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Cross-provider research synthesis

ANK2 Ankyrin B Syndrome

MONDO:0010958 Curated 2026-07-04T00:00:00Z 9 harmonized findings

falcon · 44 citations openscientist · 33 citations

Concordant asserts the finding Partial supports a weaker/qualified form Contradictory conflicts with it Silent does not address it

Harmonized findings

ANK2 ankyrin-B syndrome is an autosomal dominant, incompletely penetrant, variably expressive inherited arrhythmia disorder caused by loss-of-function ANK2 variants; originally designated long QT syndrome type 4 (LQT4), it is now termed "ankyrin-B syndrome" because the phenotype extends well beyond QT prolongation to sinus node dysfunction, atrial fibrillation, and ventricular arrhythmias.

UNANIMOUS INTEGRATED

genetic_factorphenotype

Provider	Stance	Score	Evidence
falcon	CONCORDANT	95%	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 Falcon states the autosomal-dominant loss-of-function etiology and the LQT4-to-ankyrin-B-syndrome nomenclature shift directly. DOI:10.1038/nature01335, DOI:10.3389/fcvm.2022.964675
openscientist	CONCORDANT	95%	Originally described as long QT syndrome type 4 (LQT4), the disease is now recognized as a clinically distinct entity characterized by a complex and variable cardiac phenotype including sinus bradycardia, sinus node dysfunction, atrial fibrillation, variable QT interval prolongation, catecholaminergic polymorphic ventricular tachycardia (CPVT), and risk of sudden cardiac death. OpenScientist gives the same reclassification and enumerates the broad arrhythmia spectrum that motivates the ankyrin-B syndrome label. PMID:15178757

The core molecular defect is loss of ankyrin-B scaffold/adaptor function, which fails to target key cardiac ion transporters (Na/Ca exchanger NCX1, Na/K-ATPase, InsP3 receptor) to their membrane microdomains, producing intracellular Na+/Ca2+ dysregulation and SR calcium overload.

UNANIMOUS INTEGRATED

pathophysiologygene_function

Provider	Stance	Score	Evidence
falcon	CONCORDANT	90%	disrupts membrane localization/expression of NCX, NKA, IP3R, producing defective intracellular Na+ and Ca2+ handling and SR Ca2+ overload Falcon describes loss of ankyrin-B disrupting NCX/NKA/IP3R membrane localization and driving defective Na+/Ca2+ handling and SR Ca2+ overload. DOI:10.1161/circresaha.110.224592
openscientist	CONCORDANT	95%	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 OpenScientist quotes the seminal Mohler 2003 mechanism naming the same three mistargeted ankyrin-B-binding transporters. PMID:12571597

Sinus node dysfunction with sinus bradycardia and heart-rate variability is a core, often highly penetrant manifestation, reflecting the requirement for ankyrin-B in sinoatrial node channel/transporter targeting; AnkB+/- mice phenocopy the human sinus node disease.

UNANIMOUS INTEGRATED

phenotypepathophysiology

Provider	Stance	Score	Evidence
falcon	CONCORDANT	90%	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. Falcon links SAN ankyrin-B loss to impaired automaticity, bradycardia, and escape rhythms. DOI:10.1073/pnas.0805500105
openscientist	CONCORDANT	90%	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 OpenScientist quotes Le Scouarnec 2008 mapping highly penetrant SND to ANK2 and the AnkB+/- mouse phenocopy. PMID:18832177

Atrial fibrillation susceptibility arises from reduced membrane targeting of the atrial L-type calcium channel Cav1.3, which shortens the atrial action potential and lowers the critical tissue mass required to sustain reentry.

UNANIMOUS INTEGRATED

phenotypepathophysiology

Provider	Stance	Score	Evidence
falcon	CONCORDANT	85%	and shortens atrial APs, increasing AF susceptibility Falcon attributes AF susceptibility to reduced atrial Cav1.3, decreased L-type Ca2+ current, and shortened atrial action potentials. DOI:10.1161/circulationaha.111.023986
openscientist	CONCORDANT	85%	leads to action potential shortening that reduces the critical atrial tissue mass needed to sustain reentrant activation OpenScientist gives the same computational-model Cav1.3 mechanism for AF via shortened atrial AP and reduced reentry critical mass. PMID:23436330

Many historically reported ANK2 variants are relatively common in the general population and show low or uncertain penetrance, so ANK2 has limited or disputed evidence as a monogenic long-QT/CPVT gene and variants must be interpreted with caution rather than assumed high-risk.

