ANK2 – Catecholaminergic Polymorphic Ventricular Tachycardia

ANK2 encodes the scaffolding protein ankyrin-B, and while loss-of-function variants in ANK2 are established in diverse arrhythmia syndromes, the association with catecholaminergic polymorphic ventricular tachycardia (CPVT) has been formally disputed. A ClinGen Expert Panel evaluated reported ANK2 variants in CPVT and concluded that allele frequencies in population databases exceed thresholds for pathogenicity, and no definitive segregation with CPVT was documented (PMID:34557911).

Genetic sequencing of 11 unrelated patients referred for CPVT testing failed to identify CPVT‐causing ANK2 variants; instead, variants in other arrhythmia genes explained the phenotype, illustrating phenotypic mimicry rather than true CPVT causation (PMID:16818210). Functional modeling of the ANK2 c.11218C>A (p.Leu3740Ile) variant in knock-in mice demonstrated catecholamine-triggered arrhythmias, prolonged action potentials, and afterdepolarizations consistent with arrhythmogenic potential but not specific CPVT mechanisms (PMID:27298202). Taken together, there is no robust proband or segregation evidence for ANK2 in CPVT, and existing functional data do not recapitulate hallmark CPVT calcium‐release abnormalities.

Key take-home: ANK2 should not be included in CPVT gene panels for diagnostic decision-making until further disease-specific evidence emerges.

References

• European Heart Journal • 2022 • Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death PMID:34557911
• Heart Rhythm • 2006 • Genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing PMID:16818210
• Heart Rhythm • 2016 • Common human ANK2 variant confers in vivo arrhythmia phenotypes PMID:27298202

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