP78 levels."
Mouse finding, not a human observation.
PMID:38796549 SUPPORT DIRECT Model Organism
"Data are presented as mean ± SD of 10 fields per heart sample from a single sample per genotype (n = 1)."
The apoptosis quantification rests on one heart per genotype and sex, which limits confidence.
Left Ventricular Dilatation and Systolic Dysfunction
Mechanism confidence: Established
The defining human phenotype: a dilated left ventricle with reduced ejection fraction, presenting in the teens or twenties. The upstream cellular routes are model-derived.
cardiac muscle contraction GO:0060048 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cardiac muscle contraction (GO:0060048). GO:0060048 is a biological process from the Gene Ontology.
heart left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Bag5 truncating knock-in mouse (catecholamine stress) Mouse partially recapitulates Ventricular dilatation, arrhythmogenicity and poor prognosis under catecholamine stimulation, rescued by AAV9-BAG5.
Bag5 p.Lys149fs-equivalent knock-in mouse (ER stress) Mouse partially recapitulates Reduced LVEF and LVFS only after tunicamycin; no baseline cardiomyopathy up to 12 months.
Downstream
Dilated Cardiomyopathy Ventricular dilatation with systolic dysfunction constitutes the clinical diagnosis.
Reduced Left Ventricular Ejection Fraction Systolic dysfunction is measured clinically as a reduced ejection fraction.
Left Ventricular Dilatation Ventricular dilatation is measured clinically as an enlarged end-diastolic dimension.
Congestive Heart Failure Progressive pump failure leads to advanced heart failure needing mechanical support or transplantation.
Show evidence (2 references)
PMID:38796549 SUPPORT DIRECT Human Clinical
"Probands were two brothers, III-4 and III-5, aged 17 and 15 years, whose cardiological evaluations showed definite DCM with left ventricular ejection fraction (LVEF) by echocardiography of 40% and 36%, respectively"
Human systolic dysfunction in two homozygous brothers.
PMID:38796549 SUPPORT DIRECT BACKGROUND Human Clinical
"These patients presented with severe left ventricular dysfunction, early-onset heart failure symptoms, and a high incidence of refractory ventricular arrhythmias."
Summary of the founding Japanese cohort.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cardiomyopathy Dilated 2F Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

8
Dilated Cardiomyopathy Cardiovascular HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35044787 SUPPORT DIRECT Human Clinical
"we identified that homozygous truncating mutations in the gene encoding Bcl-2–associated athanogene (BAG) co-chaperone 5 (BAG5) caused inherited DCM in five patients among four unrelated families with complete penetrance."
DCM in all five founding patients.
PMID:38796549 SUPPORT DIRECT Human Clinical
"Probands were two brothers, III-4 and III-5, aged 17 and 15 years, whose cardiological evaluations showed definite DCM with left ventricular ejection fraction (LVEF) by echocardiography of 40% and 36%, respectively"
DCM with ages at evaluation in an independent family.
Reduced Left Ventricular Ejection Fraction Cardiovascular HP:0012664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced left ventricular ejection fraction (HP:0012664). HP:0012664 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38796549 SUPPORT DIRECT Human Clinical
"III-2 had normal LV size (end-diastolic volume 90.4 mL) with mild LV dysfunction (LVEF 46%) and mild to moderate LV global hypokinesia on cardiac MRI."
A milder affected sibling.
PMID:38796549 SUPPORT DIRECT BACKGROUND Human Clinical
"These patients presented with severe left ventricular dysfunction, early-onset heart failure symptoms, and a high incidence of refractory ventricular arrhythmias."
Severe dysfunction in the founding cohort, as summarized.
Left Ventricular Dilatation Cardiovascular HP:4000141 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular dilatation (HP:4000141). HP:4000141 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38796549 SUPPORT DIRECT Human Clinical
"echocardiographic images of the proband (III-4) showing dilated left ventricle (LV) with end-diastolic dimension (EDD) of 5.8 cm"
Measured LV dilatation in the proband.
Ventricular Arrhythmia Cardiovascular HP:0004308 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular arrhythmia (HP:0004308). HP:0004308 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38796549 SUPPORT DIRECT BACKGROUND Human Clinical
"These patients presented with severe left ventricular dysfunction, early-onset heart failure symptoms, and a high incidence of refractory ventricular arrhythmias."
Refractory ventricular arrhythmias in the founding cohort.
PMID:38796549 SUPPORT DIRECT BACKGROUND Human Clinical
"Both patients presented with advanced heart failure and experienced severe ventricular arrhythmias."
Severe ventricular arrhythmias in the compound-heterozygous patients.
Congestive Heart Failure Cardiovascular HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38796549 SUPPORT DIRECT BACKGROUND Human Clinical
"Both patients presented with advanced heart failure and experienced severe ventricular arrhythmias."
Advanced heart failure in the compound-heterozygous patients.
PMID:38796549 SUPPORT DIRECT Human Clinical
"III-6 passed away at the age of 12 years old while waiting for a heart transplantation."
Death from end-stage disease awaiting transplant; this sibling was not genotyped.
Decreased QRS Voltage Cardiovascular HP:0025077 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased QRS voltage (HP:0025077). HP:0025077 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38796549 SUPPORT DIRECT Human Clinical
"Electrocardiogram (ECG) assessments showed that all available patients, III-2, III-4, and III-5 had a low voltage of the limb lead, T wave inversion in the infero-lateral leads, and poor R progression in precordial leads."
ECG finding in three affected siblings.
T-wave Inversion Cardiovascular HP:0010872 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is T-wave inversion (HP:0010872). HP:0010872 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38796549 SUPPORT DIRECT Human Clinical
"Electrocardiogram (ECG) assessments showed that all available patients, III-2, III-4, and III-5 had a low voltage of the limb lead, T wave inversion in the infero-lateral leads, and poor R progression in precordial leads."
ECG finding in three affected siblings.
Poor R-wave Progression Cardiovascular HP:6001161 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor R-wave progression (HP:6001161). HP:6001161 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38796549 SUPPORT DIRECT Human Clinical
"Electrocardiogram (ECG) assessments showed that all available patients, III-2, III-4, and III-5 had a low voltage of the limb lead, T wave inversion in the infero-lateral leads, and poor R progression in precordial leads."
ECG finding in three affected siblings.
🧬

Genetic Associations

1
BAG5 (Autosomal recessive DCM gene supported by about seven families: four Japanese families (five homozygous patients) in the founding report, two unrelated compound-heterozygous Japanese patients known here only from a secondhand summary, and one consanguineous Middle Eastern family with three affected genotyped siblings. Two recurrent nonsense alleles (p.Arg197Ter, p.Arg390Ter) appear in several Japanese families.)
Gene: BAG5 hgnc:941 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is BAG5 (hgnc:941). hgnc:941 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Show evidence (6 references)
PMID:35044787 SUPPORT DIRECT Human Clinical
"we identified that homozygous truncating mutations in the gene encoding Bcl-2–associated athanogene (BAG) co-chaperone 5 (BAG5) caused inherited DCM in five patients among four unrelated families with complete penetrance."
Founding gene-disease report.
PMID:38796549 SUPPORT DIRECT Human Clinical
"Exome and Sanger sequencing identified a novel BAG5 variant, c.444_445delGA (p.Lys149AsnfsTer6), homozygous in affected siblings and heterozygous in parents and unaffected siblings."
Independent replication with a different truncating allele.
PMID:38796549 SUPPORT DIRECT BACKGROUND Human Clinical
"Subsequently, Inoue et al. reported two unrelated cases of DCM caused by compound heterozygous truncating variants in BAG5."
Secondhand account of a further report.
+ 3 more references
💊

Medical Actions

7
Beta-blocker therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Beta-Adrenergic Antagonist NCIT:C29576 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Beta-Adrenergic Antagonist (NCIT:C29576). NCIT:C29576 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Standard heart-failure beta-blockade for left ventricular systolic dysfunction. Beta-blockade is mechanistically attractive because the mouse phenotype is provoked by catecholamines, but no BAG5-specific treatment data exist.
Mechanism Target:
Left Ventricular Dilatation and Systolic Dysfunction — Supportive heart-failure therapy; does not correct the BAG5 defect.
Show evidence (1 reference)
url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"In children with systemic LV systolic dysfunction, use of β-blockers is reasonable"
General pediatric heart-failure guidance extrapolated to adolescents with CMD2F; not genotype-specific trial evidence.
ACE inhibitor therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ACE Inhibitor NCIT:C247 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses ACE Inhibitor (NCIT:C247). NCIT:C247 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Standard ACE inhibition for left ventricular systolic dysfunction; no BAG5-specific data.
Mechanism Target:
Left Ventricular Dilatation and Systolic Dysfunction — Supportive heart-failure therapy; does not correct the BAG5 defect.
Show evidence (1 reference)
url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"In children with left ventricular systolic dysfunction, ACE inhibitors should be routinely used unless there is a specific contraindication"
General pediatric heart-failure guidance extrapolated to CMD2F.
Implantable cardioverter-defibrillator
Action: Implantable Cardioverter-Defibrillator PlacementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Implantable Cardioverter-Defibrillator Placement (NCIT:C80435). NCIT:C80435 is a clinical intervention from the NCI Thesaurus. NCIT:C80435
Platform: Device
An ICD is a standard consideration for sudden-death prevention in DCM with ventricular arrhythmias. No retrievable source documents ICD use or outcomes in CMD2F.
Mechanism Target:
Ventricular Arrhythmia — Terminates life-threatening ventricular arrhythmias; does not prevent them.
Left ventricular assist device
Action: Left Ventricular Assist Device InsertionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Left Ventricular Assist Device Insertion (NCIT:C172327). NCIT:C172327 is a clinical intervention from the NCI Thesaurus. NCIT:C172327
Platform: Device
Mechanical circulatory support as a bridge to transplantation for advanced heart failure. The founding report is said to have used LVADs, but the retrievable abstract does not state this.
Mechanism Target:
Congestive Heart Failure — Supports circulation in end-stage heart failure.
Heart transplantation
Action: Heart TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Heart Transplantation (NCIT:C15246). NCIT:C15246 is a clinical intervention from the NCI Thesaurus. NCIT:C15246
Platform: Surgery
Definitive therapy for end-stage disease. The founding report's title describes CMD2F as requiring heart transplantation, and one sibling died awaiting transplantation. Transplant outcomes specific to BAG5 have not been reported.
Mechanism Target:
Congestive Heart Failure — Replaces the failing heart.
Show evidence (2 references)
PMID:38796549 SUPPORT DIRECT Human Clinical
"III-6 passed away at the age of 12 years old while waiting for a heart transplantation."
Transplantation was the planned therapy for an affected child.
url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"In patients with severe acute HF, it is reasonable to initiate transfer to a center with pediatric HF specialists who have the expertise and ability to optimize medical therapy, evaluate for heart transplantation, and provide mechanical support"
General guidance on referral for transplant evaluation; not BAG5 specific.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Other
Discuss autosomal recessive recurrence (25% for each pregnancy of two carrier parents, a Mendelian calculation), carrier testing in consanguineous families, and cardiac screening of at-risk siblings.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"Cardiovascular screening of asymptomatic first-degree family members of an individual with DCM can allow early detection of DCM, prompt initiation of treatment, and improvement in long-term outcome"
General familial DCM guidance.
AAV9 BAG5 gene replacement (preclinical)
Action: Gene TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Gene Therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. NCIT:C15238
Platform: Gene therapy
An AAV9 vector carrying wild-type BAG5 fully ameliorated the DCM phenotypes of Bag5 mutant knock-in mice. This is a preclinical mouse result; no human trial exists.
Mechanism Target:
Loss of BAG5 Protein — Restores wild-type BAG5 in the mouse heart.
Show evidence (1 reference)
PMID:35044787 SUPPORT DIRECT Model Organism
"Bag5 mutant knock-in mice exhibited ventricular dilatation, arrhythmogenicity, and poor prognosis under catecholamine stimulation, recapitulating the human DCM phenotype, and administration of an adeno-associated virus 9 vector carrying the wild-type BAG5 gene could fully ameliorate these DCM phenotypes."
Mouse rescue, not human efficacy.
🔬