UNANIMOUS INTEGRATED

genetic_factordiagnosis

Provider	Stance	Score	Evidence
falcon	CONCORDANT	85%	were not enriched compared with population databases and often had minimal phenotype Falcon leans on the Giudicessi/Mayo referral-cohort reappraisal concluding that many alleged ankyrin-B syndrome variants are not enriched versus population databases and are unlikely to be penetrant monogenic risk alleles. DOI:10.1161/circgen.119.002851
openscientist	CONCORDANT	85%	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. OpenScientist reaches the same caution via the ClinGen Channelopathy Expert Panel reappraisal (limited/disputed for LQTS; too common for CPVT), a different sourcing than Falcon's Mayo reappraisal. PMID:31983240, PMID:34557911, PMID:16253912

Beta-blockade (metoprolol) and flecainide suppress catecholamine/stress-induced ventricular arrhythmias in the ANK2 p.Q1283H knock-in mouse, providing the mechanistic rationale for adrenergic and triggered-activity suppression in ankyrin-B syndrome.

UNANIMOUS INTEGRATED

treatment

Provider	Stance	Score	Evidence
falcon	CONCORDANT	90%	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 Falcon reports the Q1283H knock-in metoprolol/flecainide response and a corroborating clinical case. DOI:10.1161/circulationaha.118.034541
openscientist	CONCORDANT	90%	ANK2 p.Q1283H is a disease-associated variant that confers susceptibility to stress-induced arrhythmias, which may be prevented by the administration of metoprolol or flecainide OpenScientist quotes the same Q1283H knock-in finding that metoprolol or flecainide prevents stress-induced arrhythmias. PMID:30571258

A founder ANK2 membrane-binding-domain variant (p.S646F) segregates in Northern British Columbia First Nations (Gitxsan) families, a population with a markedly elevated long-QT syndrome rate, illustrating population-specific ANK2 disease burden.

UNANIMOUS INTEGRATED

genetic_factorepidemiology

Provider	Stance	Score	Evidence
falcon	CONCORDANT	85%	ANK2 p.S646F was reported in multigenerational families with a possible founder effect context Falcon reports p.S646F in multigenerational Gitxsan families with a founder effect and the ~1:125 high LQTS prevalence. DOI:10.1161/circgenetics.116.001537
openscientist	CONCORDANT	80%	variant was identified in First Nations families of Northern British Columbia OpenScientist independently notes the novel First Nations ANK2 variant in a population with ~15x higher long-QT syndrome frequency. PMID:28196901

ANK2 dysfunction can drive an arrhythmogenic cardiomyopathy with ventricular dilation, fibrosis and abnormal beta-catenin signaling, and WNT/beta-catenin activation (the GSK-3beta inhibitor SB-216763) prevents and partially reverses the cardiomyopathy in Ank2 conditional-knockout mice as a targeted therapy lead.

SINGLE LEAD

pathophysiologytreatment

Provider	Stance	Score	Evidence
falcon	CONCORDANT	90%	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 Falcon develops the Roberts 2019 ankyrin-B/beta-catenin arrhythmogenic cardiomyopathy pathway and the preclinical SB-216763 rescue in detail. DOI:10.1172/jci125538
openscientist	SILENT	—	OpenScientist notes cardiomyopathy only as a nonspecific advanced-case echo finding and heart failure in betaII-spectrin-deficient mice; it does not cover the ankyrin-B/beta-catenin arrhythmogenic-cardiomyopathy pathway or the SB-216763 targeted-therapy evidence.

Beyond the heart, ankyrin-B has critical extracardiac functions (neuronal axon guidance and growth-cone navigation, skeletal muscle, thymus), but the clinical relevance of these extracardiac roles in human ANK2 variant carriers remains largely unexplored.

