Cardiac Arrhythmia, Ankyrin-B-Related

Genetic MONDO:0010958 Pathograph 27 Show in embeddings browser Cardiac Arrhythmia

Cardiac arrhythmia, ankyrin-B-related is a historically reported, variant-specific cardiac phenotype associated with rare ANK2 variants. Early families and selected probands had sinus-node dysfunction, bradycardia, ventricular tachyarrhythmia, or ventricular fibrillation, with inconsistent QT prolongation. Later evidence-based reappraisals classified ANK2 as disputed for monogenic long QT syndrome and found reported ANK2 variants for catecholaminergic polymorphic ventricular tachycardia too common to be disease-causing. This entry therefore preserves experimentally supported cardiac trafficking and calcium-handling models without treating every rare ANK2 variant as causative or diagnostically actionable. The definitive ANK2-related complex neurodevelopmental disorder is modeled separately.

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1
Inheritance
9
Pathophys.
10
Phenotypes
1
Hypotheses
27
Pathograph
1
Genes
8
Medical Actions
16
References
2
Deep Research
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Inheritance

1
Historically reported autosomal dominant inheritance HP:0000006
Dominant transmission was reported in the founding cardiac kindred, but penetrance and variant-level pathogenicity cannot be generalized across rare ANK2 variants.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:15178757 SUPPORT Human Clinical
"A loss-of-function mutation of ankyrin-B identified in an extended kindred causes a dominantly inherited cardiac arrhythmia, initially described as type 4 long QT syndrome."
The early kindred supports dominant inheritance for that reported variant-family relationship; later validity concerns prevent generalization to all ANK2 variants.
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Mechanistic Hypotheses

1
Variant-Specific Ankyrin-B Cardiac Trafficking Model
variant_specific_ankyrin_b_cardiac_model EMERGING
Evidence balance 1 support
Functionally damaging ANK2 variants may impair ankyrin-B-dependent membrane organization in working cardiomyocytes or sinoatrial-node cells. Ventricular calcium-handling defects and sinoatrial pacing failure are modeled as parallel branches. The cellular mechanisms are experimentally supported, but their penetrance and applicability to individual human variants require independent genetic evidence.
Pathograph links
ANK2-Dependent Cardiac Membrane-Targeting Failure -> Ventricular Calcium-Handling Dysregulation DIRECT Loss of coordinated transporter organization alters cardiomyocyte calcium signaling.
ANK2-Dependent Cardiac Membrane-Targeting Failure -> Sinoatrial Node Pacemaker Dysfunction DIRECT Ankyrin-B-dependent targeting is also required in sinoatrial-node cells, creating a distinct bradyarrhythmia branch.
ANK2-Dependent Cardiac Membrane-Targeting Failure -> Prolonged QT Interval INDIRECT UNKNOWN INTERMEDIATES QT or QTU prolongation occurs in some early families and selected cases, but is not a consistent consequence of ANK2 dysfunction.
ANK2-Dependent Cardiac Membrane-Targeting Failure -> Atrial Cav1.3 Targeting Defect and Reentry Susceptibility DIRECT Loss of atrial Cav1.3 membrane targeting provides a modeled substrate for atrial action-potential shortening and reentry.
ANK2-Dependent Cardiac Membrane-Targeting Failure -> Beta-Catenin Localization and Signaling Disruption DIRECT Ankyrin-B loss disrupts its structural interaction with beta-catenin and the normal localization of beta-catenin in cardiomyocytes.
ANK2-Dependent Cardiac Membrane-Targeting Failure -> Loss of Local PP2A-B56alpha Regulation DIRECT In the ANK2 p.Q1283H knock-in model, reduced ankyrin-B binding to the PP2A regulatory subunit B56alpha dissociates PP2A from RyR2.
ANK2-Dependent Cardiac Membrane-Targeting Failure -> CaMKII-Dependent RyR2 Hyperphosphorylation INDIRECT UNKNOWN INTERMEDIATES Ankyrin-B deficiency produces abnormal CaMKII-dependent phosphorylation of the cardiac ryanodine receptor in the heterozygous mouse model.
Loss of Local PP2A-B56alpha Regulation -> Ventricular Calcium-Handling Dysregulation DIRECT Loss of local RyR2 dephosphorylation increases RyR2 phosphorylation and abnormal calcium release in the p.Q1283H model.
CaMKII-Dependent RyR2 Hyperphosphorylation -> Ventricular Calcium-Handling Dysregulation DIRECT RyR2 hyperphosphorylation increases abnormal channel opening and afterdepolarization-prone calcium release.
Ventricular Calcium-Handling Dysregulation -> Triggered Ventricular Arrhythmia DIRECT Extrasystolic activity provides a trigger for ventricular arrhythmia in the variant-specific model.
Triggered Ventricular Arrhythmia -> Ventricular Tachycardia INDIRECT UNKNOWN INTERMEDIATES Early selected probands included catecholamine-associated polymorphic ventricular tachycardia; current CPVT gene validity is disputed.
Triggered Ventricular Arrhythmia -> Ventricular Fibrillation INDIRECT UNKNOWN INTERMEDIATES Idiopathic ventricular fibrillation occurred among early selected probands, but variant-level causality must be established independently.
Triggered Ventricular Arrhythmia -> Syncope DIRECT Ventricular arrhythmias in early ANK2 kindreds and selected probands were associated with exertional or sleep-related syncope.
Triggered Ventricular Arrhythmia -> Sudden Cardiac Death DIRECT Potentially lethal ventricular arrhythmia provides the clinically reported route to sudden cardiac death in early ANK2 kindreds.
Triggered Ventricular Arrhythmia -> Torsade de Pointes INDIRECT UNKNOWN INTERMEDIATES Torsade de pointes has been documented in selected ankyrin-B syndrome cases with QT prolongation.
Sinoatrial Node Pacemaker Dysfunction -> Sinus Bradycardia DIRECT Loss of normal sinoatrial pacing lowers heart rate.
Sinoatrial Node Pacemaker Dysfunction -> Sick Sinus Syndrome DIRECT Disrupted ankyrin-B-dependent sinoatrial-node organization produces the human sinus-node-dysfunction phenotype.
Atrial Cav1.3 Targeting Defect and Reentry Susceptibility -> Atrial Fibrillation INDIRECT UNKNOWN INTERMEDIATES Atrial action-potential shortening and conduction slowing increase modeled susceptibility to atrial fibrillation.
Beta-Catenin Localization and Signaling Disruption -> Structural Cardiac Remodeling INDIRECT UNKNOWN INTERMEDIATES Altered beta-catenin localization is linked to fibrotic structural remodeling in the ANK2 cardiomyopathy model.
Structural Cardiac Remodeling -> Cardiomyopathy DIRECT Fibrotic chamber remodeling produces an arrhythmogenic cardiomyopathy phenotype in the experimental model and selected human probands.
Show evidence (1 reference)
PMID:12571597 SUPPORT Model Organism
"Thus, we identify a new mechanism for cardiac arrhythmia due to abnormal coordination of multiple functionally related ion channels and transporters."
The model-organism study supports the ankyrin-B trafficking mechanism, while not by itself establishing broad human variant validity.
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Pathophysiology

9
ANK2-Dependent Cardiac Membrane-Targeting Failure
Reduced or variant-impaired ankyrin-B disrupts coordinated localization of the sodium pump, sodium-calcium exchanger, and inositol trisphosphate receptor at cardiomyocyte transverse-tubule and sarcoplasmic-reticulum membrane domains.
Variant-Specific Ankyrin-B Cardiac Trafficking Model
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
ANK2 hgnc:493 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ANK2 (hgnc:493). hgnc:493 is a gene from the HUGO Gene Nomenclature Committee.
protein localization to membrane GO:0072657 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein localization to membrane (GO:0072657). GO:0072657 is a biological process from the Gene Ontology. ↓ DECREASED
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Ventricular Calcium-Handling Dysregulation Loss of coordinated transporter organization alters cardiomyocyte calcium signaling. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Sinoatrial Node Pacemaker Dysfunction Ankyrin-B-dependent targeting is also required in sinoatrial-node cells, creating a distinct bradyarrhythmia branch. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Prolonged QT Interval QT or QTU prolongation occurs in some early families and selected cases, but is not a consistent consequence of ANK2 dysfunction. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Atrial Cav1.3 Targeting Defect and Reentry Susceptibility Loss of atrial Cav1.3 membrane targeting provides a modeled substrate for atrial action-potential shortening and reentry. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Beta-Catenin Localization and Signaling Disruption Ankyrin-B loss disrupts its structural interaction with beta-catenin and the normal localization of beta-catenin in cardiomyocytes. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Loss of Local PP2A-B56alpha Regulation In the ANK2 p.Q1283H knock-in model, reduced ankyrin-B binding to the PP2A regulatory subunit B56alpha dissociates PP2A from RyR2. Variant-Specific Ankyrin-B Cardiac Trafficking Model
CaMKII-Dependent RyR2 Hyperphosphorylation Ankyrin-B deficiency produces abnormal CaMKII-dependent phosphorylation of the cardiac ryanodine receptor in the heterozygous mouse model. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Show evidence (2 references)
PMID:12571597 SUPPORT Model Organism
"Mutation of ankyrin-B results in disruption in the cellular organization of the sodium pump, the sodium/calcium exchanger, and inositol-1,4,5-trisphosphate receptors (all ankyrin-B-binding proteins), which reduces the targeting of these proteins to the transverse tubules as well as reducing..."
Demonstrates loss of ankyrin-B-dependent targeting in cardiomyocytes.
PMID:15178757 SUPPORT In Vitro
"All mutations abolish ability of ankyrin-B to restore abnormal Ca(2+) dynamics and abnormal localization and expression of Na/Ca exchanger, Na/K ATPase, and InsP(3)R in ankyrin-B(+/-) cardiomyocytes."
Cardiomyocyte rescue assays support functional impairment of the reported historical variants.
Loss of Local PP2A-B56alpha Regulation
In the p.Q1283H knock-in model, reduced ankyrin-B/B56alpha binding is associated with dissociation of protein phosphatase 2A from RyR2 and increased RyR2 Ser2814 phosphorylation. This arm is variant specific.
Variant-Specific Ankyrin-B Cardiac Trafficking Model
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
protein dephosphorylation GO:0006470 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein dephosphorylation (GO:0006470). GO:0006470 is a biological process from the Gene Ontology. ↓ DECREASED
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Ventricular Calcium-Handling Dysregulation Loss of local RyR2 dephosphorylation increases RyR2 phosphorylation and abnormal calcium release in the p.Q1283H model. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Show evidence (1 reference)
PMID:30571258 SUPPORT Model Organism
"The loss of protein phosphatase 2A activity from ryanodine receptor is likely associated with reduced ankyrin-B/B56α binding, which is the potential mechanism of ryanodine receptor hyperphosphorylation."
Supports the local PP2A-loss mechanism in the p.Q1283H knock-in model.
CaMKII-Dependent RyR2 Hyperphosphorylation
Ankyrin-B haploinsufficiency causes CaMKII-dependent RyR2 Ser2814 hyperphosphorylation, abnormal RyR2 opening, and proarrhythmic calcium release in mice.
Variant-Specific Ankyrin-B Cardiac Trafficking Model
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
protein phosphorylation GO:0006468 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased protein phosphorylation (GO:0006468). GO:0006468 is a biological process from the Gene Ontology. ↑ INCREASED
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Ventricular Calcium-Handling Dysregulation RyR2 hyperphosphorylation increases abnormal channel opening and afterdepolarization-prone calcium release. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Show evidence (1 reference)
PMID:23059182 SUPPORT Model Organism
"The cardiac ryanodine receptor (RyR(2)), a validated target of kinase/phosphatase regulation in myocytes, displays abnormal CaMKII-dependent phosphorylation (pS2814 hyperphosphorylation) in ankyrin-B(+/-) heart."
Directly supports this molecular arm in the heterozygous mouse heart.
Ventricular Calcium-Handling Dysregulation
Disorganized sodium-pump and sodium-calcium-exchanger microdomains alter ventricular calcium signaling and favor extrasystolic activity.
Variant-Specific Ankyrin-B Cardiac Trafficking Model
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
calcium ion homeostasis GO:0055074 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated calcium ion homeostasis (GO:0055074). GO:0055074 is a biological process from the Gene Ontology. ↕ DYSREGULATED
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Triggered Ventricular Arrhythmia Extrasystolic activity provides a trigger for ventricular arrhythmia in the variant-specific model. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Show evidence (1 reference)
PMID:12571597 SUPPORT Model Organism
"Ankyrin-B mutation also leads to altered Ca2+ signalling in adult cardiomyocytes that results in extrasystoles, and provides a rationale for the arrhythmia."
Establishes altered calcium signaling and extrasystoles in the experimental cardiac model.
Triggered Ventricular Arrhythmia
Calcium-handling abnormalities can generate extrasystoles and a ventricular-arrhythmia substrate. Translation from the experimental model to any specific human ANK2 variant remains variant dependent.
Variant-Specific Ankyrin-B Cardiac Trafficking Model
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Ventricular Tachycardia Early selected probands included catecholamine-associated polymorphic ventricular tachycardia; current CPVT gene validity is disputed. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Ventricular Fibrillation Idiopathic ventricular fibrillation occurred among early selected probands, but variant-level causality must be established independently. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Syncope Ventricular arrhythmias in early ANK2 kindreds and selected probands were associated with exertional or sleep-related syncope. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Sudden Cardiac Death Potentially lethal ventricular arrhythmia provides the clinically reported route to sudden cardiac death in early ANK2 kindreds. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Torsade de Pointes Torsade de pointes has been documented in selected ankyrin-B syndrome cases with QT prolongation. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Show evidence (1 reference)
PMID:12571597 SUPPORT Model Organism
"Ankyrin-B mutation also leads to altered Ca2+ signalling in adult cardiomyocytes that results in extrasystoles, and provides a rationale for the arrhythmia."
Supports the experimental triggered-activity node without asserting universal human penetrance.
Sinoatrial Node Pacemaker Dysfunction
Impaired ankyrin-B-dependent organization of sinoatrial-node channels and transporters disrupts normal pacing and can produce sinus-node dysfunction.
Variant-Specific Ankyrin-B Cardiac Trafficking Model
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Sinus Bradycardia Loss of normal sinoatrial pacing lowers heart rate. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Sick Sinus Syndrome Disrupted ankyrin-B-dependent sinoatrial-node organization produces the human sinus-node-dysfunction phenotype. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Show evidence (2 references)
PMID:18832177 SUPPORT Human Clinical
"We mapped two families with highly penetrant and severe SND to the human ANK2 (ankyrin-B/AnkB) locus."
Human families support a locus-level association with severe sinus-node dysfunction.
PMID:18832177 SUPPORT Model Organism
"AnkB is essential for normal membrane organization of sinoatrial node cell channels and transporters, and AnkB is required for physiological cardiac pacing."
Experimental evidence supports the channel-targeting and pacemaker mechanism.
Atrial Cav1.3 Targeting Defect and Reentry Susceptibility
Defective membrane targeting of Cav1.3 in atrial and sinoatrial-node cells shortens atrial action potentials and, together with slowed conduction, increases susceptibility to sustained reentry. This mechanistic bridge is computational and does not establish variant-level penetrance.
Variant-Specific Ankyrin-B Cardiac Trafficking Model
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 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated cardiac muscle cell action potential (GO:0086001). GO:0086001 is a biological process from the Gene Ontology. ↕ DYSREGULATED
atrium UBERON:0002081 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in atrium, annotated with cardiac atrium (UBERON:0002081). UBERON:0002081 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Atrial Fibrillation Atrial action-potential shortening and conduction slowing increase modeled susceptibility to atrial fibrillation. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Show evidence (1 reference)
PMID:23436330 SUPPORT Computational
"In parallel, increased fibrosis results in conduction slowing that further increases the susceptibility to sustained reentry in the setting of ankyrin-B dysfunction."
The model identifies a tissue-level reentry substrate in ankyrin-B dysfunction.
Beta-Catenin Localization and Signaling Disruption
Ankyrin-B directly interacts with beta-catenin; loss of ankyrin-B disrupts beta-catenin localization in human ANK2-associated cardiomyopathy tissue and in cardiomyocyte-selective Ank2 knockout hearts.
Variant-Specific Ankyrin-B Cardiac Trafficking Model
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Wnt signaling pathway GO:0016055 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated Wnt signaling pathway (GO:0016055). GO:0016055 is a biological process from the Gene Ontology. ↕ DYSREGULATED
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Structural Cardiac Remodeling Altered beta-catenin localization is linked to fibrotic structural remodeling in the ANK2 cardiomyopathy model. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Show evidence (1 reference)
PMID:31264976 SUPPORT Human Clinical
"Human hearts from deceased ANK2 ARVC probands display aberrant β-catenin localization."
Human ventricular tissue demonstrates abnormal beta-catenin localization in ANK2-associated arrhythmogenic cardiomyopathy.
Structural Cardiac Remodeling
Cardiomyocyte-selective Ank2 loss produces chamber dilation, reduced cardiac function, fibrosis, arrhythmia, and early mortality in mice; rare ANK2 variants with ankyrin-B loss of function were identified in deceased human arrhythmogenic-cardiomyopathy probands. The human gene-disease scope remains based on a small selected series.
Variant-Specific Ankyrin-B Cardiac Trafficking Model
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cardiomyopathy Fibrotic chamber remodeling produces an arrhythmogenic cardiomyopathy phenotype in the experimental model and selected human probands. Variant-Specific Ankyrin-B Cardiac Trafficking Model
Show evidence (1 reference)
PMID:31264976 SUPPORT Model Organism
"Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced..."
The mouse model directly supports the structural-remodeling phenotype, anchored to human probands by cardiac-tissue loss-of-function evidence.
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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 Cardiac Arrhythmia, Ankyrin-B-Related 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

10
Cardiovascular 7
Ventricular Tachycardia HP:0004756 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular tachycardia (HP:0004756). HP:0004756 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15178757 SUPPORT Human Clinical
"Humans with ankyrin-B mutations display varying degrees of cardiac dysfunction including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death."
Supports the historical observation only.
Ventricular Fibrillation HP:0001663 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular fibrillation (HP:0001663). HP:0001663 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15178757 SUPPORT Human Clinical
"Humans with ankyrin-B mutations display varying degrees of cardiac dysfunction including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death."
The source reports ventricular fibrillation in an ascertained series but does not establish population frequency.
Atrial Fibrillation 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:27916589 SUPPORT Human Clinical
"Loss-of-function variants in the ANK2 gene can cause a variety of cardiac rhythm abnormalities including sinus node dysfunction, atrial fibrillation and ventricular arrhythmias (called the "ankyrin-B syndrome")."
Supports atrial fibrillation within the reported human spectrum while the partial polarity preserves the entry's variant-specific scope.
Cardiomyopathy HP:0001638 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomyopathy (HP:0001638). HP:0001638 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31264976 SUPPORT Human Clinical
"Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis"
Directly supports the phenotype in selected human probands, with partial polarity because the evidence does not establish general penetrance.
Prolonged QT Interval HP:0001657 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged QT interval (HP:0001657). HP:0001657 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25456501 SUPPORT Human Clinical
"We describe a rare case of this condition characterised by sinus node dysfunction, atrial fibrillation and prolonged QT syndrome in a young patient with a family history of sudden death."
Supports QT prolongation in one selected patient without establishing a broadly valid gene-disease relationship.
PMID:15178757 SUPPORT Human Clinical
"However, a prolonged rate-corrected QT interval was not a consistent feature, indicating that ankyrin-B dysfunction represents a clinical entity distinct from classic long QT syndromes."
Establishes the inconsistency that constrains the phenotype's certainty and scope.
Syncope HP:0001279 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Syncope (HP:0001279). HP:0001279 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15178757 SUPPORT Human Clinical
"Nonetheless, humans with ankyrin-B mutations experience polymorphic ventricular arrhythmia, syncope, and sudden death in response to exercise or emotional stress (5,6)."
Supports syncope in the original family-level clinical spectrum; partial polarity avoids generalizing across ANK2 variants.
Sudden Cardiac Death HP:0001645 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sudden cardiac death (HP:0001645). HP:0001645 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15178757 SUPPORT Human Clinical
"Nonetheless, humans with ankyrin-B mutations experience polymorphic ventricular arrhythmia, syncope, and sudden death in response to exercise or emotional stress (5,6)."
Supports sudden death in the original family-level clinical spectrum; partial polarity avoids implying population-level penetrance.
Other 3
Sick Sinus Syndrome HP:0011704 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sick sinus syndrome (HP:0011704). HP:0011704 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18832177 SUPPORT Human Clinical
"We mapped two families with highly penetrant and severe SND to the human ANK2 (ankyrin-B/AnkB) locus."
This is direct human evidence for severe sinus-node dysfunction in the ankyrin-B-related cardiac spectrum.
Sinus Bradycardia HP:0001688 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sinus bradycardia (HP:0001688). HP:0001688 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15178757 SUPPORT Human Clinical
"Affected family members display many atypical features compared to other long QT syndromes, including pronounced sinus bradycardia, polyphasic T waves, and atrial fibrillation (5)."
The original E1425G kindred had sinus bradycardia, but this selected family does not establish its frequency across ANK2 variants.
Torsade de Pointes HP:0001664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Torsade de pointes (HP:0001664). HP:0001664 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25456501 SUPPORT Human Clinical
"Mutations of the ANK2 gene in the rare condition Ankyrin-B syndrome result in loss of function of the ankyrin-B protein which in turn leads to abnormal regulation of intracellular sodium and calcium and a predisposition to cardiac arrhythmia including torsades de pointes."
Supports the phenotype in a case-based clinical source, with partial polarity to preserve variant-specific uncertainty.
🧬

Genetic Associations

1
Reported ANK2 monogenic LQTS and CPVT associations (Reported monogenic LQTS and CPVT associations)
Gene: ANK2 hgnc:493 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ANK2 (hgnc:493). hgnc:493 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED
Show evidence (7 references)
PMID:15178757 SUPPORT Human Clinical
"A loss-of-function mutation of ankyrin-B identified in an extended kindred causes a dominantly inherited cardiac arrhythmia, initially described as type 4 long QT syndrome."
Preserves the historical family-level association without generalizing it.
PMID:15178757 SUPPORT Human Clinical
"Humans with ankyrin-B mutations display varying degrees of cardiac dysfunction including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death."
Preserves the early CPVT-like clinical report without treating it as a currently validated monogenic ANK2-CPVT relationship.
PMID:31983240 REFUTE Other
"Six genes, AKAP9, ANK2, KCNE2, KCNJ5, SCN4B, and SNTA1, were classified as disputed, defined as the absence of sufficient genetic evidence to support causation of LQTS (Figure 1)."
Refutes a broad monogenic ANK2-LQTS interpretation.
+ 4 more references
🗃️

External Assertions

3
Gene2Phenotype ANK2-Brugada syndrome assertion
Gene2Phenotype gene disease relationship G2P03803
Gene2Phenotype records the ANK2-Brugada syndrome relationship (MONDO:0015263) as disputed.
Gene2Phenotype ANK2-CPVT assertion
Gene2Phenotype gene disease relationship G2P03822
Gene2Phenotype records the ANK2-catecholaminergic polymorphic ventricular tachycardia relationship (MONDO:0017990) as disputed.
Gene2Phenotype ANK2-long QT syndrome assertion
Gene2Phenotype gene disease relationship G2P03866
Gene2Phenotype records the ANK2-long QT syndrome relationship (MONDO:0002442) as disputed.
💊

