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7
Pathophys.
8
Phenotypes
48
Genes
7
Treatments
5
Subtypes
1
Deep Research

Subtypes

5
Familial Dilated Cardiomyopathy
Genetically inherited form of DCM, accounting for 20-50% of cases, caused by mutations in genes encoding sarcomeric, cytoskeletal, or nuclear envelope proteins.
Show evidence (2 references)
PMID:37788487 SUPPORT
"An estimated 40% of cases of familial DCM have an identifiable genetic cause."
Confirms that familial DCM has a significant genetic basis.
PMID:39519012 SUPPORT
"rapid advances in sequencing and bioinformatics have recently revealed a complex genetic spectrum ranging from monogenic to polygenic in DCM"
Highlights the expanding understanding of genetic architecture in familial DCM, from monogenic to polygenic.
Idiopathic Dilated Cardiomyopathy
DCM without identifiable genetic or secondary cause after comprehensive evaluation.
Show evidence (1 reference)
PMID:39519012 SUPPORT
"Cases without an identified secondary cause are classified as idiopathic dilated cardiomyopathy (IDC)."
Directly defines idiopathic DCM as lacking an identified secondary cause.
Peripartum Cardiomyopathy
DCM occurring in the last month of pregnancy or within five months postpartum in women without prior heart disease.
Show evidence (1 reference)
PMID:39348083 SUPPORT Human Clinical
"Peripartum cardiomyopathy is a type of de novo heart failure that occurs in pregnant women in the late stages of pregnancy or following delivery."
Defines peripartum cardiomyopathy as de novo heart failure in late pregnancy or postpartum.
Alcoholic Cardiomyopathy
DCM resulting from chronic excessive alcohol consumption leading to direct myocardial toxicity.
Show evidence (1 reference)
PMID:39519012 SUPPORT
"These advances have also led to the discovery of causal and modifier genetic variants in secondary forms of DCM (e.g., alcohol-induced cardiomyopathy)."
Confirms that alcohol-induced cardiomyopathy is a recognized secondary form of DCM.
Tachycardia-Induced Cardiomyopathy
DCM caused by sustained tachyarrhythmias that is potentially reversible with rate or rhythm control.
Show evidence (1 reference)
PMID:39959626 SUPPORT Human Clinical
"Tachycardia-induced cardiomyopathy (TIC), also known as arrhythmia-induced cardiomyopathy or tachycardiomyopathy, is a reversible form of heart failure characterized by persistent tachyarrhythmias and associated ventricular dysfunction."
Defines TIC as a reversible form of heart failure caused by persistent tachyarrhythmias.

Pathophysiology

7
Sarcomeric and Cytoskeletal Dysfunction
Mutations in genes encoding sarcomeric proteins (e.g., TTN, MYH7, TNNT2) and cytoskeletal proteins (e.g., DES, LMNA) disrupt force generation and transmission within cardiomyocytes, leading to impaired contractility and progressive ventricular dilation. Truncating variants in TTN are the most common genetic cause, found in approximately 15% of familial DCM cases.
cardiomyocyte link
cardiac muscle contraction link
Show evidence (3 references)
PMID:37962957 SUPPORT
"Heterozygous (HET) truncating variant mutations in the TTN gene (TTNtvs), encoding the giant titin protein, are the most common genetic cause of dilated cardiomyopathy (DCM)."
Confirms TTN truncating variants as the most common genetic cause of DCM.
PMID:37962957 SUPPORT
"The occurrence of TTNtv was found to be 15% in the DCM cohort."
Provides the 15% frequency of TTNtv in a DCM cohort.
PMID:37788487 SUPPORT
"Many gene mutations have been identified that contribute to phenotypically significant cardiomyopathy. DCM genes can affect a variety of cardiomyocyte functions, and particular genes whose function affects the cell-cell junction and cytoskeleton are associated with increased risk of arrhythmias..."
Confirms that DCM genes affect cardiomyocyte functions including cytoskeletal integrity.
Neurohormonal Activation
Reduced cardiac output activates the renin-angiotensin-aldosterone system and sympathetic nervous system, causing vasoconstriction, sodium and water retention, and further myocardial stress. Chronic neurohormonal activation promotes adverse cardiac remodeling.
renin-angiotensin regulation of aldosterone production link
Show evidence (2 references)
PMID:37254024 SUPPORT Human Clinical
"renin-angiotensin system inhibitors, evidence-based β-blockers, mineralocorticoid inhibitors and sodium glucose cotransporter 2 inhibitors"
Confirms that neurohormonal blockade targeting the renin-angiotensin and sympathetic systems is the cornerstone of HFrEF therapy, validating neurohormonal activation as a key pathophysiological mechanism.
PMID:33250269 SUPPORT Human Clinical
"Treatment of myocardial diseases with renin-angiotensin system inhibitors and β-blockers has greatly contributed to improving prognosis."
Confirms the therapeutic importance of targeting neurohormonal activation in myocardial diseases including DCM.
Myocardial Fibrosis
Progressive replacement and interstitial fibrosis within the ventricular myocardium impairs diastolic filling, increases myocardial stiffness, and creates substrates for re-entrant arrhythmias. Late gadolinium enhancement on cardiac MRI is a strong predictor of adverse outcomes.
cardiac fibroblast link
extracellular matrix organization link
Show evidence (1 reference)
PMID:39298146 SUPPORT Human Clinical
"The presence and extent of LGE were associated with various adverse clinical outcomes, whereas LVEF was not significantly associated with mortality and arrhythmic end points in NIDCM."
Demonstrates the prognostic significance of myocardial fibrosis (detected as LGE) in nonischemic DCM.
RNA Splicing Dysregulation
Pathogenic variants in RBM20 disrupt alternative splicing of key cardiac genes including TTN and calcium-handling genes (CAMK2D, CACNA1C), leading to altered titin isoform expression and impaired excitation-contraction coupling. Some RBM20 variants also form toxic biomolecular condensates in the sarcoplasm.
cardiomyocyte link
Show evidence (1 reference)
PMID:38288598 SUPPORT
"pathogenic variants in RBM20 are linked to aggressive dilated cardiomyopathy with early onset heart failure and high mortality."
Confirms RBM20 variants cause aggressive DCM with poor outcomes.
Immune and Inflammatory Activation
Immune-mediated injury from viral myocarditis or autoimmune reactions can trigger or accelerate DCM progression. Chronic cardiac inflammation with distinct immune cell infiltration patterns contributes to adverse remodeling.
cardiomyocyte link
Show evidence (1 reference)
PMID:38321374 SUPPORT Computational
"Our study demonstrated the obvious different ratio of T cell CD4 memory activated, T cell regulatory Tregs, and neutrophils between DCM and control donors."
Demonstrates altered immune cell infiltration patterns in DCM hearts.
Polygenic Risk and Common Variant Burden
Large-scale genome-wide association studies have identified dozens of loci associated with DCM, highlighting the role of common genetic variation in disease susceptibility. Enrichment analyses confirm the central role of the cardiomyocyte and contractile apparatus.
Show evidence (2 references)
PMID:39572784 SUPPORT Human Clinical
"We identify 70 genome-wide significant loci, which show broad replication in independent samples and map to 63 prioritized genes. Tissue, cell type and pathway enrichment analyses highlight the central role of the cardiomyocyte and contractile apparatus in DCM pathogenesis."
GWAS meta-analysis identifies 70 loci and confirms cardiomyocyte/contractile apparatus enrichment in DCM.
PMID:39572783 SUPPORT Human Clinical
"We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants."
Demonstrates that common variant polygenic scores predict DCM risk and modify penetrance of rare pathogenic variants.
Mitochondrial Dysfunction
Impaired mitochondrial energy production, increased oxidative stress, and defective mitochondrial quality control contribute to cardiomyocyte injury and contractile failure in DCM. Disruption of mitochondrial protein homeostasis can drive disease progression.
cardiomyocyte link
mitochondrion organization link
Show evidence (1 reference)
PMID:35418250 SUPPORT Model Organism
"Doxorubicin reduced SIRT3 expression and markedly affected the cardiac mitochondrial acetylome. Increased M1-SIRT3 expression in vivo prevented doxorubicin-induced cardiac dysfunction"
Demonstrates that mitochondrial protein acetylation dysregulation drives dilated cardiomyopathy and that restoring mitochondrial deacetylase function prevents cardiac dysfunction.

Phenotypes

8
Cardiovascular 5
Dilated cardiomyopathy VERY_FREQUENT Dilated cardiomyopathy (HP:0001644)
Show evidence (1 reference)
PMID:39298146 SUPPORT Human Clinical
"Accurate risk stratification of nonischemic dilated cardiomyopathy (NIDCM) remains challenging."
Confirms DCM as the defining phenotype.
Congestive heart failure VERY_FREQUENT Congestive heart failure (HP:0001635)
Show evidence (2 references)
PMID:39519012 SUPPORT
"Dilated cardiomyopathy (DCM) is characterized by reduced systolic function and cardiac dilation."
Reduced systolic function leads to heart failure as a primary manifestation.
PMID:38966492 SUPPORT Human Clinical
"Pediatric dilated cardiomyopathy (DCM) is a rare, yet life-threatening cardiovascular condition characterized by systolic dysfunction with biventricular dilatation and reduced myocardial contractility"
Confirms systolic dysfunction and reduced contractility as hallmarks of DCM leading to heart failure.
Left ventricular systolic dysfunction VERY_FREQUENT Left ventricular systolic dysfunction (HP:0025169)
Show evidence (1 reference)
PMID:39298146 SUPPORT Human Clinical
"Left ventricular ejection fraction (LVEF) (per 1%) was not associated with all-cause mortality"
While LVEF is the standard measure of LV systolic dysfunction in DCM, this study shows it is less prognostic than fibrosis markers.
Palpitations FREQUENT Palpitations (HP:0001962)
Arrhythmia FREQUENT Arrhythmia (HP:0011675)
Show evidence (2 references)
PMID:37788487 SUPPORT
"DCM genes can affect a variety of cardiomyocyte functions, and particular genes whose function affects the cell-cell junction and cytoskeleton are associated with increased risk of arrhythmias and sudden cardiac death."
Genetic variants in DCM are associated with increased arrhythmia risk.
PMID:39298146 SUPPORT Human Clinical
"The presence and extent of LGE were associated with various adverse clinical outcomes"
Myocardial fibrosis in DCM is associated with adverse outcomes including arrhythmic events.
Metabolism 1
Peripheral edema FREQUENT Peripheral edema (HP:0012398)
Respiratory 1
Dyspnea VERY_FREQUENT Dyspnea (HP:0002094)
Constitutional 1
Fatigue VERY_FREQUENT Fatigue (HP:0012378)
🧬

