Paroxysmal Familial Ventricular Fibrillation

Genetic MONDO:0100234 Pathograph 8 Show in embeddings browser Cardiac Arrhythmia Channelopathy

Paroxysmal familial ventricular fibrillation is an inherited primary electrical disease (cardiac channelopathy) in which ventricular fibrillation arises in a structurally normal heart, without the diagnostic features of long QT, short QT, or Brugada syndrome. It is the familial, Mendelian subset of idiopathic ventricular fibrillation (IVF), in which life-threatening polymorphic ventricular arrhythmia and aborted or fatal sudden cardiac death occur at a young age with a normal resting electrocardiogram and no overt repolarization syndrome. Two gene-defined forms are recognized: an SCN5A-associated form (type 1) overlapping the cardiac sodium-channelopathy spectrum, and a DPP6-associated form (type 2) caused by cardiac overexpression of the transient-outward-current accessory subunit DPP6, which selectively accelerates Purkinje-fiber repolarization. The entry treats the parent concept (MONDO:0100234) as the disease root and the numbered loci as gene-axis subtypes, consistent with the dismech lumping convention for channelopathy series.

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1
Mappings
5
Pathophys.
4
Phenotypes
8
Pathograph
2
Genes
3
Medical Actions
2
Subtypes
🏷

Classifications

Channelopathy
cardiac channelopathy
🔗

Mappings

MONDO
MONDO:0100234 paroxysmal familial ventricular fibrillation
skos:exactMatch MONDO
Primary MONDO disease identifier for the paroxysmal familial ventricular fibrillation root entry.
◆

Subtypes

2
Ventricular fibrillation, paroxysmal familial, type 1 (SCN5A) MONDO:0011376
SCN5A hgnc:10593
SCN5A-associated form, the first molecularly defined familial idiopathic ventricular fibrillation locus. Cardiac sodium-channel (NaV1.5) dysfunction alters channel gating and inward sodium current, contributing to the arrhythmogenic substrate in a structurally normal heart. This locus overlaps the broader SCN5A-related cardiac rhythm disorder spectrum (including Brugada syndrome), and clinical/genetic boundaries between these SCN5A phenotypes are not always sharp.
Show evidence (1 reference)
PMID:9521325 SUPPORT Human Clinical
"We have now identified a missense mutation, a splice-donor mutation, and a frameshift mutation in the coding region of SCN5A in three IVF families."
Original identification of SCN5A as a cause of familial idiopathic ventricular fibrillation, establishing the SCN5A-associated locus.
Ventricular fibrillation, paroxysmal familial, 2 (DPP6) MONDO:0013063
DPP6 hgnc:3010
DPP6-associated form, caused by a chromosome 7q36 risk haplotype that drives cardiac overexpression of DPP6, an accessory subunit of the transient outward potassium current (Ito). DPP6 gain of function selectively enhances Purkinje-fiber Ito and accelerates Purkinje repolarization, producing a Purkinje-system early-repolarization substrate for ventricular fibrillation. Arrhythmic events characteristically occur at rest in a structurally normal heart with high penetrance.
Show evidence (1 reference)
PMID:19285295 SUPPORT Human Clinical
"We propose DPP6 as a gene for IVF and increased DPP6 expression as the likely pathogenetic mechanism."
Establishes DPP6 (with increased expression) as the cause of the type 2 familial idiopathic ventricular fibrillation locus.
⚙