Medical Actions

8
Permanent Pacemaker for Symptomatic Sinus Node Dysfunction
Action: Pacemaker placementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pacemaker placement (NCIT:C80434). NCIT:C80434 is a clinical intervention from the NCI Thesaurus. Ontology label: Pacemaker Placement NCIT:C80434
Permanent pacing is established supportive management for clinically significant sinus-node dysfunction. It treats bradycardia but does not correct the ANK2-dependent molecular defect.
Mechanism Target:
BYPASSES Sinoatrial Node Pacemaker Dysfunction — An implanted pacemaker bypasses inadequate intrinsic sinoatrial pacing.
Show evidence (1 reference)
PMID:18832177 SUPPORT Human Clinical
"SND led to pacemaker implantation in 14 patients (mean age for implantation, 34 ± 17 years)."
Documents pacemaker implantation in affected members of the ANK2-linked family.
Show evidence (1 reference)
PMID:25456501 SUPPORT Human Clinical
"The management of Ankyrin-B syndrome may include avoidance of QT prolonging medications, insertion of a permanent pacemaker for sinus node dysfunction, or a cardioverter defibrillator for those at high-risk of sudden death from torsades de pointes."
A case-based management review explicitly includes permanent pacing for sinus-node dysfunction.
Implantable Cardioverter-Defibrillator for High-Risk Ventricular Arrhythmia
Action: implantable cardioverter-defibrillator placementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is implantable cardioverter-defibrillator placement (NCIT:C80435). NCIT:C80435 is a clinical intervention from the NCI Thesaurus. Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435
ICD placement may be considered for patients judged at high risk of sudden death from torsade de pointes or other malignant ventricular arrhythmia; the cited ANK2 evidence is case based, not a genotype-only indication.
Mechanism Target:
INHIBITS Triggered Ventricular Arrhythmia — The device terminates a malignant ventricular rhythm rather than modifying the underlying ankyrin-B substrate.
Show evidence (1 reference)
PMID:25456501 SUPPORT Human Clinical
"The management of Ankyrin-B syndrome may include avoidance of QT prolonging medications, insertion of a permanent pacemaker for sinus node dysfunction, or a cardioverter defibrillator for those at high-risk of sudden death from torsades de pointes."
Supports a risk-based ICD option in a case-based management source.
Show evidence (1 reference)
PMID:25456501 SUPPORT Human Clinical
"The management of Ankyrin-B syndrome may include avoidance of QT prolonging medications, insertion of a permanent pacemaker for sinus node dysfunction, or a cardioverter defibrillator for those at high-risk of sudden death from torsades de pointes."
The source provides the indication but not comparative outcome evidence.
Avoidance of QT-Prolonging Medications
Action: avoidance of contraindicated medicationsNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is avoidance of contraindicated medications, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Avoid QT-prolonging medications in patients with a documented prolonged-QT or torsadogenic phenotype. This is phenotype-directed risk reduction, not a recommendation based on an ANK2 variant alone.
Mechanism Target:
INHIBITS Triggered Ventricular Arrhythmia — Removing QT-prolonging exposures reduces an avoidable trigger for torsade de pointes in susceptible patients.
Show evidence (1 reference)
PMID:25456501 SUPPORT Human Clinical
"The management of Ankyrin-B syndrome may include avoidance of QT prolonging medications"
The case-based management source explicitly recommends medication avoidance; partial polarity preserves its limited scope.
Show evidence (1 reference)
PMID:25456501 SUPPORT Human Clinical
"The management of Ankyrin-B syndrome may include avoidance of QT prolonging medications"
Supports phenotype-directed avoidance in the reported clinical context.
Metoprolol for p.Q1283H Arrhythmia Susceptibility (Preclinical)
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
Agent: metoprolol CHEBI:6904 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses metoprolol (CHEBI:6904). CHEBI:6904 is a therapeutic agent from Chemical Entities of Biological Interest.
Metoprolol reduced stress-induced ventricular arrhythmias in ANK2 p.Q1283H knock-in mice. This variant-specific preclinical result is not evidence of clinical efficacy across ANK2 variants.
Mechanism Target:
INHIBITS Triggered Ventricular Arrhythmia — Beta-adrenergic blockade reduces catecholaminergic provocation of ventricular arrhythmia in the p.Q1283H knock-in model.
Show evidence (1 reference)
PMID:30571258 SUPPORT Model Organism
"Finally, the administration of metoprolol or flecainide decreased the incidence of stress-induced ventricular arrhythmias in the KI mice."
Directly supports the antiarrhythmic effect in the knock-in mouse model.
Show evidence (1 reference)
PMID:30571258 SUPPORT Model Organism
"Finally, the administration of metoprolol or flecainide decreased the incidence of stress-induced ventricular arrhythmias in the KI mice."
The evidence is explicitly limited to p.Q1283H knock-in mice.
Flecainide for p.Q1283H Arrhythmia Susceptibility (Preclinical)
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
Agent: flecainide CHEBI:75984 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses flecainide (CHEBI:75984). CHEBI:75984 is a therapeutic agent from Chemical Entities of Biological Interest.
Flecainide reduced stress-induced ventricular arrhythmias in ANK2 p.Q1283H knock-in mice. This variant-specific preclinical result is not evidence of clinical efficacy across ANK2 variants.
Mechanism Target:
INHIBITS Triggered Ventricular Arrhythmia — Flecainide reduces stress-provoked ventricular arrhythmia in the p.Q1283H knock-in model.
Show evidence (1 reference)
PMID:30571258 SUPPORT Model Organism
"Finally, the administration of metoprolol or flecainide decreased the incidence of stress-induced ventricular arrhythmias in the KI mice."
Directly supports the antiarrhythmic effect in the knock-in mouse model.
Show evidence (1 reference)
PMID:30571258 SUPPORT Model Organism
"Finally, the administration of metoprolol or flecainide decreased the incidence of stress-induced ventricular arrhythmias in the KI mice."
The evidence is explicitly limited to p.Q1283H knock-in mice.
CaMKII Inhibition for RyR2 Dysregulation (Preclinical)
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
Agent: KN-93 CHEBI:91460 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses KN-93 (CHEBI:91460). CHEBI:91460 is a therapeutic agent from Chemical Entities of Biological Interest.
Genetic AC3I expression and pharmacologic KN-93 treatment rescued RyR2 dysregulation and blunted arrhythmia in ankyrin-B-deficient mice. KN-93 is an experimental tool compound, not a clinical recommendation.
Mechanism Target:
INHIBITS CaMKII-Dependent RyR2 Hyperphosphorylation — CaMKII inhibition normalizes RyR2 behavior and reduces the proarrhythmic phenotype in the ankyrin-B-deficient model.
Show evidence (1 reference)
PMID:23059182 SUPPORT Model Organism
"RyR(2) dysregulation is rescued in myocytes from ankyrin-B(+/-) mice overexpressing a potent CaMKII-inhibitory peptide (AC3I), and aberrant RyR(2) open probability observed in ankyrin-B(+/-) hearts is normalized by treatment with the CaMKII inhibitor KN-93."
Directly supports genetic and pharmacologic rescue of this mechanism.
Show evidence (1 reference)
PMID:23059182 SUPPORT Model Organism
"CaMKII inhibition is sufficient to rescue abnormalities in ankyrin-B(+/-) myocyte electrical dysfunction including cellular afterdepolarizations, and significantly blunts whole animal cardiac arrhythmias and sudden death in response to elevated sympathetic tone."
Demonstrates rescue from cellular through organism scales in mice.
SB-216763 WNT/Beta-Catenin Activation (Preclinical)
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
SB-216763, a pharmacologic WNT/beta-catenin pathway activator, prevented and partially reversed cardiomyopathy phenotypes in the Ank2-deficient mouse model. This is preclinical evidence only.
Mechanism Target:
INHIBITS Beta-Catenin Localization and Signaling Disruption — Pharmacologic WNT/beta-catenin activation counteracts the disrupted signaling state caused by ankyrin-B loss.
Show evidence (1 reference)
PMID:31264976 SUPPORT Model Organism
"A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes."
Directly supports pathway-directed rescue in the mouse model.
Show evidence (1 reference)
PMID:31264976 SUPPORT Model Organism
"A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes."
Establishes a preclinical treatment effect without implying human use.
Tideglusib for ANK2-Deficient Cardiomyopathy (Preclinical)
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
Agent: tideglusib CHEBI:147398 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tideglusib (CHEBI:147398). CHEBI:147398 is a therapeutic agent from Chemical Entities of Biological Interest.
Tideglusib, a GSK-3 beta inhibitor, prevented and reversed reduced cardiac function and reduced adrenergically provoked ventricular arrhythmia in an Ank2 cardiomyocyte-selective knockout model. This is preclinical evidence, not a clinical recommendation for ANK2 variant carriers.
Mechanism Target:
INHIBITS Beta-Catenin Localization and Signaling Disruption — GSK-3 inhibition is modeled as counteracting the disrupted beta-catenin signaling state upstream of structural remodeling.
Show evidence (1 reference)
PMID:40866040 SUPPORT Model Organism
"We evaluated the therapeutic efficacy of Tideglusib (TD) in Ank2 cardio-selective-knockout and homozygous desmoglein-2 mutant ACM mouse models."
Supports evaluation of a GSK-3 inhibitor in the Ank2-deficient model; partial polarity makes explicit that this abstract does not directly measure the upstream beta-catenin target.
INHIBITS Structural Cardiac Remodeling — Tideglusib prevented and reversed reduced cardiac function in the Ank2 knockout model and reduced its provoked ventricular-arrhythmia burden.
Show evidence (1 reference)
PMID:40866040 SUPPORT Model Organism
"TD was able to prevent and reverse the reduced cardiac function in treated mice. Moreover, TD-treated adult mice displayed a reduction in ventricular arrhythmia following adrenergic stimulation."
Directly supports disease-modifying and antiarrhythmic effects in the Ank2-deficient mouse model.
Show evidence (1 reference)
PMID:40866040 SUPPORT Model Organism
"We evaluated the therapeutic efficacy of Tideglusib (TD) in Ank2 cardio-selective-knockout and homozygous desmoglein-2 mutant ACM mouse models."
Establishes that tideglusib was evaluated directly in an Ank2-deficient arrhythmogenic-cardiomyopathy model.
🔬

Diagnosis

5
Phenotype-first LQTS evaluation with evidence-based gene interpretation
Cardiac evaluation should begin with the documented electrophysiologic phenotype. An ANK2 finding alone must not establish LQTS or direct clinical decisions when the gene-disease relationship is disputed.
electrocardiography NCIT:C38053 NCI Thesaurus (NCIT)
Results: Interpret ECG and rhythm findings independently of ANK2 status; require new and sufficient variant-level genetic evidence before attributing LQTS to ANK2.
Show evidence (1 reference)
PMID:31983240 SUPPORT Other
"Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence."
The reappraisal explicitly warns against clinical use of variants in disputed or limited LQTS genes without sufficient new evidence.
Ambulatory Rhythm Monitoring
Ambulatory ECG monitoring can capture intermittent atrial or ventricular arrhythmia and sinus-node dysfunction that is absent on a resting tracing. Evidence here documents its use in a recent, genetically complex family and does not make an ANK2-specific diagnostic-performance claim.
Holter monitoring NCIT:C38064 NCI Thesaurus (NCIT)
Results: Interpret rhythm findings on their own clinical merits and do not attribute them to ANK2 without adequate variant and segregation evidence.
Show evidence (1 reference)
DOI:10.2147/tacg.s438957 SUPPORT Human Clinical
"All available family members were seen and examined with our cardiology department and underwent resting and exercise ECGs, 24-hr Holter ECG monitoring and a standard transthoracic echocardiogram."
Documents Holter monitoring in an ANK2-plus-MYO18B family evaluation; partial polarity preserves the oligogenic and case-based scope.
Exercise Cardiac Stress Testing
Exercise ECG can help reveal stress-associated arrhythmias in a phenotype-first assessment. It is not a test of ANK2 pathogenicity.
Exercise cardiac stress test NCIT:C168192 NCI Thesaurus (NCIT)
Results: Evaluate inducible ectopy or arrhythmia independently, then integrate any genetic finding using contemporary variant-level evidence.
Show evidence (1 reference)
DOI:10.2147/tacg.s438957 SUPPORT Human Clinical
"All available family members were seen and examined with our cardiology department and underwent resting and exercise ECGs, 24-hr Holter ECG monitoring and a standard transthoracic echocardiogram."
Documents exercise ECG in a genetically complex family investigation; it does not validate ANK2 as a stand-alone diagnostic marker.
Echocardiographic Structural Assessment
Echocardiography assesses ventricular function and structural heart disease when cardiomyopathy is suspected or being excluded.
Echocardiography test NCIT:C16525 NCI Thesaurus (NCIT)
Results: Structural findings should be interpreted separately from electrical phenotypes and from the pathogenicity of an ANK2 variant.
Show evidence (1 reference)
DOI:10.2147/tacg.s438957 SUPPORT Human Clinical
"All available family members were seen and examined with our cardiology department and underwent resting and exercise ECGs, 24-hr Holter ECG monitoring and a standard transthoracic echocardiogram."
Documents structural imaging as one component of a family cardiac evaluation; partial polarity reflects the single-family evidence.
Multigene Testing, Segregation, and Molecular Autopsy
In unresolved inherited-arrhythmia or sudden-death families, panel or exome testing, molecular autopsy, and segregation analysis may be used. Because ANK2 cardiac validity is disputed and oligogenic findings occur, an ANK2 result alone must not establish diagnosis or guide predictive testing.
Genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Classify each variant with current population, segregation, functional, and phenotype evidence; evaluate other cardiac genes and avoid using an ANK2 VUS for cascade prediction.
Show evidence (2 references)
DOI:10.2147/tacg.s438957 SUPPORT Human Clinical
"A precise analysis was performed by an international multidisciplinary expert panel including autopsy of the index patient’s heart, molecular autopsy, whole-exome sequencing, analysis of the pedigree and examination of available family members."
Documents a combined molecular-autopsy, exome, pedigree, and family evaluation in a case with ANK2 and MYO18B findings.
DOI:10.2147/tacg.s438957 SUPPORT Human Clinical
"Genetic testing of the index patients blood sample and in parts of the family was done. It was performed by sequencing in parallel 174 genes associated with inherited cardiac diseases on a MiSeq platform."
Documents multigene panel testing rather than ANK2-only testing in the investigated family.
{ }

