Dilated Cardiomyopathy 1DD

Genetic MONDO:0013168 Pathograph 7 Show in embeddings browser Dilated Cardiomyopathy Genetic Disorder

Dilated cardiomyopathy 1DD (CMD1DD) is the RBM20-related form of familial isolated dilated cardiomyopathy, and mechanistically the most unusual member of the series: the affected protein is neither a sarcomeric nor a quality-control component but a heart-enriched splicing factor. RBM20 encodes RNA binding motif protein 20, which carries motifs prototypical of spliceosome proteins and represses inclusion of specific exons in a defined set of cardiac transcripts. Its principal client is titin: RBM20 governs the titin isoform switch between the stiff N2B and compliant N2BA forms that sets passive myocardial stiffness and ventricular filling. Loss of RBM20 function therefore causes disease one level up from the sarcomere - by mis-splicing the transcripts that build and tune it - producing pathological expression of overly compliant giant titin plus aberrant splicing of a conserved network of around 30 genes enriched for cardiomyopathy, ion-homeostasis and sarcomere biology. RBM20 was established as a DCM gene by Brauch and colleagues in 2009, who mapped overlapping loci to chromosome 10q25-q26 and found a missense mutation hotspot in the arginine/serine-rich (RS) domain. ClinGen classifies the RBM20-DCM relationship as Definitive with autosomal dominant inheritance. Clinically the entity is notable for early, malignant ventricular arrhythmia that is not predicted by left ventricular systolic function, placing it with the arrhythmogenic left ventricular cardiomyopathy genes rather than with ordinary DCM for risk stratification.

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1
Inheritance
6
Pathophys.
3
Phenotypes
2
Hypotheses
1
Gaps
7
Pathograph
1
Genes
2
Medical Actions
1
References
🏷

Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal dominant HP:0000006
CMD1DD is inherited as an autosomal dominant trait. The classic disease alleles are heterozygous missense variants clustered in the arginine/serine-rich (RS) domain encoded by exon 9, a mutation hotspot; penetrance is incomplete and age-related.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (2 references)
CGGV:assertion_3e123751-078a-4d30-9f83-847119982342-2020-08-20T160000.000Z SUPPORT Other
"RBM20 | HGNC:27424 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies the RBM20-dilated cardiomyopathy relationship as Definitive with autosomal dominant inheritance.
PMID:19712804 SUPPORT Human Clinical
"distinct heterozygous missense mutations in exon 9 of RBM20, encoding ribonucleic acid (RNA) binding motif protein 20"
Documents the heterozygous (dominant) missense alleles in exon 9 that established RBM20 as a familial dilated cardiomyopathy gene.
◈

Mechanistic Hypotheses

2
Spliceopathy Model (loss of RBM20 splicing repression)
rbm20_spliceopathy CANONICAL
Evidence balance 1 support
The long-standing model, and the one this entry's pathograph is built on: the RS-domain lesion abolishes RBM20's repression of specific exons across its cardiac target network, and the resulting mis-splicing - principally the shift to the compliant N2BA titin isoform, plus the ion-homeostasis arm of the target set - is what produces ventricular dilation, systolic dysfunction, and the arrhythmogenic substrate. It originates in Rbm20 knockout rodents.
Pathograph links
Loss of RBM20-Dependent Splicing Regulation -> Pathological Titin Isoform Switch DIRECT Loss of splicing repression at TTN shifts the titin isoform balance toward the compliant giant form.
Loss of RBM20-Dependent Splicing Regulation -> Arrhythmogenic Substrate INDIRECT UNKNOWN INTERMEDIATES Mis-splicing of the ion-homeostasis arm of the RBM20 target network is the proposed substrate for the entity's malignant ventricular arrhythmia.
Show evidence (1 reference)
PMID:38288598 SUPPORT Model Organism
"Early studies in Rbm20 knockout rodents implicated disrupted splicing of RBM20 target genes as a causative mechanism."
States the origin and content of the canonical spliceopathy model, which is the explanatory frame for the splicing-route causal edges in this entry.
Condensate / Nucleocytoplasmic Transport Model
rbm20_condensate_mislocalization EMERGING
Evidence balance 3 support
A competing, non-mutually-exclusive model in which RS-domain variants act beyond splicing: they impair RBM20's nucleocytoplasmic transport and drive the protein into biomolecular condensates in the sarcoplasm. The discriminating observation is a knock-in contrast rather than a gain of detail - mice carrying a disease-associated RRM variant mis-splice RBM20 targets yet do not remodel or die suddenly, which is difficult to reconcile with mis-splicing alone being sufficient. Sarcoplasmic condensates are not a model-system artefact: they have been observed in the myocardium of affected individuals as well as in knock-in rodents and hiPSC-derived cardiomyocytes. What is not settled is whether they are pathogenic, and the model does not cover the whole gene - exon 11 hotspot variants cause the same disease without being expected to disturb nucleocytoplasmic trafficking. No pathophysiology node is curated for this route pending that resolution, since curating one would commit this entry's pathograph to a mechanism the primary literature still describes as under debate.
Surfaced from the committed deep-research artifact research/Dilated_Cardiomyopathy-deep-research-falcon.md (section 8.2), which flagged the debate; snippets here are quoted from the primary review, not the report.
Show evidence (3 references)
PMID:38288598 SUPPORT Model Organism
"variants in a specific portion of the arginine-serine-rich domain in RBM20 not only disrupt splicing but also hinder nucleocytoplasmic transport and lead to the formation of RBM20 biomolecular condensates in the sarcoplasm"
States the emerging mechanism itself, and localizes it to the same RS-domain variant class that this entry curates as its trigger node.
PMID:38288598 SUPPORT Model Organism
"mice harboring a disease-associated variant in the RRM (RNA recognition motif) do not show evidence of adverse remodeling or exhibit sudden death despite disrupted splicing of RBM20 target genes"
The dissociation of mis-splicing from adverse remodeling in the RRM knock-in is the observation that motivates a mechanism additional to spliceopathy.
PMID:38288598 SUPPORT Human Clinical
"This phenomenon was later confirmed in the myocardium of patients with RBM20 cardiomyopathy and Rbm20 pathogenic variant knock-in (KI) animal models with the striking finding that accumulation of RBM20 in the sarcoplasm promoted liquid-liquid phase separation of the protein in biomolecular condensates."
Establishes that sarcoplasmic RBM20 condensates occur in affected human myocardium, so the open question is their pathogenicity rather than their existence or their translation from model systems.
?

