Familial Atrial Fibrillation

Genetic MONDO:0018054 Pathograph 14 Show in embeddings browser Cardiac Arrhythmia Channelopathy

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). A second group of loci reaches the same substrate without shortening the action potential: loss-of-function KCNA5 (Kv1.5/IKur) lengthens it instead, the sodium channel beta subunits SCN1B and SCN2B reduce SCN5A-mediated current, ABCC9 encodes SUR2A, the regulatory rather than pore-forming subunit of the KATP channel, and two genes that are not ion channel subunits at all - the nuclear pore component NUP155 and the atrial-selective myosin light chain MYL4 - produce AF through nucleocytoplasmic transport failure and atrial cardiomyopathy respectively. 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.

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1
Inheritance
5
Pathophys.
3
Phenotypes
14
Pathograph
13
Genes
3
Medical Actions
18
Subtypes
2
Datasets
12
References
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Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant inheritance
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Subtypes

18
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
ZFHX3 hgnc:777 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ZFHX3 (hgnc:777). hgnc:777 is a gene from the HUGO Gene Nomenclature Committee.
The 16q22 ZFHX3 locus. Unlike the other numbered entities listed here, this one did not come from family linkage: it was found by genome-wide association, and the reported signal is a common intronic variant with a per-allele odds ratio near 1.2. It is therefore a common-variant susceptibility locus sitting inside a series of otherwise Mendelian-framed entities, and this entry grades it SUSCEPTIBILITY rather than causative - see the ZFHX3 genetic record and the entry notes.
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.
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Pathophysiology

5
Atrial Ion-Channel or Coupling Variant
A germline (or, for GJA5, atrial-tissue-restricted somatic) variant alters an atrial ion channel, a gap-junction protein, or another atrial-restricted 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, SCN5A, and loss-of-function KCNA5 (IKur) variants. Three further loci reach this node without a pore-forming potassium or sodium channel being the mutated protein: ABCC9 encodes SUR2A, the regulatory rather than pore-forming subunit of the KATP channel; NUP155 is a nuclear pore component; and MYL4 encodes the atrial-selective essential myosin light chain. The sodium channel beta subunits SCN1B and SCN2B act indirectly, by reducing SCN5A-mediated current.
Atrial Cardiomyocyte CL:0002129 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Atrial Cardiomyocyte, annotated with regular atrial cardiac myocyte (CL:0002129). CL:0002129 is a cell type from the Cell Ontology.
KCNQ1 hgnc:6294 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KCNQ1 (hgnc:6294). hgnc:6294 is a gene from the HUGO Gene Nomenclature Committee. KCNE2 hgnc:6242 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KCNE2 (hgnc:6242). hgnc:6242 is a gene from the HUGO Gene Nomenclature Committee. KCNJ2 hgnc:6263 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KCNJ2 (hgnc:6263). hgnc:6263 is a gene from the HUGO Gene Nomenclature Committee. KCNA5 hgnc:6224 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KCNA5 (hgnc:6224). hgnc:6224 is a gene from the HUGO Gene Nomenclature Committee. ABCC9 hgnc:60 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ABCC9 (hgnc:60). hgnc:60 is a gene from the HUGO Gene Nomenclature Committee. GJA5 hgnc:4279 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GJA5 (hgnc:4279). hgnc:4279 is a gene from the HUGO Gene Nomenclature Committee. NPPA hgnc:7939 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NPPA (hgnc:7939). hgnc:7939 is a gene from the HUGO Gene Nomenclature Committee. SCN5A hgnc:10593 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SCN5A (hgnc:10593). hgnc:10593 is a gene from the HUGO Gene Nomenclature Committee. SCN1B hgnc:10586 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SCN1B (hgnc:10586). hgnc:10586 is a gene from the HUGO Gene Nomenclature Committee. SCN2B hgnc:10589 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SCN2B (hgnc:10589). hgnc:10589 is a gene from the HUGO Gene Nomenclature Committee. NUP155 hgnc:8063 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NUP155 (hgnc:8063). hgnc:8063 is a gene from the HUGO Gene Nomenclature Committee. MYL4 hgnc:7585 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYL4 (hgnc:7585). hgnc:7585 is a gene from the HUGO Gene Nomenclature Committee.
Cardiac conduction GO:0061337 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Cardiac conduction (GO:0061337). GO:0061337 is a biological process from the Gene Ontology.
Downstream
Shortened Atrial Action Potential and Refractoriness Gain-of-function potassium-channel variants increase repolarizing current and abbreviate the atrial action potential duration and effective refractory period.
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. KCNQ1, KCNE2 and KCNJ2 reach this node by gain of function; KCNA5 does not, and is modelled on the opposite route - loss of IKur lengthens rather than shortens the atrial action potential and produces early afterdepolarizations instead.
Atrial Cardiomyocyte CL:0002129 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Atrial Cardiomyocyte, annotated with regular atrial cardiac myocyte (CL:0002129). CL:0002129 is a cell type from the Cell Ontology.
KCNQ1 hgnc:6294 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KCNQ1 (hgnc:6294). hgnc:6294 is a gene from the HUGO Gene Nomenclature Committee. KCNE2 hgnc:6242 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KCNE2 (hgnc:6242). hgnc:6242 is a gene from the HUGO Gene Nomenclature Committee. KCNJ2 hgnc:6263 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KCNJ2 (hgnc:6263). hgnc:6263 is a gene from the HUGO Gene Nomenclature Committee.
Atrial cardiac muscle cell action potential GO:0086014 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Atrial cardiac muscle cell action potential (GO:0086014). GO:0086014 is a biological process from the Gene Ontology. Membrane repolarization during cardiac action potential GO:0086013 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Membrane repolarization during cardiac action potential, annotated with membrane repolarization during cardiac muscle cell action potential (GO:0086013). GO:0086013 is a biological process from the Gene Ontology.
Downstream
Atrial Arrhythmogenic Substrate A shortened refractory period and reduced reentry wavelength establish a substrate permissive for sustained reentrant atrial activity.
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 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Atrial Cardiomyocyte, annotated with regular atrial cardiac myocyte (CL:0002129). CL:0002129 is a cell type from the Cell Ontology.
GJA5 hgnc:4279 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GJA5 (hgnc:4279). hgnc:4279 is a gene from the HUGO Gene Nomenclature Committee.
Electrical coupling in cardiac conduction GO:0086064 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Electrical coupling in cardiac conduction, annotated with cell communication by electrical coupling involved in cardiac conduction (GO:0086064). GO:0086064 is a biological process from the Gene Ontology.
Downstream
Atrial Arrhythmogenic Substrate Impaired electrical coupling slows and disorganizes atrial conduction, contributing to the reentrant substrate.
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 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Atrial Cardiomyocyte, annotated with regular atrial cardiac myocyte (CL:0002129). CL:0002129 is a cell type from the Cell Ontology.
Cardiac muscle cell action potential GO:0086001 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Cardiac muscle cell action potential (GO:0086001). GO:0086001 is a biological process from the Gene Ontology.
Downstream
Sustained Atrial Fibrillation The reentry-prone atrial substrate manifests clinically as sustained or recurrent atrial fibrillation.
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 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Atrial Cardiomyocyte, annotated with regular atrial cardiac myocyte (CL:0002129). CL:0002129 is a cell type from the Cell Ontology.
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.
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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.
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Phenotypes

3
Atrial Fibrillation VERY_FREQUENT Cardiovascular HP:0005110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial fibrillation (HP:0005110). HP:0005110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID: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 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Palpitations (HP:0001962). HP:0001962 is a phenotype from the Human Phenotype Ontology.
Stroke Cardiovascular HP:0001297 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stroke (HP:0001297). HP:0001297 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16772329 SUPPORT BACKGROUND Human Clinical
"Predisposing to stroke and heart failure, this common condition is increasingly recognized as a heritable disorder."
Quoted from the paper's introduction, where it restates the established clinical consequence of atrial fibrillation rather than reporting this study's own finding, which is why it is marked BACKGROUND. It supports the stroke risk but says nothing specific to the familial forms.
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Genetic Associations

