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1
Inheritance
5
Pathophys.
3
Phenotypes
5
Pathograph
6
Genes
3
Medical Actions
18
Subtypes
3
References
👪

Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant inheritance

Subtypes

18
KCNQ1 gain-of-function familial AF MONDO:0011857
Autosomal dominant familial AF caused by gain-of-function KCNQ1 (KvLQT1) variants (e.g. S140G) that augment the slow delayed-rectifier IKs current and shorten atrial action potential duration and refractoriness.
KCNE2 gain-of-function familial AF MONDO:0012677
Familial AF associated with gain-of-function variants in the potassium-channel beta subunit KCNE2, which modulates KCNQ1 and other cardiac potassium currents.
KCNJ2 (Kir2.1) gain-of-function familial AF MONDO:0013513
Autosomal dominant familial AF caused by gain-of-function KCNJ2 variants (e.g. V93I) that increase the inward-rectifier IK1 current.
GJA5 (connexin 40) familial AF MONDO:0013544
AF associated with germline or atrial-tissue-restricted somatic missense variants in GJA5, encoding the atrial gap-junction protein connexin 40, which impair gap-junction assembly and intercellular electrical coupling.
NPPA (atrial natriuretic peptide) familial AF MONDO:0012816
Familial AF linked to variants in NPPA, encoding the atrial natriuretic peptide precursor.
SCN5A familial AF MONDO:0013530
Familial AF associated with variants in the cardiac sodium channel SCN5A, overlapping the broader SCN5A-related arrhythmia spectrum.
KCNA5 (Kv1.5) loss-of-function familial AF MONDO:0012828
Familial AF caused by loss-of-function variants in KCNA5, encoding the voltage-gated potassium channel Kv1.5 (ultra-rapid delayed rectifier current, IKur), which is predominantly expressed in atrial cardiomyocytes. Loss of IKur prolongs atrial action potential duration and may predispose to early afterdepolarizations and AF.
ABCC9 (SUR2A) familial AF MONDO:0013545
Familial AF associated with variants in ABCC9, which encodes the sulfonylurea receptor 2A (SUR2A), a regulatory subunit of the cardiac ATP-sensitive potassium channel (KATP). Gain-of-function variants alter KATP channel activity and atrial repolarization.
SCN1B sodium channel beta-1 familial AF MONDO:0014155
Familial AF caused by variants in SCN1B, encoding the sodium channel beta-1 subunit, which modulates Nav1.5 gating kinetics and membrane expression. Variants alter the peak and late sodium current in atrial cardiomyocytes.
SCN2B sodium channel beta-2 familial AF MONDO:0014156
Familial AF caused by variants in SCN2B, encoding the sodium channel beta-2 subunit. Like SCN1B, SCN2B modulates Nav1.5 channel function and the sodium current in atrial myocytes.
NUP155 (nucleoporin 155) familial AF MONDO:0014340
Autosomal recessive familial AF caused by loss-of-function variants in NUP155, encoding nucleoporin 155, a component of the nuclear pore complex important for nucleocytoplasmic transport and cardiac gene expression. Associated with a severe phenotype including sudden cardiac death in young individuals.
MYL4 (atrial myosin light chain) familial AF MONDO:0015001
Autosomal recessive familial AF caused by loss-of-function variants in MYL4, encoding the atrial-specific essential myosin light chain. Associated with early-onset AF, atrial myopathy, and progressive atrial cardiomyopathy.
Familial AF locus 1 (ATFB1) MONDO:0012066
A familial AF locus (ATFB1) mapped by linkage analysis without a confirmed causal gene. Represented here as a MONDO leaf-class anchor.
Familial AF locus 2 (ATFB2) MONDO:0012167
A familial AF locus (ATFB2) mapped by linkage analysis without a confirmed causal gene. Represented here as a MONDO leaf-class anchor.
Familial AF locus 5 (ATFB5) MONDO:0012678
A familial AF locus (ATFB5) without a confirmed causal gene in the MONDO disease-by-gene series. Represented here as a MONDO leaf-class anchor.
Familial AF locus 8 (ATFB8) MONDO:0013100
A familial AF locus (ATFB8) without a confirmed causal gene in the MONDO disease-by-gene series. Represented here as a MONDO leaf-class anchor.
Familial AF locus 16 (ATFB16) MONDO:0800349
A familial AF entity (ATFB16) without a confirmed causal gene or OMIM entry. Represented here as a MONDO leaf-class anchor.
Familial AF locus 17 (ATFB17) MONDO:0800345
A familial AF entity (ATFB17) without a confirmed causal gene or OMIM entry. Represented here as a MONDO leaf-class anchor.

