What is Ankyrin-B syndrome?

Ankyrin-B syndrome is due to ANK2 variants which result in ankyrin-B loss of function. Ankyrin B has roles in expression, localization and regulation of proteins important in cardiac excitability, cytoskeletal integrity and signaling [1,2]. It is a complex cardiac phenotype which may include bradycardia, conduction block, atrial fibrillation, QT interval prolongation and catecholaminergic polymorphic ventricular tachycardia (CPVT). Representative image indicates bidirectional ventricular tachycardia classical of CPVT. On a side note, other causes of bidirectional VT are digitalis toxicity and Andersen-Tawil syndrome. In CPVT, the arrhythmia can typically be reproduced by a very cautiously conducted exercise test [3].

Usually Ankyrin-B syndrome is due to ANK2 loss-of-function point mutations. An interesting situation in which large chromosomal translocations resulted in ANK2 haploinsufficiency has also been reported [4]. In the family reported, reciprocal chromosomal translocation between chromosomes 4q25 and 9q26 that transects the ANK2 gene on chromosome 4 resulted in loss-of-function of ankyrin-B. Some family members with ankyrin-B haploinsufficiency due to the translocation displayed clinical features of ankyrin-B syndrome. Evaluation of primary lymphoblasts from a carrier of translocation showed altered levels of ankyrin-B and reduced expression of downstream ankyrin-binding partners.

References

1. Koenig SN, Mohler PJ. The evolving role of ankyrin-B in cardiovascular disease. Heart Rhythm. 2017 Dec;14(12):1884-1889. doi: 10.1016/j.hrthm.2017.07.032. Epub 2017 Jul 29. PMID: 28765088; PMCID: PMC5712256.
2. Huq AJ, Pertile MD, Davis AM, Landon H, James PA, Kline CF, Vohra J, Mohler PJ, Delatycki MB. A Novel Mechanism for Human Cardiac Ankyrin-B Syndrome due to Reciprocal Chromosomal Translocation. Heart Lung Circ. 2017 Jun;26(6):612-618. doi: 10.1016/j.hlc.2016.09.013. Epub 2016 Nov 16. PMID: 27916589; PMCID: PMC5413386.
3. Song J, Sasmita BR, Deng G. Ankyrin-2 genetic variants: A case of Ankyrin-B syndrome. Ann Noninvasive Electrocardiol. 2022 Jul;27(4):e12933. doi: 10.1111/anec.12933. Epub 2022 Feb 28. PMID: 35224819; PMCID: PMC9296800.
4. Huq AJ, Pertile MD, Davis AM, Landon H, James PA, Kline CF, Vohra J, Mohler PJ, Delatycki MB. A Novel Mechanism for Human Cardiac Ankyrin-B Syndrome due to Reciprocal Chromosomal Translocation. Heart Lung Circ. 2017 Jun;26(6):612-618. doi: 10.1016/j.hlc.2016.09.013. Epub 2016 Nov 16. PMID: 27916589; PMCID: PMC5413386.