SINGLE LEAD

gene_function

Provider	Stance	Score	Evidence
openscientist	CONCORDANT	85%	Ankyrin-B has critical functions in neurons (axon guidance, growth cone navigation) and other tissues OpenScientist covers ankyrin-B neuronal/extracardiac biology (axon guidance, L1-CAM cAMP signaling, OTUD7A/15q13.3) and flags it as an open translational question. PMID:19110015
falcon	SILENT	—	Falcon's report is cardiac-focused and does not address the neuronal or other extracardiac functions of ankyrin-B.

Narrative

Overview

Both providers frame ANK2 ankyrin-B syndrome (historically LQT4) as an autosomal dominant, incompletely penetrant, variably expressive inherited arrhythmia disorder caused by loss-of-function ANK2 variants that impair the ankyrin-B membrane-cytoskeleton scaffold in cardiomyocytes and sinoatrial node cells. The shared curated concepts are the ion-transporter-targeting mechanism, the multi-phenotype arrhythmia spectrum (sinus node dysfunction, atrial fibrillation, ventricular arrhythmias, sudden death), and the pervasive problem of variant interpretation.

Agreement

The reports converge on the core scaffold mechanism (loss of ankyrin-B mistargets NCX1, Na/K-ATPase, and InsP3R, driving intracellular Ca2+ dysregulation and SR Ca2+ overload), on sinus node dysfunction as a core highly penetrant phenotype phenocopied by AnkB+/- mice, on atrial fibrillation arising from reduced atrial Cav1.3 with atrial action-potential shortening, on the Q1283H knock-in evidence that metoprolol/flecainide suppress stress-induced arrhythmias, and on the S646F founder variant in a high-LQTS First Nations population. Notably, both reach the same cautionary conclusion that many ANK2 variants are common and low-penetrance, though Falcon anchors this on the Giudicessi/Mayo referral reappraisal while OpenScientist anchors it on the ClinGen Channelopathy Expert Panel curation.

Divergence

Falcon (pathophysiology-focused) uniquely develops the ankyrin-B/beta-catenin arrhythmogenic-cardiomyopathy pathway and the preclinical GSK-3beta inhibitor SB-216763 rescue in Ank2 conditional-knockout mice, and adds granular device/ablation and 2023-2024 case-report management detail. OpenScientist (broader disease-characteristics scope) uniquely covers ankyrin-B extracardiac and neuronal biology (axon guidance, L1-CAM cAMP signaling, OTUD7A/15q13.3 microdeletion), CaMKII-dependent RyR2 hyperphosphorylation as a therapeutic target, and a fuller differential-diagnosis, model-organism, and knowledge-gap inventory. No direct contradictions were found; divergence is coverage and emphasis rather than conflicting claims.

Integration

Integrated concepts (INTEGRATED findings): the LQT4-to-ankyrin-B-syndrome reclassification and autosomal-dominant loss-of-function etiology; the scaffold ion-transporter-targeting mechanism with Ca2+ dysregulation; sinus node dysfunction and Cav1.3-driven atrial fibrillation; the disputed/ low-penetrance variant-interpretation caveat; beta-blocker/flecainide therapy from the Q1283H knock-in; and the S646F Gitxsan founder epidemiology.

Not integrated (leads)

Retained as research leads rather than promoted: the ankyrin-B/beta-catenin arrhythmogenic-cardiomyopathy pathway and the preclinical SB-216763 targeted therapy (single-provider, preclinical only), and ankyrin-B's extracardiac and neuronal functions whose human clinical relevance is unestablished.

Cross-provider synthesis comparing the falcon (pathophysiology-focused, Edison Scientific Literature) and openscientist (comprehensive, autonomous) deep-research reports for ANK2 Ankyrin-B Syndrome. No direct contradictions were identified; the two clear divergences are coverage-only (Falcon-only arrhythmogenic cardiomyopathy/SB-216763; OpenScientist-only extracardiac/neuronal biology). best_matching_text values are verbatim excerpts from the cited report files; literature evidence snippets and ontology terms are intentionally left to the main curation pipeline on the disorder YAML.