Dilated Cardiomyopathy 1E

Genetic MONDO:0011003 Pathograph 5 Show in embeddings browser Dilated Cardiomyopathy Genetic Disorder

Dilated cardiomyopathy 1E (CMD1E) is the SCN5A-related form of familial isolated dilated cardiomyopathy, and the member of the series that most challenges the boundary between electrical and structural heart disease. SCN5A encodes Nav1.5, the pore-forming subunit of the cardiac voltage-gated sodium channel - a protein with no structural role in the sarcomere, whose other disease alleles cause the primary channelopathies Brugada syndrome, LQT3 and progressive cardiac conduction disease. In CMD1E the same gene instead produces a structural cardiomyopathy accompanied by rhythm disturbance: Olson and colleagues mapped the locus and identified the missense allele Asp1275Asn, which cosegregated with an age-dependent, variably expressed phenotype combining dilated cardiomyopathy, atrial fibrillation, impaired automaticity and conduction delay. The striking observation from that work, and the reason the entity is curated with an explicit caveat, is that similar or even identical SCN5A mutations may lead to heart failure, arrhythmia, or both - so genotype does not cleanly predict which arm dominates. ClinGen classifies the SCN5A-dilated cardiomyopathy relationship as Definitive with autosomal dominant inheritance.

Ask OpenScientist

Ask a research question about Dilated Cardiomyopathy 1E. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

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

Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal dominant HP:0000006
CMD1E is inherited as an autosomal dominant trait; a single SCN5A missense allele causes disease. Expression is age-dependent and variable even within a family, with the balance between the structural and arrhythmic arms differing between carriers of the same variant.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (2 references)
CGGV:assertion_53c90d2e-4d40-48ab-8761-b0158102c977-2025-05-30T160000.000Z SUPPORT Other
"SCN5A | HGNC:10593 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies the SCN5A-dilated cardiomyopathy relationship as Definitive with autosomal dominant inheritance.
PMID:15671429 SUPPORT Human Clinical
"Mutation scans identified a missense mutation (D1275N) that cosegregated with an age-dependent, variably expressed phenotype of DCM, atrial fibrillation, impaired automaticity, and conduction delay."
Documents cosegregation of the founding SCN5A allele with the disease and its age-dependent, variably expressed character.
⚙