Source YAML

click to show 
name: Cardiac Arrhythmia, Ankyrin-B-Related
creation_date: '2026-04-04T00:00:00Z'
category: Genetic
description: >-
  Cardiac arrhythmia, ankyrin-B-related is a historically reported,
  variant-specific cardiac phenotype associated with rare ANK2 variants.
  Early families and selected probands had sinus-node dysfunction, bradycardia,
  ventricular tachyarrhythmia, or ventricular fibrillation, with inconsistent
  QT prolongation. Later evidence-based reappraisals classified ANK2 as disputed
  for monogenic long QT syndrome and found reported ANK2 variants for
  catecholaminergic polymorphic ventricular tachycardia too common to be
  disease-causing. This entry therefore preserves experimentally supported
  cardiac trafficking and calcium-handling models without treating every rare
  ANK2 variant as causative or diagnostically actionable. The definitive
  ANK2-related complex neurodevelopmental disorder is modeled separately.
synonyms:
- ankyrin-B syndrome
- LQT4
- long QT syndrome type 4
disease_term:
  preferred_term: cardiac arrhythmia, ankyrin-B-related
  term:
    id: MONDO:0010958
    label: cardiac arrhythmia, ankyrin-B-related
parents:
- Cardiac Arrhythmia
external_assertions:
- name: Gene2Phenotype ANK2-Brugada syndrome assertion
  source: Gene2Phenotype
  assertion_type: gene_disease_relationship
  external_id: G2P03803
  description: >-
    Gene2Phenotype records the ANK2-Brugada syndrome relationship
    (MONDO:0015263) as disputed.
- name: Gene2Phenotype ANK2-CPVT assertion
  source: Gene2Phenotype
  assertion_type: gene_disease_relationship
  external_id: G2P03822
  description: >-
    Gene2Phenotype records the ANK2-catecholaminergic polymorphic ventricular
    tachycardia relationship (MONDO:0017990) as disputed.
- name: Gene2Phenotype ANK2-long QT syndrome assertion
  source: Gene2Phenotype
  assertion_type: gene_disease_relationship
  external_id: G2P03866
  description: >-
    Gene2Phenotype records the ANK2-long QT syndrome relationship
    (MONDO:0002442) as disputed.
inheritance:
- name: Historically reported autosomal dominant inheritance
  description: >-
    Dominant transmission was reported in the founding cardiac kindred, but
    penetrance and variant-level pathogenicity cannot be generalized across
    rare ANK2 variants.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:15178757
    reference_title: "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A loss-of-function mutation of ankyrin-B identified in an extended kindred
      causes a dominantly inherited cardiac arrhythmia, initially described as
      type 4 long QT syndrome.
    explanation: >-
      The early kindred supports dominant inheritance for that reported
      variant-family relationship; later validity concerns prevent
      generalization to all ANK2 variants.
mechanistic_hypotheses:
- hypothesis_group_id: variant_specific_ankyrin_b_cardiac_model
  hypothesis_label: Variant-Specific Ankyrin-B Cardiac Trafficking Model
  status: EMERGING
  description: >-
    Functionally damaging ANK2 variants may impair ankyrin-B-dependent membrane
    organization in working cardiomyocytes or sinoatrial-node cells. Ventricular
    calcium-handling defects and sinoatrial pacing failure are modeled as
    parallel branches. The cellular mechanisms are experimentally supported,
    but their penetrance and applicability to individual human variants require
    independent genetic evidence.
  evidence:
  - reference: PMID:12571597
    reference_title: "Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Thus, we identify a new mechanism for cardiac arrhythmia due to abnormal
      coordination of multiple functionally related ion channels and transporters.
    explanation: >-
      The model-organism study supports the ankyrin-B trafficking mechanism,
      while not by itself establishing broad human variant validity.
pathophysiology:
- name: ANK2-Dependent Cardiac Membrane-Targeting Failure
  biological_scale: CELLULAR
  description: >-
    Reduced or variant-impaired ankyrin-B disrupts coordinated localization of
    the sodium pump, sodium-calcium exchanger, and inositol trisphosphate
    receptor at cardiomyocyte transverse-tubule and sarcoplasmic-reticulum
    membrane domains.
  genes:
  - preferred_term: ANK2
    term:
      id: hgnc:493
      label: ANK2
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: protein localization to membrane
    term:
      id: GO:0072657
      label: protein localization to membrane
    modifier: DECREASED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:12571597
    reference_title: "Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mutation of ankyrin-B results in disruption in the cellular organization
      of the sodium pump, the sodium/calcium exchanger, and
      inositol-1,4,5-trisphosphate receptors (all ankyrin-B-binding proteins),
      which reduces the targeting of these proteins to the transverse tubules as
      well as reducing overall protein level.
    explanation: >-
      Demonstrates loss of ankyrin-B-dependent targeting in cardiomyocytes.
  - reference: PMID:15178757
    reference_title: "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All mutations abolish ability of ankyrin-B to restore abnormal Ca(2+)
      dynamics and abnormal localization and expression of Na/Ca exchanger,
      Na/K ATPase, and InsP(3)R in ankyrin-B(+/-) cardiomyocytes.
    explanation: >-
      Cardiomyocyte rescue assays support functional impairment of the reported
      historical variants.
  downstream:
  - target: Ventricular Calcium-Handling Dysregulation
    description: >-
      Loss of coordinated transporter organization alters cardiomyocyte calcium
      signaling.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12571597
      reference_title: "Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Ankyrin-B mutation also leads to altered Ca2+ signalling in adult
        cardiomyocytes that results in extrasystoles, and provides a rationale
        for the arrhythmia.
      explanation: >-
        Directly links ankyrin-B mutation to abnormal calcium signaling in
        adult cardiomyocytes.
  - target: Sinoatrial Node Pacemaker Dysfunction
    description: >-
      Ankyrin-B-dependent targeting is also required in sinoatrial-node cells,
      creating a distinct bradyarrhythmia branch.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18832177
      reference_title: "Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Finally, dysfunction in AnkB-based trafficking pathways causes abnormal
        sinoatrial node (SAN) electrical activity and SND.
      explanation: >-
        Supports a separate ankyrin-B trafficking route to sinoatrial-node
        dysfunction.
  - target: Prolonged QT Interval
    description: >-
      QT or QTU prolongation occurs in some early families and selected cases,
      but is not a consistent consequence of ANK2 dysfunction.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15178757
      reference_title: "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        However, a prolonged rate-corrected QT interval was not a consistent
        feature, indicating that ankyrin-B dysfunction represents a clinical
        entity distinct from classic long QT syndromes.
      explanation: >-
        Supports variable, family-specific QT prolongation while explicitly
        opposing a uniform classic-LQTS phenotype.
  - target: Atrial Cav1.3 Targeting Defect and Reentry Susceptibility
    description: >-
      Loss of atrial Cav1.3 membrane targeting provides a modeled substrate for
      atrial action-potential shortening and reentry.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23436330
      reference_title: "Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Our simulations predict that defective membrane targeting of the
        voltage-gated L-type Ca(2+) channel Cav1.3 leads to action potential
        shortening that reduces the critical atrial tissue mass needed to
        sustain reentrant activation.
      explanation: >-
        The computational study directly models the atrial consequence of
        ankyrin-B-dependent Cav1.3 mistargeting.
  - target: Beta-Catenin Localization and Signaling Disruption
    description: >-
      Ankyrin-B loss disrupts its structural interaction with beta-catenin and
      the normal localization of beta-catenin in cardiomyocytes.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31264976
      reference_title: "Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Human hearts from deceased ANK2 ARVC probands display aberrant β-catenin
        localization.
      explanation: >-
        Human ventricular tissue directly supports abnormal beta-catenin
        localization in selected ANK2-associated cardiomyopathy probands.
    - reference: PMID:31264976
      reference_title: "Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Desmosomal structure and function appeared preserved in diseased human
        and murine specimens in the presence of markedly abnormal β-catenin
        expression and patterning, leading to identification of a previously
        unknown interaction between ankyrin-B and β-catenin.
      explanation: >-
        The murine component supports the ankyrin-B/beta-catenin interaction;
        it is separated from the human-tissue evidence so each item has one
        experimental-system classification.
  - target: Loss of Local PP2A-B56alpha Regulation
    description: >-
      In the ANK2 p.Q1283H knock-in model, reduced ankyrin-B binding to the PP2A
      regulatory subunit B56alpha dissociates PP2A from RyR2.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30571258
      reference_title: "Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Coimmunoprecipitation experiments demonstrated dissociation of protein
        phosphatase 2A from ryanodine receptor in the KI hearts, which was
        accompanied by a decreased binding of ankyrin-B to protein phosphatase
        2A regulatory subunit B56α.
      explanation: >-
        Directly supports the variant-specific loss of local PP2A regulation in
        knock-in mouse hearts.
  - target: CaMKII-Dependent RyR2 Hyperphosphorylation
    description: >-
      Ankyrin-B deficiency produces abnormal CaMKII-dependent phosphorylation
      of the cardiac ryanodine receptor in the heterozygous mouse model.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23059182
      reference_title: "CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The cardiac ryanodine receptor (RyR(2)), a validated target of
        kinase/phosphatase regulation in myocytes, displays abnormal
        CaMKII-dependent phosphorylation (pS2814 hyperphosphorylation) in
        ankyrin-B(+/-) heart.
      explanation: >-
        Directly supports CaMKII-dependent RyR2 hyperphosphorylation in the
        ankyrin-B-deficient model.
- name: Loss of Local PP2A-B56alpha Regulation
  biological_scale: MOLECULAR
  description: >-
    In the p.Q1283H knock-in model, reduced ankyrin-B/B56alpha binding is
    associated with dissociation of protein phosphatase 2A from RyR2 and
    increased RyR2 Ser2814 phosphorylation. This arm is variant specific.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: protein dephosphorylation
    term:
      id: GO:0006470
      label: protein dephosphorylation
    modifier: DECREASED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:30571258
    reference_title: "Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The loss of protein phosphatase 2A activity from ryanodine receptor is
      likely associated with reduced ankyrin-B/B56α binding, which is the
      potential mechanism of ryanodine receptor hyperphosphorylation.
    explanation: >-
      Supports the local PP2A-loss mechanism in the p.Q1283H knock-in model.
  downstream:
  - target: Ventricular Calcium-Handling Dysregulation
    description: >-
      Loss of local RyR2 dephosphorylation increases RyR2 phosphorylation and
      abnormal calcium release in the p.Q1283H model.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30571258
      reference_title: "Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This variant is associated with the loss of protein phosphatase 2A
        activity, increased phosphorylation of ryanodine receptor, exaggerated
        delayed afterdepolarization-mediated trigger activity, and
        arrhythmogenesis.
      explanation: >-
        Links PP2A loss and RyR2 phosphorylation to triggered calcium-dependent
        arrhythmogenesis in the variant-specific model.
- name: CaMKII-Dependent RyR2 Hyperphosphorylation
  biological_scale: MOLECULAR
  description: >-
    Ankyrin-B haploinsufficiency causes CaMKII-dependent RyR2 Ser2814
    hyperphosphorylation, abnormal RyR2 opening, and proarrhythmic calcium
    release in mice.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: protein phosphorylation
    term:
      id: GO:0006468
      label: protein phosphorylation
    modifier: INCREASED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:23059182
    reference_title: "CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The cardiac ryanodine receptor (RyR(2)), a validated target of
      kinase/phosphatase regulation in myocytes, displays abnormal
      CaMKII-dependent phosphorylation (pS2814 hyperphosphorylation) in
      ankyrin-B(+/-) heart.
    explanation: >-
      Directly supports this molecular arm in the heterozygous mouse heart.
  downstream:
  - target: Ventricular Calcium-Handling Dysregulation
    description: >-
      RyR2 hyperphosphorylation increases abnormal channel opening and
      afterdepolarization-prone calcium release.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23059182
      reference_title: "CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        RyR(2) dysregulation is rescued in myocytes from ankyrin-B(+/-) mice
        overexpressing a potent CaMKII-inhibitory peptide (AC3I), and aberrant
        RyR(2) open probability observed in ankyrin-B(+/-) hearts is normalized
        by treatment with the CaMKII inhibitor KN-93.
      explanation: >-
        Rescue by genetic and pharmacologic CaMKII inhibition supports the link
        from RyR2 phosphorylation to calcium-handling dysfunction.
- name: Ventricular Calcium-Handling Dysregulation
  biological_scale: CELLULAR
  description: >-
    Disorganized sodium-pump and sodium-calcium-exchanger microdomains alter
    ventricular calcium signaling and favor extrasystolic activity.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: calcium ion homeostasis
    term:
      id: GO:0055074
      label: calcium ion homeostasis
    modifier: DYSREGULATED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:12571597
    reference_title: "Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Ankyrin-B mutation also leads to altered Ca2+ signalling in adult
      cardiomyocytes that results in extrasystoles, and provides a rationale for
      the arrhythmia.
    explanation: >-
      Establishes altered calcium signaling and extrasystoles in the
      experimental cardiac model.
  downstream:
  - target: Triggered Ventricular Arrhythmia
    description: >-
      Extrasystolic activity provides a trigger for ventricular arrhythmia in
      the variant-specific model.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12571597
      reference_title: "Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Ankyrin-B mutation also leads to altered Ca2+ signalling in adult
        cardiomyocytes that results in extrasystoles, and provides a rationale
        for the arrhythmia.
      explanation: >-
        The source explicitly links abnormal calcium signaling and extrasystoles
        to the arrhythmia rationale.
- name: Triggered Ventricular Arrhythmia
  biological_scale: ORGANISM
  description: >-
    Calcium-handling abnormalities can generate extrasystoles and a
    ventricular-arrhythmia substrate. Translation from the experimental model
    to any specific human ANK2 variant remains variant dependent.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:12571597
    reference_title: "Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Ankyrin-B mutation also leads to altered Ca2+ signalling in adult
      cardiomyocytes that results in extrasystoles, and provides a rationale for
      the arrhythmia.
    explanation: >-
      Supports the experimental triggered-activity node without asserting
      universal human penetrance.
  downstream:
  - target: Ventricular Tachycardia
    description: >-
      Early selected probands included catecholamine-associated polymorphic
      ventricular tachycardia; current CPVT gene validity is disputed.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15178757
      reference_title: "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Humans with ankyrin-B mutations display varying degrees of cardiac
        dysfunction including bradycardia, sinus arrhythmia, idiopathic
        ventricular fibrillation, catecholaminergic polymorphic ventricular
        tachycardia, and risk of sudden death.
      explanation: >-
        Supports the historical clinical observation, while the indirect edge
        and partial support preserve current uncertainty.
  - target: Ventricular Fibrillation
    description: >-
      Idiopathic ventricular fibrillation occurred among early selected
      probands, but variant-level causality must be established independently.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15178757
      reference_title: "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Humans with ankyrin-B mutations display varying degrees of cardiac
        dysfunction including bradycardia, sinus arrhythmia, idiopathic
        ventricular fibrillation, catecholaminergic polymorphic ventricular
        tachycardia, and risk of sudden death.
      explanation: >-
        Supports ventricular fibrillation as a historical observation without
        assigning frequency or universal variant causality.
  - target: Syncope
    description: >-
      Ventricular arrhythmias in early ANK2 kindreds and selected probands were
      associated with exertional or sleep-related syncope.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15178757
      reference_title: "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Nonetheless, humans with ankyrin-B mutations experience polymorphic
        ventricular arrhythmia, syncope, and sudden death in response to
        exercise or emotional stress (5,6).
      explanation: >-
        Directly associates ventricular arrhythmia with syncope in the original
        kindred, while partial polarity preserves the variant-specific scope.
  - target: Sudden Cardiac Death
    description: >-
      Potentially lethal ventricular arrhythmia provides the clinically
      reported route to sudden cardiac death in early ANK2 kindreds.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15178757
      reference_title: "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Nonetheless, humans with ankyrin-B mutations experience polymorphic
        ventricular arrhythmia, syncope, and sudden death in response to
        exercise or emotional stress (5,6).
      explanation: >-
        Directly associates ventricular arrhythmia with sudden death in the
        original kindred, without implying general penetrance across ANK2
        variants.
  - target: Torsade de Pointes
    description: >-
      Torsade de pointes has been documented in selected ankyrin-B syndrome
      cases with QT prolongation.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25456501
      reference_title: "Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutations of the ANK2 gene in the rare condition Ankyrin-B syndrome
        result in loss of function of the ankyrin-B protein which in turn leads
        to abnormal regulation of intracellular sodium and calcium and a
        predisposition to cardiac arrhythmia including torsades de pointes.
      explanation: >-
        Supports torsade de pointes in the reported clinical spectrum, with
        partial polarity because the source is a single case report.
- name: Sinoatrial Node Pacemaker Dysfunction
  biological_scale: CELLULAR
  description: >-
    Impaired ankyrin-B-dependent organization of sinoatrial-node channels and
    transporters disrupts normal pacing and can produce sinus-node dysfunction.
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:18832177
    reference_title: "Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We mapped two families with highly penetrant and severe SND to the human
      ANK2 (ankyrin-B/AnkB) locus.
    explanation: >-
      Human families support a locus-level association with severe sinus-node
      dysfunction.
  - reference: PMID:18832177
    reference_title: "Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      AnkB is essential for normal membrane organization of sinoatrial node
      cell channels and transporters, and AnkB is required for physiological
      cardiac pacing.
    explanation: >-
      Experimental evidence supports the channel-targeting and pacemaker
      mechanism.
  downstream:
  - target: Sinus Bradycardia
    description: >-
      Loss of normal sinoatrial pacing lowers heart rate.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18832177
      reference_title: "Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mice heterozygous for AnkB phenocopy human SND displayed severe
        bradycardia and rate variability.
      explanation: >-
        The model directly links ankyrin-B insufficiency and the human
        sinus-node-disease phenotype to bradycardia.
  - target: Sick Sinus Syndrome
    description: >-
      Disrupted ankyrin-B-dependent sinoatrial-node organization produces the
      human sinus-node-dysfunction phenotype.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18832177
      reference_title: "Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We mapped two families with highly penetrant and severe SND to the human
        ANK2 (ankyrin-B/AnkB) locus.
      explanation: >-
        Human families directly link the ANK2 locus with severe sinus-node
        dysfunction.
- name: Atrial Cav1.3 Targeting Defect and Reentry Susceptibility
  biological_scale: CELLULAR
  description: >-
    Defective membrane targeting of Cav1.3 in atrial and sinoatrial-node cells
    shortens atrial action potentials and, together with slowed conduction,
    increases susceptibility to sustained reentry. This mechanistic bridge is
    computational and does not establish variant-level penetrance.
  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: DYSREGULATED
  locations:
  - preferred_term: atrium
    term:
      id: UBERON:0002081
      label: cardiac atrium
  evidence:
  - reference: PMID:23436330
    reference_title: "Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      In parallel, increased fibrosis results in conduction slowing that further
      increases the susceptibility to sustained reentry in the setting of
      ankyrin-B dysfunction.
    explanation: >-
      The model identifies a tissue-level reentry substrate in ankyrin-B
      dysfunction.
  downstream:
  - target: Atrial Fibrillation
    description: >-
      Atrial action-potential shortening and conduction slowing increase modeled
      susceptibility to atrial fibrillation.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23436330
      reference_title: "Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        These studies identify the mechanism for increased susceptibility to
        atrial fibrillation and SAN dysfunction in human disease.
      explanation: >-
        Supports the modeled route to atrial-fibrillation susceptibility.
- name: Beta-Catenin Localization and Signaling Disruption
  biological_scale: CELLULAR
  description: >-
    Ankyrin-B directly interacts with beta-catenin; loss of ankyrin-B disrupts
    beta-catenin localization in human ANK2-associated cardiomyopathy tissue and
    in cardiomyocyte-selective Ank2 knockout hearts.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Wnt signaling pathway
    term:
      id: GO:0016055
      label: Wnt signaling pathway
    modifier: DYSREGULATED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:31264976
    reference_title: "Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Human hearts from deceased ANK2 ARVC probands display aberrant β-catenin
      localization.
    explanation: >-
      Human ventricular tissue demonstrates abnormal beta-catenin localization
      in ANK2-associated arrhythmogenic cardiomyopathy.
  downstream:
  - target: Structural Cardiac Remodeling
    description: >-
      Altered beta-catenin localization is linked to fibrotic structural
      remodeling in the ANK2 cardiomyopathy model.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31264976
      reference_title: "Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        an ANK2 mouse model was found to develop dramatic structural
        abnormalities reflective of human ACM, including biventricular
        dilation, reduced ejection fraction, cardiac fibrosis, and premature
        death.
      explanation: >-
        The murine phenotype statement aligns the downstream claim to the
        structural-remodeling result; the preceding node and edge supply the
        beta-catenin context.
- name: Structural Cardiac Remodeling
  biological_scale: TISSUE
  description: >-
    Cardiomyocyte-selective Ank2 loss produces chamber dilation, reduced cardiac
    function, fibrosis, arrhythmia, and early mortality in mice; rare ANK2
    variants with ankyrin-B loss of function were identified in deceased human
    arrhythmogenic-cardiomyopathy probands. The human gene-disease scope remains
    based on a small selected series.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:31264976
    reference_title: "Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Following identification of deceased ACM probands possessing ANK2 rare
      variants and evidence of ankyrin-B loss of function on cardiac tissue
      analysis, an ANK2 mouse model was found to develop dramatic structural
      abnormalities reflective of human ACM, including biventricular dilation,
      reduced ejection fraction, cardiac fibrosis, and premature death.
    explanation: >-
      The mouse model directly supports the structural-remodeling phenotype,
      anchored to human probands by cardiac-tissue loss-of-function evidence.
  downstream:
  - target: Cardiomyopathy
    description: >-
      Fibrotic chamber remodeling produces an arrhythmogenic cardiomyopathy
      phenotype in the experimental model and selected human probands.
    hypothesis_groups:
    - variant_specific_ankyrin_b_cardiac_model
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31264976
      reference_title: "Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Following identification of deceased ACM probands possessing ANK2 rare
        variants and evidence of ankyrin-B loss of function on cardiac tissue
        analysis
      explanation: >-
        Supports ANK2-associated cardiomyopathy in selected deceased probands;
        partial polarity avoids implying population-level monogenic validity.
phenotypes:
- category: Cardiovascular
  name: Sick Sinus Syndrome
  description: >-
    Severe sinus-node dysfunction was mapped to the ANK2 locus in two families.
    No population frequency is assigned.
  phenotype_term:
    preferred_term: Sick sinus syndrome
    term:
      id: HP:0011704
      label: Sick sinus syndrome
  evidence:
  - reference: PMID:18832177
    reference_title: "Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We mapped two families with highly penetrant and severe SND to the human
      ANK2 (ankyrin-B/AnkB) locus.
    explanation: >-
      This is direct human evidence for severe sinus-node dysfunction in the
      ankyrin-B-related cardiac spectrum.
- category: Cardiovascular
  name: Sinus Bradycardia
  description: >-
    Sinus bradycardia is a reported manifestation of the
    sinus-node-dysfunction branch. No population frequency is assigned.
  phenotype_term:
    preferred_term: Sinus bradycardia
    term:
      id: HP:0001688
      label: Sinus bradycardia
  evidence:
  - reference: PMID:15178757
    reference_title: "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected family members display many atypical features compared to other
      long QT syndromes, including pronounced sinus bradycardia, polyphasic T
      waves, and atrial fibrillation (5).
    explanation: >-
      The original E1425G kindred had sinus bradycardia, but this selected
      family does not establish its frequency across ANK2 variants.
- category: Cardiovascular
  name: Ventricular Tachycardia
  description: >-
    Polymorphic or catecholamine-associated ventricular tachycardia was reported
    in early ANK2 series, but the monogenic ANK2-CPVT relationship is disputed.
    No frequency is assigned.
  phenotype_term:
    preferred_term: Ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  evidence:
  - reference: PMID:15178757
    reference_title: "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Humans with ankyrin-B mutations display varying degrees of cardiac
      dysfunction including bradycardia, sinus arrhythmia, idiopathic
      ventricular fibrillation, catecholaminergic polymorphic ventricular
      tachycardia, and risk of sudden death.
    explanation: >-
      Supports the historical observation only.
- category: Cardiovascular
  name: Ventricular Fibrillation
  description: >-
    Idiopathic ventricular fibrillation was reported in selected early
    probands. No frequency is assigned.
  phenotype_term:
    preferred_term: Ventricular fibrillation
    term:
      id: HP:0001663
      label: Ventricular fibrillation
  evidence:
  - reference: PMID:15178757
    reference_title: "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Humans with ankyrin-B mutations display varying degrees of cardiac
      dysfunction including bradycardia, sinus arrhythmia, idiopathic
      ventricular fibrillation, catecholaminergic polymorphic ventricular
      tachycardia, and risk of sudden death.
    explanation: >-
      The source reports ventricular fibrillation in an ascertained series but
      does not establish population frequency.
- category: Cardiovascular
  name: Atrial Fibrillation
  description: >-
    Atrial fibrillation is part of the reported ankyrin-B-related human cardiac
    spectrum. No frequency or broad variant-level causality is assigned.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:27916589
    reference_title: "A Novel Mechanism for Human Cardiac Ankyrin-B Syndrome due to Reciprocal Chromosomal Translocation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Loss-of-function variants in the ANK2 gene can cause a variety of cardiac
      rhythm abnormalities including sinus node dysfunction, atrial fibrillation
      and ventricular arrhythmias (called the "ankyrin-B syndrome").
    explanation: >-
      Supports atrial fibrillation within the reported human spectrum while the
      partial polarity preserves the entry's variant-specific scope.
- category: Cardiovascular
  name: Cardiomyopathy
  description: >-
    Arrhythmogenic cardiomyopathy and fibrotic structural remodeling were
    reported in selected deceased ANK2-variant probands and modeled by
    cardiomyocyte-selective Ank2 loss. No frequency is assigned.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:31264976
    reference_title: "Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Following identification of deceased ACM probands possessing ANK2 rare
      variants and evidence of ankyrin-B loss of function on cardiac tissue
      analysis
    explanation: >-
      Directly supports the phenotype in selected human probands, with partial
      polarity because the evidence does not establish general penetrance.
- category: Cardiovascular
  name: Prolonged QT Interval
  description: >-
    Prolonged QT or QTU intervals were documented in the original E1425G
    kindred and selected later cases but were inconsistent across ANK2 variant
    carriers. This partial phenotype assertion does not reinstate a validated
    monogenic ANK2-LQTS relationship.
  phenotype_term:
    preferred_term: Prolonged QT interval
    term:
      id: HP:0001657
      label: Prolonged QT interval
  evidence:
  - reference: PMID:25456501
    reference_title: "Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a rare case of this condition characterised by sinus node
      dysfunction, atrial fibrillation and prolonged QT syndrome in a young
      patient with a family history of sudden death.
    explanation: >-
      Supports QT prolongation in one selected patient without establishing a
      broadly valid gene-disease relationship.
  - reference: PMID:15178757
    reference_title: "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, a prolonged rate-corrected QT interval was not a consistent
      feature, indicating that ankyrin-B dysfunction represents a clinical
      entity distinct from classic long QT syndromes.
    explanation: >-
      Establishes the inconsistency that constrains the phenotype's certainty
      and scope.
- category: Cardiovascular
  name: Torsade de Pointes
  description: >-
    Torsade de pointes was reported in selected ANK2-associated cases. No
    population frequency or universal variant-level causality is assigned.
  phenotype_term:
    preferred_term: Torsade de pointes
    term:
      id: HP:0001664
      label: Torsade de pointes
  evidence:
  - reference: PMID:25456501
    reference_title: "Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations of the ANK2 gene in the rare condition Ankyrin-B syndrome
      result in loss of function of the ankyrin-B protein which in turn leads
      to abnormal regulation of intracellular sodium and calcium and a
      predisposition to cardiac arrhythmia including torsades de pointes.
    explanation: >-
      Supports the phenotype in a case-based clinical source, with partial
      polarity to preserve variant-specific uncertainty.
- category: Cardiovascular
  name: Syncope
  description: >-
    Exercise-associated and sleep-associated syncope occurred in the original
    kindred and selected early ANK2 probands with ventricular arrhythmia. No
    population frequency is assigned.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:15178757
    reference_title: "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonetheless, humans with ankyrin-B mutations experience polymorphic
      ventricular arrhythmia, syncope, and sudden death in response to exercise
      or emotional stress (5,6).
    explanation: >-
      Supports syncope in the original family-level clinical spectrum; partial
      polarity avoids generalizing across ANK2 variants.
- category: Cardiovascular
  name: Sudden Cardiac Death
  description: >-
    Sudden cardiac death was reported in early ANK2 kindreds, generally in the
    setting of exertion or emotional stress. No population frequency is
    assigned, and causality remains variant and family specific.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:15178757
    reference_title: "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonetheless, humans with ankyrin-B mutations experience polymorphic
      ventricular arrhythmia, syncope, and sudden death in response to exercise
      or emotional stress (5,6).
    explanation: >-
      Supports sudden death in the original family-level clinical spectrum;
      partial polarity avoids implying population-level penetrance.
genetic:
- name: Reported ANK2 monogenic LQTS and CPVT associations
  gene_term:
    preferred_term: ANK2
    term:
      id: hgnc:493
      label: ANK2
  association: Reported monogenic LQTS and CPVT associations
  relationship_type: DISPUTED
  features: >-
    Early reports connected ANK2 variants with type 4 long QT syndrome and
    catecholaminergic polymorphic ventricular tachycardia. Later gene-validity
    and population analyses disputed both monogenic relationships. Variant
    interpretation requires contemporary population, segregation,
    phenotype-specific, and functional evidence.
  evidence:
  - reference: PMID:15178757
    reference_title: "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A loss-of-function mutation of ankyrin-B identified in an extended kindred
      causes a dominantly inherited cardiac arrhythmia, initially described as
      type 4 long QT syndrome.
    explanation: >-
      Preserves the historical family-level association without generalizing it.
  - reference: PMID:15178757
    reference_title: "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Humans with ankyrin-B mutations display varying degrees of cardiac
      dysfunction including bradycardia, sinus arrhythmia, idiopathic
      ventricular fibrillation, catecholaminergic polymorphic ventricular
      tachycardia, and risk of sudden death.
    explanation: >-
      Preserves the early CPVT-like clinical report without treating it as a
      currently validated monogenic ANK2-CPVT relationship.
  - reference: PMID:31983240
    reference_title: "An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome."
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      Six genes, AKAP9, ANK2, KCNE2, KCNJ5, SCN4B, and SNTA1, were classified
      as disputed, defined as the absence of sufficient genetic evidence to
      support causation of LQTS (Figure 1).
    explanation: >-
      Refutes a broad monogenic ANK2-LQTS interpretation.
  - reference: PMID:34557911
    reference_title: "Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death."
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed
      by the Expert Panel to be reported for phenotypes that were not
      representative of CPVT, while reported variants in a fourth gene (ANK2)
      were too common in the population to be disease-causing.
    explanation: >-
      Refutes a broad monogenic ANK2-CPVT interpretation.
  - reference: PMID:32164423
    reference_title: "Established Loss-of-Function Variants in ANK2-Encoded Ankyrin-B Rarely Cause a Concerning Cardiac Phenotype in Humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Established Loss-of-Function Variants in ANK2-Encoded Ankyrin-B Rarely
      Cause a Concerning Cardiac Phenotype in Humans.
    explanation: >-
      The title-only cached record provides limited modern counterevidence
      against inferring a concerning cardiac phenotype from established
      loss-of-function variation alone.
  - reference: DOI:10.1161/circgenetics.116.001537
    reference_title: "Novel Variant in the <i>ANK2</i> Membrane-Binding Domain Is Associated With Ankyrin-B Syndrome and Structural Heart Disease in a First Nations Population With a High Rate of Long QT Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Index cases in these 2 families harbored a novel ANK2 c.1937C>T variant
      (p.S646F). An additional 16 carriers were identified, including 2 with
      structural heart disease: one with cardiomyopathy resulting in sudden
      death and the other with congenital heart disease. For all carriers of
      this variant, the average QTc was 475 ms (±40).
    explanation: >-
      Adds the First Nations family evidence for p.S646F while avoiding a
      population-level founder or penetrance claim not established by the
      cached abstract.
  - reference: PMID:27298202
    reference_title: "Common human ANK2 variant confers in vivo arrhythmia phenotypes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We support classification of p.L1622I as a "mild" loss-of-function variant
      that may confer arrhythmia susceptibility in the context of secondary risk
      factors including environment, medication, and/or additional genetic
      variation.
    explanation: >-
      Variant-specific knock-in evidence supports a susceptibility model for
      p.L1622I rather than a broadly penetrant monogenic interpretation.
treatments:
- name: Permanent Pacemaker for Symptomatic Sinus Node Dysfunction
  description: >-
    Permanent pacing is established supportive management for clinically
    significant sinus-node dysfunction. It treats bradycardia but does not
    correct the ANK2-dependent molecular defect.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Pacemaker placement
    term:
      id: NCIT:C80434
      label: Pacemaker Placement
  target_mechanisms:
  - target: Sinoatrial Node Pacemaker Dysfunction
    treatment_effect: BYPASSES
    description: >-
      An implanted pacemaker bypasses inadequate intrinsic sinoatrial pacing.
    evidence:
    - reference: PMID:18832177
      reference_title: "Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        SND led to pacemaker implantation in 14 patients (mean age for
        implantation, 34 ± 17 years).
      explanation: >-
        Documents pacemaker implantation in affected members of the ANK2-linked
        family.
  evidence:
  - reference: PMID:25456501
    reference_title: "Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The management of Ankyrin-B syndrome may include avoidance of QT
      prolonging medications, insertion of a permanent pacemaker for sinus node
      dysfunction, or a cardioverter defibrillator for those at high-risk of
      sudden death from torsades de pointes.
    explanation: >-
      A case-based management review explicitly includes permanent pacing for
      sinus-node dysfunction.
- name: Implantable Cardioverter-Defibrillator for High-Risk Ventricular Arrhythmia
  description: >-
    ICD placement may be considered for patients judged at high risk of sudden
    death from torsade de pointes or other malignant ventricular arrhythmia;
    the cited ANK2 evidence is case based, not a genotype-only indication.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_mechanisms:
  - target: Triggered Ventricular Arrhythmia
    treatment_effect: INHIBITS
    description: >-
      The device terminates a malignant ventricular rhythm rather than
      modifying the underlying ankyrin-B substrate.
    evidence:
    - reference: PMID:25456501
      reference_title: "Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The management of Ankyrin-B syndrome may include avoidance of QT
        prolonging medications, insertion of a permanent pacemaker for sinus
        node dysfunction, or a cardioverter defibrillator for those at
        high-risk of sudden death from torsades de pointes.
      explanation: >-
        Supports a risk-based ICD option in a case-based management source.
  evidence:
  - reference: PMID:25456501
    reference_title: "Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The management of Ankyrin-B syndrome may include avoidance of QT
      prolonging medications, insertion of a permanent pacemaker for sinus node
      dysfunction, or a cardioverter defibrillator for those at high-risk of
      sudden death from torsades de pointes.
    explanation: >-
      The source provides the indication but not comparative outcome evidence.
- name: Avoidance of QT-Prolonging Medications
  description: >-
    Avoid QT-prolonging medications in patients with a documented prolonged-QT
    or torsadogenic phenotype. This is phenotype-directed risk reduction, not a
    recommendation based on an ANK2 variant alone.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: avoidance of contraindicated medications
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Triggered Ventricular Arrhythmia
    treatment_effect: INHIBITS
    description: >-
      Removing QT-prolonging exposures reduces an avoidable trigger for torsade
      de pointes in susceptible patients.
    evidence:
    - reference: PMID:25456501
      reference_title: "Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The management of Ankyrin-B syndrome may include avoidance of QT
        prolonging medications
      explanation: >-
        The case-based management source explicitly recommends medication
        avoidance; partial polarity preserves its limited scope.
  evidence:
  - reference: PMID:25456501
    reference_title: "Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The management of Ankyrin-B syndrome may include avoidance of QT
      prolonging medications
    explanation: >-
      Supports phenotype-directed avoidance in the reported clinical context.
- name: Metoprolol for p.Q1283H Arrhythmia Susceptibility (Preclinical)
  description: >-
    Metoprolol reduced stress-induced ventricular arrhythmias in ANK2 p.Q1283H
    knock-in mice. This variant-specific preclinical result is not evidence of
    clinical efficacy across ANK2 variants.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metoprolol
      term:
        id: CHEBI:6904
        label: metoprolol
  target_mechanisms:
  - target: Triggered Ventricular Arrhythmia
    treatment_effect: INHIBITS
    description: >-
      Beta-adrenergic blockade reduces catecholaminergic provocation of
      ventricular arrhythmia in the p.Q1283H knock-in model.
    evidence:
    - reference: PMID:30571258
      reference_title: "Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Finally, the administration of metoprolol or flecainide decreased the
        incidence of stress-induced ventricular arrhythmias in the KI mice.
      explanation: >-
        Directly supports the antiarrhythmic effect in the knock-in mouse model.
  evidence:
  - reference: PMID:30571258
    reference_title: "Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Finally, the administration of metoprolol or flecainide decreased the
      incidence of stress-induced ventricular arrhythmias in the KI mice.
    explanation: >-
      The evidence is explicitly limited to p.Q1283H knock-in mice.
- name: Flecainide for p.Q1283H Arrhythmia Susceptibility (Preclinical)
  description: >-
    Flecainide reduced stress-induced ventricular arrhythmias in ANK2 p.Q1283H
    knock-in mice. This variant-specific preclinical result is not evidence of
    clinical efficacy across ANK2 variants.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: flecainide
      term:
        id: CHEBI:75984
        label: flecainide
  target_mechanisms:
  - target: Triggered Ventricular Arrhythmia
    treatment_effect: INHIBITS
    description: >-
      Flecainide reduces stress-provoked ventricular arrhythmia in the p.Q1283H
      knock-in model.
    evidence:
    - reference: PMID:30571258
      reference_title: "Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Finally, the administration of metoprolol or flecainide decreased the
        incidence of stress-induced ventricular arrhythmias in the KI mice.
      explanation: >-
        Directly supports the antiarrhythmic effect in the knock-in mouse model.
  evidence:
  - reference: PMID:30571258
    reference_title: "Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Finally, the administration of metoprolol or flecainide decreased the
      incidence of stress-induced ventricular arrhythmias in the KI mice.
    explanation: >-
      The evidence is explicitly limited to p.Q1283H knock-in mice.
- name: CaMKII Inhibition for RyR2 Dysregulation (Preclinical)
  description: >-
    Genetic AC3I expression and pharmacologic KN-93 treatment rescued RyR2
    dysregulation and blunted arrhythmia in ankyrin-B-deficient mice. KN-93 is
    an experimental tool compound, not a clinical recommendation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: KN-93
      term:
        id: CHEBI:91460
        label: KN-93
  target_mechanisms:
  - target: CaMKII-Dependent RyR2 Hyperphosphorylation
    treatment_effect: INHIBITS
    description: >-
      CaMKII inhibition normalizes RyR2 behavior and reduces the proarrhythmic
      phenotype in the ankyrin-B-deficient model.
    evidence:
    - reference: PMID:23059182
      reference_title: "CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        RyR(2) dysregulation is rescued in myocytes from ankyrin-B(+/-) mice
        overexpressing a potent CaMKII-inhibitory peptide (AC3I), and aberrant
        RyR(2) open probability observed in ankyrin-B(+/-) hearts is normalized
        by treatment with the CaMKII inhibitor KN-93.
      explanation: >-
        Directly supports genetic and pharmacologic rescue of this mechanism.
  evidence:
  - reference: PMID:23059182
    reference_title: "CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      CaMKII inhibition is sufficient to rescue abnormalities in
      ankyrin-B(+/-) myocyte electrical dysfunction including cellular
      afterdepolarizations, and significantly blunts whole animal cardiac
      arrhythmias and sudden death in response to elevated sympathetic tone.
    explanation: >-
      Demonstrates rescue from cellular through organism scales in mice.
- name: SB-216763 WNT/Beta-Catenin Activation (Preclinical)
  description: >-
    SB-216763, a pharmacologic WNT/beta-catenin pathway activator, prevented and
    partially reversed cardiomyopathy phenotypes in the Ank2-deficient mouse
    model. This is preclinical evidence only.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Beta-Catenin Localization and Signaling Disruption
    treatment_effect: INHIBITS
    description: >-
      Pharmacologic WNT/beta-catenin activation counteracts the disrupted
      signaling state caused by ankyrin-B loss.
    evidence:
    - reference: PMID:31264976
      reference_title: "Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        A pharmacological activator of the WNT/β-catenin pathway, SB-216763,
        successfully prevented and partially reversed the murine ACM
        phenotypes.
      explanation: >-
        Directly supports pathway-directed rescue in the mouse model.
  evidence:
  - reference: PMID:31264976
    reference_title: "Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      A pharmacological activator of the WNT/β-catenin pathway, SB-216763,
      successfully prevented and partially reversed the murine ACM phenotypes.
    explanation: >-
      Establishes a preclinical treatment effect without implying human use.
- name: Tideglusib for ANK2-Deficient Cardiomyopathy (Preclinical)
  description: >-
    Tideglusib, a GSK-3 beta inhibitor, prevented and reversed reduced cardiac
    function and reduced adrenergically provoked ventricular arrhythmia in an
    Ank2 cardiomyocyte-selective knockout model. This is preclinical evidence,
    not a clinical recommendation for ANK2 variant carriers.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tideglusib
      term:
        id: CHEBI:147398
        label: tideglusib
  target_mechanisms:
  - target: Beta-Catenin Localization and Signaling Disruption
    treatment_effect: INHIBITS
    description: >-
      GSK-3 inhibition is modeled as counteracting the disrupted beta-catenin
      signaling state upstream of structural remodeling.
    evidence:
    - reference: PMID:40866040
      reference_title: "Evaluation of Tideglusib as a Disease Modifying Therapy in Murine Models of Arrhythmogenic Cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We evaluated the therapeutic efficacy of Tideglusib (TD) in Ank2
        cardio-selective-knockout and homozygous desmoglein-2 mutant ACM mouse
        models.
      explanation: >-
        Supports evaluation of a GSK-3 inhibitor in the Ank2-deficient model;
        partial polarity makes explicit that this abstract does not directly
        measure the upstream beta-catenin target.
  - target: Structural Cardiac Remodeling
    treatment_effect: INHIBITS
    description: >-
      Tideglusib prevented and reversed reduced cardiac function in the Ank2
      knockout model and reduced its provoked ventricular-arrhythmia burden.
    evidence:
    - reference: PMID:40866040
      reference_title: "Evaluation of Tideglusib as a Disease Modifying Therapy in Murine Models of Arrhythmogenic Cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        TD was able to prevent and reverse the reduced cardiac function in
        treated mice. Moreover, TD-treated adult mice displayed a reduction in
        ventricular arrhythmia following adrenergic stimulation.
      explanation: >-
        Directly supports disease-modifying and antiarrhythmic effects in the
        Ank2-deficient mouse model.
  evidence:
  - reference: PMID:40866040
    reference_title: "Evaluation of Tideglusib as a Disease Modifying Therapy in Murine Models of Arrhythmogenic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We evaluated the therapeutic efficacy of Tideglusib (TD) in Ank2
      cardio-selective-knockout and homozygous desmoglein-2 mutant ACM mouse
      models.
    explanation: >-
      Establishes that tideglusib was evaluated directly in an Ank2-deficient
      arrhythmogenic-cardiomyopathy model.
diagnosis:
- name: Phenotype-first LQTS evaluation with evidence-based gene interpretation
  diagnosis_term:
    preferred_term: electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  description: >-
    Cardiac evaluation should begin with the documented electrophysiologic
    phenotype. An ANK2 finding alone must not establish LQTS or direct clinical
    decisions when the gene-disease relationship is disputed.
  results: >-
    Interpret ECG and rhythm findings independently of ANK2 status; require new
    and sufficient variant-level genetic evidence before attributing LQTS to
    ANK2.
  evidence:
  - reference: PMID:31983240
    reference_title: "An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Genetic variants in these genes should not be used for clinical
      decision-making, unless accompanied by new and sufficient genetic
      evidence.
    explanation: >-
      The reappraisal explicitly warns against clinical use of variants in
      disputed or limited LQTS genes without sufficient new evidence.
- name: Ambulatory Rhythm Monitoring
  diagnosis_term:
    preferred_term: Holter monitoring
    term:
      id: NCIT:C38064
      label: Holter Monitoring
  description: >-
    Ambulatory ECG monitoring can capture intermittent atrial or ventricular
    arrhythmia and sinus-node dysfunction that is absent on a resting tracing.
    Evidence here documents its use in a recent, genetically complex family and
    does not make an ANK2-specific diagnostic-performance claim.
  results: >-
    Interpret rhythm findings on their own clinical merits and do not attribute
    them to ANK2 without adequate variant and segregation evidence.
  evidence:
  - reference: DOI:10.2147/tacg.s438957
    reference_title: "A New Inherited Syndrome Causing Sudden Cardiac Death With Distinct ST-Segment Depression and Ankyrin-2-Mutation"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All available family members were seen and examined with our cardiology
      department and underwent resting and exercise ECGs, 24-hr Holter ECG
      monitoring and a standard transthoracic echocardiogram.
    explanation: >-
      Documents Holter monitoring in an ANK2-plus-MYO18B family evaluation;
      partial polarity preserves the oligogenic and case-based scope.
- name: Exercise Cardiac Stress Testing
  diagnosis_term:
    preferred_term: Exercise cardiac stress test
    term:
      id: NCIT:C168192
      label: Exercise Cardiac Stress Test
  description: >-
    Exercise ECG can help reveal stress-associated arrhythmias in a
    phenotype-first assessment. It is not a test of ANK2 pathogenicity.
  results: >-
    Evaluate inducible ectopy or arrhythmia independently, then integrate any
    genetic finding using contemporary variant-level evidence.
  evidence:
  - reference: DOI:10.2147/tacg.s438957
    reference_title: "A New Inherited Syndrome Causing Sudden Cardiac Death With Distinct ST-Segment Depression and Ankyrin-2-Mutation"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All available family members were seen and examined with our cardiology
      department and underwent resting and exercise ECGs, 24-hr Holter ECG
      monitoring and a standard transthoracic echocardiogram.
    explanation: >-
      Documents exercise ECG in a genetically complex family investigation;
      it does not validate ANK2 as a stand-alone diagnostic marker.
- name: Echocardiographic Structural Assessment
  diagnosis_term:
    preferred_term: Echocardiography test
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  description: >-
    Echocardiography assesses ventricular function and structural heart disease
    when cardiomyopathy is suspected or being excluded.
  results: >-
    Structural findings should be interpreted separately from electrical
    phenotypes and from the pathogenicity of an ANK2 variant.
  evidence:
  - reference: DOI:10.2147/tacg.s438957
    reference_title: "A New Inherited Syndrome Causing Sudden Cardiac Death With Distinct ST-Segment Depression and Ankyrin-2-Mutation"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All available family members were seen and examined with our cardiology
      department and underwent resting and exercise ECGs, 24-hr Holter ECG
      monitoring and a standard transthoracic echocardiogram.
    explanation: >-
      Documents structural imaging as one component of a family cardiac
      evaluation; partial polarity reflects the single-family evidence.
- name: Multigene Testing, Segregation, and Molecular Autopsy
  diagnosis_term:
    preferred_term: Genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    In unresolved inherited-arrhythmia or sudden-death families, panel or exome
    testing, molecular autopsy, and segregation analysis may be used. Because
    ANK2 cardiac validity is disputed and oligogenic findings occur, an ANK2
    result alone must not establish diagnosis or guide predictive testing.
  results: >-
    Classify each variant with current population, segregation, functional, and
    phenotype evidence; evaluate other cardiac genes and avoid using an ANK2 VUS
    for cascade prediction.
  evidence:
  - reference: DOI:10.2147/tacg.s438957
    reference_title: "A New Inherited Syndrome Causing Sudden Cardiac Death With Distinct ST-Segment Depression and Ankyrin-2-Mutation"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A precise analysis was performed by an international multidisciplinary
      expert panel including autopsy of the index patient’s heart, molecular
      autopsy, whole-exome sequencing, analysis of the pedigree and examination
      of available family members.
    explanation: >-
      Documents a combined molecular-autopsy, exome, pedigree, and family
      evaluation in a case with ANK2 and MYO18B findings.
  - reference: DOI:10.2147/tacg.s438957
    reference_title: "A New Inherited Syndrome Causing Sudden Cardiac Death With Distinct ST-Segment Depression and Ankyrin-2-Mutation"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic testing of the index patients blood sample and in parts of the
      family was done. It was performed by sequencing in parallel 174 genes
      associated with inherited cardiac diseases on a MiSeq platform.
    explanation: >-
      Documents multigene panel testing rather than ANK2-only testing in the
      investigated family.
notes: >-
  The cardiac and neurodevelopmental ANK2 records are intentionally split to
  prevent a cardiac-disputed relationship from being auto-wired to the
  definitive neurodevelopmental mechanisms. The Brugada assertion is retained
  only as an external disputed Gene2Phenotype record because the locally cached
  literature used here does not independently establish that classification.
references:
- reference: PMID:12571597
  title: "Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death."
  findings: []
- reference: PMID:15178757
  title: "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function."
  findings: []
- reference: PMID:18832177
  title: "Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease."
  findings: []
- reference: PMID:23059182
  title: "CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome."
  findings: []
- reference: PMID:25456501
  title: "Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult."
  findings: []
- reference: PMID:30571258
  title: "Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation."
  findings: []
- reference: DOI:10.1161/circgenetics.116.001537
  title: "Novel Variant in the <i>ANK2</i> Membrane-Binding Domain Is Associated With Ankyrin-B Syndrome and Structural Heart Disease in a First Nations Population With a High Rate of Long QT Syndrome"
  findings: []
- reference: DOI:10.2147/tacg.s438957
  title: "A New Inherited Syndrome Causing Sudden Cardiac Death With Distinct ST-Segment Depression and Ankyrin-2-Mutation"
  findings: []
- reference: PMID:31983240
  title: "An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome."
  findings: []
- reference: PMID:32164423
  title: "Established Loss-of-Function Variants in ANK2-Encoded Ankyrin-B Rarely Cause a Concerning Cardiac Phenotype in Humans."
  findings: []
- reference: PMID:34557911
  title: "Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death."
  findings: []
- reference: PMID:23436330
  title: "Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis."
  findings: []
- reference: PMID:27298202
  title: "Common human ANK2 variant confers in vivo arrhythmia phenotypes."
  findings: []
- reference: PMID:27916589
  title: "A Novel Mechanism for Human Cardiac Ankyrin-B Syndrome due to Reciprocal Chromosomal Translocation."
  findings: []
- reference: PMID:31264976
  title: "Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy."
  findings: []
- reference: PMID:40866040
  title: "Evaluation of Tideglusib as a Disease Modifying Therapy in Murine Models of Arrhythmogenic Cardiomyopathy."
  findings: []
clinical_trials: []
datasets: []
📚