Discussions and Knowledge Gaps

1
Is RBM20 cardiomyopathy caused by disrupted splicing of RBM20 target genes, by mislocalization of RBM20 into sarcoplasmic biomolecular condensates, or by both?
CONTROVERSY OPEN controversy_rbm20_splicing_versus_condensates
Attached to
pathophysiology#RBM20 Loss-of-Function Variant in the RS Domain pathophysiology#Loss of RBM20-Dependent Splicing Regulation mechanistic_hypotheses#rbm20_spliceopathy mechanistic_hypotheses#rbm20_condensate_mislocalization
This entry's pathograph routes every downstream consequence through loss of splicing repression, so the question is not decorative - if condensate formation is the operative lesion, the splicing edges are correlates rather than causes, and the therapeutic target moves from restoring the titin isoform balance to preventing RBM20 mislocalization. The two knock-in models point opposite ways: RS-domain variants produce both mis-splicing and condensates together, while an RRM variant produces mis-splicing without disease. The condensate model does not account for the whole gene either: exon 11 hotspot variants produce the same clinical picture without being expected to disturb nucleocytoplasmic trafficking, which either limits the condensate mechanism to nuclear-localization-signal variants or means the two variant classes reach the phenotype by different routes. Resolving this requires separating mis-splicing from mislocalization within a single model rather than comparing across models, and characterising the exon 11 class clinically, which is currently too sparsely described to compare.
Show evidence (2 references)
PMID:38288598 SUPPORT Model Organism
"whether disrupted splicing, biomolecular condensates, or both contribute to dilated cardiomyopathy is under debate"
A 2024 review states the debate explicitly and unresolved, which is what makes this a curated controversy rather than a settled mechanism.
PMID:38288598 SUPPORT Human Clinical
"pathogenic variants in the exon 11 hotspot (Figure 1C) cause RBM20 cardiomyopathy even though they are not expected to affect RBM20 nucleocytoplasmic trafficking"
Records the observation that argues against the condensate model being the whole account, which is why this is curated as an open controversy and not resolved in favour of the emerging hypothesis.
⚙

