Dilated Cardiomyopathy 1D

Genetic MONDO:0011095 Pathograph 5 Show in embeddings browser Dilated Cardiomyopathy Genetic Disorder

Dilated cardiomyopathy 1D (CMD1D) is the TNNT2-related form of familial isolated dilated cardiomyopathy. TNNT2 encodes cardiac troponin T, the tropomyosin-binding subunit that anchors the troponin complex to the thin filament and transmits the calcium signal to the actin-tropomyosin regulatory unit. CMD1D is the sharpest functional illustration in the knowledge base of how one thin-filament protein produces two opposite diseases: dilated cardiomyopathy alleles *decrease* the calcium sensitivity of force generation, while hypertrophic alleles in the same protein (curated as CMH2) *increase* it. The founding dilated allele was the in-frame deletion DeltaLys210, identified by Kamisago and colleagues in 2000 alongside the MYH7 dilated alleles; the later missense allele Arg141Trp, in the strong tropomyosin-binding region, was shown to produce the same calcium desensitization despite lying in a different part of the molecule. ClinGen classifies the TNNT2-dilated cardiomyopathy relationship as Definitive with autosomal dominant inheritance, and disease is characteristically early-onset.

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1
Inheritance
4
Pathophys.
2
Phenotypes
5
Pathograph
1
Genes
2
Medical Actions
1
References
🏷

Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal dominant HP:0000006
CMD1D is inherited as an autosomal dominant trait; a single TNNT2 allele - classically the in-frame deletion DeltaLys210 - causes disease, with characteristically early onset.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (2 references)
CGGV:assertion_20fbdfad-b2d2-45f1-9658-e2e3e02cb413-2025-05-30T160000.000Z SUPPORT Other
"TNNT2 | HGNC:11949 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies the TNNT2-dilated cardiomyopathy relationship as Definitive with autosomal dominant inheritance.
PMID:11106718 SUPPORT Human Clinical
"Analyses of this and other genes for sarcomere proteins identified disease-causing dominant mutations in four kindreds."
Documents the dominant transmission of the sarcomeric dilated cardiomyopathy alleles, including the TNNT2 DeltaLys210 deletion, in the founding kindreds.
⚙