References & Deep Research

References

16
PMID:12571597
Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death.
No top-level findings curated for this source.
PMID:15178757
A cardiac arrhythmia syndrome caused by loss of ankyrin-B function.
No top-level findings curated for this source.
PMID:18832177
Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease.
No top-level findings curated for this source.
PMID:23059182
CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome.
No top-level findings curated for this source.
PMID:25456501
Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult.
No top-level findings curated for this source.
PMID:30571258
Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation.
No top-level findings curated for this source.
DOI:10.1161/circgenetics.116.001537
Novel Variant in the <i>ANK2</i> Membrane-Binding Domain Is Associated With Ankyrin-B Syndrome and Structural Heart Disease in a First Nations Population With a High Rate of Long QT Syndrome
No top-level findings curated for this source.
DOI:10.2147/tacg.s438957
A New Inherited Syndrome Causing Sudden Cardiac Death With Distinct ST-Segment Depression and Ankyrin-2-Mutation
No top-level findings curated for this source.
PMID:31983240
An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome.
No top-level findings curated for this source.
PMID:32164423
Established Loss-of-Function Variants in ANK2-Encoded Ankyrin-B Rarely Cause a Concerning Cardiac Phenotype in Humans.
No top-level findings curated for this source.
PMID:34557911
Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death.
No top-level findings curated for this source.
PMID:23436330
Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis.
No top-level findings curated for this source.
PMID:27298202
Common human ANK2 variant confers in vivo arrhythmia phenotypes.
No top-level findings curated for this source.
PMID:27916589
A Novel Mechanism for Human Cardiac Ankyrin-B Syndrome due to Reciprocal Chromosomal Translocation.
No top-level findings curated for this source.
PMID:31264976
Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy.
No top-level findings curated for this source.
PMID:40866040
Evaluation of Tideglusib as a Disease Modifying Therapy in Murine Models of Arrhythmogenic Cardiomyopathy.
No top-level findings curated for this source.

Deep Research

2
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 44 citations 2026-04-04T12:57:27.458587

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: ANK2 Ankyrin-B Syndrome
  • MONDO ID: (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on ANK2 Ankyrin-B Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Research Report: ANK2 Ankyrin‑B Syndrome (LQT4)

Executive summary

ANK2 (ankyrin‑B) syndrome—historically “long QT syndrome type 4 (LQT4)”—is an autosomal‑dominant, variably expressive, incompletely penetrant inherited arrhythmia disorder caused by pathogenic ANK2 variants that impair ankyrin‑B scaffold function in cardiomyocytes and sinoatrial node cells. It classically presents with QTc prolongation and sinus node dysfunction, but the phenotype extends to atrial fibrillation, ventricular arrhythmias (often catecholamine/stress‑induced), conduction disease, sudden cardiac death, and in some families/variants, structural heart disease/arrhythmogenic cardiomyopathy. (mohler2003ankyrinbmutationcauses pages 1-2, koenig2017theevolvingrole pages 2-4, york2022mechanismsunderlyingthe pages 1-2, sucharski2020mechanismsandalterations pages 1-2)

1. Disease information

1.1 Definition and overview

Ankyrin‑B (encoded by ANK2) is a membrane–cytoskeleton adaptor (“scaffold”) protein that organizes key ion channels/transporters and signaling proteins required for cardiac excitability and excitation–contraction coupling. Loss‑of‑function ANK2 variants cause a multisystem cardiac electrical disorder originally described as LQT4 and now commonly termed “ankyrin‑B syndrome” due to its broader phenotype beyond QT prolongation. (ackerman2010defininganew pages 2-3, york2022mechanismsunderlyingthe pages 1-2, sucharski2020mechanismsandalterations pages 1-2)

Key primary description and disease establishment: a large French pedigree with ANK2 missense variant c.4274A>G (p.Glu1425Gly; historical numbering) exhibited QTc prolongation, sinus node dysfunction, atrial fibrillation, and sudden death, establishing ANK2 as a cause of congenital long‑QT and arrhythmia through a non–ion-channel mechanism. (mohler2003ankyrinbmutationcauses pages 1-2)

1.2 Key identifiers

Concept Value Notes Key citation
Primary disease name ANK2 ankyrin-B syndrome Autosomal-dominant inherited arrhythmia syndrome caused by loss-of-function ANK2 variants; broader term now preferred over the older LQT4 label because the phenotype extends beyond isolated QT prolongation (york2022mechanismsunderlyingthe pages 1-2, sucharski2020mechanismsandalterations pages 1-2)
Alternative names Ankyrin-B syndrome; Long QT syndrome type 4 (LQT4) Ackerman & Mohler (2010) state that “LQT4 is now more appropriately termed ankyrin-B syndrome” (york2022mechanismsunderlyingthe pages 1-2)
OMIM disease number #600919 Retrieved evidence identifies ANK2-LQTS/LQT4 under OMIM #600919 (mohler2003ankyrinbmutationcauses pages 1-2)
Causal gene ANK2 Encodes ankyrin-2; human disease-associated variants are typically heterozygous and loss-of-function or functionally deleterious (mohler2003ankyrinbmutationcauses pages 1-2, york2022mechanismsunderlyingthe pages 1-2)
Protein Ankyrin-B Scaffold/adaptor protein that organizes ion channels, transporters, structural proteins, and signaling molecules in cardiomyocytes (koenig2017theevolvingrole pages 2-4, sucharski2020mechanismsandalterations pages 1-2)
Historical classification LQT4 Original classification emphasized prolonged QT; later work showed broader manifestations including sinus node dysfunction, atrial fibrillation, conduction disease, ventricular arrhythmias, and sudden death (mohler2003ankyrinbmutationcauses pages 1-2, scouarnec2008dysfunctioninankyrinbdependent pages 1-2, sucharski2020mechanismsandalterations pages 1-2)
Disease-defining paper 1 Mohler et al., 2003, Nature “Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death”; DOI: https://doi.org/10.1038/nature01335 (mohler2003ankyrinbmutationcauses pages 1-2)
Disease-defining paper 2 Mohler et al., 2004, PNAS “A cardiac arrhythmia syndrome caused by loss of ankyrin-B function”; DOI: https://doi.org/10.1073/pnas.0402546101 (mohler2003ankyrinbmutationcauses pages 1-2)
Nomenclature-shift paper Ackerman & Mohler, 2010, Circulation Research Review arguing the phenotype is broader than classic LQTS and that “ankyrin-B syndrome” is the preferred name; DOI: https://doi.org/10.1161/CIRCRESAHA.110.224592 (york2022mechanismsunderlyingthe pages 1-2)
MONDO ID not found in retrieved evidence No disease-specific MONDO identifier for ankyrin-B syndrome was established from retrieved primary/review evidence; Open Targets returned broader long-QT MONDO associations rather than a specific ankyrin-B syndrome term (york2022mechanismsunderlyingthe pages 1-2)
Orphanet ID not found in retrieved evidence Not identified in retrieved evidence set (york2022mechanismsunderlyingthe pages 1-2)
ICD-10 / ICD-11 not found in retrieved evidence No specific ICD code for ankyrin-B syndrome was identified in retrieved evidence; patients are often captured under inherited arrhythmia/long-QT diagnostic categories (york2022mechanismsunderlyingthe pages 1-2, sucharski2020mechanismsandalterations pages 1-2)
Evidence type for nomenclature/definition Aggregated disease-level literature plus family-based human studies Core naming/definition comes from seminal family studies and later disease reviews, not EHR-derived nosology (mohler2003ankyrinbmutationcauses pages 1-2, york2022mechanismsunderlyingthe pages 1-2, sucharski2020mechanismsandalterations pages 1-2)

Table: This table summarizes the core identifiers and naming conventions for ANK2/ankyrin-B syndrome, including its historical LQT4 designation and the seminal papers that established and renamed the condition. It is useful as a compact reference for disease database curation and knowledge-base normalization.

1.3 Synonyms / alternative names

  • Ankyrin‑B syndrome (preferred) (ackerman2010defininganew pages 2-3)
  • Long QT syndrome type 4 (LQT4) (mohler2003ankyrinbmutationcauses pages 1-2)

1.4 Evidence source types

The core disease concept is derived from: * Human family studies with segregation and clinical phenotyping (e.g., Mohler 2003; Scouarnec 2008) (mohler2003ankyrinbmutationcauses pages 1-2, scouarnec2008dysfunctioninankyrinbdependent pages 1-2) * Human cohort “reappraisal” in referred patients assessing penetrance and variant validity (Giudicessi & Ackerman 2020) (giudicessi2020establishedlossoffunctionvariants pages 1-5) * Animal and cellular models (AnkB+/− mice, conditional Ank2 knockouts, knock‑in mice) used to establish mechanistic links and test targeted interventions (mohler2003ankyrinbmutationcauses pages 1-2, zhu2018ankyrinbq1283hvariant pages 1-2, roberts2019ankyrinbdysfunctionpredisposes pages 9-10)

2. Etiology

2.1 Disease causal factors

Primary cause: germline ANK2 variants that reduce ankyrin‑B function (often heterozygous loss‑of‑function or functionally deleterious missense variants), leading to abnormal targeting/localization and regulation of ion‑handling and signaling complexes. (koenig2017theevolvingrole pages 2-4, ackerman2010defininganew pages 2-3, mohler2003ankyrinbmutationcauses pages 1-2)

2.2 Risk factors

Genetic risk factors: * Pathogenic/likely pathogenic ANK2 variants in key functional regions (e.g., E1425G/E1458G, S646F, Q1283H) are associated with increased arrhythmia susceptibility. (mohler2003ankyrinbmutationcauses pages 1-2, swayne2017novelvariantin pages 1-2, zhu2018ankyrinbq1283hvariant pages 1-2) * Oligogenic/variant interpretation caveat: a large referral reappraisal concluded several historically alleged ankyrin‑B syndrome variants were not enriched compared with gnomAD and often had low/uncertain penetrance in referred individuals, cautioning against assuming monogenic high‑risk for all reported ANK2 variants. (giudicessi2020establishedlossoffunctionvariants pages 1-5)

Non‑genetic (environmental/lifestyle) risk factors: not specifically established for ankyrin‑B syndrome in the retrieved evidence. Triggering by adrenergic/catecholaminergic stress is mechanistically supported (mouse/cell models and KI model), consistent with clinical stress/exercise provocation in some patients. (zhu2018ankyrinbq1283hvariant pages 1-2, ackerman2010defininganew pages 2-3)

2.3 Protective factors

No validated protective genetic or environmental factors specific to ankyrin‑B syndrome were identified in retrieved evidence.

2.4 Gene–environment interaction

Direct gene–environment interaction data were not identified in retrieved evidence; however, catecholaminergic stimulation acts as an important physiologic “environmental” trigger for ventricular arrhythmias in models, implicating an interaction between ANK2 defects and adrenergic stress. (zhu2018ankyrinbq1283hvariant pages 1-2, ackerman2010defininganew pages 2-3)

3. Phenotypes

3.1 Core phenotype spectrum (cardiac)

Phenotype Description/clinical notes Suggested HPO term(s) Quantitative data/frequency (if available) Key supporting citations
Prolonged QTc / long QT syndrome type 4 Historical defining feature of LQT4, but QT prolongation is variably expressed and not universally present in ANK2-related disease; broader “ankyrin-B syndrome” terminology is now preferred. HP:0001657 Prolonged QT interval; HP:0005117 Long QT syndrome In the original E1425G kindred, mean QTc was ~490 ± 30 ms in adults and ~465 ± 38 ms in children; variant segregated with long-QT phenotype in 22/24 carriers. In the First Nations p.S646F cohort, average QTc was 475 ± 40 ms among carriers. (mohler2003ankyrinbmutationcauses pages 1-2, swayne2017novelvariantin pages 1-2, york2022mechanismsunderlyingthe pages 4-5) (mohler2003ankyrinbmutationcauses pages 1-2, swayne2017novelvariantin pages 1-2, york2022mechanismsunderlyingthe pages 4-5)
Sinus bradycardia / sinus node dysfunction Core and often prominent manifestation; includes sinus bradycardia, sinus arrhythmia, junctional or escape rhythms, chronotropic abnormalities, and frequent need for pacing in some families. HP:0001662 Bradycardia; HP:0001679 Cardiac conduction abnormality; HP:0001778 Sinus arrhythmia In Mohler 2003, sinus node bradycardia or junctional escape rhythm was present in 23/24 carriers. In Scouarnec 2008 Family 1, 74 relatives were screened; escape rhythm origin was SAN in 7, coronary sinus in 7, and junctional in 12; 14 family members required pacemakers. Some AnkB+/− cardiomyocyte data also showed reduced contraction rate (~144 to ~78 bpm) and Ca2+ transient frequency (~2.7 to ~1.3 Hz). (mohler2003ankyrinbmutationcauses pages 1-2, scouarnec2008dysfunctioninankyrinbdependent pages 1-2) (mohler2003ankyrinbmutationcauses pages 1-2, scouarnec2008dysfunctioninankyrinbdependent pages 1-2)
Atrial fibrillation / atrial arrhythmias Frequently reported supraventricular phenotype; may occur with sinus-node disease and may precede or accompany broader ankyrin-B syndrome. HP:0005110 Atrial fibrillation; HP:0011675 Atrial arrhythmia Mohler 2003 reported atrial fibrillation in 12 adults from the pedigree. Scouarnec 2008 Family 1 reported AF in 13 relatives, including 5 paroxysmal and 8 permanent cases; mean AF onset ~40 ± 18 years. (mohler2003ankyrinbmutationcauses pages 1-2, scouarnec2008dysfunctioninankyrinbdependent pages 1-2) (mohler2003ankyrinbmutationcauses pages 1-2, scouarnec2008dysfunctioninankyrinbdependent pages 1-2)
Ventricular arrhythmias / VT / VF / CPVT-like stress-induced arrhythmias Includes ventricular tachycardia, ventricular fibrillation, catecholaminergic/stress-induced ventricular arrhythmia susceptibility, and idiopathic VF-like presentations; mechanistically linked to abnormal Ca2+ handling and triggered activity. HP:0004756 Ventricular tachycardia; HP:0001663 Ventricular fibrillation; HP:0011677 Cardiac arrest; HP:0005110 Arrhythmia (broad) Mohler 2003 identified sudden cardiac death in the E1425G family and framed the condition as an arrhythmia syndrome with ventricular risk. Zhu 2018 identified ANK2 p.Q1283H in 25 unrelated Han Chinese probands with VT; knock-in mice showed increased stress-induced ventricular arrhythmias. Swayne 2017 notes LQTS-related risk of ventricular arrhythmias in p.S646F carriers. (mohler2003ankyrinbmutationcauses pages 1-2, swayne2017novelvariantin pages 1-2, zhu2018ankyrinbq1283hvariant pages 1-2) (mohler2003ankyrinbmutationcauses pages 1-2, swayne2017novelvariantin pages 1-2, zhu2018ankyrinbq1283hvariant pages 1-2)
Premature atrial contractions Ectopy is part of the atrial phenotype and was illustrated in ECG examples from affected individuals. HP:0011707 Atrial premature complexes ECG examples in the original report showed multiple premature atrial contractions in affected individuals; no cohort-wide count was available in retrieved evidence. (mohler2003ankyrinbmutationcauses media 3330bf40, mohler2003ankyrinbmutationcauses media b13c3b4f) (mohler2003ankyrinbmutationcauses media 3330bf40, mohler2003ankyrinbmutationcauses media b13c3b4f)
Conduction block / conduction disease Broader conduction system involvement beyond sinus-node dysfunction is recognized in reviews and clinical descriptions of ankyrin-B syndrome. HP:0001678 Atrioventricular block; HP:0000077 Abnormality of cardiac conduction Reported qualitatively as part of the phenotype spectrum in disease reviews; no family-level count for conduction block specifically was available in the retrieved core cohorts summarized here. (koenig2017theevolvingrole pages 2-4, sucharski2020mechanismsandalterations pages 1-2) (koenig2017theevolvingrole pages 2-4, sucharski2020mechanismsandalterations pages 1-2)
Structural heart disease / cardiomyopathy / arrhythmogenic cardiomyopathy Not part of the earliest LQT4 definition, but later evidence linked some ANK2 variants to congenital/adult structural disease, LV dysfunction, and arrhythmogenic cardiomyopathy. HP:0001638 Cardiomyopathy; HP:0001644 Dilated cardiomyopathy; HP:0033758 Arrhythmogenic cardiomyopathy; HP:0001642 Structural heart abnormality In Swayne 2017, among 16 additional p.S646F carriers identified by cascade testing, 2 had structural heart disease (1 cardiomyopathy with sudden death, 1 congenital heart disease). Roberts 2019 established a mechanistic ANK2-related arrhythmogenic cardiomyopathy model in mice and linked rare ANK2 variants to ACM in human probands. Giudicessi 2020 found no cardiomyopathy in their 12-variant referral cohort carrying historically alleged ABS variants, underscoring heterogeneity and disputed pathogenicity for some variants. (swayne2017novelvariantin pages 1-2, roberts2019ankyrinbdysfunctionpredisposes pages 9-10, roberts2019ankyrinbdysfunctionpredisposes pages 1-2, giudicessi2020establishedlossoffunctionvariants pages 1-5) (swayne2017novelvariantin pages 1-2, roberts2019ankyrinbdysfunctionpredisposes pages 9-10, roberts2019ankyrinbdysfunctionpredisposes pages 1-2, giudicessi2020establishedlossoffunctionvariants pages 1-5)
Sudden cardiac death Major adverse outcome and key reason for surveillance and family screening; can occur with electrical disease alone or in the setting of structural disease in some variant backgrounds. HP:0001645 Sudden cardiac death Mohler 2003 reported sudden cardiac death in the original kindred. Scouarnec 2008 described premature sudden deaths at ages 18 and 12 in Family 1. Swayne 2017 reported one cardiomyopathy-associated sudden death among p.S646F carriers. Korn 2023 described a family with 3 sudden cardiac deaths in the paternal line associated with ANK2 c.11791G>A plus MYO18B c.3761G>A. (mohler2003ankyrinbmutationcauses pages 1-2, scouarnec2008dysfunctioninankyrinbdependent pages 1-2, swayne2017novelvariantin pages 1-2, korn2023anewinherited pages 1-2) (mohler2003ankyrinbmutationcauses pages 1-2, scouarnec2008dysfunctioninankyrinbdependent pages 1-2, swayne2017novelvariantin pages 1-2, korn2023anewinherited pages 1-2)

Table: This table summarizes the core cardiac manifestations reported in ANK2/ankyrin-B syndrome, with suggested HPO mappings and quantitative data from landmark family studies and later variant-specific cohorts. It is useful for structured disease-knowledge-base curation and phenotype annotation.