Pathophysiology

6
RBM20 Loss-of-Function Variant in the RS Domain
The initiating lesion in CMD1DD is a heterozygous variant in RBM20, encoding a heart-enriched RNA binding protein with motifs prototypical of spliceosome proteins. Disease alleles cluster as a missense hotspot in the arginine/serine-rich (RS) domain encoded by exon 9, and act by loss of RBM20 splicing-regulatory function. Uniquely among the dilated cardiomyopathy genes curated here, the affected protein is a post-transcriptional regulator rather than a structural or quality-control component of the myocyte.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
RBM20 hgnc:27424 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RBM20 (hgnc:27424). hgnc:27424 is a gene from the HUGO Gene Nomenclature Committee.
RNA binding GO:0003723 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased RNA binding (GO:0003723). GO:0003723 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Loss of RBM20-Dependent Splicing Regulation The RS-domain lesion abolishes normal RBM20 splicing repression across its cardiac target transcripts.
Show evidence (3 references)
PMID:19712804 SUPPORT Human Clinical
"Our findings establish RBM20 as a DCM gene and reveal a mutation hotspot in the RS domain."
Establishes RBM20 as a dilated cardiomyopathy gene and localizes the disease alleles to the RS-domain hotspot that defines this trigger.
PMID:19712804 SUPPORT Human Clinical
"RBM20 is preferentially expressed in the heart and encodes motifs prototypical of spliceosome proteins that regulate alternative pre-messenger RNA splicing, thus implicating a functionally distinct gene in human cardiomyopathy."
Characterises RBM20 as a heart-enriched splicing regulator, the functionally distinct gene class this entity represents.
PMID:22466703 SUPPORT Model Organism
"we identified a loss-of-function mutation in the gene encoding RNA binding motif protein 20 (Rbm20) as the underlying cause of pathological titin isoform expression"
Identifies loss of Rbm20 function as the causal lesion producing pathological titin isoform expression, defining the allele's mode of action.
Loss of RBM20-Dependent Splicing Regulation
RBM20 represses inclusion of specific exons in a defined set of cardiac transcripts. Deep sequencing of the human and rat cardiac transcriptome established an RBM20-dependent programme of alternative splicing, and identified - alongside titin - a conserved set of around 30 genes whose splicing RBM20 regulates, a network enriched for genes previously linked to cardiomyopathy, ion homeostasis and sarcomere biology. Loss of RBM20 function therefore perturbs the myocyte at the level of transcript composition, and the ion-homeostasis arm of that network is the plausible substrate of the entity's arrhythmic phenotype.
Spliceopathy Model (loss of RBM20 splicing repression)
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Regulation of Alternative mRNA Splicing GO:0000381 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Regulation of Alternative mRNA Splicing, annotated with regulation of alternative mRNA splicing, via spliceosome (GO:0000381). GO:0000381 is a biological process from the Gene Ontology. ↓ DECREASED RNA Splicing GO:0008380 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal RNA Splicing (GO:0008380). GO:0008380 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Pathological Titin Isoform Switch Loss of splicing repression at TTN shifts the titin isoform balance toward the compliant giant form. Spliceopathy Model (loss of RBM20 splicing repression)
Arrhythmogenic Substrate Mis-splicing of the ion-homeostasis arm of the RBM20 target network is the proposed substrate for the entity's malignant ventricular arrhythmia. Spliceopathy Model (loss of RBM20 splicing repression)
Show evidence (3 references)
PMID:22466703 SUPPORT Model Organism
"Deep sequencing of the human and rat cardiac transcriptome revealed an RBM20-dependent regulation of alternative splicing."
Establishes the RBM20-dependent alternative splicing programme that this node represents, in human as well as rat cardiac transcriptome.
PMID:22466703 SUPPORT Model Organism
"In addition to titin (TTN), we identified a set of 30 genes with conserved splicing regulation between humans and rats"
Defines the breadth of the RBM20 splicing network beyond titin - around 30 conserved target genes.
PMID:22466703 SUPPORT Model Organism
"This network is enriched for genes that have previously been linked to cardiomyopathy, ion homeostasis and sarcomere biology."
Characterises the RBM20 target network as enriched for cardiomyopathy, ion-homeostasis and sarcomere genes - the basis for both the contractile and the arrhythmic consequences curated downstream.
Pathological Titin Isoform Switch
Titin exists in a stiff (N2B) and a compliant (N2BA) isoform, and the ratio between them sets passive myocardial stiffness and thereby ventricular filling. RBM20 is the splicing factor that governs this switch. Loss of RBM20 function produces pathological expression of the overly compliant giant titin isoform, so the ventricle loses the passive elastic restoring force it needs for normal diastolic mechanics - a defect of the sarcomere's spring rather than of its motor.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Sarcomere Organization GO:0045214 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Sarcomere Organization (GO:0045214). GO:0045214 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Ventricular Dilation and Systolic Dysfunction Altered passive stiffness and sarcomere mechanics drive chamber dilation and contractile failure.
Show evidence (2 references)
PMID:22466703 SUPPORT Model Organism
"the isoform switch of the sarcomeric protein titin, which adjusts ventricular filling"
States the physiological role of the titin isoform switch - adjusting ventricular filling - that RBM20 loss disrupts.
PMID:22466703 SUPPORT Model Organism
"we identified a loss-of-function mutation in the gene encoding RNA binding motif protein 20 (Rbm20) as the underlying cause of pathological titin isoform expression"
Directly links Rbm20 loss of function to the pathological titin isoform expression that constitutes this node.
Arrhythmogenic Substrate
RBM20-related disease is clinically distinguished by early, malignant ventricular arrhythmia that is disproportionate to the degree of systolic impairment. RBM20 sits with desmoplakin, lamin A/C, filamin-C, phospholamban and TMEM43 among the arrhythmogenic left ventricular cardiomyopathy genes, for which left ventricular systolic function is an insensitive predictor of arrhythmic risk - so risk stratification cannot rely on ejection fraction as it does in ordinary dilated cardiomyopathy. Mis-splicing of the ion-homeostasis arm of the RBM20 target network is the plausible molecular substrate, though the causal chain from specific mis-spliced transcripts to arrhythmia is not established.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Cardiac Conduction GO:0061337 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Cardiac Conduction (GO:0061337). GO:0061337 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Heart Failure and Malignant Ventricular Arrhythmia The arrhythmogenic substrate produces the malignant ventricular arrhythmia arm of the clinical endpoint.
Show evidence (2 references)
PMID:37558308 SUPPORT Human Clinical
"the authors review the literature on recent cohort studies of patients with variants in desmoplakin, lamin A/C, filamin-C, phospholamban, RBM20, TMEM43, and selected channelopathy genes also associated with structural disease."
Places RBM20 among the arrhythmogenic left ventricular cardiomyopathy genes whose cohorts show early malignant ventricular arrhythmia.
PMID:37558308 SUPPORT Human Clinical
"left ventricular systolic function is an insensitive predictor of risk in patients with these genetic diagnoses"
The clinically decisive caveat for this entity: ejection fraction does not capture arrhythmic risk in RBM20 and the other arrhythmogenic left ventricular cardiomyopathy genotypes.
Ventricular Dilation and Systolic Dysfunction
Altered titin compliance and broader sarcomeric mis-splicing produce the defining structural remodeling of dilated cardiomyopathy: left ventricular chamber enlargement with wall thinning, myocyte loss, and interstitial fibrosis, with falling ejection fraction. Rbm20-deficient rats reproduce the human pathology, confirming that loss of the splicing factor is sufficient to generate the phenotype.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology. Cardiac Fibroblast CL:0002548 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiac Fibroblast, annotated with fibroblast of cardiac tissue (CL:0002548). CL:0002548 is a cell type from the Cell Ontology.
Heart Contraction GO:0060047 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Heart Contraction (GO:0060047). GO:0060047 is a biological process from the Gene Ontology. ↓ DECREASED Extracellular Matrix Organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Extracellular Matrix Organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ↑ INCREASED
Left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Left ventricle, annotated with heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Heart Failure and Malignant Ventricular Arrhythmia
Show evidence (1 reference)
PMID:22466703 SUPPORT Model Organism
"The phenotype of Rbm20-deficient rats resembled the pathology seen in individuals with dilated cardiomyopathy caused by RBM20 mutations"
Establishes that Rbm20 deficiency reproduces the human dilated cardiomyopathy pathology, validating this node's causal chain in vivo.
Heart Failure and Malignant Ventricular Arrhythmia
The clinical endpoint of CMD1DD has two arms that must be managed separately: progressive systolic heart failure from ventricular dilation, and early malignant ventricular arrhythmia that is not predicted by systolic function. The arrhythmic arm is what distinguishes RBM20 disease from ordinary dilated cardiomyopathy and drives earlier consideration of defibrillator therapy.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Heart Contraction GO:0060047 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Heart Contraction (GO:0060047). GO:0060047 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (1 reference)
PMID:37558308 SUPPORT Human Clinical
"Arrhythmogenic left ventricular cardiomyopathy is characterized by early malignant ventricular arrhythmia associated with varying degrees and times of onset of left ventricular dysfunction."
Describes the two-armed endpoint - early malignant ventricular arrhythmia alongside variable left ventricular dysfunction - characteristic of the gene group RBM20 belongs to.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Dilated Cardiomyopathy 1DD Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

