Progressive Familial Heart Block

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Classifications

Channelopathy

🔗

Mappings

MONDO

MONDO:0019490 progressive familial heart block

Primary MONDO disease identifier for the progressive familial heart block root entry.

👪

Inheritance

1

Autosomal dominant HP:0000006

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:19726882 SUPPORT Human Clinical

"Progressive familial heart block type I (PFHBI) is a progressive cardiac bundle branch disease in the His-Purkinje system that exhibits autosomal-dominant inheritance."

Establishes autosomal-dominant inheritance for progressive familial heart block type I.

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Subtypes

2

Progressive familial heart block, type 1A (SCN5A) MONDO:0007240

SCN5A hgnc:10593

SCN5A-associated form (hereditary Lenègre disease), caused by loss-of-function variants in SCN5A producing haploinsufficiency for the cardiac sodium channel NaV1.5. Reduced peak inward sodium current slows conduction, and in combination with aging leads to progressive conduction impairment and myocardial fibrosis of the His-Purkinje system. This locus overlaps the broader SCN5A-related cardiac rhythm disorder spectrum (including Brugada syndrome and the cardiac sodium-channel overlap syndrome).

Show evidence (1 reference)

PMID:12598077 SUPPORT Human Clinical

"In a French family, we have identified a splicing mutation in the SCN5A gene leading to hereditary progressive cardiac conduction defect."

Identifies an SCN5A loss-of-function (splicing) variant as the cause of the SCN5A-associated (Lenègre) form of progressive cardiac conduction disease.

Progressive familial heart block, type 1B (TRPM4) MONDO:0011474

TRPM4 hgnc:17993

TRPM4-associated form, caused by gain-of-function variants in TRPM4, which encodes a Ca2+-activated nonselective cation channel most highly expressed in Purkinje fibers. Impaired channel endocytosis raises TRPM4 density at the cardiomyocyte surface, producing a His-Purkinje bundle-branch conduction disease with autosomal-dominant inheritance.

Show evidence (1 reference)

PMID:19726882 SUPPORT Human Clinical

"Progressive familial heart block type I (PFHBI) is a progressive cardiac bundle branch disease in the His-Purkinje system that exhibits autosomal-dominant inheritance."

Establishes the TRPM4-associated PFHB type I as an autosomal-dominant His-Purkinje bundle-branch conduction disease.

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Pathophysiology

5

Inherited Conduction-System Ion-Channel Defect

Progressive familial heart block originates in an inherited defect of a cardiac ion channel expressed in the conduction system. In the SCN5A (type 1A) form, loss-of-function variants cause haploinsufficiency for the cardiac sodium channel NaV1.5, reducing peak inward sodium current that drives the action-potential upstroke. In the TRPM4 (type 1B) form, gain-of-function variants impair channel endocytosis and increase surface density of the Ca2+-activated nonselective cation channel TRPM4, which is most highly expressed in Purkinje fibers. Both lesions perturb the excitability of conduction-system myocytes rather than producing a structural cardiomyopathy at onset.

cardiac muscle cell CL:0000746 cardiac Purkinje fiber cell CL:0002068 atrioventricular bundle (His) cell CL:0010005

membrane depolarization during action potential GO:0086010 ⚠ ABNORMAL

voltage-gated sodium channel activity GO:0005248 ↓ DECREASED

Downstream

Slowed His-Purkinje and Atrioventricular Conduction The channel defect reduces conduction-system excitability and propagation, slowing impulse conduction through the AV node and His-Purkinje system.

Show evidence (3 references)

PMID:12598077 SUPPORT In Vitro

"Functional studies show that the IVS.22+2 T-->C SCN5A mutation lead to exon 22 skipping and to a complete loss of function of the affected allele, but to a normal trafficking of the mutated gene product."

Demonstrates that the SCN5A variant produces a complete loss of function of the affected allele (haploinsufficiency), the molecular lesion of the type 1A form.

PMID:19726882 SUPPORT In Vitro

"The resulting constitutive SUMOylation of the mutant TRPM4 channel impaired endocytosis and led to elevated TRPM4 channel density at the cell surface."

Defines the TRPM4 gain-of-function lesion (elevated surface channel density from impaired endocytosis) underlying the type 1B form.

