Dilated Cardiomyopathy

Complex MONDO:0005021 Pathograph 69 Show in embeddings browser Cardiovascular Disease Genetic Disorder

Dilated cardiomyopathy (DCM) is a disease of the heart muscle defined by left ventricular (or biventricular) dilation and impaired systolic contraction in the absence of abnormal loading conditions or coronary disease sufficient to explain it. Causes include sarcomere and cytoskeletal gene mutations, myocarditis, alcohol and other toxins, and the peripartum state. Progressive ventricular remodeling leads to heart failure, arrhythmia, and sudden death.

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Subtypes

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 Other

"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 Other

"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 Other

"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 Other

"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.

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Pathophysiology

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 CL:0000746

TTN hgnc:12403 LMNA hgnc:6636 MYH7 hgnc:7577 MYH6 hgnc:7576 MYBPC3 hgnc:7551 ACTC1 hgnc:143 TPM1 hgnc:12010 TNNT2 hgnc:11949 TNNC1 hgnc:11943 TNNI3 hgnc:11947 MYL2 hgnc:7583 MYLK3 hgnc:29826 DES hgnc:2770 FLNC hgnc:3756 VCL hgnc:12665 LDB3 hgnc:15710 TCAP hgnc:11610 MYPN hgnc:23246 ANKRD1 hgnc:15819 NEXN hgnc:29557 NEBL hgnc:16932 NRAP hgnc:7988 OBSCN hgnc:15719 LMOD2 hgnc:6648 TMOD1 hgnc:11871 LAMA4 hgnc:6484 CDH2 hgnc:1759 DSG2 hgnc:3049 MYZAP hgnc:43444 BAG3 hgnc:939 FLII hgnc:3750 C10orf71 hgnc:26973 CAP2 hgnc:20039 EMD hgnc:3331

cardiac muscle contraction GO:0060048

Experimental models

Patient-specific TNNT2 R173W iPSC-derived cardiomyocytes (Clinical Trials in a Dish) IPSC DERIVED MODEL Cardiomyocytes carrying the patient's TNNT2 R173W allele reproduce the sarcomeric disorganisation and contractile failure of this node in human cells, and the phenotype is reversed by beta-blockade or SERCA2a overexpression.

Show evidence (4 references)

PMID:37962957 SUPPORT Human Clinical

"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 Human Clinical

"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 Other

"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.

+ 1 more reference

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 GO:0002018

Experimental models

Patient-specific TNNT2 R173W iPSC-derived cardiomyocytes (Clinical Trials in a Dish) IPSC DERIVED MODEL Exposing the cardiomyocytes to a beta-adrenergic agonist applies the catecholamine arm of this node directly to the cells and unmasks a genotype-dependent vulnerability that is not apparent at baseline.

Downstream

IL-11 Signalling in Cardiac Fibroblasts Neurohormonal (angiotensin II) activation drives cardiac fibroblast IL-11 induction, placing IL-11 receptor signalling downstream of the neurohormonal stress that promotes adverse remodeling.

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"

Establishes that the four foundational HFrEF drug classes act by blocking the renin-angiotensin and sympathetic systems. Note this is therapeutic rather than direct mechanistic evidence - it shows the pathway is druggable, not that it is activated.

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.

IL-11 Signalling in Cardiac Fibroblasts

Profibrotic stress upregulates IL-11 and IL11RA in cardiac fibroblasts, driving ERK-dependent (non-canonical) autocrine signalling that promotes their fibroblast-to-myofibroblast transformation and ECM gene expression. This IL-11 receptor-signalling arm is an organ-specific instance of the conserved IL-11 signalling module and feeds myocardial fibrosis; neutralizing anti-IL-11 or anti-IL11RA antibodies reduce cardiac fibrosis and ERK activation without affecting hypertrophy.

cardiac fibroblast CL:0002548

Interleukin-11-mediated signaling pathway GO:0038154 ↑ INCREASED ERK1 and ERK2 cascade GO:0070371 ↑ INCREASED

heart UBERON:0000948

Downstream

Myocardial Fibrosis

Show evidence (4 references)

PMID:33462828 SUPPORT Model Organism

"Inhibition of IL11 signalling reduced AAC-induced cardiac fibrosis and ECM gene expression as well as ERK1/2 phosphorylation but had no effect on cardiac hypertrophy."

Directly evidences that anti-IL-11 reduces cardiac fibrosis and ERK1/2 phosphorylation in a cardiac-fibroblast-driven model, grounding this node. Evidence source is MODEL_ORGANISM (mouse ascending aortic constriction).

PMID:33462828 SUPPORT Model Organism

"blocking IL11 signalling reduces cardiac fibrosis due to severe pressure overload and suggests ERK, but not STAT3, activity as the relevant underlying signalling pathway"

Identifies the non-canonical ERK arm (not canonical STAT3) as the fibrosis-relevant IL-11 pathway in the heart, consistent with the module's receptor-signalling node and its canonical-vs-non-canonical knowledge gap. Evidence source is MODEL_ORGANISM (mouse pressure-overload model plus cardiac fibroblasts).

PMID:29160304 SUPPORT Model Organism

"In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease."

Shows fibroblast IL-11 is sufficient to cause heart fibrosis and organ failure and that receptor deletion is protective. Evidence source is MODEL_ORGANISM (transgenic and Il11ra1-knockout mice).

+ 1 more reference

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 CL:0002548

extracellular matrix organization GO:0030198

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 cause an aggressive, early-onset form of dilated cardiomyopathy. RBM20 is a cardiac splicing regulator, and the proposed mechanism is disrupted alternative splicing of key cardiac genes including TTN and calcium-handling genes, with some variants reported to form toxic biomolecular condensates. The splicing and condensate detail derives from model systems and is not established by the evidence cited here.

cardiomyocyte CL:0000746

RBM20 hgnc:27424

Show evidence (1 reference)

PMID:38288598 SUPPORT Other

"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

Chronic cardiac inflammation with distinct immune cell infiltration patterns contributes to adverse remodeling in DCM. Immune-mediated injury from viral myocarditis or autoimmune reactions is a proposed trigger, but that route is not established by the deconvolution evidence cited here.

cardiomyocyte CL:0000746

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 CL:0000746

PPA2 hgnc:28883

mitochondrion organization GO:0007005

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.

Cardiomyocyte Calcium Release Dysregulation

JPH2 and RYR2 act on the sarcoplasmic reticulum calcium release step rather than on the contractile apparatus. JPH2 builds the junctional membrane complex that couples the t-tubule to the sarcoplasmic reticulum, and RYR2 is the release channel itself. The reported defect is a loss of control over when release terminates rather than a smaller release: the RyR2 exon-3 region associated with dilated cardiomyopathy lowers the luminal calcium threshold at which release ends and increases the fractional release.

cardiac muscle cell CL:0000746

JPH2 hgnc:14202 RYR2 hgnc:10484

regulation of sarcoplasmic reticulum calcium release GO:0010880 ↕ DYSREGULATED

Downstream

Left ventricular systolic dysfunction Loss of control over sarcoplasmic reticulum calcium release reduces systolic performance, and recessive loss-of-function variants in the gene that builds the release couplon give severe, early-onset dilated cardiomyopathy.

Show evidence (2 references)

PMID:34861382 SUPPORT REVIEW SYNTHESIS Human Clinical

"we found that autosomal recessive, loss-of-function variants are associated with severe, early onset DCM, while autosomal dominant missense variants are associated with a wider range of cardiac disease, including HCM, arrhythmia, SCD, and cardiac conduction disease."

Separates the two JPH2 modes of inheritance: recessive loss-of-function gives severe early-onset DCM, dominant missense a wider arrhythmic and conduction phenotype.

PMID:22374134 SUPPORT PRIMARY RESULT In Vitro

"The 35-residue exon-3 region of RyR2 is associated with dilated cardiomyopathy. Single-cell luminal Ca2+ imaging revealed that the deletion of the first 305 NH2-terminal residues encompassing exon-3 or the deletion of exon-3 itself markedly reduced the luminal Ca2+ threshold at which Ca2+..."

Ties the RyR2 exon-3 region associated with dilated cardiomyopathy to a measurable defect in termination of sarcoplasmic reticulum calcium release.

Cardiomyocyte Excitability and Conduction Instability

SCN5A, ABCC9 and TNNI3K act on the cardiomyocyte action potential rather than on calcium release or on the contractile apparatus. SCN5A carries the cardiac sodium current, ABCC9 is the SUR2 subunit of the cardiac KATP channel, and TNNI3K is a cardiac troponin I interacting kinase whose disease-causing variant disrupts its kinase domain. Disease in this group characteristically presents with conduction disease and arrhythmia alongside, or ahead of, ventricular dilatation.

cardiac muscle cell CL:0000746

SCN5A hgnc:10593 ABCC9 hgnc:60 TNNI3K hgnc:19661

cardiac muscle cell action potential GO:0086001 ↕ DYSREGULATED

Downstream

Arrhythmia Each gene on this node has a reported arrhythmic or conduction phenotype: the SCN5A families presented with conduction disorder and arrhythmia, loss-of-function ABCC9 variants with Brugada and early repolarization syndromes, and the TNNI3K family with conduction system disease and atrial tachyarrhythmia.

Left ventricular systolic dysfunction The same variants that destabilize the action potential also produce ventricular dilatation and systolic dysfunction; the SCN5A report is explicit that the cardiac sodium channel disease spectrum extends to cardiac dilation and dysfunction.

Show evidence (3 references)

PMID:15466643 SUPPORT PRIMARY RESULT Human Clinical

"Our findings expand the clinical spectrum of disorders of the cardiac sodium channel to include cardiac dilation and dysfunction"

Extends the cardiac sodium channel disease spectrum to cardiac dilation and dysfunction, which is why SCN5A is wired to this node rather than the sarcomeric one.

PMID:35495129 SUPPORT BACKGROUND Human Clinical

"Genetic variants in the ABCC9 gene, encoding the SUR2 auxiliary subunit from KATP channels, were previously linked with various inherited diseases. This wide range of congenital disorders includes multisystem and cardiovascular pathologies. The gain-of-function mutations result in Cantu..."

States that ABCC9 encodes the SUR2 subunit of the KATP channel and that loss-of-function variants have been associated with dilated cardiomyopathy.

PMID:24925317 SUPPORT PRIMARY RESULT Human Clinical

"revealing an unreported heterozygous missense mutation disrupting the highly conserved kinase domain in TNNI3K."

Locates the causal TNNI3K variant in the conserved kinase domain in a family with conduction system disease, atrial tachyarrhythmia and DCM.

Cardiomyocyte Proteostasis Failure

A second group of DCM genes act on how cardiomyocyte proteins are made, folded, delivered and cleared rather than on the contractile apparatus itself. RPL3L is a muscle-specific ribosomal protein, GET3 (ASNA1) inserts tail-anchored membrane proteins, BAG5 is a nucleotide exchange factor that activates HSC70-mediated folding, FBXO32 (atrogin-1) is the substrate-recognition subunit of an SCF ubiquitin ligase, and PLEKHM2 positions lysosomes for autophagic flux. Most are recessive and several present in the neonatal or infantile period.

cardiac muscle cell CL:0000746

BAG5 hgnc:941 FBXO32 hgnc:16731 GET3 hgnc:752 PLEKHM2 hgnc:29131 RPL3L hgnc:10351

protein folding GO:0006457 ↓ DECREASED autophagy GO:0006914 ↓ DECREASED ribosome biogenesis GO:0042254 ↓ DECREASED

Downstream

Left ventricular systolic dysfunction Loss of protein synthesis, folding, targeting or clearance capacity in the cardiomyocyte produces ventricular dilatation with systolic failure; the BAG5 families showed complete penetrance and required heart transplantation.

Show evidence (7 references)

PMID:35044787 SUPPORT PRIMARY RESULT Human Clinical

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

Establishes homozygous truncating BAG5 variants as a cause of inherited DCM with complete penetrance across four families.

PMID:35044787 SUPPORT BACKGROUND In Vitro

"BAG5 acts as a nucleotide exchange factor for heat shock cognate 71 kDa protein (HSC70), promoting adenosine diphosphate release and activating HSC70-mediated protein folding."

States the molecular function of BAG5 as a nucleotide exchange factor activating HSC70-mediated protein folding, the proteostatic step this node describes.

PMID:26753747 SUPPORT PRIMARY RESULT Human Clinical

"Our results indicate that abnormal SCF activity with subsequent impairment of the autophagic flux due to a novel FBXO32 mutation is implicated in the pathogenesis of DCM."

Ties the FBXO32 lesion to impaired SCF ubiquitin ligase activity and reduced autophagic flux in DCM.

+ 4 more references

Cardiac Transcriptional and Developmental Program Dysregulation

A third group of DCM genes encode transcriptional and developmental regulators of the ventricular myocardium. TBX20 is a cardiac T-box transcription factor that acts with NKX2-5 and GATA4, PRDM16 is the transcription factor whose loss accounts for the cardiomyopathy of monosomy 1p36, MIB1 is the NOTCH pathway E3 ubiquitin ligase whose loss arrests trabecular maturation and compaction, and GATAD1 was mapped in a family with recessive DCM. Left ventricular noncompaction overlaps this group, reflecting arrested chamber development rather than degeneration of a formed myocardium.

cardiac muscle cell CL:0000746

TBX20 hgnc:11598 PRDM16 hgnc:14000 GATAD1 hgnc:29941 MIB1 hgnc:21086

cardiac muscle cell differentiation GO:0055007 ↕ DYSREGULATED regulation of transcription by RNA polymerase II GO:0006357 ↕ DYSREGULATED Notch signaling pathway GO:0007219 ↓ DECREASED

Downstream

Left ventricular systolic dysfunction A ventricular myocardium built by a disrupted transcriptional program underperforms; MIB1 loss arrests chamber myocardium development and prevents trabecular maturation and compaction.

Show evidence (5 references)

PMID:26118961 SUPPORT PRIMARY RESULT In Vitro

"Functional assays revealed that the mutant TBX20 had significantly diminished transcriptional activity. Furthermore, the mutation markedly reduced the synergistic activation of TBX20 with NKX2-5 or GATA4."

Shows the DCM-associated TBX20 mutation reduces transcriptional activity and its synergy with NKX2-5 and GATA4.

PMID:23768516 SUPPORT PRIMARY RESULT Human Clinical

"we describe the loss of a gene within the deletion that is responsible for the cardiomyopathy associated with monosomy 1p36, and we confirm its role in nonsyndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM)."

Attributes the cardiomyopathy of monosomy 1p36 to loss of PRDM16 and confirms its role in nonsyndromic LVNC and DCM.

PMID:23314057 SUPPORT PRIMARY RESULT Human Clinical

"We show that germline mutations in human MIB1 (mindbomb homolog 1), which encodes an E3 ubiquitin ligase that promotes endocytosis of the NOTCH ligands DELTA and JAGGED, cause LVNC in autosomal-dominant pedigrees"

Establishes germline MIB1 mutations as a cause of LVNC and states that MIB1 is the E3 ubiquitin ligase regulating NOTCH ligand endocytosis.

+ 2 more references

Coenzyme A Biosynthesis Deficiency

PPCS catalyses the second of the five enzymatic steps that make coenzyme A from vitamin B5, and biallelic PPCS variants lower cellular CoA. CoA is a cofactor for a large share of cellular enzymes including those of fatty-acid handling, so this is a metabolic cofactor lesion reaching the myocardium, distinct from the sarcomeric, ion-handling, proteostatic and transcriptional routes into the same phenotype. It is also the one route here with a directly implied treatment: CoA can be made from pantethine by a route that does not use PPCS.

PPCS hgnc:25686

coenzyme A biosynthetic process GO:0015937 ↓ DECREASED

Downstream

Left ventricular systolic dysfunction The five individuals in whom biallelic PPCS variants were identified presented with dilated cardiomyopathy, and their fibroblasts showed decreased coenzyme A.

Show evidence (1 reference)

PMID:29754768 SUPPORT PRIMARY RESULT Human Clinical

"Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast and fruit flies confirmed the pathogenicity of identified mutations. Biochemical analysis..."

Reports the DCM presentation of biallelic PPCS variants and the reduced coenzyme A measured in affected individuals fibroblasts.

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Pathograph

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Phenotypes

Cardiovascular 5

Dilated cardiomyopathy VERY_FREQUENT HP:0001644

Show evidence (1 reference)

PMID:39519012 SUPPORT Other

"Dilated cardiomyopathy (DCM) is characterized by reduced systolic function and cardiac dilation."

Defines the cardinal structural and functional phenotype of dilated cardiomyopathy - ventricular dilation with reduced systolic function.

Congestive heart failure VERY_FREQUENT HP:0001635

Show evidence (2 references)

PMID:39519012 SUPPORT Other

"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 HP:0025169

Show evidence (2 references)

PMID:39519012 SUPPORT Other

"Dilated cardiomyopathy (DCM) is characterized by reduced systolic function and cardiac dilation."

Reduced systolic function is definitional for dilated cardiomyopathy, supporting left ventricular systolic dysfunction as a core phenotype.

PMID:39298146 SUPPORT Human Clinical

"Left ventricular ejection fraction (LVEF) (per 1%) was not associated with all-cause mortality"

Qualifies the phenotype rather than establishing it - in this meta-analysis LVEF, the standard measure of systolic dysfunction, was not associated with all-cause mortality, whereas fibrosis markers were.

Palpitations FREQUENT HP:0001962

Arrhythmia FREQUENT HP:0011675

Show evidence (2 references)

PMID:37788487 SUPPORT Other

"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 (late gadolinium enhancement) in DCM is associated with adverse clinical outcomes. The snippet does not itemise arrhythmic endpoints separately.

Metabolism 1

Peripheral edema FREQUENT HP:0012398

Respiratory 1

Dyspnea VERY_FREQUENT HP:0002094

Constitutional 1

Fatigue VERY_FREQUENT HP:0012378

🧬

Genetic Associations

TTN Truncating Variants (Causative)

Gene: TTN hgnc:12403 gene page

Autosomal dominant

Show evidence (2 references)

PMID:37962957 SUPPORT Human Clinical

"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.

CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2025-05-30T160000.000Z SUPPORT Other

ClinGen classifies the TTN-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.