Genetic Associations

48
TTN Truncating Variants (Causative)
Autosomal dominant
Show evidence (2 references)
PMID:37962957 SUPPORT
"Heterozygous (HET) truncating variant mutations in the TTN gene (TTNtvs), encoding the giant titin protein, are the most common genetic cause of dilated cardiomyopathy (DCM)."
Confirms TTN truncating variants as the most common genetic cause of DCM.
"TTN | HGNC:12403 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen classifies the TTN-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
LMNA Mutations (Causative)
Autosomal dominant
Show evidence (2 references)
PMID:39519012 SUPPORT
"Current guidelines recommend genetic counseling and screening, as well as endorsing a handful of genotype-specific therapies (e.g., device placement in LMNA cardiomyopathy)."
LMNA cardiomyopathy is recognized as requiring genotype-specific management including device therapy.
"LMNA | HGNC:6636 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen classifies the LMNA-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
MYH7 Mutations (Causative)
Autosomal dominant
Show evidence (2 references)
PMID:39494569 SUPPORT Human Clinical
"genetic variants in MYH7 are the most frequent cause of pediatric genetic dilated cardiomyopathy (DCM)"
Confirms MYH7 as the most frequent cause of pediatric genetic DCM.
"MYH7 | HGNC:7577 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen classifies the MYH7-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
RBM20 Mutations (Causative)
Autosomal dominant
Show evidence (2 references)
PMID:38288598 SUPPORT
"pathogenic variants in RBM20 are linked to aggressive dilated cardiomyopathy with early onset heart failure and high mortality."
Confirms RBM20 variants cause aggressive DCM with poor outcomes.
"RBM20 | HGNC:27424 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen classifies the RBM20-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
ABCC9 (Pathogenic Variants)
Show evidence (1 reference)
"ABCC9 | HGNC:60 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the ABCC9-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
ACTC1 (Pathogenic Variants)
Show evidence (1 reference)
"ACTC1 | HGNC:143 | dilated cardiomyopathy | MONDO:0005021 | AD | Moderate"
ClinGen classifies the ACTC1-dilated cardiomyopathy gene-disease relationship as moderate with autosomal dominant inheritance.
ANKRD1 (Pathogenic Variants)
Show evidence (1 reference)
"ANKRD1 | HGNC:15819 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the ANKRD1-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
BAG3 (Pathogenic Variants)
Show evidence (1 reference)
"BAG3 | HGNC:939 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen classifies the BAG3-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
BAG5 (Pathogenic Variants)
Show evidence (1 reference)
"BAG5 | HGNC:941 | dilated cardiomyopathy | MONDO:0005021 | AR | Moderate"
ClinGen classifies the BAG5-dilated cardiomyopathy gene-disease relationship as moderate with autosomal recessive inheritance.
CDH2 (Pathogenic Variants)
Show evidence (1 reference)
"CDH2 | HGNC:1759 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the CDH2-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
CTF1 (Pathogenic Variants)
Show evidence (1 reference)
"CTF1 | HGNC:2499 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the CTF1-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
DES (Pathogenic Variants)
Show evidence (1 reference)
"DES | HGNC:2770 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen classifies the DES-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
DSG2 (Pathogenic Variants)
Show evidence (1 reference)
"DSG2 | HGNC:3049 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the DSG2-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
FBXO32 (Pathogenic Variants)
Show evidence (1 reference)
"FBXO32 | HGNC:16731 | dilated cardiomyopathy | MONDO:0005021 | AR | Limited"
ClinGen classifies the FBXO32-dilated cardiomyopathy gene-disease relationship as limited with autosomal recessive inheritance.
FLII (Pathogenic Variants)
Show evidence (1 reference)
"FLII | HGNC:3750 | dilated cardiomyopathy | MONDO:0005021 | AR | Moderate"
ClinGen classifies the FLII-dilated cardiomyopathy gene-disease relationship as moderate with autosomal recessive inheritance.
FLNC (Pathogenic Variants)
Show evidence (1 reference)
"FLNC | HGNC:3756 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen classifies the FLNC-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
GATAD1 (Pathogenic Variants)
Show evidence (1 reference)
"GATAD1 | HGNC:29941 | dilated cardiomyopathy | MONDO:0005021 | AR | Limited"
ClinGen classifies the GATAD1-dilated cardiomyopathy gene-disease relationship as limited with autosomal recessive inheritance.
GET3 (Pathogenic Variants)
Show evidence (1 reference)
"GET3 | HGNC:752 | dilated cardiomyopathy | MONDO:0005021 | AR | Limited"
ClinGen classifies the GET3-dilated cardiomyopathy gene-disease relationship as limited with autosomal recessive inheritance.
JPH2 (Pathogenic Variants)
Show evidence (2 references)
"JPH2 | HGNC:14202 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the JPH2-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
"JPH2 | HGNC:14202 | dilated cardiomyopathy | MONDO:0005021 | AR | Strong"
ClinGen classifies the JPH2-dilated cardiomyopathy gene-disease relationship as strong with autosomal recessive inheritance.
LAMA4 (Pathogenic Variants)
Show evidence (1 reference)
"LAMA4 | HGNC:6484 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the LAMA4-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
LDB3 (Pathogenic Variants)
Show evidence (2 references)
"LDB3 | HGNC:15710 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the LDB3-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
"LDB3 | HGNC:15710 | dilated cardiomyopathy | MONDO:0005021 | AR | Strong"
ClinGen classifies the LDB3-dilated cardiomyopathy gene-disease relationship as strong with autosomal recessive inheritance.
LMOD2 (Pathogenic Variants)
Show evidence (1 reference)
"LMOD2 | HGNC:6648 | dilated cardiomyopathy | MONDO:0005021 | AR | Definitive"
ClinGen classifies the LMOD2-dilated cardiomyopathy gene-disease relationship as definitive with autosomal recessive inheritance.
MIB1 (Pathogenic Variants)
Show evidence (1 reference)
"MIB1 | HGNC:21086 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the MIB1-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
MYBPC3 (Pathogenic Variants)
Show evidence (2 references)
"MYBPC3 | HGNC:7551 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the MYBPC3-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
"MYBPC3 | HGNC:7551 | dilated cardiomyopathy | MONDO:0005021 | AR | Limited"
ClinGen classifies the MYBPC3-dilated cardiomyopathy gene-disease relationship as limited with autosomal recessive inheritance.
MYH6 (Pathogenic Variants)
Show evidence (1 reference)
"MYH6 | HGNC:7576 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the MYH6-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
MYL2 (Pathogenic Variants)
Show evidence (1 reference)
"MYL2 | HGNC:7583 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the MYL2-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
MYLK3 (Pathogenic Variants)
Show evidence (1 reference)
"MYLK3 | HGNC:29826 | dilated cardiomyopathy | MONDO:0005021 | AD | Moderate"
ClinGen classifies the MYLK3-dilated cardiomyopathy gene-disease relationship as moderate with autosomal dominant inheritance.
MYPN (Pathogenic Variants)
Show evidence (1 reference)
"MYPN | HGNC:23246 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the MYPN-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
MYZAP (Pathogenic Variants)
Show evidence (1 reference)
"MYZAP | HGNC:43444 | dilated cardiomyopathy | MONDO:0005021 | AR | Moderate"
ClinGen classifies the MYZAP-dilated cardiomyopathy gene-disease relationship as moderate with autosomal recessive inheritance.
NEBL (Pathogenic Variants)
Show evidence (1 reference)
"NEBL | HGNC:16932 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the NEBL-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
NEXN (Pathogenic Variants)
Show evidence (1 reference)
"NEXN | HGNC:29557 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
ClinGen classifies the NEXN-dilated cardiomyopathy gene-disease relationship as strong with autosomal dominant inheritance.
NRAP (Pathogenic Variants)
Show evidence (1 reference)
"NRAP | HGNC:7988 | dilated cardiomyopathy | MONDO:0005021 | AR | Strong"
ClinGen classifies the NRAP-dilated cardiomyopathy gene-disease relationship as strong with autosomal recessive inheritance.
OBSCN (Pathogenic Variants)
Show evidence (1 reference)
"OBSCN | HGNC:15719 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the OBSCN-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
PLEKHM2 (Pathogenic Variants)
Show evidence (1 reference)
"PLEKHM2 | HGNC:29131 | dilated cardiomyopathy | MONDO:0005021 | AR | Moderate"
ClinGen classifies the PLEKHM2-dilated cardiomyopathy gene-disease relationship as moderate with autosomal recessive inheritance.
PPA2 (Pathogenic Variants)
Show evidence (1 reference)
"PPA2 | HGNC:28883 | dilated cardiomyopathy | MONDO:0005021 | AR | Strong"
ClinGen classifies the PPA2-dilated cardiomyopathy gene-disease relationship as strong with autosomal recessive inheritance.
PRDM16 (Pathogenic Variants)
Show evidence (1 reference)
"PRDM16 | HGNC:14000 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
ClinGen classifies the PRDM16-dilated cardiomyopathy gene-disease relationship as strong with autosomal dominant inheritance.
RPL3L (Pathogenic Variants)
Show evidence (1 reference)
"RPL3L | HGNC:10351 | dilated cardiomyopathy | MONDO:0005021 | AR | Moderate"
ClinGen classifies the RPL3L-dilated cardiomyopathy gene-disease relationship as moderate with autosomal recessive inheritance.
RYR2 (Pathogenic Variants)
Show evidence (1 reference)
"RYR2 | HGNC:10484 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the RYR2-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
SCN5A (Pathogenic Variants)
Show evidence (1 reference)
"SCN5A | HGNC:10593 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen classifies the SCN5A-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
TBX20 (Pathogenic Variants)
Show evidence (1 reference)
"TBX20 | HGNC:11598 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
ClinGen classifies the TBX20-dilated cardiomyopathy gene-disease relationship as strong with autosomal dominant inheritance.
TCAP (Pathogenic Variants)
Show evidence (1 reference)
"TCAP | HGNC:11610 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen classifies the TCAP-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
TMOD1 (Pathogenic Variants)
Show evidence (1 reference)
"TMOD1 | HGNC:11871 | dilated cardiomyopathy | MONDO:0005021 | AR | Limited"
ClinGen classifies the TMOD1-dilated cardiomyopathy gene-disease relationship as limited with autosomal recessive inheritance.
TNNC1 (Pathogenic Variants)
Show evidence (1 reference)
"TNNC1 | HGNC:11943 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen classifies the TNNC1-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
TNNI3 (Pathogenic Variants)
Show evidence (2 references)
"TNNI3 | HGNC:11947 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
ClinGen classifies the TNNI3-dilated cardiomyopathy gene-disease relationship as strong with autosomal dominant inheritance.
"TNNI3 | HGNC:11947 | dilated cardiomyopathy | MONDO:0005021 | AR | Strong"
ClinGen classifies the TNNI3-dilated cardiomyopathy gene-disease relationship as strong with autosomal recessive inheritance.
TNNI3K (Pathogenic Variants)
Show evidence (1 reference)
"TNNI3K | HGNC:19661 | dilated cardiomyopathy | MONDO:0005021 | AD | Moderate"
ClinGen classifies the TNNI3K-dilated cardiomyopathy gene-disease relationship as moderate with autosomal dominant inheritance.
TNNT2 (Pathogenic Variants)
Show evidence (1 reference)
"TNNT2 | HGNC:11949 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen classifies the TNNT2-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
TPM1 (Pathogenic Variants)
Show evidence (1 reference)
"TPM1 | HGNC:12010 | dilated cardiomyopathy | MONDO:0005021 | AD | Moderate"
ClinGen classifies the TPM1-dilated cardiomyopathy gene-disease relationship as moderate with autosomal dominant inheritance.
VCL (Pathogenic Variants)
Show evidence (1 reference)
"VCL | HGNC:12665 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
ClinGen classifies the VCL-dilated cardiomyopathy gene-disease relationship as strong with autosomal dominant inheritance.
💊

Treatments

7
ACE Inhibitors / ARBs
Action: ACE inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986
First-line neurohormonal blockade to reduce afterload and prevent adverse remodeling.
Beta-Blockers
Action: beta-blocker therapy Ontology label: Pharmacotherapy NCIT:C15986
Reduce heart rate and neurohormonal activation, improving survival in heart failure with reduced ejection fraction.
SGLT2 Inhibitors
Action: SGLT2 inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986
Newer therapy shown to reduce heart failure hospitalization and cardiovascular death in HFrEF regardless of diabetes status.
Cardiac Resynchronization Therapy
Action: cardiac resynchronization therapy Ontology label: surgical procedure MAXO:0000004
Biventricular pacing for patients with wide QRS and reduced LVEF to improve synchrony and outcomes.
Heart Transplantation
Action: heart transplantation Ontology label: organ transplantation MAXO:0010039
Definitive therapy for end-stage DCM refractory to medical and device therapy.
Implantable Cardioverter-Defibrillator
Action: implantable cardioverter-defibrillator placement Ontology label: surgical procedure MAXO:0000004
Indicated for primary prevention of sudden cardiac death in patients with LVEF <=35% despite optimal medical therapy.
Genetic Counseling
Action: genetic counseling MAXO:0000079
Recommended for patients with familial or genetic DCM to guide cascade screening and family management.
Show evidence (2 references)
PMID:37788487 SUPPORT
"Through advancements in next-generation sequencing and cardiac imaging, identification of genetic DCM has improved over the past couple decades, and precision medicine is now at the forefront of treatment for these patients and their families."
Confirms the importance of genetic identification and precision medicine in DCM management.
PMID:39519012 SUPPORT
"Current guidelines recommend genetic counseling and screening, as well as endorsing a handful of genotype-specific therapies"
Guidelines explicitly recommend genetic counseling and screening for DCM.
{ }