Pathophysiology

4
TNNT2 Variant in Cardiac Troponin T
The initiating lesion in CMD1D is a heterozygous variant in TNNT2, encoding cardiac troponin T - the subunit that binds tropomyosin and anchors the troponin complex on the thin filament. The founding dilated allele is the in-frame deletion DeltaLys210; the missense allele Arg141Trp, located in the strong tropomyosin-binding region, was subsequently reported to cause the same disease. The mutant protein is incorporated into the thin filament and retunes calcium regulation rather than being lost.
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.
TNNT2 hgnc:11949 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TNNT2 (hgnc:11949). hgnc:11949 is a gene from the HUGO Gene Nomenclature Committee.
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
Troponin complex GO:0005861 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Troponin complex (GO:0005861). GO:0005861 is a cellular component from the Gene Ontology.
Downstream
Decreased Myofilament Calcium Sensitivity The mutant troponin T shifts the thin-filament calcium response downward, desensitizing force generation.
Show evidence (2 references)
PMID:14654368 SUPPORT In Vitro
"A missense mutation R141W in the strong tropomyosin-binding region of cardiac troponin T (cTnT) has recently been reported to cause dilated cardiomyopathy (DCM), following the first report of a DCM-causing deletion mutation DeltaK210."
Names both founding TNNT2 dilated cardiomyopathy alleles - DeltaK210 and R141W - and their location relative to the tropomyosin-binding region.
PMID:11106718 SUPPORT Human Clinical
"Cardiac beta-myosin heavy-chain missense mutations (Ser532Pro and Phe764Leu) and a deletion in cardiac troponin T (deltaLys210) caused early-onset ventricular dilatation (average age at diagnosis, 24 years) and diminished contractile function and frequently resulted in heart failure."
Documents the founding TNNT2 DeltaLys210 deletion and its clinical consequence - early-onset dilatation with diminished contractile function.
Decreased Myofilament Calcium Sensitivity
The defining functional lesion of CMD1D, and the axis on which dilated and hypertrophic TNNT2 disease separate. Dilated cardiomyopathy alleles decrease the calcium sensitivity of force generation: the R141W mutation does so by stabilizing the troponin T-tropomyosin interaction, and DeltaK210 produces the same desensitization from outside the strong tropomyosin-binding region, so the functional direction rather than the structural location is what tracks with the phenotype. Hypertrophic TNNT2 alleles such as R94L do the opposite, increasing calcium sensitivity. A myofilament that requires more calcium to generate the same force is hypocontractile, which is why the ventricle dilates.
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 Cardiac Muscle Contraction by Calcium GO:0010882 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Regulation of Cardiac Muscle Contraction by Calcium, annotated with regulation of cardiac muscle contraction by calcium ion signaling (GO:0010882). GO:0010882 is a biological process from the Gene Ontology. ↓ DECREASED Muscle Contraction GO:0006936 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Muscle Contraction (GO:0006936). GO:0006936 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Ventricular Dilation and Systolic Dysfunction A calcium-desensitized, hypocontractile myofilament drives chamber dilation and falling systolic performance.
Show evidence (2 references)
PMID:14654368 SUPPORT In Vitro
"R141W mutation resulted in a decrease in the Ca(2+) sensitivity of force generation, as in the case of DeltaK210 mutation lying outside the strong tropomyosin-binding region."
Demonstrates calcium desensitization for both founding dilated alleles, and that it does not depend on location within the tropomyosin-binding region.
PMID:14654368 SUPPORT In Vitro
"In contrast, a missense mutation R94L in the vicinity of the strong tropomyosin-binding region associated with hypertrophic cardiomyopathy (HCM) resulted in an increase in the Ca(2+) sensitivity of force generation, as in the case of the other HCM-causing mutations in cTnT reported previously."
The direct experimental contrast that this entry rests on: hypertrophic TNNT2 alleles increase calcium sensitivity where the dilated alleles decrease it, measured in the same system.
Ventricular Dilation and Systolic Dysfunction
Sustained hypocontractility produces the defining structural remodeling of dilated cardiomyopathy: left ventricular chamber enlargement with wall thinning, myocyte loss and interstitial fibrosis, with falling ejection fraction. In CMD1D this occurs early and without the antecedent hypertrophy or hypertrophic histopathology of the TNNT2 hypertrophic 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
Show evidence (1 reference)
PMID:11106718 SUPPORT Human Clinical
"Affected persons had neither antecedent cardiac hypertrophy (average maximal left-ventricular-wall thickness, 8.5 mm) nor histopathological findings characteristic of hypertrophy."
Establishes that the dilated sarcomeric phenotype, including the TNNT2 form, arises without a preceding hypertrophic phase.
Heart Failure
The dilated, calcium-desensitized ventricle produces progressive systolic heart failure, a frequent outcome in the founding kindreds, managed with standard heart-failure therapy and transplantation for advanced disease.
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:11106718 SUPPORT Human Clinical
"diminished contractile function and frequently resulted in heart failure"
Documents heart failure as the frequent clinical outcome of the sarcomeric dilated cardiomyopathy alleles including TNNT2 DeltaLys210.
⬡

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 1D 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

2
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:14654368 SUPPORT In Vitro
"A missense mutation R141W in the strong tropomyosin-binding region of cardiac troponin T (cTnT) has recently been reported to cause dilated cardiomyopathy (DCM), following the first report of a DCM-causing deletion mutation DeltaK210."
Establishes dilated cardiomyopathy as the phenotype caused by these TNNT2 alleles.
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:11106718 SUPPORT Human Clinical
"diminished contractile function and frequently resulted in heart failure"
Documents heart failure as a frequent outcome of this entity.
🧬

Genetic Associations

1
TNNT2
Gene: TNNT2 hgnc:11949 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TNNT2 (hgnc:11949). hgnc:11949 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
CGGV:assertion_20fbdfad-b2d2-45f1-9658-e2e3e02cb413-2025-05-30T160000.000Z SUPPORT Other
"TNNT2 | HGNC:11949 | 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:11106718 SUPPORT Human Clinical
"Analyses of this and other genes for sarcomere proteins identified disease-causing dominant mutations in four kindreds."
Establishes dominant sarcomere-protein mutations, TNNT2 among them, as disease-causing in dilated cardiomyopathy kindreds.
PMID:11106718 SUPPORT Human Clinical
"Mutations in sarcomere protein genes account for approximately 10 percent of cases of familial dilated cardiomyopathy and are particularly prevalent in families with early-onset ventricular dilatation and dysfunction."
The 10% figure is measured over sarcomere protein genes as a class, not over TNNT2. Curated PARTIAL for that reason: it bounds the TNNT2 share from above but must not be quoted as the TNNT2 case fraction, which is why no case_fractions record is recorded here.
💊