Pathophysiology

5
Atrial Ion-Channel or Coupling Variant
A germline (or, for GJA5, atrial-tissue-restricted somatic) variant alters an atrial ion channel or gap-junction protein. The best-characterized variants are gain-of-function in atrial potassium channels (KCNQ1/IKs, KCNJ2/IK1, KCNE2), with additional families carrying GJA5 (connexin 40), NPPA, and SCN5A variants.
Atrial Cardiomyocyte CL:0002129
Cardiac conduction GO:0061337 ⚠ ABNORMAL
Show evidence (2 references)
PMID:12522251 SUPPORT Human Clinical
"We studied a family with hereditary persistent AF and identified the causative mutation (S140G) in the KCNQ1 (KvLQT1) gene on chromosome 11p15.5."
Establishes a monogenic atrial-channel variant (KCNQ1 S140G) as the causative lesion in a familial AF kindred.
PMID:15922306 SUPPORT Human Clinical
"A valine-to-isoleucine mutation at position 93 (V93I) of Kir2.1 was found in all affected members in one kindred."
Supports KCNJ2 (Kir2.1) as a second atrial potassium-channel locus carrying a co-segregating variant in a familial AF kindred.
Shortened Atrial Action Potential and Refractoriness
Enhanced atrial repolarizing current shortens the atrial action potential duration and effective refractory period. A shorter refractory period reduces the wavelength of atrial reentry, allowing more simultaneous reentrant wavelets to be accommodated within the atria.
Atrial Cardiomyocyte CL:0002129
Atrial cardiac muscle cell action potential GO:0086014 ↓ DECREASED Membrane repolarization during cardiac action potential GO:0086013 ↑ INCREASED
Show evidence (2 references)
PMID:12522251 SUPPORT Human Clinical
"Thus, the S140G mutation is likely to initiate and maintain AF by reducing action potential duration and effective refractory period in atrial myocytes."
Directly supports shortened atrial action potential duration and refractory period as the mechanistic link between the gain-of-function channel variant and AF.
PMID:15922306 SUPPORT Human Clinical
"Functional analysis of the V93I mutant demonstrated a gain-of-function consequence on the Kir2.1 current."
Supports increased inward-rectifier current as a second mechanism that shortens atrial repolarization in familial AF.
Atrial Gap-Junction Coupling Defect
In GJA5-related familial AF, variants in connexin 40 impair gap-junction assembly and intercellular electrical coupling between atrial myocytes, producing heterogeneous, slowed atrial conduction that promotes reentry. This is a coupling/conduction mechanism that converges on the same arrhythmogenic substrate as the channelopathy arm.
Atrial Cardiomyocyte CL:0002129
Electrical coupling in cardiac conduction GO:0086064 ⚠ ABNORMAL
Show evidence (2 references)
PMID:16790700 SUPPORT Human Clinical
"The cardiac gap-junction protein connexin 40 is expressed selectively in atrial myocytes and mediates the coordinated electrical activation of the atria."
Establishes connexin 40 (GJA5) as an atrial-selective gap-junction protein whose dysfunction disrupts coordinated atrial activation.
PMID:16790700 SUPPORT Human Clinical
"Mutations in GJA5 may predispose patients to idiopathic atrial fibrillation by impairing gap-junction assembly or electrical coupling."
Supports impaired gap-junction coupling as the mechanism by which GJA5 variants predispose the atria to fibrillation.
Atrial Arrhythmogenic Substrate
Shortened refractoriness and/or impaired coupling create an atrial substrate that supports multiple coexisting reentrant wavelets and ectopic triggers, initiating and maintaining atrial fibrillation. As AF persists, electrical remodeling further shortens refractoriness ("AF begets AF").
Atrial Cardiomyocyte CL:0002129
Cardiac muscle cell action potential GO:0086001 ⚠ ABNORMAL
Show evidence (1 reference)
PMID:12522251 SUPPORT Human Clinical
"Atrial fibrillation (AF) is a common cardiac arrhythmia whose molecular etiology is poorly understood."
Frames the clinical endpoint (atrial fibrillation) whose monogenic molecular etiology this entry models.
Sustained Atrial Fibrillation
The clinical manifestation: paroxysmal, persistent, or permanent atrial fibrillation, typically with earlier onset than acquired AF and often in structurally normal hearts. Loss of organized atrial contraction predisposes to thromboembolism and stroke.
Atrial Cardiomyocyte CL:0002129
Show evidence (1 reference)
PMID:12522251 SUPPORT Human Clinical
"We studied a family with hereditary persistent AF and identified the causative mutation (S140G) in the KCNQ1 (KvLQT1) gene on chromosome 11p15.5."
Documents persistent atrial fibrillation as the segregating clinical phenotype in a familial AF kindred.