Diagnosis

3
Genomic testing for biallelic BAG5 variants
Exome sequencing with Sanger confirmation and family segregation identified the reported variants. BAG5 should be included when testing early-onset DCM, keeping in mind that ClinGen rates BAG5 Moderate (AR) for DCM broadly and that BAG3 is a different gene.
Show evidence (3 references)
PMID:35044787 SUPPORT INDIRECT Human Clinical
"Our study suggests that loss-of-function mutations in BAG5 can cause DCM, that BAG5 may be a target for genetic testing in cases of DCM, and that gene therapy may potentially be a treatment for this disease."
The authors recommend including BAG5 in DCM genetic testing.
PMID:38796549 SUPPORT DIRECT Human Clinical
"Exome and Sanger sequencing identified a novel BAG5 variant, c.444_445delGA (p.Lys149AsnfsTer6), homozygous in affected siblings and heterozygous in parents and unaffected siblings."
Exome plus Sanger sequencing with segregation.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"Molecular genetic testing should be offered to every individual of any age with nonischemic DCM"
General GeneReviews DCM guidance; it does not name BAG5.
Echocardiography and electrocardiography
Echocardiography documents LV dilatation and reduced ejection fraction; cardiac MRI was used in a milder sibling. ECGs in one family showed low limb-lead voltage, inferolateral T-wave inversion and poor R-wave progression; these are not specific diagnostic markers.
Show evidence (1 reference)
PMID:38796549 SUPPORT DIRECT Human Clinical
"III-2 had normal LV size (end-diastolic volume 90.4 mL) with mild LV dysfunction (LVEF 46%) and mild to moderate LV global hypokinesia on cardiac MRI."
Imaging modalities used in the family.
Family assessment
Offer genetic counselling, carrier testing and cardiac screening of siblings of an affected individual. General GeneReviews DCM advice applies; there is no BAG5-specific surveillance interval.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"Cardiovascular screening of asymptomatic first-degree family members of an individual with DCM can allow early detection of DCM, prompt initiation of treatment, and improvement in long-term outcome"
General familial DCM guidance; not BAG5 specific.
📈

Progression

2
Adolescent or young-adult presentation
Age: 12-17 years in the Middle Eastern family
The Middle Eastern probands were evaluated at 15 and 17 years with established DCM; a younger sibling died at 12 years. Ages at onset for the Japanese patients are described as early onset but are not given in the retrievable abstracts.
Show evidence (1 reference)
PMID:38796549 SUPPORT DIRECT Human Clinical
"Probands were two brothers, III-4 and III-5, aged 17 and 15 years, whose cardiological evaluations showed definite DCM with left ventricular ejection fraction (LVEF) by echocardiography of 40% and 36%, respectively"
Ages at evaluation in one family.
Advanced heart failure
Progression to advanced heart failure with ventricular arrhythmias is reported in the Japanese patients, and one Middle Eastern sibling died at 12 years awaiting transplantation. No natural-history cohort or survival statistics exist.
Show evidence (2 references)
PMID:38796549 SUPPORT DIRECT Human Clinical
"III-6 passed away at the age of 12 years old while waiting for a heart transplantation."
Fatal outcome before transplantation.
PMID:38796549 SUPPORT DIRECT BACKGROUND Human Clinical
"Both patients presented with advanced heart failure and experienced severe ventricular arrhythmias."
Advanced disease in the compound-heterozygous patients.
📊

Prevalence

1
Reported patients
Cases In Literature Ultra Rare
About ten genotyped patients from about seven families have been published (five homozygous patients from four Japanese families, two compound-heterozygous Japanese patients known secondhand, and three homozygous siblings from one Middle Eastern family), plus one deceased ungenotyped sibling. A case report of refractory arrhythmia (2022) may overlap the founding cohort. GenCC counts about 12 cases; the difference from the 10 genotyped patients counted here may reflect the 2022 case report or heterozygous carriers. This is a publication count, not a population prevalence.
Show evidence (3 references)
PMID:35044787 SUPPORT DIRECT Human Clinical
"we identified that homozygous truncating mutations in the gene encoding Bcl-2–associated athanogene (BAG) co-chaperone 5 (BAG5) caused inherited DCM in five patients among four unrelated families with complete penetrance."
Founding case count.
PMID:38796549 SUPPORT DIRECT Human Clinical
"The analysis involved three siblings affected by DCM and arrhythmia, along with their four unaffected siblings, their unaffected father, and their mother who exhibited arrhythmia."
Case count in the second independent family.
PMID:38796549 SUPPORT DIRECT BACKGROUND Human Clinical
"Subsequently, Inoue et al. reported two unrelated cases of DCM caused by compound heterozygous truncating variants in BAG5."
Further cases known from a secondhand summary.
🐁

Animal Models

2
Bag5 truncating knock-in mouse (catecholamine stress)
Knock-in mice develop ventricular dilatation, arrhythmogenicity and poor survival under catecholamine stimulation, with junctional membrane complex disruption and calcium-handling abnormalities in cardiomyocytes. AAV9 wild-type BAG5 rescues the phenotype. The exact allele and baseline phenotype are not given in the retrievable abstract.
Species
Mouse
Genotype
Bag5 mutant knock-in modelling a patient truncating allele
Publication
PMID:35044787
Pathograph links
Junctional Membrane Complex Disruption partially recapitulates fidelity: moderate observes: cellular Mutant cardiomyocytes lose functional JMC proteins and JMC structure under catecholamine stimulation.
Limitations: Requires catecholamine stimulation; not measured in patient myocardium.
Divergences from the human mechanism
species mismatch qualifying
Mouse cardiomyocytes under pharmacological adrenergic stress; whether patient myocardium shows the same JMC loss without an exogenous trigger is unknown.
Show evidence (1 reference)
PMID:35044787 SUPPORT DIRECT Model Organism
"Bag5-mutant mouse cardiomyocytes exhibited decreased abundance of functional JMC proteins under catecholamine stimulation, disrupted JMC structure, and calcium handling abnormalities."
Direct model observation.
Left Ventricular Dilatation and Systolic Dysfunction partially recapitulates fidelity: moderate observes: organism Ventricular dilatation, arrhythmogenicity and poor prognosis under catecholamine stimulation, rescued by AAV9-BAG5.
Limitations: Stress-provoked; the human disease has no identified exogenous trigger.
Divergences from the human mechanism
species mismatch qualifying
The mouse phenotype appears under catecholamine stimulation, whereas patients develop DCM without a documented trigger.
Show evidence (1 reference)
PMID:35044787 SUPPORT DIRECT Model Organism
"Bag5 mutant knock-in mice exhibited ventricular dilatation, arrhythmogenicity, and poor prognosis under catecholamine stimulation, recapitulating the human DCM phenotype, and administration of an adeno-associated virus 9 vector carrying the wild-type BAG5 gene could fully ameliorate these DCM phenotypes."
Organism-level recapitulation and rescue.
Bag5 p.Lys149fs-equivalent knock-in mouse (ER stress)
Homozygous knock-ins lack cardiac Bag5 protein yet are normal to 12 months and on treadmill testing. After tunicamycin they show reduced LVEF and LVFS and more apoptotic cardiomyocytes, and male knock-ins show sinus pauses. Groups were three mice per sex and genotype; apoptosis and immunoblots used one heart per group.
Species
Mouse
Genotype
Bag5 two-nucleotide deletion (delCA) in exon 3 corresponding to human c.444_445delGA, C57BL/6N
Publication
PMID:38796549
Pathograph links
Cardiomyocyte Apoptosis partially recapitulates fidelity: low observes: tissue More TUNEL-positive cells in tunicamycin-treated homozygous hearts.
Limitations: One heart per genotype and sex; tunicamycin is a pharmacological ER stressor; no apoptosis data from patients.
Divergences from the human mechanism
species mismatch qualifying
Apoptosis was induced by tunicamycin in mice; ER stress or apoptosis has not been measured in patient myocardium.
Show evidence (1 reference)
PMID:38796549 SUPPORT DIRECT Model Organism
"Their cardiac tissues exhibited a notable increase in apoptotic cells, despite non-distinctive changes in CHOP and GRP78 levels."
Direct model observation.
Left Ventricular Dilatation and Systolic Dysfunction partially recapitulates fidelity: low observes: organism Reduced LVEF and LVFS only after tunicamycin; no baseline cardiomyopathy up to 12 months.
Limitations: The unstressed knock-in has no cardiac phenotype, unlike patients; no histological abnormality was evident after tunicamycin.
Divergences from the human mechanism
species mismatch qualifying
Patients develop spontaneous DCM in adolescence, while the mouse shows systolic dysfunction only after a pharmacological ER stressor.
Show evidence (2 references)
PMID:38796549 SUPPORT DIRECT Model Organism
"However, following TN injection, Bag5-/- mice exhibited significantly reduced left ventricular fractional shortening (LVFS) and ejection fraction (LVEF)."
Stress-provoked systolic dysfunction.
+ 1 more reference
{ }