LMNA Mutations (Causative)

Gene: LMNA hgnc:6636 gene page

Autosomal dominant

Show evidence (2 references)

PMID:39519012 SUPPORT Other

"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.

CGGV:assertion_132ea1ec-caa9-409a-8670-3edb2ec9c889-2025-05-30T160000.000Z SUPPORT Other

ClinGen classifies the LMNA-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.

MYH7 Mutations (Causative)

Gene: MYH7 hgnc:7577 gene page

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.

CGGV:assertion_4ec27d4f-70ea-4c6a-ad67-d6260ecadcde-2025-05-30T160000.000Z SUPPORT Other

ClinGen classifies the MYH7-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.

RBM20 Mutations (Causative)

Gene: RBM20 hgnc:27424 gene page

Autosomal dominant

Show evidence (2 references)

PMID:38288598 SUPPORT Other

"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.

CGGV:assertion_3e123751-078a-4d30-9f83-847119982342-2020-08-20T160000.000Z SUPPORT Other

ClinGen classifies the RBM20-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.

ABCC9 (Pathogenic Variants)

Gene: ABCC9 hgnc:60 gene page

Show evidence (1 reference)

CGGV:assertion_8be22ebc-f0f5-4de5-9c2a-382ebd02c533-2024-11-15T170000.000Z SUPPORT Other

ClinGen classifies the ABCC9-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

ACTC1 (Pathogenic Variants)

Gene: ACTC1 hgnc:143 gene page

Show evidence (1 reference)

CGGV:assertion_3e9b4048-3003-4180-b891-fcf10d25a814-2025-04-25T040000.000Z SUPPORT Other

ClinGen classifies the ACTC1-dilated cardiomyopathy gene-disease relationship as moderate with autosomal dominant inheritance.

ANKRD1 (Pathogenic Variants)

Gene: ANKRD1 hgnc:15819

Show evidence (1 reference)

CGGV:assertion_3dcc6918-d7e7-4385-b343-bc8b8678b3a4-2025-02-07T170000.000Z SUPPORT Other

ClinGen classifies the ANKRD1-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

BAG3 (Pathogenic Variants)

Gene: BAG3 hgnc:939 gene page

Show evidence (1 reference)

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

ClinGen classifies the BAG3-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.

BAG5 (Pathogenic Variants)

Gene: BAG5 hgnc:941 gene page

Show evidence (1 reference)

CGGV:assertion_97fe83b7-fe12-4014-9706-6847446fa9bd-2024-06-14T160000.000Z SUPPORT Other

ClinGen classifies the BAG5-dilated cardiomyopathy gene-disease relationship as moderate with autosomal recessive inheritance.

CDH2 (Pathogenic Variants)

Gene: CDH2 hgnc:1759 gene page

Show evidence (1 reference)

CGGV:assertion_73900af1-14ee-4933-b5dc-832753e6cc6c-2025-05-16T160000.000Z SUPPORT Other

ClinGen classifies the CDH2-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

CTF1 (Pathogenic Variants)

Gene: CTF1 hgnc:2499

Show evidence (1 reference)

CGGV:assertion_ef19cc13-543b-451e-b278-ec1fc04f694c-2024-08-07T160000.000Z SUPPORT Other

ClinGen classifies the CTF1-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

DES (Pathogenic Variants)

Gene: DES hgnc:2770 gene page

Show evidence (1 reference)

CGGV:assertion_91b2595a-5eb9-4ac3-aa3d-d5f99cacad84-2025-05-30T160000.000Z SUPPORT Other

ClinGen classifies the DES-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.

DSG2 (Pathogenic Variants)

Gene: DSG2 hgnc:3049 gene page

Show evidence (1 reference)

CGGV:assertion_a7df1018-593f-481f-9dd0-77ce3ea829a6-2025-03-28T160000.000Z SUPPORT Other

ClinGen classifies the DSG2-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

FBXO32 (Pathogenic Variants)

Gene: FBXO32 hgnc:16731

Show evidence (1 reference)

CGGV:assertion_9f006b4e-08a3-403c-86dd-704f741494fe-2025-05-30T160000.000Z SUPPORT Other

ClinGen classifies the FBXO32-dilated cardiomyopathy gene-disease relationship as limited with autosomal recessive inheritance.

FLII (Pathogenic Variants)

Gene: FLII hgnc:3750 gene page

Show evidence (1 reference)

CGGV:assertion_660622fe-f967-42be-a565-0383e5f710c2-2024-06-14T040000.000Z SUPPORT Other

ClinGen classifies the FLII-dilated cardiomyopathy gene-disease relationship as moderate with autosomal recessive inheritance.

FLNC (Pathogenic Variants)

Gene: FLNC hgnc:3756 gene page

Show evidence (1 reference)

CGGV:assertion_edb5197f-05dc-42a4-a497-fff472985c6b-2025-05-30T160000.000Z SUPPORT Other

ClinGen classifies the FLNC-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.

GATAD1 (Pathogenic Variants)

Gene: GATAD1 hgnc:29941 gene page

Show evidence (1 reference)

CGGV:assertion_56933afb-863f-46f5-884d-17522adb31a8-2024-08-07T160000.000Z SUPPORT Other

ClinGen classifies the GATAD1-dilated cardiomyopathy gene-disease relationship as limited with autosomal recessive inheritance.

GET3 (Pathogenic Variants)

Gene: GET3 hgnc:752 gene page

Show evidence (1 reference)

CGGV:assertion_605f9805-5af1-445a-911a-d31ebff15125-2025-05-02T160000.000Z SUPPORT Other

ClinGen classifies the GET3-dilated cardiomyopathy gene-disease relationship as limited with autosomal recessive inheritance.

JPH2 (Pathogenic Variants)

Gene: JPH2 hgnc:14202 gene page

Show evidence (2 references)

CGGV:assertion_8d310e47-1f84-4c61-b06a-b273a4b1b601-2025-01-24T170000.000Z SUPPORT Other

ClinGen classifies the JPH2-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

CGGV:assertion_7aa138ae-114c-46b0-84e4-5bfc5a7db51b-2025-01-24T170000.000Z SUPPORT Other

ClinGen classifies the JPH2-dilated cardiomyopathy gene-disease relationship as strong with autosomal recessive inheritance.

LAMA4 (Pathogenic Variants)

Gene: LAMA4 hgnc:6484 gene page

Show evidence (1 reference)

CGGV:assertion_e937f98e-7577-48bd-a24a-361634ba0a8d-2024-11-15T170000.000Z SUPPORT Other

ClinGen classifies the LAMA4-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

LDB3 (Pathogenic Variants)

Gene: LDB3 hgnc:15710 gene page

Show evidence (2 references)

CGGV:assertion_7756e3c0-5a16-49b8-ac0f-220e79a4fa99-2025-03-21T040000.000Z SUPPORT Other

ClinGen classifies the LDB3-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

CGGV:assertion_c9d89b2d-2761-47d5-a773-e592f8e6d1df-2025-03-21T040000.000Z SUPPORT Other

ClinGen classifies the LDB3-dilated cardiomyopathy gene-disease relationship as strong with autosomal recessive inheritance.

LMOD2 (Pathogenic Variants)

Gene: LMOD2 hgnc:6648 gene page

Show evidence (1 reference)

CGGV:assertion_d19140d6-8200-4fce-9906-fdda527a4f7e-2024-10-04T160000.000Z SUPPORT Other

ClinGen classifies the LMOD2-dilated cardiomyopathy gene-disease relationship as definitive with autosomal recessive inheritance.

MIB1 (Pathogenic Variants)

Gene: MIB1 hgnc:21086 gene page

Show evidence (1 reference)

CGGV:assertion_d97cecce-b9a7-42fb-bc2d-034468094949-2024-10-04T160000.000Z SUPPORT Other

ClinGen classifies the MIB1-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

MYBPC3 (Pathogenic Variants)

Gene: MYBPC3 hgnc:7551 gene page

Show evidence (2 references)

CGGV:assertion_652d0370-9574-450c-b7c4-eec86ade9046-2025-05-16T160000.000Z SUPPORT Other

ClinGen classifies the MYBPC3-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

CGGV:assertion_f240fb99-f839-4b9b-8e52-f2dc49078886-2025-05-16T040000.000Z SUPPORT Other

ClinGen classifies the MYBPC3-dilated cardiomyopathy gene-disease relationship as limited with autosomal recessive inheritance.

MYH6 (Pathogenic Variants)

Gene: MYH6 hgnc:7576 gene page

Show evidence (1 reference)

CGGV:assertion_6d55ac7b-e9d8-4a97-bb20-92beeffaed96-2025-03-07T170000.000Z SUPPORT Other

ClinGen classifies the MYH6-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

MYL2 (Pathogenic Variants)

Gene: MYL2 hgnc:7583 gene page

Show evidence (1 reference)

CGGV:assertion_8405609b-1664-4849-848e-bec138350c92-2025-05-16T160000.000Z SUPPORT Other

ClinGen classifies the MYL2-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

MYLK3 (Pathogenic Variants)

Gene: MYLK3 hgnc:29826

Show evidence (1 reference)

CGGV:assertion_713bb7fc-2ae0-488f-acfa-4c0bf963e8bc-2025-07-11T160000.000Z SUPPORT Other

ClinGen classifies the MYLK3-dilated cardiomyopathy gene-disease relationship as moderate with autosomal dominant inheritance.

MYPN (Pathogenic Variants)

Gene: MYPN hgnc:23246 gene page

Show evidence (1 reference)

CGGV:assertion_ffd924ad-55ce-4b05-8a91-584ef49b4e80-2025-03-05T050000.000Z SUPPORT Other

ClinGen classifies the MYPN-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

MYZAP (Pathogenic Variants)

Gene: MYZAP hgnc:43444

Show evidence (1 reference)

CGGV:assertion_587dc3e6-fc9e-4802-8370-cbff25731f45-2024-08-23T160000.000Z SUPPORT Other

ClinGen classifies the MYZAP-dilated cardiomyopathy gene-disease relationship as moderate with autosomal recessive inheritance.

NEBL (Pathogenic Variants)

Gene: NEBL hgnc:16932

Show evidence (1 reference)

CGGV:assertion_29bc6c4f-3f2d-45e2-b796-a79616857094-2024-10-18T160000.000Z SUPPORT Other

ClinGen classifies the NEBL-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

NEXN (Pathogenic Variants)

Gene: NEXN hgnc:29557 gene page

Show evidence (1 reference)

CGGV:assertion_ffe00b43-a449-4476-b7e0-f24cf6613766-2024-11-15T050000.000Z SUPPORT Other

ClinGen classifies the NEXN-dilated cardiomyopathy gene-disease relationship as strong with autosomal dominant inheritance.

NRAP (Pathogenic Variants)

Gene: NRAP hgnc:7988 gene page

Show evidence (1 reference)

CGGV:assertion_f72c0812-9782-444c-a87c-b50286bbfd09-2024-07-26T160000.000Z SUPPORT Other

ClinGen classifies the NRAP-dilated cardiomyopathy gene-disease relationship as strong with autosomal recessive inheritance.

OBSCN (Pathogenic Variants)

Gene: OBSCN hgnc:15719 gene page

Show evidence (1 reference)

CGGV:assertion_e1b69281-f3d0-4efe-998d-db080868b57e-2025-02-07T170000.000Z SUPPORT Other

ClinGen classifies the OBSCN-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

PLEKHM2 (Pathogenic Variants)

Gene: PLEKHM2 hgnc:29131

Show evidence (1 reference)

CGGV:assertion_44c534b9-16d1-435b-9eca-fb7d1de6ea26-2024-11-15T170000.000Z SUPPORT Other

ClinGen classifies the PLEKHM2-dilated cardiomyopathy gene-disease relationship as moderate with autosomal recessive inheritance.

PPA2 (Pathogenic Variants)

Gene: PPA2 hgnc:28883 gene page

Show evidence (1 reference)

CGGV:assertion_35b7716c-4c72-4ca2-b176-e732d136ed0d-2025-05-16T160000.000Z SUPPORT Other

ClinGen classifies the PPA2-dilated cardiomyopathy gene-disease relationship as strong with autosomal recessive inheritance.

PRDM16 (Pathogenic Variants)

Gene: PRDM16 hgnc:14000 gene page

Show evidence (1 reference)

CGGV:assertion_c0a3445a-5bb0-4d77-a4f0-5b7cfceb837f-2025-05-30T160000.000Z SUPPORT Other

ClinGen classifies the PRDM16-dilated cardiomyopathy gene-disease relationship as strong with autosomal dominant inheritance.

RPL3L (Pathogenic Variants)

Gene: RPL3L hgnc:10351 gene page

Show evidence (1 reference)

CGGV:assertion_1dae12df-f703-4e4d-99b6-b38f6ed65fa0-2025-05-30T160000.000Z SUPPORT Other

ClinGen classifies the RPL3L-dilated cardiomyopathy gene-disease relationship as moderate with autosomal recessive inheritance.

RYR2 (Pathogenic Variants)

Gene: RYR2 hgnc:10484 gene page

Show evidence (1 reference)

CGGV:assertion_b35e4dc8-c7d6-4c20-995f-0b1f4508ee3d-2025-01-10T170000.000Z SUPPORT Other

ClinGen classifies the RYR2-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

SCN5A (Pathogenic Variants)

Gene: SCN5A hgnc:10593 gene page

Show evidence (1 reference)

CGGV:assertion_53c90d2e-4d40-48ab-8761-b0158102c977-2025-05-30T160000.000Z SUPPORT Other

ClinGen classifies the SCN5A-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.

TBX20 (Pathogenic Variants)

Gene: TBX20 hgnc:11598 gene page

Show evidence (1 reference)

CGGV:assertion_58a014d9-2d97-4041-961d-cfd09fa11adf-2025-05-02T160000.000Z SUPPORT Other

ClinGen classifies the TBX20-dilated cardiomyopathy gene-disease relationship as strong with autosomal dominant inheritance.

TCAP (Pathogenic Variants)

Gene: TCAP hgnc:11610 gene page

Show evidence (1 reference)

CGGV:assertion_4c8ab9d8-919a-443f-b027-5aec92b273d1-2025-04-18T040000.000Z SUPPORT Other

ClinGen classifies the TCAP-dilated cardiomyopathy gene-disease relationship as limited with autosomal dominant inheritance.

TMOD1 (Pathogenic Variants)

Gene: TMOD1 hgnc:11871

Show evidence (1 reference)

CGGV:assertion_dbcee227-6a90-474b-ba94-7714bcf704d5-2025-05-02T160000.000Z SUPPORT Other

ClinGen classifies the TMOD1-dilated cardiomyopathy gene-disease relationship as limited with autosomal recessive inheritance.

TNNC1 (Pathogenic Variants)

Gene: TNNC1 hgnc:11943 gene page

Show evidence (1 reference)

CGGV:assertion_6ad71467-74c0-4a7c-932d-c5ca5747e59e-2025-05-30T160000.000Z SUPPORT Other

ClinGen classifies the TNNC1-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.

TNNI3 (Pathogenic Variants)

Gene: TNNI3 hgnc:11947 gene page

Show evidence (2 references)

CGGV:assertion_668087ea-0d2f-42c2-a291-f73400d34023-2025-04-18T160000.000Z SUPPORT Other

ClinGen classifies the TNNI3-dilated cardiomyopathy gene-disease relationship as strong with autosomal dominant inheritance.

CGGV:assertion_b89182f6-1574-48c6-832f-add41ffbaa4c-2025-04-18T160000.000Z SUPPORT Other

ClinGen classifies the TNNI3-dilated cardiomyopathy gene-disease relationship as strong with autosomal recessive inheritance.

TNNI3K (Pathogenic Variants)

Gene: TNNI3K hgnc:19661

Show evidence (1 reference)

CGGV:assertion_f5ce5790-8940-4d7a-a85c-8682be86939d-2025-09-05T160000.000Z SUPPORT Other

ClinGen classifies the TNNI3K-dilated cardiomyopathy gene-disease relationship as moderate with autosomal dominant inheritance.

TNNT2 (Pathogenic Variants)

Gene: TNNT2 hgnc:11949 gene page

Show evidence (1 reference)

CGGV:assertion_20fbdfad-b2d2-45f1-9658-e2e3e02cb413-2025-05-30T160000.000Z SUPPORT Other

ClinGen classifies the TNNT2-dilated cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.

TPM1 (Pathogenic Variants)

Gene: TPM1 hgnc:12010 gene page

Show evidence (1 reference)

CGGV:assertion_1173d239-23cf-4c9c-9ea5-f95d9356e6c7-2025-04-04T160000.000Z SUPPORT Other

ClinGen classifies the TPM1-dilated cardiomyopathy gene-disease relationship as moderate with autosomal dominant inheritance.

VCL (Pathogenic Variants)

Gene: VCL hgnc:12665 gene page

Show evidence (1 reference)

CGGV:assertion_2d46699a-5f8c-460d-9233-bec4e2ecf560-2024-08-09T160000.000Z SUPPORT Other

ClinGen classifies the VCL-dilated cardiomyopathy gene-disease relationship as strong with autosomal dominant inheritance.

C10orf71 (Autosomal dominant causal pathogenic variant. C10orf71 encodes an intrinsically disordered, cardiomyocyte-specific protein also reported as the z-disc protein CEFIP. Frameshift variants were identified in a large family with eight affected members and in four further loss-of-function carriers across two sporadic DCM cohorts. Null cardiomyocytes lose contractile function while sarcomere structure stays intact, so the lesion is contractile rather than structural.)

Gene: C10orf71 hgnc:26973

Show evidence (3 references)

PMID:38950288 SUPPORT PRIMARY RESULT Human Clinical

"We identified candidate DCM causal gene, C10orf71, in a large family with 8 patients with DCM by whole-exome sequencing. Four loss-of-function variants of C10orf71 were subsequently identified in an additional group of492 patients with sporadic DCM from 2 independent cohorts. C10orf71 was found..."

Establishes C10orf71 as a DCM gene from a large family plus two independent sporadic cohorts, and states its cardiomyocyte-specific expression.