3
Dilated Cardiomyopathy OBLIGATE Cardiovascular HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19712804 SUPPORT Human Clinical
"Our findings establish RBM20 as a DCM gene and reveal a mutation hotspot in the RS domain."
Establishes dilated cardiomyopathy as the phenotype caused by RBM20 variants.
Ventricular Arrhythmia Cardiovascular HP:0004308 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular arrhythmia (HP:0004308). HP:0004308 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37558308 SUPPORT Human Clinical
"Arrhythmogenic left ventricular cardiomyopathy is characterized by early malignant ventricular arrhythmia associated with varying degrees and times of onset of left ventricular dysfunction."
Documents early malignant ventricular arrhythmia as the defining feature of the gene group that includes RBM20.
Congestive Heart Failure Cardiovascular HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22466703 SUPPORT Model Organism
"Our studies emphasize the key role of post-transcriptional regulation in cardiac function and provide mechanistic insights into the pathogenesis of human heart failure."
Places the RBM20 splicing mechanism in the pathogenesis of human heart failure; PARTIAL because the statement is about heart failure pathogenesis generally rather than quantifying it in RBM20 carriers.
🧬

Genetic Associations

1
RBM20
Gene: RBM20 hgnc:27424 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RBM20 (hgnc:27424). hgnc:27424 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
CGGV:assertion_3e123751-078a-4d30-9f83-847119982342-2020-08-20T160000.000Z SUPPORT Other
"RBM20 | HGNC:27424 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen's Gene Curation Expert Panel classifies this gene-disease relationship as Definitive, which is the authority for curating the gene as CAUSATIVE rather than a candidate.
PMID:19712804 SUPPORT Human Clinical
"distinct heterozygous missense mutations in exon 9 of RBM20, encoding ribonucleic acid (RNA) binding motif protein 20"
Identifies the heterozygous exon 9 missense alleles that define the gene-disease relationship, which is the variant class this entry's pathograph is built on.
💊

Medical Actions

2
Heart Failure Pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Standard guideline-directed heart-failure therapy targeting the neurohormonal drive of adverse remodeling.
Implantable Cardioverter-Defibrillator
Action: implantable cardioverter-defibrillator placementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is implantable cardioverter-defibrillator placement (NCIT:C80435). NCIT:C80435 is a clinical intervention from the NCI Thesaurus. Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435
Defibrillator therapy is considered earlier than in ordinary dilated cardiomyopathy, because left ventricular systolic function is an insensitive predictor of arrhythmic risk in RBM20 carriers.
📊

Prevalence

1
Familial dilated cardiomyopathy
Unknown Unknown
RBM20 is a definitive but numerically minor dilated cardiomyopathy gene, first mapped through overlapping familial linkage to chromosome 10q25-q26. No population-based rate is established for the RBM20-specific entity.
Show evidence (1 reference)
PMID:19712804 SUPPORT Human Clinical
"Overlapping loci for DCM were independently mapped to chromosome 10q25-q26."
Records the familial linkage mapping that localized the RBM20 dilated cardiomyopathy locus.
{ }