3.2 Phenotype characteristics (onset, severity, progression)

  • Sinus node dysfunction (SND) can be severe and highly penetrant in some families, sometimes requiring pacemakers; SND in the ANK2‑mapped kindreds included sinus bradycardia, sinus arrest/exit block, and tachyarrhythmias. (scouarnec2008dysfunctioninankyrinbdependent pages 1-2)
  • Atrial fibrillation (AF) tends to present in adulthood in reported kindreds (mean onset ~40 ± 18 years in one family). (scouarnec2008dysfunctioninankyrinbdependent pages 1-2)
  • QTc prolongation may be present in adults and children but can show incomplete penetrance, including non‑penetrant carriers with QTc ~420 ms in the original E1425G family. (mohler2003ankyrinbmutationcauses pages 1-2)
  • Ventricular arrhythmia susceptibility can be catecholamine/stress‑dependent; in a KI mouse model, stress provoked ventricular arrhythmias in the absence of structural disease. (zhu2018ankyrinbq1283hvariant pages 1-2)
  • Structural heart disease / cardiomyopathy is variably reported; some variant carriers show structural disease (e.g., 2/16 additional S646F carriers), while a referral reappraisal found no malignant echo findings in their ANK2 variant carriers, underscoring heterogeneity. (swayne2017novelvariantin pages 1-2, giudicessi2020establishedlossoffunctionvariants pages 1-5)

3.3 Quality of life impact

Disease impact is inferred from high‑burden arrhythmias, device therapy (pacemakers), and sudden death risk, but formal QoL instruments (e.g., SF‑36/EQ‑5D) were not reported in the retrieved evidence. (scouarnec2008dysfunctioninankyrinbdependent pages 1-2, mohler2003ankyrinbmutationcauses pages 1-2)

3.4 Visual clinical evidence (ECG examples)

Representative ECG panels from the original LQT4/ankyrin‑B syndrome report show bradycardia/sinus arrhythmia and atrial ectopy (premature atrial contractions). (mohler2003ankyrinbmutationcauses media 3330bf40, mohler2003ankyrinbmutationcauses media b13c3b4f)

4. Genetic / molecular information

4.1 Causal gene

ANK2 (ankyrin 2) encodes ankyrin‑B, a scaffold protein that directly binds key transporters/channels and recruits signaling complexes needed for normal cardiac electrical and Ca2+ handling function. (ackerman2010defininganew pages 2-3, koenig2017theevolvingrole pages 2-4)

4.2 Inheritance, penetrance, expressivity

  • Inheritance: autosomal dominant (koenig2017theevolvingrole pages 2-4)
  • Penetrance: incomplete (e.g., E1425G family: QT phenotype in 22/24 carriers; SND in 23/24 carriers; specific non‑penetrant examples reported). (mohler2003ankyrinbmutationcauses pages 1-2)
  • Expressivity: variable, including electrical phenotypes with/without structural disease across variants/families. (swayne2017novelvariantin pages 1-2, york2022mechanismsunderlyingthe pages 1-2)

4.3 Pathogenic variant classes and examples

  • Missense loss‑of‑function variants (e.g., E1425G/E1458G; S646F; Q1283H). (mohler2003ankyrinbmutationcauses pages 1-2, swayne2017novelvariantin pages 1-2, zhu2018ankyrinbq1283hvariant pages 1-2)
  • Loss‑of‑function variants and heterozygous null alleles are implicated in reviews and models; variant interpretation is challenging because ANK2 has many rare variants in population datasets. (koenig2017theevolvingrole pages 2-4, giudicessi2020establishedlossoffunctionvariants pages 1-5, york2022mechanismsunderlyingthe pages 4-5)
Variant (HGVS c./p.) Domain/region (if known) Evidence type (family, cohort, model) Reported phenotypes Quantitative notes (QTc, counts) Pathogenicity/interpretation notes Key citations
c.4274A>G, p.Glu1425Gly (historical) / p.Glu1458Gly (updated numbering), E1425G/E1458G Near regulatory/C-terminal region; review places p.E1458G in spectrin-binding domain context Large French family; segregation study; mouse/cardiomyocyte functional rescue model Prolonged QTc/LQT4, sinus node dysfunction/bradycardia, atrial fibrillation, sudden cardiac death 45 relatives screened; 24 carriers, 21 non-carriers; QT phenotype in 22/24 carriers; sinus node dysfunction in 23/24 carriers; 2 nonpenetrant QT carriers had QTc 420 ms; mean QTc adults ~490 ± 30 ms, children ~465 ± 38 ms Landmark disease-defining ANK2 variant; functional loss-of-function/haploinsufficiency model supported. Later review/reappraisal notes incomplete penetrance and population observations complicating interpretation in some settings (mohler2003ankyrinbmutationcauses pages 1-2, york2022mechanismsunderlyingthe pages 4-5)
c.1937C>T, p.Ser646Phe (p.S646F) Membrane-binding domain (first disease-causing ANK2 variant mapped to this domain) Multigenerational Gitxsan First Nation families; cascade screening; cultured cardiac cell/primary cardiomyocyte functional studies Ankyrin-B syndrome/LQTS, ventricular arrhythmia risk, structural heart disease in some carriers, congenital heart disease, seizures reported in extended review 16 additional carriers identified; average QTc 475 ± 40 ms; 2 carriers had structural heart disease (1 cardiomyopathy with sudden death, 1 congenital heart disease); review notes seizures in 8/18 carriers Loss-of-function allele with reduced expression, abnormal localization, and failed Na/Ca exchanger targeting; possible founder effect in Gitxsan population with high LQTS prevalence (swayne2017novelvariantin pages 1-2, york2022mechanismsunderlyingthe pages 5-6)
p.Q1283H ZU5C region Variant discovery in 25 Han Chinese VT probands; knock-in mouse model; single-cell cardiomyocyte mechanistic studies Stress-induced ventricular arrhythmias/VT susceptibility without structural abnormalities Identified in 25 unrelated VT probands screen; KI mice showed increased stress-induced ventricular arrhythmias; no human QTc summary provided in retrieved evidence Disease-associated variant causing loss of local PP2A activity, increased RyR2 Ser2814 phosphorylation, delayed afterdepolarizations/Ca2+ waves; metoprolol or flecainide reduced stress-induced arrhythmias in mice (zhu2018ankyrinbq1283hvariant pages 1-2, york2022mechanismsunderlyingthe pages 4-4)
p.Val3634Asp (historical p.Val1516Asp; V3634D) C-terminal/regulatory region Variant listed in historical ABS literature; re-evaluated in Mayo Clinic referral cohort Usually mild or absent phenotype in reappraisal cohort; possible palpitations or nonspecific ECG findings Giudicessi cohort: part of 12/1,727 referrals (0.7%) carrying 1 of 4 alleged ABS variants overall; across all 12 carriers, only 4/12 (33%) had potentially attributable symptoms, 67% asymptomatic, 6/12 (50%) had ≥1 ECG finding of uncertain significance; variant frequency comparison to gnomAD argued against enrichment Reappraisal concluded alleged ABS variants such as p.V3634D are unlikely to cause a highly penetrant monogenic SCD syndrome by themselves; pathogenicity remains uncertain/likely overcalled in older literature (giudicessi2020establishedlossoffunctionvariants pages 1-5, york2022mechanismsunderlyingthe pages 5-6)
p.Thr3744Asn (reported as p.T3744N/T3744ASN) C-terminal/regulatory region Historical alleged ABS variant; Mayo Clinic referral cohort reappraisal Mostly low-penetrance or uncertain cardiac significance in available human reappraisal Included among 4 alleged variants found in 12/1,727 referrals overall; combined carrier data: only 4/12 (33%) had potentially ABS-attributable symptoms and 6/12 (50%) had uncertain ECG findings Considered an alleged ABS-causative variant with weak human penetrance evidence in reappraisal; observed in public/population datasets and lacking robust segregation support (giudicessi2020establishedlossoffunctionvariants pages 1-5, york2022mechanismsunderlyingthe pages 4-4)
p.Arg3906Trp (p.R3906W) C-terminal/regulatory region Historical alleged ABS variant; Mayo Clinic referral cohort reappraisal Mild/uncertain phenotype spectrum; no strong malignant phenotype enrichment in reappraisal Included among the 12 carriers of 4 alleged variants in 1,727 referrals; aggregate carrier data showed low symptom burden and no overall enrichment vs gnomAD [12/1,727 (0.7%) vs 1,297/141,456 (0.9%)] Reappraisal argues low penetrance and insufficient evidence for a penetrant monogenic SCD-predisposing role for many historical ABS variants, including p.R3906W (giudicessi2020establishedlossoffunctionvariants pages 1-5, york2022mechanismsunderlyingthe pages 2-3)
p.Glu1458Gly (same variant family as historical E1425G; included in Giudicessi reappraisal) Spectrin-binding/regulatory boundary in review context Historical family-based disease report plus later referral-cohort reappraisal Classical ankyrin-B syndrome in original pedigree vs often absent/mild findings in later referrals In Giudicessi reappraisal, alleged variant carriers overall: 12/1,727 referrals; only 4/12 symptomatic, 67% asymptomatic; one variant-level comparison example 8/1,727 vs 150/141,456 in gnomAD (p=0.006) Illustrates major interpretive tension in ANK2: a historically causal family variant can appear incompletely penetrant and not strongly enriched in broad referral cohorts, suggesting context dependence/possible oligogenic contribution (giudicessi2020establishedlossoffunctionvariants pages 1-5, mohler2003ankyrinbmutationcauses pages 1-2, york2022mechanismsunderlyingthe pages 4-5)

Table: This table summarizes major ANK2 variants implicated in ankyrin-B syndrome and related cardiac phenotypes, combining landmark family studies with later variant reappraisal data. It is useful for comparing evidence strength, phenotype breadth, and the important issue of incomplete penetrance in ANK2-associated disease.

4.4 Population frequency / founder effects

A First Nations Gitxsan population was reported to have a high rate of LQTS (~15× higher; ~1:125) and ANK2 p.S646F was reported in multigenerational families with a possible founder effect context. (swayne2017novelvariantin pages 1-2)

4.5 Modifier genes / protective variants

No specific modifier genes or protective variants were established in retrieved evidence.

4.6 Chromosomal abnormalities

A reciprocal chromosomal translocation mechanism for “human cardiac ankyrin‑B syndrome” is referenced in the retrieved corpus (Huq 2017), but detailed evidence extraction for that report was not obtained in the current evidence set. (No extracted context id available for mechanistic/phenotypic specifics beyond citation metadata.)

5. Environmental information

No specific toxic, occupational, lifestyle, or infectious drivers of ankyrin‑B syndrome were identified in retrieved evidence. The main non‑genetic influence supported by mechanistic evidence is adrenergic/catecholaminergic stress precipitating ventricular arrhythmias in susceptible genotypes. (zhu2018ankyrinbq1283hvariant pages 1-2, ackerman2010defininganew pages 2-3)

6. Mechanism / pathophysiology

6.1 Current mechanistic model (causal chain)

Upstream trigger: ANK2 loss‑of‑function (haploinsufficiency or functional missense variants). (mohler2003ankyrinbmutationcauses pages 1-2, ackerman2010defininganew pages 2-3)

Core scaffold disruption: ankyrin‑B normally binds/targets ion transporters/channels and signaling proteins—including NCX1 (Na+/Ca2+ exchanger), NKA (Na+/K+ ATPase), IP3R, Kir6.2, and atrial Cav1.3—and recruits PP2A (via B56α) to regulate multiple components of Ca2+ handling. (koenig2017theevolvingrole pages 2-4, koenig2017theevolvingrole pages 1-2)

Cellular consequences (ventricular myocytes): loss of ankyrin‑B disrupts membrane localization/expression of NCX, NKA, IP3R, producing defective intracellular Na+ and Ca2+ handling and SR Ca2+ overload; during catecholaminergic stimulation this promotes afterdepolarizations and polymorphic ventricular arrhythmias. (ackerman2010defininganew pages 2-3, wolf2010definingnewinsight pages 1-1)

Quantitative cellular data (example): in AnkB+/− cardiomyocytes, spontaneous contraction rate decreased from 144 ± 10 to 78 ± 8 bpm, and Ca2+ transient frequency from ~2.7 Hz to ~1.3 Hz; wild‑type ankyrin‑B rescued these abnormalities, while E1425G ankyrin‑B did not. (mohler2003ankyrinbmutationcauses pages 1-2)

RyR2/PP2A signaling mechanism (stress‑induced VT model): ANK2 p.Q1283H reduced ankyrin‑B binding to PP2A B56α, dissociated PP2A from RyR2, and increased RyR2 Ser2814 phosphorylation, leading to DADs, Ca2+ waves/sparks, and catecholamine‑triggered ventricular arrhythmias in KI mice. (zhu2018ankyrinbq1283hvariant pages 1-2)

Atrial fibrillation mechanism: ankyrin‑B deficiency reduces atrial Cav1.3 (identified as an ankyrin‑binding partner), decreases L‑type Ca2+ current and shortens atrial APs, increasing AF susceptibility; reduced ankyrin‑B levels were also observed in human AF atrial tissue. (cunha2011defectsinankyrinbased pages 11-11)

Sinoatrial node dysfunction mechanism: ankyrin‑B is highly expressed in the SAN and required for proper channel/transporter targeting and membrane organization; dysfunction leads to abnormal Ca2+ handling, impaired automaticity, and bradycardia/escape rhythms. (scouarnec2008dysfunctioninankyrinbdependent pages 1-2)

6.2 Structural remodeling / cardiomyopathy pathway

A cardiac‑specific Ank2 conditional knockout model developed marked dilation, fibrosis and systolic dysfunction with abnormal β‑catenin patterning, supporting ankyrin‑B—β‑catenin signaling as a pathway to arrhythmogenic cardiomyopathy. (roberts2019ankyrinbdysfunctionpredisposes pages 9-10, roberts2019ankyrinbdysfunctionpredisposes pages 1-2)

Preclinical targeted therapy evidence: pharmacologic activation of WNT/β‑catenin signaling (GSK‑3β inhibitor SB‑216763) prevented and partially reversed cardiomyopathy phenotypes in Ank2‑cKO mice; figure panels show β‑catenin patterning differences and prevention/reversal of functional decline and fibrosis. (roberts2019ankyrinbdysfunctionpredisposes media 52e6c3c8, roberts2019ankyrinbdysfunctionpredisposes pages 9-10)

6.3 Suggested ontology terms (computable annotations)

GO (Biological Process) candidates (mechanistically implied by the evidence): * GO:0010038 response to metal ion (general stress) is not specific; instead suggest: calcium ion homeostasis, protein localization to membrane, regulation of cardiac conduction, regulation of heart rate, sarcoplasmic reticulum calcium ion transport (supported by disrupted Ca2+ handling and transporter targeting). (ackerman2010defininganew pages 2-3, zhu2018ankyrinbq1283hvariant pages 1-2, scouarnec2008dysfunctioninankyrinbdependent pages 1-2)

CL (Cell Ontology) candidates: * sinoatrial node pacemaker cell; atrial cardiomyocyte; ventricular cardiomyocyte (supported by SAN‑specific and atrial/ventricular mechanisms). (scouarnec2008dysfunctioninankyrinbdependent pages 1-2, cunha2011defectsinankyrinbased pages 11-11, ackerman2010defininganew pages 2-3)

UBERON candidates: * sinoatrial node; atrial myocardium; ventricular myocardium; cardiac conduction system. (scouarnec2008dysfunctioninankyrinbdependent pages 1-2, cunha2011defectsinankyrinbased pages 11-11)

7. Anatomical structures affected

Primary system: cardiovascular conduction and myocardium. * Sinoatrial node / conduction system (SND, bradycardia, escape rhythms, pacemaker requirement). (scouarnec2008dysfunctioninankyrinbdependent pages 1-2) * Atria (atrial arrhythmias/AF; Cav1.3 mechanism; atrial ectopy shown on ECG). (cunha2011defectsinankyrinbased pages 11-11, mohler2003ankyrinbmutationcauses media 3330bf40) * Ventricles (QT prolongation, ventricular arrhythmias; in some contexts cardiomyopathy/ACM remodeling). (mohler2003ankyrinbmutationcauses pages 1-2, roberts2019ankyrinbdysfunctionpredisposes pages 9-10)

8. Temporal development

  • Congenital/pediatric to adult onset: QT prolongation and SND can be present early (including pediatric cases in family studies), whereas AF tends to present in adults in reported kindreds. (mohler2003ankyrinbmutationcauses pages 1-2, scouarnec2008dysfunctioninankyrinbdependent pages 1-2, york2022mechanismsunderlyingthe pages 5-6)
  • Course: episodic arrhythmias with stress triggers for ventricular events; chronic bradycardia/SND may progress to pacemaker requirement. (zhu2018ankyrinbq1283hvariant pages 1-2, scouarnec2008dysfunctioninankyrinbdependent pages 1-2)

9. Inheritance and population

  • Autosomal dominant with incomplete penetrance and variable expressivity is supported by family segregation and reviews. (mohler2003ankyrinbmutationcauses pages 1-2, koenig2017theevolvingrole pages 2-4, york2022mechanismsunderlyingthe pages 1-2)
  • Population prevalence/incidence: a specific prevalence for ankyrin‑B syndrome is not available in the retrieved evidence. For context, LQTS overall prevalence is ~1:2,000. (spoonamore2016genetictestingand pages 6-10)
  • Founder effect / enriched populations: Gitxsan First Nation high LQTS prevalence ~1:125 with ANK2 p.S646F in families consistent with a founder context. (swayne2017novelvariantin pages 1-2)

10. Diagnostics

10.1 Clinical testing

Minimum or typical evaluation in inherited arrhythmia/genetic referrals includes: * 12‑lead ECG, Holter monitoring, echocardiography, and treadmill exercise testing (used as a standardized test battery in ANK2 variant reappraisal). (giudicessi2020establishedlossoffunctionvariants pages 1-5)

10.2 Genetic testing and molecular autopsy

  • Targeted arrhythmia gene panels (e.g., 42‑gene panel including ANK2; 174‑gene inherited cardiac disease panel on MiSeq) and WES (performed in the 2023 molecular‑autopsy family investigation) are used in real‑world settings. (haase2024asinglenucleotide pages 2-4, korn2023anewinherited pages 1-2)
  • A consensus‑style principle for inherited arrhythmias is that a pathogenic variant in a LQTS gene can establish diagnosis regardless of ECG findings, motivating cascade testing; QTc‑based screening alone can miss genotype‑positive individuals. (spoonamore2016genetictestingand pages 6-10)

10.3 Differential diagnosis

Not exhaustively extracted in the current evidence set, but clinical differential commonly includes other inherited arrhythmia/channelopathy syndromes (e.g., other LQTS subtypes, CPVT, Brugada syndrome) because ANK2 phenotypes overlap and may present without consistent QT prolongation. (koenig2017theevolvingrole pages 2-4, giudicessi2020establishedlossoffunctionvariants pages 1-5)

11. Outcome / prognosis

  • Sudden cardiac death is a central adverse outcome in multiple ANK2‑linked kindreds and recent reports. (mohler2003ankyrinbmutationcauses pages 1-2, scouarnec2008dysfunctioninankyrinbdependent pages 1-2, korn2023anewinherited pages 1-2)
  • Prognostic statistics (e.g., long‑term survival curves) specific to ankyrin‑B syndrome were not identified in retrieved evidence; prognosis appears highly variant‑ and family‑dependent, and some alleged variants may confer low risk. (giudicessi2020establishedlossoffunctionvariants pages 1-5)

12. Treatment

12.1 Current clinical management (real‑world implementation)

Management is individualized based on phenotype (SND vs AF vs ventricular arrhythmias) and standard inherited arrhythmia practice, including: * Pacemaker implantation for significant sinus node dysfunction/bradycardia (14 patients in one ANK2‑mapped SND family; pacing also used in the original LQT4 family). (scouarnec2008dysfunctioninankyrinbdependent pages 1-2, mohler2003ankyrinbmutationcauses pages 1-2) * Antiarrhythmic drugs (e.g., flecainide, mexiletine in case‑based contexts; broader antiarrhythmic approaches in ACM). (haase2024asinglenucleotide pages 1-2, roberts2019ankyrinbdysfunctionpredisposes pages 9-10) * ICD and catheter ablation in malignant ventricular arrhythmia/ACM contexts (palliative but potentially life‑saving). (roberts2019ankyrinbdysfunctionpredisposes pages 9-10)

12.2 Mechanism‑informed therapy evidence

  • In a KI mouse model of ANK2 p.Q1283H, metoprolol or flecainide reduced stress‑induced ventricular arrhythmias, supporting adrenergic suppression and triggered‑activity suppression as rational approaches for catecholamine‑provoked disease components. (zhu2018ankyrinbq1283hvariant pages 1-2)

12.3 Targeted/experimental therapies

  • WNT/β‑catenin activation with SB‑216763 prevented/partially reversed Ank2‑cKO cardiomyopathy in mice, supporting a possible targeted therapy concept for ANK2‑related structural disease; there is no human clinical‑trial evidence in the retrieved set. (roberts2019ankyrinbdysfunctionpredisposes pages 9-10, roberts2019ankyrinbdysfunctionpredisposes media 52e6c3c8)

12.4 MAXO terms

See diagnostics/management table for suggested MAXO terms. (spoonamore2016genetictestingand pages 14-17, scouarnec2008dysfunctioninankyrinbdependent pages 1-2)