PMID:38950288 SUPPORT PRIMARY RESULT In Vitro

"C10orf71-null cardiomyocytes exhibited impaired contractile function with unaffected sarcomere structure. Cardiomyocytes and heart organoids derived from human induced pluripotent stem cells with C10orf71 frameshift variants also had contractile defects with normal electrophysiological activity...."

Supports the contractile rather than structural nature of the lesion, in knockout mouse, null cardiomyocyte and human iPSC-derived organoid models.

PMID:28717008 SUPPORT PRIMARY RESULT In Vitro

"Importantly, CEFIP was located at the z-disc and was up-regulated in several models of cardiomyopathy."

Locates the C10orf71 product, CEFIP, at the cardiac z-disc, which is why this gene is wired to the sarcomeric and cytoskeletal node.

CAP2 (Autosomal recessive causal pathogenic variant. CAP2 encodes a cyclase-associated actin cytoskeleton regulatory protein required for the kinetics of actin filament repolymerization; a homozygous splice-consensus variant in a consanguineous Bedouin family caused DCM with supraventricular tachycardia, and patient fibroblasts showed altered actin repolymerization kinetics.)

Gene: CAP2 hgnc:20039 gene page

Show evidence (1 reference)

PMID:30518548 SUPPORT PRIMARY RESULT Human Clinical

"This is the first report of a recessive deleterious mutation in CAP2 and its association with DCM in humans. The clinical phenotype recapitulates the damaging effects on the heart observed in Cap2 knockout mice including DCM and cardiac conduction disease, but not the other effects on growth,..."

Reports the first recessive CAP2 variant associated with human DCM and ties it to actin polymerization kinetics.

PPCS (Autosomal recessive causal pathogenic variant. PPCS catalyses the second step of de novo coenzyme A biosynthesis from vitamin B5. Biallelic variants were found in five individuals from two unrelated families presenting with dilated cardiomyopathy, with reduced CoA levels in fibroblasts. This is a cofactor-biosynthesis lesion rather than a sarcomeric or cytoskeletal one, and CoA can be made from pantethine independently of PPCS, which is why pantethine was proposed as a targeted treatment.)

Gene: PPCS hgnc:25686 gene page

Show evidence (1 reference)

PMID:29754768 SUPPORT PRIMARY RESULT Human Clinical

Reports biallelic PPCS variants in five individuals from two families with DCM and the reduced fibroblast CoA levels that make this a coenzyme A biosynthesis lesion.

EMD (X-linked causal pathogenic variant. EMD encodes emerin, an inner nuclear membrane protein whose loss classically causes Emery-Dreifuss muscular dystrophy type 1, curated separately in this knowledge base. A distinct cardiac-only phenotype exists: the c.23C>G p.Ser8Trp missense variant co-segregated with DCM in six hemizygous males aged 36 to 50 with no muscular dystrophy, with greatly reduced myocardial emerin. The authors of that study note that before it the evidence for isolated DCM as an EMD phenotype was insufficient, so this gene is recorded here as an emerging rather than an established nonsyndromic DCM gene.)

Gene: EMD hgnc:3331 gene page

Show evidence (2 references)

PMID:40065010 SUPPORT PRIMARY RESULT Human Clinical

"We concluded that the EMD c.23C>G missense variant is associated with DCM in the absence of muscular dystrophy, thereby providing new evidence of isolated DCM as a distinct cardiac EMD-phenotype, separate from EDMD1."

Supports isolated DCM as an EMD phenotype distinct from Emery-Dreifuss muscular dystrophy type 1.

PMID:40065010 SUPPORT BACKGROUND Human Clinical

"Although an association with isolated dilated cardiomyopathy (DCM) has been suggested, evidence is currently insufficient to verify the gene-disease association."

Records the authors' own statement that, before their family study, the evidence for the EMD to isolated DCM gene-disease association was insufficient. Kept as the caveat on this record.

💊

Medical Actions

ACE Inhibitors / ARBs

Action: ACE inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: ACE inhibitor NCIT:C247 angiotensin II receptor antagonist NCIT:C66930

Platform: Small molecule

First-line neurohormonal blockade to reduce afterload and prevent adverse remodeling.

Mechanism Target:

INHIBITS Neurohormonal Activation — ACE inhibitors and ARBs block the renin-angiotensin-aldosterone axis, reducing angiotensin II-mediated vasoconstriction, aldosterone-driven fluid retention, and downstream adverse cardiac remodeling.

Beta-Blockers

Action: beta-blocker therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: beta-adrenergic antagonist NCIT:C29576

Reduce heart rate and neurohormonal activation, improving survival in heart failure with reduced ejection fraction.

Mechanism Target:

INHIBITS Neurohormonal Activation — Beta-blockers block cardiac adrenergic receptors, attenuating sympathetic neurohormonal activation, reducing heart rate, and reversing catecholamine-driven adverse remodeling in DCM.

SGLT2 Inhibitors

Action: SGLT2 inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: SGLT2 inhibitor NCIT:C98083

Newer therapy shown to reduce heart failure hospitalization and cardiovascular death in HFrEF regardless of diabetes status.

Mechanism Target:

MODULATES Mitochondrial Dysfunction — SGLT2 inhibitors promote ketone utilization as a more oxygen-efficient myocardial fuel and improve mitochondrial bioenergetics in cardiomyocytes, partially reversing the mitochondrial dysfunction that contributes to DCM progression.

Cardiac Resynchronization Therapy

Action: cardiac resynchronization therapy Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Biventricular pacing for patients with wide QRS and reduced LVEF to improve synchrony and outcomes.

Mechanism Target:

MODULATES Sarcomeric and Cytoskeletal Dysfunction — Biventricular pacing restores electromechanical synchrony, reducing dyssynchrony-driven regional wall stress and the sarcomeric and cytoskeletal maladaptation that worsens ventricular dysfunction in DCM.

Heart Transplantation

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

Platform: Surgery

Definitive therapy for end-stage DCM refractory to medical and device therapy.

Implantable Cardioverter-Defibrillator

Action: implantable cardioverter-defibrillator placement Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Indicated for primary prevention of sudden cardiac death in patients with LVEF <=35% despite optimal medical therapy.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Recommended for patients with familial or genetic DCM to guide cascade screening and family management.

Show evidence (2 references)

PMID:37788487 SUPPORT Other

"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 Other

"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.

🔬

Diagnosis

Echocardiography (Left Ventricular Ejection Fraction and End-Diastolic Diameter)

Dilated cardiomyopathy is diagnosed by echocardiographic (or other imaging-based) demonstration of left ventricular dilation together with impaired systolic contractility. The contractility criterion is operationalized as a reduced left ventricular ejection fraction (the band below, on this measurement). The dilation criterion is operationalized differently across sources: a prospective German DCM cohort (SFB/TR19 Greifswald, validated in IKARUS Marburg) defines it as a left ventricular end-diastolic diameter (LVEDD) above 117% of the age/body-surface-area predicted value by the Henry formula, at the same time requiring a different LVEF cut-off (<45%) than the StatPearls operational definition below (<40%). Because the 117% figure is a Henry-formula percent-of-predicted value rather than a length, it is recorded here in prose rather than as a `reference_ranges` band on the LVEDD measurement code, which carries length units (typically 4-6 cm) and would misrepresent a 117 cut-off as a length no real diameter reaches.

echocardiography NCIT:C16525

left ventricular ejection fraction LOINC:10230-1 left ventricular end-diastolic diameter LOINC:29436-3

Reference Ranges

Left ventricular Ejection fraction (adults (StatPearls operational definition))

Dilated cardiomyopathy (reduced ejection fraction) (< 40 %)

Dilated cardiomyopathy (reduced ejection fraction): LVEF below 40%, the contractility criterion of the operational definition of DCM; diagnosis also requires echocardiographic evidence of ventricular dilation, which this band does not capture.

A second cited source, the SFB/TR19 Greifswald / IKARUS Marburg cohort, defines the same contractility criterion at a different cut-off, LVEF <45% rather than <40%; both numbers are recorded in evidence below rather than reconciled into one band, since the sources disagree and neither is this entry's own claim to adjudicate. The band uses the StatPearls figure because it is stated as a general operational definition rather than one cohort's own inclusion criterion. That cohort's LVEDD dilation criterion (>117% of the Henry-formula predicted value) is described in this row's `description` rather than as a band, because the LVEDD measurement code is bound in length units and 117 is a percent-of-predicted value, not a length.

Show evidence (2 references)

PMID:28722940 SUPPORT REVIEW SYNTHESIS Other

"Dilated cardiomyopathy (DCM) is a disease of the heart muscle characterized by enlargement and dilation of one or both ventricles, along with impaired contractility, defined as a left ventricular ejection fraction (LVEF) less than 40%."

States the LVEF threshold, reproduced below as an interpretation band, that operationalizes the contractility half of the DCM definition.

PMID:42701412 SUPPORT BACKGROUND Human Clinical

"DCM was defined as a reduced left ventricular ejection fraction (LVEF <45%) and an increased left ventricular end-diastolic diameter according to the HENRY formula (LVEDD >117%) at the time of inclusion in the cohort study"

States the cohort's own LVEF threshold (45%, differing from the StatPearls 40% figure above) and the LVEDD dilation threshold described in this row's `description` rather than as a band (see `notes`).

📊

Related Datasets

Cardiac Fibrosis in Dilated Cardiomyopathy: Transcriptomics Insights, Histological Correlations, and Organoid Model Verifications [RNA-seq I] geo:GSE245825

Dilated cardiomyopathy (DCM) represents a leading cause of heart failure among younger adults. Despite endomyocardial biopsy (EMB) transcriptome enriching our understanding of DCM, the link between its gene expression and phenotype remains unclear. RNA-seq analysis of 58 DCM samples and 12 publicly available control samples unveiled about 25,000 transcripts. A principal component analysis highlighted a distinct DCM-control separation. WGCNA revealed four transcriptome modules strongly associated with DCM. The purple module, which is the DCM-related module, was enriched with fibrosis-related genes and showed FSTL3 as a pivotal DCM-associated gene.

human BULK RNA SEQ n=58

PMID:40934809

Identified by GEO DataSets index search for Dilated Cardiomyopathy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.

Distinct cardiac transcriptomic clustering in titin and lamin a/c-associated dilated cardiomyopathy patients geo:GSE146621

RNA profiles strongly differ in TTNtv and LMNA-mutated DCM patients, despite clinical similarities as other pathogenic variant carriers such as RBM20 and MYH7, suggesting a specific genetic effect on the cardiac transcriptome in addition to the effect of the clinical component.

human BULK RNA SEQ n=29

PMID:32955937

Simtuzumab Attenuates Loxl2-Mediated Extracellular Matrix Remodeling and Preserves Cardiac Function in LMNA Mutation-Induced Dilated Cardiomyopathy geo:GSE312730

Background | Dilated cardiomyopathy (DCM) caused by LMNA mutations is a severe cardiac condition marked by arrhythmias, contractile dysfunction, and excessive myocardial fibrosis, which collectively impair left ventricular function and increase the risk of heart failure. While the disease has been well characterized, a lack of insight into the pathogenesis has impeded the development of therapies. Methods | Here, we employed induced pluripotent stem cells (hiPSCs) derived from a patient carrying a LMNA point mutation (c.665A>C, p.His222Pro), alongside a murine model carrying the same mutation, to investigate the functional and molecular abnormalities driving DCM.

human BULK RNA SEQ n=6

PMID:41841259

Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy ega:EGAS00001002454

Background: Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits including cardiovascular diseases.Results: Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 149 (97)* patients with dilated cardiomyopathy and 113 (108)* non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage and allele specific expression.

human

PMID:28903782

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Dilated Cardiomyopathy"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Trio exome sequencing identified null mutations in ITPA as the cause of Martsolf syndrome with a lethal dilated cardiomyopathy presenting in infancy ega:EGAS00001003435

Typical Martsolf syndrome is characterized by congenital cataracts, postnatal microcephaly, developmental delay, hypotonia, short stature and biallelic hypomorphic mutations in either RAB3GAP1 or RAB3GAP2. Genetic analysis of 85 unrelated “mutation negative” probands with Martsolf or Martsolf-like syndromes identified two individuals with different homozygous null mutations in ITPA, the gene encoding inosine triphosphate pyrophosphatase (ITPase). Both probands were from multiplex families with a consistent, lethal and highly distinctive disorder; a Martsolf-like syndrome with infantile-onset dilated cardiomyopathy.

human

NGS on cardiac samples in Hungarian patients of dilated cardiomyopathy ega:EGAS50000000049

Heterozygous (HET) truncating mutations in the TTN gene (TTNtv) encoding the giant titin protein are the most common genetic cause of dilated cardiomyopathy (DCM). We investigated 127 clinically identified DCM human cardiac samples with targeted sequencing using the TruSight Cardio panel on an Illumina MiSeq system with a special focus on TTNtvs.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Dilated Cardiomyopathy"); description-level mentions were not accepted. EGA study_type: Resequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Core Functional Nodes and Sex-Specific Pathways in Human Ischemic and Dilated Cardiomyopathy metabolomics_workbench:ST001364

Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Dilated Cardiomyopathy"). Retrieved 2026-08-02.

Lipid Supplements Protect Dilated Cardiomyopathy massive:MSV000095560

Lipid (Plasmalogen) levels can be modulated via a dietary supplement called alkylglycerols (AG) which has demonstrated benefits in some disease settings. However, its therapeutic potential in cardiomyopathy remains unknown. This study explored an optimized AG supplement in restoring plasmalogen levels and attenuate cardiac dysfunction/pathology. Here, we placed a cardiac-specific transgenic cardiomyopathy mouse model, with cardiac function and molecular landscape assessed.

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Dilated Cardiomyopathy"). Retrieved 2026-08-02.

NHLBI GO-ESP: Family Studies (Dilated Cardiomyopathy) dbgap:phs000581

The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied.

Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Dilated Cardiomyopathy"). Retrieved 2026-08-02.

🧫

Experimental Models

Patient-specific TNNT2 R173W iPSC-derived cardiomyocytes (Clinical Trials in a Dish) IPSC_DERIVED_MODEL

Cardiomyocytes differentiated from induced pluripotent stem cells reprogrammed from skin fibroblasts of a three-generation family carrying the autosomal dominant sarcomeric TNNT2 R173W mutation, with mutation-negative relatives from the same family serving as isogenic-adjacent controls. A non-animal New Approach Methodology that puts the patient's own genotype into a dish and supports both disease modelling and pharmacological rescue testing.

Organism

human NCBITaxon:9606

Tissue

heart UBERON:0000948

Cell source

Patient-derived: iPSC lines reprogrammed from skin fibroblasts of four TNNT2 R173W carriers and three mutation-negative relatives in one family cohort

Culture

Embryoid-body cardiac differentiation followed by dissociated beating clusters and single cardiomyocytes, assayed by immunocytochemistry, transmission electron microscopy, calcium transient imaging, microelectrode arrays and atomic force microscopy

Publication

PMID:22517884

Pathograph links

Sarcomeric and Cytoskeletal Dysfunction partially recapitulates fidelity: moderate Cardiomyocytes carrying the patient's TNNT2 R173W allele reproduce the sarcomeric disorganisation and contractile failure of this node in human cells, and the phenotype is reversed by beta-blockade or SERCA2a overexpression.

Limitations: The authors themselves qualify the model as recapitulating the disease phenotype only to some extent. The cardiomyocytes are developmentally immature, with mitochondria and sarcoplasmic reticulum still immature at the assay stage, and the sarcomeric defect was most pronounced in single cells and at cluster edges rather than in well-coupled tissue. The cohort is a single family and a single TNNT2 allele, so the finding does not generalise across this node's other sarcomeric and cytoskeletal genes, and no chamber-level dilatation can be observed in a dish.

Readouts

Punctate sarcomeric alpha-actinin distribution

Direction: INCREASED

Interpretation: A higher proportion of patient cardiomyocytes showed disrupted sarcomeric alpha-actinin organisation than mutation-negative family controls, which is the structural correlate of this node.

Show evidence (1 reference)

PMID:22517884 SUPPORT In Vitro

"a significant higher percentage of DCM iPSC-CMs (n=391) showed a punctate distribution of sarcomeric α-actinin over one fourth of the total cellular area"

Quantifies the sarcomeric disorganisation measurement behind this readout against within-family controls.

Contractility of patient cardiomyocytes

Direction: DECREASED

Interpretation: Force production fell in mutation-carrying cardiomyocytes, linking the structural sarcomeric defect to functional impairment.

Show evidence (1 reference)

PMID:22517884 SUPPORT In Vitro

"cardiomyocytes derived from iPSCs from DCM patients exhibited altered regulation of calcium ion (Ca(2+)), decreased contractility, and abnormal distribution of sarcomeric α-actinin"

Reports the contractility and calcium-handling measurements made in this model.

Function after beta-blockade or SERCA2a overexpression

Direction: RESTORED

Interpretation: The model supports a rescue arm: both a beta-blocker and SERCA2a overexpression improved cardiomyocyte function, so the phenotype is pharmacologically reversible in vitro rather than a fixed differentiation artefact.

Show evidence (1 reference)

PMID:22517884 SUPPORT In Vitro

"Treatment with β-adrenergic blockers or overexpression of sarcoplasmic reticulum Ca(2+) adenosine triphosphatase (Serca2a) improved the function of iPSC-derived cardiomyocytes from DCM patients"

Reports the rescue measurement, in the improving direction, behind this readout.

Show evidence (1 reference)

PMID:22517884 SUPPORT DIRECT In Vitro

"iPSC-derived cardiomyocytes from DCM patients recapitulate to some extent the morphological and functional phenotypes of DCM"

Supports treating this model as informative for the node, with the authors' own partial-recapitulation qualifier carried through to the link relationship.

Neurohormonal Activation perturbs fidelity: low Exposing the cardiomyocytes to a beta-adrenergic agonist applies the catecholamine arm of this node directly to the cells and unmasks a genotype-dependent vulnerability that is not apparent at baseline.

Limitations: This is an acute pharmacological stimulus applied to isolated cardiomyocytes. It reproduces the receptor-level consequence of sympathetic drive but not neurohormonal activation as a disease process: there is no sympathetic nervous system, no renin-angiotensin-aldosterone axis, no natriuretic peptide counter-regulation and no feedback loop between cardiac output and neurohormonal tone.