PMID:19726882 SUPPORT In Vitro

"Quantitative analysis of TRPM4 mRNA content in human cardiac tissue showed the highest expression level in Purkinje fibers."

Localizes the highest TRPM4 expression to Purkinje fibers, consistent with a His-Purkinje conduction-system lesion.

Slowed His-Purkinje and Atrioventricular Conduction

The ion-channel lesion is translated into slowed cardiac impulse conduction. Reduced sodium current (type 1A) lowers conduction velocity in the His-Purkinje system, while increased TRPM4-mediated background cation current (type 1B) disturbs Purkinje-fiber excitability. The cellular result is progressive prolongation of conduction intervals (P-wave, PR, and QRS) that worsens with age.

cardiac Purkinje fiber cell CL:0002068 atrioventricular bundle (His) cell CL:0010005

cardiac conduction GO:0061337 ↓ DECREASED regulation of cardiac conduction GO:1903779 ↕ DYSREGULATED

Downstream

Progressive His-Purkinje Fibrosis and Degeneration Chronically impaired conduction, in combination with aging, is accompanied by progressive structural degeneration and fibrosis of the conduction system.

Show evidence (2 references)

PMID:12598077 SUPPORT Human Clinical

"P-wave, PR, and QRS duration increased progressively with age in gene carriers"

Documents progressive, age-dependent prolongation of atrial and His-Purkinje conduction intervals in SCN5A gene carriers.

PMID:15809371 SUPPORT Model Organism

"In Scn5a+/- mice, surface ECG recordings showed age-related lengthening of the P-wave and PR- and QRS-interval duration, coinciding with previous observations in patients with Lenègre's disease."

A heterozygous Scn5a-knockout mouse recapitulates the age-related conduction slowing of human Lenègre disease.

Progressive His-Purkinje Fibrosis and Degeneration

In the Lenègre (SCN5A) form, the primary ion-channel defect, combined with aging, leads to progressive fibrosis and degeneration of the His bundle and its branches — the structural correlate that converts a subclinical conduction defect into advancing heart block. Mouse models demonstrate that a monogenic sodium-channel defect is sufficient to drive age-dependent myocardial fibrosis, establishing a channel-to-structure pathomechanism.

cardiac fibroblast CL:0002548 atrioventricular bundle (His) cell CL:0010005

extracellular matrix organization GO:0030198 ↑ INCREASED

Downstream

Progressive Atrioventricular and Bundle-Branch Block Combined conduction slowing and conduction-system fibrosis produce advancing bundle-branch and atrioventricular block.

Show evidence (3 references)

PMID:12598077 SUPPORT Human Clinical

"Progressive cardiac conduction defect is a frequent disease commonly attributed to degeneration and fibrosis of the His bundle and its branches."

States that progressive cardiac conduction defect is attributed to degeneration and fibrosis of the His bundle and its branches.

PMID:15809371 SUPPORT Model Organism

"Old but not young Scn5a+/- mice showed extensive fibrosis of their ventricular myocardium, a feature not seen in wild-type animals."

Shows age-dependent myocardial fibrosis in the SCN5A-haploinsufficient mouse model of Lenègre disease.

PMID:15809371 SUPPORT Model Organism

"Our work provides the first demonstration that a monogenic ion channel defect can progressively lead to myocardial structural anomalies."

Establishes that a monogenic ion-channel defect can progressively cause myocardial structural anomalies (fibrosis), linking the channel lesion to conduction-system degeneration.

Progressive Atrioventricular and Bundle-Branch Block

The defining manifestation is progressive conduction block: bundle-branch block and fascicular block advance over time to high-grade and complete atrioventricular block. The block is the proximate cause of bradyarrhythmia and the indication for pacing.

atrioventricular bundle (His) cell CL:0010005

cardiac conduction GO:0061337 ⚠ ABNORMAL

Downstream

Syncope and Sudden Cardiac Death High-grade or complete atrioventricular block causes bradyarrhythmia, transient cerebral hypoperfusion (syncope), and, when not paced, sudden cardiac death.

Show evidence (1 reference)

PMID:35205305 SUPPORT Human Clinical

"he was implanted with a PM for two episodes of syncope and the presence of complete atrioventricular block (AVB)."

Documents progression to complete atrioventricular block as the defining conduction-system endpoint in a PCCD family.