Source YAML

click to show 
name: Dilated Cardiomyopathy 1DD
creation_date: "2026-08-22T00:00:00Z"
synonyms:
- CMD1DD
- RBM20 familial isolated dilated cardiomyopathy
- dilated cardiomyopathy type 1DD
- cardiomyopathy, dilated, 1DD
- RBM20-related dilated cardiomyopathy
description: >-
  Dilated cardiomyopathy 1DD (CMD1DD) is the RBM20-related form of familial
  isolated dilated cardiomyopathy, and mechanistically the most unusual member of
  the series: the affected protein is neither a sarcomeric nor a quality-control
  component but a heart-enriched splicing factor. RBM20 encodes RNA binding motif
  protein 20, which carries motifs prototypical of spliceosome proteins and
  represses inclusion of specific exons in a defined set of cardiac transcripts.
  Its principal client is titin: RBM20 governs the titin isoform switch between the
  stiff N2B and compliant N2BA forms that sets passive myocardial stiffness and
  ventricular filling. Loss of RBM20 function therefore causes disease one level up
  from the sarcomere - by mis-splicing the transcripts that build and tune it -
  producing pathological expression of overly compliant giant titin plus aberrant
  splicing of a conserved network of around 30 genes enriched for cardiomyopathy,
  ion-homeostasis and sarcomere biology. RBM20 was established as a DCM gene by
  Brauch and colleagues in 2009, who mapped overlapping loci to chromosome 10q25-q26
  and found a missense mutation hotspot in the arginine/serine-rich (RS) domain.
  ClinGen classifies the RBM20-DCM relationship as Definitive with autosomal
  dominant inheritance. Clinically the entity is notable for early, malignant
  ventricular arrhythmia that is not predicted by left ventricular systolic
  function, placing it with the arrhythmogenic left ventricular cardiomyopathy
  genes rather than with ordinary DCM for risk stratification.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: dilated cardiomyopathy 1DD
  term:
    id: MONDO:0013168
    label: dilated cardiomyopathy 1DD
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant
  description: >-
    CMD1DD is inherited as an autosomal dominant trait. The classic disease alleles
    are heterozygous missense variants clustered in the arginine/serine-rich (RS)
    domain encoded by exon 9, a mutation hotspot; penetrance is incomplete and
    age-related.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  evidence:
  - 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's Dilated Cardiomyopathy Gene Curation Expert Panel classifies the
      RBM20-dilated cardiomyopathy relationship as Definitive with autosomal
      dominant inheritance.
  - reference: PMID:19712804
    reference_title: "Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      distinct heterozygous missense mutations in exon 9 of RBM20, encoding
      ribonucleic acid (RNA) binding motif protein 20
    explanation: >-
      Documents the heterozygous (dominant) missense alleles in exon 9 that
      established RBM20 as a familial dilated cardiomyopathy gene.
prevalence:
- population: Familial dilated cardiomyopathy
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    RBM20 is a definitive but numerically minor dilated cardiomyopathy gene, first
    mapped through overlapping familial linkage to chromosome 10q25-q26. No
    population-based rate is established for the RBM20-specific entity.
  evidence:
  - reference: PMID:19712804
    reference_title: "Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overlapping loci for DCM were independently mapped to chromosome 10q25-q26."
    explanation: >-
      Records the familial linkage mapping that localized the RBM20 dilated
      cardiomyopathy locus.
pathophysiology:
- name: RBM20 Loss-of-Function Variant in the RS Domain
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The initiating lesion in CMD1DD is a heterozygous variant in RBM20, encoding a
    heart-enriched RNA binding protein with motifs prototypical of spliceosome
    proteins. Disease alleles cluster as a missense hotspot in the
    arginine/serine-rich (RS) domain encoded by exon 9, and act by loss of RBM20
    splicing-regulatory function. Uniquely among the dilated cardiomyopathy genes
    curated here, the affected protein is a post-transcriptional regulator rather
    than a structural or quality-control component of the myocyte.
  genes:
  - preferred_term: RBM20
    term:
      id: hgnc:27424
      label: RBM20
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: RNA binding
    term:
      id: GO:0003723
      label: RNA binding
    modifier: DECREASED
  evidence:
  - reference: PMID:19712804
    reference_title: "Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings establish RBM20 as a DCM gene and reveal a mutation hotspot in the RS domain."
    explanation: >-
      Establishes RBM20 as a dilated cardiomyopathy gene and localizes the disease
      alleles to the RS-domain hotspot that defines this trigger.
  - reference: PMID:19712804
    reference_title: "Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RBM20 is preferentially expressed in the heart and encodes motifs prototypical
      of spliceosome proteins that regulate alternative pre-messenger RNA splicing,
      thus implicating a functionally distinct gene in human cardiomyopathy.
    explanation: >-
      Characterises RBM20 as a heart-enriched splicing regulator, the functionally
      distinct gene class this entity represents.
  - reference: PMID:22466703
    reference_title: "RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we identified a loss-of-function mutation in the gene encoding RNA binding
      motif protein 20 (Rbm20) as the underlying cause of pathological titin isoform
      expression
    explanation: >-
      Identifies loss of Rbm20 function as the causal lesion producing pathological
      titin isoform expression, defining the allele's mode of action.
  downstream:
  - target: Loss of RBM20-Dependent Splicing Regulation
    causal_link_type: DIRECT
    description: >-
      The RS-domain lesion abolishes normal RBM20 splicing repression across its
      cardiac target transcripts.
- name: Loss of RBM20-Dependent Splicing Regulation
  biological_scale: MOLECULAR
  role: effector
  description: >-
    RBM20 represses inclusion of specific exons in a defined set of cardiac
    transcripts. Deep sequencing of the human and rat cardiac transcriptome
    established an RBM20-dependent programme of alternative splicing, and identified
    - alongside titin - a conserved set of around 30 genes whose splicing RBM20
    regulates, a network enriched for genes previously linked to cardiomyopathy,
    ion homeostasis and sarcomere biology. Loss of RBM20 function therefore
    perturbs the myocyte at the level of transcript composition, and the
    ion-homeostasis arm of that network is the plausible substrate of the
    entity's arrhythmic phenotype.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Regulation of Alternative mRNA Splicing
    term:
      id: GO:0000381
      label: regulation of alternative mRNA splicing, via spliceosome
    modifier: DECREASED
  - preferred_term: RNA Splicing
    term:
      id: GO:0008380
      label: RNA splicing
    modifier: ABNORMAL
  evidence:
  - reference: PMID:22466703
    reference_title: "RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Deep sequencing of the human and rat cardiac transcriptome revealed an
      RBM20-dependent regulation of alternative splicing.
    explanation: >-
      Establishes the RBM20-dependent alternative splicing programme that this node
      represents, in human as well as rat cardiac transcriptome.
  - reference: PMID:22466703
    reference_title: "RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In addition to titin (TTN), we identified a set of 30 genes with conserved
      splicing regulation between humans and rats
    explanation: >-
      Defines the breadth of the RBM20 splicing network beyond titin - around 30
      conserved target genes.
  - reference: PMID:22466703
    reference_title: "RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This network is enriched for genes that have previously been linked to
      cardiomyopathy, ion homeostasis and sarcomere biology.
    explanation: >-
      Characterises the RBM20 target network as enriched for cardiomyopathy,
      ion-homeostasis and sarcomere genes - the basis for both the contractile and
      the arrhythmic consequences curated downstream.
  downstream:
  - target: Pathological Titin Isoform Switch
    causal_link_type: DIRECT
    hypothesis_groups:
    - rbm20_spliceopathy
    description: >-
      Loss of splicing repression at TTN shifts the titin isoform balance toward the
      compliant giant form.
  - target: Arrhythmogenic Substrate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - rbm20_spliceopathy
    description: >-
      Mis-splicing of the ion-homeostasis arm of the RBM20 target network is the
      proposed substrate for the entity's malignant ventricular arrhythmia.
- name: Pathological Titin Isoform Switch
  biological_scale: MOLECULAR
  role: effector
  description: >-
    Titin exists in a stiff (N2B) and a compliant (N2BA) isoform, and the ratio
    between them sets passive myocardial stiffness and thereby ventricular filling.
    RBM20 is the splicing factor that governs this switch. Loss of RBM20 function
    produces pathological expression of the overly compliant giant titin isoform,
    so the ventricle loses the passive elastic restoring force it needs for normal
    diastolic mechanics - a defect of the sarcomere's spring rather than of its
    motor.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Sarcomere Organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:22466703
    reference_title: "RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the isoform switch of the sarcomeric protein titin, which adjusts ventricular
      filling
    explanation: >-
      States the physiological role of the titin isoform switch - adjusting
      ventricular filling - that RBM20 loss disrupts.
  - reference: PMID:22466703
    reference_title: "RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we identified a loss-of-function mutation in the gene encoding RNA binding
      motif protein 20 (Rbm20) as the underlying cause of pathological titin isoform
      expression
    explanation: >-
      Directly links Rbm20 loss of function to the pathological titin isoform
      expression that constitutes this node.
  downstream:
  - target: Ventricular Dilation and Systolic Dysfunction
    causal_link_type: DIRECT
    description: >-
      Altered passive stiffness and sarcomere mechanics drive chamber dilation and
      contractile failure.
- name: Arrhythmogenic Substrate
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    RBM20-related disease is clinically distinguished by early, malignant
    ventricular arrhythmia that is disproportionate to the degree of systolic
    impairment. RBM20 sits with desmoplakin, lamin A/C, filamin-C, phospholamban and
    TMEM43 among the arrhythmogenic left ventricular cardiomyopathy genes, for which
    left ventricular systolic function is an insensitive predictor of arrhythmic
    risk - so risk stratification cannot rely on ejection fraction as it does in
    ordinary dilated cardiomyopathy. Mis-splicing of the ion-homeostasis arm of the
    RBM20 target network is the plausible molecular substrate, though the causal
    chain from specific mis-spliced transcripts to arrhythmia is not established.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiac Conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37558308