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.
Heart Transplantation
Action: organ transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is organ transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. Ontology label: Organ Transplantation NCIT:C15289
Advanced, refractory disease is an indication for transplantation.
📊

Prevalence

1
Familial dilated cardiomyopathy
Unknown Unknown
Sarcomere protein gene mutations collectively account for roughly 10% of familial dilated cardiomyopathy, of which TNNT2 is one contributor; no population rate is established for the TNNT2-specific entity.
Show evidence (1 reference)
PMID:11106718 SUPPORT Human Clinical
"Mutations in sarcomere protein genes account for approximately 10 percent of cases of familial dilated cardiomyopathy and are particularly prevalent in families with early-onset ventricular dilatation and dysfunction."
Gives the collective share of familial dilated cardiomyopathy attributable to sarcomere protein genes, the class to which TNNT2 belongs.
{ }

Source YAML

click to show 
name: Dilated Cardiomyopathy 1D
creation_date: "2026-08-23T00:00:00Z"
synonyms:
- CMD1D
- TNNT2 familial isolated dilated cardiomyopathy
- dilated cardiomyopathy type 1D
- cardiomyopathy, dilated, 1D
- cardiac troponin T dilated cardiomyopathy
description: >-
  Dilated cardiomyopathy 1D (CMD1D) is the TNNT2-related form of familial isolated
  dilated cardiomyopathy. TNNT2 encodes cardiac troponin T, the tropomyosin-binding
  subunit that anchors the troponin complex to the thin filament and transmits the
  calcium signal to the actin-tropomyosin regulatory unit. CMD1D is the sharpest
  functional illustration in the knowledge base of how one thin-filament protein
  produces two opposite diseases: dilated cardiomyopathy alleles *decrease* the
  calcium sensitivity of force generation, while hypertrophic alleles in the same
  protein (curated as CMH2) *increase* it. The founding dilated allele was the
  in-frame deletion DeltaLys210, identified by Kamisago and colleagues in 2000
  alongside the MYH7 dilated alleles; the later missense allele Arg141Trp, in the
  strong tropomyosin-binding region, was shown to produce the same calcium
  desensitization despite lying in a different part of the molecule. ClinGen
  classifies the TNNT2-dilated cardiomyopathy relationship as Definitive with
  autosomal dominant inheritance, and disease is characteristically early-onset.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: dilated cardiomyopathy 1D
  term:
    id: MONDO:0011095
    label: dilated cardiomyopathy 1D
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant
  description: >-
    CMD1D is inherited as an autosomal dominant trait; a single TNNT2 allele -
    classically the in-frame deletion DeltaLys210 - causes disease, with
    characteristically early onset.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  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's Dilated Cardiomyopathy Gene Curation Expert Panel classifies the
      TNNT2-dilated cardiomyopathy relationship as Definitive with autosomal
      dominant inheritance.
  - reference: PMID:11106718
    reference_title: "Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analyses of this and other genes for sarcomere proteins identified
      disease-causing dominant mutations in four kindreds.
    explanation: >-
      Documents the dominant transmission of the sarcomeric dilated cardiomyopathy
      alleles, including the TNNT2 DeltaLys210 deletion, in the founding kindreds.
prevalence:
- population: Familial dilated cardiomyopathy
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Sarcomere protein gene mutations collectively account for roughly 10% of
    familial dilated cardiomyopathy, of which TNNT2 is one contributor; no
    population rate is established for the TNNT2-specific entity.
  evidence:
  - reference: PMID:11106718
    reference_title: "Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in sarcomere protein genes account for approximately 10 percent of
      cases of familial dilated cardiomyopathy and are particularly prevalent in
      families with early-onset ventricular dilatation and dysfunction.
    explanation: >-
      Gives the collective share of familial dilated cardiomyopathy attributable to
      sarcomere protein genes, the class to which TNNT2 belongs.
pathophysiology:
- name: TNNT2 Variant in Cardiac Troponin T
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The initiating lesion in CMD1D is a heterozygous variant in TNNT2, encoding
    cardiac troponin T - the subunit that binds tropomyosin and anchors the troponin
    complex on the thin filament. The founding dilated allele is the in-frame
    deletion DeltaLys210; the missense allele Arg141Trp, located in the strong
    tropomyosin-binding region, was subsequently reported to cause the same disease.
    The mutant protein is incorporated into the thin filament and retunes calcium
    regulation rather than being lost.
  genes:
  - preferred_term: TNNT2
    term:
      id: hgnc:11949
      label: TNNT2
  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
  cellular_components:
  - preferred_term: Troponin complex
    term:
      id: GO:0005861
      label: troponin complex
  evidence:
  - reference: PMID:14654368