Syncope and Sudden Cardiac Death

High-grade and complete atrioventricular block produce bradyarrhythmia and ventricular asystole, causing syncope and Stokes-Adams attacks and, when the bradyarrhythmia is not corrected by pacing, sudden cardiac death. These endpoints define the clinical severity of progressive familial heart block and may be the sentinel manifestation.

Show evidence (1 reference)

PMID:35205305 SUPPORT Human Clinical

"whose younger brother died at 25 years of unexplained sudden cardiac death."

Documents young-onset sudden cardiac death within a familial progressive cardiac conduction disease pedigree.

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Pathograph

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Phenotypes

5

Cardiovascular 3

Atrioventricular block Atrioventricular block HP:0001678

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:35205305 SUPPORT Human Clinical

"he was implanted with a PM for two episodes of syncope and the presence of complete atrioventricular block (AVB)."

Supports complete atrioventricular block as a defining phenotype of progressive familial heart block.

Syncope Syncope HP:0001279

Show evidence (1 reference)

PMID:35205305 SUPPORT Human Clinical

"he was implanted with a PM for two episodes of syncope and the presence of complete atrioventricular block (AVB)."

Supports syncope as a clinical manifestation of high-grade atrioventricular block in PCCD.

Sudden cardiac death Sudden cardiac death HP:0001645

Show evidence (1 reference)

PMID:35205305 SUPPORT Human Clinical

"whose younger brother died at 25 years of unexplained sudden cardiac death."

Supports young-onset sudden cardiac death as an outcome within a PCCD pedigree.

Other 2

Bundle branch block Bundle branch block HP:0011710

Show evidence (1 reference)

PMID:19726882 SUPPORT Human Clinical

"Progressive familial heart block type I (PFHBI) is a progressive cardiac bundle branch disease in the His-Purkinje system that exhibits autosomal-dominant inheritance."

Supports progressive bundle-branch (His-Purkinje) conduction disease as a core phenotype.

Prolonged QRS complex Prolonged QRS complex HP:0006677

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:12598077 SUPPORT Human Clinical

"P-wave, PR, and QRS duration increased progressively with age in gene carriers"

Supports age-progressive QRS prolongation in SCN5A gene carriers.

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Genetic Associations

2

SCN5A loss-of-function variants (Causative)

Gene: SCN5A hgnc:10593 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:10471492 SUPPORT Human Clinical

"Cardiac conduction defects associate with mutations in SCN5A."

Seminal report establishing the association between SCN5A mutations and inherited cardiac conduction defects.

PMID:12598077 SUPPORT Human Clinical

"Our findings demonstrate that hereditary Lenègre disease is caused by a haploinsufficiency mechanism, which in combination with aging leads to progressive alteration in conduction velocity."

Establishes SCN5A haploinsufficiency, combined with aging, as the causative mechanism of the type 1A (Lenègre) form.

TRPM4 gain-of-function variants (Causative)

Gene: TRPM4 hgnc:17993 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:19726882 SUPPORT Human Clinical

"we identified the mutation c.19G-->A in the transient receptor potential cation channel, subfamily M, member 4 gene (TRPM4)"

Identifies the founding TRPM4 variant causing the type 1B form of progressive familial heart block.

PMID:35205305 SUPPORT Human Clinical

"Variations in TRPM4 have been shown to cause an increase in cell surface current density, which results in a gain of gene function."

Confirms the TRPM4 gain-of-function mechanism (increased surface current density) in progressive cardiac conduction disease.

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Medical Actions

1

Permanent pacemaker implantation

Action: pacemaker implantation MAXO:0009034

Permanent cardiac pacemaker implantation is the mainstay of treatment for symptomatic bradyarrhythmia and high-grade or complete atrioventricular block in progressive familial heart block. Pacing bypasses the failing conduction system to maintain ventricular rate and prevent syncope and bradyarrhythmic sudden death, but does not modify the underlying channel/conduction-system pathology.

Mechanism Target:

MODULATES Progressive Atrioventricular and Bundle-Branch Block — The pacemaker delivers electrical stimulation distal to the conduction block, maintaining ventricular activation and rate despite atrioventricular and bundle-branch block, without altering the underlying conduction-system lesion.