Pathophysiology

4
SCN5A Missense Variant in the Cardiac Sodium Channel
The initiating lesion in CMD1E is a heterozygous missense variant in SCN5A, encoding the alpha subunit of the cardiac voltage-gated sodium channel Nav1.5. The founding allele is Asp1275Asn (D1275N), identified after refined locus mapping in a family with dilated cardiomyopathy and rhythm disturbance. Unlike every other gene in this series, the affected protein has no structural role in the contractile apparatus - it is an ion channel, and the same gene's other alleles cause the primary channelopathies curated elsewhere in the knowledge base (Brugada syndrome, progressive cardiac conduction 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.
SCN5A hgnc:10593 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SCN5A (hgnc:10593). hgnc:10593 is a gene from the HUGO Gene Nomenclature Committee.
Voltage-gated sodium channel activity GO:0005248 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal Voltage-gated sodium channel activity (GO:0005248). GO:0005248 is a molecular function from the Gene Ontology. ⚠ ABNORMAL
Downstream
Altered Sodium Current with Conduction and Automaticity Impairment The variant channel disturbs the cardiac sodium current, impairing impulse conduction and automaticity.
Show evidence (2 references)
PMID:15671429 SUPPORT Human Clinical
"Refined locus mapping revealed SCN5A, encoding the cardiac sodium channel, as a candidate gene."
Documents the mapping that identified SCN5A as the causal gene for this dilated cardiomyopathy entity.
PMID:15671429 SUPPORT Human Clinical
"Mutation scans identified a missense mutation (D1275N) that cosegregated with an age-dependent, variably expressed phenotype of DCM, atrial fibrillation, impaired automaticity, and conduction delay."
Names the founding SCN5A dilated cardiomyopathy allele and the composite structural-plus-electrical phenotype it produces.
Altered Sodium Current with Conduction and Automaticity Impairment
The mutant Nav1.5 channel disturbs the depolarizing sodium current that drives the action potential upstroke and propagates the impulse. Clinically this manifests as conduction delay, impaired automaticity, and a high burden of atrial fibrillation, which in this entity accompany rather than follow the ventricular disease. This node is the electrical arm of the phenotype and is the point of contact with the primary SCN5A channelopathies; how the same current disturbance also produces ventricular dilation is the entity's open mechanistic question.
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 Cardiac Muscle Cell Action Potential GO:0086001 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Cardiac Muscle Cell Action Potential (GO:0086001). GO:0086001 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Ventricular Dilation and Systolic Dysfunction The route from a sodium-channel defect to structural ventricular dilation is not established; the association is curated without asserting the intervening steps.
Show evidence (1 reference)
PMID:15671429 SUPPORT Human Clinical
"Mutation scans identified a missense mutation (D1275N) that cosegregated with an age-dependent, variably expressed phenotype of DCM, atrial fibrillation, impaired automaticity, and conduction delay."
Documents the conduction delay, impaired automaticity and atrial fibrillation that constitute the electrical arm of this node.
Ventricular Dilation and Systolic Dysfunction
Carriers develop the defining structural remodeling of dilated cardiomyopathy - left ventricular chamber enlargement with impaired systolic function - with characteristically early onset. That an ion-channel defect produces structural remodeling at all is the notable feature of this entity; a comparable channel-to-structure progression is documented in SCN5A-linked progressive cardiac conduction disease, where the sodium-channel deficit drives myocardial fibrosis with age.
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 Atrial Fibrillation
Show evidence (2 references)
PMID:15671429 SUPPORT Human Clinical
"Heritable SCN5A defects are associated with susceptibility to early-onset DCM and atrial fibrillation."
Establishes early-onset dilated cardiomyopathy as a consequence of heritable SCN5A defects.
PMID:15809371 SUPPORT Model Organism
"a monogenic ion channel defect can progressively lead to myocardial structural anomalies"
Independent demonstration that an SCN5A channel defect can drive myocardial structural change, supporting the plausibility of the channel-to-structure link. PARTIAL because the model is of the conduction-disease phenotype rather than of this dilated cardiomyopathy entity.
Heart Failure and Atrial Fibrillation
The clinical endpoint of CMD1E has two arms that do not track together: progressive systolic heart failure from ventricular dilation, and atrial fibrillation with conduction disturbance from the channel defect. The founding study's central caution is preserved here - similar or even identical SCN5A mutations may lead to heart failure, arrhythmia, or both - so the genotype does not predict which arm will dominate in a given carrier.
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:15671429 SUPPORT Human Clinical
"Similar or even identical mutations may lead to heart failure, arrhythmia, or both."
The genotype-phenotype caveat that defines this endpoint: the same SCN5A allele can present as heart failure, as arrhythmia, or as both.
⬡

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 1E 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

4
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:15671429 SUPPORT Human Clinical
"Heritable SCN5A defects are associated with susceptibility to early-onset DCM and atrial fibrillation."
Establishes early-onset dilated cardiomyopathy as the structural phenotype of this entity.
Atrial Fibrillation Cardiovascular HP:0005110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial fibrillation (HP:0005110). HP:0005110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15671429 SUPPORT Human Clinical
"Heritable SCN5A defects are associated with susceptibility to early-onset DCM and atrial fibrillation."
Documents atrial fibrillation as a defining feature of heritable SCN5A dilated cardiomyopathy.
Cardiac Conduction Abnormality Cardiovascular HP:0031546 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiac conduction abnormality (HP:0031546). HP:0031546 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15671429 SUPPORT Human Clinical
"Mutation scans identified a missense mutation (D1275N) that cosegregated with an age-dependent, variably expressed phenotype of DCM, atrial fibrillation, impaired automaticity, and conduction delay."
Documents conduction delay and impaired automaticity in carriers of the founding allele.
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:15671429 SUPPORT Human Clinical
"Similar or even identical mutations may lead to heart failure, arrhythmia, or both."
Documents heart failure as one of the two possible dominant presentations.
🧬

