ANK2 – Cardiac Arrhythmia, Ankyrin-B-related

ANK2 encodes ankyrin-B, a scaffolding protein critical for the membrane targeting and regulation of cardiac ion channels and transporters. Heterozygous loss-of-function variants in ANK2 cause an autosomal dominant arrhythmia syndrome characterised by sinus node dysfunction, atrial fibrillation, prolonged QT and ventricular arrhythmias (PMID:25456501).

Inheritance is autosomal dominant with incomplete penetrance. Segregation of clinical arrhythmia phenotypes has been observed in a multigenerational kindred carrying a reciprocal translocation disrupting ANK2, with at least 6 affected relatives displaying sinus node dysfunction and atrial and ventricular arrhythmias (PMID:27916589).

Case series include a single young adult proband with family history of sudden death presenting with sinus node dysfunction, atrial fibrillation and prolonged QT (PMID:25456501), and a family with chromosomal translocation–mediated haploinsufficiency (PMID:27916589).

Targeted mutational screening in 541 unrelated LQTS referrals identified 14 distinct nonsynonymous ANK2 variants in 9 genotype-negative patients (3.3% of 269 LQTS-negative cases) (PMID:16253912). Variants span missense (e.g., c.1937C>T (p.Ser646Phe)) and intronic changes. A recurrent hypomorphic allele p.Leu1622Ile shows population heterogeneity and mild loss-of-function in knock-in mice (PMID:27298202).

Functional studies demonstrate ankyrin-B haploinsufficiency as the pathogenic mechanism. In vitro cardiomyocyte assays reveal a spectrum of loss-of-function cellular phenotypes across variants (PMID:17242276). Knock-in mice harboring p.Glu1458Gly exhibit stress-induced bradycardia, structural remodeling and ventricular arrhythmias, confirming in vivo arrhythmogenicity (PMID:37182735).

Conflicting evidence arises from whole-exome sequencing in 7,244 pediatric cases, where incidental ANK2 variants occur at similar frequencies in healthy controls and LQTS referrals (38.3% vs 38.4%), suggesting background variation and the need for cautious interpretation (PMID:29501670).

Collectively, heterozygous ANK2 loss-of-function variants show consistent genetic segregation and concordant functional data supporting autosomal dominant cardiac arrhythmia. Further studies are warranted to refine penetrance estimates and identify modifiers. Key take-home: ANK2 sequencing should be included in arrhythmia panels, and carriers of pathogenic ANK2 variants may benefit from tailored therapy including pacing or defibrillator placement.

References

• Heart, lung & circulation • 2015 • Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult. PMID:25456501
• Heart, lung & circulation • 2017 • A Novel Mechanism for Human Cardiac Ankyrin-B Syndrome due to Reciprocal Chromosomal Translocation. PMID:27916589
• Heart rhythm • 2005 • Targeted mutational analysis of ankyrin-B in 541 consecutive, unrelated patients referred for long QT syndrome genetic testing and 200 healthy subjects. PMID:16253912
• Circulation. Cardiovascular genetics • 2017 • 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. PMID:28196901
• Heart rhythm • 2016 • Common human ANK2 variant confers in vivo arrhythmia phenotypes. PMID:27298202
• The Journal of biological chemistry • 2023 • Impact of stress on cardiac phenotypes in mice harboring an ankyrin-B disease variant. PMID:37182735
• Heart rhythm • 2018 • Amino acid-level signal-to-noise analysis of incidentally identified variants in genes associated with long QT syndrome during pediatric whole exome sequencing reflects background genetic noise. PMID:29501670

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