ANK2-related ankyrin-B syndrome encompasses a spectrum of cardiac and neurodevelopmental phenotypes caused by loss-of-function variants in the ANK2 gene encoding ankyrin-B. Ankyrin-B is a scaffolding protein that anchors ion channels and transporters (Na/Ca exchanger, Na/K ATPase, InsP3 receptor) at transverse-tubule/sarcoplasmic reticulum sites in cardiomyocytes, and regulates axonal development and synaptic organization in neurons. Cardiac manifestations include bradycardia, sinus arrhythmia, ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death. The condition was originally classified as long QT syndrome type 4 (LQT4), but prolonged QT interval is not a consistent feature, and ankyrin-B dysfunction is now recognized as a distinct clinical entity. Neurodevelopmental manifestations, primarily associated with de novo loss-of-function variants, include intellectual disability, autism spectrum disorder, and early-onset epilepsy. Inheritance is autosomal dominant with incomplete penetrance and variable expressivity. This entry absorbs 4 Gene2Phenotype rows for ANK2: disputed Brugada syndrome, disputed CPVT, disputed long QT syndrome, and limited neurodevelopmental disorder (LOF).
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name: ANK2 Ankyrin-B Syndrome
creation_date: '2026-04-04T00:00:00Z'
updated_date: '2026-05-05T08:31:14Z'
description: >-
ANK2-related ankyrin-B syndrome encompasses a spectrum of cardiac and
neurodevelopmental phenotypes caused by loss-of-function variants in the ANK2
gene encoding ankyrin-B. Ankyrin-B is a scaffolding protein that anchors ion
channels and transporters (Na/Ca exchanger, Na/K ATPase, InsP3 receptor) at
transverse-tubule/sarcoplasmic reticulum sites in cardiomyocytes, and
regulates axonal development and synaptic organization in neurons. Cardiac
manifestations include bradycardia, sinus arrhythmia, ventricular
fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk
of sudden death. The condition was originally classified as long QT syndrome
type 4 (LQT4), but prolonged QT interval is not a consistent feature, and
ankyrin-B dysfunction is now recognized as a distinct clinical entity.
Neurodevelopmental manifestations, primarily associated with de novo
loss-of-function variants, include intellectual disability, autism spectrum
disorder, and early-onset epilepsy. Inheritance is autosomal dominant with
incomplete penetrance and variable expressivity. This entry absorbs 4
Gene2Phenotype rows for ANK2: disputed Brugada syndrome, disputed CPVT,
disputed long QT syndrome, and limited neurodevelopmental disorder (LOF).
synonyms:
- ankyrin-B syndrome
- LQT4
- long QT syndrome type 4
- cardiac arrhythmia, ankyrin-B-related
category: Genetic
disease_term:
preferred_term: cardiac arrhythmia, ankyrin-B-related
term:
id: MONDO:0010958
label: cardiac arrhythmia, ankyrin-B-related
parents:
- Cardiac Arrhythmia
- Channelopathy
- Neurodevelopmental Disorder
inheritance:
- name: Autosomal dominant
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: Establishes dominant inheritance of ANK2-related cardiac arrhythmia.
pathophysiology:
- name: Disrupted Ion Channel and Transporter Localization in Cardiomyocytes
description: >-
Ankyrin-B is required for coordinated assembly of the Na/Ca exchanger, Na/K
ATPase, and inositol trisphosphate receptor at transverse-tubule/sarcoplasmic
reticulum sites in cardiomyocytes. Loss-of-function mutations disrupt this
scaffolding, reducing the targeting and expression of these proteins at the
transverse tubules, which alters calcium signaling and produces extrasystoles
that predispose to arrhythmias.
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
- 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 that ankyrin-B mutation disrupts the localization of multiple
ion channels and transporters at T-tubule/SR sites in cardiomyocytes.
- 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: >-
Links ankyrin-B mutation to altered calcium signaling and extrasystoles as
the mechanism underlying arrhythmia.
downstream:
- target: Cardiac Arrhythmia Susceptibility
description: >-
Abnormal calcium signaling due to mislocalized ion channels and
transporters produces extrasystoles that can trigger ventricular
arrhythmias, bradycardia, and ventricular fibrillation.
- name: Cardiac Arrhythmia Susceptibility
description: >-
Loss of ankyrin-B function produces a broad spectrum of cardiac arrhythmias
including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation,
catecholaminergic polymorphic ventricular tachycardia, and risk of sudden
cardiac death. The clinical phenotype is variable, with some mutation carriers
showing QT prolongation while others do not, establishing this as a distinct
entity from classic long QT syndrome.
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: >-
Defines the broad cardiac arrhythmia spectrum associated with ankyrin-B
loss of function.
- reference: PMID:15178757
reference_title: A cardiac arrhythmia syndrome caused by loss of ankyrin-B function.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
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 that ankyrin-B syndrome is distinct from classic long QT
syndrome despite the historical LQT4 designation.