Genetic Associations

1
SCN5A
Gene: SCN5A hgnc:10593 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SCN5A (hgnc:10593). hgnc:10593 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
CGGV:assertion_53c90d2e-4d40-48ab-8761-b0158102c977-2025-05-30T160000.000Z SUPPORT Other
"SCN5A | HGNC:10593 | 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:15671429 SUPPORT Human Clinical
"Mutation scans identified a missense mutation (D1275N) that cosegregated with an age-dependent, variably expressed phenotype of DCM, atrial fibrillation, impaired automaticity, and conduction delay."
Cosegregation of the D1275N allele with the composite dilated-cardiomyopathy, atrial-fibrillation and conduction phenotype is the founding gene-disease observation for this entry.
PMID:15671429 SUPPORT Human Clinical
"Heritable SCN5A defects are associated with susceptibility to early-onset DCM and atrial fibrillation."
States the gene-disease relationship in susceptibility terms, which together with the incomplete penetrance recorded under inheritance is why the allele is curated as causative with variable expression rather than fully penetrant.
💊

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 for the structural arm.
Rhythm and Conduction Management
Action: pacemaker placementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is pacemaker placement (NCIT:C80434). NCIT:C80434 is a clinical intervention from the NCI Thesaurus. Ontology label: Pacemaker Placement NCIT:C80434
Management of atrial fibrillation and conduction disease, including anticoagulation where indicated and pacing for symptomatic bradyarrhythmia, addresses the electrical arm of the phenotype.
📊

Prevalence

1
Dilated cardiomyopathy cohorts
Unknown Unknown
SCN5A is a definitive but numerically minor dilated cardiomyopathy gene; no population-based rate is established for the SCN5A-specific entity.
Show evidence (1 reference)
PMID:15671429 SUPPORT Human Clinical
"Heritable SCN5A defects are associated with susceptibility to early-onset DCM and atrial fibrillation."
Establishes the association of heritable SCN5A defects with early-onset dilated cardiomyopathy in a dilated cardiomyopathy cohort study.
{ }