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KCNQ1 gain-of-function variants (Causative)
Gene: KCNQ1 hgnc:6294 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KCNQ1 (hgnc:6294). hgnc:6294 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant
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 S140G as the causative mutation in a family with hereditary persistent AF, which is the human genetic basis for listing KCNQ1 as a causative gene here.
PMID:12522251 SUPPORT In Vitro
"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 the gain-of-function direction, distinct from the loss-of-function KCNQ1 mechanism of long QT syndrome. Graded IN_VITRO because the measurement is heterologous-expression electrophysiology in COS cells rather than a human observation.
KCNJ2 gain-of-function variants (Causative)
Gene: KCNJ2 hgnc:6263 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KCNJ2 (hgnc:6263). hgnc:6263 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
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 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GJA5 (hgnc:4279). hgnc:4279 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE_AND_SOMATIC
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 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KCNE2 (hgnc:6242). hgnc:6242 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant
Show evidence (3 references)
PMID:15368194 SUPPORT Human Clinical
"The mutation was present in all affected members in the two kindreds and was absent in 462 healthy unrelated Chinese subjects."
Cosegregation in two kindreds with absence from a large control set, the human-genetic basis of the KCNE2 claim.
PMID:15368194 SUPPORT Human Clinical
"An arginine-to-cysteine mutation at position 27 (R27C) of KCNE2, the beta subunit of the KCNQ1-KCNE2 channel responsible for a background potassium current, was found in 2 of the 28 probands."
The variant and the 2-of-28 yield quoted in this record's note.
PMID:15368194 SUPPORT In Vitro
"Similar to KCNQ1 S140G, the mutation had a gain-of-function effect on the KCNQ1-KCNE2 channel; unlike long QT syndrome-associated KCNE2 mutations, it did not alter HERG-KCNE2 current."
Functional demonstration that the AF-associated KCNE2 variant acts by gain of function, and distinguishes it from the long-QT KCNE2 mechanism.
NPPA variants (Causative)
Gene: NPPA hgnc:7939 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NPPA (hgnc:7939). hgnc:7939 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant
Show evidence (3 references)
PMID:18614783 SUPPORT Human Clinical
"In a family with 11 clinically affected members, we mapped an atrial fibrillation locus to chromosome 1p36-p35 and identified a heterozygous frameshift mutation in the gene encoding atrial natriuretic peptide."
The linkage and variant identification behind the NPPA claim, with the size of the informative family.
PMID:18614783 SUPPORT Human Clinical
"Circulating chimeric atrial natriuretic peptide (ANP) was detected in high concentration in subjects with the mutation"
The human half of the mechanism: carriers of the frameshift circulate the chimeric peptide at high concentration, which is what makes the peptide rather than loss of normal ANP the candidate mediator.
PMID:18614783 SUPPORT Model Organism
"shortened atrial action potentials were seen in an isolated heart model, creating a possible substrate for atrial fibrillation"
Links the NPPA frameshift to atrial action potential shortening, the mechanism this entry models; the electrophysiology is from isolated perfused rat heart rather than from patients, so this half is graded MODEL_ORGANISM.
SCN5A variants (Associated)
Gene: SCN5A hgnc:10593 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SCN5A (hgnc:10593). hgnc:10593 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: RISK_FACTOR variant_origin: GERMLINE
Autosomal dominant
Show evidence (3 references)
PMID:18378609 SUPPORT Human Clinical
"In 10 probands (2.7%), 8 novel variants not found in the control population (0%; P=0.001) were identified."
The yield of novel SCN5A variants in a resequenced AF cohort against matched controls.
PMID:18378609 SUPPORT Human Clinical
"Mutations or rare variants in SCN5A may predispose patients with or without underlying heart disease to AF."
The authors' own hedged conclusion, and the reason this record is graded as a risk factor rather than as causative.
PMID:18378609 SUPPORT Human Clinical
"We also identified 11 rare missense variants in 12 probands (3.2%) that have previously been associated with inherited arrhythmia syndromes (eg, congenital long-QT syndrome and Brugada syndrome)."
The overlap with long-QT and Brugada variants quoted in this record's note, at a share comparable to the novel-variant yield above it.
KCNA5 loss-of-function variants (Causative)
Gene: KCNA5 hgnc:6224 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KCNA5 (hgnc:6224). hgnc:6224 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant
Show evidence (3 references)
PMID:16772329 SUPPORT Human Clinical
"The heterozygous E375X mutation, present in a familial case of atrial fibrillation and absent in 540 unrelated control individuals, introduced a premature stop codon disrupting the Kv1.5 channel protein."
The human variant and its absence from controls, the genetic basis of the KCNA5 claim.
PMID:16772329 SUPPORT Human Clinical
"Genomic DNA scanning revealed a nonsense mutation in KCNA5 that encodes Kv1.5, a voltage-gated potassium channel expressed in human atria."
Source for the atrial expression of Kv1.5 recorded in this record's note.
PMID:16772329 SUPPORT In Vitro
"Loss of channel function translated into action potential prolongation and early after-depolarization in human atrial myocytes, increasing vulnerability to stress-provoked triggered activity."
The mechanism recorded in the note above: IKur loss lengthens rather than shortens the atrial action potential.
ABCC9 (SUR2A) variant (Reported in a single adrenergic AF proband)
Gene: ABCC9 hgnc:60 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ABCC9 (hgnc:60). hgnc:60 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: UNKNOWN variant_origin: GERMLINE
Show evidence (2 references)
PMID:17245405 SUPPORT Human Clinical
"K(ATP) channelopathy caused by missense mutation (Thr1547Ile) of the ABCC9 gene conferring predisposition to adrenergic AF originating from the vein of Marshall."
The diagnosis line of the single case report that is the whole human basis of the ABCC9 claim.
PMID:17245405 SUPPORT Human Clinical
"A 53-year-old female presented with a 10-year history of paroxysmal atrial fibrillation (AF), precipitated by activity and refractory to medical therapy."
Establishes that the report concerns one patient, which is the reason for the UNKNOWN grading.
SCN1B loss-of-function variants (Reported in AF probands without family segregation)
Gene: SCN1B hgnc:10586 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SCN1B (hgnc:10586). hgnc:10586 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: UNKNOWN variant_origin: GERMLINE
Show evidence (3 references)
PMID:19808477 SUPPORT Human Clinical
"We identified 2 nonsynonymous variants in SCN1B (resulting in R85H, D153N) and 2 in SCN2B (R28Q, R28W) in patients with AF."
The variant identification behind both the SCN1B and the SCN2B records.
PMID:19808477 SUPPORT Human Clinical
"Screening for mutations in the 4 beta-subunit genes was performed in 480 patients with AF (118 patients with lone AF and 362 patients with AF and cardiovascular disease) and 548 control subjects (188 ethnically defined anonymized subjects and 360 subjects without AF)."
The screen and its denominators, quoted in this record's note.
PMID:19808477 SUPPORT Human Clinical
"In 3 of 4 mutation carriers, the ECGs showed saddleback-type ST-segment elevation in the right precordial leads."
The Brugada-overlap electrocardiographic phenotype recorded in the note.
SCN2B loss-of-function variants (Reported in AF probands without family segregation)
Gene: SCN2B hgnc:10589 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SCN2B (hgnc:10589). hgnc:10589 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: UNKNOWN variant_origin: GERMLINE
Show evidence (2 references)
PMID:19808477 SUPPORT Human Clinical
"We identified 2 nonsynonymous variants in SCN1B (resulting in R85H, D153N) and 2 in SCN2B (R28Q, R28W) in patients with AF."
The variant identification behind this record.
PMID:19808477 SUPPORT In Vitro
"In heterologous expression studies using Chinese hamster ovary cells, the mutant beta1- or beta2-subunits reduced SCN5A-mediated current and altered channel gating compared with coexpression of wild-type subunits."
The functional effect shared by the SCN1B and SCN2B variants: reduced sodium current through the Nav1.5 alpha subunit.
NUP155 biallelic loss-of-function variants (Causative)
Gene: NUP155 hgnc:8063 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NUP155 (hgnc:8063). hgnc:8063 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal recessive
Show evidence (3 references)
PMID:19070573 SUPPORT Human Clinical
"We have identified a homozygous mutation, R391H, in NUP155 that cosegregates with AF, affects nuclear localization of NUP155, and reduces nuclear envelope permeability."
Cosegregation of a homozygous NUP155 variant with AF, plus its cell biological effect.
PMID:19070573 SUPPORT Model Organism
"Homozygous NUP155(-/-) knockout mice die before E8.5, but heterozygous NUP155(+/-) mice show the AF phenotype."
Model-organism support that reduced NUP155 dosage is sufficient for an AF phenotype.
PMID:19070573 SUPPORT In Vitro
"The R391H mutation and reduction of NUP155 are associated with inhibition of both export of Hsp70 mRNA and nuclear import of Hsp70 protein."
The specific transport defect named in this record's note.
MYL4 biallelic loss-of-function variant (Causative)
Gene: MYL4 hgnc:7585 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYL4 (hgnc:7585). hgnc:7585 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal recessive
Show evidence (7 references)
PMID:27742809 SUPPORT Human Clinical
"We found eight homozygous carriers of the mutation, all of whom had early-onset AF."
The homozygote count and the complete penetrance among them.
PMID:27742809 SUPPORT Human Clinical
"We discovered a rare frameshift deletion in the myosin MYL4 gene (c.234delC) that associates with early-onset AF under a recessive mode of inheritance (allelic frequency = 0.58%)."
The variant, its frequency, and the recessive mode of inheritance recorded above.
PMID:27742809 SUPPORT Human Clinical
"Through a population approach we found a loss of function mutation in the myosin gene MYL4 that, in the homozygous state, is completely penetrant for early-onset AF."
The penetrance claim and the population-based study design.
+ 4 more references
ZFHX3 common-variant susceptibility locus (Common-variant association at 16q22, not a Mendelian locus)
Gene: ZFHX3 hgnc:777 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ZFHX3 (hgnc:777). hgnc:777 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (6 references)
PMID:19597491 SUPPORT Human Clinical
"A variant in the ZFHX3 gene on chromosome 16q22, rs7193343-T, associated significantly with AF (odds ratio OR = 1.21, P = 1.4 x 10(-10))."
The association and its effect size, which is the basis for grading this locus SUSCEPTIBILITY rather than causative.
PMID:19597491 SUPPORT Human Clinical
"The sequence variant rs7193343 is an intronic SNP located in the zinc finger homeobox 3 (ZFHX3) gene on chromosome 16q22, also called AT motif-binding factor 1 (ATBF1)."
Establishes that the reported variant is a common intronic polymorphism rather than a coding change.
PMID:19597491 SUPPORT Human Clinical
"We did not observe an association of rs7193343 with the expression of ZFHX3 in blood or adipose tissue."
Supports the caveat that the causal gene at this locus is assigned by proximity rather than by a demonstrated effect on ZFHX3.
+ 3 more references
💊

