Two siblings with early repolarization syndrome: clinical and genetic characterization by whole-exome sequencing

Abstract

Aims: The early repolarization syndrome (ERS) can cause ventricular fibrillation (VF) and sudden death in young, otherwise healthy individuals. There are limited data suggesting that ERS might be heritable. The aim of this study was to characterize the clinical phenotype and to identify a causal variant in an affected family using an exome-sequencing approach.

Methods and results: Early repolarization syndrome was diagnosed according to the recently proposed Shanghai ERS Score. After sequencing of known ERS candidate genes, whole-exome sequencing (WES) was performed. The index patient (23 years, female) showed a dynamic inferolateral early repolarization (ER) pattern and electrical storm with intractable VF. Isoproterenol enabled successful termination of electrical storm with no recurrence on hydroquinidine therapy during 33 months of follow-up. The index patient's brother (25 years) had a persistent inferior ER pattern with malignant features and a history of syncope. Both parents were asymptomatic and showed no ER pattern. While there was no pathogenic variant in candidate genes, WES detected a novel missense variant affecting a highly conserved residue (p. H2245R) in the ANK3 gene encoding Ankyrin-G in the two siblings and the father.

Conclusion: We identified two siblings with a malignant ERS phenotype sharing a novel ANK3 variant. A potentially pathogenic role of the novel ANK3 variant is suggested by the direct interaction of Ankyrin-G with the cardiac sodium channel, however, more patients with ANK3 variants and ERS would be required to establish ANK3 as novel ERS susceptibility gene. Our study provides additional evidence that ERS might be a heritable condition.

Keywords: ANK3; Ankyrin-G; Early repolarization; Electrical storm; Exome sequencing; Hydroquinidine; Isoproterenol; Sodium channel; Ventricular fibrillation.

Figure 1

Pedigree and 12-lead electrocardiograms of the two siblings with early repolarization syndrome. (A) The index patient is marked with an arrow. Men are denoted by squares and women by circles. Solid symbols indicate individuals with early repolarization syndrome. Plus symbols next to each individual indicate carrier of the novel ANK3 H2245R variant; minus symbol indicates wild type. (B) Diagnostic inferior early repolarization pattern with high Jp amplitudes of ≥0.35 mV, slurred QRS and horizontal ST-segments in the index patient’s brother. (C) Diagnostic inferolaterlal early repolarization pattern in the index patient with maximal J peak (Jp) amplitudes of 0.20–0.25 mV and slurred QRS in lateral leads.

Figure 2

Electrical storm with dynamic early repolarization. Continuous electrocardiographic tracings from the telemetry monitor in the index patient: lead II demonstrates a distinct inferior J-wave with pause-dependent augmentation (red circles) and a monomorphic short-coupled premature ventricular complex triggering polymorphic ventricular tachycardia that rapidly degenerates into ventricular fibrillation. A further increase of the J-wave amplitude (red circles) precedes recurrent ventricular fibrillation. Following each defibrillation there is instantaneous ventricular fibrillation recurrence after four, respectively, two normal beats triggered by the very first monomorphic premature ventricular complex, resulting in three ventricular fibrillation episodes within 30 s. After this last defibrillation, the patient remained in ongoing VF for >1 h due to intractable ventricular fibrillation while being protected by venoarterial extracorporeal membrane oxygenation (VA-ECMO).

Figure 3

Termination of electrical storm and suppression of early repolarization. (A) Continuous electrocardiographic tracings from the telemetry monitor in the index patient: prior to the external shock shown isoproterenol was given for 2 min during ongoing ventricular fibrillation. Isoproterenol resulted in successful defibrillation, suppression of the early repolarization pattern (red circle) and of the ventricular fibrillation trigger (note absence of short-coupled premature beats). (B) Synopsis of electrical storm in the index patient: Conventional anti-arrhythmic drugs failed and, by slowing heart rate, retrospectively even increased the number of ventricular fibrillation episodes. Isoproterenol led to sinus tachycardia and suppression of any further ventricular fibrillation episode. VA-ECMO, venoarterial extracorporeal membrane oxygenation.

Figure 4

Alignment with ClustalW of the ANK3 protein in the region of the variant p. H2245R. The histidine at this position is conserved in fish, birds, mammals, marsupials and human.