Source YAML

click to show 
name: Dilated Cardiomyopathy 1E
creation_date: "2026-08-23T00:00:00Z"
synonyms:
- CMD1E
- SCN5A familial isolated dilated cardiomyopathy
- dilated cardiomyopathy type 1E
- cardiomyopathy, dilated, 1E
- SCN5A dilated cardiomyopathy with conduction disease
description: >-
  Dilated cardiomyopathy 1E (CMD1E) is the SCN5A-related form of familial isolated
  dilated cardiomyopathy, and the member of the series that most challenges the
  boundary between electrical and structural heart disease. SCN5A encodes Nav1.5,
  the pore-forming subunit of the cardiac voltage-gated sodium channel - a protein
  with no structural role in the sarcomere, whose other disease alleles cause the
  primary channelopathies Brugada syndrome, LQT3 and progressive cardiac conduction
  disease. In CMD1E the same gene instead produces a structural cardiomyopathy
  accompanied by rhythm disturbance: Olson and colleagues mapped the locus and
  identified the missense allele Asp1275Asn, which cosegregated with an
  age-dependent, variably expressed phenotype combining dilated cardiomyopathy,
  atrial fibrillation, impaired automaticity and conduction delay. The striking
  observation from that work, and the reason the entity is curated with an explicit
  caveat, is that similar or even identical SCN5A mutations may lead to heart
  failure, arrhythmia, or both - so genotype does not cleanly predict which arm
  dominates. ClinGen classifies the SCN5A-dilated cardiomyopathy relationship as
  Definitive with autosomal dominant inheritance.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: dilated cardiomyopathy 1E
  term:
    id: MONDO:0011003
    label: dilated cardiomyopathy 1E
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant
  description: >-
    CMD1E is inherited as an autosomal dominant trait; a single SCN5A missense
    allele causes disease. Expression is age-dependent and variable even within a
    family, with the balance between the structural and arrhythmic arms differing
    between carriers of the same variant.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  evidence:
  - reference: CGGV:assertion_53c90d2e-4d40-48ab-8761-b0158102c977-2025-05-30T160000.000Z
    reference_title: "SCN5A / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SCN5A | HGNC:10593 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: >-
      ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies the
      SCN5A-dilated cardiomyopathy relationship as Definitive with autosomal
      dominant inheritance.
  - reference: PMID:15671429
    reference_title: "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation scans identified a missense mutation (D1275N) that cosegregated with
      an age-dependent, variably expressed phenotype of DCM, atrial fibrillation,
      impaired automaticity, and conduction delay.
    explanation: >-
      Documents cosegregation of the founding SCN5A allele with the disease and its
      age-dependent, variably expressed character.
prevalence:
- population: Dilated cardiomyopathy cohorts
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    SCN5A is a definitive but numerically minor dilated cardiomyopathy gene; no
    population-based rate is established for the SCN5A-specific entity.
  evidence:
  - reference: PMID:15671429
    reference_title: "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heritable SCN5A defects are associated with susceptibility to early-onset DCM
      and atrial fibrillation.
    explanation: >-
      Establishes the association of heritable SCN5A defects with early-onset
      dilated cardiomyopathy in a dilated cardiomyopathy cohort study.
pathophysiology:
- name: SCN5A Missense Variant in the Cardiac Sodium Channel
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The initiating lesion in CMD1E is a heterozygous missense variant in SCN5A,
    encoding the alpha subunit of the cardiac voltage-gated sodium channel Nav1.5.
    The founding allele is Asp1275Asn (D1275N), identified after refined locus
    mapping in a family with dilated cardiomyopathy and rhythm disturbance. Unlike
    every other gene in this series, the affected protein has no structural role in
    the contractile apparatus - it is an ion channel, and the same gene's other
    alleles cause the primary channelopathies curated elsewhere in the knowledge
    base (Brugada syndrome, progressive cardiac conduction disease).
  genes:
  - preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: Voltage-gated sodium channel activity
    term:
      id: GO:0005248
      label: voltage-gated sodium channel activity
    modifier: ABNORMAL
  evidence:
  - reference: PMID:15671429
    reference_title: "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Refined locus mapping revealed SCN5A, encoding the cardiac sodium channel, as
      a candidate gene.
    explanation: >-
      Documents the mapping that identified SCN5A as the causal gene for this
      dilated cardiomyopathy entity.
  - reference: PMID:15671429
    reference_title: "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation scans identified a missense mutation (D1275N) that cosegregated with
      an age-dependent, variably expressed phenotype of DCM, atrial fibrillation,
      impaired automaticity, and conduction delay.
    explanation: >-
      Names the founding SCN5A dilated cardiomyopathy allele and the composite