Medical Actions

3
Oral Anticoagulation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Anticoagulation for stroke prevention, guided by individual thromboembolic risk, as in other forms of atrial fibrillation.
Rate or Rhythm Control
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Antiarrhythmic drugs, atrioventricular nodal rate-control agents, or catheter ablation to control ventricular rate or restore/maintain sinus rhythm.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling for affected families given autosomal dominant inheritance, with consideration of cascade screening of first-degree relatives.
📊

Related Datasets

2
Gene-Gene Interactions Between A LMNA Variant and Common Polymorphisms Drive Early-Onset Atrial Fibrillation [ATAC-seq] geo:GSE295056
Atrial fibrillation (AF) is a common arrhythmia with a complex genetic basis, yet the molecular mechanisms linking rare and common variants remain unclear. Using induced pluripotent stem cell-derived atrial cardiomyocytes, we uncover a novel mechanism by which a rare pathogenic LMNA variant encoding Lamin A/C disrupts chromatin accessibility and gene regulation at AF-associated loci. Specifically, reduced accessibility at an SCN5A enhancer harboring an AF-associated variant leads to reduced sodium current, conduction abnormalities, and re-entrant AF.
human ATAC SEQ n=9
PMID:42156780
Identified by GEO DataSets index search for Familial Atrial Fibrillation (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Whole exome sequencing of 76 individuals with familial atrial fibrillation ega:EGAS00001003207
We investigated genetic background of familial and early onset atrial fibrillation (AF) with the aim of identify genes involved in atrial fibrillation pathology and are highly predisposing risk factors. We performed whole exome sequencing on 24 families where three or more family members suffered from AF.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Familial Atrial Fibrillation"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
{ }