- name: Impaired Axonal Development and AIS Structure
description: >-
The neurospecific giant ankyrin-B (440 kDa) isoform normally limits axon
branching through interaction with L1CAM and cortical microtubules. Loss of
giant ankyrin-B promotes ectopic axon branching, aberrant connectivity, and
impaired axon initial segment (AIS) structure and plasticity. These
structural defects alter neuronal circuit formation during development.
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: axonogenesis
term:
id: GO:0007409
label: axonogenesis
modifier: DYSREGULATED
locations:
- preferred_term: brain
term:
id: UBERON:0000955
label: brain
evidence:
- reference: PMID:31285321
reference_title: >-
ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and
ectopic connectivity.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We report that a mouse model for human ASD mutation of giant ankB
exhibits increased axonal branching in cultured neurons with ectopic CNS
axon connectivity, as well as with a transient increase in excitatory
synapses during postnatal development.
explanation: >-
Directly demonstrates that giant ankyrin-B mutation promotes increased
axon branching and ectopic connectivity in the mouse model.
downstream:
- target: Neuronal Network Hyperactivity
description: >-
Aberrant axonal connectivity and impaired AIS plasticity lead to
hyperactive and desynchronized neuronal networks.
- name: Neuronal Network Hyperactivity
description: >-
De novo loss-of-function ANK2 variants lead to hyperactive and
desynchronized neuronal networks with increased somatodendritic complexity.
Impaired axon initial segment plasticity prevents normal homeostatic
regulation of neuronal excitability, contributing to seizure susceptibility
and neurodevelopmental dysfunction.
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
locations:
- preferred_term: brain
term:
id: UBERON:0000955
label: brain
evidence:
- reference: PMID:37195288
reference_title: >-
ANK2 loss-of-function variants are associated with epilepsy, and lead to
impaired axon initial segment plasticity and hyperactive network activity
in hiPSC-derived neuronal networks.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
hiPSC-derived neurons with heterozygous LoF of ANK2 show a hyperactive
and desynchronized neuronal network
explanation: >-
Demonstrates that ANK2 haploinsufficiency in human neurons leads to
hyperactive network activity.
downstream:
- target: Neurodevelopmental Phenotypes
description: >-
Hyperactive neuronal networks and impaired homeostatic plasticity
contribute to intellectual disability, autism spectrum disorder, and
epilepsy.
- name: Neurodevelopmental Phenotypes
description: >-
De novo loss-of-function ANK2 variants cause a broad neurodevelopmental
disorder comprising intellectual disability, autism spectrum disorder, and
early-onset epilepsy. The neurodevelopmental phenotype is distinct from the
cardiac phenotype and is primarily associated with truncating or frameshift
variants affecting the giant ankyrin-B isoform.
evidence:
- reference: PMID:37195288
reference_title: >-
ANK2 loss-of-function variants are associated with epilepsy, and lead to
impaired axon initial segment plasticity and hyperactive network activity
in hiPSC-derived neuronal networks.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found a broad neurodevelopmental disorder (NDD), comprising intellectual
disability, autism spectrum disorders and early onset epilepsy
explanation: >-
Clinical characterization of 12 patients with ANK2 LOF variants defines
the neurodevelopmental phenotype spectrum.
- reference: PMID:39631164
reference_title: >-
Roles of ANK2/ankyrin-B in neurodevelopmental disorders: Isoform functions
and implications for autism spectrum disorder and epilepsy.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The ANK2 gene, encoding ankyrin-B, is a high-confidence risk factor for
neurodevelopmental disorders (NDDs)
explanation: >-
Establishes ANK2 as a high-confidence NDD risk gene based on cumulative
exome sequencing evidence.
phenotypes:
- category: Cardiovascular
name: Bradycardia
description: >-
Slower than normal heart rate is a common cardiac manifestation of ankyrin-B
syndrome, reflecting disrupted cardiac conduction.
frequency: FREQUENT
phenotype_term:
preferred_term: Bradycardia
term:
id: HP:0001662
label: 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: >-
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: Bradycardia is listed among the cardiac manifestations of ankyrin-B syndrome.
- category: Cardiovascular
name: Ventricular Fibrillation
description: >-
Idiopathic ventricular fibrillation can occur in ankyrin-B syndrome,
representing a severe arrhythmia with risk of sudden cardiac death.
frequency: OCCASIONAL
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: Idiopathic ventricular fibrillation is a recognized cardiac manifestation.
- category: Cardiovascular
name: Ventricular Tachycardia
description: >-
Catecholaminergic polymorphic ventricular tachycardia has been reported in
ankyrin-B syndrome carriers, though the specific association with CPVT is
disputed in Gene2Phenotype.
frequency: OCCASIONAL
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: CPVT is part of the arrhythmia spectrum in ankyrin-B syndrome.
- category: Cardiovascular
name: Prolonged QT Interval
description: >-
QT prolongation was the originally described feature leading to the LQT4
designation, but it is not a consistent feature of ankyrin-B syndrome.