    reference_title: "Genetic Risk Stratification in Arrhythmogenic Left Ventricular Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the authors review the literature on recent cohort studies of patients with
      variants in desmoplakin, lamin A/C, filamin-C, phospholamban, RBM20, TMEM43,
      and selected channelopathy genes also associated with structural disease.
    explanation: >-
      Places RBM20 among the arrhythmogenic left ventricular cardiomyopathy genes
      whose cohorts show early malignant ventricular arrhythmia.
  - reference: PMID:37558308
    reference_title: "Genetic Risk Stratification in Arrhythmogenic Left Ventricular Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      left ventricular systolic function is an insensitive predictor of risk in
      patients with these genetic diagnoses
    explanation: >-
      The clinically decisive caveat for this entity: ejection fraction does not
      capture arrhythmic risk in RBM20 and the other arrhythmogenic left
      ventricular cardiomyopathy genotypes.
  downstream:
  - target: Heart Failure and Malignant Ventricular Arrhythmia
    causal_link_type: DIRECT
    description: >-
      The arrhythmogenic substrate produces the malignant ventricular arrhythmia
      arm of the clinical endpoint.
- name: Ventricular Dilation and Systolic Dysfunction
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    Altered titin compliance and broader sarcomeric mis-splicing produce the
    defining structural remodeling of dilated cardiomyopathy: left ventricular
    chamber enlargement with wall thinning, myocyte loss, and interstitial fibrosis,
    with falling ejection fraction. Rbm20-deficient rats reproduce the human
    pathology, confirming that loss of the splicing factor is sufficient to generate
    the phenotype.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: Cardiac Fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: Heart Contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: DECREASED
  - preferred_term: Extracellular Matrix Organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  locations:
  - preferred_term: Left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:22466703
    reference_title: "RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The phenotype of Rbm20-deficient rats resembled the pathology seen in
      individuals with dilated cardiomyopathy caused by RBM20 mutations
    explanation: >-
      Establishes that Rbm20 deficiency reproduces the human dilated cardiomyopathy
      pathology, validating this node's causal chain in vivo.
  downstream:
  - target: Heart Failure and Malignant Ventricular Arrhythmia
    causal_link_type: DIRECT
- name: Heart Failure and Malignant Ventricular Arrhythmia
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    The clinical endpoint of CMD1DD has two arms that must be managed separately:
    progressive systolic heart failure from ventricular dilation, and early
    malignant ventricular arrhythmia that is not predicted by systolic function.
    The arrhythmic arm is what distinguishes RBM20 disease from ordinary dilated
    cardiomyopathy and drives earlier consideration of defibrillator therapy.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Heart Contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37558308
    reference_title: "Genetic Risk Stratification in Arrhythmogenic Left Ventricular Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arrhythmogenic left ventricular cardiomyopathy is characterized by early
      malignant ventricular arrhythmia associated with varying degrees and times of
      onset of left ventricular dysfunction.
    explanation: >-
      Describes the two-armed endpoint - early malignant ventricular arrhythmia
      alongside variable left ventricular dysfunction - characteristic of the gene
      group RBM20 belongs to.
phenotypes:
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: >-
    Left ventricular dilation with systolic dysfunction is the defining structural
    feature of CMD1DD.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  frequency: OBLIGATE
  evidence:
  - reference: PMID:19712804
    reference_title: "Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings establish RBM20 as a DCM gene and reveal a mutation hotspot in the RS domain."
    explanation: >-
      Establishes dilated cardiomyopathy as the phenotype caused by RBM20 variants.
- name: Ventricular Arrhythmia
  category: Cardiovascular
  description: >-
    Early, malignant ventricular arrhythmia disproportionate to systolic impairment
    is the clinically distinguishing feature of RBM20-related disease.
  phenotype_term:
    preferred_term: Ventricular arrhythmia
    term:
      id: HP:0004308
      label: Ventricular arrhythmia
  evidence:
  - reference: PMID:37558308
    reference_title: "Genetic Risk Stratification in Arrhythmogenic Left Ventricular Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arrhythmogenic left ventricular cardiomyopathy is characterized by early
      malignant ventricular arrhythmia associated with varying degrees and times of
      onset of left ventricular dysfunction.
    explanation: >-
      Documents early malignant ventricular arrhythmia as the defining feature of
      the gene group that includes RBM20.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    Progressive systolic dysfunction produces heart failure.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:22466703
    reference_title: "RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our studies emphasize the key role of post-transcriptional regulation in
      cardiac function and provide mechanistic insights into the pathogenesis of
      human heart failure.
    explanation: >-
      Places the RBM20 splicing mechanism in the pathogenesis of human heart
      failure; PARTIAL because the statement is about heart failure pathogenesis
      generally rather than quantifying it in RBM20 carriers.
genetic:
- name: RBM20
  gene_term:
    preferred_term: RBM20
    term:
      id: hgnc:27424
      label: RBM20
  relationship_type: CAUSATIVE
  frequency: >-
    Definitive but numerically minor cause of familial dilated cardiomyopathy;
    no case fraction has been reported in a screened cohort.
  evidence:
  - 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's Gene Curation Expert Panel classifies this gene-disease
      relationship as Definitive, which is the authority for curating the gene
      as CAUSATIVE rather than a candidate.
  - reference: PMID:19712804
    reference_title: "Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      distinct heterozygous missense mutations in exon 9 of RBM20, encoding
      ribonucleic acid (RNA) binding motif protein 20
    explanation: >-
      Identifies the heterozygous exon 9 missense alleles that define the
      gene-disease relationship, which is the variant class this entry's
      pathograph is built on.
treatments:
- name: Heart Failure Pharmacotherapy
  description: >-
    Standard guideline-directed heart-failure therapy targeting the neurohormonal
    drive of adverse remodeling.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Implantable Cardioverter-Defibrillator
  description: >-
    Defibrillator therapy is considered earlier than in ordinary dilated
    cardiomyopathy, because left ventricular systolic function is an insensitive
    predictor of arrhythmic risk in RBM20 carriers.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
mechanistic_hypotheses:
- hypothesis_group_id: rbm20_spliceopathy
  hypothesis_label: Spliceopathy Model (loss of RBM20 splicing repression)
  status: CANONICAL
  description: >-
    The long-standing model, and the one this entry's pathograph is built on: the
    RS-domain lesion abolishes RBM20's repression of specific exons across its
    cardiac target network, and the resulting mis-splicing - principally the shift
    to the compliant N2BA titin isoform, plus the ion-homeostasis arm of the target
    set - is what produces ventricular dilation, systolic dysfunction, and the
    arrhythmogenic substrate. It originates in Rbm20 knockout rodents.
  evidence:
  - reference: PMID:38288598
    reference_title: "Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Early studies in Rbm20 knockout rodents implicated disrupted splicing of RBM20
      target genes as a causative mechanism.
    explanation: >-
      States the origin and content of the canonical spliceopathy model, which is the
      explanatory frame for the splicing-route causal edges in this entry.
- hypothesis_group_id: rbm20_condensate_mislocalization
  hypothesis_label: Condensate / Nucleocytoplasmic Transport Model
  status: EMERGING
  description: >-
    A competing, non-mutually-exclusive model in which RS-domain variants act beyond
    splicing: they impair RBM20's nucleocytoplasmic transport and drive the protein
    into biomolecular condensates in the sarcoplasm. The discriminating observation
    is a knock-in contrast rather than a gain of detail - mice carrying a
    disease-associated RRM variant mis-splice RBM20 targets yet do not remodel or die
    suddenly, which is difficult to reconcile with mis-splicing alone being
    sufficient. Sarcoplasmic condensates are not a model-system artefact: they have
    been observed in the myocardium of affected individuals as well as in knock-in
    rodents and hiPSC-derived cardiomyocytes. What is not settled is whether they are
    pathogenic, and the model does not cover the whole gene - exon 11 hotspot
    variants cause the same disease without being expected to disturb
    nucleocytoplasmic trafficking. No pathophysiology node is curated for this route
    pending that resolution, since curating one would commit this entry's pathograph
    to a mechanism the primary literature still describes as under debate.
  evidence:
  - reference: PMID:38288598
    reference_title: "Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      variants in a specific portion of the arginine-serine-rich domain in RBM20 not
      only disrupt splicing but also hinder nucleocytoplasmic transport and lead to
      the formation of RBM20 biomolecular condensates in the sarcoplasm
    explanation: >-
      States the emerging mechanism itself, and localizes it to the same RS-domain
      variant class that this entry curates as its trigger node.
  - reference: PMID:38288598
    reference_title: "Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      mice harboring a disease-associated variant in the RRM (RNA recognition motif)
      do not show evidence of adverse remodeling or exhibit sudden death despite
      disrupted splicing of RBM20 target genes
    explanation: >-
      The dissociation of mis-splicing from adverse remodeling in the RRM knock-in is
      the observation that motivates a mechanism additional to spliceopathy.
  - reference: PMID:38288598
    reference_title: "Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This phenomenon was later confirmed in the myocardium of patients with RBM20
      cardiomyopathy and Rbm20 pathogenic variant knock-in (KI) animal models with the
      striking finding that accumulation of RBM20 in the sarcoplasm promoted
      liquid-liquid phase separation of the protein in biomolecular condensates.
    explanation: >-
      Establishes that sarcoplasmic RBM20 condensates occur in affected human
      myocardium, so the open question is their pathogenicity rather than their
      existence or their translation from model systems.
  notes: >-
    Surfaced from the committed deep-research artifact
    research/Dilated_Cardiomyopathy-deep-research-falcon.md (section 8.2), which
    flagged the debate; snippets here are quoted from the primary review, not the
    report.