Pathophysiology

5
Cardiac Ion-Channel Variant
Paroxysmal familial ventricular fibrillation originates in an inherited cardiac ion-channel defect in a structurally normal heart. In the type 1 form, SCN5A variants perturb the cardiac sodium channel (NaV1.5) and inward sodium current; in the type 2 form, a 7q36 risk haplotype drives a large increase in DPP6, an accessory subunit of the transient outward potassium current. Both converge on an inherited primary electrical (channelopathy) lesion rather than a structural cardiomyopathy.
cardiomyocyte CL:0000746 cardiac Purkinje fiber cell CL:0002068
potassium ion transport GO:0006813 ⚠ ABNORMAL sodium ion transport GO:0006814 ⚠ ABNORMAL
monoatomic ion channel activity GO:0005216 ⚠ ABNORMAL
Downstream
Accelerated Purkinje Repolarization and Altered Excitability The ion-channel lesion changes Purkinje-fiber and ventricular action-potential currents, altering repolarization and excitability.
Show evidence (2 references)
PMID:19285295 SUPPORT Human Clinical
"The shared chromosomal segment harbors part of the DPP6 gene, which encodes a putative component of the transient outward current in the heart."
Identifies the DPP6-encoded transient-outward-current component as the inherited ion-channel lesion underlying the type 2 form.
PMID:9521325 SUPPORT Human Clinical
"Our results indicate that mutations in cardiac ion-channel genes contribute to the risk of developing IVF."
Supports an inherited cardiac ion-channel defect as the primary lesion in familial idiopathic ventricular fibrillation.
Accelerated Purkinje Repolarization and Altered Excitability
The molecular lesion is translated into altered cellular electrophysiology. In the DPP6 (type 2) form, DPP6 overexpression selectively augments Purkinje-fiber transient outward current, accelerating Purkinje repolarization and producing a Purkinje-system early-repolarization phenotype; in the SCN5A (type 1) form, altered sodium-channel gating changes excitability and recovery. The result is regional heterogeneity of action-potential repolarization that destabilizes the ventricle.
cardiac Purkinje fiber cell CL:0002068 ventricular cardiomyocyte CL:2000046
membrane repolarization GO:0086009 ↑ INCREASED cardiac muscle cell action potential GO:0086001 ⚠ ABNORMAL
Downstream
Arrhythmogenic Substrate and Triggered Activity Heterogeneous, accelerated Purkinje repolarization creates dispersion of repolarization and triggered ectopy that initiate ventricular fibrillation.
Show evidence (2 references)
PMID:23532596 SUPPORT In Vitro
"DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I(to) density and tetraethylammonium sensitivity in canine PF but not in ventricular muscle cells."
Demonstrates that DPP6 gain of function selectively enhances Purkinje-fiber transient outward current, the cellular mechanism of the type 2 form.
PMID:23532596 SUPPORT Computational
"A mathematical model of cardiac PF action potentials showed that I(to) enhancement can greatly accelerate PF repolarization."
In silico modeling links enhanced Purkinje Ito to accelerated Purkinje-fiber repolarization, the basis of the early-repolarization substrate.
Arrhythmogenic Substrate and Triggered Activity
Regional dispersion of repolarization, dominated by the Purkinje-conduction system in the DPP6 form, provides the arrhythmogenic substrate. Premature ventricular complexes arising from the Purkinje system act as triggers that initiate reentry and degenerate into ventricular fibrillation. Events characteristically occur at rest in a structurally normal heart, with DPP6 additionally implicated in autonomic modulation of arrhythmia onset.
cardiac Purkinje fiber cell CL:0002068 ventricular cardiomyocyte CL:2000046
regulation of cardiac conduction GO:1903779 ↕ DYSREGULATED membrane repolarization during ventricular cardiac muscle cell action potential GO:0098915 ⚠ ABNORMAL
Downstream
Ventricular Fibrillation Triggered Purkinje ectopy acting on a dispersed-repolarization substrate degenerates into ventricular fibrillation.
Show evidence (2 references)
PMID:23532596 SUPPORT In Vitro
"and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of idiopathic ventricular fibrillation."
Frames a Purkinje-fiber early-repolarization substrate as the proposed arrhythmogenic mechanism for the DPP6 form.
PMID:34757187 SUPPORT Human Clinical
"Sixteen of 17 VF episodes occurred at rest."
Documents the rest-triggered arrhythmia pattern characteristic of DPP6 risk-haplotype carriers.
Ventricular Fibrillation
The defining arrhythmia is paroxysmal ventricular fibrillation occurring in a structurally normal heart. It presents as aborted or fatal cardiac arrest and is the proximate cause of the syndrome's high mortality.
ventricular cardiomyocyte CL:2000046
cardiac conduction GO:0061337 ⚠ ABNORMAL
Downstream
Syncope and Sudden Cardiac Death Sustained ventricular fibrillation abolishes effective cardiac output, producing syncope and, if not terminated, sudden cardiac death.
Show evidence (1 reference)
PMID:19285295 SUPPORT Human Clinical
"Idiopathic Ventricular Fibrillation (IVF) is defined as spontaneous VF without any known structural or electrical heart disease."
Establishes spontaneous ventricular fibrillation in a structurally normal heart as the defining clinical event.
Syncope and Sudden Cardiac Death
Loss of effective cardiac output from sustained ventricular fibrillation causes transient cerebral hypoperfusion (syncope) and, when the arrhythmia does not self-terminate, sudden cardiac death. In familial idiopathic ventricular fibrillation these endpoints occur at young age and with high penetrance, frequently as the sentinel manifestation.
Show evidence (1 reference)
PMID:19285295 SUPPORT Human Clinical
"Penetrance of IVF was high; 50% of risk-haplotype carriers experienced (aborted) sudden cardiac death before the age of 58 years."
Documents the high penetrance and young-onset (aborted) sudden cardiac death that define the clinical outcome.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Paroxysmal Familial Ventricular Fibrillation 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
Ventricular fibrillation Cardiovascular HP:0001663
Show evidence (1 reference)
PMID:19285295 SUPPORT Human Clinical
"Idiopathic Ventricular Fibrillation (IVF) is defined as spontaneous VF without any known structural or electrical heart disease."
Supports spontaneous ventricular fibrillation in a structurally normal heart as the hallmark phenotype.
Cardiac arrest Cardiovascular HP:0001695
Show evidence (1 reference)
PMID:31114860 SUPPORT Human Clinical
"Idiopathic ventricular fibrillation (IVF) is a rare cause of sudden cardiac arrest."
Supports sudden cardiac arrest as the characteristic clinical presentation of idiopathic ventricular fibrillation.
Sudden cardiac death Cardiovascular HP:0001645
Show evidence (1 reference)
PMID:19285295 SUPPORT Human Clinical
"Penetrance of IVF was high; 50% of risk-haplotype carriers experienced (aborted) sudden cardiac death before the age of 58 years."
Supports young-onset sudden cardiac death with high penetrance as a core phenotype.
Syncope Cardiovascular HP:0001279
🧬