Domain Intervention/test Details Suggested MAXO term(s) where appropriate Evidence notes/quantitative data Key citations
Diagnostics 12-lead ECG Core first-line evaluation for QTc prolongation, sinus bradycardia/sinus arrhythmia, premature atrial beats, conduction disease, and ST-segment abnormalities in some newer ANK2-associated families MAXO:0000001 clinical examination; MAXO:0000487 electrocardiography Original E1425G family had mean QTc ~490 ± 30 ms in adults and ~465 ± 38 ms in children; ECG examples showed bradycardia/sinus arrhythmia and multiple premature atrial contractions; one 2024 case reported QT 470 ms (mohler2003ankyrinbmutationcauses pages 1-2, mohler2003ankyrinbmutationcauses media 3330bf40, mohler2003ankyrinbmutationcauses media b13c3b4f, haase2024asinglenucleotide pages 2-4)
Diagnostics Holter / ambulatory rhythm monitoring Used to capture intermittent ventricular tachycardia, sinus-node dysfunction, escape rhythms, and atrial arrhythmias not evident on resting ECG MAXO:0000487 electrocardiography 24-hour Holter was used in 2023 family investigation; 2024 case used patch Holter/Kardia tracings showing salvos of VT (korn2023anewinherited pages 1-2, haase2024asinglenucleotide pages 2-4)
Diagnostics Exercise stress testing / treadmill testing Helps reveal exercise- or catecholamine-associated ventricular ectopy/arrhythmia and may support phenotype clarification in inherited arrhythmia clinics MAXO:0001024 exercise test Giudicessi 2020 minimum evaluation included treadmill exercise testing in all referred individuals with alleged ANK2 variants; 2023 family workup included exercise ECGs (giudicessi2020establishedlossoffunctionvariants pages 1-5, korn2023anewinherited pages 1-2)
Diagnostics Transthoracic echocardiography Used to exclude or define structural heart disease, cardiomyopathy, ventricular dysfunction, or congenital heart disease in ANK2 carriers MAXO:0000372 echocardiography Giudicessi 2020 included echocardiography in all cases; 2023 family evaluation used standard TTE; important because some ANK2 variants are associated with structural disease/ACM while others are not (giudicessi2020establishedlossoffunctionvariants pages 1-5, korn2023anewinherited pages 1-2, swayne2017novelvariantin pages 1-2)
Diagnostics Family history and pedigree assessment Essential because disease is typically autosomal dominant with incomplete penetrance and variable expressivity MAXO:0000127 genetic counseling Mohler 2003 screened 45 relatives (24 carriers); Scouarnec 2008 screened 74 relatives and identified 25 affected by SND; 2023 multidisciplinary workup emphasized pedigree analysis (mohler2003ankyrinbmutationcauses pages 1-2, scouarnec2008dysfunctioninankyrinbdependent pages 1-2, korn2023anewinherited pages 1-2)
Diagnostics Targeted inherited-arrhythmia gene panel Preferred clinical genetic approach in many inherited arrhythmia settings; can include ANK2 with other LQTS/SND/arrhythmia genes MAXO:0000129 genetic testing 2024 case used a 42-gene arrhythmia panel; 2023 molecular-autopsy/family workup used a 174-gene inherited-cardiac-disease panel on MiSeq; targeted panels are generally favored for depth and coverage (haase2024asinglenucleotide pages 2-4, korn2023anewinherited pages 1-2, spoonamore2016genetictestingand pages 14-17)
Diagnostics Whole-exome sequencing (WES) Useful when phenotype is heterogeneous, syndromic, or panel testing is unrevealing; may help discover atypical ANK2-associated syndromes MAXO:0000129 genetic testing 2023 SCD family study performed WES on the index patient plus 2 affected relatives; general inherited-arrhythmia guidance notes WES is increasingly used but may have lower depth and incidental findings (korn2023anewinherited pages 1-2, spoonamore2016genetictestingand pages 10-14, spoonamore2016genetictestingand pages 14-17)
Diagnostics Variant interpretation (ACMG/ClinVar/gnomAD comparison) Needed because ANK2 has disputed/low-penetrance variants and population frequency can complicate causality assessment MAXO:0000129 genetic testing 2023 family report used ACMG revised criteria; Giudicessi 2020 compared 1,727 referrals with gnomAD and found no overall enrichment of 4 alleged ABS variants [12/1,727 (0.7%) vs 1,297/141,456 (0.9%)] (korn2023anewinherited pages 1-2, giudicessi2020establishedlossoffunctionvariants pages 1-5)
Diagnostics Molecular autopsy Post-mortem genetic testing in unexplained young sudden death to identify ANK2 and other inherited arrhythmia causes MAXO:0000129 genetic testing 2023 study combined autopsy, preserved heart analysis, gene panel testing, and WES; broader inherited-arrhythmia review notes postmortem molecular autopsy yields ~20–50% in cohorts and can be especially useful in pediatric SCD (korn2023anewinherited pages 1-2, spoonamore2016genetictestingand pages 14-17)
Diagnostics / Prevention Cascade screening of relatives Genetic and clinical evaluation of at-risk relatives once a pathogenic/likely pathogenic familial variant is identified MAXO:0000129 genetic testing; MAXO:0000127 genetic counseling Recommended across inherited arrhythmia practice; relatives positive for the familial pathogenic variant should undergo surveillance, whereas genotype-negative relatives generally do not require surveillance; VUS should not be used for predictive testing (spoonamore2016genetictestingand pages 14-17, spoonamore2016genetictestingand pages 6-10, scouarnec2008dysfunctioninankyrinbdependent pages 1-2)
Treatment Beta-blockers Mechanistically rational for catecholamine/stress-triggered ventricular arrhythmias in ANK2-related disease MAXO:0000014 drug therapy; MAXO:0000120 beta-adrenergic receptor antagonist therapy In the p.Q1283H knock-in model, metoprolol reduced stress-induced ventricular arrhythmias; 2024 ANK2-variant myocarditis case also reported suppression of VT with beta-blockers in combination therapy (zhu2018ankyrinbq1283hvariant pages 1-2, haase2024asinglenucleotide pages 1-2)
Treatment Flecainide Antiarrhythmic option supported by preclinical ANK2 evidence for stress-induced VT susceptibility MAXO:0000014 drug therapy; MAXO:0000058 anti-arrhythmic agent therapy In p.Q1283H knock-in mice, flecainide decreased catecholamine-induced ventricular arrhythmias; a 2024 case report used flecainide early in management of recurrent VT (zhu2018ankyrinbq1283hvariant pages 1-2, haase2024asinglenucleotide pages 1-2)
Treatment Mexiletine Used in a recent mechanistically selected case with ANK2 variant and VT; may be considered case-by-case rather than disease-standard therapy MAXO:0000014 drug therapy; MAXO:0000058 anti-arrhythmic agent therapy 2024 case report described mexiletine plus beta-blockers suppressing highly symptomatic VT and coinciding with QT normalization as myocarditis resolved (haase2024asinglenucleotide pages 1-2)
Treatment Pacemaker implantation Important for severe sinus-node dysfunction/bradycardia in ANK2 families MAXO:0000582 cardiac pacemaker implantation Mohler 2003 noted some affected individuals required atrial pacing; Scouarnec 2008 reported pacemaker implantation in 14 patients from the mapped SND kindreds (mohler2003ankyrinbmutationcauses pages 1-2, scouarnec2008dysfunctioninankyrinbdependent pages 1-2)
Treatment Implantable cardioverter-defibrillator (ICD) Used for prevention of sudden cardiac death in malignant ventricular arrhythmia syndromes / ACM settings when clinically indicated MAXO:0000445 implantable cardioverter-defibrillator implantation Roberts 2019 notes ICDs can be life-saving in ACM management, though such therapy is palliative and does not correct underlying ANK2 pathophysiology (roberts2019ankyrinbdysfunctionpredisposes pages 9-10, roberts2019ankyrinbdysfunctionpredisposes pages 1-2)
Treatment Catheter ablation May be useful for suppression of malignant ventricular arrhythmias or recurrent arrhythmic burden in selected patients MAXO:0000005 catheter-based procedure; MAXO:0000944 catheter ablation Roberts 2019 notes catheter ablation may be effective in suppressing malignant ventricular arrhythmias in ACM, but does not target root disease mechanism (roberts2019ankyrinbdysfunctionpredisposes pages 9-10, roberts2019ankyrinbdysfunctionpredisposes pages 1-2)
Treatment Standard acute VT care (e.g., cardioversion; amiodarone in selected settings) Relevant for unstable sustained VT regardless of ANK2 status; supportive rather than genotype-specific MAXO:0000514 cardioversion; MAXO:0000014 drug therapy 2024 case report explicitly discusses prompt cardioversion for hemodynamically unstable sustained VT and mentions amiodarone as an option for recurrent monomorphic VT (haase2024asinglenucleotide pages 1-2)
Experimental treatment SB-216763 / WNT-β-catenin pathway activation Preclinical targeted therapy for ANK2-related arrhythmogenic cardiomyopathy caused by ankyrin-B dysfunction and abnormal β-catenin signaling MAXO:0000014 drug therapy In Ank2-cKO mice, SB-216763 prevented disease when started at 4 weeks and partially reversed established disease; figure evidence showed prevention/reversal of EF/FS decline and fibrosis; no human trial evidence retrieved (roberts2019ankyrinbdysfunctionpredisposes pages 9-10, roberts2019ankyrinbdysfunctionpredisposes pages 1-2, roberts2019ankyrinbdysfunctionpredisposes media 52e6c3c8)
Prevention Ongoing surveillance of ANK2 variant carriers Serial clinical follow-up for arrhythmia and cardiomyopathy given incomplete penetrance and age-dependent expression MAXO:0000408 monitoring York 2022 recommends monitoring carriers of functional ANK2 variants for arrhythmia and cardiomyopathy; inherited-arrhythmia guidance recommends surveillance for relatives who carry the familial pathogenic variant (york2022mechanismsunderlyingthe pages 14-16, spoonamore2016genetictestingand pages 14-17)
Prevention Genetic counseling / family planning counseling Important because disease is usually autosomal dominant and expression is variable MAXO:0000127 genetic counseling General inherited-arrhythmia guidance recommends testing/counseling at diagnosis, at transition of care, and during family planning; counseling is also crucial when ANK2 findings are VUS or low-penetrance alleles (spoonamore2016genetictestingand pages 10-14, spoonamore2016genetictestingand pages 14-17, giudicessi2020establishedlossoffunctionvariants pages 1-5)

Table: This table summarizes the main diagnostic tests, genetic workflows, management strategies, and prevention measures reported or recommended for ANK2/ankyrin-B syndrome. It integrates primary family studies, recent case reports, and inherited-arrhythmia practice guidance, while distinguishing established clinical care from preclinical ANK2-targeted therapy.

13. Prevention

  • Cascade screening and genetic counseling are central preventive strategies in inherited arrhythmias, enabling early identification and surveillance of at‑risk relatives when a pathogenic familial variant is known; VUS results should not be used for predictive testing. (spoonamore2016genetictestingand pages 14-17)
  • Surveillance is recommended because of incomplete penetrance/age‑dependent expression and possible cardiomyopathy risk in some variants: “monitoring carriers of ANK2 functional variants for arrhythmia and cardiomyopathy” is emphasized in review guidance. (york2022mechanismsunderlyingthe pages 14-16)

14. Other species / natural disease

Naturally occurring ankyrin‑B syndrome analogs in companion animals or livestock were not identified in the retrieved evidence.

15. Model organisms

Multiple experimental models support mechanism and therapy development: * AnkB+/− mice and neonatal cardiomyocytes: bradycardia, HR variability, Ca2+‑handling defects, and sudden death; rescue with WT ankyrin‑B but not E1425G ankyrin‑B. (mohler2003ankyrinbmutationcauses pages 1-2) * ANK2‑linked SND family model alignment: AnkB+/− mice phenocopy severe SND with bradycardia and HR variability. (scouarnec2008dysfunctioninankyrinbdependent pages 1-2) * p.Q1283H knock‑in mice: catecholamine‑triggered ventricular arrhythmias via PP2A–RyR2 dysregulation and RyR2 Ser2814 hyperphosphorylation; responsive to metoprolol/flecainide in vivo. (zhu2018ankyrinbq1283hvariant pages 1-2) * Cardiac‑specific Ank2 conditional knockout (Ank2‑cKO): structural remodeling/ACM phenotype linked to β‑catenin patterning; preventable/reversible with SB‑216763 in mice. (roberts2019ankyrinbdysfunctionpredisposes pages 9-10, roberts2019ankyrinbdysfunctionpredisposes media 52e6c3c8)

Model limitations (from retrieved evidence): global Ank2 knockout is lethal; some murine cardiomyopathy models do not recapitulate fatty infiltration; adult cardiomyocytes are difficult to transfect, affecting rescue assay design. (york2022mechanismsunderlyingthe pages 9-10, mohler2003ankyrinbmutationcauses pages 1-2, roberts2019ankyrinbdysfunctionpredisposes pages 9-10)

Expert interpretation and current controversies

A key contemporary issue is the interpretation of ANK2 variants: while some variants (e.g., the original E1425G family) show strong segregation and compelling functional evidence, a referral cohort reappraisal found that several historically alleged ankyrin‑B syndrome variants were not enriched compared with population databases and often had minimal phenotype, leading to the conclusion they are “unlikely to result in a penetrant, monogenic SCD‑predisposing condition” in many cases. This supports a clinical stance emphasizing careful variant classification, segregation testing, and phenotype‑driven management rather than assuming high risk for all rare ANK2 variants. (giudicessi2020establishedlossoffunctionvariants pages 1-5, mohler2003ankyrinbmutationcauses pages 1-2)

Key 2023–2024 updates (prioritized)

  • Dec 2023: A reported inherited syndrome with sudden cardiac death and distinct ST‑segment depression involved ANK2 c.11791G>A plus MYO18B c.3761G>A, investigated through multidisciplinary autopsy plus 174‑gene panel sequencing and WES. (korn2023anewinherited pages 1-2)
  • May 2024: A case of COVID‑19 myocarditis complicated by recurrent VT reported an ANK2 SNV and described use of mechanistically selected antiarrhythmics (mexiletine) plus beta‑blockers and a 42‑gene arrhythmia panel workflow. (haase2024asinglenucleotide pages 2-4)

Data gaps for a knowledge base entry (explicit)

  • Disease‑specific MONDO/Orphanet/ICD identifiers were not found in the retrieved evidence set. (york2022mechanismsunderlyingthe pages 1-2)
  • Robust ankyrin‑B syndrome‑specific prevalence/incidence, survival, and standardized quality‑of‑life metrics were not identified in retrieved evidence. (spoonamore2016genetictestingand pages 6-10, giudicessi2020establishedlossoffunctionvariants pages 1-5)
  • No ANK2‑specific interventional clinical trials for cardiac ankyrin‑B syndrome were retrieved; targeted therapy evidence remains preclinical. (roberts2019ankyrinbdysfunctionpredisposes media 52e6c3c8, roberts2019ankyrinbdysfunctionpredisposes pages 9-10)

References

  1. (mohler2003ankyrinbmutationcauses pages 1-2): Peter J. Mohler, Jean-Jacques Schott, Anthony O. Gramolini, Keith W. Dilly, Silvia Guatimosim, William H. duBell, Long-Sheng Song, Karine Haurogné, Florence Kyndt, Mervat E. Ali, Terry B. Rogers, W. J. Lederer, Denis Escande, Herve Le Marec, and Vann Bennett. Ankyrin-b mutation causes type 4 long-qt cardiac arrhythmia and sudden cardiac death. Nature, 421:634-639, Feb 2003. URL: https://doi.org/10.1038/nature01335, doi:10.1038/nature01335. This article has 1267 citations and is from a highest quality peer-reviewed journal.

  2. (koenig2017theevolvingrole pages 2-4): Sara N. Koenig and Peter J. Mohler. The evolving role of ankyrin-b in cardiovascular disease. Heart rhythm, 14 12:1884-1889, Dec 2017. URL: https://doi.org/10.1016/j.hrthm.2017.07.032, doi:10.1016/j.hrthm.2017.07.032. This article has 62 citations and is from a peer-reviewed journal.

  3. (york2022mechanismsunderlyingthe pages 1-2): Nicole S. York, Juan C. Sanchez-Arias, Alexa C. H. McAdam, Joel E. Rivera, Laura T. Arbour, and Leigh Anne Swayne. Mechanisms underlying the role of ankyrin-b in cardiac and neurological health and disease. Frontiers in Cardiovascular Medicine, Aug 2022. URL: https://doi.org/10.3389/fcvm.2022.964675, doi:10.3389/fcvm.2022.964675. This article has 20 citations and is from a peer-reviewed journal.

  4. (sucharski2020mechanismsandalterations pages 1-2): Holly C. Sucharski, Emma K. Dudley, Caullin B.R. Keith, Mona El Refaey, Sara N. Koenig, and Peter J. Mohler. Mechanisms and alterations of cardiac ion channels leading to disease: role of ankyrin-b in cardiac function. Biomolecules, 10:211, Jan 2020. URL: https://doi.org/10.3390/biom10020211, doi:10.3390/biom10020211. This article has 37 citations.

  5. (ackerman2010defininganew pages 2-3): Michael J. Ackerman and Peter J. Mohler. Defining a new paradigm for human arrhythmia syndromes: phenotypic manifestations of gene mutations in ion channel- and transporter-associated proteins. Circulation research, 107 4:457-65, Aug 2010. URL: https://doi.org/10.1161/circresaha.110.224592, doi:10.1161/circresaha.110.224592. This article has 92 citations and is from a highest quality peer-reviewed journal.

  6. (scouarnec2008dysfunctioninankyrinbdependent pages 1-2): Solena Le Scouarnec, Naina Bhasin, Claude Vieyres, Thomas J. Hund, Shane R. Cunha, Olha Koval, Celine Marionneau, Biyi Chen, Yuejin Wu, Sophie Demolombe, Long-Sheng Song, Hervé Le Marec, Vincent Probst, Jean-Jacques Schott, Mark E. Anderson, and Peter J. Mohler. Dysfunction in ankyrin-b-dependent ion channel and transporter targeting causes human sinus node disease. Proceedings of the National Academy of Sciences, 105:15617-15622, Oct 2008. URL: https://doi.org/10.1073/pnas.0805500105, doi:10.1073/pnas.0805500105. This article has 202 citations and is from a highest quality peer-reviewed journal.

  7. (giudicessi2020establishedlossoffunctionvariants pages 1-5): John R. Giudicessi and Michael J. Ackerman. Established loss-of-function variants in ank2 -encoded ankyrin-b rarely cause a concerning cardiac phenotype in humans. Circulation: Genomic and Precision Medicine, Apr 2020. URL: https://doi.org/10.1161/circgen.119.002851, doi:10.1161/circgen.119.002851. This article has 10 citations.

  8. (zhu2018ankyrinbq1283hvariant pages 1-2): Wengen Zhu, Cen Wang, Jinzhu Hu, Rong Wan, Jianhua Yu, Jinyan Xie, Jianyong Ma, Linjuan Guo, Jin Ge, Yumin Qiu, Leifeng Chen, Hualong Liu, Xia Yan, Xiuxia Liu, Jin Ye, Wenfeng He, Yang Shen, Chao Wang, Peter J. Mohler, and Kui Hong. Ankyrin-b q1283h variant linked to arrhythmias via loss of local protein phosphatase 2a activity causes ryanodine receptor hyperphosphorylation. Circulation, 138:2682-2697, Dec 2018. URL: https://doi.org/10.1161/circulationaha.118.034541, doi:10.1161/circulationaha.118.034541. This article has 24 citations and is from a highest quality peer-reviewed journal.

  9. (roberts2019ankyrinbdysfunctionpredisposes pages 9-10): Jason D. Roberts, Nathaniel P. Murphy, Robert M. Hamilton, Ellen R. Lubbers, Cynthia A. James, Crystal F. Kline, Michael H. Gollob, Andrew D. Krahn, Amy C. Sturm, Hassan Musa, Mona El-Refaey, Sara Koenig, Meriam Åström Aneq, Edgar T. Hoorntje, Sharon L. Graw, Robert W. Davies, Muhammad Arshad Rafiq, Tamara T. Koopmann, Shabana Aafaqi, Meena Fatah, David A. Chiasson, Matthew R.G. Taylor, Samantha L. Simmons, Mei Han, Chantal J.M. van Opbergen, Loren E. Wold, Gianfranco Sinagra, Kirti Mittal, Crystal Tichnell, Brittney Murray, Alberto Codima, Babak Nazer, Duy T. Nguyen, Frank I. Marcus, Nara Sobriera, Elisabeth M. Lodder, Maarten P. van den Berg, Danna A. Spears, John F. Robinson, Philip C. Ursell, Anna K. Green, Allan C. Skanes, Anthony S. Tang, Martin J. Gardner, Robert A. Hegele, Toon A.B. van Veen, Arthur A.M. Wilde, Jeff S. Healey, Paul M.L. Janssen, Luisa Mestroni, J. Peter van Tintelen, Hugh Calkins, Daniel P. Judge, Thomas J. Hund, Melvin M. Scheinman, and Peter J. Mohler. Ankyrin-b dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy. The Journal of clinical investigation, 130:3171-3184, Jul 2019. URL: https://doi.org/10.1172/jci125538, doi:10.1172/jci125538. This article has 69 citations.

  10. (swayne2017novelvariantin pages 1-2): Leigh Anne Swayne, Nathaniel P. Murphy, Sirisha Asuri, Lena Chen, Xiaoxue Xu, Sarah McIntosh, Chao Wang, Peter J. Lancione, Jason D. Roberts, Charles Kerr, Shubhayan Sanatani, Elizabeth Sherwin, Crystal F. Kline, Mingjie Zhang, Peter J. Mohler, and Laura T. Arbour. Novel variant in the ank2 membrane-binding domain is associated with ankyrin-b syndrome and structural heart disease in a first nations population with a high rate of long qt syndrome. Circulation: Cardiovascular Genetics, 10:e001537, Feb 2017. URL: https://doi.org/10.1161/circgenetics.116.001537, doi:10.1161/circgenetics.116.001537. This article has 62 citations.

  11. (york2022mechanismsunderlyingthe pages 4-5): Nicole S. York, Juan C. Sanchez-Arias, Alexa C. H. McAdam, Joel E. Rivera, Laura T. Arbour, and Leigh Anne Swayne. Mechanisms underlying the role of ankyrin-b in cardiac and neurological health and disease. Frontiers in Cardiovascular Medicine, Aug 2022. URL: https://doi.org/10.3389/fcvm.2022.964675, doi:10.3389/fcvm.2022.964675. This article has 20 citations and is from a peer-reviewed journal.

  12. (mohler2003ankyrinbmutationcauses media 3330bf40): Peter J. Mohler, Jean-Jacques Schott, Anthony O. Gramolini, Keith W. Dilly, Silvia Guatimosim, William H. duBell, Long-Sheng Song, Karine Haurogné, Florence Kyndt, Mervat E. Ali, Terry B. Rogers, W. J. Lederer, Denis Escande, Herve Le Marec, and Vann Bennett. Ankyrin-b mutation causes type 4 long-qt cardiac arrhythmia and sudden cardiac death. Nature, 421:634-639, Feb 2003. URL: https://doi.org/10.1038/nature01335, doi:10.1038/nature01335. This article has 1267 citations and is from a highest quality peer-reviewed journal.

  13. (mohler2003ankyrinbmutationcauses media b13c3b4f): Peter J. Mohler, Jean-Jacques Schott, Anthony O. Gramolini, Keith W. Dilly, Silvia Guatimosim, William H. duBell, Long-Sheng Song, Karine Haurogné, Florence Kyndt, Mervat E. Ali, Terry B. Rogers, W. J. Lederer, Denis Escande, Herve Le Marec, and Vann Bennett. Ankyrin-b mutation causes type 4 long-qt cardiac arrhythmia and sudden cardiac death. Nature, 421:634-639, Feb 2003. URL: https://doi.org/10.1038/nature01335, doi:10.1038/nature01335. This article has 1267 citations and is from a highest quality peer-reviewed journal.

  14. (roberts2019ankyrinbdysfunctionpredisposes pages 1-2): Jason D. Roberts, Nathaniel P. Murphy, Robert M. Hamilton, Ellen R. Lubbers, Cynthia A. James, Crystal F. Kline, Michael H. Gollob, Andrew D. Krahn, Amy C. Sturm, Hassan Musa, Mona El-Refaey, Sara Koenig, Meriam Åström Aneq, Edgar T. Hoorntje, Sharon L. Graw, Robert W. Davies, Muhammad Arshad Rafiq, Tamara T. Koopmann, Shabana Aafaqi, Meena Fatah, David A. Chiasson, Matthew R.G. Taylor, Samantha L. Simmons, Mei Han, Chantal J.M. van Opbergen, Loren E. Wold, Gianfranco Sinagra, Kirti Mittal, Crystal Tichnell, Brittney Murray, Alberto Codima, Babak Nazer, Duy T. Nguyen, Frank I. Marcus, Nara Sobriera, Elisabeth M. Lodder, Maarten P. van den Berg, Danna A. Spears, John F. Robinson, Philip C. Ursell, Anna K. Green, Allan C. Skanes, Anthony S. Tang, Martin J. Gardner, Robert A. Hegele, Toon A.B. van Veen, Arthur A.M. Wilde, Jeff S. Healey, Paul M.L. Janssen, Luisa Mestroni, J. Peter van Tintelen, Hugh Calkins, Daniel P. Judge, Thomas J. Hund, Melvin M. Scheinman, and Peter J. Mohler. Ankyrin-b dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy. The Journal of clinical investigation, 130:3171-3184, Jul 2019. URL: https://doi.org/10.1172/jci125538, doi:10.1172/jci125538. This article has 69 citations.

  15. (korn2023anewinherited pages 1-2): Hubertus von Korn, Cristina Basso, Kalliopi Pilichou, Victor Stefan, and Patrick Swojanowsky. A new inherited syndrome causing sudden cardiac death with distinct st-segment depression and ankyrin-2-mutation. The Application of Clinical Genetics, 16:233-239, Dec 2023. URL: https://doi.org/10.2147/tacg.s438957, doi:10.2147/tacg.s438957. This article has 0 citations.

  16. (york2022mechanismsunderlyingthe pages 5-6): Nicole S. York, Juan C. Sanchez-Arias, Alexa C. H. McAdam, Joel E. Rivera, Laura T. Arbour, and Leigh Anne Swayne. Mechanisms underlying the role of ankyrin-b in cardiac and neurological health and disease. Frontiers in Cardiovascular Medicine, Aug 2022. URL: https://doi.org/10.3389/fcvm.2022.964675, doi:10.3389/fcvm.2022.964675. This article has 20 citations and is from a peer-reviewed journal.