      structural-plus-electrical phenotype it produces.
  downstream:
  - target: Altered Sodium Current with Conduction and Automaticity Impairment
    causal_link_type: DIRECT
    description: >-
      The variant channel disturbs the cardiac sodium current, impairing impulse
      conduction and automaticity.
- name: Altered Sodium Current with Conduction and Automaticity Impairment
  biological_scale: CELLULAR
  role: effector
  description: >-
    The mutant Nav1.5 channel disturbs the depolarizing sodium current that drives
    the action potential upstroke and propagates the impulse. Clinically this
    manifests as conduction delay, impaired automaticity, and a high burden of
    atrial fibrillation, which in this entity accompany rather than follow the
    ventricular disease. This node is the electrical arm of the phenotype and is the
    point of contact with the primary SCN5A channelopathies; how the same current
    disturbance also produces ventricular dilation is the entity's open mechanistic
    question.
  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
  - preferred_term: Cardiac Muscle Cell Action Potential
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
    modifier: ABNORMAL
  evidence:
  - reference: PMID:15671429
    reference_title: "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation scans identified a missense mutation (D1275N) that cosegregated with
      an age-dependent, variably expressed phenotype of DCM, atrial fibrillation,
      impaired automaticity, and conduction delay.
    explanation: >-
      Documents the conduction delay, impaired automaticity and atrial fibrillation
      that constitute the electrical arm of this node.
  downstream:
  - target: Ventricular Dilation and Systolic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The route from a sodium-channel defect to structural ventricular dilation is
      not established; the association is curated without asserting the intervening
      steps.
- name: Ventricular Dilation and Systolic Dysfunction
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    Carriers develop the defining structural remodeling of dilated cardiomyopathy -
    left ventricular chamber enlargement with impaired systolic function - with
    characteristically early onset. That an ion-channel defect produces structural
    remodeling at all is the notable feature of this entity; a comparable
    channel-to-structure progression is documented in SCN5A-linked progressive
    cardiac conduction disease, where the sodium-channel deficit drives myocardial
    fibrosis with age.
  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:15671429
    reference_title: "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heritable SCN5A defects are associated with susceptibility to early-onset DCM
      and atrial fibrillation.
    explanation: >-
      Establishes early-onset dilated cardiomyopathy as a consequence of heritable
      SCN5A defects.
  - reference: PMID:15809371
    reference_title: "Mouse model of SCN5A-linked hereditary Lenègre's disease: age-related conduction slowing and myocardial fibrosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      a monogenic ion channel defect can progressively lead to myocardial structural
      anomalies
    explanation: >-
      Independent demonstration that an SCN5A channel defect can drive myocardial
      structural change, supporting the plausibility of the channel-to-structure
      link. PARTIAL because the model is of the conduction-disease phenotype rather
      than of this dilated cardiomyopathy entity.
  downstream:
  - target: Heart Failure and Atrial Fibrillation
    causal_link_type: DIRECT
- name: Heart Failure and Atrial Fibrillation
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    The clinical endpoint of CMD1E has two arms that do not track together:
    progressive systolic heart failure from ventricular dilation, and atrial
    fibrillation with conduction disturbance from the channel defect. The founding
    study's central caution is preserved here - similar or even identical SCN5A
    mutations may lead to heart failure, arrhythmia, or both - so the genotype does
    not predict which arm will dominate in a given carrier.
  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:15671429
    reference_title: "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similar or even identical mutations may lead to heart failure, arrhythmia, or
      both.
    explanation: >-
      The genotype-phenotype caveat that defines this endpoint: the same SCN5A
      allele can present as heart failure, as arrhythmia, or as both.
phenotypes:
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: >-
    Left ventricular dilation with systolic dysfunction, characteristically
    early-onset, is the structural arm of CMD1E.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  frequency: OBLIGATE
  evidence:
  - reference: PMID:15671429
    reference_title: "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heritable SCN5A defects are associated with susceptibility to early-onset DCM
      and atrial fibrillation.
    explanation: >-
      Establishes early-onset dilated cardiomyopathy as the structural phenotype of
      this entity.
- name: Atrial Fibrillation
  category: Cardiovascular
  description: >-
    Atrial fibrillation is a prominent and characteristic feature, reflecting the