    reference_title: "Cardiac troponin T mutation R141W found in dilated cardiomyopathy stabilizes the troponin T-tropomyosin interaction and causes a Ca2+ desensitization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A missense mutation R141W in the strong tropomyosin-binding region of cardiac
      troponin T (cTnT) has recently been reported to cause dilated cardiomyopathy
      (DCM), following the first report of a DCM-causing deletion mutation
      DeltaK210.
    explanation: >-
      Names both founding TNNT2 dilated cardiomyopathy alleles - DeltaK210 and
      R141W - and their location relative to the tropomyosin-binding region.
  - reference: PMID:11106718
    reference_title: "Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac beta-myosin heavy-chain missense mutations (Ser532Pro and Phe764Leu)
      and a deletion in cardiac troponin T (deltaLys210) caused early-onset
      ventricular dilatation (average age at diagnosis, 24 years) and diminished
      contractile function and frequently resulted in heart failure.
    explanation: >-
      Documents the founding TNNT2 DeltaLys210 deletion and its clinical
      consequence - early-onset dilatation with diminished contractile function.
  downstream:
  - target: Decreased Myofilament Calcium Sensitivity
    causal_link_type: DIRECT
    description: >-
      The mutant troponin T shifts the thin-filament calcium response downward,
      desensitizing force generation.
- name: Decreased Myofilament Calcium Sensitivity
  biological_scale: MOLECULAR
  role: effector
  description: >-
    The defining functional lesion of CMD1D, and the axis on which dilated and
    hypertrophic TNNT2 disease separate. Dilated cardiomyopathy alleles decrease the
    calcium sensitivity of force generation: the R141W mutation does so by
    stabilizing the troponin T-tropomyosin interaction, and DeltaK210 produces the
    same desensitization from outside the strong tropomyosin-binding region, so the
    functional direction rather than the structural location is what tracks with the
    phenotype. Hypertrophic TNNT2 alleles such as R94L do the opposite, increasing
    calcium sensitivity. A myofilament that requires more calcium to generate the
    same force is hypocontractile, which is why the ventricle dilates.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Regulation of Cardiac Muscle Contraction by Calcium
    term:
      id: GO:0010882
      label: regulation of cardiac muscle contraction by calcium ion signaling
    modifier: DECREASED
  - preferred_term: Muscle Contraction
    term:
      id: GO:0006936
      label: muscle contraction
    modifier: DECREASED
  evidence:
  - reference: PMID:14654368
    reference_title: "Cardiac troponin T mutation R141W found in dilated cardiomyopathy stabilizes the troponin T-tropomyosin interaction and causes a Ca2+ desensitization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      R141W mutation resulted in a decrease in the Ca(2+) sensitivity of force
      generation, as in the case of DeltaK210 mutation lying outside the strong
      tropomyosin-binding region.
    explanation: >-
      Demonstrates calcium desensitization for both founding dilated alleles, and
      that it does not depend on location within the tropomyosin-binding region.
  - reference: PMID:14654368
    reference_title: "Cardiac troponin T mutation R141W found in dilated cardiomyopathy stabilizes the troponin T-tropomyosin interaction and causes a Ca2+ desensitization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In contrast, a missense mutation R94L in the vicinity of the strong
      tropomyosin-binding region associated with hypertrophic cardiomyopathy (HCM)
      resulted in an increase in the Ca(2+) sensitivity of force generation, as in
      the case of the other HCM-causing mutations in cTnT reported previously.
    explanation: >-
      The direct experimental contrast that this entry rests on: hypertrophic TNNT2
      alleles increase calcium sensitivity where the dilated alleles decrease it,
      measured in the same system.
  downstream:
  - target: Ventricular Dilation and Systolic Dysfunction
    causal_link_type: DIRECT
    description: >-
      A calcium-desensitized, hypocontractile myofilament drives chamber dilation
      and falling systolic performance.
- name: Ventricular Dilation and Systolic Dysfunction
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    Sustained hypocontractility produces the defining structural remodeling of
    dilated cardiomyopathy: left ventricular chamber enlargement with wall thinning,
    myocyte loss and interstitial fibrosis, with falling ejection fraction. In CMD1D
    this occurs early and without the antecedent hypertrophy or hypertrophic
    histopathology of the TNNT2 hypertrophic 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:11106718
    reference_title: "Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected persons had neither antecedent cardiac hypertrophy (average maximal
      left-ventricular-wall thickness, 8.5 mm) nor histopathological findings
      characteristic of hypertrophy.
    explanation: >-
      Establishes that the dilated sarcomeric phenotype, including the TNNT2 form,
      arises without a preceding hypertrophic phase.
  downstream:
  - target: Heart Failure
    causal_link_type: DIRECT
- name: Heart Failure