Show evidence (1 reference)

PMID:35205305 SUPPORT Human Clinical

"We describe a family with a large number of individuals necessitating pacemaker implantation, likely due to varying degrees of PCCD."

Supports pacemaker implantation as the established treatment for the conduction block of progressive cardiac conduction disease.

{ }

Source YAML

click to show

name: Progressive Familial Heart Block
creation_date: '2026-06-21T00:00:00Z'
description: >-
  Progressive familial heart block (PFHB), also called hereditary progressive
  cardiac conduction disease (PCCD) or Lenègre-Lev disease, is an inherited
  disorder of the cardiac conduction system characterized by age-dependent,
  progressive impairment of impulse propagation through the atrioventricular
  node and the His-Purkinje system. Conduction slows over decades from
  first-degree atrioventricular delay and bundle-branch block toward complete
  atrioventricular block, manifesting as syncope, Stokes-Adams attacks, and
  sudden cardiac death. Unlike the ventricular repolarization channelopathies,
  the primary lesion is reduced or dysregulated conduction (depolarization and
  cell-to-cell propagation) accompanied, in the Lenègre form, by progressive
  fibrosis and degeneration of the His bundle and its branches. Two
  molecularly defined gene-axis forms are recognized: a loss-of-function
  SCN5A-associated form (type 1A; haploinsufficiency for the cardiac sodium
  channel NaV1.5) and a gain-of-function TRPM4-associated form (type 1B;
  increased cell-surface density of the Ca2+-activated cation channel TRPM4 in
  the His-Purkinje system). The entry treats the parent concept
  (MONDO:0019490, progressive familial heart block) as the disease root and the
  numbered loci as gene-axis subtypes, consistent with the dismech lumping
  convention for inherited-arrhythmia series.
synonyms:
- PFHB
- Progressive cardiac conduction disease
- PCCD
- Lenègre-Lev disease
- Lenègre disease
- Hereditary bundle branch defect
category: Genetic
disease_term:
  preferred_term: Progressive familial heart block
  term:
    id: MONDO:0019490
    label: progressive familial heart block
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019490
      label: progressive familial heart block
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for the progressive familial heart block root entry.
parents:
- Cardiac Conduction Disorder
- Cardiogenetic Rhythm Disorder
classifications:
  channelopathy_category:
    classification_value: cardiac channelopathy
has_subtypes:
- name: Type 1A
  display_name: Progressive familial heart block, type 1A (SCN5A)
  subtype_term:
    preferred_term: Progressive familial heart block, type 1A
    term:
      id: MONDO:0007240
      label: progressive familial heart block, type 1A
  description: >-
    SCN5A-associated form (hereditary Lenègre disease), caused by
    loss-of-function variants in SCN5A producing haploinsufficiency for the
    cardiac sodium channel NaV1.5. Reduced peak inward sodium current slows
    conduction, and in combination with aging leads to progressive conduction
    impairment and myocardial fibrosis of the His-Purkinje system. This locus
    overlaps the broader SCN5A-related cardiac rhythm disorder spectrum
    (including Brugada syndrome and the cardiac sodium-channel overlap
    syndrome).
  genes:
  - preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  evidence:
  - reference: PMID:12598077
    reference_title: Haploinsufficiency in combination with aging causes SCN5A-linked hereditary Lenègre disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a French family, we have identified a splicing mutation in the SCN5A gene leading to hereditary progressive cardiac conduction defect."
    explanation: Identifies an SCN5A loss-of-function (splicing) variant as the cause of the SCN5A-associated (Lenègre) form of progressive cardiac conduction disease.
- name: Type 1B
  display_name: Progressive familial heart block, type 1B (TRPM4)
  subtype_term:
    preferred_term: Progressive familial heart block type IB
    term:
      id: MONDO:0011474
      label: progressive familial heart block type IB
  description: >-
    TRPM4-associated form, caused by gain-of-function variants in TRPM4, which
    encodes a Ca2+-activated nonselective cation channel most highly expressed
    in Purkinje fibers. Impaired channel endocytosis raises TRPM4 density at the
    cardiomyocyte surface, producing a His-Purkinje bundle-branch conduction
    disease with autosomal-dominant inheritance.
  genes:
  - preferred_term: TRPM4
    term:
      id: hgnc:17993
      label: TRPM4
  evidence:
  - reference: PMID:19726882
    reference_title: Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive familial heart block type I (PFHBI) is a progressive cardiac bundle branch disease in the His-Purkinje system that exhibits autosomal-dominant inheritance."