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). A second group of
  loci reaches the same substrate without shortening the action potential:
  loss-of-function KCNA5 (Kv1.5/IKur) lengthens it instead, the sodium channel
  beta subunits SCN1B and SCN2B reduce SCN5A-mediated current, ABCC9 encodes
  SUR2A, the regulatory rather than pore-forming subunit of the KATP channel,
  and two genes that are not ion channel subunits at all - the nuclear pore
  component NUP155 and the atrial-selective myosin light chain MYL4 - produce AF
  through nucleocytoplasmic transport failure and atrial cardiomyopathy
  respectively.
  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.
  genes:
  - preferred_term: KCNQ1
    term:
      id: hgnc:6294
      label: KCNQ1
  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: >-
      The human linkage result behind this subtype: the S140G variant is the
      causative mutation in a family with hereditary persistent AF.
  - reference: PMID:12522251
    reference_title: "KCNQ1 gain-of-function mutation in familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    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 the gain-of-function direction that defines this subtype, and
      distinguishes it from the loss-of-function KCNQ1 variants of long QT
      syndrome, which is why the same gene supports two separate diseases. The
      quoted result is heterologous-expression electrophysiology in COS cells,
      not a human observation, so it is graded IN_VITRO.
- 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.
  genes:
  - preferred_term: KCNE2
    term:
      id: hgnc:6242
      label: KCNE2
  evidence:
  - reference: PMID:15368194
    reference_title: "Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An arginine-to-cysteine mutation at position 27 (R27C) of KCNE2, the beta subunit of the KCNQ1-KCNE2 channel responsible for a background potassium current, was found in 2 of the 28 probands."
    explanation: >-
      Names the variant and the channel it modulates, with a counted denominator
      of 28 unrelated kindreds screened across eight potassium-channel genes.
  - reference: PMID:15368194
    reference_title: "Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation was present in all affected members in the two kindreds and was absent in 462 healthy unrelated Chinese subjects."
    explanation: >-
      Co-segregation in both kindreds with absence from 462 controls, which is
      what separates a causative variant from a rare benign one.
- 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.
  genes:
  - preferred_term: KCNJ2
    term:
      id: hgnc:6263
      label: KCNJ2
  evidence:
  - 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: >-
      Documents the variant named in this subtype's description and its
      co-segregation within the kindred.
- 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.
  genes:
  - preferred_term: GJA5
    term:
      id: hgnc:4279
      label: GJA5
  evidence:
  - 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: >-
      States the proposed mechanism for this subtype in the authors' own hedged
      terms, which is the level of confidence the description should carry.
- 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. The mechanism is not a channel defect: a frameshift
    produces a circulating chimeric peptide, and the proposal is that this
    peptide, rather than loss of the normal one, shortens the atrial action
    potential. The circulating peptide is documented in human carriers, but the
    shortening step is shown in isolated perfused rat heart rather than in human
    atrium, so the peptide-to-substrate link remains an inference from a model
    system.
  genes:
  - preferred_term: NPPA
    term:
      id: hgnc:7939
      label: NPPA
  evidence:
  - reference: PMID:18614783
    reference_title: Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we mapped an atrial fibrillation locus to chromosome 1p36-p35 and identified a heterozygous frameshift mutation in the gene encoding atrial natriuretic peptide"
    explanation: >-
      Identifies the variant in a family with 11 clinically affected members,
      which is the linkage evidence behind this subtype.
  - reference: PMID:18614783
    reference_title: Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Circulating chimeric atrial natriuretic peptide (ANP) was detected in high concentration in subjects with the mutation"
    explanation: >-
      The human half of the mechanism: carriers of the frameshift actually
      circulate the chimeric peptide at high concentration, which is what makes
      the peptide rather than loss of normal ANP the candidate mediator.
  - reference: PMID:18614783
    reference_title: Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "shortened atrial action potentials were seen in an isolated heart model, creating a possible substrate for atrial fibrillation"
    explanation: >-
      Supplies the step from circulating peptide to arrhythmic substrate, and
      shows it converges on the same shortened atrial action potential as the
      potassium-channel arm by a route that involves no channel variant at all.
      The "isolated heart model" is isolated perfused rat heart, not human
      tissue, so this half is graded MODEL_ORGANISM. The authors write "possible
      substrate", and this subtype should not claim more than that.
- 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.
  genes:
  - preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  evidence:
  - reference: PMID:18378609
    reference_title: Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 6 families with >1 affected member, the novel variant cosegregated with AF."
    explanation: >-
      Co-segregation in six families is what makes this a familial subtype rather
      than an association from a case-control resequencing series.
  - reference: PMID:18378609
    reference_title: Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations or rare variants in SCN5A may predispose patients with or without underlying heart disease to AF."
    explanation: >-
      States the overlap with the broader SCN5A arrhythmia spectrum that this
      subtype's description records, and does so in the authors' own hedged
      terms, which is why the matching genetic entry is graded Associated rather
      than Causative.
- 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. This subtype runs the entry's main mechanism
    backwards: the potassium-channel arm shortens the atrial action potential and
    this one lengthens it, so a shortened refractory period is not a necessary
    condition for familial AF.
  genes:
  - preferred_term: KCNA5
    term:
      id: hgnc:6224
      label: KCNA5
  evidence:
  - reference: PMID:16772329
    reference_title: Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genomic DNA scanning revealed a nonsense mutation in KCNA5 that encodes Kv1.5, a voltage-gated potassium channel expressed in human atria."
    explanation: >-
      Identifies the loss-of-function lesion behind this subtype in a familial
      case, absent from 540 unrelated controls.
  - reference: PMID:16772329
    reference_title: Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Loss of channel function translated into action potential prolongation and early after-depolarization in human atrial myocytes, increasing vulnerability to stress-provoked triggered activity."
    explanation: >-
      Measured in human atrial myocytes rather than in patients, so graded
      IN_VITRO. It supplies both halves of this subtype's mechanistic claim,
      prolongation of the action potential and early afterdepolarizations, and it
      is the direct opposite of the shortening asserted for the KCNQ1 and KCNJ2
      subtypes.
- 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: >-
    AF associated with variants in ABCC9, which encodes the sulfonylurea
    receptor 2A (SUR2A), a regulatory subunit of the cardiac ATP-sensitive
    potassium channel (KATP). The reported Thr1547Ile variant impairs
    ADP-dependent channel opening while leaving ATP-induced inhibition intact,
    so the defect is a loss of stress-responsive KATP activation rather than a
    gain of function. The index report is a single patient whose relatives
    declined testing, so no co-segregation was established and the "familial"
    label here rests on the MONDO class rather than on demonstrated inheritance.
  genes:
  - preferred_term: ABCC9
    term:
      id: hgnc:60
      label: ABCC9
  evidence:
  - reference: PMID:17245405
    reference_title: "KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "K(ATP) channelopathy caused by missense mutation (Thr1547Ile) of the ABCC9 gene conferring predisposition to adrenergic AF originating from the vein of Marshall."
    explanation: >-
      The human genetic finding behind this subtype: an ABCC9 missense variant
      in a patient with adrenergically triggered AF and a structurally normal
      heart.
  - reference: PMID:17245405
    reference_title: "KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "retained ATP-induced inhibition of potassium current, but demonstrated a blunted response to ADP"
    explanation: >-
      Patch-clamp of mutant SUR2A co-expressed with Kir6.2 gives the direction of
      the channel defect, and is why this subtype's description says impaired
      ADP-dependent opening rather than gain of function. Graded IN_VITRO
      because the recording is in a heterologous expression system.
  - reference: PMID:17245405
    reference_title: "KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient’s first-degree relatives did not consent to clinical or genetic testing, precluding segregation analysis."
    explanation: >-
      Records the limit on this subtype's evidence: inheritance was never
      demonstrated for the index case, which is why the description does not
      claim co-segregation.
- 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: >-
    AF associated with variants in SCN1B, encoding the sodium channel beta-1
    subunit, which modulates Nav1.5 gating kinetics and membrane expression.
    The reported variants reduce SCN5A-mediated current, placing this subtype
    with the reduced-sodium-current arm rather than the repolarization arm. The
    index report is a case-control screen of 480 AF patients rather than a
    pedigree study, so these are susceptibility variants absent from controls
    rather than demonstrated Mendelian segregation.
  genes:
  - preferred_term: SCN1B
    term:
      id: hgnc:10586
      label: SCN1B
  evidence:
  - reference: PMID:19808477
    reference_title: "Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 2 nonsynonymous variants in SCN1B (resulting in R85H, D153N) and 2 in SCN2B (R28Q, R28W) in patients with AF. These occur at residues highly conserved across mammals and were absent in control subjects."
    explanation: >-
      The human genetic basis for both beta-subunit subtypes: rare conserved-residue
      variants found in AF patients and absent from the control cohorts.
  - reference: PMID:19808477
    reference_title: "Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In heterologous expression studies using Chinese hamster ovary cells, the mutant beta1- or beta2-subunits reduced SCN5A-mediated current and altered channel gating compared with coexpression of wild-type subunits."
    explanation: >-
      Gives the functional direction this subtype records, and grounds the claim
      that the beta-subunit variants act by reducing sodium current. Graded
      IN_VITRO because the measurement is in CHO cells.
- 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: >-
    AF associated with 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, and the reported R28Q and R28W variants reduce
    SCN5A-mediated current. Identified in the same case-control screen as the
    SCN1B variants, so the same caveat applies: these are susceptibility
    variants absent from controls rather than demonstrated Mendelian segregation.
  genes:
  - preferred_term: SCN2B
    term:
      id: hgnc:10589
      label: SCN2B
  evidence:
  - reference: PMID:19808477
    reference_title: "Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 2 nonsynonymous variants in SCN1B (resulting in R85H, D153N) and 2 in SCN2B (R28Q, R28W) in patients with AF. These occur at residues highly conserved across mammals and were absent in control subjects."
    explanation: >-
      Names the two SCN2B variants (R28Q, R28W) that define this subtype and
      records their absence from the control cohorts.
  - reference: PMID:19808477
    reference_title: "Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In heterologous expression studies using Chinese hamster ovary cells, the mutant beta1- or beta2-subunits reduced SCN5A-mediated current and altered channel gating compared with coexpression of wild-type subunits."
    explanation: >-
      Supports the reduced-sodium-current mechanism this subtype records; the
      beta2 mutants were tested in the same CHO co-expression system as beta1.
      Graded IN_VITRO for that reason.
- 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.
  genes:
  - preferred_term: NUP155
    term:
      id: hgnc:8063
      label: NUP155
  evidence:
  - reference: PMID:19070573
    reference_title: Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified a homozygous mutation, R391H, in NUP155 that cosegregates with AF, affects nuclear localization of NUP155, and reduces nuclear envelope permeability."
    explanation: >-
      Names the homozygous variant, which is what makes this the recessive
      subtype, and gives the molecular consequence at the nuclear pore.
  - reference: PMID:19070573
    reference_title: Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "We previously mapped an AF locus to chromosome 5p13 in an AF family with sudden death in early childhood."
    explanation: >-
      Supports the severe phenotype this subtype records. Quoted from the paper's
      restatement of its own earlier linkage work rather than from the results
      reported here, which is why it is marked BACKGROUND.
- 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. Unlike
    the channelopathy subtypes, this one is a structural atrial disease, so the
    entry's framing of familial AF as arising in structurally normal hearts does
    not hold here.
  genes:
  - preferred_term: MYL4
    term:
      id: hgnc:7585
      label: MYL4
  evidence:
  - reference: PMID:29080865
    reference_title: "Dysfunction of Myosin Light-Chain 4 (MYL4) Leads to Heritable Atrial Cardiomyopathy With Electrical, Contractile, and Structural Components: Evidence From Genetically-Engineered Rats."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation cosegregated with atrial standstill (selected as the principal
      presenting trait) with a logarithm of the odds score of 5.3.
    explanation: >-
      Co-segregation in a large multiplex pedigree at a LOD score of 5.3, which is
      the human genetic basis of this subtype. Note the trait selected for linkage
      was atrial standstill rather than fibrillation.
  - reference: PMID:29080865
    reference_title: "Dysfunction of Myosin Light-Chain 4 (MYL4) Leads to Heritable Atrial Cardiomyopathy With Electrical, Contractile, and Structural Components: Evidence From Genetically-Engineered Rats."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Both MYL4 p.E11K knock-in rats and MYL4 knockout rats showed progressive
      atrial electrophysiological, contractile, and fibrotic abnormalities,
      similar to affected patients.
    explanation: >-
      Knock-in and knockout rats reproduce the progressive atrial cardiomyopathy,
      which is what supports calling this subtype structural rather than purely
      electrical. Graded MODEL_ORGANISM because the progression is measured in
      rats.
- 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: >-
    The 16q22 ZFHX3 locus. Unlike the other numbered entities listed here, this
    one did not come from family linkage: it was found by genome-wide
    association, and the reported signal is a common intronic variant with a
    per-allele odds ratio near 1.2. It is therefore a common-variant
    susceptibility locus sitting inside a series of otherwise Mendelian-framed
    entities, and this entry grades it SUSCEPTIBILITY rather than causative -
    see the ZFHX3 genetic record and the entry notes.
  genes:
  - preferred_term: ZFHX3
    term:
      id: hgnc:777
      label: ZFHX3