Readouts

Contractile function under beta-adrenergic agonist stress

Direction: DECREASED

Interpretation: Under adrenergic stimulation patient cardiomyocytes slowed and lost contractile function, showing that catecholamine exposure degrades pump function in cells already carrying the sarcomeric lesion.

Show evidence (1 reference)

PMID:22517884 SUPPORT In Vitro

"When stimulated with a β-adrenergic agonist, DCM iPSC-derived cardiomyocytes showed characteristics of cellular stress such as reduced beating rates, compromised contraction, and a greater number of cells with abnormal sarcomeric α-actinin distribution"

Reports the beating-rate and contraction measurements made under the adrenergic perturbation behind this readout.

Sarcomeric disorganisation under beta-adrenergic agonist stress

Direction: INCREASED

Interpretation: The same adrenergic exposure spread sarcomeric disorganisation to more cells, so catecholamine stress aggravates the structural lesion and not only the functional one.

Show evidence (1 reference)

PMID:22517884 SUPPORT In Vitro

The same sentence reports the rise in cells with abnormal sarcomeric α-actinin distribution that this readout records.

Show evidence (1 reference)

PMID:22517884 SUPPORT INDIRECT In Vitro

Supports the model as informative for the adrenergic component of this node, while the systemic neurohormonal axes remain outside what a dish can represent.

Notes

Curated from the NAMeRS 2026 symposium New Approach Methodology tracker (monarch-initiative/dismech#4873), Panel 1 Clinical Trials in a Dish case study. No `namo_type` is recorded. NAMO defines no iPSC-derived model class (checked against its 56 classes) and its CellularSystem parent is abstract, so the choice was among the concrete culture-format siblings, and none of the three describes this system: CellLineModel is scoped to immortalized lines; ThreeDCellCulture fits the embryoid-body differentiation stage but not cells assayed after dissociation; TwoDCellCulture fits the single cardiomyocytes on atomic force microscopy and microelectrode arrays but not the 3D stage that produced them. The system spans two formats and NAMO has no value for the derivation that actually distinguishes it, so the slot is left absent rather than made to pick a half. `experimental_model_type: IPSC_DERIVED_MODEL` carries the distinction instead, and the upstream gap is monarch-initiative/namo#24. An earlier revision of this record used a coined InducedPluripotentStemCellDerivedModel CURIE (written here without its prefix so that prefix censuses over `kb/` do not match this file), which does not exist in NAMO; nothing validates `namo_type`, so it passed every gate. The adrenergic-stress readouts are split by direction because the source sentence reports both a fall in beating rate and contraction and a rise in cells with abnormal sarcomeric alpha-actinin, and `direction` is single-valued. The underlying evidence item was already cited on the Sarcomeric and Cytoskeletal Dysfunction node; this section adds the structured model record, its pathograph links and the rescue and adrenergic-stress readouts.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy
creation_date: '2026-03-06T00:00:00Z'
synonyms:
- DCM
- dilated cardiomyopathy
- congestive cardiomyopathy
- IDC
- idiopathic dilated cardiomyopathy
description: >-
  Dilated cardiomyopathy (DCM) is a disease of the heart muscle defined by left
  ventricular (or biventricular) dilation and impaired systolic contraction in
  the absence of abnormal loading conditions or coronary disease sufficient to
  explain it. Causes include sarcomere and cytoskeletal gene mutations,
  myocarditis, alcohol and other toxins, and the peripartum state. Progressive
  ventricular remodeling leads to heart failure, arrhythmia, and sudden death.
notes: >-
  Parent anchor. MONDO:0005021 "dilated cardiomyopathy" is the right term for
  this entry: it is the umbrella concept, not a gene-named leaf standing in
  for one. Its three direct MONDO children are viral, familial and
  non-familial dilated cardiomyopathy, which is the same clinical and
  etiologic axis the has_subtypes rows here use. No anchor change was needed.

  Why the numbered loci are not has_subtypes rows here. The numbered CMD and
  DCM designations sit two MONDO levels below this entry, as children of
  familial dilated cardiomyopathy (MONDO:0016333) or familial isolated dilated
  cardiomyopathy (MONDO:0700335), not as children of MONDO:0005021. This
  knowledge base already curates that level as standalone Disease entries: 32
  of them exist, and 13 more are queued in stubs/. Adding some of the same
  concepts as subtype rows on this umbrella would put a gene-locus axis and a
  clinical-etiology axis in one flat list and would duplicate entries that
  already carry the MONDO bindings. So the ruling for this entry is that the
  numbered loci stay standalone, and what belongs here is the gene panel with
  each gene wired to the mechanism it acts through.

  Genes added and genes dispositioned. Four genes that had no binding on this
  entry were added, each wired to a node: C10orf71, CAP2, PPCS and EMD. Two
  were not added, for reasons recorded rather than assumed.

  CSRP3. ClinGen rates CSRP3 Definitive for hypertrophic cardiomyopathy and
  only Limited for dilated cardiomyopathy 1M (MONDO:0011840), the numbered
  term curated in Dilated_Cardiomyopathy_1M. For the umbrella dilated
  cardiomyopathy term, the committed cache/clingen/gene_validity.csv holds an
  earlier (2025-05-30) record of that assertion classified No Known Disease
  Relationship. The 2008 study that established CSRP3 as a
  hypertrophic cardiomyopathy gene states that earlier work had associated
  CSRP3 missense mutations with either dilated cardiomyopathy or hypertrophic
  cardiomyopathy without comprehensive genetic evidence for a causative role.
  CSRP3's high-evidence relationship is curated on Hypertrophic_Cardiomyopathy,
  and it is left off this panel. The dilated designation CMD1M is curated in
  Dilated_Cardiomyopathy_1M.

  RAF1. RAF1's Definitive ClinGen relationship in the committed cache is with
  Noonan syndrome, and the dilated cardiomyopathy concept MONDO points at,
  dilated cardiomyopathy 1NN (MONDO:0014396), already has its own curated
  entry, Dilated_Cardiomyopathy_1NN, where RAF1 is bound. RAF1 is a RASopathy
  gene whose cardiomyopathy is part of that syndromic spectrum, so it is not
  added to this nonsyndromic panel.

  EMD was added despite being an Emery-Dreifuss muscular dystrophy gene,
  because a cardiac-only emerinopathy is a documented separate phenotype; the
  evidence item on that record carries the authors' own statement that the
  evidence had been insufficient before their study, so it is recorded as
  emerging rather than established.

  Mechanism nodes added. Before this pass, 33 of the 48 genes on this entry
  reached a pathophysiology node; the other 15 were listed with a ClinGen
  validity assertion and nothing else. Five nodes were added so that each
  reaches the step it acts at rather than a single sarcomeric list: calcium
  release dysregulation (JPH2, RYR2), excitability and conduction instability
  (SCN5A, ABCC9, TNNI3K), proteostasis (BAG5, FBXO32, GET3, PLEKHM2, RPL3L),
  transcriptional and developmental program (TBX20, PRDM16, GATAD1, MIB1), and
  coenzyme A biosynthesis (PPCS). Calcium release and membrane excitability are
  separate steps with separate consequences - the calcium genes are argued to
  systolic dysfunction and the channel and kinase genes to arrhythmia - so they
  are two nodes rather than one.

  CTF1 is the one gene left unwired, deliberately. ClinGen classifies CTF1 to
  dilated cardiomyopathy as Limited. Cardiotrophin-1 is an interleukin-6
  family cytokine signalling through gp130, so the nearest node here is IL-11
  signalling in cardiac fibroblasts, which is scoped to IL-11 in fibroblasts
  specifically and not to the cytokine family; the neurohormonal node
  describes renin-angiotensin and sympathetic activation, which a cytokine
  gene does not cause. Two PubMed searches were run to check for a mechanism
  to attach the gene to. "(CTF1[Title/Abstract] OR
  cardiotrophin-1[Title/Abstract]) AND (dilated cardiomyopathy[Title/Abstract])"
  returns ten records, of which one is a human genetic study: a 2000 report of
  promoter and coding variants in patients (PMID:11058912). The other nine
  measure cardiotrophin-1 expression, plasma level or downstream signalling
  rather than the consequence of a CTF1 variant. "cardiotrophin-1 AND dilated
  cardiomyopathy AND (mutation OR variant OR polymorphism)" returns that same
  single record. So no source was found tying a CTF1 variant to a specific
  myocardial mechanism. Rather than attach the gene to a node
  its evidence does not reach, it is left listed and this is recorded.

  ClinGen disagrees with its own publication on JPH2. The committed ClinGen
  gene validity snapshot, pinned in data/clingen/MANIFEST.yaml at 2026-08-13,
  carries two JPH2 assertions for dilated cardiomyopathy from the Dilated
  Cardiomyopathy Gene Curation Expert Panel, both dated 2025-01-24: autosomal
  recessive Strong and autosomal dominant Limited. The same panel's 2026 publication reports the pair the
  other way round, as autosomal dominant Strong and autosomal recessive
  Limited. The two JPH2 evidence items on this entry quote the cached rows
  exactly and were left as they are; the discrepancy is recorded here rather
  than resolved, because nothing in this repository can settle which direction
  is correct.

  NEXN has two numbered classes. MONDO attributes NEXN to both dilated
  cardiomyopathy 1CC (MONDO:0013147, OMIM:613122) and cardiomyopathy, dilated,
  2M (MONDO:0979243, OMIM:621261). These are two separate OMIM entries, so
  this is not a duplicate MONDO term pair. What distinguishes them was not
  established here, and neither is curated as a row on this entry under the
  ruling above.

  GeneReviews baseline. The Dilated Cardiomyopathy Overview chapter
  (PMID:20301486) is tagged in the references block. Its cached record is the
  chapter's purpose statement only, four numbered aims and no clinical or
  genetic content, so no evidence was mined from it. The LMNA-Related Dilated
  Cardiomyopathy chapter (PMID:20301717) also matches this entry's name by
  substring. It is tagged in the references block as the GeneReviews chapter
  it is, but it is a gene-specific chapter whose subject is the LMNA locus -
  curated in this knowledge base as Dilated_Cardiomyopathy_1A, which cites it
  throughout - so it is not this umbrella's baseline chapter and nothing is
  mined from it here.
references:
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20301717
  title: LMNA-Related Dilated Cardiomyopathy.
  tags:
  - GeneReviews
  findings: []
- reference: PMID:42708185
  title: "An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy."
  findings:
  - statement: >-
      The 2026 ClinGen Dilated Cardiomyopathy Gene Curation Expert Panel
      reassessment reports JPH2 as autosomal dominant Strong and autosomal
      recessive Limited, the opposite way round from the committed ClinGen
      gene validity snapshot. The discrepancy is recorded in this entry's
      notes and not resolved here.
    evidence:
    - reference: PMID:42708185
      reference_title: "An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Four previously evaluated genes were curated for both AD and AR MOIs:
        JPH2 (AD-Strong, AR-Limited), LDB3 (AD-Limited, AR-Strong), MYBPC3
        (AD-Limited, AR-Limited), and TNNI3 (AD- and AR- Strong).
      explanation: >-
        Carries the published JPH2 mode-of-inheritance classifications that
        disagree with the cached ClinGen assertion rows quoted on the JPH2
        genetic record.
- reference: PMID:18505755
  title: "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy."
  findings:
  - statement: >-
      CSRP3 is confirmed as a hypertrophic cardiomyopathy gene, and the
      earlier association of CSRP3 missense mutations with dilated
      cardiomyopathy was judged to lack comprehensive genetic evidence for a
      causative role. This is the basis for not adding CSRP3 to this entry's
      gene panel.
    evidence:
    - reference: PMID:18505755
      reference_title: "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        Previous studies have shown an association between CSRP3 missense
        mutations and either dilated cardiomyopathy (DCM) or HCM, but all
        these studies were unable to provide comprehensive genetic evidence
        for a causative role of CSRP3 mutations.
      explanation: >-
        States that the earlier CSRP3 to dilated cardiomyopathy association
        lacked comprehensive genetic evidence for causation.
    - reference: PMID:18505755
      reference_title: "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        We used linkage analysis and identified a CSRP3 missense mutation in a
        large German family affected by HCM. We confirmed CSRP3 as an HCM
        disease gene.
      explanation: >-
        Reports the linkage study that established CSRP3 as a hypertrophic
        cardiomyopathy gene, which is where this knowledge base binds it.
- reference: PMID:8864356
  title: "Cardiotrophin-1: a multifunctional cytokine that signals via LIF receptor-gp 130 dependent pathways."
  findings:
  - statement: >-
      Cardiotrophin-1, the CTF1 product, is an interleukin-6 family cytokine
      acting through the shared gp130 signalling subunit. This is the basis
      for the note explaining why CTF1 is left unwired rather than attached to
      this entry's IL-11 fibroblast node.
    evidence:
    - reference: PMID:8864356
      reference_title: "Cardiotrophin-1: a multifunctional cytokine that signals via LIF receptor-gp 130 dependent pathways."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        CT-1 is a new member of the IL-6 family of cytokines that induce their
        biological effects through the shared signaling subunit, gp 130.
      explanation: >-
        Identifies cardiotrophin-1 as an IL-6 family cytokine signalling
        through gp130.
category: Complex
disease_term:
  preferred_term: dilated cardiomyopathy
  term:
    id: MONDO:0005021
    label: dilated cardiomyopathy
gene_sets:
- gene_set: MYGENESET:KEGG_DILATED_CARDIOMYOPATHY
  relationship: CANONICAL_PATHWAY
  note: >-
    KEGG dilated cardiomyopathy pathway.
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
    evidence_source: OTHER
    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
    evidence_source: OTHER
    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
    evidence_source: OTHER
    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
    evidence_source: OTHER
    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.
  notes: "From the Stanford iPSC-cardiomyocyte \"clinical-trials-in-a-dish\" program (Joseph Wu group) presented at the NAMeRS 2026 symposium (issue #4873).\n"
  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
  genes:
  - preferred_term: TTN
    term:
      id: hgnc:12403
      label: TTN
  - preferred_term: LMNA
    term:
      id: hgnc:6636
      label: LMNA
  - preferred_term: MYH7
    term:
      id: hgnc:7577
      label: MYH7
  - preferred_term: MYH6
    term:
      id: hgnc:7576
      label: MYH6
  - preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  - preferred_term: ACTC1
    term:
      id: hgnc:143
      label: ACTC1
  - preferred_term: TPM1
    term:
      id: hgnc:12010
      label: TPM1
  - preferred_term: TNNT2
    term:
      id: hgnc:11949
      label: TNNT2
  - preferred_term: TNNC1
    term:
      id: hgnc:11943
      label: TNNC1
  - preferred_term: TNNI3
    term:
      id: hgnc:11947
      label: TNNI3
  - preferred_term: MYL2
    term:
      id: hgnc:7583
      label: MYL2
  - preferred_term: MYLK3
    term:
      id: hgnc:29826
      label: MYLK3
  - preferred_term: DES
    term:
      id: hgnc:2770
      label: DES
  - preferred_term: FLNC
    term:
      id: hgnc:3756
      label: FLNC
  - preferred_term: VCL
    term:
      id: hgnc:12665
      label: VCL
  - preferred_term: LDB3
    term:
      id: hgnc:15710
      label: LDB3
  - preferred_term: TCAP
    term:
      id: hgnc:11610
      label: TCAP
  - preferred_term: MYPN
    term:
      id: hgnc:23246
      label: MYPN
  - preferred_term: ANKRD1
    term:
      id: hgnc:15819
      label: ANKRD1
  - preferred_term: NEXN
    term:
      id: hgnc:29557
      label: NEXN
  - preferred_term: NEBL
    term:
      id: hgnc:16932
      label: NEBL
  - preferred_term: NRAP
    term:
      id: hgnc:7988
      label: NRAP
  - preferred_term: OBSCN
    term:
      id: hgnc:15719
      label: OBSCN
  - preferred_term: LMOD2
    term:
      id: hgnc:6648
      label: LMOD2
  - preferred_term: TMOD1
    term:
      id: hgnc:11871
      label: TMOD1
  - preferred_term: LAMA4
    term:
      id: hgnc:6484
      label: LAMA4
  - preferred_term: CDH2
    term:
      id: hgnc:1759
      label: CDH2
  - preferred_term: DSG2
    term:
      id: hgnc:3049
      label: DSG2
  - preferred_term: MYZAP
    term:
      id: hgnc:43444
      label: MYZAP
  - preferred_term: BAG3
    term:
      id: hgnc:939
      label: BAG3
  - preferred_term: FLII
    term:
      id: hgnc:3750
      label: FLII
  - preferred_term: C10orf71
    term:
      id: hgnc:26973
      label: C10orf71
  - preferred_term: CAP2
    term:
      id: hgnc:20039
      label: CAP2
  - preferred_term: EMD
    term:
      id: hgnc:3331
      label: EMD
  evidence:
  - reference: PMID:37962957
    reference_title: "Truncated titin is structurally integrated into the human dilated cardiomyopathic sarcomere."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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
    evidence_source: HUMAN_CLINICAL
    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
    evidence_source: OTHER
    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.
  - reference: PMID:22517884
    reference_title: "Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "cardiomyocytes derived from iPSCs from DCM patients exhibited altered regulation of calcium ion (Ca(2+)), decreased contractility, and abnormal distribution of sarcomeric α-actinin."
    explanation: >
      New Approach Methodology (NAM) "disease-in-a-dish" model: patient-specific
      iPSC-derived cardiomyocytes from a family carrying the sarcomeric TNNT2 R173W
      mutation recapitulate this node's sarcomeric-dysfunction to impaired-contractility
      mechanism in vitro, without an animal model.
- 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: Establishes that the four foundational HFrEF drug classes act by blocking the renin-angiotensin and sympathetic systems. Note this is therapeutic rather than direct mechanistic evidence - it shows the pathway is druggable, not that it is activated.
    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
  downstream:
  - target: IL-11 Signalling in Cardiac Fibroblasts
    description: >-
      Neurohormonal (angiotensin II) activation drives cardiac fibroblast IL-11
      induction, placing IL-11 receptor signalling downstream of the
      neurohormonal stress that promotes adverse remodeling.
    evidence:
    - reference: PMID:29160304
      reference_title: "IL-11 is a crucial determinant of cardiovascular fibrosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        established stimuli for cardiac fibrosis (endothelin-1 (END1),
        angiotensin II (AngII) and PDGF)
      explanation: >-
        Identifies angiotensin II - the effector of neurohormonal activation -
        among the established cardiac-fibrosis stimuli tested for IL-11
        induction in cardiac fibroblasts. Evidence source is IN_VITRO (primary
        human cardiac fibroblasts).
    - reference: PMID:29160304
      reference_title: "IL-11 is a crucial determinant of cardiovascular fibrosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        All pro-fibrotic stimuli that were tested induced changes in IL-11
        protein levels but not mRNA
      explanation: >-
        Shows the tested pro-fibrotic stimuli, angiotensin II among them, induce
        cardiac fibroblast IL-11 protein, supporting this neurohormonal-to-IL-11
        edge. Evidence source is IN_VITRO (primary human cardiac fibroblasts).
- name: IL-11 Signalling in Cardiac Fibroblasts
  conforms_to: "il11_erk_ampk_mtor_aging#IL-11 Receptor Signalling Activation"
  role: amplifier
  biological_scale: MOLECULAR
  description: >-
    Profibrotic stress upregulates IL-11 and IL11RA in cardiac fibroblasts,
    driving ERK-dependent (non-canonical) autocrine signalling that promotes
    their fibroblast-to-myofibroblast transformation and ECM gene expression.
    This IL-11 receptor-signalling arm is an organ-specific instance of the
    conserved IL-11 signalling module and feeds myocardial fibrosis; neutralizing
    anti-IL-11 or anti-IL11RA antibodies reduce cardiac fibrosis and ERK
    activation without affecting hypertrophy.
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  cell_types:
  - preferred_term: cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: Interleukin-11-mediated signaling pathway
    term:
      id: GO:0038154
      label: interleukin-11-mediated signaling pathway
    modifier: INCREASED
  - preferred_term: ERK1 and ERK2 cascade
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
    modifier: INCREASED
  evidence:
  - reference: PMID:33462828
    reference_title: "Antibody-mediated neutralization of IL11 signalling reduces ERK activation and cardiac fibrosis in a mouse model of severe pressure overload."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Inhibition of IL11 signalling reduced AAC-induced cardiac fibrosis and ECM
      gene expression as well as ERK1/2 phosphorylation but had no effect on
      cardiac hypertrophy.
    explanation: >-
      Directly evidences that anti-IL-11 reduces cardiac fibrosis and ERK1/2
      phosphorylation in a cardiac-fibroblast-driven model, grounding this node.
      Evidence source is MODEL_ORGANISM (mouse ascending aortic constriction).
  - reference: PMID:33462828
    reference_title: "Antibody-mediated neutralization of IL11 signalling reduces ERK activation and cardiac fibrosis in a mouse model of severe pressure overload."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      blocking IL11 signalling reduces cardiac fibrosis due to severe pressure
      overload and suggests ERK, but not STAT3, activity as the relevant
      underlying signalling pathway
    explanation: >-
      Identifies the non-canonical ERK arm (not canonical STAT3) as the
      fibrosis-relevant IL-11 pathway in the heart, consistent with the module's
      receptor-signalling node and its canonical-vs-non-canonical knowledge gap.
      Evidence source is MODEL_ORGANISM (mouse pressure-overload model plus
      cardiac fibroblasts).
  - reference: PMID:29160304
    reference_title: "IL-11 is a crucial determinant of cardiovascular fibrosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In mice, fibroblast-specific Il11 transgene expression or Il-11 injection
      causes heart and kidney fibrosis and organ failure, whereas genetic
      deletion of Il11ra1 protects against disease.
    explanation: >-
      Shows fibroblast IL-11 is sufficient to cause heart fibrosis and organ
      failure and that receptor deletion is protective. Evidence source is
      MODEL_ORGANISM (transgenic and Il11ra1-knockout mice).
  - reference: PMID:29160304
    reference_title: "IL-11 is a crucial determinant of cardiovascular fibrosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts,
      in which they drive non-canonical, ERK-dependent autocrine signalling that
      is required for fibrogenic protein synthesis.
    explanation: >-
      Establishes the ERK-dependent autocrine IL-11 receptor-signalling arm in
      fibroblasts modeled by this node. Evidence source is IN_VITRO (primary
      human cardiac fibroblasts).
  downstream:
  - target: Myocardial Fibrosis