    explanation: Establishes the TRPM4-associated PFHB type I as an autosomal-dominant His-Purkinje bundle-branch conduction disease.
pathophysiology:
- name: Inherited Conduction-System Ion-Channel Defect
  role: trigger
  description: >-
    Progressive familial heart block originates in an inherited defect of a
    cardiac ion channel expressed in the conduction system. In the SCN5A (type
    1A) form, loss-of-function variants cause haploinsufficiency for the cardiac
    sodium channel NaV1.5, reducing peak inward sodium current that drives the
    action-potential upstroke. In the TRPM4 (type 1B) form, gain-of-function
    variants impair channel endocytosis and increase surface density of the
    Ca2+-activated nonselective cation channel TRPM4, which is most highly
    expressed in Purkinje fibers. Both lesions perturb the excitability of
    conduction-system myocytes rather than producing a structural
    cardiomyopathy at onset.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: cardiac Purkinje fiber cell
    term:
      id: CL:0002068
      label: Purkinje myocyte
  - preferred_term: atrioventricular bundle (His) cell
    term:
      id: CL:0010005
      label: atrioventricular bundle cell
  molecular_functions:
  - preferred_term: voltage-gated sodium channel activity
    term:
      id: GO:0005248
      label: voltage-gated sodium channel activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: membrane depolarization during action potential
    term:
      id: GO:0086010
      label: membrane depolarization during action potential
    modifier: ABNORMAL
  evidence:
  - reference: PMID:12598077
    reference_title: Haploinsufficiency in combination with aging causes SCN5A-linked hereditary Lenègre disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies show that the IVS.22+2 T-->C SCN5A mutation lead to exon 22 skipping and to a complete loss of function of the affected allele, but to a normal trafficking of the mutated gene product."
    explanation: Demonstrates that the SCN5A variant produces a complete loss of function of the affected allele (haploinsufficiency), the molecular lesion of the type 1A form.
  - reference: PMID:19726882
    reference_title: Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The resulting constitutive SUMOylation of the mutant TRPM4 channel impaired endocytosis and led to elevated TRPM4 channel density at the cell surface."
    explanation: Defines the TRPM4 gain-of-function lesion (elevated surface channel density from impaired endocytosis) underlying the type 1B form.
  - reference: PMID:19726882
    reference_title: Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Quantitative analysis of TRPM4 mRNA content in human cardiac tissue showed the highest expression level in Purkinje fibers."
    explanation: Localizes the highest TRPM4 expression to Purkinje fibers, consistent with a His-Purkinje conduction-system lesion.
  downstream:
  - target: Slowed His-Purkinje and Atrioventricular Conduction
    description: The channel defect reduces conduction-system excitability and propagation, slowing impulse conduction through the AV node and His-Purkinje system.
- name: Slowed His-Purkinje and Atrioventricular Conduction
  role: amplifier
  description: >-
    The ion-channel lesion is translated into slowed cardiac impulse
    conduction. Reduced sodium current (type 1A) lowers conduction velocity in
    the His-Purkinje system, while increased TRPM4-mediated background cation
    current (type 1B) disturbs Purkinje-fiber excitability. The cellular result
    is progressive prolongation of conduction intervals (P-wave, PR, and QRS)
    that worsens with age.
  cell_types:
  - preferred_term: cardiac Purkinje fiber cell
    term:
      id: CL:0002068
      label: Purkinje myocyte
  - preferred_term: atrioventricular bundle (His) cell
    term:
      id: CL:0010005
      label: atrioventricular bundle cell
  biological_processes:
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: DECREASED
  - preferred_term: regulation of cardiac conduction
    term:
      id: GO:1903779
      label: regulation of cardiac conduction
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:12598077
    reference_title: Haploinsufficiency in combination with aging causes SCN5A-linked hereditary Lenègre disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P-wave, PR, and QRS duration increased progressively with age in gene carriers"
    explanation: Documents progressive, age-dependent prolongation of atrial and His-Purkinje conduction intervals in SCN5A gene carriers.
  - 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: "In Scn5a+/- mice, surface ECG recordings showed age-related lengthening of the P-wave and PR- and QRS-interval duration, coinciding with previous observations in patients with Lenègre's disease."