Penetrance and expressivity are highly variable.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Prolonged QT interval
term:
id: HP:0001657
label: Prolonged QT interval
evidence:
- reference: PMID:15178757
reference_title: A cardiac arrhythmia syndrome caused by loss of ankyrin-B function.
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
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: >-
QT prolongation occurs in some but not all carriers, hence the reclassification
from LQT4 to ankyrin-B syndrome.
- category: Cardiovascular
name: Cardiac Arrhythmia
description: >-
A broad predisposition to cardiac arrhythmias including supraventricular and
ventricular arrhythmias is the hallmark cardiac feature. The specific
arrhythmia type varies among carriers.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Arrhythmia
term:
id: HP:0011675
label: Arrhythmia
evidence:
- reference: PMID:35990955
reference_title: Mechanisms underlying the role of ankyrin-B in cardiac and neurological health and disease.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Certain loss-of-function ANK2 variants are associated with a primarily
cardiac-presenting autosomal-dominant condition with incomplete penetrance
and variable expressivity characterized by a predisposition to
supraventricular and ventricular arrhythmias, arrhythmogenic
cardiomyopathy, congenital and adult-onset structural heart disease, and
sudden death
explanation: >-
Comprehensive review establishing the broad arrhythmia susceptibility in
ankyrin-B syndrome.
- category: Cardiovascular
name: Syncope
description: >-
Transient loss of consciousness due to arrhythmia-mediated cerebral
hypoperfusion, often stress- or exercise-induced.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Syncope
term:
id: HP:0001279
label: Syncope
evidence:
- reference: PMID:17242276
reference_title: >-
Defining the cellular phenotype of "ankyrin-B syndrome" variants: human
ANK2 variants associated with clinical phenotypes display a spectrum of
activities in cardiomyocytes.
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
the clinical phenotypes associated with these variants vary strikingly,
from no obvious phenotype to manifest long-QT syndrome and sudden death
explanation: >-
Snippet describes the clinical severity spectrum but does not explicitly
mention syncope; syncope is inferred as an intermediate presentation
between asymptomatic carriers and sudden death.
- category: Cardiovascular
name: Sudden Cardiac Death
description: >-
Risk of sudden cardiac death due to severe ventricular arrhythmias is the
most feared complication of ankyrin-B syndrome.
frequency: OCCASIONAL
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: >-
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: Sudden death is a recognized risk of ankyrin-B syndrome.
- category: Neurological
name: Epilepsy
description: >-
Early-onset epilepsy is a core feature of the neurodevelopmental phenotype
associated with de novo ANK2 loss-of-function variants. Seizures are often
self-limited and pharmaco-responsive.
frequency: FREQUENT
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:37195288
reference_title: >-
ANK2 loss-of-function variants are associated with epilepsy, and lead to
impaired axon initial segment plasticity and hyperactive network activity
in hiPSC-derived neuronal networks.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found a broad neurodevelopmental disorder (NDD), comprising intellectual
disability, autism spectrum disorders and early onset epilepsy
explanation: >-
Clinical cohort of 12 patients with ANK2 LOF variants shows early-onset
epilepsy as a core feature.
- category: Neurological
name: Intellectual Disability
description: >-
Intellectual disability of variable severity is part of the
neurodevelopmental disorder associated with de novo ANK2 loss-of-function
variants.
frequency: FREQUENT
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:37195288
reference_title: >-
ANK2 loss-of-function variants are associated with epilepsy, and lead to
impaired axon initial segment plasticity and hyperactive network activity
in hiPSC-derived neuronal networks.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found a broad neurodevelopmental disorder (NDD), comprising intellectual
disability, autism spectrum disorders and early onset epilepsy
explanation: >-
Intellectual disability is a core feature of the ANK2-associated
neurodevelopmental syndrome.
- category: Neurological
name: Autism Spectrum Disorder
description: >-
Autism spectrum disorder features are associated with ANK2 variants,
particularly those affecting the neurospecific giant ankyrin-B isoform.
ANK2 is a high-confidence ASD risk gene. Notably, some ANK2-related ASD
can occur with normal IQ.
frequency: FREQUENT
phenotype_term:
preferred_term: Autistic behavior
term:
id: HP:0000729
label: Autistic behavior
evidence:
- reference: PMID:39631164
reference_title: >-
Roles of ANK2/ankyrin-B in neurodevelopmental disorders: Isoform functions
and implications for autism spectrum disorder and epilepsy.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Evidence from exome sequencing studies have repeatedly implicated rare
variants in ANK2 in autism spectrum disorder
explanation: ANK2 is established as a high-confidence ASD risk gene.