Source YAML

click to show
name: Dilated Cardiomyopathy
creation_date: '2026-03-06T00:00:00Z'
updated_date: '2026-03-08T00:00:00Z'
synonyms:
- DCM
- dilated cardiomyopathy
- congestive cardiomyopathy
- IDC
- idiopathic dilated cardiomyopathy
category: Complex
disease_term:
  preferred_term: dilated cardiomyopathy
  term:
    id: MONDO:0005021
    label: dilated cardiomyopathy
parents:
- Cardiovascular Disease
- Genetic Disorder
has_subtypes:
- name: Familial Dilated Cardiomyopathy
  description: Genetically inherited form of DCM, accounting for 20-50% of cases, caused by mutations in genes encoding sarcomeric, cytoskeletal, or nuclear envelope proteins.
  evidence:
  - reference: PMID:37788487
    reference_title: "Genetics of Dilated Cardiomyopathy."
    supports: SUPPORT
    snippet: An estimated 40% of cases of familial DCM have an identifiable genetic cause.
    explanation: Confirms that familial DCM has a significant genetic basis.
  - reference: PMID:39519012
    reference_title: "Dilated Cardiomyopathy: A Genetic Journey from Past to Future."
    supports: SUPPORT
    snippet: rapid advances in sequencing and bioinformatics have recently revealed a complex genetic spectrum ranging from monogenic to polygenic in DCM
    explanation: Highlights the expanding understanding of genetic architecture in familial DCM, from monogenic to polygenic.
- name: Idiopathic Dilated Cardiomyopathy
  description: DCM without identifiable genetic or secondary cause after comprehensive evaluation.
  evidence:
  - reference: PMID:39519012
    reference_title: "Dilated Cardiomyopathy: A Genetic Journey from Past to Future."
    supports: SUPPORT
    snippet: Cases without an identified secondary cause are classified as idiopathic dilated cardiomyopathy (IDC).
    explanation: Directly defines idiopathic DCM as lacking an identified secondary cause.
- name: Peripartum Cardiomyopathy
  description: DCM occurring in the last month of pregnancy or within five months postpartum in women without prior heart disease.
  evidence:
  - reference: PMID:39348083
    reference_title: "Peripartum cardiomyopathy: a comprehensive and contemporary review."
    supports: SUPPORT
    snippet: Peripartum cardiomyopathy is a type of de novo heart failure that occurs in pregnant women in the late stages of pregnancy or following delivery.
    explanation: Defines peripartum cardiomyopathy as de novo heart failure in late pregnancy or postpartum.
    evidence_source: HUMAN_CLINICAL
- name: Alcoholic Cardiomyopathy
  description: DCM resulting from chronic excessive alcohol consumption leading to direct myocardial toxicity.
  evidence:
  - reference: PMID:39519012
    reference_title: "Dilated Cardiomyopathy: A Genetic Journey from Past to Future."
    supports: SUPPORT
    snippet: These advances have also led to the discovery of causal and modifier genetic variants in secondary forms of DCM (e.g., alcohol-induced cardiomyopathy).
    explanation: Confirms that alcohol-induced cardiomyopathy is a recognized secondary form of DCM.
- name: Tachycardia-Induced Cardiomyopathy
  description: DCM caused by sustained tachyarrhythmias that is potentially reversible with rate or rhythm control.
  evidence:
  - reference: PMID:39959626
    reference_title: "Tachycardia-Induced Cardiomyopathy: A Case Series and a Literature Review."
    supports: SUPPORT
    snippet: Tachycardia-induced cardiomyopathy (TIC), also known as arrhythmia-induced cardiomyopathy or tachycardiomyopathy, is a reversible form of heart failure characterized by persistent tachyarrhythmias and associated ventricular dysfunction.
    explanation: Defines TIC as a reversible form of heart failure caused by persistent tachyarrhythmias.
    evidence_source: HUMAN_CLINICAL
pathophysiology:
- name: Sarcomeric and Cytoskeletal Dysfunction
  description: >
    Mutations in genes encoding sarcomeric proteins (e.g., TTN, MYH7, TNNT2)
    and cytoskeletal proteins (e.g., DES, LMNA) disrupt force generation and
    transmission within cardiomyocytes, leading to impaired contractility and
    progressive ventricular dilation. Truncating variants in TTN are the most
    common genetic cause, found in approximately 15% of familial DCM cases.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
  evidence:
  - reference: PMID:37962957
    reference_title: "Truncated titin is structurally integrated into the human dilated cardiomyopathic sarcomere."
    supports: SUPPORT
    snippet: Heterozygous (HET) truncating variant mutations in the TTN gene (TTNtvs), encoding the giant titin protein, are the most common genetic cause of dilated cardiomyopathy (DCM).
    explanation: Confirms TTN truncating variants as the most common genetic cause of DCM.
  - reference: PMID:37962957
    reference_title: "Truncated titin is structurally integrated into the human dilated cardiomyopathic sarcomere."
    supports: SUPPORT
    snippet: The occurrence of TTNtv was found to be 15% in the DCM cohort.
    explanation: Provides the 15% frequency of TTNtv in a DCM cohort.
  - reference: PMID:37788487
    reference_title: "Genetics of Dilated Cardiomyopathy."
    supports: SUPPORT
    snippet: Many gene mutations have been identified that contribute to phenotypically significant cardiomyopathy. DCM genes can affect a variety of cardiomyocyte functions, and particular genes whose function affects the cell-cell junction and cytoskeleton are associated with increased risk of arrhythmias and sudden cardiac death.
    explanation: Confirms that DCM genes affect cardiomyocyte functions including cytoskeletal integrity.
- name: Neurohormonal Activation
  description: >
    Reduced cardiac output activates the renin-angiotensin-aldosterone system
    and sympathetic nervous system, causing vasoconstriction, sodium and water
    retention, and further myocardial stress. Chronic neurohormonal activation
    promotes adverse cardiac remodeling.
  biological_processes:
  - preferred_term: renin-angiotensin regulation of aldosterone production
    term:
      id: GO:0002018
      label: renin-angiotensin regulation of aldosterone production
  evidence:
  - reference: PMID:37254024
    reference_title: "Guideline-Directed Medical Therapy for the Treatment of Heart Failure with Reduced Ejection Fraction."
    supports: SUPPORT
    snippet: "renin-angiotensin system inhibitors, evidence-based β-blockers, mineralocorticoid inhibitors and sodium glucose cotransporter 2 inhibitors"
    explanation: Confirms that neurohormonal blockade targeting the renin-angiotensin and sympathetic systems is the cornerstone of HFrEF therapy, validating neurohormonal activation as a key pathophysiological mechanism.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:33250269
    reference_title: "New treatment for myocardial diseases."
    supports: SUPPORT
    snippet: "Treatment of myocardial diseases with renin-angiotensin system inhibitors and β-blockers has greatly contributed to improving prognosis."
    explanation: Confirms the therapeutic importance of targeting neurohormonal activation in myocardial diseases including DCM.
    evidence_source: HUMAN_CLINICAL
- name: Myocardial Fibrosis
  description: >
    Progressive replacement and interstitial fibrosis within the ventricular
    myocardium impairs diastolic filling, increases myocardial stiffness, and
    creates substrates for re-entrant arrhythmias. Late gadolinium enhancement
    on cardiac MRI is a strong predictor of adverse outcomes.
  cell_types:
  - preferred_term: cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:39298146
    reference_title: "Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    snippet: The presence and extent of LGE were associated with various adverse clinical outcomes, whereas LVEF was not significantly associated with mortality and arrhythmic end points in NIDCM.
    explanation: Demonstrates the prognostic significance of myocardial fibrosis (detected as LGE) in nonischemic DCM.
    evidence_source: HUMAN_CLINICAL
- name: RNA Splicing Dysregulation
  description: >
    Pathogenic variants in RBM20 disrupt alternative splicing of key cardiac genes
    including TTN and calcium-handling genes (CAMK2D, CACNA1C), leading to altered
    titin isoform expression and impaired excitation-contraction coupling. Some
    RBM20 variants also form toxic biomolecular condensates in the sarcoplasm.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:38288598
    reference_title: "Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems."
    supports: SUPPORT
    snippet: pathogenic variants in RBM20 are linked to aggressive dilated cardiomyopathy with early onset heart failure and high mortality.
    explanation: Confirms RBM20 variants cause aggressive DCM with poor outcomes.
- name: Immune and Inflammatory Activation
  description: >
    Immune-mediated injury from viral myocarditis or autoimmune reactions can
    trigger or accelerate DCM progression. Chronic cardiac inflammation with
    distinct immune cell infiltration patterns contributes to adverse remodeling.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:38321374
    reference_title: "Construction and evaluation of immune-related diagnostic model in patients with heart failure caused by idiopathic dilated cardiomyopathy."
    supports: SUPPORT
    snippet: Our study demonstrated the obvious different ratio of T cell CD4 memory activated, T cell regulatory Tregs, and neutrophils between DCM and control donors.
    explanation: Demonstrates altered immune cell infiltration patterns in DCM hearts.
    evidence_source: COMPUTATIONAL
- name: Polygenic Risk and Common Variant Burden
  description: >
    Large-scale genome-wide association studies have identified dozens of loci
    associated with DCM, highlighting the role of common genetic variation in
    disease susceptibility. Enrichment analyses confirm the central role of the
    cardiomyocyte and contractile apparatus.
  evidence:
  - reference: PMID:39572784
    reference_title: "Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience."
    supports: SUPPORT
    snippet: We identify 70 genome-wide significant loci, which show broad replication in independent samples and map to 63 prioritized genes. Tissue, cell type and pathway enrichment analyses highlight the central role of the cardiomyocyte and contractile apparatus in DCM pathogenesis.
    explanation: GWAS meta-analysis identifies 70 loci and confirms cardiomyocyte/contractile apparatus enrichment in DCM.
    evidence_source: HUMAN_CLINICAL
  - reference: PMID:39572783
    reference_title: "Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy."
    supports: SUPPORT
    snippet: We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants.
    explanation: Demonstrates that common variant polygenic scores predict DCM risk and modify penetrance of rare pathogenic variants.
    evidence_source: HUMAN_CLINICAL
- name: Mitochondrial Dysfunction
  description: >
    Impaired mitochondrial energy production, increased oxidative stress, and
    defective mitochondrial quality control contribute to cardiomyocyte injury
    and contractile failure in DCM. Disruption of mitochondrial protein
    homeostasis can drive disease progression.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: mitochondrion organization
    term:
      id: GO:0007005
      label: mitochondrion organization
  evidence:
  - reference: PMID:35418250
    reference_title: "Mitochondrial Sirtuin-3 (SIRT3) Prevents Doxorubicin-Induced Dilated Cardiomyopathy by Modulating Protein Acetylation and Oxidative Stress."
    supports: SUPPORT
    snippet: Doxorubicin reduced SIRT3 expression and markedly affected the cardiac mitochondrial acetylome. Increased M1-SIRT3 expression in vivo prevented doxorubicin-induced cardiac dysfunction
    explanation: Demonstrates that mitochondrial protein acetylation dysregulation drives dilated cardiomyopathy and that restoring mitochondrial deacetylase function prevents cardiac dysfunction.
    evidence_source: MODEL_ORGANISM
phenotypes:
- category: Cardiovascular
  name: Dilated cardiomyopathy
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:39298146
    reference_title: "Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    snippet: Accurate risk stratification of nonischemic dilated cardiomyopathy (NIDCM) remains challenging.
    explanation: Confirms DCM as the defining phenotype.
    evidence_source: HUMAN_CLINICAL
- category: Cardiovascular
  name: Congestive heart failure
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:39519012
    reference_title: "Dilated Cardiomyopathy: A Genetic Journey from Past to Future."
    supports: SUPPORT
    snippet: Dilated cardiomyopathy (DCM) is characterized by reduced systolic function and cardiac dilation.
    explanation: Reduced systolic function leads to heart failure as a primary manifestation.
  - reference: PMID:38966492
    reference_title: "Pediatric dilated cardiomyopathy: a review of current clinical approaches and pathogenesis."
    supports: SUPPORT
    snippet: Pediatric dilated cardiomyopathy (DCM) is a rare, yet life-threatening cardiovascular condition characterized by systolic dysfunction with biventricular dilatation and reduced myocardial contractility
    explanation: Confirms systolic dysfunction and reduced contractility as hallmarks of DCM leading to heart failure.
    evidence_source: HUMAN_CLINICAL
- category: Cardiovascular
  name: Left ventricular systolic dysfunction
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Left ventricular systolic dysfunction
    term:
      id: HP:0025169
      label: Left ventricular systolic dysfunction
  evidence:
  - reference: PMID:39298146
    reference_title: "Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    snippet: Left ventricular ejection fraction (LVEF) (per 1%) was not associated with all-cause mortality
    explanation: While LVEF is the standard measure of LV systolic dysfunction in DCM, this study shows it is less prognostic than fibrosis markers.
    evidence_source: HUMAN_CLINICAL
- category: Respiratory
  name: Dyspnea
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
- category: Cardiovascular
  name: Palpitations
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Palpitations
    term:
      id: HP:0001962
      label: Palpitations
- category: Cardiovascular
  name: Arrhythmia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:37788487
    reference_title: "Genetics of Dilated Cardiomyopathy."
    supports: SUPPORT
    snippet: DCM genes can affect a variety of cardiomyocyte functions, and particular genes whose function affects the cell-cell junction and cytoskeleton are associated with increased risk of arrhythmias and sudden cardiac death.
    explanation: Genetic variants in DCM are associated with increased arrhythmia risk.
  - reference: PMID:39298146
    reference_title: "Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    snippet: The presence and extent of LGE were associated with various adverse clinical outcomes