    explanation: A heterozygous Scn5a-knockout mouse recapitulates the age-related conduction slowing of human Lenègre disease.
  downstream:
  - target: Progressive His-Purkinje Fibrosis and Degeneration
    description: Chronically impaired conduction, in combination with aging, is accompanied by progressive structural degeneration and fibrosis of the conduction system.
- name: Progressive His-Purkinje Fibrosis and Degeneration
  role: amplifier
  description: >-
    In the Lenègre (SCN5A) form, the primary ion-channel defect, combined with
    aging, leads to progressive fibrosis and degeneration of the His bundle and
    its branches — the structural correlate that converts a subclinical
    conduction defect into advancing heart block. Mouse models demonstrate that
    a monogenic sodium-channel defect is sufficient to drive age-dependent
    myocardial fibrosis, establishing a channel-to-structure pathomechanism.
  cell_types:
  - preferred_term: cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  - preferred_term: atrioventricular bundle (His) cell
    term:
      id: CL:0010005
      label: atrioventricular bundle cell
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  evidence:
  - reference: PMID:12598077
    reference_title: Haploinsufficiency in combination with aging causes SCN5A-linked hereditary Lenègre disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive cardiac conduction defect is a frequent disease commonly attributed to degeneration and fibrosis of the His bundle and its branches."
    explanation: States that progressive cardiac conduction defect is attributed to degeneration and fibrosis of the His bundle and its branches.
  - 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: "Old but not young Scn5a+/- mice showed extensive fibrosis of their ventricular myocardium, a feature not seen in wild-type animals."
    explanation: Shows age-dependent myocardial fibrosis in the SCN5A-haploinsufficient mouse model of Lenègre disease.
  - 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: "Our work provides the first demonstration that a monogenic ion channel defect can progressively lead to myocardial structural anomalies."
    explanation: Establishes that a monogenic ion-channel defect can progressively cause myocardial structural anomalies (fibrosis), linking the channel lesion to conduction-system degeneration.
  downstream:
  - target: Progressive Atrioventricular and Bundle-Branch Block
    description: Combined conduction slowing and conduction-system fibrosis produce advancing bundle-branch and atrioventricular block.
- name: Progressive Atrioventricular and Bundle-Branch Block
  role: effector
  description: >-
    The defining manifestation is progressive conduction block: bundle-branch
    block and fascicular block advance over time to high-grade and complete
    atrioventricular block. The block is the proximate cause of bradyarrhythmia
    and the indication for pacing.
  cell_types:
  - preferred_term: atrioventricular bundle (His) cell
    term:
      id: CL:0010005
      label: atrioventricular bundle cell
  biological_processes:
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:35205305
    reference_title: "The Role of TRPM4 Gene Mutations in Causing Familial Progressive Cardiac Conduction Disease: A Further Contribution."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "he was implanted with a PM for two episodes of syncope and the presence of complete atrioventricular block (AVB)."
    explanation: Documents progression to complete atrioventricular block as the defining conduction-system endpoint in a PCCD family.
  downstream:
  - target: Syncope and Sudden Cardiac Death
    description: High-grade or complete atrioventricular block causes bradyarrhythmia, transient cerebral hypoperfusion (syncope), and, when not paced, sudden cardiac death.
- name: Syncope and Sudden Cardiac Death
  role: outcome
  description: >-
    High-grade and complete atrioventricular block produce bradyarrhythmia and
    ventricular asystole, causing syncope and Stokes-Adams attacks and, when
    the bradyarrhythmia is not corrected by pacing, sudden cardiac death. These
    endpoints define the clinical severity of progressive familial heart block
    and may be the sentinel manifestation.
  evidence:
  - reference: PMID:35205305
    reference_title: "The Role of TRPM4 Gene Mutations in Causing Familial Progressive Cardiac Conduction Disease: A Further Contribution."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "whose younger brother died at 25 years of unexplained sudden cardiac death."
    explanation: Documents young-onset sudden cardiac death within a familial progressive cardiac conduction disease pedigree.
phenotypes:
- category: Cardiovascular
  name: Atrioventricular block
  diagnostic: true
  description: >-