- 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, a gap-junction protein, or another atrial-restricted
    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, SCN5A, and loss-of-function KCNA5 (IKur)
    variants. Three further loci reach this node without a pore-forming
    potassium or sodium channel being the mutated protein: ABCC9 encodes SUR2A,
    the regulatory rather than pore-forming subunit of the KATP channel; NUP155
    is a nuclear pore component; and MYL4 encodes the atrial-selective essential
    myosin light chain. The sodium channel beta subunits SCN1B and SCN2B act indirectly, by
    reducing SCN5A-mediated current.
  genes:
  - preferred_term: KCNQ1
    term:
      id: hgnc:6294
      label: KCNQ1
  - preferred_term: KCNE2
    term:
      id: hgnc:6242
      label: KCNE2
  - preferred_term: KCNJ2
    term:
      id: hgnc:6263
      label: KCNJ2
  - preferred_term: KCNA5
    term:
      id: hgnc:6224
      label: KCNA5
  - preferred_term: ABCC9
    term:
      id: hgnc:60
      label: ABCC9
  - preferred_term: GJA5
    term:
      id: hgnc:4279
      label: GJA5
  - preferred_term: NPPA
    term:
      id: hgnc:7939
      label: NPPA
  - preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  - preferred_term: SCN1B
    term:
      id: hgnc:10586
      label: SCN1B
  - preferred_term: SCN2B
    term:
      id: hgnc:10589
      label: SCN2B
  - preferred_term: NUP155
    term:
      id: hgnc:8063
      label: NUP155
  - preferred_term: MYL4
    term:
      id: hgnc:7585
      label: MYL4
  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. KCNQ1, KCNE2 and KCNJ2 reach
    this node by gain of function; KCNA5 does not, and is modelled on the
    opposite route - loss of IKur lengthens rather than shortens the atrial
    action potential and produces early afterdepolarizations instead.
  genes:
  - preferred_term: KCNQ1
    term:
      id: hgnc:6294
      label: KCNQ1
  - preferred_term: KCNE2
    term:
      id: hgnc:6242
      label: KCNE2
  - preferred_term: KCNJ2
    term:
      id: hgnc:6263
      label: KCNJ2
  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.
  genes:
  - preferred_term: GJA5
    term:
      id: hgnc:4279
      label: GJA5
  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
  evidence:
  - reference: PMID:16772329
    reference_title: Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Predisposing to stroke and heart failure, this common condition is increasingly recognized as a heritable disorder."
    explanation: >-
      Quoted from the paper's introduction, where it restates the established
      clinical consequence of atrial fibrillation rather than reporting this
      study's own finding, which is why it is marked BACKGROUND. It supports the
      stroke risk but says nothing specific to the familial forms.
genetic:
- name: KCNQ1 gain-of-function variants
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: KCNQ1-related
  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: >-
      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 S140G as the causative mutation in a family with hereditary
      persistent AF, which is the human genetic basis for listing KCNQ1 as a
      causative gene here.
  - reference: PMID:12522251
    reference_title: "KCNQ1 gain-of-function mutation in familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    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 the gain-of-function direction, distinct from the
      loss-of-function KCNQ1 mechanism of long QT syndrome. Graded IN_VITRO
      because the measurement is heterologous-expression electrophysiology in
      COS cells rather than a human observation.
- name: KCNJ2 gain-of-function variants
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: KCNJ2-related
  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
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE_AND_SOMATIC
  subtype: GJA5-related
  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
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: KCNE2-related
  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
  notes: >-
    The reported lesion is a single recurrent substitution, R27C, found in 2 of
    28 unrelated Chinese AF kindreds, cosegregating with disease in both and
    absent from 462 controls. Its functional effect parallels KCNQ1 S140G - a
    gain of function on the KCNQ1-KCNE2 channel - which is why the two are
    modelled on the same repolarization-shortening arm of this entry.
  evidence:
  - reference: PMID:15368194
    reference_title: "Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation was present in all affected members in the two kindreds and
      was absent in 462 healthy unrelated Chinese subjects.
    explanation: >-
      Cosegregation in two kindreds with absence from a large control set, the
      human-genetic basis of the KCNE2 claim.
  - reference: PMID:15368194
    reference_title: "Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An arginine-to-cysteine mutation at position 27 (R27C) of KCNE2, the beta
      subunit of the KCNQ1-KCNE2 channel responsible for a background potassium
      current, was found in 2 of the 28 probands.
    explanation: >-
      The variant and the 2-of-28 yield quoted in this record's note.
  - reference: PMID:15368194
    reference_title: "Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Similar to KCNQ1 S140G, the mutation had a gain-of-function effect on the
      KCNQ1-KCNE2 channel; unlike long QT syndrome-associated KCNE2 mutations,
      it did not alter HERG-KCNE2 current.
    explanation: >-
      Functional demonstration that the AF-associated KCNE2 variant acts by gain
      of function, and distinguishes it from the long-QT KCNE2 mechanism.
- name: NPPA variants
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: NPPA-related
  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
  notes: >-
    NPPA is the one locus in this entry whose product is a circulating hormone
    rather than an ion channel or a junctional protein. The defining family was
    mapped by linkage to 1p36-p35 and carries a heterozygous frameshift; the
    mutant peptide circulates at high concentration and shortens the atrial
    action potential, which is how the entry connects it to the shared
    re-entry-prone substrate.
  evidence:
  - reference: PMID:18614783
    reference_title: "Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a family with 11 clinically affected members, we mapped an atrial
      fibrillation locus to chromosome 1p36-p35 and identified a heterozygous
      frameshift mutation in the gene encoding atrial natriuretic peptide.
    explanation: >-
      The linkage and variant identification behind the NPPA claim, with the
      size of the informative family.
  - reference: PMID:18614783
    reference_title: "Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Circulating chimeric atrial natriuretic peptide (ANP) was detected in high
      concentration in subjects with the mutation
    explanation: >-
      The human half of the mechanism: carriers of the frameshift circulate the
      chimeric peptide at high concentration, which is what makes the peptide
      rather than loss of normal ANP the candidate mediator.
  - reference: PMID:18614783
    reference_title: "Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      shortened atrial action potentials were seen in an isolated heart model,
      creating a possible substrate for atrial fibrillation
    explanation: >-
      Links the NPPA frameshift to atrial action potential shortening, the
      mechanism this entry models; the electrophysiology is from isolated
      perfused rat heart rather than from patients, so this half is graded
      MODEL_ORGANISM.
- name: SCN5A variants
  association: Associated
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  subtype: SCN5A-related
  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
  notes: >-
    Graded RISK_FACTOR rather than CAUSATIVE deliberately. The largest
    resequencing study found novel variants in 2.7% of AF probands with
    cosegregation in six informative families, but its own conclusion is that
    such variants "may predispose" to AF, and a further 3.2% of probands carried
    rare variants already attributed to long-QT or Brugada syndrome. SCN5A is
    therefore better read as a shared arrhythmia-susceptibility locus whose AF
    phenotype overlaps other sodium-channel syndromes than as a dedicated
    familial-AF gene.
  evidence:
  - reference: PMID:18378609
    reference_title: "Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 10 probands (2.7%), 8 novel variants not found in the control
      population (0%; P=0.001) were identified.
    explanation: >-
      The yield of novel SCN5A variants in a resequenced AF cohort against
      matched controls.
  - reference: PMID:18378609
    reference_title: "Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations or rare variants in SCN5A may predispose patients with or
      without underlying heart disease to AF.
    explanation: >-
      The authors' own hedged conclusion, and the reason this record is graded
      as a risk factor rather than as causative.
  - reference: PMID:18378609
    reference_title: "Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also identified 11 rare missense variants in 12 probands (3.2%) that
      have previously been associated with inherited arrhythmia syndromes (eg,
      congenital long-QT syndrome and Brugada syndrome).
    explanation: >-
      The overlap with long-QT and Brugada variants quoted in this record's
      note, at a share comparable to the novel-variant yield above it.
- name: KCNA5 loss-of-function variants
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: KCNA5-related
  features: >-
    A heterozygous nonsense variant, E375X, truncates Kv1.5 before the voltage
    sensor and pore, abolishing the atrial-selective ultrarapid delayed rectifier
    current IKur and acting dominant-negatively on the wild-type channel.
  gene_term:
    preferred_term: KCNA5
    term:
      id: hgnc:6224
      label: KCNA5
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    KCNA5 runs opposite to the potassium-channel subtypes above: KCNQ1, KCNE2
    and KCNJ2 act by gain of function and shorten the atrial action potential,
    whereas KCNA5 loss of IKur prolongs it and produces early afterdepolarization
    and triggered activity. Both routes converge on an arrhythmogenic atrium,
    which is worth keeping visible because it means action potential shortening
    is not a necessary feature of monogenic AF.