    explanation: Myocardial fibrosis in DCM is associated with adverse outcomes including arrhythmic events.
    evidence_source: HUMAN_CLINICAL
- category: General
  name: Fatigue
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Cardiovascular
  name: Peripheral edema
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Peripheral edema
    term:
      id: HP:0012398
      label: Peripheral edema
genetic:
- name: TTN Truncating Variants
  gene_term:
    preferred_term: TTN
    term:
      id: hgnc:12403
      label: TTN
  association: Causative
  inheritance:
  - name: Autosomal dominant
  features: >
    Truncating variants in TTN (titin) are the most common genetic cause
    of familial DCM, found in approximately 15% of cases. Truncated titin
    integrates structurally into the sarcomere, causing defects at the I/A
    junction and M-band that impair mechanosensing.
  evidence:
  - reference: PMID:37962957
    reference_title: "Truncated titin is structurally integrated into the human dilated cardiomyopathic sarcomere."
    supports: SUPPORT
    snippet: Heterozygous (HET) truncating variant mutations in the TTN gene (TTNtvs), encoding the giant titin protein, are the most common genetic cause of dilated cardiomyopathy (DCM).
    explanation: Confirms TTN truncating variants as the most common genetic cause of DCM.
  - reference: CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2025-05-30T160000.000Z
    reference_title: "TTN / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TTN | HGNC:12403 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: ClinGen classifies the TTN-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
- name: LMNA Mutations
  gene_term:
    preferred_term: LMNA
    term:
      id: hgnc:6636
      label: LMNA
  association: Causative
  inheritance:
  - name: Autosomal dominant
  features: >
    Mutations in LMNA (lamin A/C) cause DCM frequently associated with
    conduction system disease and arrhythmias, representing one of the most
    malignant genetic forms. Found in 4-8% of all DCM cases.
  evidence:
  - reference: PMID:39519012
    reference_title: "Dilated Cardiomyopathy: A Genetic Journey from Past to Future."
    supports: SUPPORT
    snippet: Current guidelines recommend genetic counseling and screening, as well as endorsing a handful of genotype-specific therapies (e.g., device placement in LMNA cardiomyopathy).
    explanation: LMNA cardiomyopathy is recognized as requiring genotype-specific management including device therapy.
  - reference: CGGV:assertion_132ea1ec-caa9-409a-8670-3edb2ec9c889-2025-05-30T160000.000Z
    reference_title: "LMNA / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LMNA | HGNC:6636 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: ClinGen classifies the LMNA-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
- name: MYH7 Mutations
  gene_term:
    preferred_term: MYH7
    term:
      id: hgnc:7577
      label: MYH7
  association: Causative
  inheritance:
  - name: Autosomal dominant
  features: >
    Missense mutations in MYH7 (beta-myosin heavy chain) cause DCM through
    impaired sarcomeric function, representing the most frequent cause of
    pediatric genetic DCM.
  evidence:
  - reference: PMID:39494569
    reference_title: "Clinical Features and Outcomes of Pediatric MYH7-Related Dilated Cardiomyopathy."
    supports: SUPPORT
    snippet: genetic variants in MYH7 are the most frequent cause of pediatric genetic dilated cardiomyopathy (DCM)
    explanation: Confirms MYH7 as the most frequent cause of pediatric genetic DCM.
    evidence_source: HUMAN_CLINICAL
  - reference: CGGV:assertion_4ec27d4f-70ea-4c6a-ad67-d6260ecadcde-2025-05-30T160000.000Z
    reference_title: "MYH7 / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYH7 | HGNC:7577 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: ClinGen classifies the MYH7-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
- name: RBM20 Mutations
  gene_term:
    preferred_term: RBM20
    term:
      id: hgnc:27424
      label: RBM20
  association: Causative
  inheritance:
  - name: Autosomal dominant
  features: >
    Mutations in RBM20 cause aggressive DCM with early onset heart failure
    and high mortality through disrupted RNA splicing of TTN and calcium-handling
    genes.
  evidence:
  - reference: PMID:38288598
    reference_title: "Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems."
    supports: SUPPORT
    snippet: pathogenic variants in RBM20 are linked to aggressive dilated cardiomyopathy with early onset heart failure and high mortality.
    explanation: Confirms RBM20 variants cause aggressive DCM with poor outcomes.
  - reference: CGGV:assertion_3e123751-078a-4d30-9f83-847119982342-2020-08-20T160000.000Z
    reference_title: "RBM20 / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RBM20 | HGNC:27424 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: ClinGen classifies the RBM20-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
- name: ABCC9
  gene_term:
    preferred_term: ABCC9
    term:
      id: hgnc:60
      label: ABCC9
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_8be22ebc-f0f5-4de5-9c2a-382ebd02c533-2024-11-15T170000.000Z
    reference_title: "ABCC9 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ABCC9 | HGNC:60 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the ABCC9-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
- name: ACTC1
  gene_term:
    preferred_term: ACTC1
    term:
      id: hgnc:143
      label: ACTC1
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_3e9b4048-3003-4180-b891-fcf10d25a814-2025-04-25T040000.000Z
    reference_title: "ACTC1 / dilated cardiomyopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ACTC1 | HGNC:143 | dilated cardiomyopathy | MONDO:0005021 | AD | Moderate"
    explanation: ClinGen classifies the ACTC1-dilated cardiomyopathy gene-disease relationship as moderate with autosomal dominant inheritance.
- name: ANKRD1
  gene_term:
    preferred_term: ANKRD1
    term:
      id: hgnc:15819
      label: ANKRD1
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_3dcc6918-d7e7-4385-b343-bc8b8678b3a4-2025-02-07T170000.000Z
    reference_title: "ANKRD1 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ANKRD1 | HGNC:15819 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the ANKRD1-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
- name: BAG3
  gene_term:
    preferred_term: BAG3
    term:
      id: hgnc:939
      label: BAG3
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_1bec07e1-0186-4f45-bd8e-7d8a0f2547a9-2025-05-30T160000.000Z
    reference_title: "BAG3 / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BAG3 | HGNC:939 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: ClinGen classifies the BAG3-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
- name: BAG5
  gene_term:
    preferred_term: BAG5
    term:
      id: hgnc:941
      label: BAG5
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_97fe83b7-fe12-4014-9706-6847446fa9bd-2024-06-14T160000.000Z
    reference_title: "BAG5 / dilated cardiomyopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BAG5 | HGNC:941 | dilated cardiomyopathy | MONDO:0005021 | AR | Moderate"
    explanation: ClinGen classifies the BAG5-dilated cardiomyopathy gene-disease relationship as moderate with autosomal recessive inheritance.
- name: CDH2
  gene_term:
    preferred_term: CDH2
    term:
      id: hgnc:1759
      label: CDH2
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_73900af1-14ee-4933-b5dc-832753e6cc6c-2025-05-16T160000.000Z
    reference_title: "CDH2 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CDH2 | HGNC:1759 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the CDH2-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
- name: CTF1
  gene_term:
    preferred_term: CTF1
    term:
      id: hgnc:2499
      label: CTF1
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_ef19cc13-543b-451e-b278-ec1fc04f694c-2024-08-07T160000.000Z
    reference_title: "CTF1 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CTF1 | HGNC:2499 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the CTF1-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
- name: DES
  gene_term:
    preferred_term: DES
    term:
      id: hgnc:2770
      label: DES
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_91b2595a-5eb9-4ac3-aa3d-d5f99cacad84-2025-05-30T160000.000Z
    reference_title: "DES / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DES | HGNC:2770 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: ClinGen classifies the DES-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
- name: DSG2
  gene_term:
    preferred_term: DSG2
    term:
      id: hgnc:3049
      label: DSG2
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_a7df1018-593f-481f-9dd0-77ce3ea829a6-2025-03-28T160000.000Z
    reference_title: "DSG2 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DSG2 | HGNC:3049 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the DSG2-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
- name: FBXO32
  gene_term:
    preferred_term: FBXO32
    term:
      id: hgnc:16731
      label: FBXO32
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_9f006b4e-08a3-403c-86dd-704f741494fe-2025-05-30T160000.000Z
    reference_title: "FBXO32 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "FBXO32 | HGNC:16731 | dilated cardiomyopathy | MONDO:0005021 | AR | Limited"
    explanation: ClinGen classifies the FBXO32-dilated cardiomyopathy gene-disease relationship as limited with autosomal recessive inheritance.
- name: FLII
  gene_term:
    preferred_term: FLII
    term:
      id: hgnc:3750
      label: FLII
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_660622fe-f967-42be-a565-0383e5f710c2-2024-06-14T040000.000Z
    reference_title: "FLII / dilated cardiomyopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "FLII | HGNC:3750 | dilated cardiomyopathy | MONDO:0005021 | AR | Moderate"
    explanation: ClinGen classifies the FLII-dilated cardiomyopathy gene-disease relationship as moderate with autosomal recessive inheritance.
- name: FLNC
  gene_term:
    preferred_term: FLNC
    term:
      id: hgnc:3756
      label: FLNC
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_edb5197f-05dc-42a4-a497-fff472985c6b-2025-05-30T160000.000Z
    reference_title: "FLNC / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "FLNC | HGNC:3756 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: ClinGen classifies the FLNC-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
- name: GATAD1
  gene_term:
    preferred_term: GATAD1
    term:
      id: hgnc:29941
      label: GATAD1
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_56933afb-863f-46f5-884d-17522adb31a8-2024-08-07T160000.000Z
    reference_title: "GATAD1 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GATAD1 | HGNC:29941 | dilated cardiomyopathy | MONDO:0005021 | AR | Limited"
    explanation: ClinGen classifies the GATAD1-dilated cardiomyopathy gene-disease relationship as limited with autosomal recessive inheritance.
- name: GET3
  gene_term:
    preferred_term: GET3
    term:
      id: hgnc:752
      label: GET3
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_605f9805-5af1-445a-911a-d31ebff15125-2025-05-02T160000.000Z
    reference_title: "GET3 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GET3 | HGNC:752 | dilated cardiomyopathy | MONDO:0005021 | AR | Limited"
    explanation: ClinGen classifies the GET3-dilated cardiomyopathy gene-disease relationship as limited with autosomal recessive inheritance.
- name: JPH2
  gene_term:
    preferred_term: JPH2
    term:
      id: hgnc:14202
      label: JPH2
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_8d310e47-1f84-4c61-b06a-b273a4b1b601-2025-01-24T170000.000Z
    reference_title: "JPH2 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "JPH2 | HGNC:14202 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the JPH2-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
  - reference: CGGV:assertion_7aa138ae-114c-46b0-84e4-5bfc5a7db51b-2025-01-24T170000.000Z
    reference_title: "JPH2 / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "JPH2 | HGNC:14202 | dilated cardiomyopathy | MONDO:0005021 | AR | Strong"
    explanation: ClinGen classifies the JPH2-dilated cardiomyopathy gene-disease relationship as strong with autosomal recessive inheritance.
- name: LAMA4
  gene_term:
    preferred_term: LAMA4
    term:
      id: hgnc:6484
      label: LAMA4
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_e937f98e-7577-48bd-a24a-361634ba0a8d-2024-11-15T170000.000Z
    reference_title: "LAMA4 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LAMA4 | HGNC:6484 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the LAMA4-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
- name: LDB3
  gene_term:
    preferred_term: LDB3
    term:
      id: hgnc:15710
      label: LDB3
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_7756e3c0-5a16-49b8-ac0f-220e79a4fa99-2025-03-21T040000.000Z
    reference_title: "LDB3 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LDB3 | HGNC:15710 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the LDB3-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
  - reference: CGGV:assertion_c9d89b2d-2761-47d5-a773-e592f8e6d1df-2025-03-21T040000.000Z
    reference_title: "LDB3 / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LDB3 | HGNC:15710 | dilated cardiomyopathy | MONDO:0005021 | AR | Strong"
    explanation: ClinGen classifies the LDB3-dilated cardiomyopathy gene-disease relationship as strong with autosomal recessive inheritance.
- name: LMOD2
  gene_term:
    preferred_term: LMOD2
    term:
      id: hgnc:6648
      label: LMOD2
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_d19140d6-8200-4fce-9906-fdda527a4f7e-2024-10-04T160000.000Z
    reference_title: "LMOD2 / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LMOD2 | HGNC:6648 | dilated cardiomyopathy | MONDO:0005021 | AR | Definitive"
    explanation: ClinGen classifies the LMOD2-dilated cardiomyopathy gene-disease relationship as definitive with autosomal recessive inheritance.
- name: MIB1
  gene_term:
    preferred_term: MIB1
    term:
      id: hgnc:21086
      label: MIB1
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_d97cecce-b9a7-42fb-bc2d-034468094949-2024-10-04T160000.000Z
    reference_title: "MIB1 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MIB1 | HGNC:21086 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the MIB1-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
- name: MYBPC3
  gene_term:
    preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_652d0370-9574-450c-b7c4-eec86ade9046-2025-05-16T160000.000Z
