ANK2 – Brugada syndrome

In a cohort of 45 SCN5A-negative Brugada syndrome patients, targeted resequencing of 28 arrhythmia genes identified five rare ANK2 variants in four unrelated probands, including c.7334A>G (p.Asp2445Gly) (PMID:26230511). A subsequent Vietnamese whole-exome study of 50 confirmed BrS cases detected two additional ANK2 missense variants, representing <10% of probands (PMID:39895654). No family segregation data were reported. These variants localize to the membrane-binding and C-terminal regulatory domains of ankyrin-B and are consistent with an autosomal dominant inheritance pattern with incomplete penetrance.

Functional knock-in mouse models support a loss-of-function mechanism. Ankyrin-B p.Leu1622Ile knock-in mice exhibit reduced ANKB expression, mislocalization of the Na/Ca exchanger, slowed conduction, catecholamine-dependent ventricular arrhythmias, and delayed afterdepolarizations mirroring BrS physiology (PMID:27298202). Similarly, mice harboring the human ANK2 p.Glu1458Gly variant develop stress-induced ventricular arrhythmias, structural remodeling, and fibrosis (PMID:37182735). These data demonstrate that ankyrin-B deficiency disrupts ion channel scaffolding and calcium homeostasis. However, the overall genetic evidence is limited by small case numbers, absence of documented segregation, and lack of type 1 Brugada ECG confirmation. Additional replication and family studies are needed.

Key take-home: ANK2 variants may underlie Brugada syndrome in a minority of patients and should be considered in comprehensive genetic testing panels.

References

• PloS one | 2015 | Genetic Analysis of Arrhythmogenic Diseases in the Era of NGS: The Complexity of Clinical Decision-Making in Brugada Syndrome. PMID:26230511
• JRSM cardiovascular disease | 2025 | Genetic background and clinical phenotype in a Vietnamese cohort with Brugada syndrome: A whole exome sequencing study. PMID:39895654
• 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

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