Source YAML

click to show 
name: Cardiomyopathy Dilated 2F
creation_date: "2026-10-08T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: cardiomyopathy, dilated, 2F
  term:
    id: MONDO:0030680
    label: cardiomyopathy, dilated, 2F
synonyms:
- CMD2F
- cardiomyopathy, dilated, 2F
- BAG5-related dilated cardiomyopathy
- BAG5-associated dilated cardiomyopathy
description: >-
  Cardiomyopathy, dilated, 2F (CMD2F) is an autosomal recessive dilated
  cardiomyopathy caused by biallelic truncating variants in BAG5, which
  encodes a five-BAG-domain co-chaperone that acts as a nucleotide exchange
  factor for HSC70/Hsp70. Affected individuals present in adolescence or
  young adulthood with left ventricular dilatation, reduced ejection fraction,
  advanced heart failure and ventricular arrhythmias that can be refractory.
  The clinical evidence base is small: five patients from four Japanese
  families in the founding report, two further compound-heterozygous patients
  known here only through a later summary, and three affected siblings from
  one consanguineous Middle Eastern family. Two mechanisms have been proposed,
  both from stress-provoked mouse models: disruption of junctional membrane
  complexes with abnormal calcium handling under catecholamine stimulation,
  and an impaired endoplasmic reticulum stress response with excess
  cardiomyocyte apoptosis. Wild-type BAG5 delivered by AAV9 rescued one mouse
  model; this is not a human treatment. BAG5 is distinct from BAG3, a separate
  autosomal dominant dilated cardiomyopathy gene.
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic truncating BAG5 variants (homozygous, or compound heterozygous
    in a later report) segregate with disease. The founding report describes
    complete penetrance in five biallelic patients; this is a small-sample
    observation, not a population penetrance estimate. Heterozygous parents
    were clinically unaffected, although minor ECG changes were noted in two
    of three female carriers in one family.
  evidence:
  - reference: PMID:35044787
    reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: we identified that homozygous truncating mutations in the gene encoding Bcl-2–associated athanogene (BAG) co-chaperone 5 (BAG5) caused inherited DCM in five patients among four unrelated families with complete penetrance.
    explanation: Homozygous truncating variants in four unrelated families support recessive inheritance.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Exome and Sanger sequencing identified a novel BAG5 variant, c.444_445delGA (p.Lys149AsnfsTer6), homozygous in affected siblings and heterozygous in parents and unaffected siblings.
    explanation: Segregation in an independent consanguineous family is consistent with recessive inheritance.
  - reference: CGGV:assertion_97fe83b7-fe12-4014-9706-6847446fa9bd-2024-06-14T160000.000Z
    reference_title: BAG5 / dilated cardiomyopathy (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: BAG5 | HGNC:941 | dilated cardiomyopathy | MONDO:0005021 | AR | Moderate
    explanation: ClinGen records an autosomal recessive mode for BAG5; the record is for the parent dilated cardiomyopathy term, not CMD2F itself.
pathophysiology:
- name: Biallelic BAG5 Truncating Variants
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: PROVISIONAL
  description: >-
    Reported pathogenic alleles are nonsense or frameshift variants
    (p.Arg197Ter, p.Arg390Ter and p.His7ThrfsTer5 in Japanese families;
    p.Lys149AsnfsTer6 in a Middle Eastern family), carried homozygously or in
    compound heterozygosity. The gene-disease link rests on about seven
    families, so the trigger is graded provisional rather than established.
  genes:
  - preferred_term: BAG5
    term:
      id: hgnc:941
      label: BAG5
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    allele_type: nonsense and frameshift
    description: >-
      Most reported patients are homozygous; two Japanese patients are
      reported, secondhand, as compound heterozygous for p.Arg197Ter and
      p.Arg390Ter. Loss of function is inferred from the truncating allele
      class, absent Bag5 protein in a knock-in mouse, and reduced BAG5
      immunostaining in patient myocardium.
  evidence:
  - reference: PMID:35044787
    reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: we identified that homozygous truncating mutations in the gene encoding Bcl-2–associated athanogene (BAG) co-chaperone 5 (BAG5) caused inherited DCM in five patients among four unrelated families with complete penetrance.
    explanation: The founding gene-disease report.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Exome and Sanger sequencing identified a novel BAG5 variant, c.444_445delGA (p.Lys149AsnfsTer6), homozygous in affected siblings and heterozygous in parents and unaffected siblings.
    explanation: An independent family with a different truncating allele.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: BACKGROUND
    snippet: Subsequently, Inoue et al. reported two unrelated cases of DCM caused by compound heterozygous truncating variants in BAG5.
    explanation: Secondhand summary of the 2023 compound-heterozygous report, whose own text could not be retrieved.
  downstream:
  - target: Loss of BAG5 Protein
    causal_link_type: DIRECT
    description: Truncating alleles are expected to abolish or markedly reduce BAG5 protein.
    evidence:
    - reference: PMID:38796549
      reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: Western blot analysis revealed that the expression of Bag5 protein in cardiac tissue was completely absent in Bag5−/− mice and decreased in Bag5+/− mice, when compared to that in Bag5+/+ mice
      explanation: The mouse equivalent of p.Lys149AsnfsTer6 abolishes cardiac Bag5 protein when homozygous.
    - reference: PMID:38796549
      reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      quote_role: BACKGROUND
      snippet: Immunohistochemical analysis of heart tissue from these patients revealed a significant reduction in BAG5 and SERCA2 protein expression.
      explanation: Reduced BAG5 in compound-heterozygous patient myocardium, as summarized by a later paper.
- name: Loss of BAG5 Protein
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    BAG5 is a co-chaperone with five BAG domains. Its fifth BAG domain binds
    the Hsp70 nucleotide-binding domain and promotes ADP release. Absence of
    BAG5 protein is shown in the knock-in mouse heart and reduced BAG5 is
    reported in patient myocardium.
  genes:
  - preferred_term: BAG5
    term:
      id: hgnc:941
      label: BAG5
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Western blot analysis revealed that the expression of Bag5 protein in cardiac tissue was completely absent in Bag5−/− mice and decreased in Bag5+/− mice, when compared to that in Bag5+/+ mice
    explanation: Protein loss measured in mouse heart.
  downstream:
  - target: Impaired HSC70 Nucleotide Exchange and Protein Refolding
    causal_link_type: DIRECT
    description: Without BAG5, its nucleotide-exchange activity on HSC70/Hsp70 is lost. The biochemistry is in vitro; that this deficit operates in patient cardiomyocytes is inferred.
    evidence:
    - reference: PMID:20223214
      reference_title: The C-terminal BAG domain of BAG5 induces conformational changes of the Hsp70 nucleotide-binding domain for ADP-ATP exchange.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: BACKGROUND
      snippet: Therefore, BAG5 can function as the nucleotide exchange factor of Hsp70 for the enhancement of protein refolding.
      explanation: Structural and refolding assays establish the normal activity whose loss is inferred.
  - target: Impaired Cardiomyocyte ER Stress Response
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: In cultured rat cardiomyocytes Bag5 rises in the ER during ER stress and stabilizes GRP78; loss of this buffer is proposed to leave cardiomyocytes vulnerable to ER stress.
    evidence:
    - reference: PMID:26729625
      reference_title: GRP78 Interacting Partner Bag5 Responds to ER Stress and Protects Cardiomyocytes From ER Stress-Induced Apoptosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: Mechanistically, we found that Bag5 protein expression is significantly increased in the ER during ER stress and that this in turn modulates GRP78 protein stability and reduces ER stress.
      explanation: Neonatal rat cardiomyocyte data on normal Bag5 function; not a disease-allele experiment.
- name: Impaired HSC70 Nucleotide Exchange and Protein Refolding
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: HYPOTHETICAL
  genes:
  - preferred_term: BAG5
    term:
      id: hgnc:941
      label: BAG5
  description: >-
    BAG5 accelerates ADP release from HSC70/Hsp70 and enhances
    chaperone-mediated refolding in vitro. Loss of this co-chaperone activity
    is the presumed proximal molecular lesion, but no assay has measured
    HSC70 cycling or client folding in BAG5-deficient cardiomyocytes.
  molecular_functions:
  - preferred_term: adenyl-nucleotide exchange factor activity
    modifier: DECREASED
    term:
      id: GO:0000774
      label: adenyl-nucleotide exchange factor activity
  biological_processes:
  - preferred_term: protein refolding
    modifier: DECREASED
    term:
      id: GO:0042026
      label: protein refolding
  evidence:
  - reference: PMID:35044787
    reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    quote_role: BACKGROUND
    snippet: BAG5 acts as a nucleotide exchange factor for heat shock cognate 71 kDa protein (HSC70), promoting adenosine diphosphate release and activating HSC70-mediated protein folding.
    explanation: States the normal co-chaperone function whose loss is proposed.
  - reference: PMID:20223214
    reference_title: The C-terminal BAG domain of BAG5 induces conformational changes of the Hsp70 nucleotide-binding domain for ADP-ATP exchange.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    quote_role: BACKGROUND
    snippet: In fact, BD5 reduced the affinity of the NBD for ADP.
    explanation: Biochemical basis of the nucleotide-exchange activity.
  downstream:
  - target: Junctional Membrane Complex Disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The founding study proposes that BAG5 maintains functional junctional membrane complex proteins; which HSC70 clients are involved is not established in the available abstract.
    evidence:
    - reference: PMID:35044787
      reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: Immunocytochemical analysis revealed that BAG5 localized to junctional membrane complexes (JMCs), critical microdomains for calcium handling.
      explanation: Localization places BAG5 at the structure that fails; it shows where BAG5 sits, not that loss of HSC70 nucleotide exchange causes junctional membrane complex loss.
- name: Junctional Membrane Complex Disruption
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Under catecholamine stimulation, Bag5-mutant mouse cardiomyocytes lose
    functional junctional membrane complex proteins and the complex structure
    is disrupted. Shown in mice; not measured in patient tissue.
  cellular_components:
  - preferred_term: junctional membrane complex
    modifier: ABNORMAL
    term:
      id: GO:0030314
      label: junctional membrane complex
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:35044787
    reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Bag5-mutant mouse cardiomyocytes exhibited decreased abundance of functional JMC proteins under catecholamine stimulation, disrupted JMC structure, and calcium handling abnormalities.
    explanation: Mouse cardiomyocyte data under catecholamine stress.
  downstream:
  - target: Abnormal Cardiomyocyte Calcium Handling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Junctional membrane complexes couple sarcolemmal calcium entry to sarcoplasmic reticulum release; their disruption accompanies calcium-handling abnormalities in mutant cardiomyocytes.
    evidence:
    - reference: PMID:35044787
      reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: Bag5-mutant mouse cardiomyocytes exhibited decreased abundance of functional JMC proteins under catecholamine stimulation, disrupted JMC structure, and calcium handling abnormalities.
      explanation: Structural disruption and calcium mishandling were observed together in the same mutant cells.
    - reference: PMID:35044787
      reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: Immunocytochemical analysis revealed that BAG5 localized to junctional membrane complexes (JMCs), critical microdomains for calcium handling.
      explanation: Identifies the complexes as calcium-handling microdomains.
- name: Abnormal Cardiomyocyte Calcium Handling
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Calcium-handling abnormalities in Bag5-mutant mouse cardiomyocytes are
    proposed to drive both arrhythmia and contractile failure. Human support
    is indirect: reduced SERCA2 immunostaining was reported in
    compound-heterozygous patient myocardium.
  biological_processes:
  - preferred_term: intracellular calcium ion homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:35044787
    reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Bag5-mutant mouse cardiomyocytes exhibited decreased abundance of functional JMC proteins under catecholamine stimulation, disrupted JMC structure, and calcium handling abnormalities.
    explanation: Calcium-handling abnormalities in mutant mouse cardiomyocytes.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: BACKGROUND
    snippet: Immunohistochemical analysis of heart tissue from these patients revealed a significant reduction in BAG5 and SERCA2 protein expression.
    explanation: Reduced SERCA2 in patient tissue is compatible with, but does not demonstrate, a calcium-handling defect.
  downstream:
  - target: Ventricular Arrhythmia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Mutant mice became arrhythmogenic under catecholamine stimulation, alongside the calcium-handling defect; the arrhythmia mechanism (triggered activity or re-entry) was not resolved in the abstract.
    evidence:
    - reference: PMID:35044787
      reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: Bag5 mutant knock-in mice exhibited ventricular dilatation, arrhythmogenicity, and poor prognosis under catecholamine stimulation, recapitulating the human DCM phenotype, and administration of an adeno-associated virus 9 vector carrying the wild-type BAG5 gene could fully ameliorate these DCM phenotypes.
      explanation: Arrhythmogenicity co-occurs with the calcium defect in the same model; the causal step is inferred.
  - target: Left Ventricular Dilatation and Systolic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Calcium mishandling is proposed to impair contraction and lead to dilatation under adrenergic stress in mice.
    evidence:
    - reference: PMID:35044787
      reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: Bag5 mutant knock-in mice exhibited ventricular dilatation, arrhythmogenicity, and poor prognosis under catecholamine stimulation, recapitulating the human DCM phenotype, and administration of an adeno-associated virus 9 vector carrying the wild-type BAG5 gene could fully ameliorate these DCM phenotypes.
      explanation: Dilatation and its rescue by wild-type BAG5 occur in the model that shows the calcium defect.
- name: Impaired Cardiomyocyte ER Stress Response
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: HYPOTHETICAL
  description: >-
    A second proposed branch. In neonatal rat cardiomyocytes Bag5 protects
    against ER stress-induced death, and Bag5 knock-in mice develop systolic
    dysfunction only after tunicamycin-induced ER stress. GRP78 and CHOP did
    not differ by genotype in mouse hearts (n = 1 per genotype), so the
    effector pathway is unresolved. The two branches are not mutually
    exclusive.
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    modifier: ABNORMAL
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:26729625
    reference_title: GRP78 Interacting Partner Bag5 Responds to ER Stress and Protects Cardiomyocytes From ER Stress-Induced Apoptosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: Adenoviral mediated expression of Bag5 significantly decreased cell death as well as improved cellular viability in ER stress.
    explanation: Gain-of-function evidence for a protective role in cultured rat cardiomyocytes.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: To develop DCM in Bag5 point mutant KI mice, ER stress is required.
    explanation: The knock-in phenotype is stress dependent.
  downstream:
  - target: Cardiomyocyte Apoptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: ER stress produced more apoptotic cells in Bag5-deficient mouse hearts, independent of measurable differences in CHOP or GRP78.
    evidence:
    - reference: PMID:38796549
      reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: Their cardiac tissues exhibited a notable increase in apoptotic cells, despite non-distinctive changes in CHOP and GRP78 levels.
      explanation: TUNEL data in tunicamycin-treated knock-in hearts, one heart per genotype and sex.
    - reference: PMID:26729625
      reference_title: GRP78 Interacting Partner Bag5 Responds to ER Stress and Protects Cardiomyocytes From ER Stress-Induced Apoptosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: Conversely, we found that siRNA-mediated knockdown of Bag5 caused cell death, increased cytotoxicity, and decreased cellular viability in cardiomyocytes.
      explanation: Acute knockdown in cultured neonatal rat cardiomyocytes increased cell death at baseline, not specifically under ER stress, so it supports the ER-stress-to-apoptosis step only by inference.
- name: Cardiomyocyte Apoptosis
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Excess cardiomyocyte apoptosis was seen in ER-stressed Bag5 knock-in mouse
    hearts. Sample sizes were minimal and apoptosis has not been examined in
    patient myocardium.
  biological_processes:
  - preferred_term: cardiac muscle cell apoptotic process
    modifier: INCREASED
    term:
      id: GO:0010659
      label: cardiac muscle cell apoptotic process
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Their cardiac tissues exhibited a notable increase in apoptotic cells, despite non-distinctive changes in CHOP and GRP78 levels.
    explanation: Mouse finding, not a human observation.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Data are presented as mean ± SD of 10 fields per heart sample from a single sample per genotype (n = 1).