- name: Myocardial Fibrosis
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  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 cause an aggressive, early-onset form of dilated
    cardiomyopathy. RBM20 is a cardiac splicing regulator, and the proposed mechanism
    is disrupted alternative splicing of key cardiac genes including TTN and
    calcium-handling genes, with some variants reported to form toxic biomolecular
    condensates. The splicing and condensate detail derives from model systems and is
    not established by the evidence cited here.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  genes:
  - preferred_term: RBM20
    term:
      id: hgnc:27424
      label: RBM20
  evidence:
  - reference: PMID:38288598
    reference_title: "Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems."
    supports: SUPPORT
    evidence_source: OTHER
    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: >
    Chronic cardiac inflammation with distinct immune cell infiltration patterns
    contributes to adverse remodeling in DCM. Immune-mediated injury from viral
    myocarditis or autoimmune reactions is a proposed trigger, but that route is not
    established by the deconvolution evidence cited here.
  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
  genes:
  - preferred_term: PPA2
    term:
      id: hgnc:28883
      label: PPA2
  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
- name: Cardiomyocyte Calcium Release Dysregulation
  biological_scale: CELLULAR
  description: >-
    JPH2 and RYR2 act on the sarcoplasmic reticulum calcium release step rather
    than on the contractile apparatus. JPH2 builds the junctional membrane
    complex that couples the t-tubule to the sarcoplasmic reticulum, and RYR2 is
    the release channel itself. The reported defect is a loss of control over
    when release terminates rather than a smaller release: the RyR2 exon-3
    region associated with dilated cardiomyopathy lowers the luminal calcium
    threshold at which release ends and increases the fractional release.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: regulation of sarcoplasmic reticulum calcium release
    term:
      id: GO:0010880
      label: regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    modifier: DYSREGULATED
  genes:
  - preferred_term: JPH2
    term:
      id: hgnc:14202
      label: JPH2
  - preferred_term: RYR2
    term:
      id: hgnc:10484
      label: RYR2
  evidence:
  - reference: PMID:34861382
    reference_title: "One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      we found that autosomal recessive, loss-of-function variants are
      associated with severe, early onset DCM, while autosomal dominant
      missense variants are associated with a wider range of cardiac disease,
      including HCM, arrhythmia, SCD, and cardiac conduction disease.
    explanation: >-
      Separates the two JPH2 modes of inheritance: recessive loss-of-function
      gives severe early-onset DCM, dominant missense a wider arrhythmic and
      conduction phenotype.
  - reference: PMID:22374134
    reference_title: "Abnormal termination of Ca2+ release is a common defect of RyR2 mutations associated with cardiomyopathies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      The 35-residue exon-3 region of RyR2 is associated with dilated
      cardiomyopathy. Single-cell luminal Ca2+ imaging revealed that the
      deletion of the first 305 NH2-terminal residues encompassing exon-3 or
      the deletion of exon-3 itself markedly reduced the luminal Ca2+
      threshold at which Ca2+ release terminates and increased the fractional
      Ca2+ release.
    explanation: >-
      Ties the RyR2 exon-3 region associated with dilated cardiomyopathy to a
      measurable defect in termination of sarcoplasmic reticulum calcium
      release.
  downstream:
  - target: Left ventricular systolic dysfunction
    causal_link_type: DIRECT
    description: >-
      Loss of control over sarcoplasmic reticulum calcium release reduces
      systolic performance, and recessive loss-of-function variants in the gene
      that builds the release couplon give severe, early-onset dilated
      cardiomyopathy.
    evidence:
    - reference: PMID:22374134
      reference_title: "Abnormal termination of Ca2+ release is a common defect of RyR2 mutations associated with cardiomyopathies."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        The 35-residue exon-3 region of RyR2 is associated with dilated
        cardiomyopathy. Single-cell luminal Ca2+ imaging revealed that the
        deletion of the first 305 NH2-terminal residues encompassing exon-3 or
        the deletion of exon-3 itself markedly reduced the luminal Ca2+
        threshold at which Ca2+ release terminates and increased the
        fractional Ca2+ release.
      explanation: >-
        Ties the RyR2 exon-3 region associated with dilated cardiomyopathy to
        a measurable defect in termination of sarcoplasmic reticulum calcium
        release.
    - reference: PMID:34861382
      reference_title: "One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        we found that autosomal recessive, loss-of-function variants are
        associated with severe, early onset DCM, while autosomal dominant
        missense variants are associated with a wider range of cardiac disease,
        including HCM, arrhythmia, SCD, and cardiac conduction disease.
      explanation: >-
        Records that recessive loss-of-function JPH2 variants give severe,
        early-onset dilated cardiomyopathy.
- name: Cardiomyocyte Excitability and Conduction Instability
  biological_scale: CELLULAR
  description: >-
    SCN5A, ABCC9 and TNNI3K act on the cardiomyocyte action potential rather
    than on calcium release or on the contractile apparatus. SCN5A carries the
    cardiac sodium current, ABCC9 is the SUR2 subunit of the cardiac KATP
    channel, and TNNI3K is a cardiac troponin I interacting kinase whose
    disease-causing variant disrupts its kinase domain. Disease in this group
    characteristically presents with conduction disease and arrhythmia
    alongside, or ahead of, ventricular dilatation.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle cell action potential
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
    modifier: DYSREGULATED
  genes:
  - preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  - preferred_term: ABCC9
    term:
      id: hgnc:60
      label: ABCC9
  - preferred_term: TNNI3K
    term:
      id: hgnc:19661
      label: TNNI3K
  evidence:
  - reference: PMID:15466643
    reference_title: "SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Our findings expand the clinical spectrum of disorders of the cardiac
      sodium channel to include cardiac dilation and dysfunction
    explanation: >-
      Extends the cardiac sodium channel disease spectrum to cardiac dilation
      and dysfunction, which is why SCN5A is wired to this node rather than
      the sarcomeric one.
  - reference: PMID:35495129
    reference_title: "Case Report: Loss-of-Function ABCC9 Genetic Variant Associated With Ventricular Fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Genetic variants in the ABCC9 gene, encoding the SUR2 auxiliary subunit
      from KATP channels, were previously linked with various inherited
      diseases. This wide range of congenital disorders includes multisystem
      and cardiovascular pathologies. The gain-of-function mutations result in
      Cantu syndrome, acromegaloid facial appearance, hypertrichosis, and
      acromegaloid facial features. The loss-of-function mutations in the
      ABCC9 gene were associated with the Brugada syndrome, early
      repolarization syndrome, and dilated cardiomyopathy.
    explanation: >-
      States that ABCC9 encodes the SUR2 subunit of the KATP channel and that
      loss-of-function variants have been associated with dilated
      cardiomyopathy.
  - reference: PMID:24925317
    reference_title: "TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      revealing an unreported heterozygous missense mutation disrupting the
      highly conserved kinase domain in TNNI3K.
    explanation: >-
      Locates the causal TNNI3K variant in the conserved kinase domain in a
      family with conduction system disease, atrial tachyarrhythmia and DCM.
  downstream:
  - target: Arrhythmia
    causal_link_type: DIRECT
    description: >-
      Each gene on this node has a reported arrhythmic or conduction phenotype:
      the SCN5A families presented with conduction disorder and arrhythmia,
      loss-of-function ABCC9 variants with Brugada and early repolarization
      syndromes, and the TNNI3K family with conduction system disease and
      atrial tachyarrhythmia.
    evidence:
    - reference: PMID:24925317
      reference_title: "TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        revealing an unreported heterozygous missense mutation disrupting the
        highly conserved kinase domain in TNNI3K.
      explanation: >-
        Identifies the causal variant in the family whose syndrome is
        conduction system disease with atrial tachyarrhythmia and DCM.
    - reference: PMID:35495129
      reference_title: "Case Report: Loss-of-Function ABCC9 Genetic Variant Associated With Ventricular Fibrillation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        The loss-of-function mutations in the ABCC9 gene were associated with
        the Brugada syndrome, early repolarization syndrome, and dilated
        cardiomyopathy.
      explanation: >-
        Associates loss-of-function ABCC9 variants with two arrhythmia
        syndromes alongside dilated cardiomyopathy.
  - target: Left ventricular systolic dysfunction
    causal_link_type: DIRECT
    description: >-
      The same variants that destabilize the action potential also produce
      ventricular dilatation and systolic dysfunction; the SCN5A report is
      explicit that the cardiac sodium channel disease spectrum extends to
      cardiac dilation and dysfunction.
    evidence:
    - reference: PMID:15466643
      reference_title: "SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Our findings expand the clinical spectrum of disorders of the cardiac
        sodium channel to include cardiac dilation and dysfunction
      explanation: >-
        States that cardiac sodium channel disease extends to cardiac dilation
        and dysfunction.
- name: Cardiomyocyte Proteostasis Failure
  biological_scale: CELLULAR
  description: >-
    A second group of DCM genes act on how cardiomyocyte proteins are made,
    folded, delivered and cleared rather than on the contractile apparatus
    itself. RPL3L is a muscle-specific ribosomal protein, GET3 (ASNA1) inserts
    tail-anchored membrane proteins, BAG5 is a nucleotide exchange factor that
    activates HSC70-mediated folding, FBXO32 (atrogin-1) is the
    substrate-recognition subunit of an SCF ubiquitin ligase, and PLEKHM2
    positions lysosomes for autophagic flux. Most are recessive and several
    present in the neonatal or infantile period.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: DECREASED
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: DECREASED
  - preferred_term: ribosome biogenesis
    term:
      id: GO:0042254
      label: ribosome biogenesis
    modifier: DECREASED
  genes:
  - preferred_term: BAG5
    term:
      id: hgnc:941
      label: BAG5
  - preferred_term: FBXO32
    term:
      id: hgnc:16731
      label: FBXO32
  - preferred_term: GET3
    term:
      id: hgnc:752
      label: GET3
  - preferred_term: PLEKHM2
    term:
      id: hgnc:29131
      label: PLEKHM2
  - preferred_term: RPL3L
    term:
      id: hgnc:10351
      label: RPL3L
  evidence:
  - reference: PMID:35044787
    reference_title: "Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      we identified that homozygous truncating mutations in the gene encoding
      Bcl-2–associated athanogene (BAG) co-chaperone 5 (BAG5) caused inherited
      DCM in five patients among four unrelated families with complete
      penetrance.
    explanation: >-
      Establishes homozygous truncating BAG5 variants as a cause of inherited
      DCM with complete penetrance across four families.
  - reference: PMID:35044787
    reference_title: "Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: >-
      BAG5 acts as a nucleotide exchange factor for heat shock cognate 71 kDa
      protein (HSC70), promoting adenosine diphosphate release and activating
      HSC70-mediated protein folding.
    explanation: >-
      States the molecular function of BAG5 as a nucleotide exchange factor
      activating HSC70-mediated protein folding, the proteostatic step this
      node describes.
  - reference: PMID:26753747
    reference_title: "FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Our results indicate that abnormal SCF activity with subsequent
      impairment of the autophagic flux due to a novel FBXO32 mutation is
      implicated in the pathogenesis of DCM.
    explanation: >-
      Ties the FBXO32 lesion to impaired SCF ubiquitin ligase activity and
      reduced autophagic flux in DCM.
  - reference: PMID:31461301
    reference_title: "Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We identified compound heterozygous variants in the highly conserved
      ASNA1 gene (arsA arsenite transporter, ATP-binding, homolog), which
      encodes an ATPase required for post-translational membrane insertion of
      tail-anchored proteins.
    explanation: >-
      Identifies biallelic ASNA1/GET3 variants in siblings with rapidly
      progressive DCM and states the gene product inserts tail-anchored
      membrane proteins.
  - reference: PMID:26464484
    reference_title: "PLEKHM2 mutation leads to abnormal localization of lysosomes, impaired autophagy flux and associates with recessive dilated cardiomyopathy and left ventricular noncompaction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      lysosomes appeared to be concentrated in the perinuclear region, and
      autophagy flux was impaired.
    explanation: >-
      Reports the lysosomal mispositioning and impaired autophagic flux
      measured in fibroblasts of the recessive PLEKHM2 DCM family.
  - reference: PMID:32514796
    reference_title: "Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      we identified causative, compound heterozygous missense variants in
      RPL3L (ribosomal protein L3-like) in all the affected individuals.
    explanation: >-
      Identifies biallelic RPL3L variants as causative in five individuals
      with neonatal DCM, placing a muscle-specific ribosomal protein in this
      group.
  - reference: PMID:32514796
    reference_title: "Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      alter the interaction of RPL3L with the RNA components of the 60S
      ribosomal subunit and thus destabilize its binding to the 60S subunit
    explanation: >-
      Places the RPL3L lesion at incorporation of the protein into the 60S
      ribosomal subunit, the ribosome biogenesis step bound on this node.
      Graded computational because the finding comes from three-dimensional
      homology modeling and in silico analysis.
  downstream:
  - target: Left ventricular systolic dysfunction
    causal_link_type: DIRECT
    description: >-
      Loss of protein synthesis, folding, targeting or clearance capacity in
      the cardiomyocyte produces ventricular dilatation with systolic failure;
      the BAG5 families showed complete penetrance and required heart
      transplantation.
    evidence:
    - reference: PMID:35044787
      reference_title: "Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        we identified that homozygous truncating mutations in the gene
        encoding Bcl-2–associated athanogene (BAG) co-chaperone 5 (BAG5)
        caused inherited DCM in five patients among four unrelated families
        with complete penetrance.
      explanation: >-
        Establishes homozygous truncating BAG5 variants as a cause of
        inherited DCM with complete penetrance across four families.
- name: Cardiac Transcriptional and Developmental Program Dysregulation
  biological_scale: CELLULAR
  description: >-
    A third group of DCM genes encode transcriptional and developmental
    regulators of the ventricular myocardium. TBX20 is a cardiac T-box
    transcription factor that acts with NKX2-5 and GATA4, PRDM16 is the
    transcription factor whose loss accounts for the cardiomyopathy of
    monosomy 1p36, MIB1 is the NOTCH pathway E3 ubiquitin ligase whose loss
    arrests trabecular maturation and compaction, and GATAD1 was mapped in a
    family with recessive DCM. Left ventricular noncompaction overlaps this
    group, reflecting arrested chamber development rather than degeneration of
    a formed myocardium.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle cell differentiation
    term:
      id: GO:0055007
      label: cardiac muscle cell differentiation
    modifier: DYSREGULATED
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DYSREGULATED
  - preferred_term: Notch signaling pathway
    term:
      id: GO:0007219
      label: Notch signaling pathway
    modifier: DECREASED
  genes:
  - preferred_term: TBX20
    term:
      id: hgnc:11598
      label: TBX20
  - preferred_term: PRDM16
    term:
      id: hgnc:14000
      label: PRDM16
  - preferred_term: GATAD1
    term:
      id: hgnc:29941
      label: GATAD1
  - preferred_term: MIB1
    term:
      id: hgnc:21086
      label: MIB1
  evidence:
  - reference: PMID:26118961
    reference_title: "TBX20 loss-of-function mutation associated with familial dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Functional assays revealed that the mutant TBX20 had significantly
      diminished transcriptional activity. Furthermore, the mutation markedly
      reduced the synergistic activation of TBX20 with NKX2-5 or GATA4.
    explanation: >-
      Shows the DCM-associated TBX20 mutation reduces transcriptional activity
      and its synergy with NKX2-5 and GATA4.
  - reference: PMID:23768516
    reference_title: "Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      we describe the loss of a gene within the deletion that is responsible
      for the cardiomyopathy associated with monosomy 1p36, and we confirm its
      role in nonsyndromic left ventricular noncompaction cardiomyopathy
      (LVNC) and dilated cardiomyopathy (DCM).
    explanation: >-
      Attributes the cardiomyopathy of monosomy 1p36 to loss of PRDM16 and
      confirms its role in nonsyndromic LVNC and DCM.
  - reference: PMID:23314057
    reference_title: "Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We show that germline mutations in human MIB1 (mindbomb homolog 1),
      which encodes an E3 ubiquitin ligase that promotes endocytosis of the
      NOTCH ligands DELTA and JAGGED, cause LVNC in autosomal-dominant
      pedigrees
    explanation: >-
      Establishes germline MIB1 mutations as a cause of LVNC and states that
      MIB1 is the E3 ubiquitin ligase regulating NOTCH ligand endocytosis.
  - reference: PMID:23314057
    reference_title: "Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      These results implicate NOTCH signaling in LVNC and indicate that MIB1
      mutations arrest chamber myocardium development, preventing trabecular
      maturation and compaction.
    explanation: >-
      States the developmental mechanism: MIB1 mutations arrest chamber
      myocardium development and prevent trabecular maturation and compaction.
  - reference: PMID:21965549
    reference_title: "Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We performed genome-wide mapping and exome sequencing in a unique family
      wherein DCM segregated as an autosomal recessive (AR) trait.
    explanation: >-
      Records the genome-wide mapping and exome sequencing in the
      consanguineous family in which DCM segregated recessively, the study
      that implicated GATAD1.
  downstream:
  - target: Left ventricular systolic dysfunction
    causal_link_type: DIRECT
    description: >-
      A ventricular myocardium built by a disrupted transcriptional program
      underperforms; MIB1 loss arrests chamber myocardium development and
      prevents trabecular maturation and compaction.
    evidence:
    - reference: PMID:23314057
      reference_title: "Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        These results implicate NOTCH signaling in LVNC and indicate that MIB1
        mutations arrest chamber myocardium development, preventing trabecular
        maturation and compaction.
      explanation: >-
        States the developmental mechanism: MIB1 mutations arrest chamber
        myocardium development and prevent trabecular maturation and
        compaction.
- name: Coenzyme A Biosynthesis Deficiency
  biological_scale: MOLECULAR
  description: >-
    PPCS catalyses the second of the five enzymatic steps that make coenzyme A
    from vitamin B5, and biallelic PPCS variants lower cellular CoA. CoA is a
    cofactor for a large share of cellular enzymes including those of
    fatty-acid handling, so this is a metabolic cofactor lesion reaching the
    myocardium, distinct from the sarcomeric, ion-handling, proteostatic and
    transcriptional routes into the same phenotype. It is also the one route
    here with a directly implied treatment: CoA can be made from pantethine by
    a route that does not use PPCS.
  biological_processes:
  - preferred_term: coenzyme A biosynthetic process
    term:
      id: GO:0015937
      label: coenzyme A biosynthetic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: coenzyme A
    term:
      id: CHEBI:15346
      label: coenzyme A
    modifier: DECREASED
  genes:
  - preferred_term: PPCS
    term:
      id: hgnc:25686
      label: PPCS
  evidence:
  - reference: PMID:29754768
    reference_title: "Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Exome sequencing in five individuals from two unrelated families
      presenting with dilated cardiomyopathy revealed biallelic mutations in
      PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast
      and fruit flies confirmed the pathogenicity of identified mutations.
      Biochemical analysis revealed a decrease in CoA levels in fibroblasts of
      all affected individuals.
    explanation: >-
      Reports the DCM presentation of biallelic PPCS variants and the reduced
      coenzyme A measured in affected individuals fibroblasts.
  downstream:
  - target: Left ventricular systolic dysfunction
    causal_link_type: DIRECT
    description: >-
      The five individuals in whom biallelic PPCS variants were identified
      presented with dilated cardiomyopathy, and their fibroblasts showed
      decreased coenzyme A.
    evidence:
    - reference: PMID:29754768
      reference_title: "Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Exome sequencing in five individuals from two unrelated families
        presenting with dilated cardiomyopathy revealed biallelic mutations in
        PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast
        and fruit flies confirmed the pathogenicity of identified mutations.
        Biochemical analysis revealed a decrease in CoA levels in fibroblasts
        of all affected individuals.
      explanation: >-
        Reports the DCM presentation of biallelic PPCS variants and the
        reduced coenzyme A measured in affected individuals fibroblasts.
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:39519012
    reference_title: "Dilated Cardiomyopathy: A Genetic Journey from Past to Future."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dilated cardiomyopathy (DCM) is characterized by reduced systolic function and cardiac dilation."
    explanation: Defines the cardinal structural and functional phenotype of dilated cardiomyopathy - ventricular dilation with reduced systolic function.
- 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
    evidence_source: OTHER
    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:39519012
    reference_title: "Dilated Cardiomyopathy: A Genetic Journey from Past to Future."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dilated cardiomyopathy (DCM) is characterized by reduced systolic function and cardiac dilation."
    explanation: Reduced systolic function is definitional for dilated cardiomyopathy, supporting left ventricular systolic dysfunction as a core phenotype.
  - reference: PMID:39298146
    reference_title: "Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Left ventricular ejection fraction (LVEF) (per 1%) was not associated with all-cause mortality"
    explanation: Qualifies the phenotype rather than establishing it - in this meta-analysis LVEF, the standard measure of systolic dysfunction, was not associated with all-cause mortality, whereas fibrosis markers were.
- 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
    evidence_source: OTHER
    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 (late gadolinium enhancement) in DCM is associated with adverse clinical outcomes. The snippet does not itemise arrhythmic endpoints separately.
    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
diagnosis:
- name: Echocardiography (Left Ventricular Ejection Fraction and End-Diastolic Diameter)
  description: >-
    Dilated cardiomyopathy is diagnosed by echocardiographic (or other
    imaging-based) demonstration of left ventricular dilation together with
    impaired systolic contractility. The contractility criterion is
    operationalized as a reduced left ventricular ejection fraction (the band
    below, on this measurement). The dilation criterion is operationalized
    differently across sources: a prospective German DCM cohort (SFB/TR19
    Greifswald, validated in IKARUS Marburg) defines it as a left ventricular
    end-diastolic diameter (LVEDD) above 117% of the age/body-surface-area
    predicted value by the Henry formula, at the same time requiring a
    different LVEF cut-off (<45%) than the StatPearls operational definition
    below (<40%). Because the 117% figure is a Henry-formula percent-of-predicted
    value rather than a length, it is recorded here in prose rather than as a
    `reference_ranges` band on the LVEDD measurement code, which carries length
    units (typically 4-6 cm) and would misrepresent a 117 cut-off as a length no
    real diameter reaches.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  measurements:
  - preferred_term: left ventricular ejection fraction
    term:
      id: LOINC:10230-1
      label: Left ventricular Ejection fraction
  - preferred_term: left ventricular end-diastolic diameter
    term:
      id: LOINC:29436-3
      label: Left ventricular Internal diameter minor axis diastole by US
  reference_ranges:
  - loinc_term:
      id: LOINC:10230-1
      label: Left ventricular Ejection fraction
    unit: '%'
    population: adults (StatPearls operational definition)
    notes: >-
      A second cited source, the SFB/TR19 Greifswald / IKARUS Marburg cohort,
      defines the same contractility criterion at a different cut-off, LVEF
      <45% rather than <40%; both numbers are recorded in evidence below
      rather than reconciled into one band, since the sources disagree and
      neither is this entry's own claim to adjudicate. The band uses the
      StatPearls figure because it is stated as a general operational
      definition rather than one cohort's own inclusion criterion. That
      cohort's LVEDD dilation criterion (>117% of the Henry-formula predicted
      value) is described in this row's `description` rather than as a band,
      because the LVEDD measurement code is bound in length units and 117 is
      a percent-of-predicted value, not a length.
    evidence:
    - reference: PMID:28722940
      reference_title: "Dilated Cardiomyopathy."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Dilated cardiomyopathy (DCM) is a disease of the heart muscle characterized by enlargement and dilation of one or both ventricles, along with impaired contractility, defined as a left ventricular ejection fraction (LVEF) less than 40%."
      explanation: States the LVEF threshold, reproduced below as an interpretation band, that operationalizes the contractility half of the DCM definition.
    - reference: PMID:42701412