Genetic Associations

2
DPP6 overexpression risk haplotype (Causative)
Gene: DPP6 hgnc:3010 relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:19285295 SUPPORT Human Clinical
"We demonstrated a 20-fold increase in DPP6 mRNA levels in the myocardium of carriers as compared to controls."
Quantifies the cardiac DPP6 overexpression that defines the type 2 risk haplotype.
PMID:34757187 SUPPORT Human Clinical
"A recently discovered sudden cardiac arrest (SCA) syndrome is linked to a risk haplotype that harbors the dipeptidyl-peptidase 6 (DPP6) gene as a plausible culprit."
Independent confirmation that the DPP6 risk haplotype underlies this inherited sudden cardiac arrest syndrome.
SCN5A variants (Causative)
Gene: SCN5A hgnc:10593 relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:9521325 SUPPORT In Vitro
"We show that sodium channels with the missense mutation recover from inactivation more rapidly than normal and that the frameshift mutation causes the sodium channel to be non-functional."
Defines the SCN5A gating defects underlying the type 1 form; the functional characterization was performed in Xenopus oocytes (heterologous expression system).
💊

Medical Actions

3
Implantable cardioverter-defibrillator placement
Action: implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435
Implantable cardioverter-defibrillator (ICD) implantation is the mainstay of treatment, providing protection against sudden death from recurrent ventricular fibrillation. In idiopathic ventricular fibrillation it is currently the only definitive treatment option.
Mechanism Target:
MODULATES Ventricular Fibrillation — The ICD detects and terminates ventricular fibrillation with defibrillation shocks, preventing sudden cardiac death without altering the underlying arrhythmogenic substrate.
Show evidence (1 reference)
PMID:31114860 SUPPORT Human Clinical
"Implantable cardioverter-defibrillator (ICD) implantation is currently the only treatment option."
Supports ICD implantation as the primary established treatment for idiopathic ventricular fibrillation.
Quinidine
Action: Pharmacotherapy NCIT:C15986
Agent: quinidine CHEBI:28593
Quinidine is used as antiarrhythmic pharmacotherapy to suppress recurrent ventricular fibrillation and electrical storm in idiopathic ventricular fibrillation, particularly as an adjunct to ICD therapy. It blocks the transient outward potassium current (Ito), the current augmented in the DPP6 form.
Mechanism Target:
INHIBITS Accelerated Purkinje Repolarization and Altered Excitability — Quinidine blocks the transient outward potassium current (Ito), opposing the DPP6-driven enhancement of Purkinje-fiber Ito and its accelerated repolarization.
Show evidence (1 reference)
PMID:40750064 SUPPORT Other
"ventricular arrhythmias occurring in patients with no organic heart disease (Idiopathic ventricular fibrillation, Brugada syndrome, Early repolarization syndrome, Short QT syndrome, Multifocal ectopic Purkinje-related premature contractions)"
Supports quinidine as a recognized antiarrhythmic option for idiopathic ventricular fibrillation and related primary electrical syndromes.
Cardiac ablation of Purkinje triggers
Action: cardiac ablation Ontology label: Cardiac Ablation NCIT:C100068
Catheter ablation targeting Purkinje-system premature ventricular complexes that trigger ventricular fibrillation is used in selected patients with recurrent, trigger-dependent arrhythmia, consistent with the Purkinje-system origin implicated in the DPP6 form.
Mechanism Target:
INHIBITS Arrhythmogenic Substrate and Triggered Activity — Ablating Purkinje-derived premature complexes removes the triggers that initiate ventricular fibrillation on the dispersed-repolarization substrate.
Show evidence (1 reference)
PMID:23532596 SUPPORT Human Clinical
"Clinical data in 5 idiopathic ventricular fibrillation patients suggested arrhythmia origin in the PF-conducting system."
Supports the Purkinje-system (PF-conducting system) origin of arrhythmia that rationalizes ablation of Purkinje triggers.
{ }