discussions:
- discussion_id: controversy_rbm20_splicing_versus_condensates
  prompt: >-
    Is RBM20 cardiomyopathy caused by disrupted splicing of RBM20 target genes, by
    mislocalization of RBM20 into sarcoplasmic biomolecular condensates, or by both?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#RBM20 Loss-of-Function Variant in the RS Domain
  - pathophysiology#Loss of RBM20-Dependent Splicing Regulation
  - mechanistic_hypotheses#rbm20_spliceopathy
  - mechanistic_hypotheses#rbm20_condensate_mislocalization
  rationale: >-
    This entry's pathograph routes every downstream consequence through loss of
    splicing repression, so the question is not decorative - if condensate formation
    is the operative lesion, the splicing edges are correlates rather than causes,
    and the therapeutic target moves from restoring the titin isoform balance to
    preventing RBM20 mislocalization. The two knock-in models point opposite ways:
    RS-domain variants produce both mis-splicing and condensates together, while an
    RRM variant produces mis-splicing without disease. The condensate model does not
    account for the whole gene either: exon 11 hotspot variants produce the same
    clinical picture without being expected to disturb nucleocytoplasmic trafficking,
    which either limits the condensate mechanism to nuclear-localization-signal
    variants or means the two variant classes reach the phenotype by different routes.
    Resolving this requires separating mis-splicing from mislocalization within a
    single model rather than comparing across models, and characterising the exon 11
    class clinically, which is currently too sparsely described to compare.
  evidence:
  - reference: PMID:38288598
    reference_title: "Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      whether disrupted splicing, biomolecular condensates, or both contribute to
      dilated cardiomyopathy is under debate
    explanation: >-
      A 2024 review states the debate explicitly and unresolved, which is what makes
      this a curated controversy rather than a settled mechanism.
  - reference: PMID:38288598
    reference_title: "Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      pathogenic variants in the exon 11 hotspot (Figure 1C) cause RBM20
      cardiomyopathy even though they are not expected to affect RBM20
      nucleocytoplasmic trafficking
    explanation: >-
      Records the observation that argues against the condensate model being the whole
      account, which is why this is curated as an open controversy and not resolved in
      favour of the emerging hypothesis.