    explanation: The apoptosis quantification rests on one heart per genotype and sex, which limits confidence.
  downstream:
  - target: Left Ventricular Dilatation and Systolic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of cardiomyocytes is proposed to reduce systolic function; in mice, tunicamycin lowered ejection fraction in knock-ins without overt histological change.
    evidence:
    - reference: PMID:38796549
      reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: However, following TN injection, Bag5-/- mice exhibited significantly reduced left ventricular fractional shortening (LVFS) and ejection fraction (LVEF).
      explanation: Systolic dysfunction accompanies the apoptotic response in the same ER-stressed mice; the causal link between them is inferred.
- name: Left Ventricular Dilatation and Systolic Dysfunction
  biological_scale: TISSUE
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    The defining human phenotype: a dilated left ventricle with reduced
    ejection fraction, presenting in the teens or twenties. The upstream
    cellular routes are model-derived.
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  biological_processes:
  - preferred_term: cardiac muscle contraction
    modifier: DECREASED
    term:
      id: GO:0060048
      label: cardiac muscle contraction
  evidence:
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Probands were two brothers, III-4 and III-5, aged 17 and 15 years, whose cardiological evaluations showed definite DCM with left ventricular ejection fraction (LVEF) by echocardiography of 40% and 36%, respectively
    explanation: Human systolic dysfunction in two homozygous brothers.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: BACKGROUND
    snippet: These patients presented with severe left ventricular dysfunction, early-onset heart failure symptoms, and a high incidence of refractory ventricular arrhythmias.
    explanation: Summary of the founding Japanese cohort.
  downstream:
  - target: Dilated Cardiomyopathy
    causal_link_type: DIRECT
    description: Ventricular dilatation with systolic dysfunction constitutes the clinical diagnosis.
    evidence:
    - reference: PMID:38796549
      reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: Probands were two brothers, III-4 and III-5, aged 17 and 15 years, whose cardiological evaluations showed definite DCM with left ventricular ejection fraction (LVEF) by echocardiography of 40% and 36%, respectively
      explanation: Reduced ejection fraction with a DCM diagnosis.
  - target: Reduced Left Ventricular Ejection Fraction
    causal_link_type: DIRECT
    description: Systolic dysfunction is measured clinically as a reduced ejection fraction.
    evidence:
    - reference: PMID:38796549
      reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: Probands were two brothers, III-4 and III-5, aged 17 and 15 years, whose cardiological evaluations showed definite DCM with left ventricular ejection fraction (LVEF) by echocardiography of 40% and 36%, respectively
      explanation: Measured LVEF in two homozygous brothers.
  - target: Left Ventricular Dilatation
    causal_link_type: DIRECT
    description: Ventricular dilatation is measured clinically as an enlarged end-diastolic dimension.
    evidence:
    - reference: PMID:38796549
      reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: echocardiographic images of the proband (III-4) showing dilated left ventricle (LV) with end-diastolic dimension (EDD) of 5.8 cm
      explanation: Measured LV dilatation in the proband.
  - target: Congestive Heart Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Progressive pump failure leads to advanced heart failure needing mechanical support or transplantation.
    evidence:
    - reference: PMID:38796549
      reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      quote_role: BACKGROUND
      snippet: Both patients presented with advanced heart failure and experienced severe ventricular arrhythmias.
      explanation: Advanced heart failure in the compound-heterozygous patients, as summarized secondhand.
phenotypes:
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: >-
    Present in all reported biallelic patients (five in the founding report,
    three genotyped siblings in the Middle Eastern family). Onset is in
    adolescence or young adulthood; the Middle Eastern probands were 15 and
    17 years old at evaluation. These are ascertained cases and do not
    establish a population frequency.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:35044787
    reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: we identified that homozygous truncating mutations in the gene encoding Bcl-2–associated athanogene (BAG) co-chaperone 5 (BAG5) caused inherited DCM in five patients among four unrelated families with complete penetrance.
    explanation: DCM in all five founding patients.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Probands were two brothers, III-4 and III-5, aged 17 and 15 years, whose cardiological evaluations showed definite DCM with left ventricular ejection fraction (LVEF) by echocardiography of 40% and 36%, respectively
    explanation: DCM with ages at evaluation in an independent family.
- name: Reduced Left Ventricular Ejection Fraction
  category: Cardiovascular
  description: >-
    LVEF of 36-46% in the three genotyped Middle Eastern siblings; the
    Japanese patients are described as having severe left ventricular
    dysfunction. One sibling had normal LV size with mildly reduced LVEF,
    showing variable expressivity.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: III-2 had normal LV size (end-diastolic volume 90.4 mL) with mild LV dysfunction (LVEF 46%) and mild to moderate LV global hypokinesia on cardiac MRI.
    explanation: A milder affected sibling.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: BACKGROUND
    snippet: These patients presented with severe left ventricular dysfunction, early-onset heart failure symptoms, and a high incidence of refractory ventricular arrhythmias.
    explanation: Severe dysfunction in the founding cohort, as summarized.
- name: Left Ventricular Dilatation
  category: Cardiovascular
  description: The proband of the Middle Eastern family had a left ventricular end-diastolic dimension of 5.8 cm (Z score +4.8).
  phenotype_term:
    preferred_term: Left ventricular dilatation
    term:
      id: HP:4000141
      label: Left ventricular dilatation
  evidence:
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: echocardiographic images of the proband (III-4) showing dilated left ventricle (LV) with end-diastolic dimension (EDD) of 5.8 cm
    explanation: Measured LV dilatation in the proband.
- name: Ventricular Arrhythmia
  category: Cardiovascular
  description: >-
    Ventricular arrhythmias, often refractory, are a prominent feature in the
    Japanese patients, and the Middle Eastern siblings were described as
    affected by DCM and arrhythmia. The specific rhythms (ventricular
    tachycardia or fibrillation) are reported in case reports whose text could
    not be retrieved, so the general term is used.
  phenotype_term:
    preferred_term: Ventricular arrhythmia
    term:
      id: HP:0004308
      label: Ventricular arrhythmia
  evidence:
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: BACKGROUND
    snippet: These patients presented with severe left ventricular dysfunction, early-onset heart failure symptoms, and a high incidence of refractory ventricular arrhythmias.
    explanation: Refractory ventricular arrhythmias in the founding cohort.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: BACKGROUND
    snippet: Both patients presented with advanced heart failure and experienced severe ventricular arrhythmias.
    explanation: Severe ventricular arrhythmias in the compound-heterozygous patients.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    Advanced heart failure is typical. The founding report's title states that
    the disease required heart transplantation; one Middle Eastern sibling
    died at 12 years while awaiting transplantation.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: BACKGROUND
    snippet: Both patients presented with advanced heart failure and experienced severe ventricular arrhythmias.
    explanation: Advanced heart failure in the compound-heterozygous patients.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: III-6 passed away at the age of 12 years old while waiting for a heart transplantation.
    explanation: Death from end-stage disease awaiting transplant; this sibling was not genotyped.
- name: Decreased QRS Voltage
  category: Cardiovascular
  description: Low limb-lead voltage in all three genotyped affected siblings of one family; not reported for other families.
  phenotype_term:
    preferred_term: Decreased QRS voltage
    term:
      id: HP:0025077
      label: Decreased QRS voltage
  evidence:
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Electrocardiogram (ECG) assessments showed that all available patients, III-2, III-4, and III-5 had a low voltage of the limb lead, T wave inversion in the infero-lateral leads, and poor R progression in precordial leads.
    explanation: ECG finding in three affected siblings.
- name: T-wave Inversion
  category: Cardiovascular
  description: Inferolateral T-wave inversion in all three genotyped affected siblings of one family.
  phenotype_term:
    preferred_term: T-wave inversion
    term:
      id: HP:0010872
      label: T-wave inversion
  evidence:
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Electrocardiogram (ECG) assessments showed that all available patients, III-2, III-4, and III-5 had a low voltage of the limb lead, T wave inversion in the infero-lateral leads, and poor R progression in precordial leads.
    explanation: ECG finding in three affected siblings.
- name: Poor R-wave Progression
  category: Cardiovascular
  description: Poor precordial R-wave progression in all three genotyped affected siblings of one family.
  phenotype_term:
    preferred_term: Poor R-wave progression
    term:
      id: HP:6001161
      label: Poor R-wave progression
  evidence:
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Electrocardiogram (ECG) assessments showed that all available patients, III-2, III-4, and III-5 had a low voltage of the limb lead, T wave inversion in the infero-lateral leads, and poor R progression in precordial leads.
    explanation: ECG finding in three affected siblings.
genetic:
- name: BAG5
  gene_term:
    preferred_term: BAG5
    term:
      id: hgnc:941
      label: BAG5
  variant_origin: GERMLINE
  association: >-
    Autosomal recessive DCM gene supported by about seven families: four
    Japanese families (five homozygous patients) in the founding report, two
    unrelated compound-heterozygous Japanese patients known here only from a
    secondhand summary, and one consanguineous Middle Eastern family with
    three affected genotyped siblings. Two recurrent nonsense alleles
    (p.Arg197Ter, p.Arg390Ter) appear in several Japanese families.
  notes: >-
    ClinGen classifies BAG5 for the broader term dilated cardiomyopathy
    (MONDO:0005021), autosomal recessive, Moderate (2024-06-14). Because that
    record is not for MONDO:0030680 or an exact-match term,
    gene_disease_validity is left empty. relationship_type is left unset
    because the schema defines CAUSATIVE as ClinGen Definitive or Strong, and
    ClinGen rates BAG5 Moderate (AR) under the parent term. The 2026 ClinGen DCM panel
    reassessment lists BAG5 among newly assessed high-evidence genes, a
    category that includes Moderate. Heterozygous truncating BAG5 variants
    were also reported in three patients with tachycardia-induced
    cardiomyopathy; that is a separate, unconfirmed susceptibility claim and
    not part of CMD2F.
  evidence:
  - reference: PMID:35044787
    reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: we identified that homozygous truncating mutations in the gene encoding Bcl-2–associated athanogene (BAG) co-chaperone 5 (BAG5) caused inherited DCM in five patients among four unrelated families with complete penetrance.
    explanation: Founding gene-disease report.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Exome and Sanger sequencing identified a novel BAG5 variant, c.444_445delGA (p.Lys149AsnfsTer6), homozygous in affected siblings and heterozygous in parents and unaffected siblings.
    explanation: Independent replication with a different truncating allele.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: BACKGROUND
    snippet: Subsequently, Inoue et al. reported two unrelated cases of DCM caused by compound heterozygous truncating variants in BAG5.
    explanation: Secondhand account of a further report.
  - reference: CGGV:assertion_97fe83b7-fe12-4014-9706-6847446fa9bd-2024-06-14T160000.000Z
    reference_title: BAG5 / dilated cardiomyopathy (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: BAG5 | HGNC:941 | dilated cardiomyopathy | MONDO:0005021 | AR | Moderate
    explanation: ClinGen Moderate for the broader dilated cardiomyopathy term; not copied into gene_disease_validity because the MONDO term differs.
  - reference: PMID:42708185
    reference_title: An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: 'Nine newly assessed genes were classified as high evidence: BAG5, FLII, LMOD2, MYLK3, MYZAP, NRAP, PPA2, PPP1R13L, and RPL3L.'
    explanation: Expert-panel reassessment places BAG5 in the high-evidence group.
  - reference: PMID:35044787
    reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: We also identified heterozygous truncating mutations in three patients with tachycardia-induced cardiomyopathy, a reversible DCM subtype associated with abnormal calcium homeostasis.
    explanation: A heterozygous susceptibility observation in a different phenotype; it neither supports nor refutes the recessive CMD2F relationship.
prevalence:
- population: Reported patients
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    About ten genotyped patients from about seven families have been published
    (five homozygous patients from four Japanese families, two
    compound-heterozygous Japanese patients known secondhand, and three
    homozygous siblings from one Middle Eastern family), plus one deceased
    ungenotyped sibling. A case report of refractory arrhythmia (2022) may
    overlap the founding cohort. GenCC counts about 12 cases; the difference
    from the 10 genotyped patients counted here may reflect the 2022 case
    report or heterozygous carriers. This is a publication count, not a
    population prevalence.
  evidence:
  - reference: PMID:35044787
    reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: we identified that homozygous truncating mutations in the gene encoding Bcl-2–associated athanogene (BAG) co-chaperone 5 (BAG5) caused inherited DCM in five patients among four unrelated families with complete penetrance.
    explanation: Founding case count.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The analysis involved three siblings affected by DCM and arrhythmia, along with their four unaffected siblings, their unaffected father, and their mother who exhibited arrhythmia.
    explanation: Case count in the second independent family.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: BACKGROUND
    snippet: Subsequently, Inoue et al. reported two unrelated cases of DCM caused by compound heterozygous truncating variants in BAG5.
    explanation: Further cases known from a secondhand summary.
progression:
- phase: Adolescent or young-adult presentation
  age_range: 12-17 years in the Middle Eastern family
  notes: >-
    The Middle Eastern probands were evaluated at 15 and 17 years with
    established DCM; a younger sibling died at 12 years. Ages at onset for the
    Japanese patients are described as early onset but are not given in the
    retrievable abstracts.
  evidence:
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Probands were two brothers, III-4 and III-5, aged 17 and 15 years, whose cardiological evaluations showed definite DCM with left ventricular ejection fraction (LVEF) by echocardiography of 40% and 36%, respectively
    explanation: Ages at evaluation in one family.
- phase: Advanced heart failure
  notes: >-
    Progression to advanced heart failure with ventricular arrhythmias is
    reported in the Japanese patients, and one Middle Eastern sibling died at
    12 years awaiting transplantation. No natural-history cohort or survival
    statistics exist.
  evidence:
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: III-6 passed away at the age of 12 years old while waiting for a heart transplantation.
    explanation: Fatal outcome before transplantation.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: BACKGROUND
    snippet: Both patients presented with advanced heart failure and experienced severe ventricular arrhythmias.
    explanation: Advanced disease in the compound-heterozygous patients.
diagnosis:
- name: Genomic testing for biallelic BAG5 variants
  description: >-
    Exome sequencing with Sanger confirmation and family segregation
    identified the reported variants. BAG5 should be included when testing
    early-onset DCM, keeping in mind that ClinGen rates BAG5 Moderate (AR) for
    DCM broadly and that BAG3 is a different gene.
  evidence:
  - reference: PMID:35044787
    reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: Our study suggests that loss-of-function mutations in BAG5 can cause DCM, that BAG5 may be a target for genetic testing in cases of DCM, and that gene therapy may potentially be a treatment for this disease.
    explanation: The authors recommend including BAG5 in DCM genetic testing.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Exome and Sanger sequencing identified a novel BAG5 variant, c.444_445delGA (p.Lys149AsnfsTer6), homozygous in affected siblings and heterozygous in parents and unaffected siblings.
    explanation: Exome plus Sanger sequencing with segregation.
  - 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
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Molecular genetic testing should be offered to every individual of any age with nonischemic DCM
    explanation: General GeneReviews DCM guidance; it does not name BAG5.
- name: Echocardiography and electrocardiography
  description: >-
    Echocardiography documents LV dilatation and reduced ejection fraction;
    cardiac MRI was used in a milder sibling. ECGs in one family showed low