    The channel is described by its discoverers as expressed in human atria,
    which is the reason a defect in it produces an atrial arrhythmia.
  evidence:
  - reference: PMID:16772329
    reference_title: "Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The heterozygous E375X mutation, present in a familial case of atrial
      fibrillation and absent in 540 unrelated control individuals, introduced a
      premature stop codon disrupting the Kv1.5 channel protein.
    explanation: >-
      The human variant and its absence from controls, the genetic basis of the
      KCNA5 claim.
  - reference: PMID:16772329
    reference_title: "Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genomic DNA scanning revealed a nonsense mutation in KCNA5 that encodes
      Kv1.5, a voltage-gated potassium channel expressed in human atria.
    explanation: >-
      Source for the atrial expression of Kv1.5 recorded in this record's note.
  - reference: PMID:16772329
    reference_title: "Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Loss of channel function translated into action potential prolongation and
      early after-depolarization in human atrial myocytes, increasing
      vulnerability to stress-provoked triggered activity.
    explanation: >-
      The mechanism recorded in the note above: IKur loss lengthens rather than
      shortens the atrial action potential.
- name: ABCC9 (SUR2A) variant
  association: Reported in a single adrenergic AF proband
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  subtype: ABCC9-related
  features: >-
    A missense substitution, Thr1547Ile, in the KATP channel regulatory subunit
    SUR2A, reported in one woman with activity-precipitated paroxysmal AF
    originating from the vein of Marshall.
  gene_term:
    preferred_term: ABCC9
    term:
      id: hgnc:60
      label: ABCC9
  notes: >-
    Graded UNKNOWN rather than CAUSATIVE because the human evidence is a single
    proband. The report is a clinical case with supporting molecular phenotyping
    and a targeted knockout, not a family with segregation, and no independent
    AF family was found when PubMed was searched for ABCC9 with atrial
    fibrillation, and for SUR2A with KATP channel and atrial fibrillation, in
    September 2026: those searches returned this case report and reviews citing
    it, and no independent family series. MONDO nevertheless lists the gene as
    the causal gene of atrial fibrillation, familial, 12, which is what this
    record reconciles against; the disagreement is about strength of evidence
    rather than about whether the observation exists.

    No inheritance block is recorded here on purpose: a single proband does not
    establish a mode of inheritance.
  evidence:
  - reference: PMID:17245405
    reference_title: "KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      K(ATP) channelopathy caused by missense mutation (Thr1547Ile) of the ABCC9
      gene conferring predisposition to adrenergic AF originating from the vein
      of Marshall.
    explanation: >-
      The diagnosis line of the single case report that is the whole human basis
      of the ABCC9 claim.
  - reference: PMID:17245405
    reference_title: "KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 53-year-old female presented with a 10-year history of paroxysmal atrial
      fibrillation (AF), precipitated by activity and refractory to medical
      therapy.
    explanation: >-
      Establishes that the report concerns one patient, which is the reason for
      the UNKNOWN grading.
- name: SCN1B loss-of-function variants
  association: Reported in AF probands without family segregation
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  subtype: SCN1B-related
  features: >-
    Two nonsynonymous variants, R85H and D153N, identified in AF probands and
    absent from controls; both reduce SCN5A-mediated current when coexpressed.
  gene_term:
    preferred_term: SCN1B
    term:
      id: hgnc:10586
      label: SCN1B
  notes: >-
    SCN1B and SCN2B were reported together in one screen of 480 AF patients
    against 548 controls. The variants are rare, at conserved residues, absent
    from controls, and reduce sodium current in heterologous expression - but
    the report describes probands rather than pedigrees, so cosegregation is not
    established and the grading here is UNKNOWN.

    A detail worth carrying: three of the four beta-subunit variant carriers had
    saddleback right-precordial ST elevation, which places these variants in the
    Brugada-overlap part of the sodium-channel spectrum rather than in isolated
    AF.
  evidence:
  - reference: PMID:19808477
    reference_title: "Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 2 nonsynonymous variants in SCN1B (resulting in R85H, D153N)
      and 2 in SCN2B (R28Q, R28W) in patients with AF.
    explanation: >-
      The variant identification behind both the SCN1B and the SCN2B records.
  - reference: PMID:19808477
    reference_title: "Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Screening for mutations in the 4 beta-subunit genes was performed in 480
      patients with AF (118 patients with lone AF and 362 patients with AF and
      cardiovascular disease) and 548 control subjects (188 ethnically defined
      anonymized subjects and 360 subjects without AF).
    explanation: >-
      The screen and its denominators, quoted in this record's note.
  - reference: PMID:19808477
    reference_title: "Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 3 of 4 mutation carriers, the ECGs showed saddleback-type ST-segment
      elevation in the right precordial leads.
    explanation: >-
      The Brugada-overlap electrocardiographic phenotype recorded in the note.
- name: SCN2B loss-of-function variants
  association: Reported in AF probands without family segregation
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  subtype: SCN2B-related
  features: >-
    Two nonsynonymous variants at the same residue, R28Q and R28W, identified in
    AF probands and absent from controls; both reduce SCN5A-mediated current when
    coexpressed.
  gene_term:
    preferred_term: SCN2B
    term:
      id: hgnc:10589
      label: SCN2B
  notes: >-
    From the same screen as SCN1B above and graded the same way, for the same
    reason: probands rather than pedigrees. The functional direction is shared
    with SCN5A loss of function, which is the mechanistic argument the authors
    make for a sodium-current route to AF.
  evidence:
  - reference: PMID:19808477
    reference_title: "Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 2 nonsynonymous variants in SCN1B (resulting in R85H, D153N)
      and 2 in SCN2B (R28Q, R28W) in patients with AF.
    explanation: >-
      The variant identification behind this record.
  - reference: PMID:19808477
    reference_title: "Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In heterologous expression studies using Chinese hamster ovary cells, the
      mutant beta1- or beta2-subunits reduced SCN5A-mediated current and altered
      channel gating compared with coexpression of wild-type subunits.
    explanation: >-
      The functional effect shared by the SCN1B and SCN2B variants: reduced
      sodium current through the Nav1.5 alpha subunit.
- name: NUP155 biallelic loss-of-function variants
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: NUP155-related
  features: >-
    A homozygous R391H substitution in the nucleoporin NUP155 that cosegregates
    with AF in the family in which the 5p13 locus was mapped, mislocalizes the
    protein, and reduces nuclear envelope permeability.
  gene_term:
    preferred_term: NUP155
    term:
      id: hgnc:8063
      label: NUP155
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    The only nuclear pore gene in this entry, and the one whose mechanism is
    furthest from ion flux: the reported defect is in nucleocytoplasmic
    transport, specifically of Hsp70 message and protein. It is also the
    strongest of the newer loci on human-plus-model evidence, since the
    heterozygous knockout mouse reproduces the AF phenotype even though the
    human variant is homozygous.
  evidence:
  - reference: PMID:19070573
    reference_title: "Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified a homozygous mutation, R391H, in NUP155 that
      cosegregates with AF, affects nuclear localization of NUP155, and reduces
      nuclear envelope permeability.
    explanation: >-
      Cosegregation of a homozygous NUP155 variant with AF, plus its cell
      biological effect.
  - reference: PMID:19070573
    reference_title: "Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Homozygous NUP155(-/-) knockout mice die before E8.5, but heterozygous
      NUP155(+/-) mice show the AF phenotype.
    explanation: >-
      Model-organism support that reduced NUP155 dosage is sufficient for an AF
      phenotype.
  - reference: PMID:19070573
    reference_title: "Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The R391H mutation and reduction of NUP155 are associated with inhibition
      of both export of Hsp70 mRNA and nuclear import of Hsp70 protein.
    explanation: >-
      The specific transport defect named in this record's note.
- name: MYL4 biallelic loss-of-function variant
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: MYL4-related
  features: >-
    A rare frameshift deletion, c.234delC, in the atrial-specific essential
    myosin light chain, fully penetrant for early-onset AF in the homozygous
    state.
  gene_term:
    preferred_term: MYL4
    term:
      id: hgnc:7585
      label: MYL4
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    MYL4 is the clearest demonstration in this entry that a monogenic AF gene
    need not be a channel: the product is the atrial-selective essential myosin
    light chain, and the phenotype is an atrial cardiomyopathy that includes
    sick sinus syndrome, stroke and sudden death alongside the arrhythmia. An
    independent family, reported separately, cosegregated a different MYL4
    missense variant with atrial standstill, and knock-in and knockout rats
    reproduced the progressive electrical, contractile and fibrotic phenotype.