Source YAML

click to show 
name: Paroxysmal Familial Ventricular Fibrillation
creation_date: '2026-06-14T00:00:00Z'
description: >-
  Paroxysmal familial ventricular fibrillation is an inherited primary
  electrical disease (cardiac channelopathy) in which ventricular fibrillation
  arises in a structurally normal heart, without the diagnostic features of
  long QT, short QT, or Brugada syndrome. It is the familial, Mendelian subset
  of idiopathic ventricular fibrillation (IVF), in which life-threatening
  polymorphic ventricular arrhythmia and aborted or fatal sudden cardiac death
  occur at a young age with a normal resting electrocardiogram and no overt
  repolarization syndrome. Two gene-defined forms are recognized: an
  SCN5A-associated form (type 1) overlapping the cardiac sodium-channelopathy
  spectrum, and a DPP6-associated form (type 2) caused by cardiac
  overexpression of the transient-outward-current accessory subunit DPP6, which
  selectively accelerates Purkinje-fiber repolarization. The entry treats the
  parent concept (MONDO:0100234) as the disease root and the numbered loci as
  gene-axis subtypes, consistent with the dismech lumping convention for
  channelopathy series.
synonyms:
- PFVF
- Familial idiopathic ventricular fibrillation
- Paroxysmal familial ventricular fibrillation
category: Genetic
disease_term:
  preferred_term: Paroxysmal familial ventricular fibrillation
  term:
    id: MONDO:0100234
    label: paroxysmal familial ventricular fibrillation
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0100234
      label: paroxysmal familial ventricular fibrillation
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for the paroxysmal familial ventricular fibrillation root entry.
parents:
- Cardiac Arrhythmia
- Channelopathy
classifications:
  channelopathy_category:
    classification_value: cardiac channelopathy
has_subtypes:
- name: Type 1
  display_name: Ventricular fibrillation, paroxysmal familial, type 1 (SCN5A)
  subtype_term:
    preferred_term: Ventricular fibrillation, paroxysmal familial, type 1
    term:
      id: MONDO:0011376
      label: ventricular fibrillation, paroxysmal familial, type 1
  description: >-
    SCN5A-associated form, the first molecularly defined familial idiopathic
    ventricular fibrillation locus. Cardiac sodium-channel (NaV1.5) dysfunction
    alters channel gating and inward sodium current, contributing to the
    arrhythmogenic substrate in a structurally normal heart. This locus
    overlaps the broader SCN5A-related cardiac rhythm disorder spectrum
    (including Brugada syndrome), and clinical/genetic boundaries between these
    SCN5A phenotypes are not always sharp.
  genes:
  - preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  evidence:
  - reference: PMID:9521325
    reference_title: Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have now identified a missense mutation, a splice-donor mutation, and a frameshift mutation in the coding region of SCN5A in three IVF families."
    explanation: Original identification of SCN5A as a cause of familial idiopathic ventricular fibrillation, establishing the SCN5A-associated locus.
- name: Type 2
  display_name: Ventricular fibrillation, paroxysmal familial, 2 (DPP6)
  subtype_term:
    preferred_term: Ventricular fibrillation, paroxysmal familial, 2
    term:
      id: MONDO:0013063
      label: ventricular fibrillation, paroxysmal familial, 2
  description: >-
    DPP6-associated form, caused by a chromosome 7q36 risk haplotype that
    drives cardiac overexpression of DPP6, an accessory subunit of the
    transient outward potassium current (Ito). DPP6 gain of function
    selectively enhances Purkinje-fiber Ito and accelerates Purkinje
    repolarization, producing a Purkinje-system early-repolarization substrate
    for ventricular fibrillation. Arrhythmic events characteristically occur at
    rest in a structurally normal heart with high penetrance.
  genes:
  - preferred_term: DPP6
    term:
      id: hgnc:3010
      label: DPP6
  evidence:
  - reference: PMID:19285295
    reference_title: Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose DPP6 as a gene for IVF and increased DPP6 expression as the likely pathogenetic mechanism."
    explanation: Establishes DPP6 (with increased expression) as the cause of the type 2 familial idiopathic ventricular fibrillation locus.
pathophysiology:
- name: Cardiac Ion-Channel Variant
  conforms_to: "cardiac_ion_channel_repolarization#Cardiac Ion-Channel or Calcium-Handling Variant"
  role: trigger
  description: >-
    Paroxysmal familial ventricular fibrillation originates in an inherited