- reference: PMID:31285321
reference_title: >-
ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and
ectopic connectivity.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Giant ankB mutation or deficiency results in a dominantly inherited
impairment in selected communicative and social behaviors combined with
superior executive function
explanation: >-
Mouse model recapitulates social and communicative behavioral deficits
relevant to ASD.
genetic:
- name: ANK2 loss-of-function variants (cardiac)
association: Causative
features: >-
Missense loss-of-function variants in the ANK2 regulatory domain cause the
cardiac arrhythmia phenotype. These variants abolish the ability of ankyrin-B
to restore normal calcium dynamics and normal localization of Na/Ca exchanger,
Na/K ATPase, and InsP3 receptor. Nine human ANK2 loss-of-function variants
have been identified, displaying a spectrum of cellular phenotypes from
wild-type to severe loss of function. The cardiac phenotype shows autosomal
dominant inheritance with incomplete penetrance and variable expressivity.
The associations with specific arrhythmia subtypes (Brugada, CPVT, long QT)
are disputed in Gene2Phenotype.
gene_term:
preferred_term: ANK2
term:
id: hgnc:493
label: ANK2
evidence:
- reference: PMID:17242276
reference_title: >-
Defining the cellular phenotype of "ankyrin-B syndrome" variants: human
ANK2 variants associated with clinical phenotypes display a spectrum of
activities in cardiomyocytes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Including the 4 new variants, 9 human ANK2 loss-of-function variants have
been identified. However, the clinical phenotypes associated with these
variants vary strikingly, from no obvious phenotype to manifest long-QT
syndrome and sudden death
explanation: >-
Comprehensive characterization of ANK2 variants establishes the spectrum
of cardiac phenotypes and cellular loss-of-function activity.
- reference: PMID:15178757
reference_title: A cardiac arrhythmia syndrome caused by loss of ankyrin-B function.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
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: >-
Establishes the molecular mechanism: all cardiac-associated mutations impair
ankyrin-B scaffolding function for ion channels and transporters.
- name: ANK2 loss-of-function variants (neurodevelopmental)
association: Causative
features: >-
De novo truncating and frameshift variants in ANK2 cause a neurodevelopmental
disorder comprising intellectual disability, autism spectrum disorder, and
early-onset epilepsy. The giant ankyrin-B isoform (440 kDa), expressed
exclusively in the nervous system, is particularly important for axonal
development. ANK2 is a high-confidence autism risk gene based on multiple
exome sequencing studies. This is the best-supported association in the
Gene2Phenotype curation (limited evidence for LOF mechanism).
gene_term:
preferred_term: ANK2
term:
id: hgnc:493
label: ANK2
evidence:
- reference: PMID:37195288
reference_title: >-
ANK2 loss-of-function variants are associated with epilepsy, and lead to
impaired axon initial segment plasticity and hyperactive network activity
in hiPSC-derived neuronal networks.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Phenotypic characterization of patients with de novo ANK2 LoF variants
defines a novel NDD with early onset epilepsy
explanation: >-
Defines the neurodevelopmental phenotype of de novo ANK2 loss-of-function
variants in a cohort of 12 patients.
- reference: PMID:39631164
reference_title: >-
Roles of ANK2/ankyrin-B in neurodevelopmental disorders: Isoform functions
and implications for autism spectrum disorder and epilepsy.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The ANK2 gene, encoding ankyrin-B, is a high-confidence risk factor for
neurodevelopmental disorders (NDDs)
explanation: >-
Review establishing ANK2 as a high-confidence NDD risk gene based on
cumulative genetic evidence.
treatments:
- name: Beta-Blocker Therapy
description: >-
Beta-blockers are used for arrhythmia management in ankyrin-B syndrome,
analogous to their use in other cardiac channelopathies. Exercise restriction
and avoidance of QT-prolonging drugs may also be recommended.
treatment_term:
preferred_term: beta-blocker therapy
term:
id: NCIT:C15986
label: Pharmacotherapy
notes: >-
Beta-blocker use is inferred from standard cardiac channelopathy management
practice. No direct evidence for beta-blocker efficacy in ankyrin-B syndrome
was found in the cited literature.
- name: Genetic Counseling
description: >-
Genetic counseling is important for families with ANK2 variants, given the
autosomal dominant inheritance, incomplete penetrance, and the dual cardiac
and neurodevelopmental phenotype spectrum. Family screening with ECG and
genetic testing is recommended for at-risk relatives.
treatment_term:
preferred_term: genetic counseling
term:
id: MAXO:0000079
label: genetic counseling
evidence:
- reference: PMID:17242276
reference_title: >-
Defining the cellular phenotype of "ankyrin-B syndrome" variants: human
ANK2 variants associated with clinical phenotypes display a spectrum of
activities in cardiomyocytes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the clinical phenotypes associated with these variants vary strikingly,
from no obvious phenotype to manifest long-QT syndrome and sudden death,
suggesting that mutants confer a spectrum of cellular phenotypes
explanation: >-
The extreme clinical variability necessitates careful genetic counseling
for variant carriers and their families.