      reference_title: "Cellular communication network factor 1 (CCN1) associates with all-cause mortality in patients with dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "DCM was defined as a reduced left ventricular ejection fraction (LVEF <45%) and an increased left ventricular end-diastolic diameter according to the HENRY formula (LVEDD >117%) at the time of inclusion in the cohort study"
      explanation: >-
        States the cohort's own LVEF threshold (45%, differing from the
        StatPearls 40% figure above) and the LVEDD dilation threshold
        described in this row's `description` rather than as a band (see
        `notes`).
    interpretation_bands:
    - name: Dilated cardiomyopathy (reduced ejection fraction)
      upper_bound: 40
      unit: '%'
      abnormal_flag: LOW
      interpretation: >-
        LVEF below 40%, the contractility criterion of the operational
        definition of DCM; diagnosis also requires echocardiographic evidence
        of ventricular dilation, which this band does not capture.
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
    evidence_source: HUMAN_CLINICAL
    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
    evidence_source: OTHER
    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
    evidence_source: OTHER
    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
  notes: >-
    MYPN reaches the dilated pattern, but not only that pattern: MONDO:0014100
    spans dilated, hypertrophic and restrictive MYPN cardiomyopathy in one class,
    and is curated at the gene level as `MYPN-Related_Cardiomyopathy`
    (dismech#10635), where the allele-dependent branch point between the three
    patterns is modelled. MYPN is retained here as a gene arm of the dilated
    pattern, and likewise in `Restrictive_Cardiomyopathy` for the restrictive one.
  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.
- name: C10orf71
  gene_term:
    preferred_term: C10orf71
    term:
      id: hgnc:26973
      label: C10orf71
  association: >-
    Autosomal dominant causal pathogenic variant. C10orf71 encodes an
    intrinsically disordered, cardiomyocyte-specific protein also reported as
    the z-disc protein CEFIP. Frameshift variants were identified in a large
    family with eight affected members and in four further loss-of-function
    carriers across two sporadic DCM cohorts. Null cardiomyocytes lose
    contractile function while sarcomere structure stays intact, so the lesion
    is contractile rather than structural.
  evidence:
  - reference: PMID:38950288
    reference_title: "Frameshift variants in C10orf71 cause dilated cardiomyopathy in human, mouse, and organoid models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We identified candidate DCM causal gene, C10orf71, in a large family
      with 8 patients with DCM by whole-exome sequencing. Four
      loss-of-function variants of C10orf71 were subsequently identified in an
      additional group of492 patients with sporadic DCM from 2 independent
      cohorts. C10orf71 was found to be an intrinsically disordered protein
      specifically expressed in cardiomyocytes.
    explanation: >-
      Establishes C10orf71 as a DCM gene from a large family plus two
      independent sporadic cohorts, and states its cardiomyocyte-specific
      expression.
  - reference: PMID:38950288
    reference_title: "Frameshift variants in C10orf71 cause dilated cardiomyopathy in human, mouse, and organoid models."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      C10orf71-null cardiomyocytes exhibited impaired contractile function
      with unaffected sarcomere structure. Cardiomyocytes and heart organoids
      derived from human induced pluripotent stem cells with C10orf71
      frameshift variants also had contractile defects with normal
      electrophysiological activity. A rescue study using a cardiac myosin
      activator, omecamtiv mecarbil, restored contractile function in
      C10orf71-KO mice. These data support C10orf71 as a causal gene for DCM
      by contributing to the contractile function of cardiomyocytes.
    explanation: >-
      Supports the contractile rather than structural nature of the lesion, in
      knockout mouse, null cardiomyocyte and human iPSC-derived organoid
      models.
  - reference: PMID:28717008
    reference_title: "The novel cardiac z-disc protein CEFIP regulates cardiomyocyte hypertrophy by modulating calcineurin signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Importantly, CEFIP was located at the z-disc and was up-regulated in
      several models of cardiomyopathy.
    explanation: >-
      Locates the C10orf71 product, CEFIP, at the cardiac z-disc, which is why
      this gene is wired to the sarcomeric and cytoskeletal node.
- name: CAP2
  gene_term:
    preferred_term: CAP2
    term:
      id: hgnc:20039
      label: CAP2
  association: >-
    Autosomal recessive causal pathogenic variant. CAP2 encodes a
    cyclase-associated actin cytoskeleton regulatory protein required for the
    kinetics of actin filament repolymerization; a homozygous splice-consensus
    variant in a consanguineous Bedouin family caused DCM with
    supraventricular tachycardia, and patient fibroblasts showed altered actin
    repolymerization kinetics.
  evidence:
  - reference: PMID:30518548
    reference_title: "CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      This is the first report of a recessive deleterious mutation in CAP2 and
      its association with DCM in humans. The clinical phenotype recapitulates
      the damaging effects on the heart observed in Cap2 knockout mice
      including DCM and cardiac conduction disease, but not the other effects
      on growth, viability, wound healing and eye development. Our data
      underscore the importance of the proper kinetics of actin polymerization
      for normal function of the human heart.
    explanation: >-
      Reports the first recessive CAP2 variant associated with human DCM and
      ties it to actin polymerization kinetics.
- name: PPCS
  gene_term:
    preferred_term: PPCS
    term:
      id: hgnc:25686
      label: PPCS
  association: >-
    Autosomal recessive causal pathogenic variant. PPCS catalyses the second
    step of de novo coenzyme A biosynthesis from vitamin B5. Biallelic
    variants were found in five individuals from two unrelated families
    presenting with dilated cardiomyopathy, with reduced CoA levels in
    fibroblasts. This is a cofactor-biosynthesis lesion rather than a
    sarcomeric or cytoskeletal one, and CoA can be made from pantethine
    independently of PPCS, which is why pantethine was proposed as a targeted
    treatment.
  evidence:
  - reference: PMID:29754768
    reference_title: "Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Exome sequencing in five individuals from two unrelated families
      presenting with dilated cardiomyopathy revealed biallelic mutations in
      PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast
      and fruit flies confirmed the pathogenicity of identified mutations.
      Biochemical analysis revealed a decrease in CoA levels in fibroblasts of
      all affected individuals.
    explanation: >-
      Reports biallelic PPCS variants in five individuals from two families
      with DCM and the reduced fibroblast CoA levels that make this a coenzyme
      A biosynthesis lesion.
- name: EMD
  gene_term:
    preferred_term: EMD
    term:
      id: hgnc:3331
      label: EMD
  association: >-
    X-linked causal pathogenic variant. EMD encodes emerin, an inner nuclear
    membrane protein whose loss classically causes Emery-Dreifuss muscular
    dystrophy type 1, curated separately in this knowledge base. A distinct
    cardiac-only phenotype exists: the c.23C>G p.Ser8Trp missense variant
    co-segregated with DCM in six hemizygous males aged 36 to 50 with no
    muscular dystrophy, with greatly reduced myocardial emerin. The authors of
    that study note that before it the evidence for isolated DCM as an EMD
    phenotype was insufficient, so this gene is recorded here as an emerging
    rather than an established nonsyndromic DCM gene.
  evidence:
  - reference: PMID:40065010
    reference_title: "EMD missense variant causes X-linked isolated dilated cardiomyopathy with myocardial emerin deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We concluded that the EMD c.23C>G missense variant is associated with
      DCM in the absence of muscular dystrophy, thereby providing new evidence
      of isolated DCM as a distinct cardiac EMD-phenotype, separate from
      EDMD1.
    explanation: >-
      Supports isolated DCM as an EMD phenotype distinct from Emery-Dreifuss
      muscular dystrophy type 1.
  - reference: PMID:40065010
    reference_title: "EMD missense variant causes X-linked isolated dilated cardiomyopathy with myocardial emerin deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Although an association with isolated dilated cardiomyopathy (DCM) has
      been suggested, evidence is currently insufficient to verify the
      gene-disease association.
    explanation: >-
      Records the authors' own statement that, before their family study, the
      evidence for the EMD to isolated DCM gene-disease association was
      insufficient. Kept as the caveat on this record.
treatments:
- name: ACE Inhibitors / ARBs
  description: First-line neurohormonal blockade to reduce afterload and prevent adverse remodeling.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: ACE inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: angiotensin II receptor antagonist
      term:
        id: NCIT:C66930
        label: Angiotensin II Receptor Antagonist
  target_mechanisms:
  - target: Neurohormonal Activation
    treatment_effect: INHIBITS
    description: >-
      ACE inhibitors and ARBs block the renin-angiotensin-aldosterone axis,
      reducing angiotensin II-mediated vasoconstriction, aldosterone-driven
      fluid retention, and downstream adverse cardiac remodeling.
- 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
    therapeutic_agent:
    - preferred_term: beta-adrenergic antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
  target_mechanisms:
  - target: Neurohormonal Activation
    treatment_effect: INHIBITS
    description: >-
      Beta-blockers block cardiac adrenergic receptors, attenuating sympathetic
      neurohormonal activation, reducing heart rate, and reversing catecholamine-driven
      adverse remodeling in DCM.
- 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
    therapeutic_agent:
    - preferred_term: SGLT2 inhibitor
      term:
        id: NCIT:C98083
        label: SGLT2 Inhibitor
  target_mechanisms:
  - target: Mitochondrial Dysfunction
    treatment_effect: MODULATES
    description: >-
      SGLT2 inhibitors promote ketone utilization as a more oxygen-efficient
      myocardial fuel and improve mitochondrial bioenergetics in cardiomyocytes,
      partially reversing the mitochondrial dysfunction that contributes to
      DCM progression.
- name: Cardiac Resynchronization Therapy
  description: Biventricular pacing for patients with wide QRS and reduced LVEF to improve synchrony and outcomes.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cardiac resynchronization therapy
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Sarcomeric and Cytoskeletal Dysfunction
    treatment_effect: MODULATES
    description: >-
      Biventricular pacing restores electromechanical synchrony, reducing
      dyssynchrony-driven regional wall stress and the sarcomeric and
      cytoskeletal maladaptation that worsens ventricular dysfunction in DCM.
- name: Heart Transplantation
  description: Definitive therapy for end-stage DCM refractory to medical and device therapy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15289
      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.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C15329
      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: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37788487
    reference_title: "Genetics of Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    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
    evidence_source: OTHER
    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.
experimental_models:
- name: Patient-specific TNNT2 R173W iPSC-derived cardiomyocytes (Clinical Trials in a Dish)
  description: >-
    Cardiomyocytes differentiated from induced pluripotent stem cells reprogrammed from
    skin fibroblasts of a three-generation family carrying the autosomal dominant
    sarcomeric TNNT2 R173W mutation, with mutation-negative relatives from the same
    family serving as isogenic-adjacent controls. A non-animal New Approach Methodology
    that puts the patient's own genotype into a dish and supports both disease
    modelling and pharmacological rescue testing.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  cell_types:
  - preferred_term: iPSC-derived cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  conditions:
  - familial dilated cardiomyopathy with the TNNT2 R173W sarcomeric mutation
  - beta-adrenergic agonist stress with norepinephrine
  - beta-blocker and SERCA2a rescue
  cell_source: >-
    Patient-derived: iPSC lines reprogrammed from skin fibroblasts of four TNNT2 R173W
    carriers and three mutation-negative relatives in one family cohort
  culture_system: >-
    Embryoid-body cardiac differentiation followed by dissociated beating clusters and
    single cardiomyocytes, assayed by immunocytochemistry, transmission electron
    microscopy, calcium transient imaging, microelectrode arrays and atomic force
    microscopy
  publication: PMID:22517884
  modeled_mechanisms:
  - target: Sarcomeric and Cytoskeletal Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Cardiomyocytes carrying the patient's TNNT2 R173W allele reproduce the sarcomeric
      disorganisation and contractile failure of this node in human cells, and the
      phenotype is reversed by beta-blockade or SERCA2a overexpression.
    limitations: >-
      The authors themselves qualify the model as recapitulating the disease phenotype
      only to some extent. The cardiomyocytes are developmentally immature, with
      mitochondria and sarcoplasmic reticulum still immature at the assay stage, and the
      sarcomeric defect was most pronounced in single cells and at cluster edges rather
      than in well-coupled tissue. The cohort is a single family and a single TNNT2
      allele, so the finding does not generalise across this node's other sarcomeric and
      cytoskeletal genes, and no chamber-level dilatation can be observed in a dish.
    readouts:
    - name: Punctate sarcomeric alpha-actinin distribution
      target: Sarcomeric and Cytoskeletal Dysfunction
      direction: INCREASED
      interpretation: >-
        A higher proportion of patient cardiomyocytes showed disrupted sarcomeric
        alpha-actinin organisation than mutation-negative family controls, which is the
        structural correlate of this node.
      evidence:
      - reference: PMID:22517884
        reference_title: "Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: a significant higher percentage of DCM iPSC-CMs (n=391) showed a punctate distribution of sarcomeric α-actinin over one fourth of the total cellular area
        explanation: >-
          Quantifies the sarcomeric disorganisation measurement behind this readout
          against within-family controls.
    - name: Contractility of patient cardiomyocytes
      target: Sarcomeric and Cytoskeletal Dysfunction
      direction: DECREASED
      interpretation: >-
        Force production fell in mutation-carrying cardiomyocytes, linking the structural
        sarcomeric defect to functional impairment.
      evidence:
      - reference: PMID:22517884
        reference_title: "Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: cardiomyocytes derived from iPSCs from DCM patients exhibited altered regulation of calcium ion (Ca(2+)), decreased contractility, and abnormal distribution of sarcomeric α-actinin
        explanation: >-
          Reports the contractility and calcium-handling measurements made in this model.
    - name: Function after beta-blockade or SERCA2a overexpression
      target: Sarcomeric and Cytoskeletal Dysfunction
      direction: RESTORED
      interpretation: >-
        The model supports a rescue arm: both a beta-blocker and SERCA2a overexpression
        improved cardiomyocyte function, so the phenotype is pharmacologically reversible
        in vitro rather than a fixed differentiation artefact.
      evidence:
      - reference: PMID:22517884
        reference_title: "Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Treatment with β-adrenergic blockers or overexpression of sarcoplasmic reticulum Ca(2+) adenosine triphosphatase (Serca2a) improved the function of iPSC-derived cardiomyocytes from DCM patients
        explanation: >-
          Reports the rescue measurement, in the improving direction, behind this readout.
    evidence:
    - reference: PMID:22517884
      reference_title: "Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: iPSC-derived cardiomyocytes from DCM patients recapitulate to some extent the morphological and functional phenotypes of DCM
      explanation: >-
        Supports treating this model as informative for the node, with the authors' own
        partial-recapitulation qualifier carried through to the link relationship.
  - target: Neurohormonal Activation
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      Exposing the cardiomyocytes to a beta-adrenergic agonist applies the catecholamine
      arm of this node directly to the cells and unmasks a genotype-dependent
      vulnerability that is not apparent at baseline.
    limitations: >-
      This is an acute pharmacological stimulus applied to isolated cardiomyocytes. It
      reproduces the receptor-level consequence of sympathetic drive but not neurohormonal
      activation as a disease process: there is no sympathetic nervous system, no
      renin-angiotensin-aldosterone axis, no natriuretic peptide counter-regulation and no
      feedback loop between cardiac output and neurohormonal tone.
    readouts:
    - name: Contractile function under beta-adrenergic agonist stress
      target: Neurohormonal Activation
      direction: DECREASED
      interpretation: >-
        Under adrenergic stimulation patient cardiomyocytes slowed and lost contractile
        function, showing that catecholamine exposure degrades pump function in cells
        already carrying the sarcomeric lesion.
      evidence:
      - reference: PMID:22517884
        reference_title: "Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: When stimulated with a β-adrenergic agonist, DCM iPSC-derived cardiomyocytes showed characteristics of cellular stress such as reduced beating rates, compromised contraction, and a greater number of cells with abnormal sarcomeric α-actinin distribution
        explanation: >-
          Reports the beating-rate and contraction measurements made under the adrenergic
          perturbation behind this readout.
    - name: Sarcomeric disorganisation under beta-adrenergic agonist stress
      target: Neurohormonal Activation
      direction: INCREASED
      interpretation: >-
        The same adrenergic exposure spread sarcomeric disorganisation to more cells, so
        catecholamine stress aggravates the structural lesion and not only the functional
        one.
      evidence:
      - reference: PMID:22517884
        reference_title: "Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: When stimulated with a β-adrenergic agonist, DCM iPSC-derived cardiomyocytes showed characteristics of cellular stress such as reduced beating rates, compromised contraction, and a greater number of cells with abnormal sarcomeric α-actinin distribution
        explanation: >-
          The same sentence reports the rise in cells with abnormal sarcomeric
          α-actinin distribution that this readout records.
    evidence:
    - reference: PMID:22517884
      reference_title: "Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: When stimulated with a β-adrenergic agonist, DCM iPSC-derived cardiomyocytes showed characteristics of cellular stress such as reduced beating rates, compromised contraction, and a greater number of cells with abnormal sarcomeric α-actinin distribution
      explanation: >-
        Supports the model as informative for the adrenergic component of this node, while
        the systemic neurohormonal axes remain outside what a dish can represent.
  notes: >-
    Curated from the NAMeRS 2026 symposium New Approach Methodology tracker
    (monarch-initiative/dismech#4873), Panel 1 Clinical Trials in a Dish case study.
    No `namo_type` is recorded. NAMO defines no iPSC-derived model class (checked
    against its 56 classes) and its CellularSystem parent is abstract, so the choice
    was among the concrete culture-format siblings, and none of the three describes
    this system: CellLineModel is scoped to immortalized lines; ThreeDCellCulture fits
    the embryoid-body differentiation stage but not cells assayed after dissociation;
    TwoDCellCulture fits the single cardiomyocytes on atomic force microscopy and
    microelectrode arrays but not the 3D stage that produced them. The system spans two
    formats and NAMO has no value for the derivation that actually distinguishes it, so
    the slot is left absent rather than made to pick a half. `experimental_model_type:
    IPSC_DERIVED_MODEL` carries the distinction instead, and the upstream gap is
    monarch-initiative/namo#24. An earlier revision of this record used a coined
    InducedPluripotentStemCellDerivedModel CURIE (written here without its prefix so
    that prefix censuses over `kb/` do not match this file), which does not exist in
    NAMO; nothing validates `namo_type`, so it passed every gate. The adrenergic-stress
    readouts are split by direction because the source sentence reports both a fall in
    beating rate and contraction and a rise in cells with abnormal sarcomeric
    alpha-actinin, and `direction` is single-valued. The underlying evidence item was
    already cited on the Sarcomeric and Cytoskeletal Dysfunction node; this section adds
    the structured model record, its pathograph links and the rescue and
    adrenergic-stress readouts.
datasets:
- accession: geo:GSE245825
  title: 'Cardiac Fibrosis in Dilated Cardiomyopathy: Transcriptomics Insights, Histological Correlations, and Organoid Model Verifications [RNA-seq I]'
  description: Dilated cardiomyopathy (DCM) represents a leading cause of heart failure among younger adults. Despite endomyocardial biopsy (EMB) transcriptome enriching our understanding of DCM, the link between its gene expression and phenotype remains unclear. RNA-seq analysis of 58 DCM samples and 12 publicly available control samples unveiled about 25,000 transcripts. A principal component analysis highlighted a distinct DCM-control separation. WGCNA revealed four transcriptome modules strongly associated with DCM. The purple module, which is the DCM-related module, was enriched with fibrosis-related genes and showed FSTL3 as a pivotal DCM-associated gene.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 58
  publication: PMID:40934809
  notes: Identified by GEO DataSets index search for Dilated Cardiomyopathy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE146621
  title: Distinct cardiac transcriptomic clustering in titin and lamin a/c-associated dilated cardiomyopathy patients
  description: RNA profiles strongly differ in TTNtv and LMNA-mutated DCM patients, despite clinical similarities as other pathogenic variant carriers such as RBM20 and MYH7, suggesting a specific genetic effect on the cardiac transcriptome in addition to the effect of the clinical component.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 29
  publication: PMID:32955937
  notes: Identified by GEO DataSets index search for Dilated Cardiomyopathy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE312730
  title: ' Simtuzumab Attenuates Loxl2-Mediated Extracellular Matrix Remodeling and Preserves Cardiac Function in LMNA Mutation-Induced Dilated Cardiomyopathy'
  description: Background | Dilated cardiomyopathy (DCM) caused by LMNA mutations is a severe cardiac condition marked by arrhythmias, contractile dysfunction, and excessive myocardial fibrosis, which collectively impair left ventricular function and increase the risk of heart failure. While the disease has been well characterized, a lack of insight into the pathogenesis has impeded the development of therapies. Methods | Here, we employed induced pluripotent stem cells (hiPSCs) derived from a patient carrying a LMNA point mutation (c.665A>C, p.His222Pro), alongside a murine model carrying the same mutation, to investigate the functional and molecular abnormalities driving DCM.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 6
  publication: PMID:41841259
  notes: Identified by GEO DataSets index search for Dilated Cardiomyopathy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001002454
  title: Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy
  description: 'Background: Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits including cardiovascular diseases.Results: Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 149 (97)* patients with dilated cardiomyopathy and 113 (108)* non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage and allele specific expression.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:28903782
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Dilated Cardiomyopathy"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001003435
  title: Trio exome sequencing identified null mutations in ITPA as the cause of Martsolf syndrome with a lethal dilated cardiomyopathy presenting in infancy
  description: Typical Martsolf syndrome is characterized by congenital cataracts, postnatal microcephaly, developmental delay, hypotonia, short stature and biallelic hypomorphic mutations in either RAB3GAP1 or RAB3GAP2. Genetic analysis of 85 unrelated “mutation negative” probands with Martsolf or Martsolf-like syndromes identified two individuals with different homozygous null mutations in ITPA, the gene encoding inosine triphosphate pyrophosphatase (ITPase). Both probands were from multiplex families with a consistent, lethal and highly distinctive disorder; a Martsolf-like syndrome with infantile-onset dilated cardiomyopathy.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Dilated Cardiomyopathy"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS50000000049
  title: NGS on cardiac samples in Hungarian patients of dilated cardiomyopathy
  description: Heterozygous (HET) truncating mutations in the TTN gene (TTNtv) encoding the giant titin protein are the most common genetic cause of dilated cardiomyopathy (DCM). We investigated 127 clinically identified DCM human cardiac samples with targeted sequencing using the TruSight Cardio panel on an Illumina MiSeq system with a special focus on TTNtvs.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Dilated Cardiomyopathy"); description-level mentions were not accepted. EGA study_type: Resequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: metabolomics_workbench:ST001364
  title: Core Functional Nodes and Sex-Specific Pathways in Human Ischemic and Dilated Cardiomyopathy
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Dilated Cardiomyopathy"). Retrieved 2026-08-02.
- accession: massive:MSV000095560
  title: Lipid Supplements Protect Dilated Cardiomyopathy
  description: Lipid (Plasmalogen) levels can be modulated via a dietary supplement called alkylglycerols (AG) which has demonstrated benefits in some disease settings. However, its therapeutic potential in cardiomyopathy remains unknown. This study explored an optimized AG supplement in restoring plasmalogen levels and attenuate cardiac dysfunction/pathology. Here, we placed a cardiac-specific transgenic cardiomyopathy mouse model, with cardiac function and molecular landscape assessed.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Dilated Cardiomyopathy"). Retrieved 2026-08-02.
- accession: dbgap:phs000581
  title: 'NHLBI GO-ESP: Family Studies (Dilated Cardiomyopathy)'
  description: The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Dilated Cardiomyopathy"). Retrieved 2026-08-02.