    It is also the only locus here found by a population approach rather than by
    following a family, which is why the penetrance statement is unusually
    strong for this list. No case fraction is recorded: the study reports the
    allelic frequency and a homozygote count rather than a share of cases, and
    computing one from those two numbers would not be a reported figure.
  evidence:
  - reference: PMID:27742809
    reference_title: "A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found eight homozygous carriers of the mutation, all of whom had
      early-onset AF.
    explanation: >-
      The homozygote count and the complete penetrance among them.
  - reference: PMID:27742809
    reference_title: "A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We discovered a rare frameshift deletion in the myosin MYL4 gene
      (c.234delC) that associates with early-onset AF under a recessive mode of
      inheritance (allelic frequency = 0.58%).
    explanation: >-
      The variant, its frequency, and the recessive mode of inheritance recorded
      above.
  - reference: PMID:27742809
    reference_title: "A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through a population approach we found a loss of function mutation in the
      myosin gene MYL4 that, in the homozygous state, is completely penetrant
      for early-onset AF.
    explanation: >-
      The penetrance claim and the population-based study design.
  - reference: PMID:27742809
    reference_title: "A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three of the homozygotes had received pacemaker implantations due to sick
      sinus syndrome, three had suffered an ischemic stroke, and one suffered
      sudden cardiac death.
    explanation: >-
      The sick sinus syndrome, stroke and sudden death recorded in this record's
      note as the wider atrial-cardiomyopathy phenotype.
  - reference: PMID:29080865
    reference_title: >-
      Dysfunction of Myosin Light-Chain 4 (MYL4) Leads to Heritable Atrial
      Cardiomyopathy With Electrical, Contractile, and Structural Components:
      Evidence From Genetically-Engineered Rats.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myosin light-chain 4 (MYL4), encoding the atrial-selective essential
      myosin light chain, was identified as a candidate gene.
    explanation: >-
      Source for describing MYL4's product as the atrial-selective essential
      myosin light chain.
  - reference: PMID:29080865
    reference_title: >-
      Dysfunction of Myosin Light-Chain 4 (MYL4) Leads to Heritable Atrial
      Cardiomyopathy With Electrical, Contractile, and Structural Components:
      Evidence From Genetically-Engineered Rats.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation cosegregated with atrial standstill (selected as the
      principal presenting trait) with a logarithm of the odds score of 5.3.
    explanation: >-
      The independent family and cosegregation supporting MYL4 beyond the
      Icelandic population study.
  - reference: PMID:29080865
    reference_title: >-
      Dysfunction of Myosin Light-Chain 4 (MYL4) Leads to Heritable Atrial
      Cardiomyopathy With Electrical, Contractile, and Structural Components:
      Evidence From Genetically-Engineered Rats.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Both MYL4 p.E11K knock-in rats and MYL4 knockout rats showed progressive
      atrial electrophysiological, contractile, and fibrotic abnormalities,
      similar to affected patients.
    explanation: >-
      Model-organism support for the atrial cardiomyopathy phenotype recorded in
      this record's note.
- name: ZFHX3 common-variant susceptibility locus
  association: Common-variant association at 16q22, not a Mendelian locus
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  subtype: ATFB8-locus
  features: >-
    An intronic single-nucleotide polymorphism, rs7193343-T, in ZFHX3 on 16q22,
    associated with AF at genome-wide significance with a per-allele odds ratio
    of 1.21 and also with cardioembolic stroke.
  gene_term:
    preferred_term: ZFHX3
    term:
      id: hgnc:777
      label: ZFHX3
  notes: >-
    This record exists to reconcile a MONDO assertion this entry disagrees with.
    MONDO relates atrial fibrillation, familial, 8 to ZFHX3 with RO:0004003,
    "has material basis in germline mutation in" - the same relation it uses for
    KCNQ1 and MYL4. The underlying finding is not of that kind. It is a
    genome-wide association signal at a common intronic variant with an odds
    ratio of about 1.2, discovered in 2,385 cases and 33,752 controls and
    replicated in Norwegian and US samples; no rare coding variant, no family,
    and no segregation is reported.

    Three further features mark it as a common-variant locus rather than a
    Mendelian one. The risk allele did not reach significance in a Han Chinese
    cohort, where it is also far more common (control frequency 0.68 against
    0.14-0.20 in the European samples). The same variant associates with
    ischaemic and cardioembolic stroke, as a downstream consequence of AF. And
    the authors found no association between the variant and ZFHX3 expression in
    the tissues they tested, so even the gene assignment within the locus is by
    proximity rather than by demonstrated effect.

    It is retained, and bound, because the association itself is solid: it was
    replicated in two independent non-Icelandic samples in the original report,
    and in the same study only the previously known 4q25/PITX2 signal was more
    significant. What is wrong is the relation, not the fact.
  evidence:
  - reference: PMID:19597491
    reference_title: "A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A variant in the ZFHX3 gene on chromosome 16q22, rs7193343-T, associated
      significantly with AF (odds ratio OR = 1.21, P = 1.4 x 10(-10)).
    explanation: >-
      The association and its effect size, which is the basis for grading this
      locus SUSCEPTIBILITY rather than causative.
  - reference: PMID:19597491
    reference_title: "A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The sequence variant rs7193343 is an intronic SNP located in the zinc
      finger homeobox 3 (ZFHX3) gene on chromosome 16q22, also called AT
      motif-binding factor 1 (ATBF1).
    explanation: >-
      Establishes that the reported variant is a common intronic polymorphism
      rather than a coding change.
  - reference: PMID:19597491
    reference_title: "A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We did not observe an association of rs7193343 with the expression of
      ZFHX3 in blood or adipose tissue.
    explanation: >-
      Supports the caveat that the causal gene at this locus is assigned by
      proximity rather than by a demonstrated effect on ZFHX3.
  - reference: PMID:19597491
    reference_title: "A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To search for additional variants that associate with AF, we have
      increased the sample size of this association study to 2,385 AF/AFl cases
      and 33,752 controls
    explanation: >-
      The discovery sample size quoted in this record's note.
  - reference: PMID:19597491
    reference_title: "A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, the T allele of rs7193343 is much more frequent in the Han
      Chinese population (the allelic frequency in controls is 0.68) than the
      samples of European descent (the allelic frequency in controls is between
      0.14 and 0.20).
    explanation: >-
      The allele frequencies quoted in this record's note, and the reason the
      European risk allele is not rare.
  - reference: PMID:19597491
    reference_title: "A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We assessed the association of rs7193343-T with AF in a Han Chinese
      population from Hong Kong, consisting of 286 AF cases and 2763 controls.
    explanation: >-
      The Han Chinese cohort in which the association did not reach
      significance, as recorded in this record's note.
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.