notes: >-
This entry lumps 4 Gene2Phenotype rows for ANK2. (1) Brugada syndrome
(disputed): the association of ANK2 with Brugada syndrome is disputed and
not well established. (2) CPVT (disputed): while CPVT-like arrhythmias
occur in ankyrin-B syndrome, ANK2 is not a canonical CPVT gene. (3) Long QT
syndrome (disputed): ANK2 was originally classified as LQT4, but QT
prolongation is inconsistent, and the condition is now recognized as a
distinct entity. (4) Neurodevelopmental disorder (limited, LOF): this is
the best-supported G2P association, with de novo loss-of-function variants
causing intellectual disability, ASD, and epilepsy. The cardiac and
neurodevelopmental phenotypes appear to involve different variant types:
cardiac phenotypes associate with missense variants in the regulatory domain,
while NDD phenotypes associate with de novo truncating variants affecting
the giant ankyrin-B isoform.
references:
- reference: DOI:10.1016/j.hrthm.2015.11.013
title: Genetic testing and genetic counseling in patients with sudden death risk due to heritable arrhythmias
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-falcon.md
findings:
- statement: Genetic testing and genetic counseling in patients with sudden death risk due to heritable arrhythmias
supporting_text: Genetic testing and genetic counseling in patients with sudden death risk due to heritable arrhythmias
- reference: DOI:10.1016/j.hrthm.2017.07.032
title: The evolving role of ankyrin-B in cardiovascular disease
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-falcon.md
findings:
- statement: The evolving role of ankyrin-B in cardiovascular disease
supporting_text: The evolving role of ankyrin-B in cardiovascular disease
- reference: DOI:10.1073/pnas.0805500105
title: Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-falcon.md
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: The identification of nearly a dozen ion channel genes involved in the genesis of human atrial and ventricular arrhythmias has been critical for the diagnosis and treatment of fatal cardiovascular diseases.
supporting_text: The identification of nearly a dozen ion channel genes involved in the genesis of human atrial and ventricular arrhythmias has been critical for the diagnosis and treatment of fatal cardiovascular diseases.
- reference: DOI:10.1152/ajpheart.00503.2010
title: 'Defining new insight into atypical arrhythmia: a computational model of ankyrin-B syndrome'
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-falcon.md
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: Normal cardiac excitability depends on the coordinated activity of specific ion channels and transporters within specialized domains at the plasma membrane and sarcoplasmic reticulum.
supporting_text: Normal cardiac excitability depends on the coordinated activity of specific ion channels and transporters within specialized domains at the plasma membrane and sarcoplasmic reticulum.
- reference: DOI:10.1161/circgen.119.002851
title: Established Loss-of-Function Variants in <i>ANK2</i> -Encoded Ankyrin-B Rarely Cause a Concerning Cardiac Phenotype in Humans
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-falcon.md
findings:
- statement: Established Loss-of-Function Variants in <i>ANK2</i> -Encoded Ankyrin-B Rarely Cause a Concerning Cardiac Phenotype in Humans
supporting_text: Established Loss-of-Function Variants in <i>ANK2</i> -Encoded Ankyrin-B Rarely Cause a Concerning Cardiac Phenotype in Humans
- 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
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-falcon.md
findings:
- statement: — Long QT syndrome confers susceptibility to ventricular arrhythmia, predisposing to syncope, seizures, and sudden death.
supporting_text: — Long QT syndrome confers susceptibility to ventricular arrhythmia, predisposing to syncope, seizures, and sudden death.
- reference: DOI:10.1161/circresaha.110.224592
title: Defining a New Paradigm for Human Arrhythmia Syndromes
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-falcon.md
findings:
- statement: Defining a New Paradigm for Human Arrhythmia Syndromes
supporting_text: Over the past 15 years, gene mutations in cardiac ion channels have been linked to a host of potentially fatal human arrhythmias including long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia.
- reference: DOI:10.1161/circulationaha.111.023986
title: Defects in Ankyrin-Based Membrane Protein Targeting Pathways Underlie Atrial Fibrillation
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-falcon.md
findings:
- statement: — Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting >2 million patients in the United States alone.
supporting_text: — Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting >2 million patients in the United States alone.
- reference: DOI:10.1161/circulationaha.118.034541
title: Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-falcon.md
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: Human loss-of-function variants of ANK2 (ankyrin-B) are linked to arrhythmias and sudden cardiac death.
supporting_text: Human loss-of-function variants of ANK2 (ankyrin-B) are linked to arrhythmias and sudden cardiac death.
- reference: DOI:10.1172/jci125538
title: Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-falcon.md
findings:
- statement: Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy
supporting_text: Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy
- reference: DOI:10.2147/tacg.s438957
title: A New Inherited Syndrome Causing Sudden Cardiac Death with Distinct ST-Segment Depression and Ankyrin-2-Mutation
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-falcon.md
findings:
- statement: A New Inherited Syndrome Causing Sudden Cardiac Death with Distinct ST-Segment Depression and Ankyrin-2-Mutation
supporting_text: A New Inherited Syndrome Causing Sudden Cardiac Death with Distinct ST-Segment Depression and Ankyrin-2-Mutation
- reference: DOI:10.3390/biom10020211
title: 'Mechanisms and Alterations of Cardiac Ion Channels Leading to Disease: Role of Ankyrin-B in Cardiac Function'
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-falcon.md
findings:
- statement: Ankyrin-B (encoded by ANK2), originally identified as a key cytoskeletal-associated protein in the brain, is highly expressed in the heart and plays critical roles in cardiac physiology and cell biology.
supporting_text: Ankyrin-B (encoded by ANK2), originally identified as a key cytoskeletal-associated protein in the brain, is highly expressed in the heart and plays critical roles in cardiac physiology and cell biology.