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Familial Atrial 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

3
Atrial Fibrillation VERY_FREQUENT Cardiovascular HP:0005110
Show evidence (1 reference)
PMID:12522251 SUPPORT Human Clinical
"We studied a family with hereditary persistent AF and identified the causative mutation (S140G) in the KCNQ1 (KvLQT1) gene on chromosome 11p15.5."
Documents persistent atrial fibrillation as the segregating phenotype.
Palpitations Cardiovascular HP:0001962
Stroke Cardiovascular HP:0001297
🧬

Genetic Associations

6
KCNQ1 gain-of-function variants (Causative)
Gene: KCNQ1 hgnc:6294
Autosomal dominant
Show evidence (1 reference)
PMID:12522251 SUPPORT Human Clinical
"Functional analysis of the S140G mutant revealed a gain-of-function effect on the KCNQ1/KCNE1 and the KCNQ1/KCNE2 currents, which contrasts with the dominant negative or loss-of-function effects of the KCNQ1 mutations previously identified in patients with long QT syndrome."
Establishes KCNQ1 gain-of-function (distinct from the loss-of-function long-QT mechanism) as causative in familial AF.
KCNJ2 gain-of-function variants (Causative)
Gene: KCNJ2 hgnc:6263
Autosomal dominant
Show evidence (1 reference)
PMID:15922306 SUPPORT Human Clinical
"Kir2.1 V93I mutation may play a role in initiating and/or maintaining AF by increasing the activity of the inward rectifier K(+) channel."
Supports KCNJ2 gain-of-function as a causative familial-AF mechanism via increased IK1.
GJA5 (connexin 40) variants (Causative)
Gene: GJA5 hgnc:4279
Autosomal dominant
Show evidence (1 reference)
PMID:16790700 SUPPORT Human Clinical
"Four novel heterozygous missense mutations were identified in 4 of the 15 patients."
Documents GJA5 missense variants (somatic and germline) in patients with idiopathic AF.
KCNE2 gain-of-function variants (Causative)
Gene: KCNE2 hgnc:6242
Autosomal dominant
NPPA variants (Causative)
Gene: NPPA hgnc:7939
Autosomal dominant
SCN5A variants (Associated)
Gene: SCN5A hgnc:10593
Autosomal dominant
💊

Medical Actions

3
Oral Anticoagulation
Action: Pharmacotherapy NCIT:C15986
Anticoagulation for stroke prevention, guided by individual thromboembolic risk, as in other forms of atrial fibrillation.
Rate or Rhythm Control
Action: Pharmacotherapy NCIT:C15986
Antiarrhythmic drugs, atrioventricular nodal rate-control agents, or catheter ablation to control ventricular rate or restore/maintain sinus rhythm.
Genetic Counseling
Action: Genetic Counseling NCIT:C15240
Counseling for affected families given autosomal dominant inheritance, with consideration of cascade screening of first-degree relatives.
{ }