  How the genes are graded. The numbered ATFB series looks uniform from the
  outside and is not: the evidence behind the twelve gene-bound entities ranges
  from a fully penetrant recessive variant found by sequencing a national
  population to a single case report. Rather than record them all as causative,
  this entry applies one rule and states it here. CAUSATIVE is used where a
  family or population study showed segregation or complete penetrance together
  with supporting functional work: KCNQ1, KCNE2, KCNJ2, GJA5, KCNA5, NUP155,
  MYL4. UNKNOWN is used where the report describes unrelated probands without
  pedigrees, or a single patient: SCN1B, SCN2B, ABCC9. SCN5A is RISK_FACTOR,
  following its own study's conclusion that such variants "may predispose" and
  the observation that a comparable share of AF probands carried rare variants
  already attributed to long-QT or Brugada syndrome. ZFHX3 is SUSCEPTIBILITY -
  see below.

  Read those gradings against the background that the largest unbiased test of
  monogenic AF in the general population, an exome-wide rare loss-of-function
  burden scan across 9,099 genes in the UK Biobank, found a significant
  association for one gene only, and it was TTN rather than any of the numbered
  ATFB loci. That does not refute the families reported here, which are real and
  in several cases functionally worked out; it does mean these loci explain very
  little AF at population scale, and it is the reason this entry is careful
  about the word causative.

  Where this entry disagrees with MONDO. MONDO relates atrial fibrillation,
  familial, 8 (MONDO:0013100) to ZFHX3 with RO:0004003, "has material basis in
  germline mutation in" - the same relation it uses for KCNQ1 and MYL4. The
  finding behind ATFB8 is a genome-wide association signal at a common intronic
  SNP with an odds ratio near 1.2, not a rare germline mutation in a family.
  This entry binds ZFHX3, because the association is solid and repeatedly
  replicated, but grades it SUSCEPTIBILITY and records the reasoning on the
  ZFHX3 genetic entry. The disagreement is about the relation, not about the
  fact.

  Still without a gene. Six of the eighteen MONDO ATFB entities carry no
  causal-gene relation in MONDO: ATFB1, ATFB2, ATFB5, ATFB10, ATFB16 and ATFB17.
  Five of those six stay unbound here too and are retained as MONDO leaf-class
  anchors. The exception is ATFB10, which MONDO leaves gene-less but which this
  entry binds to SCN5A from the literature, with the RISK_FACTOR grading
  explained above. The remaining twelve entities each carry one MONDO gene, and
  every one of those twelve is now bound on its subtype row and carries a
  genetic record with its own evidence.

  TTN is not curated in this entry at all. The TTN association is with
  early-onset AF as a presentation of an inherited cardiomyopathy rather than
  with the Mendelian atrial channelopathy spectrum this entry models, so it
  belongs with the cardiomyopathy entries; it is named above only because it is
  the comparator that shows how small the numbered loci are at population
  scale.
references:
- reference: PMID:31691645
  title: "Monogenic and Polygenic Contributions to Atrial Fibrillation Risk: Results From a National Biobank."
  findings:
  - statement: >-
      An unbiased exome-wide rare loss-of-function burden scan for atrial
      fibrillation in the UK Biobank found a significant association in one gene
      only, TTN - none of the numbered ATFB loci reached significance.
    supporting_text: >-
      In an analysis of 9099 genes with sufficient LOF variant carriers, a
      significant association between AF and rare LOF variants was observed in a
      single gene, TTN (odds ratio, 2.71, P=2.50×10-8).
    evidence:
    - reference: PMID:31691645
      reference_title: "Monogenic and Polygenic Contributions to Atrial Fibrillation Risk: Results From a National Biobank."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In an analysis of 9099 genes with sufficient LOF variant carriers, a
        significant association between AF and rare LOF variants was observed in
        a single gene, TTN (odds ratio, 2.71, P=2.50×10-8).
      explanation: >-
        Source for the population-scale caveat in the entry notes: the only gene
        reaching exome-wide significance in a rare loss-of-function burden scan
        for AF was TTN.
- 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: []
- reference: PMID:15368194
  title: "Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation."
  findings: []
- reference: PMID:16772329
  title: "Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation."
  findings: []
- reference: PMID:18378609
  title: "Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation."
  findings: []
- reference: PMID:18614783
  title: "Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation."
  findings: []
- reference: PMID:19070573
  title: "Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death."
  findings: []
- reference: PMID:29080865
  title: "Dysfunction of Myosin Light-Chain 4 (MYL4) Leads to Heritable Atrial Cardiomyopathy With Electrical, Contractile, and Structural Components: Evidence From Genetically-Engineered Rats."
  findings: []
- reference: PMID:17245405
  title: "KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation."
  findings: []
- reference: PMID:19808477
  title: "Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation."
  findings: []
datasets:
- accession: geo:GSE295056
  title: Gene-Gene Interactions Between A LMNA Variant and Common Polymorphisms Drive Early-Onset Atrial Fibrillation [ATAC-seq]
  description: Atrial fibrillation (AF) is a common arrhythmia with a complex genetic basis, yet the molecular mechanisms linking rare and common variants remain unclear. Using induced pluripotent stem cell-derived atrial cardiomyocytes, we uncover a novel mechanism by which a rare pathogenic LMNA variant encoding Lamin A/C disrupts chromatin accessibility and gene regulation at AF-associated loci. Specifically, reduced accessibility at an SCN5A enhancer harboring an AF-associated variant leads to reduced sodium current, conduction abnormalities, and re-entrant AF.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: ATAC_SEQ
  sample_count: 9
  publication: PMID:42156780
  notes: Identified by GEO DataSets index search for Familial Atrial Fibrillation (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001003207
  title: Whole exome sequencing of 76 individuals with familial atrial fibrillation
  description: We investigated genetic background of familial and early onset atrial fibrillation (AF) with the aim of identify genes involved in atrial fibrillation pathology and are highly predisposing risk factors. We performed whole exome sequencing on 24 families where three or more family members suffered from AF.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Familial Atrial Fibrillation"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
📚

References & Deep Research

References

12
PMID:31691645
Monogenic and Polygenic Contributions to Atrial Fibrillation Risk: Results From a National Biobank.
1 finding
An unbiased exome-wide rare loss-of-function burden scan for atrial fibrillation in the UK Biobank found a significant association in one gene only, TTN - none of the numbered ATFB loci reached significance.
"In an analysis of 9099 genes with sufficient LOF variant carriers, a significant association between AF and rare LOF variants was observed in a single gene, TTN (odds ratio, 2.71, P=2.50×10-8)."
Show evidence (1 reference)
PMID:31691645 SUPPORT Human Clinical
"In an analysis of 9099 genes with sufficient LOF variant carriers, a significant association between AF and rare LOF variants was observed in a single gene, TTN (odds ratio, 2.71, P=2.50×10-8)."
Source for the population-scale caveat in the entry notes: the only gene reaching exome-wide significance in a rare loss-of-function burden scan for AF was TTN.
PMID:12522251
KCNQ1 gain-of-function mutation in familial atrial fibrillation.
No top-level findings curated for this source.
PMID:15922306
A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation.
No top-level findings curated for this source.
PMID:16790700
Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation.
No top-level findings curated for this source.
PMID:15368194
Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation.
No top-level findings curated for this source.
PMID:16772329
Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation.
No top-level findings curated for this source.
PMID:18378609
Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.
No top-level findings curated for this source.
PMID:18614783
Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation.
No top-level findings curated for this source.
PMID:19070573
Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death.
No top-level findings curated for this source.
PMID:29080865
Dysfunction of Myosin Light-Chain 4 (MYL4) Leads to Heritable Atrial Cardiomyopathy With Electrical, Contractile, and Structural Components: Evidence From Genetically-Engineered Rats.
No top-level findings curated for this source.
PMID:17245405
KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation.
No top-level findings curated for this source.
PMID:19808477
Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation.
No top-level findings curated for this source.