references:
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
notes: >-
  CMD1DD is the RBM20 member of the numbered dilated cardiomyopathy series and
  carries ClinGen Definitive gene-disease validity. It conforms to the shared
  cardiomyopathy_maladaptive_remodeling module.

  Mechanistic distinctiveness is the point of this entry, and it completes a
  three-way contrast within the DCM series curated alongside it: TTN (CMD1G) is a
  structural sarcomeric lesion, BAG3 (CMD1HH) is a protein-quality-control lesion,
  and RBM20 is a post-transcriptional lesion - a splicing factor that mis-builds the
  sarcomere's transcripts, with titin as its principal client. The titin link is
  explicit rather than incidental: RBM20 governs the N2B/N2BA isoform switch that
  sets passive stiffness, so CMD1DD and CMD1G converge on titin from opposite
  directions.

  Two caveats preserved. (1) The arrhythmogenic arm is curated as a parallel
  amplifier node with an explicitly unestablished causal chain - the ion-homeostasis
  enrichment of the RBM20 splicing network is a plausible substrate, not a
  demonstrated route from a specific mis-spliced transcript to arrhythmia. (2) The
  clinically decisive point is recorded on both that node and the treatment: left
  ventricular systolic function is an insensitive predictor of arrhythmic risk in
  this genotype, so ejection-fraction-based risk stratification under-calls it.

  GeneReviews scope. The GeneReviews resource applicable to this entry is the
  disease-level "Dilated Cardiomyopathy Overview" (PMID:20301486), tagged
  accordingly in `references`. Its indexed PubMed record is content_type
  abstract_only and carries only the chapter's purpose statement, not the
  Clinical Characteristics, Management, or Genetic Counseling sections, so
  section-by-section GeneReviews mining is not possible from the cache and no
  snippet is quoted from it. The clinical-characteristics baseline for this
  entry is therefore built from the primary RBM20 cohort and pedigree literature
  cited throughout, principally PMID:19712804, PMID:37558308, PMID:22466703.
📚

References & Deep Research

References

1
PMID:20301486
Dilated Cardiomyopathy Overview.
No top-level findings curated for this source.