- reference: DOI:10.3390/cardiogenetics14020007
title: A Single Nucleotide Variant in Ankyrin-2 Influencing Ventricular Tachycardia in COVID-19 Associated Myocarditis
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-falcon.md
findings:
- statement: This paper explores the potential influence of a single nucleotide variant in the ANK-2 gene on COVID-19 myocarditis-related ventricular tachycardia.
supporting_text: This paper explores the potential influence of a single nucleotide variant in the ANK-2 gene on COVID-19 myocarditis-related ventricular tachycardia.
- reference: PMID:10579720
title: Ankyrin-B is required for intracellular sorting of structurally diverse Ca2+ homeostasis proteins.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '1999 Nov 29;147(5):995-1008. doi: 10.1083/jcb.147.5.995.'
supporting_text: '1999 Nov 29;147(5):995-1008. doi: 10.1083/jcb.147.5.995.'
- reference: PMID:11781319
title: The ankyrin-B C-terminal domain determines activity of ankyrin-B/G chimeras in rescue of abnormal inositol 1,4,5-trisphosphate and ryanodine receptor distribution in ankyrin-B (-/-) neonatal cardiomyocytes.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2002 Mar 22;277(12):10599-607. doi: 10.1074/jbc.M110958200.'
supporting_text: '2002 Mar 22;277(12):10599-607. doi: 10.1074/jbc.M110958200.'
- reference: PMID:14722080
title: Inositol 1,4,5-trisphosphate receptor localization and stability in neonatal cardiomyocytes requires interaction with ankyrin-B.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2004 Mar 26;279(13):12980-7. doi: 10.1074/jbc.M313979200.'
supporting_text: '2004 Mar 26;279(13):12980-7. doi: 10.1074/jbc.M313979200.'
- reference: PMID:15262991
title: Ankyrin-B targets beta2-spectrin to an intracellular compartment in neonatal cardiomyocytes.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2004 Sep 17;279(38):40185-93. doi: 10.1074/jbc.M406018200.'
supporting_text: '2004 Sep 17;279(38):40185-93. doi: 10.1074/jbc.M406018200.'
- reference: PMID:16253912
title: Targeted mutational analysis of ankyrin-B in 541 consecutive, unrelated patients referred for long QT syndrome genetic testing and 200 healthy subjects.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: Mutations in ANK2-encoded ankyrin-B underlie long QT syndrome type 4 (LQT4) and various other dysrhythmia phenotypes.
supporting_text: Mutations in ANK2-encoded ankyrin-B underlie long QT syndrome type 4 (LQT4) and various other dysrhythmia phenotypes.
- reference: PMID:17416611
title: Molecular basis for PP2A regulatory subunit B56alpha targeting in cardiomyocytes.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2007 Jul;293(1):H109-19. doi: 10.1152/ajpheart.00059.2007.'
supporting_text: '2007 Jul;293(1):H109-19. doi: 10.1152/ajpheart.00059.2007.'
- reference: PMID:17940615
title: 'Ankyrin-B syndrome: enhanced cardiac function balanced by risk of cardiac death and premature senescence.'
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2007 Oct 17;2(10):e1051. doi: 10.1371/journal.pone.0001051.'
supporting_text: '2007 Oct 17;2(10):e1051. doi: 10.1371/journal.pone.0001051.'
- reference: PMID:18782775
title: Obscurin targets ankyrin-B and protein phosphatase 2A to the cardiac M-line.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2008 Nov 14;283(46):31968-80. doi: 10.1074/jbc.M806050200.'
supporting_text: '2008 Nov 14;283(46):31968-80. doi: 10.1074/jbc.M806050200.'
- reference: PMID:19110015
title: The cell adhesion molecule L1 controls growth cone navigation via ankyrin(B)-dependent modulation of cyclic AMP.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2009 Mar;63(3):224-6. doi: 10.1016/j.neures.2008.11.009.'
supporting_text: '2009 Mar;63(3):224-6. doi: 10.1016/j.neures.2008.11.009.'
- reference: PMID:19394342
title: Cardiac ankyrins in health and disease.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2009 Aug;47(2):203-9. doi: 10.1016/j.yjmcc.2009.04.010.'
supporting_text: '2009 Aug;47(2):203-9. doi: 10.1016/j.yjmcc.2009.04.010.'
- reference: PMID:19530973
title: 'Genetic variation in the rhythmonome: ethnic variation and haplotype structure in candidate genes for arrhythmias.'