    reference_title: "MYBPC3 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYBPC3 | HGNC:7551 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the MYBPC3-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
  - reference: CGGV:assertion_f240fb99-f839-4b9b-8e52-f2dc49078886-2025-05-16T040000.000Z
    reference_title: "MYBPC3 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYBPC3 | HGNC:7551 | dilated cardiomyopathy | MONDO:0005021 | AR | Limited"
    explanation: ClinGen classifies the MYBPC3-dilated cardiomyopathy gene-disease relationship as limited with autosomal recessive inheritance.
- name: MYH6
  gene_term:
    preferred_term: MYH6
    term:
      id: hgnc:7576
      label: MYH6
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_6d55ac7b-e9d8-4a97-bb20-92beeffaed96-2025-03-07T170000.000Z
    reference_title: "MYH6 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYH6 | HGNC:7576 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the MYH6-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
- name: MYL2
  gene_term:
    preferred_term: MYL2
    term:
      id: hgnc:7583
      label: MYL2
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_8405609b-1664-4849-848e-bec138350c92-2025-05-16T160000.000Z
    reference_title: "MYL2 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYL2 | HGNC:7583 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the MYL2-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
- name: MYLK3
  gene_term:
    preferred_term: MYLK3
    term:
      id: hgnc:29826
      label: MYLK3
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_713bb7fc-2ae0-488f-acfa-4c0bf963e8bc-2025-07-11T160000.000Z
    reference_title: "MYLK3 / dilated cardiomyopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYLK3 | HGNC:29826 | dilated cardiomyopathy | MONDO:0005021 | AD | Moderate"
    explanation: ClinGen classifies the MYLK3-dilated cardiomyopathy gene-disease relationship as moderate with autosomal dominant inheritance.
- name: MYPN
  gene_term:
    preferred_term: MYPN
    term:
      id: hgnc:23246
      label: MYPN
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_ffd924ad-55ce-4b05-8a91-584ef49b4e80-2025-03-05T050000.000Z
    reference_title: "MYPN / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYPN | HGNC:23246 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the MYPN-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
- name: MYZAP
  gene_term:
    preferred_term: MYZAP
    term:
      id: hgnc:43444
      label: MYZAP
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_587dc3e6-fc9e-4802-8370-cbff25731f45-2024-08-23T160000.000Z
    reference_title: "MYZAP / dilated cardiomyopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYZAP | HGNC:43444 | dilated cardiomyopathy | MONDO:0005021 | AR | Moderate"
    explanation: ClinGen classifies the MYZAP-dilated cardiomyopathy gene-disease relationship as moderate with autosomal recessive inheritance.
- name: NEBL
  gene_term:
    preferred_term: NEBL
    term:
      id: hgnc:16932
      label: NEBL
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_29bc6c4f-3f2d-45e2-b796-a79616857094-2024-10-18T160000.000Z
    reference_title: "NEBL / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NEBL | HGNC:16932 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the NEBL-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
- name: NEXN
  gene_term:
    preferred_term: NEXN
    term:
      id: hgnc:29557
      label: NEXN
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_ffe00b43-a449-4476-b7e0-f24cf6613766-2024-11-15T050000.000Z
    reference_title: "NEXN / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NEXN | HGNC:29557 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
    explanation: ClinGen classifies the NEXN-dilated cardiomyopathy gene-disease relationship as strong with autosomal dominant inheritance.
- name: NRAP
  gene_term:
    preferred_term: NRAP
    term:
      id: hgnc:7988
      label: NRAP
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_f72c0812-9782-444c-a87c-b50286bbfd09-2024-07-26T160000.000Z
    reference_title: "NRAP / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NRAP | HGNC:7988 | dilated cardiomyopathy | MONDO:0005021 | AR | Strong"
    explanation: ClinGen classifies the NRAP-dilated cardiomyopathy gene-disease relationship as strong with autosomal recessive inheritance.
- name: OBSCN
  gene_term:
    preferred_term: OBSCN
    term:
      id: hgnc:15719
      label: OBSCN
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_e1b69281-f3d0-4efe-998d-db080868b57e-2025-02-07T170000.000Z
    reference_title: "OBSCN / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OBSCN | HGNC:15719 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the OBSCN-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
- name: PLEKHM2
  gene_term:
    preferred_term: PLEKHM2
    term:
      id: hgnc:29131
      label: PLEKHM2
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_44c534b9-16d1-435b-9eca-fb7d1de6ea26-2024-11-15T170000.000Z
    reference_title: "PLEKHM2 / dilated cardiomyopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PLEKHM2 | HGNC:29131 | dilated cardiomyopathy | MONDO:0005021 | AR | Moderate"
    explanation: ClinGen classifies the PLEKHM2-dilated cardiomyopathy gene-disease relationship as moderate with autosomal recessive inheritance.
- name: PPA2
  gene_term:
    preferred_term: PPA2
    term:
      id: hgnc:28883
      label: PPA2
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_35b7716c-4c72-4ca2-b176-e732d136ed0d-2025-05-16T160000.000Z
    reference_title: "PPA2 / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PPA2 | HGNC:28883 | dilated cardiomyopathy | MONDO:0005021 | AR | Strong"
    explanation: ClinGen classifies the PPA2-dilated cardiomyopathy gene-disease relationship as strong with autosomal recessive inheritance.
- name: PRDM16
  gene_term:
    preferred_term: PRDM16
    term:
      id: hgnc:14000
      label: PRDM16
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_c0a3445a-5bb0-4d77-a4f0-5b7cfceb837f-2025-05-30T160000.000Z
    reference_title: "PRDM16 / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PRDM16 | HGNC:14000 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
    explanation: ClinGen classifies the PRDM16-dilated cardiomyopathy gene-disease relationship as strong with autosomal dominant inheritance.
- name: RPL3L
  gene_term:
    preferred_term: RPL3L
    term:
      id: hgnc:10351
      label: RPL3L
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_1dae12df-f703-4e4d-99b6-b38f6ed65fa0-2025-05-30T160000.000Z
    reference_title: "RPL3L / dilated cardiomyopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RPL3L | HGNC:10351 | dilated cardiomyopathy | MONDO:0005021 | AR | Moderate"
    explanation: ClinGen classifies the RPL3L-dilated cardiomyopathy gene-disease relationship as moderate with autosomal recessive inheritance.
- name: RYR2
  gene_term:
    preferred_term: RYR2
    term:
      id: hgnc:10484
      label: RYR2
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_b35e4dc8-c7d6-4c20-995f-0b1f4508ee3d-2025-01-10T170000.000Z
    reference_title: "RYR2 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RYR2 | HGNC:10484 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the RYR2-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
- name: SCN5A
  gene_term:
    preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_53c90d2e-4d40-48ab-8761-b0158102c977-2025-05-30T160000.000Z
    reference_title: "SCN5A / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SCN5A | HGNC:10593 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: ClinGen classifies the SCN5A-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
- name: TBX20
  gene_term:
    preferred_term: TBX20
    term:
      id: hgnc:11598
      label: TBX20
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_58a014d9-2d97-4041-961d-cfd09fa11adf-2025-05-02T160000.000Z
    reference_title: "TBX20 / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TBX20 | HGNC:11598 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
    explanation: ClinGen classifies the TBX20-dilated cardiomyopathy gene-disease relationship as strong with autosomal dominant inheritance.
- name: TCAP
  gene_term:
    preferred_term: TCAP
    term:
      id: hgnc:11610
      label: TCAP
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_4c8ab9d8-919a-443f-b027-5aec92b273d1-2025-04-18T040000.000Z
    reference_title: "TCAP / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TCAP | HGNC:11610 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: ClinGen classifies the TCAP-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.
- name: TMOD1
  gene_term:
    preferred_term: TMOD1
    term:
      id: hgnc:11871
      label: TMOD1
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_dbcee227-6a90-474b-ba94-7714bcf704d5-2025-05-02T160000.000Z
    reference_title: "TMOD1 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TMOD1 | HGNC:11871 | dilated cardiomyopathy | MONDO:0005021 | AR | Limited"
    explanation: ClinGen classifies the TMOD1-dilated cardiomyopathy gene-disease relationship as limited with autosomal recessive inheritance.
- name: TNNC1
  gene_term:
    preferred_term: TNNC1
    term:
      id: hgnc:11943
      label: TNNC1
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_6ad71467-74c0-4a7c-932d-c5ca5747e59e-2025-05-30T160000.000Z
    reference_title: "TNNC1 / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TNNC1 | HGNC:11943 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: ClinGen classifies the TNNC1-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
- name: TNNI3
  gene_term:
    preferred_term: TNNI3
    term:
      id: hgnc:11947
      label: TNNI3
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_668087ea-0d2f-42c2-a291-f73400d34023-2025-04-18T160000.000Z
    reference_title: "TNNI3 / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TNNI3 | HGNC:11947 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
    explanation: ClinGen classifies the TNNI3-dilated cardiomyopathy gene-disease relationship as strong with autosomal dominant inheritance.
  - reference: CGGV:assertion_b89182f6-1574-48c6-832f-add41ffbaa4c-2025-04-18T160000.000Z
    reference_title: "TNNI3 / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TNNI3 | HGNC:11947 | dilated cardiomyopathy | MONDO:0005021 | AR | Strong"
    explanation: ClinGen classifies the TNNI3-dilated cardiomyopathy gene-disease relationship as strong with autosomal recessive inheritance.
- name: TNNI3K
  gene_term:
    preferred_term: TNNI3K
    term:
      id: hgnc:19661
      label: TNNI3K
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_f5ce5790-8940-4d7a-a85c-8682be86939d-2025-09-05T160000.000Z
    reference_title: "TNNI3K / dilated cardiomyopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TNNI3K | HGNC:19661 | dilated cardiomyopathy | MONDO:0005021 | AD | Moderate"
    explanation: ClinGen classifies the TNNI3K-dilated cardiomyopathy gene-disease relationship as moderate with autosomal dominant inheritance.
- name: TNNT2
  gene_term:
    preferred_term: TNNT2
    term:
      id: hgnc:11949
      label: TNNT2
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_20fbdfad-b2d2-45f1-9658-e2e3e02cb413-2025-05-30T160000.000Z
    reference_title: "TNNT2 / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TNNT2 | HGNC:11949 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: ClinGen classifies the TNNT2-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.
- name: TPM1
  gene_term:
    preferred_term: TPM1
    term:
      id: hgnc:12010
      label: TPM1
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_1173d239-23cf-4c9c-9ea5-f95d9356e6c7-2025-04-04T160000.000Z
    reference_title: "TPM1 / dilated cardiomyopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TPM1 | HGNC:12010 | dilated cardiomyopathy | MONDO:0005021 | AD | Moderate"
    explanation: ClinGen classifies the TPM1-dilated cardiomyopathy gene-disease relationship as moderate with autosomal dominant inheritance.
- name: VCL
  gene_term:
    preferred_term: VCL
    term:
      id: hgnc:12665
      label: VCL
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_2d46699a-5f8c-460d-9233-bec4e2ecf560-2024-08-09T160000.000Z
    reference_title: "VCL / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "VCL | HGNC:12665 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
    explanation: ClinGen classifies the VCL-dilated cardiomyopathy gene-disease relationship as strong with autosomal dominant inheritance.
treatments:
- name: ACE Inhibitors / ARBs
  description: First-line neurohormonal blockade to reduce afterload and prevent adverse remodeling.
  treatment_term:
    preferred_term: ACE inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Beta-Blockers
  description: Reduce heart rate and neurohormonal activation, improving survival in heart failure with reduced ejection fraction.
  treatment_term:
    preferred_term: beta-blocker therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: SGLT2 Inhibitors
  description: Newer therapy shown to reduce heart failure hospitalization and cardiovascular death in HFrEF regardless of diabetes status.
  treatment_term:
    preferred_term: SGLT2 inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Cardiac Resynchronization Therapy
  description: Biventricular pacing for patients with wide QRS and reduced LVEF to improve synchrony and outcomes.
  treatment_term:
    preferred_term: cardiac resynchronization therapy
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Heart Transplantation
  description: Definitive therapy for end-stage DCM refractory to medical and device therapy.
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
- name: Implantable Cardioverter-Defibrillator
  description: Indicated for primary prevention of sudden cardiac death in patients with LVEF <=35% despite optimal medical therapy.
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Genetic Counseling
  description: Recommended for patients with familial or genetic DCM to guide cascade screening and family management.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:37788487
    reference_title: "Genetics of Dilated Cardiomyopathy."
    supports: SUPPORT
    snippet: Through advancements in next-generation sequencing and cardiac imaging, identification of genetic DCM has improved over the past couple decades, and precision medicine is now at the forefront of treatment for these patients and their families.
    explanation: Confirms the importance of genetic identification and precision medicine in DCM management.
  - reference: PMID:39519012
    reference_title: "Dilated Cardiomyopathy: A Genetic Journey from Past to Future."
    supports: SUPPORT
    snippet: Current guidelines recommend genetic counseling and screening, as well as endorsing a handful of genotype-specific therapies
    explanation: Guidelines explicitly recommend genetic counseling and screening for DCM.
📚