    cardiac ion-channel defect in a structurally normal heart. In the type 1
    form, SCN5A variants perturb the cardiac sodium channel (NaV1.5) and inward
    sodium current; in the type 2 form, a 7q36 risk haplotype drives a large
    increase in DPP6, an accessory subunit of the transient outward potassium
    current. Both converge on an inherited primary electrical (channelopathy)
    lesion rather than a structural cardiomyopathy.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: cardiac Purkinje fiber cell
    term:
      id: CL:0002068
      label: Purkinje myocyte
  molecular_functions:
  - preferred_term: monoatomic ion channel activity
    term:
      id: GO:0005216
      label: monoatomic ion channel activity
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: potassium ion transport
    term:
      id: GO:0006813
      label: potassium ion transport
    modifier: ABNORMAL
  - preferred_term: sodium ion transport
    term:
      id: GO:0006814
      label: sodium ion transport
    modifier: ABNORMAL
  evidence:
  - reference: PMID:19285295
    reference_title: Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The shared chromosomal segment harbors part of the DPP6 gene, which encodes a putative component of the transient outward current in the heart."
    explanation: Identifies the DPP6-encoded transient-outward-current component as the inherited ion-channel lesion underlying the type 2 form.
  - reference: PMID:9521325
    reference_title: Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results indicate that mutations in cardiac ion-channel genes contribute to the risk of developing IVF."
    explanation: Supports an inherited cardiac ion-channel defect as the primary lesion in familial idiopathic ventricular fibrillation.
  downstream:
  - target: Accelerated Purkinje Repolarization and Altered Excitability
    description: The ion-channel lesion changes Purkinje-fiber and ventricular action-potential currents, altering repolarization and excitability.
- name: Accelerated Purkinje Repolarization and Altered Excitability
  conforms_to: "cardiac_ion_channel_repolarization#Altered Action Potential and Calcium Handling"
  role: amplifier
  description: >-
    The molecular lesion is translated into altered cellular electrophysiology.
    In the DPP6 (type 2) form, DPP6 overexpression selectively augments
    Purkinje-fiber transient outward current, accelerating Purkinje
    repolarization and producing a Purkinje-system early-repolarization
    phenotype; in the SCN5A (type 1) form, altered sodium-channel gating
    changes excitability and recovery. The result is regional heterogeneity of
    action-potential repolarization that destabilizes the ventricle.
  cell_types:
  - preferred_term: cardiac Purkinje fiber cell
    term:
      id: CL:0002068
      label: Purkinje myocyte
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:2000046
      label: ventricular cardiac muscle cell
  biological_processes:
  - preferred_term: membrane repolarization
    term:
      id: GO:0086009
      label: membrane repolarization
    modifier: INCREASED
  - preferred_term: cardiac muscle cell action potential
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
    modifier: ABNORMAL
  evidence:
  - reference: PMID:23532596
    reference_title: "Unique cardiac Purkinje fiber transient outward current β-subunit composition: a potential molecular link to idiopathic ventricular fibrillation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I(to) density and tetraethylammonium sensitivity in canine PF but not in ventricular muscle cells."
    explanation: Demonstrates that DPP6 gain of function selectively enhances Purkinje-fiber transient outward current, the cellular mechanism of the type 2 form.
  - reference: PMID:23532596
    reference_title: "Unique cardiac Purkinje fiber transient outward current β-subunit composition: a potential molecular link to idiopathic ventricular fibrillation."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "A mathematical model of cardiac PF action potentials showed that I(to) enhancement can greatly accelerate PF repolarization."
    explanation: In silico modeling links enhanced Purkinje Ito to accelerated Purkinje-fiber repolarization, the basis of the early-repolarization substrate.
  downstream:
  - target: Arrhythmogenic Substrate and Triggered Activity
    description: Heterogeneous, accelerated Purkinje repolarization creates dispersion of repolarization and triggered ectopy that initiate ventricular fibrillation.
- name: Arrhythmogenic Substrate and Triggered Activity
  conforms_to: "cardiac_ion_channel_repolarization#Arrhythmogenic Substrate and Triggered Activity"
  role: amplifier