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2009 Jun;10(6):1043-53. doi: 10.2217/pgs.09.67.'
supporting_text: '2009 Jun;10(6):1043-53. doi: 10.2217/pgs.09.67.'
- reference: PMID:22406428
title: Ankyrin-B reduction enhances Ca spark-mediated SR Ca release promoting cardiac myocyte arrhythmic activity.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2012 Jun;52(6):1240-8. doi: 10.1016/j.yjmcc.2012.02.010.'
supporting_text: '2012 Jun;52(6):1240-8. doi: 10.1016/j.yjmcc.2012.02.010.'
- reference: PMID:23059182
title: CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: Cardiovascular disease is a leading cause of death worldwide.
supporting_text: Cardiovascular disease is a leading cause of death worldwide.
- reference: PMID:23436330
title: 'Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis.'
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2013 May;304(9):H1253-66. doi: 10.1152/ajpheart.00734.2012.'
supporting_text: '2013 May;304(9):H1253-66. doi: 10.1152/ajpheart.00734.2012.'
- reference: PMID:24759929
title: EHD3-dependent endosome pathway regulates cardiac membrane excitability and physiology.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2014 Jun 20;115(1):68-78. doi: 10.1161/CIRCRESAHA.115.304149.'
supporting_text: '2014 Jun 20;115(1):68-78. doi: 10.1161/CIRCRESAHA.115.304149.'
- reference: PMID:25456501
title: 'Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult.'
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2015 Feb;24(2):e31-4. doi: 10.1016/j.hlc.2014.09.013.'
supporting_text: '2015 Feb;24(2):e31-4. doi: 10.1016/j.hlc.2014.09.013.'
- reference: PMID:25632041
title: Dysfunction in the βII spectrin-dependent cytoskeleton underlies human arrhythmia.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease.
supporting_text: The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease.
- reference: PMID:27298202
title: Common human ANK2 variant confers in vivo arrhythmia phenotypes.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: Human ANK2 (ankyrin-B) loss-of-function variants are directly linked with arrhythmia phenotypes.
supporting_text: Human ANK2 (ankyrin-B) loss-of-function variants are directly linked with arrhythmia phenotypes.
- reference: PMID:27784853
title: Phenotypic Variability of ANK2 Mutations in Patients With Inherited Primary Arrhythmia Syndromes.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: Mutations inANK2have been reported to cause various arrhythmia phenotypes.
supporting_text: Mutations inANK2have been reported to cause various arrhythmia phenotypes.
- reference: PMID:27916589
title: A Novel Mechanism for Human Cardiac Ankyrin-B Syndrome due to Reciprocal Chromosomal Translocation.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: Cardiac rhythm abnormalities are a leading cause of morbidity and mortality in developed countries.
supporting_text: Cardiac rhythm abnormalities are a leading cause of morbidity and mortality in developed countries.
- reference: PMID:28196901
title: 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.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: Long QT syndrome confers susceptibility to ventricular arrhythmia, predisposing to syncope, seizures, and sudden death.
supporting_text: Long QT syndrome confers susceptibility to ventricular arrhythmia, predisposing to syncope, seizures, and sudden death.
- reference: PMID:30929919
title: ANK2 functionally interacts with KCNH2 aggravating long QT syndrome in a double mutation carrier.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2019 May 14;512(4):845-851. doi: 10.1016/j.bbrc.2019.03.162.'
supporting_text: '2019 May 14;512(4):845-851. doi: 10.1016/j.bbrc.2019.03.162.'
- reference: PMID:30949686
title: Coupling of the Na+/K+-ATPase to Ankyrin B controls Na+/Ca2+ exchanger activity in cardiomyocytes.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2020 Jan 1;116(1):78-90. doi: 10.1093/cvr/cvz087.'
supporting_text: '2020 Jan 1;116(1):78-90. doi: 10.1093/cvr/cvz087.'
- reference: PMID:31983240
title: An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia.
supporting_text: Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia.
- reference: PMID:34557911
title: Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2022 Apr 14;43(15):1500-1510. doi: 10.1093/eurheartj/ehab687.'
supporting_text: '2022 Apr 14;43(15):1500-1510. doi: 10.1093/eurheartj/ehab687.'
- reference: PMID:36604605
title: Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2023 Apr;28(4):1747-1769. doi: 10.1038/s41380-022-01937-5.'
supporting_text: '2023 Apr;28(4):1747-1769. doi: 10.1038/s41380-022-01937-5.'
- reference: PMID:37182735
title: Impact of stress on cardiac phenotypes in mice harboring an ankyrin-B disease variant.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2023 Jun;299(6):104818. doi: 10.1016/j.jbc.2023.104818.'
supporting_text: '2023 Jun;299(6):104818. doi: 10.1016/j.jbc.2023.104818.'