    limb-lead voltage, inferolateral T-wave inversion and poor R-wave
    progression; these are not specific diagnostic markers.
  evidence:
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: III-2 had normal LV size (end-diastolic volume 90.4 mL) with mild LV dysfunction (LVEF 46%) and mild to moderate LV global hypokinesia on cardiac MRI.
    explanation: Imaging modalities used in the family.
- name: Family assessment
  description: >-
    Offer genetic counselling, carrier testing and cardiac screening of
    siblings of an affected individual. General GeneReviews DCM advice applies;
    there is no BAG5-specific surveillance interval.
  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
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Cardiovascular screening of asymptomatic first-degree family members of an individual with DCM can allow early detection of DCM, prompt initiation of treatment, and improvement in long-term outcome
    explanation: General familial DCM guidance; not BAG5 specific.
treatments:
- name: Beta-blocker therapy
  description: >-
    Standard heart-failure beta-blockade for left ventricular systolic
    dysfunction. Beta-blockade is mechanistically attractive because the mouse
    phenotype is provoked by catecholamines, but no BAG5-specific treatment
    data exist.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Left Ventricular Dilatation and Systolic Dysfunction
    description: Supportive heart-failure therapy; does not correct the BAG5 defect.
  evidence:
  - reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    reference_title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: In children with systemic LV systolic dysfunction, use of β-blockers is reasonable
    explanation: General pediatric heart-failure guidance extrapolated to adolescents with CMD2F; not genotype-specific trial evidence.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Beta-Adrenergic Antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
- name: ACE inhibitor therapy
  description: Standard ACE inhibition for left ventricular systolic dysfunction; no BAG5-specific data.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Left Ventricular Dilatation and Systolic Dysfunction
    description: Supportive heart-failure therapy; does not correct the BAG5 defect.
  evidence:
  - reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    reference_title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: In children with left ventricular systolic dysfunction, ACE inhibitors should be routinely used unless there is a specific contraindication
    explanation: General pediatric heart-failure guidance extrapolated to CMD2F.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE Inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
- name: Implantable cardioverter-defibrillator
  description: >-
    An ICD is a standard consideration for sudden-death prevention in DCM with
    ventricular arrhythmias. No retrievable source documents ICD use or
    outcomes in CMD2F.
  therapeutic_modality: DEVICE
  notes: No cached source documents ICD use in BAG5 patients; included as standard care for ventricular arrhythmia in DCM without evidence items.
  target_mechanisms:
  - target: Ventricular Arrhythmia
    description: Terminates life-threatening ventricular arrhythmias; does not prevent them.
  treatment_term:
    preferred_term: Implantable Cardioverter-Defibrillator Placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
- name: Left ventricular assist device
  description: >-
    Mechanical circulatory support as a bridge to transplantation for advanced
    heart failure. The founding report is said to have used LVADs, but the
    retrievable abstract does not state this.
  therapeutic_modality: DEVICE
  notes: No retrievable snippet documents LVAD use in CMD2F; included as standard advanced heart-failure care without evidence items.
  target_mechanisms:
  - target: Congestive Heart Failure
    description: Supports circulation in end-stage heart failure.
  treatment_term:
    preferred_term: Left Ventricular Assist Device Insertion
    term:
      id: NCIT:C172327
      label: Left Ventricular Assist Device Insertion
- name: Heart transplantation
  description: >-
    Definitive therapy for end-stage disease. The founding report's title
    describes CMD2F as requiring heart transplantation, and one sibling died
    awaiting transplantation. Transplant outcomes specific to BAG5 have not
    been reported.
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Congestive Heart Failure
    description: Replaces the failing heart.
  evidence:
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: III-6 passed away at the age of 12 years old while waiting for a heart transplantation.
    explanation: Transplantation was the planned therapy for an affected child.
  - reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    reference_title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: In patients with severe acute HF, it is reasonable to initiate transfer to a center with pediatric HF specialists who have the expertise and ability to optimize medical therapy, evaluate for heart transplantation, and provide mechanical support
    explanation: General guidance on referral for transplant evaluation; not BAG5 specific.
  treatment_term:
    preferred_term: Heart Transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
- name: Genetic counseling
  description: >-
    Discuss autosomal recessive recurrence (25% for each pregnancy of two
    carrier parents, a Mendelian calculation), carrier testing in
    consanguineous families, and cardiac screening of at-risk siblings.
  therapeutic_modality: OTHER
  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
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Cardiovascular screening of asymptomatic first-degree family members of an individual with DCM can allow early detection of DCM, prompt initiation of treatment, and improvement in long-term outcome
    explanation: General familial DCM guidance.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: AAV9 BAG5 gene replacement (preclinical)
  description: >-
    An AAV9 vector carrying wild-type BAG5 fully ameliorated the DCM
    phenotypes of Bag5 mutant knock-in mice. This is a preclinical mouse
    result; no human trial exists.
  therapeutic_modality: GENE_THERAPY
  target_mechanisms:
  - target: Loss of BAG5 Protein
    description: Restores wild-type BAG5 in the mouse heart.
  evidence:
  - reference: PMID:35044787
    reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Bag5 mutant knock-in mice exhibited ventricular dilatation, arrhythmogenicity, and poor prognosis under catecholamine stimulation, recapitulating the human DCM phenotype, and administration of an adeno-associated virus 9 vector carrying the wild-type BAG5 gene could fully ameliorate these DCM phenotypes.
    explanation: Mouse rescue, not human efficacy.
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
animal_models:
- name: Bag5 truncating knock-in mouse (catecholamine stress)
  species: Mouse
  genotype: Bag5 mutant knock-in modelling a patient truncating allele
  publication: PMID:35044787
  description: >-
    Knock-in mice develop ventricular dilatation, arrhythmogenicity and poor
    survival under catecholamine stimulation, with junctional membrane complex
    disruption and calcium-handling abnormalities in cardiomyocytes. AAV9
    wild-type BAG5 rescues the phenotype. The exact allele and baseline
    phenotype are not given in the retrievable abstract.
  modeled_mechanisms:
  - target: Junctional Membrane Complex Disruption
    model_scale: CELLULAR
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Mutant cardiomyocytes lose functional JMC proteins and JMC structure under catecholamine stimulation.
    limitations: Requires catecholamine stimulation; not measured in patient myocardium.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Mouse cardiomyocytes under pharmacological adrenergic stress; whether patient myocardium shows the same JMC loss without an exogenous trigger is unknown.
    evidence:
    - reference: PMID:35044787
      reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: Bag5-mutant mouse cardiomyocytes exhibited decreased abundance of functional JMC proteins under catecholamine stimulation, disrupted JMC structure, and calcium handling abnormalities.
      explanation: Direct model observation.
  - target: Left Ventricular Dilatation and Systolic Dysfunction
    model_scale: ORGANISM
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Ventricular dilatation, arrhythmogenicity and poor prognosis under catecholamine stimulation, rescued by AAV9-BAG5.
    limitations: Stress-provoked; the human disease has no identified exogenous trigger.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: The mouse phenotype appears under catecholamine stimulation, whereas patients develop DCM without a documented trigger.
    evidence:
    - reference: PMID:35044787
      reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: Bag5 mutant knock-in mice exhibited ventricular dilatation, arrhythmogenicity, and poor prognosis under catecholamine stimulation, recapitulating the human DCM phenotype, and administration of an adeno-associated virus 9 vector carrying the wild-type BAG5 gene could fully ameliorate these DCM phenotypes.
      explanation: Organism-level recapitulation and rescue.
- name: Bag5 p.Lys149fs-equivalent knock-in mouse (ER stress)
  species: Mouse
  genotype: Bag5 two-nucleotide deletion (delCA) in exon 3 corresponding to human c.444_445delGA, C57BL/6N
  publication: PMID:38796549
  description: >-
    Homozygous knock-ins lack cardiac Bag5 protein yet are normal to 12 months
    and on treadmill testing. After tunicamycin they show reduced LVEF and
    LVFS and more apoptotic cardiomyocytes, and male knock-ins show sinus
    pauses. Groups were three mice per sex and genotype; apoptosis and
    immunoblots used one heart per group.
  modeled_mechanisms:
  - target: Cardiomyocyte Apoptosis
    model_scale: TISSUE
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: More TUNEL-positive cells in tunicamycin-treated homozygous hearts.
    limitations: One heart per genotype and sex; tunicamycin is a pharmacological ER stressor; no apoptosis data from patients.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Apoptosis was induced by tunicamycin in mice; ER stress or apoptosis has not been measured in patient myocardium.
    evidence:
    - reference: PMID:38796549
      reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: Their cardiac tissues exhibited a notable increase in apoptotic cells, despite non-distinctive changes in CHOP and GRP78 levels.
      explanation: Direct model observation.
  - target: Left Ventricular Dilatation and Systolic Dysfunction
    model_scale: ORGANISM
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Reduced LVEF and LVFS only after tunicamycin; no baseline cardiomyopathy up to 12 months.
    limitations: The unstressed knock-in has no cardiac phenotype, unlike patients; no histological abnormality was evident after tunicamycin.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Patients develop spontaneous DCM in adolescence, while the mouse shows systolic dysfunction only after a pharmacological ER stressor.
    evidence:
    - reference: PMID:38796549
      reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: However, following TN injection, Bag5-/- mice exhibited significantly reduced left ventricular fractional shortening (LVFS) and ejection fraction (LVEF).
      explanation: Stress-provoked systolic dysfunction.
    - reference: PMID:38796549
      reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: Bag5-/- mice displayed no abnormalities up to 12 months old and showed no anomalies during an exercise stress test.
      explanation: Without stress the model does not reproduce spontaneous DCM.
discussions:
- discussion_id: cmd2f_small_evidence_base
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: How representative is the reported CMD2F phenotype, given that it rests on about seven families, two of them known here only secondhand?
  attaches_to:
  - genetic#BAG5
  rationale: >-
    Five founding patients, two compound-heterozygous patients summarized by
    a later paper, and three genotyped siblings in one consanguineous family
    make up the clinical record. The case report of refractory arrhythmia and
    the compound-heterozygous report could not be retrieved, and patient
    counts may overlap. Phenotype frequencies, penetrance and prognosis
    cannot be estimated from these data.
  evidence:
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: BACKGROUND
    snippet: Notably, all individuals carrying homozygous or compound heterozygous BAG5 variants developed DCM, highlighting a strong genotype–phenotype correlation.
    explanation: The penetrance claim rests on a handful of patients.
- discussion_id: cmd2f_stress_dependent_mouse_models
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Patients develop DCM without a known trigger, but both knock-in mice need an exogenous stressor; which mechanism, if either, operates in human myocardium?
  attaches_to:
  - pathophysiology#Junctional Membrane Complex Disruption
  - pathophysiology#Impaired Cardiomyocyte ER Stress Response
  - pathophysiology#Cardiomyocyte Apoptosis
  rationale: >-
    One mouse needs catecholamine stimulation and the other tunicamycin to
    show cardiac dysfunction; the unstressed p.Lys149fs-equivalent mouse is
    normal to 12 months. The ER-stress study found no genotype difference in
    CHOP or GRP78 and used one heart per group for apoptosis. Arrhythmia
    appeared only in male mice, whereas ECG changes among human carriers
    appeared only in females. Patient-derived cardiomyocytes or explanted
    myocardium would be needed to tell the branches apart.
  evidence:
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Bag5-/- mice displayed no abnormalities up to 12 months old and showed no anomalies during an exercise stress test.
    explanation: The unstressed model lacks the human phenotype.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Interestingly, only Bag5 KI male mice demonstrated arrhythmia, which was more pronounced in Bag5-/- than in Bag5+/-males.
    explanation: Sex pattern opposite to that seen in human carriers.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: These findings suggest that BAG5 might potentially exert a protective role in mitigating ER stress-induced cardiomyocyte apoptosis through alternative pathways, possibly involving ATF6 or XBP1, warranting further exploration.
    explanation: The ER-stress effector pathway is unresolved.
  proposed_experiments:
  - experiment_id: exp_cmd2f_ipsc_cardiomyocytes
    name: Compare JMC integrity, calcium transients and ER-stress apoptosis in BAG5-null iPSC cardiomyocytes
    description: >-
      Derive iPSC cardiomyocytes from a biallelic BAG5 patient with isogenic
      corrected controls. Measure junctional membrane complex protein
      abundance and calcium transients with and without isoproterenol, and
      apoptosis and UPR branch activation (ATF6, XBP1 splicing) with and
      without tunicamycin, to test which branch is present without in vivo
      stress.
- discussion_id: cmd2f_heterozygous_carriers
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Do heterozygous BAG5 truncating variants carry any cardiac risk?
  attaches_to:
  - genetic#BAG5
  rationale: >-
    Heterozygous truncations were reported in three patients with
    tachycardia-induced cardiomyopathy, and two of three female heterozygous
    relatives in one family had borderline ECG changes. Both observations are
    small and unconfirmed, and they are not part of the recessive CMD2F
    phenotype.
  evidence:
  - reference: PMID:35044787
    reference_title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: We also identified heterozygous truncating mutations in three patients with tachycardia-induced cardiomyopathy, a reversible DCM subtype associated with abnormal calcium homeostasis.
    explanation: Possible heterozygous susceptibility in a different phenotype.
  - reference: PMID:38796549
    reference_title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: suggesting a potential predisposition to arrhythmia in female carriers of the BAG5 variant.
    explanation: Based on two female carriers with borderline ECG changes.
references:
- reference: PMID:35044787
  title: Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
- reference: PMID:38796549
  title: A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
- reference: PMID:26729625
  title: GRP78 Interacting Partner Bag5 Responds to ER Stress and Protects Cardiomyocytes From ER Stress-Induced Apoptosis.
- reference: PMID:20223214
  title: The C-terminal BAG domain of BAG5 induces conformational changes of the Hsp70 nucleotide-binding domain for ADP-ATP exchange.
- reference: PMID:42708185
  title: An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy.
- reference: CGGV:assertion_97fe83b7-fe12-4014-9706-6847446fa9bd-2024-06-14T160000.000Z
  title: BAG5 / dilated cardiomyopathy (Moderate)
- 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
  findings:
  - statement: Full GeneReviews chapter Dilated Cardiomyopathy Overview (NBK1309), used for general family assessment. It does not discuss BAG5.
- reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
  title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
  findings:
  - statement: The 2025 ISHLT pediatric heart-failure guideline, used for general supportive care; it does not establish BAG5-specific efficacy.
notes: >-
  BAG5 (hgnc:941) is distinct from BAG3, an autosomal dominant DCM gene; no
  BAG3 evidence is used here. Two primary reports could not be quoted because
  their text was unavailable to the reference fetcher: Inoue et al. 2023
  (PMID:37873655, compound heterozygous BAG5 variants) and Hakui et al. 2022
  (PMID:36130910, refractory ventricular arrhythmias); their content enters
  only through the summary in PMID:38796549. The ClinGen BAG5 assertion
  (Moderate, AR) is for MONDO:0005021 and is therefore not recorded in
  gene_disease_validity. GeneReviews check (just check-genereviews --online,
  2026-10-08) found no BAG5- or CMD2F-specific GeneReviews or StatPearls
  chapter; the general Dilated Cardiomyopathy Overview (NBK1309) is used
  only for family-assessment guidance. Supportive treatments are extrapolated
  from general heart-failure guidance.
📚