References & Deep Research

Deep Research

1
Falcon
Disease Pathophysiology Research Template
Edison Scientific Literature 41 citations 2026-03-06T04:24:09.427570

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

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

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

Disease Pathophysiology Research Template

Target Disease

  • Disease Name: Dilated Cardiomyopathy
  • MONDO ID: (if available)
  • Category: Complex

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Dilated Cardiomyopathy. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

  • What are the primary pathophysiological mechanisms?
  • What molecular pathways are dysregulated?
  • What cellular processes are affected?

2. Key Molecular Players

  • Genes/Proteins: Which genes are causally involved or implicated?
  • Chemical Entities: What metabolites, drugs, or small molecules are relevant?
  • Cell Types: Which cell types are primarily affected?
  • Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

  • What biological processes (GO terms) are disrupted?
  • Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

  • Where in the cell do key processes occur?
  • Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

  • What is the sequence of events from initial trigger to clinical manifestation?
  • Are there distinct stages or phases?

6. Phenotypic Manifestations

  • What are the key clinical phenotypes?
  • How do they relate to the underlying mechanisms?

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Comprehensive Research Report: Dilated Cardiomyopathy (DCM) Pathophysiology (Molecular & Cellular)

Disease identifiers

  • Disease name: Dilated cardiomyopathy (DCM)
  • Category: Complex (heterogeneous; monogenic + polygenic + acquired contributors)
  • Ontology examples in recent resources: Open Targets uses EFO:0000407 (dilated cardiomyopathy) and HP:0001644 (Dilated cardiomyopathy phenotype) (not a MONDO mapping in the retrieved evidence). (arnautu2024geneticsandmolecular pages 5-7)

1) Key concepts and definitions (current understanding)

Clinical definition (phenotype-level)

DCM is characterized by left-ventricular or biventricular dilatation and systolic dysfunction not explained by abnormal loading conditions or ischemic heart disease (non-ischemic DCM definitions are explicitly stated in the CMR risk meta-analysis). (eichhorn2024riskstratificationin pages 1-2)

Genetic architecture: monogenic → oligogenic/polygenic spectrum

Recent authoritative reviews emphasize that DCM frequently reflects a final common pathway reached through diverse genetic and acquired perturbations, and that many cases fall on a monogenic-to-polygenic continuum. - Eldemire et al. note that “Up to 50% of nonischemic DCM is genetic or idiopathic” and that gene–environment interactions modify phenotypic expression. (eldemire2024geneticsofdilated pages 1-3) - Newman & Burke frame DCM genetics as a spectrum: “a complex genetic spectrum ranging from monogenic to polygenic” and state that prevalence estimates derived from population imaging support a higher background burden than historically recognized. (newman2024dilatedcardiomyopathya pages 1-2) - Oligogenic contributions are highlighted: “20–38% of DCM may have an oligogenic basis” (multiple rare variants contributing to similar phenotype). (eldemire2024geneticsofdilated pages 1-3)

Epidemiology (recently updated estimates)

Population estimates have been revised upward compared with older registry estimates. - Newman & Burke summarize that revised population estimates place prevalence near 1:250 (0.4%), with UK Biobank cardiac MRI ~1 in 220 (0.45%, 95% CI 0.39–0.53%). (newman2024dilatedcardiomyopathya pages 1-2)


2) Core pathophysiology: primary mechanisms and dysregulated pathways

DCM progression is driven by contractile failure and maladaptive remodeling, typically involving (i) impaired force generation and/or transmission, (ii) stress-response pathway activation, and (iii) myocardial remodeling with fibrosis and arrhythmogenic substrate.

2.1 Sarcomere dysfunction and mechanosensing failure (central mechanism)

A unifying mechanism across many genetic DCM forms is depressed tension generation with altered mechanotransduction. - Solaro et al. summarize the prevailing concept: variants in sarcomeric/cytoskeletal proteins “cause a decrease in tension by the myofilaments,” leading to signaling abnormalities and later “structural and functional maladaptations, leading to heart failure.” (solaro2024emergingconceptsof pages 1-2)

TTN truncating variants (TTNtv) are the most common monogenic contributors in adult DCM and are strongly tied to sarcomere integrity and mechanosensing. - In a human explanted-heart cohort (n=127 DCM samples), Kellermayer et al. report: “The occurrence of TTNtv was found to be 15% in the DCM cohort.” They also report reduced full-length titin in TTNtv+ samples and show sarcomere-localization evidence using proteomics and STED microscopy. (kellermayer2024truncatedtitinis pages 1-2) - Their abstract summarizes a key mechanistic inference: sarcomeric epitope analyses pointed to “possible structural defects in the I/A junction and the M-band of TTNtv+ sarcomeres, which probably contribute, possibly via faulty mechanosensor function, to the development of manifest DCM.” (kellermayer2024truncatedtitinis pages 1-2)

Direct visual evidence: STED super-resolution microscopy images show preserved gross sarcomeric registry in TTNtv+ tissue compared with TTNtv− and controls, supporting structural integration of titin epitopes in sarcomeres rather than diffuse mislocalization. (kellermayer2024truncatedtitinis media 0d428a5a, kellermayer2024truncatedtitinis media 3e1be5e2)

2.2 RNA processing and alternative splicing dysregulation (RBM20 axis)

RBM20 cardiomyopathy illustrates how gene-expression regulation can drive DCM by altering protein isoforms (notably titin). - Gregorich et al. describe that pathogenic RBM20 variants are “linked to aggressive dilated cardiomyopathy with early onset heart failure and high mortality.” Mechanistically, certain variants “not only disrupt splicing but also hinder nucleocytoplasmic transport and lead to the formation of RBM20 biomolecular condensates in the sarcoplasm.” (gregorich2024mechanismsofrbm20 pages 1-3) - Newman & Burke further connect RBM20 dysfunction to titin isoforms and arrhythmia mechanisms, noting RBM20-mediated splicing changes shift titin toward more compliant isoforms and affect Ca2+ handling genes (e.g., CACNA1C, CAMK2D). (newman2024dilatedcardiomyopathya pages 7-8)

2.3 Nuclear envelope / mechanotransduction defects (LMNA axis)

Nuclear structural instability and altered mechanotransduction contribute to arrhythmia-prone and progressive DCM. - Newman & Burke characterize LMNA cardiomyopathy as “the most malignant genetic DCM,” with “a high burden of conduction system disease… malignant VAs,” and “very high rates of progression to end-stage HF.” (newman2024dilatedcardiomyopathya pages 13-14)

2.4 Inflammation and immune activation (especially inflammatory DCM / myocarditis transition)

Immune-mediated injury can be causal (primary) or act as an accelerator of remodeling. - Xu et al. outline a canonical myocarditis-to-DCM progression model with three phases, stating that chronic phases “can last from months to years” and that “chronic cardiac inflammation can finally result in the incidence of DCM.” (xu2024constructionandevaluation pages 1-2) - Vicenzetto et al. note that virus-negative and/or virus-positive inflammatory cardiomyopathy has drawn attention because of emerging etiologic treatments, linking inflammatory cardiomyopathy to the “onset and progression of dilated cardiomyopathy (DCM).” (vicenzetto2024theroleof pages 1-2)