    channel defect rather than being merely secondary to ventricular disease.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:15671429
    reference_title: "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heritable SCN5A defects are associated with susceptibility to early-onset DCM
      and atrial fibrillation.
    explanation: >-
      Documents atrial fibrillation as a defining feature of heritable SCN5A
      dilated cardiomyopathy.
- name: Cardiac Conduction Abnormality
  category: Cardiovascular
  description: >-
    Conduction delay and impaired automaticity accompany the ventricular disease,
    reflecting the sodium-channel lesion.
  phenotype_term:
    preferred_term: Cardiac conduction abnormality
    term:
      id: HP:0031546
      label: Cardiac conduction abnormality
  evidence:
  - reference: PMID:15671429
    reference_title: "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation scans identified a missense mutation (D1275N) that cosegregated with
      an age-dependent, variably expressed phenotype of DCM, atrial fibrillation,
      impaired automaticity, and conduction delay.
    explanation: >-
      Documents conduction delay and impaired automaticity in carriers of the
      founding allele.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    Progressive systolic dysfunction produces heart failure in a subset of carriers.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:15671429
    reference_title: "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similar or even identical mutations may lead to heart failure, arrhythmia, or
      both.
    explanation: >-
      Documents heart failure as one of the two possible dominant presentations.
genetic:
- name: SCN5A
  gene_term:
    preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  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_53c90d2e-4d40-48ab-8761-b0158102c977-2025-05-30T160000.000Z
    reference_title: "SCN5A / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SCN5A | HGNC:10593 | dilated cardiomyopathy | MONDO:0005021 | AD |
      Definitive
    explanation: >-
      ClinGen'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:15671429
    reference_title: "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation scans identified a missense mutation (D1275N) that cosegregated
      with an age-dependent, variably expressed phenotype of DCM, atrial
      fibrillation, impaired automaticity, and conduction delay.
    explanation: >-
      Cosegregation of the D1275N allele with the composite
      dilated-cardiomyopathy, atrial-fibrillation and conduction phenotype is
      the founding gene-disease observation for this entry.
  - reference: PMID:15671429
    reference_title: "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heritable SCN5A defects are associated with susceptibility to
      early-onset DCM and atrial fibrillation.
    explanation: >-
      States the gene-disease relationship in susceptibility terms, which
      together with the incomplete penetrance recorded under inheritance is
      why the allele is curated as causative with variable expression rather
      than fully penetrant.
treatments:
- name: Heart Failure Pharmacotherapy
  description: >-
    Standard guideline-directed heart-failure therapy for the structural arm.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Rhythm and Conduction Management
  description: >-
    Management of atrial fibrillation and conduction disease, including
    anticoagulation where indicated and pacing for symptomatic bradyarrhythmia,
    addresses the electrical arm of the phenotype.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: pacemaker placement
    term:
      id: NCIT:C80434
      label: Pacemaker Placement
references:
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
notes: >-
  CMD1E is the SCN5A member of the numbered dilated cardiomyopathy series and
  carries ClinGen Definitive gene-disease validity. It conforms to the shared
  cardiomyopathy_maladaptive_remodeling module.

  It is the mechanistic outlier of the series and is curated as such. Every other
  member's causal protein has a structural, regulatory or maintenance role in the
  cardiomyocyte; SCN5A encodes an ion channel, and its other alleles cause the
  primary channelopathies curated elsewhere here - Brugada syndrome and Progressive
  Cardiac Conduction Disease. The entity therefore sits at the boundary between
  electrical and structural heart disease.

  Two caveats preserved rather than smoothed over. (1) The link from the channel
  defect to ventricular dilation is curated as
  INDIRECT_UNKNOWN_INTERMEDIATES: the association is well established but the
  intervening mechanism is not, and the supporting evidence that a monogenic channel
  defect can drive structural change comes from a model of the *conduction-disease*
  phenotype, so it is marked PARTIAL. (2) The founding study's own caution is
  curated on the endpoint node - similar or even identical SCN5A mutations may lead
  to heart failure, arrhythmia, or both - so this entry does not claim that genotype
  predicts which arm dominates.

  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 SCN5A cohort and pedigree literature
  cited throughout, principally PMID:15671429.
📚

References & Deep Research

References

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