References & Deep Research

References

8
PMID:35044787
Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
No top-level findings curated for this source.
PMID:38796549
A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.
No top-level findings curated for this source.
PMID:26729625
GRP78 Interacting Partner Bag5 Responds to ER Stress and Protects Cardiomyocytes From ER Stress-Induced Apoptosis.
No top-level findings curated for this source.
PMID:20223214
The C-terminal BAG domain of BAG5 induces conformational changes of the Hsp70 nucleotide-binding domain for ADP-ATP exchange.
No top-level findings curated for this source.
PMID:42708185
An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy.
No top-level findings curated for this source.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
1 finding
Full GeneReviews chapter Dilated Cardiomyopathy Overview (NBK1309), used for general family assessment. It does not discuss BAG5.
url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
1 finding
The 2025 ISHLT pediatric heart-failure guideline, used for general supportive care; it does not establish BAG5-specific efficacy.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Cardiomyopathy_Dilated_2F · 2026-10-08T18:58:06Z · View source

Curated CMD2F (MONDO:0030680, BAG5, OMIM 619747; claim issue #13719) from the claude_code deep-research report (falcon fallback). Mechanism chain: biallelic BAG5 truncating variants -> loss of BAG5 protein -> impaired HSC70 nucleotide exchange -> junctional membrane complex disruption -> abnormal cardiomyocyte calcium handling -> ventricular arrhythmia and LV dilatation/systolic dysfunction; parallel hypothetical ER-stress branch -> cardiomyocyte apoptosis. Key PMIDs: 35044787 (Hakui 2022, 5 patients/4 families, knock-in mouse, AAV9 rescue), 38796549 (Wongong 2024, 3 siblings/1 family, ER-stress knock-in mouse), 26729625 (Gupta 2016, rat cardiomyocytes), 20223214 (Arakawa 2010, BAG5 NEF biochemistry), 42708185 (ClinGen DCM reassessment 2026). ClinGen CGGV BAG5 assertion is for MONDO:0005021 (Moderate AR), so gene_disease_validity left empty. PMID:37873655 (Inoue 2023) and PMID:36130910 (Hakui 2022 Circ J) had no retrievable text; not cited. 8 phenotypes. GeneReviews check: only the general DCM Overview (NBK1309) applies. Validation: just validate passed; count-verified-snippets 77/77; entity-refs, causal-targets, enum-values, duplicate-keys OK; model-scale-audit 4 links scale-determined. Review fixes: added BAG5 gene to the HSC70 node (gene-activity grounding gate); added LV-dysfunction edges to Reduced LVEF and LV Dilatation phenotypes (5/8 phenotypes connected, ECG findings left unconnected); JMC->calcium and calcium->arrhythmia edges set to INDIRECT_UNKNOWN_INTERMEDIATES; inheritance evidence now the BAG5 CGGV row (OTHER, INDIRECT) instead of the Jordan 2026 sentence; rat siRNA and JMC-localization items set INDIRECT; relationship_type CAUSATIVE removed (ClinGen Moderate AR under parent term); added GeneReviews genetic-testing snippet, ClinGen-qualified validity wording, and GenCC ~12-case note. Age-34 onset not added (no cached source). count-verified-snippets 80/80.

Claude Code ▸
Cardiomyopathy, Dilated, 2F (CMD2F; BAG5-related autosomal recessive dilated cardiomyopathy): research report
claude-haiku-5-5, claude-opus-5-5 17 citations 2026-10-08T14:34:18.049153

Let me fetch the primary abstracts for exact quotes and PMIDs.

I'm pulling the BAG5/CMD2F primary papers into the reference cache so the report can quote their exact wording. Next I'll read them.

Reading the cached Gupta 2016 paper and confirming the BAG5–Hsp70 structural paper; the report comes after that.

Cardiomyopathy, Dilated, 2F (CMD2F; BAG5-related autosomal recessive dilated cardiomyopathy): research report

Prepared 2026-10-08 for the dismech entry kb/disorders/Cardiomyopathy_Dilated_2F.yaml. Quotes marked "verbatim" are copied from cached abstracts or full texts in references_cache/. Ontology terms marked ✔ were checked against the local cache/<prefix>/terms.csv label caches. Those caches confirm that a CURIE exists and has that label. They do not confirm membership in a dynamic enum.

Summary

CMD2F is a rare, early-onset, severe dilated cardiomyopathy. It is caused by biallelic loss-of-function (truncating) variants in BAG5 (hgnc:941 ✔). BAG5 encodes a five-BAG-domain co-chaperone that acts as a nucleotide exchange factor for HSC70/Hsp70. Patients present in the teens or twenties with severe systolic dysfunction and refractory ventricular arrhythmias. Many progress to an LVAD or heart transplantation.

Two mechanisms have been proposed, both from mouse work: - Junctional membrane complex and calcium-handling failure under catecholamine stress (Hakui 2022). - An impaired cardiomyocyte ER-stress response leading to apoptosis (Wongong 2024; Gupta 2016).