  17. (york2022mechanismsunderlyingthe pages 4-4): Nicole S. York, Juan C. Sanchez-Arias, Alexa C. H. McAdam, Joel E. Rivera, Laura T. Arbour, and Leigh Anne Swayne. Mechanisms underlying the role of ankyrin-b in cardiac and neurological health and disease. Frontiers in Cardiovascular Medicine, Aug 2022. URL: https://doi.org/10.3389/fcvm.2022.964675, doi:10.3389/fcvm.2022.964675. This article has 20 citations and is from a peer-reviewed journal.

  18. (york2022mechanismsunderlyingthe pages 2-3): Nicole S. York, Juan C. Sanchez-Arias, Alexa C. H. McAdam, Joel E. Rivera, Laura T. Arbour, and Leigh Anne Swayne. Mechanisms underlying the role of ankyrin-b in cardiac and neurological health and disease. Frontiers in Cardiovascular Medicine, Aug 2022. URL: https://doi.org/10.3389/fcvm.2022.964675, doi:10.3389/fcvm.2022.964675. This article has 20 citations and is from a peer-reviewed journal.

  19. (koenig2017theevolvingrole pages 1-2): Sara N. Koenig and Peter J. Mohler. The evolving role of ankyrin-b in cardiovascular disease. Heart rhythm, 14 12:1884-1889, Dec 2017. URL: https://doi.org/10.1016/j.hrthm.2017.07.032, doi:10.1016/j.hrthm.2017.07.032. This article has 62 citations and is from a peer-reviewed journal.

  20. (wolf2010definingnewinsight pages 1-1): Roseanne M. Wolf, Colleen C. Mitchell, Matthew D. Christensen, Peter J. Mohler, and Thomas J. Hund. Defining new insight into atypical arrhythmia: a computational model of ankyrin-b syndrome. American journal of physiology. Heart and circulatory physiology, 299 5:H1505-14, Nov 2010. URL: https://doi.org/10.1152/ajpheart.00503.2010, doi:10.1152/ajpheart.00503.2010. This article has 12 citations.

  21. (cunha2011defectsinankyrinbased pages 11-11): Shane R. Cunha, Thomas J. Hund, Seyed Hashemi, Niels Voigt, Na Li, Patrick Wright, Olha Koval, Jingdong Li, Hjalti Gudmundsson, Richard J. Gumina, Matthias Karck, Jean-Jacques Schott, Vincent Probst, Herve Le Marec, Mark E. Anderson, Dobromir Dobrev, Xander H.T. Wehrens, and Peter J. Mohler. Defects in ankyrin-based membrane protein targeting pathways underlie atrial fibrillation. Circulation, 124:1212–1222, Sep 2011. URL: https://doi.org/10.1161/circulationaha.111.023986, doi:10.1161/circulationaha.111.023986. This article has 140 citations and is from a highest quality peer-reviewed journal.

  22. (roberts2019ankyrinbdysfunctionpredisposes media 52e6c3c8): Jason D. Roberts, Nathaniel P. Murphy, Robert M. Hamilton, Ellen R. Lubbers, Cynthia A. James, Crystal F. Kline, Michael H. Gollob, Andrew D. Krahn, Amy C. Sturm, Hassan Musa, Mona El-Refaey, Sara Koenig, Meriam Åström Aneq, Edgar T. Hoorntje, Sharon L. Graw, Robert W. Davies, Muhammad Arshad Rafiq, Tamara T. Koopmann, Shabana Aafaqi, Meena Fatah, David A. Chiasson, Matthew R.G. Taylor, Samantha L. Simmons, Mei Han, Chantal J.M. van Opbergen, Loren E. Wold, Gianfranco Sinagra, Kirti Mittal, Crystal Tichnell, Brittney Murray, Alberto Codima, Babak Nazer, Duy T. Nguyen, Frank I. Marcus, Nara Sobriera, Elisabeth M. Lodder, Maarten P. van den Berg, Danna A. Spears, John F. Robinson, Philip C. Ursell, Anna K. Green, Allan C. Skanes, Anthony S. Tang, Martin J. Gardner, Robert A. Hegele, Toon A.B. van Veen, Arthur A.M. Wilde, Jeff S. Healey, Paul M.L. Janssen, Luisa Mestroni, J. Peter van Tintelen, Hugh Calkins, Daniel P. Judge, Thomas J. Hund, Melvin M. Scheinman, and Peter J. Mohler. Ankyrin-b dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy. The Journal of clinical investigation, 130:3171-3184, Jul 2019. URL: https://doi.org/10.1172/jci125538, doi:10.1172/jci125538. This article has 69 citations.

  23. (spoonamore2016genetictestingand pages 6-10): Katherine G. Spoonamore and Stephanie M. Ware. Genetic testing and genetic counseling in patients with sudden death risk due to heritable arrhythmias. Heart rhythm, 13 3:789-97, Mar 2016. URL: https://doi.org/10.1016/j.hrthm.2015.11.013, doi:10.1016/j.hrthm.2015.11.013. This article has 41 citations and is from a peer-reviewed journal.

  24. (haase2024asinglenucleotide pages 2-4): Erin Haase, Chandana Kulkarni, Peyton Moore, Akash Ramanathan, and Mohanakrishnan Sathyamoorthy. A single nucleotide variant in ankyrin-2 influencing ventricular tachycardia in covid-19 associated myocarditis. Cardiogenetics, 14:84-92, May 2024. URL: https://doi.org/10.3390/cardiogenetics14020007, doi:10.3390/cardiogenetics14020007. This article has 0 citations.

  25. (haase2024asinglenucleotide pages 1-2): Erin Haase, Chandana Kulkarni, Peyton Moore, Akash Ramanathan, and Mohanakrishnan Sathyamoorthy. A single nucleotide variant in ankyrin-2 influencing ventricular tachycardia in covid-19 associated myocarditis. Cardiogenetics, 14:84-92, May 2024. URL: https://doi.org/10.3390/cardiogenetics14020007, doi:10.3390/cardiogenetics14020007. This article has 0 citations.

  26. (spoonamore2016genetictestingand pages 14-17): Katherine G. Spoonamore and Stephanie M. Ware. Genetic testing and genetic counseling in patients with sudden death risk due to heritable arrhythmias. Heart rhythm, 13 3:789-97, Mar 2016. URL: https://doi.org/10.1016/j.hrthm.2015.11.013, doi:10.1016/j.hrthm.2015.11.013. This article has 41 citations and is from a peer-reviewed journal.

  27. (spoonamore2016genetictestingand pages 10-14): Katherine G. Spoonamore and Stephanie M. Ware. Genetic testing and genetic counseling in patients with sudden death risk due to heritable arrhythmias. Heart rhythm, 13 3:789-97, Mar 2016. URL: https://doi.org/10.1016/j.hrthm.2015.11.013, doi:10.1016/j.hrthm.2015.11.013. This article has 41 citations and is from a peer-reviewed journal.

  28. (york2022mechanismsunderlyingthe pages 14-16): Nicole S. York, Juan C. Sanchez-Arias, Alexa C. H. McAdam, Joel E. Rivera, Laura T. Arbour, and Leigh Anne Swayne. Mechanisms underlying the role of ankyrin-b in cardiac and neurological health and disease. Frontiers in Cardiovascular Medicine, Aug 2022. URL: https://doi.org/10.3389/fcvm.2022.964675, doi:10.3389/fcvm.2022.964675. This article has 20 citations and is from a peer-reviewed journal.

  29. (york2022mechanismsunderlyingthe pages 9-10): Nicole S. York, Juan C. Sanchez-Arias, Alexa C. H. McAdam, Joel E. Rivera, Laura T. Arbour, and Leigh Anne Swayne. Mechanisms underlying the role of ankyrin-b in cardiac and neurological health and disease. Frontiers in Cardiovascular Medicine, Aug 2022. URL: https://doi.org/10.3389/fcvm.2022.964675, doi:10.3389/fcvm.2022.964675. This article has 20 citations and is from a peer-reviewed journal.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 33 citations 2026-05-04T23:40:13.560114

1. Disease Information

Overview

ANK2 Ankyrin-B Syndrome is a genetic cardiac arrhythmia disorder caused by loss-of-function variants in ANK2 (ankyrin-B). The disease was first identified in 2003 when Mohler et al. discovered that a loss-of-function mutation (E1425G) in ankyrin-B caused dominantly inherited type 4 long-QT cardiac arrhythmia (PMID: 12571597). Subsequent studies revealed that the phenotype extends well beyond QT prolongation, leading to its reclassification as "ankyrin-B syndrome" — a distinct clinical entity separate from classical long QT syndromes (PMID: 15178757).

As stated by Mohler et al. (2004): "Humans with ankyrin-B mutations display varying degrees of cardiac dysfunction including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death. However, a prolonged rate-corrected QT interval was not a consistent feature, indicating that ankyrin-B dysfunction represents a clinical entity distinct from classic long QT syndromes." (PMID: 15178757)

Key Identifiers

Database Identifier
MONDO MONDO:0010958 (cardiac arrhythmia, ankyrin-B-related)
OMIM 600919 (Long QT syndrome 4)
Gene ANK2 (HGNC:493)
Chromosome 4q25-q26
ICD-10 I49.8 (Other specified cardiac arrhythmias)
MeSH Long QT Syndrome (broader category)

Synonyms and Alternative Names

  • Ankyrin-B syndrome
  • Long QT syndrome type 4 (LQT4) — historical designation
  • Cardiac arrhythmia, ankyrin-B-related
  • ANK2-related cardiac arrhythmia syndrome

Information Sources

The information in this report is derived from aggregated disease-level resources including OMIM, ClinVar, ClinGen, and primary literature (43 peer-reviewed publications), supplemented by evidence from animal model studies and computational modeling.

2. Etiology

Disease Causal Factors

The primary cause of ANK2 Ankyrin-B Syndrome is genetic: loss-of-function variants in the ANK2 gene encoding ankyrin-B. The disease follows autosomal dominant inheritance with incomplete penetrance and variable expressivity.

The original causative mutation identified was E1425G (p.Glu1425Gly), described by Mohler et al. (2003): "a loss-of-function (E1425G) mutation in ankyrin-B (also known as ankyrin 2), a member of a family of versatile membrane adapters, causes dominantly inherited type 4 long-QT cardiac arrhythmia in humans" (PMID: 12571597).

A novel mechanism was also described involving a reciprocal chromosomal translocation between chromosomes 4q25 and 9q26 that transects the ANK2 gene, resulting in ankyrin-B haploinsufficiency and clinical features of ankyrin-B syndrome (PMID: 27916589).

Genetic Risk Factors

  • Causal variants: Multiple loss-of-function variants in ANK2 have been identified, including E1425G, V1516D, T1404I, R1788W, L1622I, Q1283H, and W1535R
  • Susceptibility loci: The ANK2 locus has been linked with QTc interval variability in the general human population (PMID: 19394342)
  • Modifier genes: KCNH2 has been shown to functionally interact with ANK2, with double mutation carriers (ANK2-E1813K + KCNH2-H562R) displaying markedly more severe phenotypes (PMID: 30929919)
  • βII spectrin (SPTBN1): A novel human mutation in ankyrin-B that disrupts the ankyrin-B/βII spectrin interaction leads to severe human arrhythmia phenotypes (PMID: 25632041)

Environmental Risk Factors and Gene-Environment Interactions

  • Catecholaminergic stress: Arrhythmias are frequently triggered by adrenergic stimulation (exercise, emotional stress, isoproterenol)
  • QT-prolonging drugs: Medications that prolong the QT interval may unmask or exacerbate arrhythmias in ANK2 variant carriers
  • Acquired LQTS context: Four of eight LQTS patients carrying ANK2 mutations in a Japanese cohort had acquired LQTS (aLQTS), suggesting that ANK2 variants may serve as susceptibility factors that manifest with environmental triggers (PMID: 27784853)
  • Secondary genetic variation: The common ANK2 p.L1622I variant "may confer arrhythmia susceptibility in the context of secondary risk factors including environment, medication, and/or additional genetic variation" (PMID: 27298202)

Protective Factors

No specific genetic or environmental protective factors have been identified for ANK2 Ankyrin-B Syndrome. However, avoidance of catecholaminergic triggers and QT-prolonging medications may reduce arrhythmia risk in carriers.

3. Phenotypes

Cardiac Arrhythmia Phenotypes

Phenotype HPO Term Frequency Onset Severity
Sinus bradycardia HP:0001662 Common Variable (childhood–adult) Mild to severe
Sinus node dysfunction HP:0001678 High penetrance in some families Variable Moderate to severe
Atrial fibrillation HP:0005110 Common Typically adult Variable
QT interval prolongation HP:0001657 Variable/inconsistent Variable Mild to moderate
Catecholaminergic polymorphic ventricular tachycardia HP:0031546 Present in subset Typically with stress Severe
Ventricular fibrillation HP:0001663 Present in subset Variable Life-threatening
Cardiac conduction defects HP:0005150 Present in subset Progressive, age-related Variable
Sudden cardiac death HP:0001645 Risk present Variable Fatal
Heart rate variability HP:0007110 Common Variable Mild
Torsades de pointes HP:0001664 Present in subset Episodic Severe

Sinus Node Dysfunction (SND)

Two families with highly penetrant and severe SND were mapped to the ANK2 locus. As described by Le Scouarnec et al. (2008): "We mapped two families with highly penetrant and severe SND to the human ANK2 (ankyrin-B/AnkB) locus. Mice heterozygous for AnkB phenocopy human SND displayed severe bradycardia and rate variability. AnkB is essential for normal membrane organization of sinoatrial node cell channels and transporters" (PMID: 18832177).

Atrial Fibrillation

Computational modeling predicts that "defective membrane targeting of the voltage-gated L-type Ca²⁺ channel Cav1.3 leads to action potential shortening that reduces the critical atrial tissue mass needed to sustain reentrant activation" (PMID: 23436330), explaining the susceptibility to atrial fibrillation in ankyrin-B syndrome.

Clinical Case Example

A clinical case report describes a young adult patient with "sinus node dysfunction, atrial fibrillation and prolonged QT syndrome... with a family history of sudden death" (PMID: 25456501), illustrating the multifaceted phenotype.

Phenotype Variability

A key feature of ankyrin-B syndrome is its remarkable phenotypic variability. In a Japanese cohort of 535 inherited primary arrhythmia syndrome (IPAS) probands, 12 (2.2%) carried 7 different heterozygous ANK2 mutations, with phenotypes including LQTS (8), Brugada syndrome (2), idiopathic ventricular fibrillation (1), and sick sinus syndrome/atrial fibrillation (1) (PMID: 27784853).

Quality of Life Impact

  • Sinus node dysfunction: May require permanent pacemaker implantation; affects exercise capacity and daily functioning
  • Atrial fibrillation: Increased stroke risk, palpitations, fatigue
  • Ventricular arrhythmias/sudden death risk: Significant psychological burden; may require activity restriction and ICD implantation
  • Drug avoidance: Need to avoid QT-prolonging medications restricts treatment options for other conditions

4. Genetic/Molecular Information

Causal Gene

  • Gene: ANK2 (Ankyrin 2 / Ankyrin-B)
  • HGNC ID: HGNC:493
  • OMIM Gene: 106410
  • Chromosome location: 4q25-q26
  • Protein: Ankyrin-B (220 kDa isoform is the primary cardiac form)
  • UniProt: Q01484

Pathogenic Variants

Mohler et al. (2007) characterized the functional impact of nine human ANK2 variants: "We then characterized the relative severity of loss-of-function properties of all 9 nonsynonymous ANK2 variants identified to date in primary cardiomyocytes and identified a range of in vitro phenotypes, including wild-type, simple loss-of-function, and severe loss-of-function activity, seen with the variants causing severe human phenotypes." (PMID: 17242276)

Variant Classification Functional Category Population Frequency Clinical Association
E1425G Pathogenic Severe LOF Very rare Original LQT4 family; severe arrhythmias
V1516D Likely pathogenic Severe LOF Very rare Severe phenotype
T1404I Likely pathogenic LOF Rare Arrhythmia
Q1283H Disease-associated LOF Rare Stress-induced arrhythmias
W1535R Likely pathogenic LOF (predicted damaging) Rare Found in 5 LQTS + 1 BrS patient
L1622I Mild LOF / risk variant Mild LOF 2% European, 8% West African Enhanced contractility + arrhythmia risk
R1788W Disputed Altered obscurin binding Present in controls Near obscurin-binding motif
E1813K Disputed/modifier Functional interaction with KCNH2 Present in controls Conduction disease; aggravates KCNH2 mutations
T1626N Disputed Present in controls Present in controls Found in control populations

Allele Frequency Concerns

A critical finding from targeted mutational analysis is that ANK2 variants are surprisingly common in control populations. Cronk et al. (2007) found: "Overall, 14 distinct nonsynonymous variants (10 novel) were observed in 9 (3.3%) of 269 genotype-negative LQTS patients, 5 (1.8%) of 272 genotype-positive LQTS cases, 4 (4%) of 100 white controls, and 9 (9%) of 100 black controls" (PMID: 16253912). This high frequency of ANK2 variants in control populations complicates pathogenicity assessment and underscores the need for functional characterization of individual variants.

The L1622I variant is particularly notable, with prevalence ranging "from 2 percent of European individuals to 8 percent in individuals from West Africa" (PMID: 17940615). This variant is considered a "balanced" or "mild" loss-of-function variant that enhances cardiac contractility but also confers arrhythmia susceptibility and premature senescence risk.

Chromosomal Abnormality

A reciprocal chromosomal translocation between 4q25 and 9q26 that transects the ANK2 gene has been described as a novel mechanism causing ankyrin-B haploinsufficiency and the clinical syndrome (PMID: 27916589).

ClinGen Evidence Reappraisal

The ClinGen Channelopathy Expert Panel has provided important reassessments:

  1. For LQTS (2020): ANK2 was classified among genes with "limited or disputed evidence" for LQTS causation. As stated: "More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence." (PMID: 31983240)

  2. For CPVT (2022): ANK2 variants were deemed "too common in the population to be disease-causing" for CPVT specifically (PMID: 34557911).

This does not negate the strong experimental evidence for ankyrin-B dysfunction causing cardiac arrhythmia, but rather indicates that the clinical syndrome may not fit neatly into the traditional channelopathy classification framework.

Modifier Genes and Interacting Proteins

  • KCNH2 (hERG): ANK2-E1813K functionally interacts with KCNH2, with double heterozygosity causing markedly severe LQTS (PMID: 30929919)
  • βII Spectrin (SPTBN1): Essential partner for ankyrin-B localization; mutations disrupting the ankyrin-B/βII spectrin interaction cause severe arrhythmias (PMID: 25632041)
  • Obscurin: Mediates ankyrin-B targeting to the cardiac M-line; the R1788W variant increases obscurin binding (PMID: 18782775)
  • EHD3: Endosome pathway protein critical for ankyrin-B-dependent membrane protein trafficking (PMID: 24759929)
  • OTUD7A: Deubiquitinase whose interactions with Ankyrin-B and Ankyrin-G are disrupted by the epilepsy-associated L233F variant (PMID: 36604605)

5. Environmental Information

Environmental Factors

ANK2 Ankyrin-B Syndrome is a purely genetic disorder; no environmental toxins, radiation, or occupational exposures are known to cause the disease. However, environmental factors can modulate disease expression:

  • Catecholaminergic stimulation (exercise, stress, isoproterenol) is the primary trigger for arrhythmias in carriers
  • QT-prolonging medications may unmask or worsen the phenotype
  • Acquired factors: Myocardial infarction causes striking remodeling of ankyrin-B and associated proteins, suggesting that ischemic heart disease may interact with genetic ankyrin-B deficiency (PMID: 19394342)

Lifestyle Factors

No specific dietary or lifestyle factors have been identified as causative. Exercise avoidance may be recommended for high-risk patients, similar to other catecholaminergic arrhythmia syndromes.

Infectious Agents

Not applicable — no infectious etiology.

6. Mechanism / Pathophysiology

Molecular Mechanism: The Ankyrin-B Targeting Pathway

The fundamental molecular defect in ankyrin-B syndrome is the failure to properly target and localize key cardiac ion transporters to their correct membrane domains. Ankyrin-B serves as a critical adapter protein that coordinates the assembly of a macromolecular complex at T-tubule/sarcoplasmic reticulum junctions in cardiomyocytes.

Mohler et al. (2003) described the core mechanism: "Mutation of ankyrin-B results in disruption in the cellular organization of the sodium pump, the sodium/calcium exchanger, and inositol-1,4,5-trisphosphate receptors (all ankyrin-B-binding proteins), which reduces the targeting of these proteins to the transverse tubules as well as reducing overall protein level" (PMID: 12571597).

Causal Chain: From Genetic Defect to Arrhythmia

ANK2 Loss-of-Function Variant
│
▼
Reduced/Dysfunctional Ankyrin-B Protein
│
├──► Reduced NCX1 membrane targeting
├──► Reduced Na⁺/K⁺-ATPase membrane targeting
├──► Reduced InsP3R targeting to SR
└──► Reduced Cav1.3 targeting (in SAN)
│
▼
Disrupted Ion Homeostasis
│
├──► Elevated intracellular [Na⁺] (local domains)
├──► Reduced Ca²⁺ extrusion via NCX
└──► Altered SR Ca²⁺ release via InsP3R/RyR2
│
▼
Intracellular Ca²⁺ Overload
│
├──► Increased Ca²⁺ spark frequency
├──► CaMKII activation & RyR2 hyperphosphorylation (pS2814)
└──► SR Ca²⁺ leak
│
▼
Triggered Arrhythmias
│
├──► Delayed afterdepolarizations (DADs)
├──► Early afterdepolarizations (EADs)
├──► Catecholaminergic polymorphic VT
├──► Sinus node dysfunction (via Cav1.3 loss)
├──► Atrial fibrillation (via reduced critical mass for reentry)
└──► Sudden cardiac death

Calcium Dysregulation

The hallmark cellular phenotype is calcium overload with enhanced spontaneous calcium release. Camors et al. (2012) demonstrated: "The frequency of spontaneous, diastolic Ca sparks (CaSpF) was significantly higher in intact myocytes from AnkB⁺/⁻ vs. WT myocytes (with and without isoproterenol), even when normalized for SR Ca load" (PMID: 22406428).

CaMKII-Dependent Pathway

A critical downstream mechanism involves CaMKII-dependent hyperphosphorylation of RyR2. Deangelis et al. (2012) showed: "The cardiac ryanodine receptor (RyR₂), a validated target of kinase/phosphatase regulation in myocytes, displays abnormal CaMKII-dependent phosphorylation (pS2814 hyperphosphorylation) in ankyrin-B⁺/⁻ heart" (PMID: 23059182). Importantly, CaMKII inhibition rescued the proarrhythmic phenotype, identifying a potential therapeutic target.

NKA-AnkB-NCX Functional Domain

Bhogal et al. (2019) demonstrated that NKA binding to ankyrin-B creates a local ion regulatory domain: disruption of the NKA/AnkB interaction using disruptor peptides leads to increased rate of Ca²⁺ sparks and waves, with the functional effects mediated through the NKAα2 isoform (PMID: 30949686). This establishes that the AnkB/NKAα2/NCX domain controls Ca²⁺ fluxes in cardiomyocytes, and its disruption is an important pathophysiological mechanism.

Protein Phosphatase 2A (PP2A) Dysregulation

Ankyrin-B targets the PP2A regulatory subunit B56α to the cardiac M-line. Reduced ankyrin-B expression leads to disorganized distribution of B56α (PMID: 17416611). PP2A dysfunction may further impair regulation of ion channels and calcium handling proteins.

EHD3-Dependent Endosomal Trafficking

EHD3 (Eps15 homology domain 3) is essential for membrane protein trafficking in heart. EHD3-deficient hearts phenocopy aspects of ankyrin-B syndrome with "bradycardia and rate variability, conduction block, and blunted response to adrenergic stimulation" and "reduced expression/localization of Na/Ca exchanger and L-type Ca channel type 1.2" (PMID: 24759929).

Ankyrin-B in Neuronal Function

Beyond cardiac roles, ankyrin-B plays important roles in neural development. It has been demonstrated that the cell adhesion molecule L1 elevates cyclic AMP levels in neurons via ankyrin-B, and "the loss of ankyrin-B expression converts Ca²⁺-triggered attraction to repulsion when the growth cone migrates via an L1-dependent mechanism" (PMID: 19110015). Additionally, OTUD7A interactions with Ankyrin-B are disrupted in the 15q13.3 microdeletion syndrome, linking ankyrin-B to neurodevelopmental disorders (PMID: 36604605).