    Progressive atrioventricular block, advancing to complete (third-degree)
    block, is the defining manifestation of progressive familial heart block.
  phenotype_term:
    preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:35205305
    reference_title: "The Role of TRPM4 Gene Mutations in Causing Familial Progressive Cardiac Conduction Disease: A Further Contribution."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "he was implanted with a PM for two episodes of syncope and the presence of complete atrioventricular block (AVB)."
    explanation: Supports complete atrioventricular block as a defining phenotype of progressive familial heart block.
- category: Cardiovascular
  name: Bundle branch block
  description: >-
    Bundle-branch and fascicular block in the His-Purkinje system is an early
    and characteristic conduction abnormality that progresses over time.
  phenotype_term:
    preferred_term: Bundle branch block
    term:
      id: HP:0011710
      label: Bundle branch block
  evidence:
  - reference: PMID:19726882
    reference_title: Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive familial heart block type I (PFHBI) is a progressive cardiac bundle branch disease in the His-Purkinje system that exhibits autosomal-dominant inheritance."
    explanation: Supports progressive bundle-branch (His-Purkinje) conduction disease as a core phenotype.
- category: Cardiovascular
  name: Prolonged QRS complex
  description: >-
    Progressive widening of the QRS complex reflects slowed His-Purkinje
    conduction and worsens with age in gene carriers.
  phenotype_term:
    preferred_term: Prolonged QRS complex
    term:
      id: HP:0006677
      label: Prolonged QRS complex
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:12598077
    reference_title: Haploinsufficiency in combination with aging causes SCN5A-linked hereditary Lenègre disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P-wave, PR, and QRS duration increased progressively with age in gene carriers"
    explanation: Supports age-progressive QRS prolongation in SCN5A gene carriers.
- category: Cardiovascular
  name: Syncope
  description: >-
    Syncope and Stokes-Adams attacks result from bradyarrhythmia during
    high-grade atrioventricular block.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:35205305
    reference_title: "The Role of TRPM4 Gene Mutations in Causing Familial Progressive Cardiac Conduction Disease: A Further Contribution."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "he was implanted with a PM for two episodes of syncope and the presence of complete atrioventricular block (AVB)."
    explanation: Supports syncope as a clinical manifestation of high-grade atrioventricular block in PCCD.
- category: Cardiovascular
  name: Sudden cardiac death
  description: >-
    Sudden cardiac death may occur from bradyarrhythmic complete heart block,
    sometimes at a young age, when the conduction block is not corrected by
    pacing.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:35205305
    reference_title: "The Role of TRPM4 Gene Mutations in Causing Familial Progressive Cardiac Conduction Disease: A Further Contribution."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "whose younger brother died at 25 years of unexplained sudden cardiac death."
    explanation: Supports young-onset sudden cardiac death as an outcome within a PCCD pedigree.
genetic:
- name: SCN5A loss-of-function variants
  association: Causative
  relationship_type: CAUSATIVE
  subtype: Type 1A
  features: >-
    Loss-of-function SCN5A variants (missense, splicing, frameshift) reduce
    cardiac sodium current and cause haploinsufficiency for NaV1.5. The original
    description linked cardiac conduction defects to SCN5A mutations, and
    detailed pedigree analysis showed that haploinsufficiency, in combination
    with aging, produces progressive conduction slowing (hereditary Lenègre
    disease).
  gene_term:
    preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  evidence:
  - reference: PMID:10471492
    reference_title: Cardiac conduction defects associate with mutations in SCN5A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac conduction defects associate with mutations in SCN5A."
    explanation: Seminal report establishing the association between SCN5A mutations and inherited cardiac conduction defects.
  - reference: PMID:12598077
    reference_title: Haploinsufficiency in combination with aging causes SCN5A-linked hereditary Lenègre disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings demonstrate that hereditary Lenègre disease is caused by a haploinsufficiency mechanism, which in combination with aging leads to progressive alteration in conduction velocity."
    explanation: Establishes SCN5A haploinsufficiency, combined with aging, as the causative mechanism of the type 1A (Lenègre) form.