Source YAML

click to show
name: Familial Atrial Fibrillation
creation_date: '2026-06-25T00:00:00Z'
description: >-
  Familial (monogenic) atrial fibrillation is a Mendelian, early-onset form of
  atrial fibrillation occurring in structurally normal hearts and segregating in
  families, distinct from the common acquired/complex atrial fibrillation that
  arises on a background of hypertension, structural heart disease, and aging.
  The best-characterized subtypes are autosomal dominant gain-of-function
  potassium-channel defects (KCNQ1, KCNE2, KCNJ2) that shorten the atrial action
  potential duration and effective refractory period, creating a re-entry-prone
  atrial substrate; additional families carry variants in the atrial
  gap-junction protein connexin 40 (GJA5), the atrial natriuretic peptide
  precursor (NPPA), and the cardiac sodium channel (SCN5A). The shared final
  common mechanism is an electrically remodeled atrium predisposed to the
  initiation and maintenance of fibrillation. This entry models the inherited
  channelopathy spectrum and is distinct from the general Atrial Fibrillation
  entry (MONDO:0004981); the monogenic loci are lumped here as has_subtypes
  rather than as separate gene-level files.
synonyms:
- familial AF
- monogenic atrial fibrillation
- hereditary atrial fibrillation
- ATFB
category: Genetic
disease_term:
  preferred_term: familial atrial fibrillation
  term:
    id: MONDO:0018054
    label: familial atrial fibrillation
parents:
- Cardiac Arrhythmia
- Channelopathy
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
has_subtypes:
- name: KCNQ1-related
  display_name: KCNQ1 gain-of-function familial AF
  subtype_term:
    preferred_term: KCNQ1 familial atrial fibrillation
    term:
      id: MONDO:0011857
      label: atrial fibrillation, familial, 3
  description: >-
    Autosomal dominant familial AF caused by gain-of-function KCNQ1 (KvLQT1)
    variants (e.g. S140G) that augment the slow delayed-rectifier IKs current and
    shorten atrial action potential duration and refractoriness.
- name: KCNE2-related
  display_name: KCNE2 gain-of-function familial AF
  subtype_term:
    preferred_term: KCNE2 familial atrial fibrillation
    term:
      id: MONDO:0012677
      label: atrial fibrillation, familial, 4
  description: >-
    Familial AF associated with gain-of-function variants in the potassium-channel
    beta subunit KCNE2, which modulates KCNQ1 and other cardiac potassium currents.
- name: KCNJ2-related
  display_name: KCNJ2 (Kir2.1) gain-of-function familial AF
  subtype_term:
    preferred_term: KCNJ2 familial atrial fibrillation
    term:
      id: MONDO:0013513
      label: atrial fibrillation, familial, 9
  description: >-
    Autosomal dominant familial AF caused by gain-of-function KCNJ2 variants
    (e.g. V93I) that increase the inward-rectifier IK1 current.
- name: GJA5-related
  display_name: GJA5 (connexin 40) familial AF
  subtype_term:
    preferred_term: GJA5 familial atrial fibrillation
    term:
      id: MONDO:0013544
      label: atrial fibrillation, familial, 11
  description: >-
    AF associated with germline or atrial-tissue-restricted somatic missense
    variants in GJA5, encoding the atrial gap-junction protein connexin 40, which
    impair gap-junction assembly and intercellular electrical coupling.
- name: NPPA-related
  display_name: NPPA (atrial natriuretic peptide) familial AF
  subtype_term:
    preferred_term: NPPA familial atrial fibrillation
    term:
      id: MONDO:0012816
      label: atrial fibrillation, familial, 6
  description: >-
    Familial AF linked to variants in NPPA, encoding the atrial natriuretic
    peptide precursor.
- name: SCN5A-related
  display_name: SCN5A familial AF
  subtype_term:
    preferred_term: SCN5A familial atrial fibrillation
    term:
      id: MONDO:0013530
      label: atrial fibrillation, familial, 10
  description: >-
    Familial AF associated with variants in the cardiac sodium channel SCN5A,
    overlapping the broader SCN5A-related arrhythmia spectrum.
- name: KCNA5-related
  display_name: KCNA5 (Kv1.5) loss-of-function familial AF
  subtype_term:
    preferred_term: KCNA5 familial atrial fibrillation
    term:
      id: MONDO:0012828
      label: atrial fibrillation, familial, 7
  description: >-
    Familial AF caused by loss-of-function variants in KCNA5, encoding the
    voltage-gated potassium channel Kv1.5 (ultra-rapid delayed rectifier current,
    IKur), which is predominantly expressed in atrial cardiomyocytes. Loss of IKur
    prolongs atrial action potential duration and may predispose to early
    afterdepolarizations and AF.
- name: ABCC9-related
  display_name: ABCC9 (SUR2A) familial AF
  subtype_term:
    preferred_term: ABCC9 familial atrial fibrillation
