Ankyrin‐2 genetic variants: A case of Ankyrin‐B syndrome

Abstract Inherited cardiac arrhythmias (ICA) have become one of the leading causes of sudden cardiac death in people under 40 years old. Variants in the ankyrin‐B or ankyrin‐2 genes will result in several cardiac arrhythmias ranging from sinus node dysfunction to life‐threatening arrhythmias. In this case study, we report a typical ankyrin‐2 variant, in which ventricular tachyarrhythmias might be reproduced through exercise or stress tests.


| C A S E REP ORT
A 20-year-old Asian man, due to "exercise-related syncope for 4 years" was presented to the outpatient department. He was having syncopal episodes with spontaneous resolution in a few minutes of rest. Before the syncope, he may experience chest discomfort, fatigue, and diaphoresis. He was a non-smoker, and there was no history of drug abuse. Family history was negative for sudden cardiac death (SCD) or cardiac diseases.
The physical examination was presented without any abnormal findings. Admission laboratory findings include thyroid function, and cardiac biomarker was normal. Resting electrocardiogram (ECG) showed a resting heart rate (HR) of 78 beats/minute (bpm). Cardiac Echocardiographic and MRI showed asymmetric left ventricular hypertrophy, decreased diastolic function, normal cardiac structure, therefore, non-obstructive hypertrophic cardiomyopathy was diagnosed (Figures 1 and 2). Coronary angiography and pulmonary angiography examinations were done to rule out the possibility of coronary artery disease or pulmonary embolism, the results were negative.
As we suspect, the possibility of cardiac abnormal rhythm, under the supervision of a cardiologist, as well as advanced life support equipment, we ordered a treadmill stress test. The examination was done with Bruce's protocol stress test, during examination, patient's heart rate (HR) was stimulated up to 160 bpm, and ECG showed wide-QRS complex tachycardia with ventricular rhythm 218 bpm with obvious A-V dissociation. The stress test was immediately terminated, and 4 min after patient's ECG showed a sequence of changes from sinus arrest to cardiac arrest, and eventually to junctional escape rhythm; therefore, we consider the patient had a binodal disease (BND), which coexistence of atrioventricular conduction disturbances with sick sinus syndrome (SSS) (Figure 3a-c). After a thorough examination, our initial diagnoses were 1. Non-obstructive hypertrophic cardiomyopathy; 2. Catecholaminergic ventricular tachycardia.
As the patient's cardiac echocardiography was remarkable, genetic examination was performed to rule out inherited cardiac arrhythmias. Genetic examination was carried out on patient's family and himself. Around 5ml of blood was collected in K2-EDTA tubes, following accepted principles for blood drawing and blood collection. Genetic sequencing was performed on the Illumina HiSeq system, while genomic analysis was performed by using WuXi NextCode Clinical Sequence Analyzer (CSA) to identify clinically relevant phenotype-associated genes and variants from family members. After DNA capture, sequencing was done by using Illumina Cluster and SBS reagents to reach a mean coverage depth of more than 90× per sample, with 95% of the After diagnosis was confirmed, the patient was given metoprolol succinate 23.75 mg QD, and we advised the patient to do a regular check-up every 1-3 months. Unfortunately, the patient was not doing a monthly check-up at our hospital; therefore, we do a follow-up to the patient, and he mentioned that he deliberately stopped the medication, moreover, the aforementioned symptoms still persist, especially after strenuous exercise.

| DISCUSS ION
In this case report, we presented a patient with what we called "Ankyrin-B syndrome", a type of inherited cardiac arrhythmias (ICA) that account for 1% of the cases. ICA are abnormal heart rhythms that are passed down from family members, ranging from benign to life-threatening arrhythmia. Most people with ICA are young people and may present with or without structural changes of the heart. ICA has long been associated with abnormality in the cardiac ion channels and sodium channel integral membrane protein, which disrupt normal cardiac conduction system, hence arrhythmias were manifested. However, this theory was not last long until Schott in  (Mohler et al., 2005). As for ventricular tachyarrhythmia, several studies believe 2 main mechanisms come to exist. First, ankyrin-B mutations presented with the phenotypes of cardiac voltage-gated sodium channel (SCN5A), a variant that abolishes binding of Na v 1.5 with ankyrin-G resulting in Brugada syndrome. Second, loss-of-function ankyrin-B presented with decreased expression of Na/Ca exchanger, which led to sarcoplasmic reticulum calcium overload, and eventually increased F I G U R E 3 (a) During the second treadmill stress test, HR rise up to 160 bpm, and then ventricular premature beat triggered a wide-QRS complex tachycardia (ventricular rate 218 bpm); (b) Termination of ventricular tachycardia followed with sinus arrest (red arrow: sinus rhythm 83 bpm); (c) Termination of ventricular tachycardia followed with cardiac arrest, junctional escape beat, R-R interval greater than 4 s, and binodal disease should be done to reduce the risk of sudden cardiac death.

CO N FLI C T O F I NTE R E S T
The authors declare no competing interests.

AUTH O R CO NTR I B UTI O N S
J.S and S.B.R contributed to the conception and design of the work and drafted the manuscript. G.L.D revised and directed the manuscript.

E TH I C A L A PPROVA L
This study was performed in accordance with the principle of the Declaration of Helsinki and the research protocol was approved by the institutional ethical review board of the first affiliated hospital of Chongqing medical university (April 29, 2020, No.2020.

I N FO R M E D CO N S E NT
A written informed consent for publication was obtained from the patient.

DATA AVA I L A B I L I T Y S TAT E M E N T
All data relevant to the study are included in the article or uploaded as supplementary files. Data can also be requested from the corresponding author. F I G U R E 4 Genetic examination showed that the patient had ankyrin 2 (ANK2) c.10310T > C variant, while patient's mother presented with ANK2 compound heterozygous mutation