  description: >-
    Regional dispersion of repolarization, dominated by the Purkinje-conduction
    system in the DPP6 form, provides the arrhythmogenic substrate. Premature
    ventricular complexes arising from the Purkinje system act as triggers that
    initiate reentry and degenerate into ventricular fibrillation. Events
    characteristically occur at rest in a structurally normal heart, with DPP6
    additionally implicated in autonomic modulation of arrhythmia onset.
  cell_types:
  - preferred_term: cardiac Purkinje fiber cell
    term:
      id: CL:0002068
      label: Purkinje myocyte
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:2000046
      label: ventricular cardiac muscle cell
  biological_processes:
  - preferred_term: regulation of cardiac conduction
    term:
      id: GO:1903779
      label: regulation of cardiac conduction
    modifier: DYSREGULATED
  - preferred_term: membrane repolarization during ventricular cardiac muscle cell action potential
    term:
      id: GO:0098915
      label: membrane repolarization during ventricular cardiac muscle cell action potential
    modifier: ABNORMAL
  evidence:
  - reference: PMID:23532596
    reference_title: "Unique cardiac Purkinje fiber transient outward current β-subunit composition: a potential molecular link to idiopathic ventricular fibrillation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of idiopathic ventricular fibrillation."
    explanation: Frames a Purkinje-fiber early-repolarization substrate as the proposed arrhythmogenic mechanism for the DPP6 form.
  - reference: PMID:34757187
    reference_title: An inherited sudden cardiac arrest syndrome may be based on primary myocardial and autonomic nervous system abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sixteen of 17 VF episodes occurred at rest."
    explanation: Documents the rest-triggered arrhythmia pattern characteristic of DPP6 risk-haplotype carriers.
  downstream:
  - target: Ventricular Fibrillation
    description: Triggered Purkinje ectopy acting on a dispersed-repolarization substrate degenerates into ventricular fibrillation.
- name: Ventricular Fibrillation
  conforms_to: "cardiac_ion_channel_repolarization#Ventricular Tachyarrhythmia"
  role: effector
  description: >-
    The defining arrhythmia is paroxysmal ventricular fibrillation occurring in
    a structurally normal heart. It presents as aborted or fatal cardiac arrest
    and is the proximate cause of the syndrome's high mortality.
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:2000046
      label: ventricular cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:19285295
    reference_title: Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Idiopathic Ventricular Fibrillation (IVF) is defined as spontaneous VF without any known structural or electrical heart disease."
    explanation: Establishes spontaneous ventricular fibrillation in a structurally normal heart as the defining clinical event.
  downstream:
  - target: Syncope and Sudden Cardiac Death
    description: Sustained ventricular fibrillation abolishes effective cardiac output, producing syncope and, if not terminated, sudden cardiac death.
- name: Syncope and Sudden Cardiac Death
  conforms_to: "cardiac_ion_channel_repolarization#Syncope and Sudden Cardiac Death"
  role: outcome
  description: >-
    Loss of effective cardiac output from sustained ventricular fibrillation
    causes transient cerebral hypoperfusion (syncope) and, when the arrhythmia
    does not self-terminate, sudden cardiac death. In familial idiopathic
    ventricular fibrillation these endpoints occur at young age and with high
    penetrance, frequently as the sentinel manifestation.
  evidence:
  - reference: PMID:19285295
    reference_title: Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Penetrance of IVF was high; 50% of risk-haplotype carriers experienced (aborted) sudden cardiac death before the age of 58 years."
    explanation: Documents the high penetrance and young-onset (aborted) sudden cardiac death that define the clinical outcome.
phenotypes:
- category: Cardiovascular
  name: Ventricular fibrillation
  diagnostic: true
  description: >-
    Spontaneous, paroxysmal ventricular fibrillation in a structurally normal
    heart is the defining manifestation of familial idiopathic ventricular
    fibrillation.
  phenotype_term:
    preferred_term: Ventricular fibrillation
    term:
      id: HP:0001663
      label: Ventricular fibrillation
  evidence:
  - reference: PMID:19285295
    reference_title: Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Idiopathic Ventricular Fibrillation (IVF) is defined as spontaneous VF without any known structural or electrical heart disease."