    term:
      id: MONDO:0013545
      label: atrial fibrillation, familial, 12
  description: >-
    Familial AF associated with variants in ABCC9, which encodes the sulfonylurea
    receptor 2A (SUR2A), a regulatory subunit of the cardiac ATP-sensitive
    potassium channel (KATP). Gain-of-function variants alter KATP channel activity
    and atrial repolarization.
- name: SCN1B-related
  display_name: SCN1B sodium channel beta-1 familial AF
  subtype_term:
    preferred_term: SCN1B familial atrial fibrillation
    term:
      id: MONDO:0014155
      label: atrial fibrillation, familial, 13
  description: >-
    Familial AF caused by variants in SCN1B, encoding the sodium channel beta-1
    subunit, which modulates Nav1.5 gating kinetics and membrane expression.
    Variants alter the peak and late sodium current in atrial cardiomyocytes.
- name: SCN2B-related
  display_name: SCN2B sodium channel beta-2 familial AF
  subtype_term:
    preferred_term: SCN2B familial atrial fibrillation
    term:
      id: MONDO:0014156
      label: atrial fibrillation, familial, 14
  description: >-
    Familial AF caused by variants in SCN2B, encoding the sodium channel beta-2
    subunit. Like SCN1B, SCN2B modulates Nav1.5 channel function and the sodium
    current in atrial myocytes.
- name: NUP155-related
  display_name: NUP155 (nucleoporin 155) familial AF
  subtype_term:
    preferred_term: NUP155 familial atrial fibrillation
    term:
      id: MONDO:0014340
      label: atrial fibrillation, familial, 15
  description: >-
    Autosomal recessive familial AF caused by loss-of-function variants in NUP155,
    encoding nucleoporin 155, a component of the nuclear pore complex important
    for nucleocytoplasmic transport and cardiac gene expression. Associated with a
    severe phenotype including sudden cardiac death in young individuals.
- name: MYL4-related
  display_name: MYL4 (atrial myosin light chain) familial AF
  subtype_term:
    preferred_term: MYL4 familial atrial fibrillation
    term:
      id: MONDO:0015001
      label: atrial fibrillation, familial, 18
  description: >-
    Autosomal recessive familial AF caused by loss-of-function variants in MYL4,
    encoding the atrial-specific essential myosin light chain. Associated with
    early-onset AF, atrial myopathy, and progressive atrial cardiomyopathy.
- name: ATFB1-locus
  display_name: Familial AF locus 1 (ATFB1)
  subtype_term:
    preferred_term: atrial fibrillation, familial, 1
    term:
      id: MONDO:0012066
      label: atrial fibrillation, familial, 1
  description: >-
    A familial AF locus (ATFB1) mapped by linkage analysis without a confirmed
    causal gene. Represented here as a MONDO leaf-class anchor.
- name: ATFB2-locus
  display_name: Familial AF locus 2 (ATFB2)
  subtype_term:
    preferred_term: atrial fibrillation, familial, 2
    term:
      id: MONDO:0012167
      label: atrial fibrillation, familial, 2
  description: >-
    A familial AF locus (ATFB2) mapped by linkage analysis without a confirmed
    causal gene. Represented here as a MONDO leaf-class anchor.
- name: ATFB5-locus
  display_name: Familial AF locus 5 (ATFB5)
  subtype_term:
    preferred_term: atrial fibrillation, familial, 5
    term:
      id: MONDO:0012678
      label: atrial fibrillation, familial, 5
  description: >-
    A familial AF locus (ATFB5) without a confirmed causal gene in the
    MONDO disease-by-gene series. Represented here as a MONDO leaf-class anchor.
- name: ATFB8-locus
  display_name: Familial AF locus 8 (ATFB8)
  subtype_term:
    preferred_term: atrial fibrillation, familial, 8
    term:
      id: MONDO:0013100
      label: atrial fibrillation, familial, 8
  description: >-
    A familial AF locus (ATFB8) without a confirmed causal gene in the
    MONDO disease-by-gene series. Represented here as a MONDO leaf-class anchor.
- name: ATFB16-locus
  display_name: Familial AF locus 16 (ATFB16)
  subtype_term:
    preferred_term: atrial fibrillation, familial, 16
    term:
      id: MONDO:0800349
      label: atrial fibrillation, familial, 16
  description: >-
    A familial AF entity (ATFB16) without a confirmed causal gene or OMIM entry.
    Represented here as a MONDO leaf-class anchor.
- name: ATFB17-locus
  display_name: Familial AF locus 17 (ATFB17)
  subtype_term:
    preferred_term: atrial fibrillation, familial, 17
    term:
      id: MONDO:0800345
      label: atrial fibrillation, familial, 17
  description: >-
    A familial AF entity (ATFB17) without a confirmed causal gene or OMIM entry.
    Represented here as a MONDO leaf-class anchor.
pathophysiology:
- name: Atrial Ion-Channel or Coupling Variant
  conforms_to: "cardiac_ion_channel_repolarization#Cardiac Ion-Channel or Calcium-Handling Variant"
  description: >-