2.5 Fibrosis and adverse myocardial remodeling (ECM + scar as a downstream integrator)

Fibrosis (replacement and interstitial) is a common downstream consequence across genetic and acquired DCM, contributing to systolic dysfunction and arrhythmogenesis. - In the largest recent quantitative synthesis, a JAMA systematic review/meta-analysis (103 studies; 29,687 patients) reported that late gadolinium enhancement (LGE) is strongly prognostic: LGE presence associated with all-cause mortality (HR 1.81) and arrhythmic events (HR 2.69), among other outcomes. (eichhorn2024riskstratificationin pages 1-2)

2.6 Polygenic mechanisms and myocardial resilience (GWAS-era insights)

Recent 2024 Nature Genetics GWAS analyses reinforce that cardiomyocytes and the contractile apparatus are central, while also identifying non-cardiomyocyte states and intercellular signaling. - Jurgens et al. performed GWAS/MTAG with 9,365 cases and 946,368 controls, finding 70 genome-wide significant loci; enrichment analyses highlighted “the central role of the cardiomyocyte and contractile apparatus.” (jurgens2024genomewideassociationstudy pages 1-2) - Zheng et al. identified 80 loci (59 genome-wide + 21 FDR 1%) and used single-nucleus transcriptomics of end-stage DCM hearts to identify noncardiomyocyte states and pathway signals (e.g., Ephrin-B/BMP6 pathway involvement). (zheng2024genomewideassociationanalysis pages 10-11)


3) Key molecular players, cell types, and anatomical locations

3.1 Genes/proteins (representative, evidence-supported)

Key gene classes include sarcomere/contractility (TTN, MYH7, troponins), nuclear envelope (LMNA), RNA splicing (RBM20), cytoskeleton/desmosome (FLNC, DSP, DES), protein quality control (BAG3), and ion handling. (newman2024dilatedcardiomyopathya pages 4-6, newman2024dilatedcardiomyopathya pages 13-14, gregorich2024mechanismsofrbm20 pages 1-3, newman2024dilatedcardiomyopathya pages 7-8)

3.2 Cell types

  • Cardiomyocytes are central (contractile and mechanosensing enrichment in GWAS; sarcomere defects; nuclear/splicing pathology). (jurgens2024genomewideassociationstudy pages 1-2, kellermayer2024truncatedtitinis pages 1-2)
  • Immune cells (T cells, macrophages, neutrophils) contribute particularly in inflammatory DCM/myocarditis-associated DCM; computational deconvolution reported differences in activated CD4 memory T cells, Tregs, and neutrophils. (xu2024constructionandevaluation pages 1-2)

3.3 Anatomical locations

  • Predominant phenotype arises in the left ventricle, often biventricular; this is reflected in imaging-based phenotyping and outcomes. (eichhorn2024riskstratificationin pages 1-2)

3.4 Chemical entities

  • Calcium ion (Ca2+) is mechanistically implicated through excitation–contraction coupling and splicing effects (RBM20 targets) and arrhythmogenesis. (newman2024dilatedcardiomyopathya pages 7-8)
  • Gadolinium contrast is used for CMR LGE, a fibrosis surrogate with strong prognostic hazard ratios in DCM. (eichhorn2024riskstratificationin pages 1-2)

4) Biological processes (GO-style) disrupted (for knowledge-base annotation)

A minimal, evidence-aligned GO-style set includes: - Sarcomere organization / muscle contraction / mechanosensing (TTN, MYH7 and sarcomeric tension model). (solaro2024emergingconceptsof pages 1-2, kellermayer2024truncatedtitinis pages 1-2) - Alternative splicing / mRNA processing (RBM20). (gregorich2024mechanismsofrbm20 pages 1-3, newman2024dilatedcardiomyopathya pages 7-8) - Immune response / cytokine-mediated signaling (myocarditis transition to DCM; immune infiltration signatures). (vicenzetto2024theroleof pages 1-2, xu2024constructionandevaluation pages 1-2) - Extracellular matrix organization / fibrosis (scar formation) (LGE-associated outcomes). (eichhorn2024riskstratificationin pages 1-2)


5) Cellular components (GO-CC style) where key processes occur

  • Sarcomere substructures (I/A junction; M-band): implicated as structurally perturbed regions in TTNtv+ DCM sarcomeres. (kellermayer2024truncatedtitinis pages 1-2)
  • Sarcoplasm: site of RBM20 biomolecular condensates in certain pathogenic variants. (gregorich2024mechanismsofrbm20 pages 1-3)
  • Nuclear envelope / nuclear lamina: LMNA-driven disease mechanism (nuclear structure/function). (newman2024dilatedcardiomyopathya pages 13-14)

6) Disease progression: sequence of events (trigger → phenotype)

Stage model (integrated)

  1. Initial trigger: rare pathogenic variant (e.g., TTNtv, LMNA, RBM20) and/or acquired injury (e.g., viral myocarditis, toxins), often with gene–environment interaction and sometimes oligogenic background. (eldemire2024geneticsofdilated pages 1-3, newman2024dilatedcardiomyopathya pages 13-14)
  2. Primary cellular dysfunction:
  3. Reduced tension generation and altered mechanotransduction (sarcomere dysfunction). (solaro2024emergingconceptsof pages 1-2, kellermayer2024truncatedtitinis pages 1-2)
  4. Spliceopathy with altered titin isoforms and potentially Ca2+ handling gene splicing (RBM20). (gregorich2024mechanismsofrbm20 pages 1-3, newman2024dilatedcardiomyopathya pages 7-8)
  5. Nuclear envelope dysfunction and conduction/arrhythmia susceptibility (LMNA). (newman2024dilatedcardiomyopathya pages 13-14)
  6. Immune activation and chronic inflammatory injury (myocarditis-to-DCM phases). (xu2024constructionandevaluation pages 1-2)
  7. Maladaptive remodeling: ventricular dilatation, wall thinning, fibrosis, electrical remodeling → arrhythmogenic substrate. (solaro2024emergingconceptsof pages 1-2, eichhorn2024riskstratificationin pages 1-2)
  8. Clinical syndrome: progressive HF, arrhythmias, thromboembolism risk, and in advanced cases transplantation/VAD. Pediatric outcomes can be severe early (nearly 40% transplant/death within 2 years in pediatric DCM review). (malinow2024pediatricdilatedcardiomyopathy pages 1-2)

7) Phenotypic manifestations (clinical phenotypes linked to mechanisms)

  • Systolic dysfunction with chamber dilation (definitional phenotype). (eichhorn2024riskstratificationin pages 1-2)
  • Arrhythmias and sudden cardiac death risk, particularly in arrhythmogenic genetic subtypes (e.g., LMNA, FLNC, RBM20). (newman2024dilatedcardiomyopathya pages 13-14, gregorich2024mechanismsofrbm20 pages 1-3)
  • Fibrosis/scar detectable by CMR LGE, strongly associated with mortality and arrhythmic outcomes. (eichhorn2024riskstratificationin pages 1-2)

8) Recent developments (prioritizing 2023–2024)

8.1 Human-tissue mechanistic resolution of TTNtv controversy (2024)

Kellermayer et al. used NGS + proteomics + STED microscopy in human DCM myocardium, supporting sarcomere integration of truncated titin and pointing to I/A junction and M-band defects as mechanistic contributors. (kellermayer2024truncatedtitinis pages 1-2, kellermayer2024truncatedtitinis media 0d428a5a, kellermayer2024truncatedtitinis media 3e1be5e2)

8.2 RBM20 condensates as a candidate disease mechanism (2024)

RBM20 pathogenic variants may act beyond splice disruption, involving altered nucleocytoplasmic transport and formation of sarcoplasmic condensates, with ongoing debate on which mechanism is causal. (gregorich2024mechanismsofrbm20 pages 1-3)

8.3 GWAS and single-nucleus transcriptomics define pathways and cell states (2024)

Large-scale GWAS/MTAG (2024) identifies dozens of loci and reinforces cardiomyocyte contractile apparatus enrichment; complementary analyses implicate noncardiomyocyte states and signaling pathways in end-stage myocardium. (jurgens2024genomewideassociationstudy pages 1-2, zheng2024genomewideassociationanalysis pages 10-11)

8.4 Imaging biomarkers outrank LVEF for certain endpoints (2024)

In nonischemic DCM, LGE presence/extent is consistently associated with mortality and arrhythmic outcomes, while LVEF was not significantly associated with mortality/arrhythmic endpoints in the meta-analysis. (eichhorn2024riskstratificationin pages 1-2)


9) Current applications and real-world implementations

9.1 Genetic evaluation, counseling, and cascade screening

  • Eldemire et al. emphasize genetic testing as integral to diagnosis, prognostication, and treatment, alongside detailed family history and rhythm monitoring. (eldemire2024geneticsofdilated pages 1-3, eldemire2024geneticsofdilated pages 3-5)
  • Newman & Burke report real-world testing yield and implementation considerations (VUS burden; cost-effectiveness of cascade testing vs periodic surveillance; society-level guideline differences). (newman2024dilatedcardiomyopathya pages 14-17)

9.2 CMR tissue characterization for risk stratification

  • Eldemire et al. describe CMRI as a gold standard for volumes/function and tissue characterization, while outcome associations for LGE are emphasized. (eldemire2024geneticsofdilated pages 3-5)
  • The 2024 JAMA meta-analysis provides quantitative risk estimates supporting LGE-based stratification. (eichhorn2024riskstratificationin pages 1-2)

9.3 Precision medicine direction: genotype-informed management

  • Reviews emphasize the move toward mechanism-specific therapies and genotype-informed decisions (e.g., LMNA-associated device decisions; potential future polygenic risk integration). (eldemire2024geneticsofdilated pages 1-3, newman2024dilatedcardiomyopathya pages 13-14)

10) Key statistics and recent quantitative findings (selected)

  • Prevalence (revised): ~1:250 overall; UK Biobank CMR ~1 in 220. (newman2024dilatedcardiomyopathya pages 1-2)
  • Familial/genetic: ~40% of familial DCM has an identifiable genetic cause. (eldemire2024geneticsofdilated pages 1-3)
  • Oligogenic basis: 20–38% may be oligogenic. (eldemire2024geneticsofdilated pages 1-3)
  • TTNtv in human DCM myocardium: 15% in 127 explanted DCM samples. (kellermayer2024truncatedtitinis pages 1-2)
  • TTNtv frequencies in cohorts: ~11–15% sporadic adult DCM; 23–27% familial DCM (review synthesis). (newman2024dilatedcardiomyopathya pages 7-8)
  • CMR outcomes: LGE presence HR 1.81 (all-cause mortality) and HR 2.69 (arrhythmic events) in 29,687-patient meta-analysis. (eichhorn2024riskstratificationin pages 1-2)
  • GWAS scale: 9,365 cases/946,368 controls; 70 loci; 63 prioritized genes (2024). (jurgens2024genomewideassociationstudy pages 1-2)