- name: TRPM4 gain-of-function variants
  association: Causative
  relationship_type: CAUSATIVE
  subtype: Type 1B
  features: >-
    Gain-of-function TRPM4 variants increase cell-surface density of the
    Ca2+-activated nonselective cation channel TRPM4 through impaired
    endocytosis (constitutive SUMOylation), raising background cation current in
    the His-Purkinje system. The founding mutation (c.19G>A, p.E7K) was
    identified in a South African Afrikaner pedigree, and additional TRPM4
    variants have since been reported in PCCD families.
  gene_term:
    preferred_term: TRPM4
    term:
      id: hgnc:17993
      label: TRPM4
  evidence:
  - reference: PMID:19726882
    reference_title: Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified the mutation c.19G-->A in the transient receptor potential cation channel, subfamily M, member 4 gene (TRPM4)"
    explanation: Identifies the founding TRPM4 variant causing the type 1B form of progressive familial heart block.
  - reference: PMID:35205305
    reference_title: "The Role of TRPM4 Gene Mutations in Causing Familial Progressive Cardiac Conduction Disease: A Further Contribution."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variations in TRPM4 have been shown to cause an increase in cell surface current density, which results in a gain of gene function."
    explanation: Confirms the TRPM4 gain-of-function mechanism (increased surface current density) in progressive cardiac conduction disease.
treatments:
- name: Permanent pacemaker implantation
  description: >-
    Permanent cardiac pacemaker implantation is the mainstay of treatment for
    symptomatic bradyarrhythmia and high-grade or complete atrioventricular
    block in progressive familial heart block. Pacing bypasses the failing
    conduction system to maintain ventricular rate and prevent syncope and
    bradyarrhythmic sudden death, but does not modify the underlying
    channel/conduction-system pathology.
  treatment_term:
    preferred_term: pacemaker implantation
    term:
      id: MAXO:0009034
      label: pacemaker implantation
  evidence:
  - reference: PMID:35205305
    reference_title: "The Role of TRPM4 Gene Mutations in Causing Familial Progressive Cardiac Conduction Disease: A Further Contribution."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a family with a large number of individuals necessitating pacemaker implantation, likely due to varying degrees of PCCD."
    explanation: Supports pacemaker implantation as the established treatment for the conduction block of progressive cardiac conduction disease.
  target_mechanisms:
  - target: Progressive Atrioventricular and Bundle-Branch Block
    treatment_effect: MODULATES
    description: >-
      The pacemaker delivers electrical stimulation distal to the conduction
      block, maintaining ventricular activation and rate despite atrioventricular
      and bundle-branch block, without altering the underlying conduction-system
      lesion.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:19726882
    reference_title: Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive familial heart block type I (PFHBI) is a progressive cardiac bundle branch disease in the His-Purkinje system that exhibits autosomal-dominant inheritance."
    explanation: Establishes autosomal-dominant inheritance for progressive familial heart block type I.
notes: >-
  Curated as the gene-axis lumped root for progressive familial heart block
  (MONDO:0019490) with two molecularly defined subtypes: type 1A =
  SCN5A-associated, loss-of-function/haploinsufficiency (MONDO:0007240,
  OMIM:113900; hereditary Lenègre disease) and type 1B = TRPM4-associated,
  gain-of-function (MONDO:0011474, OMIM:604559). A third historically defined
  locus, progressive familial heart block type II (MONDO:0007701, OMIM:140400),
  is recognized clinically but has no MONDO-asserted causal gene and is
  therefore not curated as a gene-anchored subtype here; additional PCCD genes
  (SCN1B, LMNA, GJA5) reported in the literature are likewise not yet curated as
  subtypes pending gene-specific evidence. The mechanism modeled here is
  conduction slowing/block plus age-dependent His-Purkinje fibrosis, which is
  distinct from the ventricular-repolarization pathway of the
  cardiac_ion_channel_repolarization module; this entry therefore deliberately
  does NOT declare conforms_to. Whether progressive familial heart block (a
  conduction-system / bradyarrhythmia entity) should be admitted to the
  Inherited Arrhythmia Syndromes grouping, or curated under a sibling
  conduction-disease grouping, is the open broaden-vs-sibling scope decision
  raised in issue #4242; grouping membership is deliberately left to that
  maintainer decision and is not asserted here.

Progressive Familial Heart Block

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