    A germline (or, for GJA5, atrial-tissue-restricted somatic) variant alters an
    atrial ion channel or gap-junction protein. The best-characterized variants
    are gain-of-function in atrial potassium channels (KCNQ1/IKs, KCNJ2/IK1,
    KCNE2), with additional families carrying GJA5 (connexin 40), NPPA, and SCN5A
    variants.
  cell_types:
  - preferred_term: Atrial Cardiomyocyte
    term:
      id: CL:0002129
      label: regular atrial cardiac myocyte
  biological_processes:
  - preferred_term: Cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:12522251
    reference_title: "KCNQ1 gain-of-function mutation in familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied a family with hereditary persistent AF and identified the
      causative mutation (S140G) in the KCNQ1 (KvLQT1) gene on chromosome
      11p15.5.
    explanation: >-
      Establishes a monogenic atrial-channel variant (KCNQ1 S140G) as the
      causative lesion in a familial AF kindred.
  - reference: PMID:15922306
    reference_title: "A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A valine-to-isoleucine mutation at position 93 (V93I) of Kir2.1 was found
      in all affected members in one kindred.
    explanation: >-
      Supports KCNJ2 (Kir2.1) as a second atrial potassium-channel locus carrying
      a co-segregating variant in a familial AF kindred.
  downstream:
  - target: Shortened Atrial Action Potential and Refractoriness
    causal_link_type: DIRECT
    description: >-
      Gain-of-function potassium-channel variants increase repolarizing current
      and abbreviate the atrial action potential duration and effective
      refractory period.
- name: Shortened Atrial Action Potential and Refractoriness
  conforms_to: "cardiac_ion_channel_repolarization#Altered Action Potential and Calcium Handling"
  description: >-
    Enhanced atrial repolarizing current shortens the atrial action potential
    duration and effective refractory period. A shorter refractory period reduces
    the wavelength of atrial reentry, allowing more simultaneous reentrant
    wavelets to be accommodated within the atria.
  cell_types:
  - preferred_term: Atrial Cardiomyocyte
    term:
      id: CL:0002129
      label: regular atrial cardiac myocyte
  biological_processes:
  - preferred_term: Atrial cardiac muscle cell action potential
    term:
      id: GO:0086014
      label: atrial cardiac muscle cell action potential
    modifier: DECREASED
  - preferred_term: Membrane repolarization during cardiac action potential
    term:
      id: GO:0086013
      label: membrane repolarization during cardiac muscle cell action potential
    modifier: INCREASED
  evidence:
  - reference: PMID:12522251
    reference_title: "KCNQ1 gain-of-function mutation in familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, the S140G mutation is likely to initiate and maintain AF by reducing
      action potential duration and effective refractory period in atrial
      myocytes.
    explanation: >-
      Directly supports shortened atrial action potential duration and refractory
      period as the mechanistic link between the gain-of-function channel variant
      and AF.
  - reference: PMID:15922306
    reference_title: "A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Functional analysis of the V93I mutant demonstrated a gain-of-function
      consequence on the Kir2.1 current.
    explanation: >-
      Supports increased inward-rectifier current as a second mechanism that
      shortens atrial repolarization in familial AF.
  downstream:
  - target: Atrial Arrhythmogenic Substrate
    causal_link_type: DIRECT
    description: >-
      A shortened refractory period and reduced reentry wavelength establish a
      substrate permissive for sustained reentrant atrial activity.
- name: Atrial Gap-Junction Coupling Defect
  description: >-
    In GJA5-related familial AF, variants in connexin 40 impair gap-junction
    assembly and intercellular electrical coupling between atrial myocytes,
    producing heterogeneous, slowed atrial conduction that promotes reentry. This
    is a coupling/conduction mechanism that converges on the same arrhythmogenic
    substrate as the channelopathy arm.
  cell_types:
  - preferred_term: Atrial Cardiomyocyte
    term:
      id: CL:0002129
      label: regular atrial cardiac myocyte
  biological_processes:
  - preferred_term: Electrical coupling in cardiac conduction
    term:
      id: GO:0086064
      label: cell communication by electrical coupling involved in cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:16790700
    reference_title: "Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cardiac gap-junction protein connexin 40 is expressed selectively in
      atrial myocytes and mediates the coordinated electrical activation of the