Knowledge-base-ready structured artifacts

Mechanisms summary table

Mechanism Key Genes/Proteins (HGNC) Affected Cell Types (CL) Dysregulated Processes (GO-like) Evidence/Data Points Key Citations
Sarcomere Dysfunction TTN, MYH7, TNNT2, TNNC1 Cardiomyocyte Muscle contraction, sarcomere organization, mechanosensing TTN truncations (TTNtv) found in 15-25% of familial DCM; truncated titin integrates into sarcomeres ("poison peptide" effect) causing structural defects; altered length-dependent activation. (arnautu2024geneticsandmolecular pages 5-7, kellermayer2024truncatedtitinis pages 1-2, newman2024dilatedcardiomyopathya pages 7-8, kellermayer2024truncatedtitinis pages 6-7)
Nuclear Envelope Instability LMNA Cardiomyocyte, Fibroblast Nuclear organization, chromatin regulation, mechanotransduction LMNA variants found in 4-8% of all DCM and up to 30% of familial cases with conduction disease; associated with "malignant" phenotype: high fibrosis, arrhythmias, and progression to end-stage HF. (arnautu2024geneticsandmolecular pages 5-7, arnautu2024geneticsandmolecular pages 7-8, newman2024dilatedcardiomyopathya pages 13-14)
Defective RNA Splicing RBM20 Cardiomyocyte mRNA processing, alternative splicing RBM20 dysfunction causes aberrant splicing of TTN (shift to compliant N2BA isoform) and Ca2+ handling genes (CAMK2D, CACNA1C); forms toxic sarcoplasmic ribonucleoprotein condensates. (arnautu2024geneticsandmolecular pages 5-7, gregorich2024mechanismsofrbm20 pages 1-3, newman2024dilatedcardiomyopathya pages 7-8)
Cytoskeletal & Desmosomal Integrity DES, FLNC, DSP, PKP2 Cardiomyocyte Intermediate filament organization, cell-cell adhesion FLNC variants linked to high arrhythmic risk even with mild LV dysfunction; DSP variants found in ~13% of transplant cases; disruption leads to cell death and fibrofatty replacement. (arnautu2024geneticsandmolecular pages 5-7, arnautu2024geneticsandmolecular pages 7-8, newman2024dilatedcardiomyopathya pages 13-14)
Fibrosis & Structural Remodeling Polygenic loci (e.g., HSPB7, BAG3) Fibroblast, Cardiomyocyte Extracellular matrix organization, tissue fibrosis Presence of Late Gadolinium Enhancement (LGE) on CMR is a strong predictor of adverse outcomes: HR 1.81 for all-cause mortality, HR 2.69 for arrhythmic events. (jurgens2024genomewideassociationstudy pages 1-2, zheng2024genomewideassociationanalysis pages 10-11, eichhorn2024riskstratificationin pages 1-2)
Immune & Inflammatory Activation HLA alleles, Cytokines T cell (CD3+), Macrophage Innate/adaptive immune response, cytokine production Persistence of viral genome or autoimmune reaction triggers chronic inflammation; single-cell transcriptomics reveal distinct immune cell states (e.g., exhausted CD8+ T cells) in DCM hearts. (vicenzetto2024theroleof pages 1-2, xu2024constructionandevaluation pages 1-2)
Ion Channel Dysregulation SCN5A, PLN Cardiomyocyte Cardiac conduction, calcium ion transport PLN and SCN5A variants disrupt excitation-contraction coupling and impulse propagation, significantly increasing the risk of ventricular arrhythmias and sudden cardiac death. (arnautu2024geneticsandmolecular pages 5-7, newman2024dilatedcardiomyopathya pages 4-6)

Table: A summary of core mechanistic pathways in DCM, linking genetic and molecular drivers to specific cellular consequences and clinical evidence from recent literature (2023–2024).

Ontology-style entity mapping table

Category Entity (Symbol/ID) Mechanism & Role in DCM Supporting Contexts
Gene TTN (HGNC:12403) Titin: Giant sarcomeric protein. Truncating variants (TTNtv) occur in 15–25% of familial DCM. Mechanisms include haploinsufficiency and a "poison peptide" effect where truncated proteins integrate into the sarcomere, causing structural defects and altered mechanosensing. (arnautu2024geneticsandmolecular pages 5-7, kellermayer2024truncatedtitinis pages 1-2, newman2024dilatedcardiomyopathya pages 7-8, kellermayer2024truncatedtitinis pages 6-7)
Gene LMNA (HGNC:6636) Lamin A/C: Nuclear envelope protein. Variants cause "malignant" DCM with high risks of conduction disease, arrhythmia, and sudden death (SCD); prevalence 4–8% overall, up to 30% in familial cases with conduction defects. (arnautu2024geneticsandmolecular pages 5-7, arnautu2024geneticsandmolecular pages 7-8, newman2024dilatedcardiomyopathya pages 13-14)
Gene RBM20 (HGNC:9907) RNA Binding Motif 20: Splicing regulator. Dysfunction leads to aberrant splicing of TTN (shift to compliant N2BA isoform) and Ca2+ handling genes (CAMK2D, CACNA1C); formation of toxic sarcoplasmic ribonucleoprotein condensates. (solaro2024emergingconceptsof pages 1-2, gregorich2024mechanismsofrbm20 pages 1-3, newman2024dilatedcardiomyopathya pages 7-8)
Gene MYH7 (HGNC:7577) Myosin Heavy Chain 7: Sarcomere motor protein. Variants alter contractile force generation; high penetrance (~90% by age 60); associated with LV noncompaction overlap. (arnautu2024geneticsandmolecular pages 5-7, newman2024dilatedcardiomyopathya pages 13-14)
Gene FLNC (HGNC:3754) Filamin C: Cytoskeletal crosslinker. Truncations linked to high arrhythmic risk (ventricular arrhythmias) and fibrosis, even with mild LV dysfunction. (arnautu2024geneticsandmolecular pages 5-7, arnautu2024geneticsandmolecular pages 7-8, newman2024dilatedcardiomyopathya pages 13-14)
Gene DSP (HGNC:3052) Desmoplakin: Desmosomal plaque protein. Variants impair cell-cell adhesion; found in ~13% of end-stage DCM/transplant cases; overlap with arrhythmogenic cardiomyopathy. (arnautu2024geneticsandmolecular pages 5-7, arnautu2024geneticsandmolecular pages 7-8)
Gene BAG3 (HGNC:937) BAG Cochaperone 3: Chaperone involved in protein quality control/autophagy. Variants cause rapid progression and high penetrance (>80% by age 40). (arnautu2024geneticsandmolecular pages 5-7, newman2024dilatedcardiomyopathya pages 13-14)
Cell Type Cardiomyocyte (CL:0000746) Primary affected cell type; central to GWAS enrichment signals; site of sarcomere/nuclear/splicing defects leading to contractile failure. (jurgens2024genomewideassociationstudy pages 1-2, malinow2024pediatricdilatedcardiomyopathy pages 1-2)
Cell Type T cell (CL:0000084) Immune infiltration (CD3+, CD4+, CD8+) observed in inflammatory DCM/myocarditis; exhausted/cytotoxic subtypes identified by single-cell sequencing. (vicenzetto2024theroleof pages 1-2, xu2024constructionandevaluation pages 1-2)
Anatomy Left Ventricle (UBERON:0002084) Site of primary phenotype: dilation and reduced systolic function (LVEF); remodeling correlates with genetic drivers. (zheng2024genomewideassociationanalysis pages 10-11, eichhorn2024riskstratificationin pages 1-2)
Process Sarcomere Organization (GO:0045214) Disrupted by TTN, MYH7, TNNT2 variants; leads to impaired tension generation and faulty mechanotransduction. (solaro2024emergingconceptsof pages 1-2, kellermayer2024truncatedtitinis pages 1-2, kellermayer2024truncatedtitinis pages 6-7)
Process Alternative Splicing (GO:0000380) Dysregulated by RBM20 defects; affects protein isoforms determining myocardial stiffness (TTN) and excitation-contraction coupling. (gregorich2024mechanismsofrbm20 pages 1-3, newman2024dilatedcardiomyopathya pages 7-8)
Component Nuclear Lamina (GO:0005652) Structural support for nucleus; compromised by LMNA mutations leading to nuclear fragility and altered gene expression. (arnautu2024geneticsandmolecular pages 3-5, newman2024dilatedcardiomyopathya pages 4-6)
Component Sarcoplasm (GO:0016528) Site of mutant RBM20 accumulation into biomolecular condensates (processing bodies/granules), interfering with normal physiology. (gregorich2024mechanismsofrbm20 pages 1-3)
Chemical Calcium Ion (CHEBI:29108) Intracellular handling disrupted by PLN and RBM20-spliced targets (CACNA1C, CAMK2D); central to arrhythmia mechanism. (arnautu2024geneticsandmolecular pages 5-7, newman2024dilatedcardiomyopathya pages 7-8)
Chemical Gadolinium (CHEBI:37402) Contrast agent for CMR. Late Gadolinium Enhancement (LGE) marks fibrosis; predicts mortality (HR 1.81) and arrhythmic events (HR 2.69). (eichhorn2024riskstratificationin pages 1-2)

Table: A structured overview of major genes, cell types, anatomical structures, and processes implicated in DCM pathophysiology, mapped to ontology categories and supported by recent evidence.


Evidence items (PMID-first requirement: limitation note)

The retrieved full-text excerpts used in this run primarily exposed DOIs and URLs but did not consistently include PMIDs in the extracted snippets for the key 2023–2024 mechanistic papers (e.g., JCI 2024 TTNtv; JAMA 2024 CMR meta-analysis; Nature Genetics 2024 GWAS; Circ Genom Precis Med 2024 RBM20). Therefore, the report provides publication dates and DOIs/URLs from the retrieved sources, while citing mechanistic claims using the context evidence IDs above. (kellermayer2024truncatedtitinis pages 1-2, eichhorn2024riskstratificationin pages 1-2, gregorich2024mechanismsofrbm20 pages 1-3, jurgens2024genomewideassociationstudy pages 1-2, zheng2024genomewideassociationanalysis pages 10-11)


Source URLs and publication dates (2023–2024 priority)

  • Eldemire et al. Genetics of Dilated Cardiomyopathy. Annual Review of Medicine. Published Jan 29, 2024. https://doi.org/10.1146/annurev-med-052422-020535 (eldemire2024geneticsofdilated pages 1-3)
  • Kellermayer et al. Truncated titin is structurally integrated into the human dilated cardiomyopathic sarcomere. J Clin Invest. Published Jan 16, 2024. https://doi.org/10.1172/JCI169753 (kellermayer2024truncatedtitinis pages 1-2)
  • Gregorich et al. Mechanisms of RBM20 Cardiomyopathy. Circ Genom Precis Med. Feb 2024 issue (manuscript indicates Jan 2024 availability). https://doi.org/10.1161/CIRCGEN.123.004355 (gregorich2024mechanismsofrbm20 pages 1-3)
  • Eichhorn et al. Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging. JAMA. Published online Sep 19, 2024. https://doi.org/10.1001/jama.2024.13946 (eichhorn2024riskstratificationin pages 1-2)
  • Jurgens et al. GWAS reveals mechanisms underlying DCM and myocardial resilience. Nature Genetics. Nov 2024. https://doi.org/10.1038/s41588-024-01975-5 (jurgens2024genomewideassociationstudy pages 1-2)
  • Zheng et al. GWAS analysis provides insights into the molecular etiology of DCM. Nature Genetics. Nov 2024. https://doi.org/10.1038/s41588-024-01952-y (zheng2024genomewideassociationanalysis pages 10-11)
  • Xu et al. Immune-related diagnostic model in idiopathic DCM HF. BMC Cardiovascular Disorders. Feb 2024. https://doi.org/10.1186/s12872-023-03666-1 (xu2024constructionandevaluation pages 1-2)
  • Vicenzetto et al. Immune system in myocarditis pathobiology/therapy. Biomedicines. Published May 23, 2024. https://doi.org/10.3390/biomedicines12061156 (vicenzetto2024theroleof pages 1-2)
  • Solaro et al. Mechanisms controlling cardiac tension in familial DCM. Biomedicines. May 2024. https://doi.org/10.3390/biomedicines12050999 (solaro2024emergingconceptsof pages 1-2)
  • Malinow et al. Pediatric DCM pathogenesis review. Frontiers in Pediatrics. Jun 19, 2024. https://doi.org/10.3389/fped.2024.1404942 (malinow2024pediatricdilatedcardiomyopathy pages 1-2)

References

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