AAV9-BAG5 gene replacement rescued the knock-in mouse phenotype. About 12 cases from roughly 7 families have been published, so the evidence base is small.

1. Disease information

Field Value Source / status
MONDO MONDO:0030680 "cardiomyopathy, dilated, 2F" ✔ local MONDO cache
OMIM phenotype 619747 (CMD2F) secondary sources (MGI disease page, DrugMap); confirm on OMIM
OMIM gene 603885 (BAG5) PanelApp Australia via search snippet; confirm
DOID DOID:0081162 Disease Ontology
Orphanet No disease-specific ORPHA code found Probably sits under familial isolated DCM; not verified
ICD-10-CM / ICD-11 No specific code. Generic DCM codes apply (ICD-10 I42.0) —
Synonyms CMD2F; BAG5-related dilated cardiomyopathy; autosomal recessive DCM due to BAG5 deficiency —
Gene locus 14q32 (per DOID) —

All information comes from aggregated case reports and family studies. There is no EHR- or registry-level data.

Grouping context: CMD2F belongs to the recessive "CMD2" series (2A TNNI3, 2B GATAD1, 2C PPCS, 2D RPL3L, …), and to the BAG family of cardiomyopathy genes alongside BAG3 (autosomal dominant CMD1HH). The 2026 ClinGen DCM reassessment lists BAG5 among nine newly assessed genes classified as high evidence (PMID:42708185):

"Nine newly assessed genes were classified as high evidence: BAG5, FLII, LMOD2, MYLK3, MYZAP, NRAP, PPA2, PPP1R13L, and RPL3L. Twelve genes (11 newly appraised) were rated as high evidence with an autosomal recessive (AR) MOI." (verbatim)

2. Etiology

Primary cause: biallelic germline truncating BAG5 variants (PMID:35044787):

"we identified that homozygous truncating mutations in the gene encoding Bcl-2–associated athanogene (BAG) co-chaperone 5 (BAG5) caused inherited DCM in five patients among four unrelated families with complete penetrance." (verbatim)

Genetic risk factors - Biallelic truncation is the cause: homozygous, or compound heterozygous as in Inoue 2023 (PMID:37873655). - Heterozygous truncation may predispose to tachycardia-induced cardiomyopathy, but this has not been established. PMID:35044787 reports:

"We also identified heterozygous truncating mutations in three patients with tachycardia-induced cardiomyopathy, a reversible DCM subtype associated with abnormal calcium homeostasis." (verbatim)

This is a separate, susceptibility-level claim. Do not fold it into the CMD2F inheritance block. - Heterozygous carriers were clinically unaffected in Hakui 2022. In Wongong 2024, two of three female heterozygous relatives had mild or borderline ECG abnormalities (PMID:38796549):

"suggesting a potential predisposition to arrhythmia in female carriers of the BAG5 variant." (verbatim)

Environmental and stress modifiers. These are inferred from mouse models only: - Catecholamine (β-adrenergic) stimulation unmasked dilatation, arrhythmia and death in Bag5 knock-in mice (PMID:35044787). - ER stress (tunicamycin) was required to reveal systolic dysfunction in a second knock-in line (PMID:38796549):

"To develop DCM in Bag5 point mutant KI mice, ER stress is required." (verbatim; full-text Discussion)

The equivalent human triggers have not been identified. Tachyarrhythmia, adrenergic surges and intercurrent illness are plausible candidates but unproven.

Protective factors and gene-environment interactions: none reported in humans. The mouse data suggest a gene × adrenergic/ER-stress interaction, which is a hypothesis.

3. Phenotypes

Phenotype HPO (✔ = cache-verified) Onset / frequency Key evidence
Dilated cardiomyopathy HP:0001644 ✔ Second decade in 4 of 5, age 34 in 1 (Hakui cohort, per PanelApp); ages 12–17 in Wongong family; 100% of biallelic cases PMID:35044787; PMID:38796549
Reduced LVEF HP:0012664 ✔ All. LVEF 36–46% in the Thai/Middle Eastern sibship; "severely reduced" in the Japanese cases PMID:38796549 (verbatim: "definite DCM with left ventricular ejection fraction (LVEF) by echocardiography of 40% and 36%, respectively")
Left ventricular dilatation Use DCM term, or check "Left ventricular dilatation" in HPO Proband LVEDD 5.8 cm, Z +4.8 PMID:38796549
Ventricular arrhythmia (refractory VT/VF) HP:0004308 ✔ / HP:0004756 ✔ / HP:0001663 ✔ Frequent, a defining feature PMID:36130910 (Hakui 2022 Circ J case; no abstract cached); PMID:37873655
Congestive heart failure, advanced HP:0001635 ✔ All Japanese cases needed an LVAD; at least one was transplanted PMID:35044787 title; PanelApp
Sudden cardiac death / death awaiting transplant HP:0001645 ✔ One sibling died at 12 years awaiting transplant PMID:38796549 (verbatim: "III-6 passed away at the age of 12 years old while waiting for a heart transplantation.")
ECG abnormalities (low limb-lead voltage, inferolateral T-wave inversion, poor R progression) HP:0003115 Abnormal EKG ✔ (more specific HPO terms should be looked up) 3 of 3 affected siblings PMID:38796549 (verbatim: "all available patients, III-2, III-4, and III-5 had a low voltage of the limb lead, T wave inversion in the infero-lateral leads, and poor R progression in precordial leads")
Elevated BNP Laboratory finding. LOINC BNP / NT-proBNP; HPO term to look up Reported in the Japanese cases PanelApp summary (secondary)
  • Severity: severe and progressive. Wongong 2024 describes "consistently severe manifestations of the disease."
  • Quality of life: no formal measures have been published. The burden is that of NYHA III–IV heart failure in adolescents and young adults, including an LVAD and/or transplant, an ICD and recurrent shocks.
  • Extracardiac features: none reported. Note that Bag5-null male mice are infertile (IMPC), but human fertility has not been studied.

4. Genetic and molecular information

Gene: BAG5 (BCL2-associated athanogene 5), hgnc:941 ✔, chromosome 14q32. RefSeq used by Wongong: NM_001015049.2.

Reported pathogenic alleles. Variant list per Wongong 2024 discussion (PMID:38796549, verbatim: "c.589C > T (p.Arg197Ter), c.1168C > T (p.Arg390Ter) and c.18dupA (p.His7ThrTer5)"):

Variant Type Zygosity / families Source
c.589C>T, p.Arg197Ter Nonsense Homozygous (Hakui 2022); compound heterozygous with p.Arg390Ter (Inoue 2023) PMID:35044787; PMID:37873655
c.1168C>T, p.Arg390Ter Nonsense Homozygous (Hakui 2022); compound heterozygous (Inoue 2023) same
c.18dupA, p.His7ThrfsTer5 Frameshift Homozygous (Hakui 2022) PMID:35044787
c.444_445delGA, p.Lys149AsnfsTer6 Frameshift Homozygous, 3 siblings, consanguineous Middle Eastern family; ClinVar VCV003918808.1 PMID:38796549

Caveats on this table - Wongong describes the Hakui variants as "de novo homozygous". That wording is almost certainly inaccurate, because homozygosity implies inheritance. Do not copy it. - The Inoue 2023 variant assignments come from Wongong's summary. The Inoue abstract could not be retrieved (PMID_37873655.md is cached as content_type: unavailable).

Other gene-level facts - ACMG/ClinGen: ClinGen Gene-Disease Validity, BAG5–dilated cardiomyopathy (MONDO:0005021), AR, Moderate, DCM GCEP, 2024-06-14 (cached CGGV:assertion_97fe83b7-…-2024-06-14T160000.000Z). Quotable row: BAG5 | HGNC:941 | dilated cardiomyopathy | MONDO:0005021 | AR | Moderate. - The assertion is for the broader DCM term, not MONDO:0030680. Under the repository's Gene-Disease Validity Is Copied, Never Assigned rule, check whether it counts as "this entry's disease" before recording it in gene_disease_validity. - GenCC also lists a Moderate AR submission. PanelApp Australia rates BAG5 Green. - Variant class / functional consequence: all reported alleles are truncating. The proposed mechanism is loss of function. Hakui showed reduced protein; Wongong found Bag5 protein "completely absent" in knock-in hearts. Inoue reported reduced BAG5 and SERCA2 immunostaining in patient myocardium, per Wongong's summary. Suggested slot value: functional_impact_category: LOSS_OF_FUNCTION. - Origin: germline. - Allele frequency: not systematically reported. Wongong filtered at <1% in gnomAD and 1000 Genomes. Check gnomAD for p.Arg197Ter and p.Arg390Ter, because recurrence in Japanese families raises the possibility of a founder allele. This is unverified. - Modifier genes, epigenetics, chromosomal abnormalities: none reported. - Lesurf 2022 (npj Genomic Medicine 7:18, a whole-genome sequencing study of early-onset cardiomyopathy) is listed by GenCC as a BAG5 evidence source. Its BAG5-specific finding was not verified.

5. Environmental information

There is no environmental, lifestyle or infectious cause. The only "exposures" with data are experimental stressors in mice: isoproterenol/catecholamine and tunicamycin. These belong in animal_models or experimental_models, not in environmental:.

6. Mechanism and pathophysiology

Causal chain

  1. Biallelic truncating BAG5 variants lead to loss of BAG5 protein through nonsense-mediated decay or truncation. This is demonstrated in knock-in mouse hearts and inferred from reduced immunostaining in patient tissue.
  2. Loss of BAG5 leads to loss of nucleotide-exchange activity on HSC70/Hsp70, so ADP release slows and chaperone-mediated folding is less efficient. The biochemistry is demonstrated in vitro (Arakawa 2010, PMID:20223214; PMID:35044787: "BAG5 acts as a nucleotide exchange factor for heat shock cognate 71 kDa protein (HSC70), promoting adenosine diphosphate release and activating HSC70-mediated protein folding"). That this is the operative cardiac lesion is inferred.
  3. The pathway then branches:
  4. 3a. JMC/calcium branch (Hakui 2022, mouse plus cardiomyocytes). Under catecholamine stimulation, BAG5 deficiency leads to reduced abundance of functional junctional membrane complex (JMC) proteins and disrupted JMC structure, which results in abnormal Ca²⁺ handling. PMID:35044787 (verbatim): "BAG5 localized to junctional membrane complexes (JMCs), critical microdomains for calcium handling. Bag5-mutant mouse cardiomyocytes exhibited decreased abundance of functional JMC proteins under catecholamine stimulation, disrupted JMC structure, and calcium handling abnormalities."
    • The specific JMC proteins named in the full text (e.g., JPH2, RyR2, LTCC) were not verified from the abstract.
    • Human support for this branch is reduced SERCA2 in patient myocardium (Inoue 2023, as reported secondhand by Wongong).
  5. 3b. ER-stress branch (Wongong 2024; Gupta 2016). During ER stress, BAG5 normally stabilises GRP78 (HSPA5) and limits CHOP-mediated apoptosis (in vitro, rat cardiomyocytes). PMID:26729625 (verbatim): "Bag5 protein expression is significantly increased in the ER during ER stress and that this in turn modulates GRP78 protein stability and reduces ER stress." Without BAG5, ER stress leads to excess cardiomyocyte apoptosis (TUNEL in knock-in mice, n = 1 per genotype). PMID:38796549 (verbatim): "Their cardiac tissues exhibited a notable increase in apoptotic cells, despite non-distinctive changes in CHOP and GRP78 levels." The CHOP-independent result means the downstream effector is unresolved. The authors suggest ATF6 or XBP1, which is speculation.
  6. Ca²⁺ mishandling leads to triggered and re-entrant ventricular arrhythmias (mouse arrhythmogenicity under catecholamine stress; refractory VT/VF in patients). It also contributes to contractile dysfunction.
  7. Cardiomyocyte loss and contractile failure lead to LV dilatation and systolic dysfunction (DCM), then advanced heart failure (LVAD or transplant), and sudden death. The step from 3a/3b to DCM is shown in mice under stress. In humans it is inferred.