      atria.
    explanation: >-
      Establishes connexin 40 (GJA5) as an atrial-selective gap-junction protein
      whose dysfunction disrupts coordinated atrial activation.
  - reference: PMID:16790700
    reference_title: "Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in GJA5 may predispose patients to idiopathic atrial fibrillation
      by impairing gap-junction assembly or electrical coupling.
    explanation: >-
      Supports impaired gap-junction coupling as the mechanism by which GJA5
      variants predispose the atria to fibrillation.
  downstream:
  - target: Atrial Arrhythmogenic Substrate
    causal_link_type: DIRECT
    description: >-
      Impaired electrical coupling slows and disorganizes atrial conduction,
      contributing to the reentrant substrate.
- name: Atrial Arrhythmogenic Substrate
  conforms_to: "cardiac_ion_channel_repolarization#Arrhythmogenic Substrate and Triggered Activity"
  description: >-
    Shortened refractoriness and/or impaired coupling create an atrial substrate
    that supports multiple coexisting reentrant wavelets and ectopic triggers,
    initiating and maintaining atrial fibrillation. As AF persists, electrical
    remodeling further shortens refractoriness ("AF begets AF").
  cell_types:
  - preferred_term: Atrial Cardiomyocyte
    term:
      id: CL:0002129
      label: regular atrial cardiac myocyte
  biological_processes:
  - preferred_term: Cardiac muscle cell action potential
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
    modifier: ABNORMAL
  evidence:
  - reference: PMID:12522251
    reference_title: "KCNQ1 gain-of-function mutation in familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atrial fibrillation (AF) is a common cardiac arrhythmia whose molecular
      etiology is poorly understood.
    explanation: >-
      Frames the clinical endpoint (atrial fibrillation) whose monogenic
      molecular etiology this entry models.
  downstream:
  - target: Sustained Atrial Fibrillation
    causal_link_type: DIRECT
    description: >-
      The reentry-prone atrial substrate manifests clinically as sustained or
      recurrent atrial fibrillation.
- name: Sustained Atrial Fibrillation
  description: >-
    The clinical manifestation: paroxysmal, persistent, or permanent atrial
    fibrillation, typically with earlier onset than acquired AF and often in
    structurally normal hearts. Loss of organized atrial contraction predisposes
    to thromboembolism and stroke.
  cell_types:
  - preferred_term: Atrial Cardiomyocyte
    term:
      id: CL:0002129
      label: regular atrial cardiac myocyte
  evidence:
  - reference: PMID:12522251
    reference_title: "KCNQ1 gain-of-function mutation in familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied a family with hereditary persistent AF and identified the
      causative mutation (S140G) in the KCNQ1 (KvLQT1) gene on chromosome
      11p15.5.
    explanation: >-
      Documents persistent atrial fibrillation as the segregating clinical
      phenotype in a familial AF kindred.
phenotypes:
- name: Atrial Fibrillation
  category: Cardiovascular
  frequency: VERY_FREQUENT
  description: >-
    Irregularly irregular atrial tachyarrhythmia, the defining phenotype, often
    of earlier onset than acquired AF.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:12522251
    reference_title: "KCNQ1 gain-of-function mutation in familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied a family with hereditary persistent AF and identified the
      causative mutation (S140G) in the KCNQ1 (KvLQT1) gene on chromosome
      11p15.5.
    explanation: >-
      Documents persistent atrial fibrillation as the segregating phenotype.
- name: Palpitations
  category: Cardiovascular
  description: Awareness of rapid or irregular heartbeat during AF episodes.
  phenotype_term:
    preferred_term: Palpitations
    term:
      id: HP:0001962
      label: Palpitations
- name: Stroke
  category: Cardiovascular
  description: >-
    Cardioembolic stroke from left atrial appendage thrombus, the major
    complication of AF.
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
genetic:
- name: KCNQ1 gain-of-function variants
  association: Causative
  features: >-
    Gain-of-function KCNQ1 (KvLQT1) variants such as S140G augment the IKs
    current and shorten atrial refractoriness, the first identified monogenic
    cause of familial AF.
  gene_term:
    preferred_term: KCNQ1
    term:
      id: hgnc:6294
      label: KCNQ1
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:12522251
    reference_title: "KCNQ1 gain-of-function mutation in familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Functional analysis of the S140G mutant revealed a gain-of-function effect