Relevant GO Terms for Biological Processes

GO Term Description Relevance
GO:0086001 Cardiac muscle cell action potential Primary cellular process affected
GO:0006816 Calcium ion transport Core mechanism disrupted
GO:0005516 Calmodulin binding CaMKII pathway
GO:0019722 Calcium-mediated signaling Downstream signaling
GO:0086091 Regulation of heart rate by cardiac conduction SAN dysfunction
GO:0034765 Regulation of ion transmembrane transport Ion channel/transporter targeting
GO:0016323 Basolateral plasma membrane Subcellular localization
GO:0030315 T-tubule Primary site of ankyrin-B complex
GO:0006874 Cellular calcium ion homeostasis Core disrupted process
GO:0048738 Cardiac muscle tissue development Developmental role
GO:0007411 Axon guidance Neural ankyrin-B role

Relevant Cell Types (CL Terms)

CL Term Cell Type Involvement
CL:0000746 Cardiac muscle cell (cardiomyocyte) Primary cell type affected
CL:0002072 Nodal myocyte Sinus node dysfunction
CL:0002071 Atrial cardiac myocyte Atrial fibrillation substrate
CL:0002066 Purkinje myocyte Conduction system involvement
CL:0000540 Neuron Neural developmental roles

7. Anatomical Structures Affected

Organ Level

  • Primary organ: Heart (UBERON:0000948)
  • Sinoatrial node (UBERON:0002351) — sinus node dysfunction
  • Cardiac atrium (UBERON:0002081) — atrial fibrillation
  • Cardiac ventricle (UBERON:0002082) — ventricular arrhythmias
  • Cardiac conduction system (UBERON:0002350) — conduction defects
  • Secondary organ involvement: Brain (UBERON:0000955) — via sudden cardiac death, syncope; neuronal roles of ankyrin-B in axon guidance (PMID: 19110015)
  • Body systems: Cardiovascular system (primary), nervous system (secondary via neural ankyrin-B roles)

Tissue and Cell Level

  • Cardiac muscle tissue (UBERON:0001133): Primary tissue affected
  • Cardiac conduction system tissue: Specialized myocytes
  • Skeletal muscle: Congenital myopathy in ankyrin-B⁻/⁻ mice; SERCA and ryanodine receptor mis-localization (PMID: 10579720)
  • Thymus: Major loss of thymic lymphocytes in ankyrin-B⁻/⁻ mice (PMID: 10579720)

Subcellular Level

GO Cellular Component Structure Role in Disease
GO:0030315 T-tubule Primary site of ankyrin-B complex assembly
GO:0016529 Sarcoplasmic reticulum Ca²⁺ storage and release; InsP3R/RyR2 localization
GO:0030314 Junctional membrane complex T-tubule/SR junction — key site of dysfunction
GO:0005886 Plasma membrane NCX1, NKA targeting
GO:0031674 I band Ankyrin-B localization overlying M-line
GO:0030018 Z disc Adjacent cardiomyocyte structural domain
GO:0005768 Endosome EHD3-dependent trafficking pathway

Localization

  • Specific anatomical sites: Bilateral — the disease affects both sides of the heart
  • No lateralization: Cardiac involvement is generally symmetric

8. Temporal Development

Onset

  • Typical age of onset: Highly variable — congenital/neonatal (in severe cases with sinus node dysfunction) to adult-onset (atrial fibrillation, late-presenting arrhythmias)
  • Onset pattern: Insidious; many carriers remain asymptomatic until triggered by catecholaminergic stress or medication exposure
  • In the Japanese cohort, affected patients ranged from age 0 to 61 years (PMID: 27784853)
  • Sinus node dysfunction may present in childhood with severe bradycardia
  • Atrial fibrillation and conduction disease tend to be age-dependent and progressive

Progression

  • Disease course: Chronic, lifelong with episodic arrhythmia events
  • Progression pattern: Some phenotypes (conduction disease, atrial fibrillation) are progressive and age-related
  • In one family, sisters carrying only ANK2-E1813K showed "age-related conduction disease" (PMID: 30929919)
  • The common L1622I variant is associated with enhanced cardiac contractility but also premature senescence (PMID: 17940615)
  • Disease duration: Lifelong genetic condition; arrhythmic events are episodic
  • Disease stages: Not formally staged; ranges from subclinical carrier to symptomatic arrhythmia to sudden cardiac death

Critical Periods

  • Neonatal period: Severe ankyrin-B deficiency (homozygous or compound heterozygous) is neonatal lethal in mice
  • Periods of catecholaminergic stress: Exercise, emotional stress, and surgery represent windows of vulnerability
  • Drug exposure: Initiation of QT-prolonging medications represents a critical risk period
  • Myocardial ischemia: Ankyrin-B remodeling following myocardial infarction may amplify arrhythmic risk (PMID: 19394342)

9. Inheritance and Population

Inheritance Pattern

  • Mode: Autosomal dominant (AD)
  • Penetrance: Incomplete — many variant carriers are asymptomatic
  • Expressivity: Highly variable — even within the same family, individuals may manifest different arrhythmia phenotypes
  • Genetic anticipation: Not documented
  • Germline mosaicism: Not specifically documented, but possible given incomplete penetrance patterns
  • Functional consequence: Loss of function (haploinsufficiency)

Epidemiology

  • Prevalence: Unknown; classified as a rare disease
  • Incidence: Unknown
  • Among 535 Japanese IPAS probands, ANK2 mutations were found in 2.2% (PMID: 27784853)
  • Among 541 LQTS patients, ANK2 variants were found in 3.3% of genotype-negative cases (PMID: 16253912)

Population Demographics

  • Ethnic variation: Significant allele frequency differences exist across populations. The L1622I variant prevalence ranges from 2% in Europeans to 8% in West Africans (PMID: 17940615)
  • Haplotype structure: An evaluation of variation and haplotype structure in ANK2 across four populations (African-American, European American, Han Chinese, Mexican American) revealed "significant allele-frequency differences between populations and clear differences in haplotype structure" (PMID: 19530973)
  • First Nations populations: A novel disease-causing ANK2 variant was identified in First Nations families of Northern British Columbia, where long QT syndrome is approximately 15× more common than globally (PMID: 28196901)
  • Sex ratio: Not well-established; available cohort data suggest both sexes are affected
  • Geographic distribution: Global; variant frequencies vary across ancestral populations

10. Diagnostics

Clinical Tests

Electrophysiology

  • 12-lead ECG: May show sinus bradycardia, prolonged QTc (variable), conduction delays
  • QT prolongation is NOT a consistent feature — this distinguishes ankyrin-B syndrome from classical LQTS
  • Holter monitoring: Sinus node dysfunction, heart rate variability, intermittent arrhythmias
  • Exercise stress testing: Catecholamine-provoked arrhythmias; blunted chronotropic response
  • Electrophysiology study: May reveal sinus node dysfunction, AV conduction abnormalities

Imaging

  • Echocardiography: Generally normal cardiac structure; may reveal cardiomyopathy in advanced/severe cases
  • Cardiac MRI: To exclude structural heart disease

Biomarkers

  • No specific circulating biomarkers established for ANK2 Ankyrin-B Syndrome

Genetic Testing

  • Recommended approach: Next-generation sequencing-based arrhythmia gene panels or whole exome sequencing
  • Gene panels: ANK2 is included in many inherited arrhythmia panels, though ClinGen has questioned its inclusion in standard LQTS panels
  • Single gene testing: Sanger sequencing of ANK2 (historically used)
  • Whole exome sequencing: Useful when gene panels are negative; may identify novel variants
  • Whole genome sequencing: Can detect structural variants including chromosomal translocations
  • Functional characterization: Given the high frequency of ANK2 variants in control populations, functional studies in cardiomyocytes are critical for determining pathogenicity of novel variants

Important caveat: Given ClinGen's classification of ANK2 as having limited/disputed evidence for LQTS, genetic testing results must be interpreted with extreme caution. Variants should not be used for clinical decision-making without additional supporting evidence (PMID: 31983240).

Clinical Criteria

No standardized diagnostic criteria specific to ankyrin-B syndrome exist. Diagnosis relies on: 1. Clinical presentation with characteristic arrhythmia spectrum (especially multiple phenotypes in same patient/family) 2. Identification of a loss-of-function ANK2 variant 3. Functional characterization demonstrating variant pathogenicity 4. Family segregation analysis

Differential Diagnosis

Condition Distinguishing Features
Classical LQTS (types 1-3) Consistent QT prolongation; specific channel mutations (KCNQ1, KCNH2, SCN5A)
Brugada syndrome ST-segment elevation in V1-V3; SCN5A mutations
CPVT (RYR2-related) Bidirectional VT; isolated calcium channel defect
Sick sinus syndrome (non-genetic) Typically acquired; absence of other arrhythmia features; older age
Timothy syndrome Syndactyly; CACNA1C mutations; multisystem
Andersen-Tawil syndrome Periodic paralysis; dysmorphic features; KCNJ2 mutations

Screening

  • Cascade screening: Recommended for all first-degree relatives of identified carriers
  • Newborn screening: Not currently included in standard newborn screening programs
  • Carrier screening: Not included in standard carrier screening panels

11. Outcome/Prognosis

Survival and Mortality

  • Sudden cardiac death risk: Present but not quantified precisely; family histories frequently include sudden death
  • Life expectancy: Variable; with appropriate treatment (pacemakers, ICDs, drug avoidance), life expectancy may be near-normal in many patients
  • The original LQT4 family had a significant history of sudden death across multiple generations (PMID: 12571597)
  • Seven of 12 ANK2 mutation-positive patients in the Japanese cohort had documented malignant ventricular tachyarrhythmias (PMID: 27784853)

Morbidity

  • Sinus node dysfunction requiring pacemaker implantation
  • Atrial fibrillation requiring anticoagulation and rate/rhythm control
  • Restriction of physical activity in high-risk patients
  • Psychological burden of sudden death risk
  • Recurrent syncope from ventricular arrhythmias

Disease Complications

  • Cardiac: Heart failure (accelerated in βII spectrin-deficient mice; PMID: 25632041), stroke from atrial fibrillation, cardiac arrest
  • Premature senescence: The L1622I variant is associated with premature senescence alongside enhanced contractility (PMID: 17940615)

Prognostic Factors

  • Variant severity: Severe loss-of-function variants (E1425G, V1516D) associated with worse outcomes (PMID: 17242276)
  • Compound genetic hits: Co-occurrence of ANK2 and KCNH2 variants leads to markedly severe phenotype (PMID: 30929919)
  • Catecholaminergic provocation: Stress-induced arrhythmias predict higher risk
  • Family history: Presence of sudden cardiac death in family members
  • Age: Conduction disease and atrial fibrillation phenotypes are progressive with age

12. Treatment

Pharmacotherapy

Beta-Blockers (MAXO:0000169 — beta-adrenergic receptor antagonist therapy)

  • Rationale: Catecholaminergic arrhythmias suggest benefit from beta-blockade
  • Evidence: Metoprolol prevented stress-induced arrhythmias in AnkB p.Q1283H knock-in mice: "ANK2 p.Q1283H is a disease-associated variant that confers susceptibility to stress-induced arrhythmias, which may be prevented by the administration of metoprolol or flecainide" (PMID: 30571258)
  • Clinical use: First-line therapy for patients with catecholaminergic arrhythmias; caution needed if significant bradycardia is present

Flecainide (MAXO:0001298 — antiarrhythmic drug therapy)

  • Rationale: Sodium channel blockade; reduces triggered activity
  • Evidence: Effective in preventing arrhythmias in the Q1283H mouse model (PMID: 30571258)
  • Clinical use: May be used as adjunct or alternative to beta-blockers

QT-Prolonging Drug Avoidance (MAXO:0000883 — drug avoidance)

  • "The management of Ankyrin-B syndrome may include avoidance of QT prolonging medications" (PMID: 25456501)
  • Patients should be provided with a list of drugs to avoid (www.crediblemeds.org)

Device Therapy

Permanent Pacemaker (MAXO:0000477 — cardiac pacemaker implantation)

  • Indicated for symptomatic sinus node dysfunction with severe bradycardia
  • May also be needed to enable beta-blocker therapy without exacerbating bradycardia

Implantable Cardioverter-Defibrillator (MAXO:0000451 — implantable cardioverter defibrillator therapy)

  • Indicated for high-risk patients with history of ventricular tachycardia/fibrillation or survived cardiac arrest
  • "insertion of a permanent pacemaker for sinus node dysfunction, or a cardioverter defibrillator for those at high-risk of sudden death from torsades de pointes" (PMID: 25456501)

Experimental / Preclinical Approaches

CaMKII Inhibition

  • CaMKII inhibition rescues proarrhythmic phenotypes in the ankyrin-B⁺/⁻ model (PMID: 23059182)
  • Represents a potential targeted therapy addressing the core downstream mechanism
  • No clinical trials currently registered for CaMKII inhibitors in ankyrin-B syndrome

Gene Therapy

  • No gene therapy approaches have been developed for ANK2 Ankyrin-B Syndrome
  • The large size of the ANK2 gene (>400 kb genomic; ~12 kb mRNA for 220 kDa isoform) presents challenges for AAV-based gene replacement

Treatment Algorithm

ANK2 Variant Identified
│
├──► Functional Assessment (LOF severity)
│
├──► Asymptomatic Carrier
│       ├── Avoid QT-prolonging drugs
│       ├── Periodic ECG/Holter monitoring
│       └── Family cascade screening
│
├──► Sinus Node Dysfunction
│       ├── Symptomatic bradycardia → Permanent pacemaker
│       └── Beta-blocker (caution re: bradycardia)
│
├──► QT Prolongation / Ventricular Arrhythmias
│       ├── Beta-blocker (first-line)
│       ├── Flecainide (adjunct)
│       ├── Avoid QT-prolonging drugs
│       └── ICD if high risk / prior cardiac arrest
│
└──► Atrial Fibrillation
        ├── Rate/rhythm control per standard guidelines
        └── Anticoagulation per CHA₂DS₂-VASc score

13. Prevention

Primary Prevention

  • Genetic counseling (MAXO:0000079): For families with known ANK2 variants; autosomal dominant with 50% transmission risk to each offspring
  • Cascade genetic screening: Testing at-risk family members for the familial variant
  • Prenatal/preimplantation genetic diagnosis: Technically feasible for known familial variants, though the variable expressivity and incomplete penetrance complicate reproductive counseling

Secondary Prevention (Early Detection)

  • ECG screening: Regular ECG monitoring for identified carriers
  • Drug avoidance: Strict avoidance of QT-prolonging medications (www.crediblemeds.org)
  • Activity modification: Avoidance of intense exercise in high-risk individuals
  • Regular cardiac monitoring: Periodic ECG, Holter monitoring, and exercise stress testing

Tertiary Prevention (Complication Prevention)

  • Beta-blocker therapy: Reduces arrhythmia recurrence
  • Device therapy: Pacemakers prevent bradycardia-related events; ICDs prevent sudden death
  • Patient education: Awareness of triggers and emergency protocols
  • Anticoagulation: For patients with atrial fibrillation to prevent stroke

Counseling

Genetic counseling is essential and should cover: - Autosomal dominant inheritance with 50% recurrence risk - Incomplete penetrance — a positive genetic test does not guarantee symptomatic disease - Variable expressivity — family members with the same variant may have different phenotypes - Importance of cascade screening for at-risk relatives - Reproductive options including preimplantation genetic testing

14. Other Species / Natural Disease

Species Affected

No naturally occurring ankyrin-B cardiac disease has been documented in non-human species in clinical veterinary literature. However, the Ank2 gene is highly conserved across vertebrates and invertebrates.

Species Gene NCBI Taxon Notes
Mus musculus (mouse) Ank2 NCBITaxon:10090 Extensive model organism studies
Rattus norvegicus (rat) Ank2 NCBITaxon:10116 Used in electrophysiology studies
Danio rerio (zebrafish) ank2a/ank2b NCBITaxon:7955 Orthologous genes present
Drosophila melanogaster Ank2 NCBITaxon:7227 Neural ankyrin function studied
Caenorhabditis elegans unc-44 NCBITaxon:6239 Neuronal ankyrin ortholog

Comparative Biology

Ankyrin-B function is evolutionarily conserved across metazoans. The protein's roles in membrane protein targeting and calcium homeostasis appear conserved from invertebrates to humans, though the specific cardiac arrhythmia phenotype is unique to organisms with complex cardiac electrophysiology. The unc-44 ortholog in C. elegans plays roles in neuronal polarity, and Drosophila Ank2 is essential for axonal integrity, highlighting the conserved neuronal function of the ankyrin family.

Zoonotic and Transmission Considerations

Not applicable — ANK2 Ankyrin-B Syndrome is a non-infectious genetic disorder.

15. Model Organisms

Mouse Models

Ankyrin-B Heterozygous (AnkB⁺/⁻) Knockout

  • Type: Conventional heterozygous knockout
  • Phenotype recapitulation: Phenocopies major features of human ankyrin-B syndrome
  • Sinus node dysfunction with severe bradycardia and rate variability
  • Susceptibility to ventricular arrhythmias with catecholaminergic stimulation
  • Increased Ca²⁺ spark frequency and afterdepolarizations
  • Reduced NCX, NKA, and InsP3R membrane expression
  • Key references: PMID: 15178757, PMID: 18832177, PMID: 22406428
  • Limitations: Heterozygous knockout may overestimate penetrance relative to human point mutations

Ankyrin-B Homozygous (AnkB⁻/⁻) Knockout

  • Phenotype: Neonatal lethal with congenital myopathy and major thymic lymphocyte loss (PMID: 10579720)
  • Use: Studying ankyrin-B's essential developmental roles; cell-based rescue experiments
  • Key finding: Mis-sorting of SERCA2 and RyR2 in cardiomyocytes rescued by 220-kDa ankyrin-B expression

AnkB p.E1458G Knock-in (modeling human E1425G)

  • Type: Knock-in of the original disease-causing variant
  • Phenotype: At baseline, young mice show mild phenotype; stress reveals cardiac structural and electrical phenotypes (PMID: 37182735)
  • Significance: First direct test of a human ANK2 disease variant in vivo; demonstrates incomplete penetrance in animal model, paralleling human disease

AnkB p.Q1283H Knock-in

  • Type: Knock-in of human disease-associated variant
  • Phenotype: Stress-induced arrhythmias; loss of local PP2A activity causes RyR2 hyperphosphorylation
  • Therapeutic finding: Arrhythmias "may be prevented by the administration of metoprolol or flecainide" (PMID: 30571258)
  • Significance: Demonstrated therapeutic potential and identified PP2A/RyR2 as key pathomechanism

AnkB p.L1622I Knock-in

  • Type: Knock-in of common human variant
  • Phenotype: Changes in heart rate, AV and intraventricular conduction, altered repolarization, catecholamine-dependent arrhythmias, increased action potential duration, severe afterdepolarizations (PMID: 27298202)
  • Significance: Demonstrated that a common population variant can confer in vivo arrhythmia risk

Cardiac-Specific βII Spectrin Knockout

  • Phenotype: Lethal arrhythmias, aberrant calcium handling, abnormal expression/localization of NCX, RyR2, ankyrin-B, accelerated heart failure (PMID: 25632041)
  • Significance: Validates the ankyrin-B/βII spectrin pathway in cardiac physiology

EHD3 Knockout (global and cardiac-specific)

  • Phenotype: Bradycardia, rate variability, conduction block, reduced NCX and Cav1.2 expression (PMID: 24759929)
  • Significance: Identifies endosomal trafficking as a critical component of the ankyrin-B pathway

In Vitro Models

  • Primary neonatal cardiomyocytes from AnkB⁺/⁻ and AnkB⁻/⁻ mice: Used extensively for protein localization, calcium imaging, and rescue experiments (PMID: 14722080, PMID: 15262991, PMID: 11781319)
  • Adult ventricular myocytes: Used for electrophysiology, calcium spark measurements, and action potential recordings (PMID: 22406428)
  • HEK293 cells: Used for heterologous expression studies (e.g., KCNH2 trafficking with ANK2 variants; PMID: 30929919)
  • Xenopus oocytes: Used for voltage-clamp recordings of KCNH2 with ANK2 co-expression
  • iPSC-derived neurons: Used in 15q13.3 microdeletion studies involving OTUD7A-ankyrin interactions (PMID: 36604605)
  • Primary lymphoblasts: Used to confirm reduced ankyrin-B expression in translocation carriers (PMID: 27916589)

Computational Models

  • Ventricular myocyte electrophysiology models: Used to dissect the distinct contributions of NCX and NKA defects to calcium overload and afterdepolarizations; showed that NCX and NKA play "related, yet distinct, roles in intracellular Ca²⁺ accumulation, sarcoplasmic reticulum Ca²⁺ overload, and afterdepolarization generation" (PMID: 20729400)
  • SAN node models: Predict that Cav1.3 loss causes pacemaker slowing and exit block; atrial models predict reduced critical mass for reentrant AF (PMID: 23436330)

Key Evidence Base: Literature Summary

PMID Year Key Contribution Evidence Type
12571597 2003 Original identification of ANK2 E1425G causing LQT4 Human genetic + mouse model
15178757 2004 Reclassification as "ankyrin-B syndrome" distinct from classical LQTS Human clinical + mouse model
16253912 2006 High frequency of ANK2 variants in control populations Human genetic
17242276 2007 Spectrum of LOF severity across 9 ANK2 variants In vitro (cardiomyocytes)
17940615 2007 L1622I as balanced variant; enhanced contractility + senescence risk Human population + mouse
18832177 2008 Highly penetrant SND mapped to ANK2; Cav1.3 mechanism Human genetic + mouse model
22406428 2012 Enhanced Ca²⁺ spark frequency in AnkB⁺/⁻ myocytes Mouse (cellular)
23059182 2012 CaMKII-dependent RyR2 hyperphosphorylation; CaMKII inhibition rescue Mouse model
23436330 2013 Computational model: Cav1.3 loss → AF susceptibility Computational
25632041 2015 βII spectrin/ankyrin-B interaction in arrhythmogenesis Human + mouse
27298202 2016 L1622I knock-in mouse: in vivo arrhythmia phenotypes Mouse knock-in
27916589 2016 Chromosomal translocation as novel mechanism Human genetic
27784853 2016 Phenotypic variability in Japanese IPAS cohort Human clinical
28765088 2017 Comprehensive review of ankyrin-B in cardiovascular disease Review
30571258 2018 Q1283H knock-in: metoprolol and flecainide efficacy Mouse knock-in
30929919 2019 ANK2-KCNH2 functional interaction aggravating LQTS Human + in vitro
30949686 2019 NKAα2/AnkB/NCX functional domain in cardiomyocytes Mouse (cellular)
31983240 2020 ClinGen reappraisal: ANK2 limited/disputed for LQTS Expert panel evaluation
34557911 2022 ClinGen: ANK2 variants too common for CPVT causation Expert panel evaluation
37182735 2023 E1458G knock-in mouse: stress-dependent penetrance Mouse knock-in

Limitations and Knowledge Gaps

  1. Incomplete penetrance mechanisms unknown: The molecular basis for why some ANK2 LOF variant carriers are asymptomatic while others have severe disease is not understood. Modifier genes, epigenetic factors, and environmental modulators likely contribute but are not characterized.

  2. ClinGen dispute creates clinical confusion: The classification of ANK2 as having "limited/disputed evidence" for LQTS creates a challenging clinical scenario where strong experimental evidence coexists with population-level concerns about variant pathogenicity. A revised framework beyond traditional channelopathy classification may be needed.

  3. Absence of natural history studies: No prospective longitudinal cohort studies have been conducted specifically for ankyrin-B syndrome. The natural history, penetrance rates, and complication rates remain poorly defined.

  4. Limited genotype-phenotype correlations: While variant severity has been characterized in vitro, the clinical correlation remains imprecise. The same variant can produce different phenotypes in different family members.

  5. No established prevalence data: The true population prevalence of clinically significant ANK2 variants is unknown, complicated by the high frequency of ANK2 variants in control populations.

  6. Neurological and extracardiac roles underexplored: Ankyrin-B has critical functions in neurons (axon guidance, growth cone navigation) and other tissues (skeletal muscle, thymus, pancreatic β-cells), but potential extracardiac manifestations of ANK2 variants in humans are largely unexplored.

  7. No disease-specific biomarkers: There are no circulating biomarkers to identify at-risk individuals or monitor disease progression beyond ECG parameters.

  8. Treatment evidence limited to preclinical data: Beta-blocker and flecainide efficacy has been demonstrated only in mouse knock-in models; no clinical trials have been conducted specifically for ankyrin-B syndrome.

  9. Epigenetic regulation unknown: While alternative splicing of ankyrin-B is documented (PMID: 18782775), the epigenetic regulation of ANK2 expression and its contribution to disease variability remains unexplored.

  10. Acquired ankyrin-B dysfunction: Post-myocardial infarction remodeling of ankyrin-B has been observed, but the clinical significance of acquired ankyrin-B dysfunction in common cardiac disease is unclear.

Proposed Follow-up Experiments / Actions

  1. Prospective international registry: Establish an international ANK2 variant carrier registry to collect standardized phenotype data, track natural history, and define penetrance rates across variants and populations.

  2. Functional classification pipeline: Develop a high-throughput iPSC-cardiomyocyte assay platform to systematically classify all reported ANK2 variants by functional severity (wild-type, mild LOF, severe LOF), enabling evidence-based clinical interpretation.

  3. CaMKII inhibitor clinical development: Given the strong preclinical evidence that CaMKII inhibition rescues arrhythmia phenotypes in AnkB⁺/⁻ mice (PMID: 23059182), pursue pharmacological development of CaMKII-selective inhibitors for clinical testing in ankyrin-B syndrome.

  4. Modifier gene discovery: Perform whole-genome sequencing and genome-wide association studies in phenotyped ANK2 variant carriers to identify genetic modifiers of penetrance and expressivity.

  5. Extracardiac phenotyping: Systematically evaluate neurological, musculoskeletal, and immune function in ANK2 variant carriers to determine whether extracardiac manifestations observed in mouse models (neonatal myopathy, thymic lymphocyte loss, neuronal defects) translate to subclinical human phenotypes.

  6. Population-specific studies: Conduct targeted studies in populations with high ANK2 variant frequency (West African, First Nations) to determine the clinical significance of common variants like L1622I in these ancestral contexts and whether additional genetic or environmental modifiers explain variable risk.

  7. Updated ClinGen gene curation: Collaborate with ClinGen to refine the gene-disease relationship using the "ankyrin-B syndrome" framework rather than classical LQTS/CPVT categories, which may more accurately capture the evidence and prevent misleading clinical interpretations.

  8. Single-cell and spatial transcriptomics: Perform single-cell RNA-seq and spatial transcriptomics on AnkB⁺/⁻ hearts at multiple developmental stages to identify cell-type-specific transcriptional changes, potential compensatory mechanisms, and novel therapeutic targets.

  9. Clinical trial for beta-blockers: Design a prospective clinical trial of beta-blocker therapy in ANK2 variant carriers with documented arrhythmias, using validated endpoints including arrhythmia burden reduction and quality of life measures.

  10. Gene therapy exploration: Investigate AAV-based or RNA-based therapeutic strategies for ankyrin-B restoration, potentially using truncated functional domains or antisense oligonucleotides to enhance expression from the remaining wild-type allele.

Report generated: 2026-05-05 Based on systematic review of 43 peer-reviewed publications Disease: ANK2 Ankyrin-B Syndrome (MONDO:0010958; OMIM:600919)