📚

References & Deep Research

References

PMID:20301486

Dilated Cardiomyopathy Overview.

No top-level findings curated for this source.

PMID:20301717

LMNA-Related Dilated Cardiomyopathy.

No top-level findings curated for this source.

PMID:42708185

An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy.

1 finding

The 2026 ClinGen Dilated Cardiomyopathy Gene Curation Expert Panel reassessment reports JPH2 as autosomal dominant Strong and autosomal recessive Limited, the opposite way round from the committed ClinGen gene validity snapshot. The discrepancy is recorded in this entry's notes and not resolved here.

Show evidence (1 reference)

PMID:42708185 SUPPORT REVIEW SYNTHESIS Human Clinical

"Four previously evaluated genes were curated for both AD and AR MOIs: JPH2 (AD-Strong, AR-Limited), LDB3 (AD-Limited, AR-Strong), MYBPC3 (AD-Limited, AR-Limited), and TNNI3 (AD- and AR- Strong)."

Carries the published JPH2 mode-of-inheritance classifications that disagree with the cached ClinGen assertion rows quoted on the JPH2 genetic record.

PMID:18505755

Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy.

1 finding

CSRP3 is confirmed as a hypertrophic cardiomyopathy gene, and the earlier association of CSRP3 missense mutations with dilated cardiomyopathy was judged to lack comprehensive genetic evidence for a causative role. This is the basis for not adding CSRP3 to this entry's gene panel.

Show evidence (2 references)

PMID:18505755 SUPPORT BACKGROUND Human Clinical

"Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations."

States that the earlier CSRP3 to dilated cardiomyopathy association lacked comprehensive genetic evidence for causation.

+ 1 more reference

PMID:8864356

Cardiotrophin-1: a multifunctional cytokine that signals via LIF receptor-gp 130 dependent pathways.

1 finding

Cardiotrophin-1, the CTF1 product, is an interleukin-6 family cytokine acting through the shared gp130 signalling subunit. This is the basis for the note explaining why CTF1 is left unwired rather than attached to this entry's IL-11 fibroblast node.

Show evidence (1 reference)

PMID:8864356 SUPPORT PRIMARY RESULT In Vitro

"CT-1 is a new member of the IL-6 family of cytokines that induce their biological effects through the shared signaling subunit, gp 130."

Identifies cardiotrophin-1 as an IL-6 family cytokine signalling through gp130.