    explanation: Supports spontaneous ventricular fibrillation in a structurally normal heart as the hallmark phenotype.
- category: Cardiovascular
  name: Cardiac arrest
  description: >-
    Aborted or fatal sudden cardiac arrest is the typical presentation, often
    occurring at rest in a previously asymptomatic young individual.
  phenotype_term:
    preferred_term: Cardiac arrest
    term:
      id: HP:0001695
      label: Cardiac arrest
  evidence:
  - reference: PMID:31114860
    reference_title: Incidence and predictors of implantable cardioverter-defibrillator therapy and its complications in idiopathic ventricular fibrillation patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Idiopathic ventricular fibrillation (IVF) is a rare cause of sudden cardiac arrest."
    explanation: Supports sudden cardiac arrest as the characteristic clinical presentation of idiopathic ventricular fibrillation.
- category: Cardiovascular
  name: Sudden cardiac death
  description: >-
    Sudden cardiac death results when paroxysmal ventricular fibrillation is
    not promptly terminated; in familial forms it occurs at young age with high
    penetrance.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:19285295
    reference_title: Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Penetrance of IVF was high; 50% of risk-haplotype carriers experienced (aborted) sudden cardiac death before the age of 58 years."
    explanation: Supports young-onset sudden cardiac death with high penetrance as a core phenotype.
- category: Cardiovascular
  name: Syncope
  description: >-
    Syncope from self-terminating ventricular fibrillation is a common
    presenting symptom in paroxysmal familial ventricular fibrillation.
    Transient loss of consciousness results from cerebral hypoperfusion when
    VF briefly abolishes effective cardiac output before spontaneous
    termination; such events frequently precede recognized cardiac arrest and
    correspond to the "Syncope and Sudden Cardiac Death" pathophysiology node
    outcome.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
genetic:
- name: DPP6 overexpression risk haplotype
  association: Causative
  relationship_type: CAUSATIVE
  subtype: Type 2
  features: >-
    A conserved chromosome 7q36 risk haplotype causes cardiac overexpression of
    DPP6, an accessory subunit of the transient outward potassium current. The
    increased expression (rather than a coding loss-of-function) is the proposed
    pathogenetic mechanism, selectively enhancing Purkinje-fiber Ito.
  gene_term:
    preferred_term: DPP6
    term:
      id: hgnc:3010
      label: DPP6
  evidence:
  - reference: PMID:19285295
    reference_title: Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We demonstrated a 20-fold increase in DPP6 mRNA levels in the myocardium of carriers as compared to controls."
    explanation: Quantifies the cardiac DPP6 overexpression that defines the type 2 risk haplotype.
  - reference: PMID:34757187
    reference_title: An inherited sudden cardiac arrest syndrome may be based on primary myocardial and autonomic nervous system abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A recently discovered sudden cardiac arrest (SCA) syndrome is linked to a risk haplotype that harbors the dipeptidyl-peptidase 6 (DPP6) gene as a plausible culprit."
    explanation: Independent confirmation that the DPP6 risk haplotype underlies this inherited sudden cardiac arrest syndrome.
- name: SCN5A variants
  association: Causative
  relationship_type: CAUSATIVE
  subtype: Type 1
  features: >-
    Pathogenic SCN5A variants alter cardiac sodium-channel (NaV1.5) gating and
    current. The original report identified missense, splice-donor, and
    frameshift variants in idiopathic ventricular fibrillation families, with
    one missense variant accelerating recovery from inactivation and the
    frameshift abolishing channel function. This locus overlaps the broader
    SCN5A-related cardiac rhythm disorder spectrum.
  gene_term:
    preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  evidence:
  - reference: PMID:9521325
    reference_title: Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that sodium channels with the missense mutation recover from inactivation more rapidly than normal and that the frameshift mutation causes the sodium channel to be non-functional."
    explanation: Defines the SCN5A gating defects underlying the type 1 form; the functional characterization was performed in Xenopus oocytes (heterologous expression system).
treatments:
- name: Implantable cardioverter-defibrillator placement
  description: >-