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    The dilated, calcium-desensitized ventricle produces progressive systolic heart
    failure, a frequent outcome in the founding kindreds, managed with standard
    heart-failure therapy and transplantation for advanced disease.
  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:11106718
    reference_title: "Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      diminished contractile function and frequently resulted in heart failure
    explanation: >-
      Documents heart failure as the frequent clinical outcome of the sarcomeric
      dilated cardiomyopathy alleles including TNNT2 DeltaLys210.
phenotypes:
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: >-
    Left ventricular dilation with systolic dysfunction, without antecedent
    hypertrophy, is the defining feature of CMD1D.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  frequency: OBLIGATE
  evidence:
  - reference: PMID:14654368
    reference_title: "Cardiac troponin T mutation R141W found in dilated cardiomyopathy stabilizes the troponin T-tropomyosin interaction and causes a Ca2+ desensitization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A missense mutation R141W in the strong tropomyosin-binding region of cardiac
      troponin T (cTnT) has recently been reported to cause dilated cardiomyopathy
      (DCM), following the first report of a DCM-causing deletion mutation
      DeltaK210.
    explanation: >-
      Establishes dilated cardiomyopathy as the phenotype caused by these TNNT2
      alleles.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    Progressive systolic dysfunction produces heart failure, frequently in early
    adulthood.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:11106718
    reference_title: "Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      diminished contractile function and frequently resulted in heart failure
    explanation: >-
      Documents heart failure as a frequent outcome of this entity.
genetic:
- name: TNNT2
  gene_term:
    preferred_term: TNNT2
    term:
      id: hgnc:11949
      label: TNNT2
  relationship_type: CAUSATIVE
  frequency: >-
    Minority cause of familial dilated cardiomyopathy. Sarcomere protein genes
    as a class account for roughly 10% of familial cases; TNNT2 is one
    contributor to that class and no TNNT2-specific share has been reported.
  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'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:11106718
    reference_title: "Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analyses of this and other genes for sarcomere proteins identified
      disease-causing dominant mutations in four kindreds.
    explanation: >-
      Establishes dominant sarcomere-protein mutations, TNNT2 among them, as
      disease-causing in dilated cardiomyopathy kindreds.
  - reference: PMID:11106718
    reference_title: "Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in sarcomere protein genes account for approximately 10
      percent of cases of familial dilated cardiomyopathy and are particularly
      prevalent in families with early-onset ventricular dilatation and
      dysfunction.
    explanation: >-
      The 10% figure is measured over sarcomere protein genes as a class, not
      over TNNT2. Curated PARTIAL for that reason: it bounds the TNNT2 share
      from above but must not be quoted as the TNNT2 case fraction, which is
      why no case_fractions record is recorded here.
treatments:
- name: Heart Failure Pharmacotherapy
  description: >-
    Standard guideline-directed heart-failure therapy targeting the neurohormonal
    drive of adverse remodeling.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Heart Transplantation
  description: >-
    Advanced, refractory disease is an indication for transplantation.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
references:
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
notes: >-
  CMD1D is the TNNT2 member of the numbered dilated cardiomyopathy series and
  carries ClinGen Definitive gene-disease validity. It conforms to the shared
  cardiomyopathy_maladaptive_remodeling module.

  Like CMD1S (MYH7), this entry exists partly to record an allelic contrast, and
  here the contrast is measured rather than inferred: in one experimental system,
  the dilated alleles (R141W, DeltaK210) decreased the calcium sensitivity of force
  generation while the hypertrophic allele R94L increased it. That is the
  functional axis separating CMD1D from Hypertrophic Cardiomyopathy 2, the TNNT2
  hypertrophic entry, and both sides of it are curated as evidence on the effector
  node.

  A second point the evidence makes and the entry preserves: the two dilated
  alleles sit in different parts of the molecule - R141W inside the strong
  tropomyosin-binding region, DeltaK210 outside it - yet produce the same
  desensitization. The direction of the calcium-sensitivity shift, not the
  structural location of the variant, is what tracks with the phenotype, so the
  entry does not assert a domain-based rule.

  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 TNNT2 cohort and pedigree literature
  cited throughout, principally PMID:14654368, PMID:11106718.
📚

References & Deep Research

References

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