Which steps are upstream: steps 1–2 are upstream and certain. Branch 3a has the stronger evidence: a rescue experiment plus the arrhythmia phenotype. Branch 3b rests on small-n data. The two branches are not mutually exclusive.

Suggested annotations (✔ cache-verified)

Category Terms
Molecular function GO:0000774 adenyl-nucleotide exchange factor activity ✔
Biological processes GO:0006457 protein folding ✔; GO:0034976 response to endoplasmic reticulum stress ✔; GO:0030968 endoplasmic reticulum unfolded protein response ✔; GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress ✔; GO:0006874 intracellular calcium ion homeostasis ✔; GO:0010881 regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion ✔; GO:0060048 cardiac muscle contraction ✔
Cellular component GO:0014701 junctional sarcoplasmic reticulum membrane ✔ is the closest cached term to "JMC". Search GO for a better JMC term before binding.
Cell types CL:0000746 cardiac muscle cell ✔
Anatomy UBERON:0002084 heart left ventricle ✔; UBERON:0000948 heart ✔

Molecular profiling, single-cell, spatial and CRISPR data

None has been published for CMD2F. No GEO datasets were identified. The structural PDB entry 3A8Y covers the BAG5 BD5–Hsp70 NBD complex (Arakawa 2010).

7. Anatomical structures affected

  • Organ: the heart. The left ventricle is primary (UBERON:0002084 ✔). Right-ventricular involvement is not well described.
  • Tissue and cells: ventricular myocardium and cardiomyocytes (CL:0000746 ✔).
  • Subcellular: junctional membrane complexes (sarcolemma/T-tubule–junctional SR dyads) and the ER/SR. BAG5 also has reported mitochondrial and cytosolic roles in non-cardiac cells, which may not be relevant here.
  • Secondary organs: those affected by low-output heart failure.
  • Laterality: not applicable.

8. Temporal development

  • Onset: adolescence to young adulthood. The youngest reported death was at 12 years and the oldest diagnosis at 34. Onset is insidious, sometimes first noticed as an arrhythmia.
  • Progression: rapid and progressive toward advanced heart failure. Wongong describes "consistently severe" disease that is less variable than BAG3 DCM. There are no natural-history cohorts, and no remission has been reported.
  • Suggested progression: phases: preclinical (carrier or presymptomatic homozygote); symptomatic DCM with arrhythmia; advanced HF needing mechanical support or transplant.

9. Inheritance and population

  • Inheritance: autosomal recessive (HP:0000007 ✔), with complete penetrance in biallelic individuals (PMID:35044787).
  • Expressivity: severe but variable. In the Wongong sibship LVEF ranged from 36% to 46%, and one sibling had a normal LV size.
  • Heterozygotes: possible minor ECG findings in women, and possible susceptibility to tachycardia-induced cardiomyopathy. Both are unconfirmed.
  • Consanguinity: one Middle Eastern consanguineous family (PMID:38796549).
  • Populations: Japanese (Hakui and Inoue, Osaka and Tokyo) and Middle Eastern (studied in Thailand).
  • Prevalence: unknown, ultra-rare. About 12 published patients (GenCC counts 12 cases across 5 publications). Suggested encoding: measure_type: CASES_IN_LITERATURE.
  • Sex ratio, anticipation, mosaicism: not reported, and anticipation is not expected for this mechanism.

10. Diagnostics

  • Genetic testing: a DCM multigene panel, exome or genome sequencing. BAG5 is now on PanelApp Green lists, and Hakui 2022 recommends adding it to testing. Confirm biallelic status with parental segregation and Sanger sequencing. Truncating variants are well detected by exome sequencing.
  • Imaging: echocardiography (LVEDD Z-score, LVEF) and cardiac MRI (hypokinesia). LGE patterns have not been reported.
  • ECG and Holter: low limb-lead voltage, inferolateral T-wave inversion, poor R progression, and VT/VF.
  • Biomarkers: BNP/NT-proBNP elevated (non-specific).
  • Histology: reduced BAG5 and SERCA2 immunostaining in explanted myocardium (Inoue 2023). This is research-level, not diagnostic.
  • Differential diagnosis:
  • other recessive and early-onset DCMs: TNNI3-AR, GATAD1, RPL3L, NRAP, PPA2, PLEKHM2;
  • BAG3 DCM (dominant, broader age range);
  • arrhythmogenic cardiomyopathy (DSP, FLNC, PLN — overlapping arrhythmic DCM);
  • myocarditis;
  • tachycardia-induced cardiomyopathy (reversible after rate control);
  • neuromuscular and metabolic DCMs (Duchenne/Becker, Barth, mitochondrial).
  • Screening: cascade testing of siblings in affected families, followed by echo and ECG surveillance of biallelic relatives.

11. Outcome and prognosis

  • Reported outcomes are poor. Every patient in the founding Japanese cohort needed an LVAD and at least one was transplanted (PanelApp summary of PMID:35044787). One Middle Eastern sibling died at 12 years awaiting transplant.
  • Arrhythmic burden is high and refractory (PMID:36130910).
  • No survival statistics exist.
  • Prognostic factors are not established. Biallelic truncation appears uniformly severe.

12. Treatment

No disease-specific therapy is approved. Management follows standard heart-failure care for DCM.

Intervention Suggested NCIT ✔ Notes
Guideline-directed HF pharmacotherapy (β-blocker, ACEi/ARNI, MRA, SGLT2i) NCIT:C15986 Pharmacotherapy ✔; agent NCIT:C29576 Beta-Adrenergic Antagonist ✔ β-blockade is mechanistically attractive given the catecholamine-triggered phenotype in mice. This is an inference, not trial evidence.
ICD NCIT:C80435 Implantable Cardioverter-Defibrillator Placement ✔ Refractory VT/VF
LVAD NCIT:C172327 Left Ventricular Assist Device Insertion ✔ Used in all Hakui patients
Heart transplantation NCIT:C15246 Heart Transplantation ✔ Definitive therapy
AAV9-BAG5 gene replacement (preclinical) NCIT:C15238 Gene Therapy ✔; modality GENE_THERAPY; delivery VIRAL_VECTOR PMID:35044787 (verbatim): "administration of an adeno-associated virus 9 vector carrying the wild-type BAG5 gene could fully ameliorate these DCM phenotypes"
  • Clinical trials: no NCT or ICTRP trials specific to BAG5 were found.
  • Pharmacogenomics: none.

13. Prevention

  • Primary prevention: genetic counselling (NCIT:C15240), carrier testing in consanguineous kindreds, and prenatal or preimplantation diagnosis for families with known variants.
  • Secondary prevention: cascade genotyping of siblings, then echo and ECG surveillance of biallelic relatives.
  • Tertiary prevention: an ICD to prevent sudden death and early referral for advanced HF therapy.
  • Avoiding catecholamine excess: plausible from mouse data, but not validated.

14. Other species and natural disease

No naturally occurring BAG5 cardiomyopathy has been reported in animals, and OMIA lists none. The mouse orthologue is Bag5 (MGI:1917619). BAG5 is conserved across vertebrates.

15. Model organisms

Model Genotype Phenotype Fidelity and limitations Ref
Bag5 mutant knock-in mouse (Osaka) Patient-equivalent truncation Ventricular dilatation, arrhythmogenicity and poor survival under catecholamine stimulation; JMC disruption; Ca²⁺ mishandling; rescued by AAV9-BAG5 Recapitulates DCM plus arrhythmia, but only under stress (catecholamine). The human disease appears without a known trigger. PMID:35044787 (verbatim: "Bag5 mutant knock-in mice exhibited ventricular dilatation, arrhythmogenicity, and poor prognosis under catecholamine stimulation, recapitulating the human DCM phenotype")
Bag5 p.Lys149fs-equivalent knock-in mouse (delCA, C57BL/6N; Chulalongkorn) +/− and −/− Normal to 12 months and on treadmill testing. After tunicamycin (2 mg/kg IP), LVEF and LVFS fall, apoptosis rises, and sinus pauses occur in males only; one −/− male died suddenly. Stress-dependent; n = 3 per group; sex-discordant with the human carrier findings (ECG changes were in human females but mouse males). Suited to a HUMAN_MODEL_MISMATCH discussion. PMID:38796549 (verbatim: "Bag5-/- mice displayed no abnormalities up to 12 months old and showed no anomalies during an exercise stress test.")
IMPC Bag5 knockout (Bag5^em1(IMPC)Mbp) Null Male infertility (acephalic sperm); eye and brain calls. Cardiac phenotype not highlighted. Supports a non-cardiac function; human fertility unknown IMPC MGI:1917619
Neonatal rat ventricular cardiomyocytes (in vitro) Bag5 siRNA knockdown or adenoviral overexpression Knockdown leads to cell death; overexpression protects against ER-stress apoptosis and lowers CHOP Rat, neonatal, acute knockdown; not a disease model PMID:26729625 (evidence_source: IN_VITRO)

Key references

PMID Citation Cache status
35044787 Hakui H et al. Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation. Sci Transl Med 2022;14:eabf3274 abstract cached
36130910 Hakui H et al. Refractory ventricular arrhythmias in a patient with DCM caused by a nonsense mutation in BAG5. Circ J 2022;86:2043 no quotable text; do not cite snippets
37873655 Inoue S et al. Compound heterozygous truncating variants in the BAG5 gene as a cause of early-onset DCM. Circ Genom Precis Med 2023;16:e004282 no quotable text; retry with --force
38796549 Wongong R et al. A novel BAG5 variant impairs the ER stress response pathway, causing DCM and arrhythmia. Sci Rep 2024;14:11980 full text cached
26729625 Gupta MK et al. GRP78 interacting partner Bag5 responds to ER stress and protects cardiomyocytes from ER stress-induced apoptosis. J Cell Biochem 2016;117:1813 full text cached
20223214 Arakawa A et al. BAG5 as Hsp70 NEF (structure). Structure 2010;18:309 not cached
42708185 Jordan E et al. An updated evidence assessment of the genetic causes of DCM. Circulation 2026 abstract cached
CGGV:assertion_97fe83b7-…-2024-06-14T160000.000Z ClinGen BAG5 / DCM, AR, Moderate cached

Gaps: - The Inoue 2023 and Hakui 2022 Circ J abstracts could not be retrieved. - The JMC protein names and per-patient clinical details from Hakui 2022 need the full text. - The OMIM numbers come from secondary sources. - There are no prevalence, natural-history or trial data.

Repository note: this research run added the following files to references_cache/, generated with just fetch-reference: - PMID_35044787.md, PMID_38796549.md, PMID_42708185.md, PMID_26729625.md — usable. - PMID_37873655.md, PMID_36130910.md — cached with no quotable text. - PMID_39712638.md — an unrelated sevoflurane paper picked up by the PubMed search. My attempt to delete it was not approved. Delete it before committing.

Sources: - Osaka University press release (Hakui/Asano 2022) - GenCC BAG5 submission - GenCC SGC-106981.2 - GenCC BAG5 gene page - Wongong et al. 2024, PMC11127938 - PanelApp Australia BAG5 - MGI OMIM:619747 - Disease Ontology DOID:0081162 - DrugMap DIS6YW38 - genebe BAG5 - NORD MONDO page - Gupta et al. 2016, PMC4909508 - RCSB PDB 3A8Y - IMPC Bag5 - Cyagen Bag5 KO - Lesurf 2022 (BSC record) - medRxiv Lesurf preprint

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 9
Resolved 9
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 9
On topic 6
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 34
Resolved 31
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 3
Terms whose name was checked 3
Terms named correctly 0
Terms named as a different term 1
Terms whose name is worth a second look 2

Terms the report names something else

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

  • DOID:0081162 (5 mentions) - the report calls it "DOID"; DOID calls it dilated cardiomyopathy 2F

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • MONDO:0005021 (2 mentions) - the report calls it "ACMG/ClinGen: ClinGen Gene-Disease Validity, BAG5–dilated cardiomyopathy"; MONDO calls it dilated cardiomyopathy**, and lists "familial dilated cardiomyopathy" among its other names
  • NCIT:C15240 (1 mention) - the report calls it "Primary prevention: genetic counselling"; NCIT calls it Genetic Counseling**

Prefixes with no resolver

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