    Implantable cardioverter-defibrillator (ICD) implantation is the mainstay
    of treatment, providing protection against sudden death from recurrent
    ventricular fibrillation. In idiopathic ventricular fibrillation it is
    currently the only definitive treatment option.
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  evidence:
  - reference: PMID:31114860
    reference_title: Incidence and predictors of implantable cardioverter-defibrillator therapy and its complications in idiopathic ventricular fibrillation patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Implantable cardioverter-defibrillator (ICD) implantation is currently the only treatment option."
    explanation: Supports ICD implantation as the primary established treatment for idiopathic ventricular fibrillation.
  target_mechanisms:
  - target: Ventricular Fibrillation
    treatment_effect: MODULATES
    description: >-
      The ICD detects and terminates ventricular fibrillation with
      defibrillation shocks, preventing sudden cardiac death without altering
      the underlying arrhythmogenic substrate.
- name: Quinidine
  description: >-
    Quinidine is used as antiarrhythmic pharmacotherapy to suppress recurrent
    ventricular fibrillation and electrical storm in idiopathic ventricular
    fibrillation, particularly as an adjunct to ICD therapy. It blocks the
    transient outward potassium current (Ito), the current augmented in the
    DPP6 form.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: quinidine
      term:
        id: CHEBI:28593
        label: quinidine
  evidence:
  - reference: PMID:40750064
    reference_title: Theory and practice of present clinical use of Quinidine in the management of cardiac arrhythmias.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ventricular arrhythmias occurring in patients with no organic heart disease (Idiopathic ventricular fibrillation, Brugada syndrome, Early repolarization syndrome, Short QT syndrome, Multifocal ectopic Purkinje-related premature contractions)"
    explanation: Supports quinidine as a recognized antiarrhythmic option for idiopathic ventricular fibrillation and related primary electrical syndromes.
  target_mechanisms:
  - target: Accelerated Purkinje Repolarization and Altered Excitability
    treatment_effect: INHIBITS
    description: >-
      Quinidine blocks the transient outward potassium current (Ito), opposing
      the DPP6-driven enhancement of Purkinje-fiber Ito and its accelerated
      repolarization.
- name: Cardiac ablation of Purkinje triggers
  description: >-
    Catheter ablation targeting Purkinje-system premature ventricular complexes
    that trigger ventricular fibrillation is used in selected patients with
    recurrent, trigger-dependent arrhythmia, consistent with the
    Purkinje-system origin implicated in the DPP6 form.
  treatment_term:
    preferred_term: cardiac ablation
    term:
      id: NCIT:C100068
      label: Cardiac Ablation
  evidence:
  - reference: PMID:23532596
    reference_title: "Unique cardiac Purkinje fiber transient outward current β-subunit composition: a potential molecular link to idiopathic ventricular fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical data in 5 idiopathic ventricular fibrillation patients suggested arrhythmia origin in the PF-conducting system."
    explanation: Supports the Purkinje-system (PF-conducting system) origin of arrhythmia that rationalizes ablation of Purkinje triggers.
  target_mechanisms:
  - target: Arrhythmogenic Substrate and Triggered Activity
    treatment_effect: INHIBITS
    description: >-
      Ablating Purkinje-derived premature complexes removes the triggers that
      initiate ventricular fibrillation on the dispersed-repolarization
      substrate.
notes: >-
  Curated as the gene-axis lumped root for paroxysmal familial ventricular
  fibrillation (MONDO:0100234) with two subtypes: type 1 = SCN5A-associated
  (MONDO:0011376; an is-a descendant of SCN5A-related cardiac rhythm disorder)
  and type 2 = DPP6-associated (MONDO:0013063). NOTE: gene-to-locus attribution
  was verified with OAK against MONDO RO:0004003/subClassOf, correcting the
  draft guidance in issue #4242, which had transposed the genes (it labeled
  type 1 as DPP6; MONDO classifies type 1 as SCN5A-related and type 2 as DPP6).
  This is a member of the Inherited Arrhythmia Syndromes grouping and conforms
  to the cardiac_ion_channel_repolarization module. The atrial-fibrillation and
  progressive-cardiac-conduction-disease arms surfaced in issue #4242 are
  deliberately NOT curated here; they remain gated on the maintainer
  broaden-vs-sibling-grouping scope decision.