      on the KCNQ1/KCNE1 and the KCNQ1/KCNE2 currents, which contrasts with the
      dominant negative or loss-of-function effects of the KCNQ1 mutations
      previously identified in patients with long QT syndrome.
    explanation: >-
      Establishes KCNQ1 gain-of-function (distinct from the loss-of-function
      long-QT mechanism) as causative in familial AF.
- name: KCNJ2 gain-of-function variants
  association: Causative
  features: >-
    Gain-of-function KCNJ2 (Kir2.1) variants such as V93I increase the
    inward-rectifier IK1 current and shorten atrial repolarization.
  gene_term:
    preferred_term: KCNJ2
    term:
      id: hgnc:6263
      label: KCNJ2
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:15922306
    reference_title: "A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Kir2.1 V93I mutation may play a role in initiating and/or maintaining AF by
      increasing the activity of the inward rectifier K(+) channel.
    explanation: >-
      Supports KCNJ2 gain-of-function as a causative familial-AF mechanism via
      increased IK1.
- name: GJA5 (connexin 40) variants
  association: Causative
  features: >-
    Germline or atrial-tissue-restricted somatic GJA5 missense variants impair
    connexin-40 gap-junction assembly and atrial electrical coupling.
  gene_term:
    preferred_term: GJA5
    term:
      id: hgnc:4279
      label: GJA5
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:16790700
    reference_title: "Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four novel heterozygous missense mutations were identified in 4 of the 15
      patients.
    explanation: >-
      Documents GJA5 missense variants (somatic and germline) in patients with
      idiopathic AF.
- name: KCNE2 gain-of-function variants
  association: Causative
  features: >-
    Gain-of-function variants in the potassium-channel beta subunit KCNE2 are
    associated with familial AF through enhancement of cardiac potassium current.
  gene_term:
    preferred_term: KCNE2
    term:
      id: hgnc:6242
      label: KCNE2
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
- name: NPPA variants
  association: Causative
  features: >-
    Variants in NPPA (atrial natriuretic peptide precursor) are linked to
    familial AF.
  gene_term:
    preferred_term: NPPA
    term:
      id: hgnc:7939
      label: NPPA
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
- name: SCN5A variants
  association: Associated
  features: >-
    Cardiac sodium-channel SCN5A variants are associated with familial AF as part
    of the broader SCN5A arrhythmia spectrum.
  gene_term:
    preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
treatments:
- name: Oral Anticoagulation
  description: >-
    Anticoagulation for stroke prevention, guided by individual thromboembolic
    risk, as in other forms of atrial fibrillation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Rate or Rhythm Control
  description: >-
    Antiarrhythmic drugs, atrioventricular nodal rate-control agents, or
    catheter ablation to control ventricular rate or restore/maintain sinus
    rhythm.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Genetic Counseling
  description: >-
    Counseling for affected families given autosomal dominant inheritance, with
    consideration of cascade screening of first-degree relatives.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
notes: >-
  Familial AF is genetically heterogeneous; OMIM enumerates numerous ATFB loci
  (familial AF 1-18 in MONDO). The well-validated, mechanistically informative
  subtypes are represented here as has_subtypes rather than as separate
  gene-level files, consistent with the issue #4242 recommendation to prefer a
  single lumped entry. This entry is distinct from the general/acquired Atrial
  Fibrillation entry (MONDO:0004981). The grouping-membership decision for the
  Inherited Arrhythmia Syndromes grouping (broaden vs. spin off an atrial/
  conduction sibling grouping) is deferred to maintainers per #4242.
references:
- reference: PMID:12522251
  title: "KCNQ1 gain-of-function mutation in familial atrial fibrillation."
  findings: []
- reference: PMID:15922306
  title: "A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation."
  findings: []
- reference: PMID:16790700
  title: "Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation."
  findings: []
📚

References & Deep Research

References

3
KCNQ1 gain-of-function mutation in familial atrial fibrillation.
No top-level findings curated for this source.
A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation.
No top-level findings curated for this source.
Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation.
No top-level findings curated for this source.