- reference: DOI:10.1038/nature01335
title: Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-falcon.md
findings:
- statement: Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death
supporting_text: Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death
- reference: DOI:10.1073/pnas.0402546101
title: A cardiac arrhythmia syndrome caused by loss of ankyrin-B function
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-falcon.md
findings:
- statement: 220-kDa ankyrin-B is required for coordinated assembly of Na/Ca exchanger, Na/K ATPase, and inositol trisphosphate (Ins P 3 ) receptor at transverse-tubule/sarcoplasmic reticulum sites in cardiomyocytes.
supporting_text: 220-kDa ankyrin-B is required for coordinated assembly of Na/Ca exchanger, Na/K ATPase, and inositol trisphosphate (Ins P 3 ) receptor at transverse-tubule/sarcoplasmic reticulum sites in cardiomyocytes.
- reference: DOI:10.3389/fcvm.2022.964675
title: Mechanisms underlying the role of ankyrin-B in cardiac and neurological health and disease
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-falcon.md
findings:
- statement: The ANK2 gene encodes for ankyrin-B (ANKB), one of 3 members of the ankyrin family of proteins, whose name is derived from the Greek word for anchor.
supporting_text: The ANK2 gene encodes for ankyrin-B (ANKB), one of 3 members of the ankyrin family of proteins, whose name is derived from the Greek word for anchor.
- reference: PMID:18832177
title: Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2008 Oct 7;105(40):15617-22. doi: 10.1073/pnas.0805500105.'
supporting_text: '2008 Oct 7;105(40):15617-22. doi: 10.1073/pnas.0805500105.'
- reference: PMID:20729400
title: 'Defining new insight into atypical arrhythmia: a computational model of ankyrin-B syndrome.'
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2010 Nov;299(5):H1505-14. doi: 10.1152/ajpheart.00503.2010.'
supporting_text: '2010 Nov;299(5):H1505-14. doi: 10.1152/ajpheart.00503.2010.'
- reference: PMID:30571258
title: Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: Human loss-of-function variants of ANK2 (ankyrin-B) are linked to arrhythmias and sudden cardiac death.
supporting_text: Human loss-of-function variants of ANK2 (ankyrin-B) are linked to arrhythmias and sudden cardiac death.
- reference: PMID:12571597
title: Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2003 Feb 6;421(6923):634-9. doi: 10.1038/nature01335.'
supporting_text: '2003 Feb 6;421(6923):634-9. doi: 10.1038/nature01335.'
- reference: PMID:15178757
title: A cardiac arrhythmia syndrome caused by loss of ankyrin-B function.
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: '2004 Jun 15;101(24):9137-42. doi: 10.1073/pnas.0402546101.'
supporting_text: '2004 Jun 15;101(24):9137-42. doi: 10.1073/pnas.0402546101.'
- reference: PMID:17242276
title: 'Defining the cellular phenotype of "ankyrin-B syndrome" variants: human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes.'
found_in:
- ANK2_Ankyrin_B_Syndrome-deep-research-openscientist.md
findings:
- statement: Mutations in the ankyrin-B gene (ANK2) cause type 4 long-QT syndrome and have been described in kindreds with other arrhythmias.
supporting_text: Mutations in the ankyrin-B gene (ANK2) cause type 4 long-QT syndrome and have been described in kindreds with other arrhythmias.
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.
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.
Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed
Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Search first: CTD, PubMed, PheGenI, GxE databases
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
Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser
Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Search first: CDC databases, WHO, PubMed, NHANES
Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON
Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Search first: PubMed, Gene Ontology, Reactome
Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
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
Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Search first: OMIM, Orphanet, HPO, PubMed
Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.
Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Search first: NSGC resources, ACMG guidelines, GeneReviews
Search first: Clinical guidelines, FDA approvals, PubMed
Search first: NCBI Taxonomy
Search first: VBO (Vertebrate Breed Ontology)
Search first: NCBI Gene
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
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)
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)
| 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.
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)
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)
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)
No validated protective genetic or environmental factors specific to ankyrin‑B syndrome were identified in retrieved evidence.
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)
| 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.
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)
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)
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)
| 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.
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)
No specific modifier genes or protective variants were established in retrieved evidence.
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.)
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)
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)
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)
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)
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)
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)
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)
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)
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.
Naturally occurring ankyrin‑B syndrome analogs in companion animals or livestock were not identified in the retrieved evidence.
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)
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)
References
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(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.
(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.
(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.
(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.
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)
| 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) |
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.
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).
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.
| 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 |
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).
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.
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.
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).
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 |
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.
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).
The ClinGen Channelopathy Expert Panel has provided important reassessments:
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)
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.
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:
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.
Not applicable — no infectious etiology.
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).
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
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).
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.
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.
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 (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).
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).
| 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 |
| 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 |
| 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 |
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).
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
| 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 |
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
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
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 |
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.
Not applicable — ANK2 Ankyrin-B Syndrome is a non-infectious genetic disorder.
| 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 |
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.
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.
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.
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.
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.
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.
No disease-specific biomarkers: There are no circulating biomarkers to identify at-risk individuals or monitor disease progression beyond ECG parameters.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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)