Deep Research

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

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)

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)
Primary cellular dysfunction:
Reduced tension generation and altered mechanotransduction (sarcomere dysfunction). (solaro2024emergingconceptsof pages 1-2, kellermayer2024truncatedtitinis pages 1-2)
Spliceopathy with altered titin isoforms and potentially Ca2+ handling gene splicing (RBM20). (gregorich2024mechanismsofrbm20 pages 1-3, newman2024dilatedcardiomyopathya pages 7-8)
Nuclear envelope dysfunction and conduction/arrhythmia susceptibility (LMNA). (newman2024dilatedcardiomyopathya pages 13-14)
Immune activation and chronic inflammatory injury (myocarditis-to-DCM phases). (xu2024constructionandevaluation pages 1-2)
Maladaptive remodeling: ventricular dilatation, wall thinning, fibrosis, electrical remodeling → arrhythmogenic substrate. (solaro2024emergingconceptsof pages 1-2, eichhorn2024riskstratificationin pages 1-2)
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

(arnautu2024geneticsandmolecular pages 5-7): Diana-Aurora Arnautu, Octavian-Marius Cretu, Daniel Florin Lighezan, Minodora Andor, Ioana Citu, Dragoș Cozma, Brenda-Cristiana Bernad, Adrian-Pavel Trifa, Diana Lighezan, Elena-Silvia Bernad, Dragos Catalin Jianu, Cristian Oancea, Ioan-Radu Lala, Sergiu-Florin Arnautu, and Mirela-Cleopatra Tomescu. Genetics and molecular mechanisms of idiopathic dilated cardiomyopathy, a possible guide to individualized management. Apr 2024. URL: https://doi.org/10.20944/preprints202404.1054.v1, doi:10.20944/preprints202404.1054.v1.
(eichhorn2024riskstratificationin pages 1-2): Christian Eichhorn, David Koeckerling, Rohin K Reddy, Maddalena Ardissino, Marek Rogowski, Bernadette Coles, Lukas Hunziker, Simon Greulich, Isaac Shiri, Norbert Frey, Jens Eckstein, Stephan Windecker, Raymond Y Kwong, George C M Siontis, and Christoph Gräni. Risk stratification in nonischemic dilated cardiomyopathy using cmr imaging: a systematic review and meta-analysis. JAMA, Sep 2024. URL: https://doi.org/10.1001/jama.2024.13946, doi:10.1001/jama.2024.13946. This article has 34 citations.
(eldemire2024geneticsofdilated pages 1-3): Ramone Eldemire, Luisa Mestroni, and Matthew R.G. Taylor. Genetics of dilated cardiomyopathy. Annual Review of Medicine, 75:417-426, Jan 2024. URL: https://doi.org/10.1146/annurev-med-052422-020535, doi:10.1146/annurev-med-052422-020535. This article has 57 citations and is from a domain leading peer-reviewed journal.
(newman2024dilatedcardiomyopathya pages 1-2): Noah A. Newman and Michael A. Burke. Dilated cardiomyopathy: a genetic journey from past to future. International Journal of Molecular Sciences, 25:11460, Oct 2024. URL: https://doi.org/10.3390/ijms252111460, doi:10.3390/ijms252111460. This article has 19 citations.
(solaro2024emergingconceptsof pages 1-2): R. Solaro, Paul Goldspink, and Beata Wolska. Emerging concepts of mechanisms controlling cardiac tension: focus on familial dilated cardiomyopathy (dcm) and sarcomere-directed therapies. Biomedicines, 12:999, May 2024. URL: https://doi.org/10.3390/biomedicines12050999, doi:10.3390/biomedicines12050999. This article has 5 citations.
(kellermayer2024truncatedtitinis pages 1-2): Dalma Kellermayer, Hedvig Tordai, Balázs Kiss, György Török, Dániel M. Péter, Alex Ali Sayour, Miklós Pólos, István Hartyánszky, Bálint Szilveszter, Siegfried Labeit, Ambrus Gángó, Gábor Bedics, Csaba Bödör, Tamás Radovits, Béla Merkely, and Miklós S.Z. Kellermayer. Truncated titin is structurally integrated into the human dilated cardiomyopathic sarcomere. Journal of Clinical Investigation, Jan 2024. URL: https://doi.org/10.1172/jci169753, doi:10.1172/jci169753. This article has 26 citations and is from a highest quality peer-reviewed journal.
(kellermayer2024truncatedtitinis media 0d428a5a): Dalma Kellermayer, Hedvig Tordai, Balázs Kiss, György Török, Dániel M. Péter, Alex Ali Sayour, Miklós Pólos, István Hartyánszky, Bálint Szilveszter, Siegfried Labeit, Ambrus Gángó, Gábor Bedics, Csaba Bödör, Tamás Radovits, Béla Merkely, and Miklós S.Z. Kellermayer. Truncated titin is structurally integrated into the human dilated cardiomyopathic sarcomere. Journal of Clinical Investigation, Jan 2024. URL: https://doi.org/10.1172/jci169753, doi:10.1172/jci169753. This article has 26 citations and is from a highest quality peer-reviewed journal.
(kellermayer2024truncatedtitinis media 3e1be5e2): Dalma Kellermayer, Hedvig Tordai, Balázs Kiss, György Török, Dániel M. Péter, Alex Ali Sayour, Miklós Pólos, István Hartyánszky, Bálint Szilveszter, Siegfried Labeit, Ambrus Gángó, Gábor Bedics, Csaba Bödör, Tamás Radovits, Béla Merkely, and Miklós S.Z. Kellermayer. Truncated titin is structurally integrated into the human dilated cardiomyopathic sarcomere. Journal of Clinical Investigation, Jan 2024. URL: https://doi.org/10.1172/jci169753, doi:10.1172/jci169753. This article has 26 citations and is from a highest quality peer-reviewed journal.
(gregorich2024mechanismsofrbm20 pages 1-3): Zachery R. Gregorich, Yanghai Zhang, Timothy J. Kamp, Henk L. Granzier, and Wei Guo. Mechanisms of rbm20 cardiomyopathy: insights from model systems. Circulation: Genomic and Precision Medicine, Feb 2024. URL: https://doi.org/10.1161/circgen.123.004355, doi:10.1161/circgen.123.004355. This article has 21 citations.
(newman2024dilatedcardiomyopathya pages 7-8): Noah A. Newman and Michael A. Burke. Dilated cardiomyopathy: a genetic journey from past to future. International Journal of Molecular Sciences, 25:11460, Oct 2024. URL: https://doi.org/10.3390/ijms252111460, doi:10.3390/ijms252111460. This article has 19 citations.
(newman2024dilatedcardiomyopathya pages 13-14): Noah A. Newman and Michael A. Burke. Dilated cardiomyopathy: a genetic journey from past to future. International Journal of Molecular Sciences, 25:11460, Oct 2024. URL: https://doi.org/10.3390/ijms252111460, doi:10.3390/ijms252111460. This article has 19 citations.
(xu2024constructionandevaluation pages 1-2): Sichi Xu, Zhaogui Wu, and Haihua Chen. Construction and evaluation of immune-related diagnostic model in patients with heart failure caused by idiopathic dilated cardiomyopathy. BMC Cardiovascular Disorders, Feb 2024. URL: https://doi.org/10.1186/s12872-023-03666-1, doi:10.1186/s12872-023-03666-1. This article has 6 citations and is from a peer-reviewed journal.
(vicenzetto2024theroleof pages 1-2): Cristina Vicenzetto, Andrea Giordani, Caterina Menghi, Anna Baritussio, Maria Peloso Cattini, Elena Pontara, Elisa Bison, Stefania Rizzo, Monica De Gaspari, Cristina Basso, Gaetano Thiene, Sabino Iliceto, Renzo Marcolongo, and Alida Caforio. The role of the immune system in pathobiology and therapy of myocarditis: a review. Biomedicines, 12:1156, May 2024. URL: https://doi.org/10.3390/biomedicines12061156, doi:10.3390/biomedicines12061156. This article has 13 citations.
(jurgens2024genomewideassociationstudy pages 1-2): S. Jurgens, Joel T. Rämö, D. Kramarenko, L. Wijdeveld, Jan Haas, M. Chaffin, S. Garnier, L. Gaziano, L. Weng, Alex Lipov, S. Zheng, Albert Henry, J. Huffman, Saketh Challa, Frank Rühle, Carmen Diaz Verdugo, C. Krijger Juárez, Shinwan Kany, C. A. van Orsouw, K. Biddinger, Edwin Poel, Amanda L Elliott, Xin Wang, C. Francis, Richard Ruan, Satoshi Koyama, L. Beekman, Dominic S Zimmerman, J. Deleuze, E. Villard, D. Trégouët, Richard Isnard, Joel T. Amanda L. Juha Teemu Jari Aarno Mark Rämö Elliott Sinisalo Niiranen Laukkanen Palotie D, J. Sinisalo, T. Niiranen, J. Laukkanen, A. Palotie, Mark Daly, Jennifer E. Kyong-Mi Philip S. Krishna G. Huffman Chang Tsao Aragam, Kyong-Mi Chang, Phil Tsao, Krishna G. Aragam, Sean L. Albert Kiran James S. R. Thomas Patrick T. Kris Zheng Henry Biddinger Ware Lumbers Ellinor Aragam, James S. Ware, R. Lumbers, P. Ellinor, D. Boomsma, E. D. de Geus, R. Tadros, Y. Pinto, A. Wilde, J. Hottenga, Roddy Walsh, A. F. Schmidt, Seung Hoan Choi, P. Matthews, S. N. van der Crabben, Ahmad S. Amin, P. Charron, Benjamin Meder, and C. Bezzina. Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience. Nature Genetics, 56:2636-2645, Nov 2024. URL: https://doi.org/10.1038/s41588-024-01975-5, doi:10.1038/s41588-024-01975-5. This article has 42 citations and is from a highest quality peer-reviewed journal.
(zheng2024genomewideassociationanalysis pages 10-11): Sean L. Zheng, Albert Henry, Douglas Cannie, Michael Lee, David Miller, Kathryn A. McGurk, Isabelle Bond, Xiao Xu, Hanane Issa, Catherine Francis, Antonio De Marvao, Pantazis I. Theotokis, Rachel J. Buchan, Doug Speed, Erik Abner, Lance Adams, Krishna G. Aragam, Johan Ärnlöv, Anna Axelsson Raja, Joshua D. Backman, John Baksi, Paul J. R. Barton, Kiran J. Biddinger, Eric Boersma, Jeffrey Brandimarto, Søren Brunak, Henning Bundgaard, David J. Carey, Philippe Charron, James P. Cook, Stuart A. Cook, Spiros Denaxas, Jean-François Deleuze, Alexander S. Doney, Perry Elliott, Christian Erikstrup, Tõnu Esko, Eric H. Farber-Eger, Chris Finan, Sophie Garnier, Jonas Ghouse, Vilmantas Giedraitis, Daniel F. Guðbjartsson, Christopher M. Haggerty, Brian P. Halliday, Anna Helgadottir, Harry Hemingway, Hans L. Hillege, Isabella Kardys, Lars Lind, Cecilia M. Lindgren, Brandon D. Lowery, Charlotte Manisty, Kenneth B. Margulies, James C. Moon, Ify R. Mordi, Michael P. Morley, Andrew D. Morris, Andrew P. Morris, Lori Morton, Mahdad Noursadeghi, Sisse R. Ostrowski, Anjali T. Owens, Colin N. A. Palmer, Antonis Pantazis, Ole B. V. Pedersen, Sanjay K. Prasad, Akshay Shekhar, Diane T. Smelser, Sundararajan Srinivasan, Kari Stefansson, Garðar Sveinbjörnsson, Petros Syrris, Mari-Liis Tammesoo, Upasana Tayal, Maris Teder-Laving, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Vinicius Tragante, David-Alexandre Trégouët, Thomas A. Treibel, Henrik Ullum, Ana M. Valdes, Jessica van Setten, Marion van Vugt, Abirami Veluchamy, W. M. Monique Verschuren, Eric Villard, Yifan Yang, Mahdad Noursadeghi, Ole B. V. Pedersen, Kari Stefansson, Unnur Thorsteinsdottir, Henrik Ullum, Folkert W. Asselbergs, Antonio De Marvao, Marie-Pierre Dube, Michael E. Dunn, Patrick T. Ellinor, Sophie Garnier, Chim C. Lang, Andrew P. Morris, Lori Morton, Colin N. A. Palmer, Nilesh J. Samani, Svati H. Shah, Akshay Shekhar, J. Gustav Smith, Sundarajan Srinivasan, Guðmundur Thorgeirsson, Ramachandran S. Vasan, Jessica van Setten, Marion van Vugt, Abirami Veluchamy, W. M. Monique Verschuuren, Eric Villard, Quinn Wells, Folkert W. Asselbergs, Thomas P. Cappola, Marie-Pierre Dube, Michael E. Dunn, Patrick T. Ellinor, Aroon D. Hingorani, Chim C. Lang, Nilesh J. Samani, Svati H. Shah, J. Gustav Smith, Ramachandran S. Vasan, Declan P. O’Regan, Hilma Holm, Michela Noseda, Quinn Wells, James S. Ware, and R. Thomas Lumbers. Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy. Nature Genetics, 56:2646-2658, Nov 2024. URL: https://doi.org/10.1038/s41588-024-01952-y, doi:10.1038/s41588-024-01952-y. This article has 46 citations and is from a highest quality peer-reviewed journal.
(newman2024dilatedcardiomyopathya pages 4-6): Noah A. Newman and Michael A. Burke. Dilated cardiomyopathy: a genetic journey from past to future. International Journal of Molecular Sciences, 25:11460, Oct 2024. URL: https://doi.org/10.3390/ijms252111460, doi:10.3390/ijms252111460. This article has 19 citations.
(malinow2024pediatricdilatedcardiomyopathy pages 1-2): Ian Malinow, Daniel C. Fong, Matthew Miyamoto, Sarah Badran, and Charles C. Hong. Pediatric dilated cardiomyopathy: a review of current clinical approaches and pathogenesis. Frontiers in Pediatrics, Jun 2024. URL: https://doi.org/10.3389/fped.2024.1404942, doi:10.3389/fped.2024.1404942. This article has 23 citations.
(eldemire2024geneticsofdilated pages 3-5): Ramone Eldemire, Luisa Mestroni, and Matthew R.G. Taylor. Genetics of dilated cardiomyopathy. Annual Review of Medicine, 75:417-426, Jan 2024. URL: https://doi.org/10.1146/annurev-med-052422-020535, doi:10.1146/annurev-med-052422-020535. This article has 57 citations and is from a domain leading peer-reviewed journal.
(newman2024dilatedcardiomyopathya pages 14-17): Noah A. Newman and Michael A. Burke. Dilated cardiomyopathy: a genetic journey from past to future. International Journal of Molecular Sciences, 25:11460, Oct 2024. URL: https://doi.org/10.3390/ijms252111460, doi:10.3390/ijms252111460. This article has 19 citations.
(kellermayer2024truncatedtitinis pages 6-7): Dalma Kellermayer, Hedvig Tordai, Balázs Kiss, György Török, Dániel M. Péter, Alex Ali Sayour, Miklós Pólos, István Hartyánszky, Bálint Szilveszter, Siegfried Labeit, Ambrus Gángó, Gábor Bedics, Csaba Bödör, Tamás Radovits, Béla Merkely, and Miklós S.Z. Kellermayer. Truncated titin is structurally integrated into the human dilated cardiomyopathic sarcomere. Journal of Clinical Investigation, Jan 2024. URL: https://doi.org/10.1172/jci169753, doi:10.1172/jci169753. This article has 26 citations and is from a highest quality peer-reviewed journal.
(arnautu2024geneticsandmolecular pages 7-8): Diana-Aurora Arnautu, Octavian-Marius Cretu, Daniel Florin Lighezan, Minodora Andor, Ioana Citu, Dragoș Cozma, Brenda-Cristiana Bernad, Adrian-Pavel Trifa, Diana Lighezan, Elena-Silvia Bernad, Dragos Catalin Jianu, Cristian Oancea, Ioan-Radu Lala, Sergiu-Florin Arnautu, and Mirela-Cleopatra Tomescu. Genetics and molecular mechanisms of idiopathic dilated cardiomyopathy, a possible guide to individualized management. Apr 2024. URL: https://doi.org/10.20944/preprints202404.1054.v1, doi:10.20944/preprints202404.1054.v1.
(arnautu2024geneticsandmolecular pages 3-5): Diana-Aurora Arnautu, Octavian-Marius Cretu, Daniel Florin Lighezan, Minodora Andor, Ioana Citu, Dragoș Cozma, Brenda-Cristiana Bernad, Adrian-Pavel Trifa, Diana Lighezan, Elena-Silvia Bernad, Dragos Catalin Jianu, Cristian Oancea, Ioan-Radu Lala, Sergiu-Florin Arnautu, and Mirela-Cleopatra Tomescu. Genetics and molecular mechanisms of idiopathic dilated cardiomyopathy, a possible guide to individualized management. Apr 2024. URL: https://doi.org/10.20944/preprints202404.1054.v1, doi:10.20944/preprints202404.1054.v1.

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References

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Disease Pathophysiology Research Template

Target Disease

Research Objectives

Required Information

1. Core Pathophysiology

2. Key Molecular Players

3. Biological Processes (for GO annotation)

4. Cellular Components

5. Disease Progression

6. Phenotypic Manifestations

Citation Requirements

Output Format

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

Disease identifiers

1) Key concepts and definitions (current understanding)

Clinical definition (phenotype-level)

Genetic architecture: monogenic → oligogenic/polygenic spectrum

Epidemiology (recently updated estimates)

2) Core pathophysiology: primary mechanisms and dysregulated pathways

2.1 Sarcomere dysfunction and mechanosensing failure (central mechanism)

2.2 RNA processing and alternative splicing dysregulation (RBM20 axis)

2.3 Nuclear envelope / mechanotransduction defects (LMNA axis)

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

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

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

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

3.1 Genes/proteins (representative, evidence-supported)

3.2 Cell types

3.3 Anatomical locations

3.4 Chemical entities

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

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

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

Stage model (integrated)

7) Phenotypic manifestations (clinical phenotypes linked to mechanisms)

8) Recent developments (prioritizing 2023–2024)

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

8.2 RBM20 condensates as a candidate disease mechanism (2024)

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

8.4 Imaging biomarkers outrank LVEF for certain endpoints (2024)

9) Current applications and real-world implementations

9.1 Genetic evaluation, counseling, and cascade screening

9.2 CMR tissue characterization for risk stratification

9.3 Precision medicine direction: genotype-informed management

10) Key statistics and recent quantitative findings (selected)

Knowledge-base-ready structured artifacts

Mechanisms summary table

Ontology-style entity mapping table

Evidence items (PMID-first requirement: limitation note)

Source URLs and publication dates (2023–2024 priority)