Hostname: page-component-74656f9884-7drmj Total loading time: 0 Render date: 2026-11-05T00:54:14.291Z Has data issue: false hasContentIssue false
  • English
  • Français

Two novel ryanodine receptor 2 mutations associated with catecholaminergic polymorphic ventricular tachycardia in children: two case reports and literature review

Published online by Cambridge University Press:  16 April 2026

Runmei Zou ,
Shuo Wang Open the ORCID record for Shuo Wang [Opens in a new window] ,
Ping Liu ,
Hong Cai ,
Liping Liu ,
Fang Li ,
Yuwen Wang  and
Cheng Wang
Runmei Zou
Affiliation:
Pediatric Cardiovasology, Children’s Medical Center, The Second Xiangya Hospital of Central South University, Changsha, China
Shuo Wang
Affiliation:
Pediatric Cardiovasology, Children’s Medical Center, The Second Xiangya Hospital of Central South University, Changsha, China
Ping Liu
Affiliation:
Pediatric Cardiovasology, Children’s Medical Center, The Second Xiangya Hospital of Central South University, Changsha, China
Hong Cai
Affiliation:
Pediatric Cardiovasology, Children’s Medical Center, The Second Xiangya Hospital of Central South University, Changsha, China
Liping Liu
Affiliation:
Pediatric Cardiovasology, The First Affiliated Hospital of Hunan Normal University, Changsha, China
Fang Li
Affiliation:
Pediatric Cardiovasology, Children’s Medical Center, The Second Xiangya Hospital of Central South University, Changsha, China
Yuwen Wang
Affiliation:
Pediatric Cardiovasology, Children’s Medical Center, The Second Xiangya Hospital of Central South University, Changsha, China
Cheng Wang*
Affiliation:
Pediatric Cardiovasology, Children’s Medical Center, The Second Xiangya Hospital of Central South University, Changsha, China
*
Corresponding author: Cheng Wang; Email: wangcheng2nd@csu.edu.cn
Rights & Permissions [Opens in a new window]

Abstract

Introduction:

The ryanodine receptor 2 gene mutation associated with catecholaminergic polymorphic ventricular tachycardia is one of the aetiologies of cardiac syncope and has the risk of sudden cardiac death. This study reported two novel ryanodine receptor 2 gene variants.

Case description:

We described two 9-year-old girls with recurrent syncope during exercise or stress presenting two novel ryanodine receptor 2 gene variants (c.6938T>G/p. Val2313Gly and c.12263A>C/p. His4088Pro) associated with catecholaminergic polymorphic ventricular tachycardia through a comprehensive review of medical history, examination findings and genetic testing. Propranolol was used for treatment, and the two patients didn’t experience episodes of syncope during follow-up for 6 months. Besides, literature associated with catecholaminergic polymorphic ventricular tachycardia and ryanodine receptor 2 mutations was reviewed.

Conclusions:

Recurrent syncope during exertion or stress should be focused on catecholaminergic polymorphic ventricular tachycardia caused by ryanodine receptor 2 gene mutations. The genetic testing is a crucial tool in confirming the mutation of catecholaminergic polymorphic ventricular tachycardia. Early recognition of this disease, timely diagnosis of ryanodine receptor 2 gene mutations, and administration of appropriate pharmacological agents or ICD implantation are critical to ensure favourable clinical outcomes.

Keywords

Catecholaminergic polymorphic ventricular tachycardiagene mutationryanodine receptor 2case report

Information

Type
Case Report
Information
Cardiology in the Young , Volume 36 , Issue 4 , April 2026 , pp. 826 - 831
Check for updates
Copyright
© The Author(s), 2026. Published by Cambridge University Press

Introduction

Syncope is a common symptom in children and adolescents, accounting for 1–2% of emergency visits. About 17.37% of children and adolescents younger than 18 years old experience at least one episode of syncope. Reference Hu, Liu, Chen and Wang1 The causes of syncope in children include neurally mediated syncope, cardiac syncope, and unexplained syncop. Reference Wang, Liao and Wang2 Neurally mediated syncope is the most common cause of syncope with a better prognosis. Cardiac syncope is relatively rare but has a poor prognosis due to the risk of sudden cardiac death. Reference Schunk and Ruttan3 It is critical to recognise cardiac syncope as early as possible to reduce the risk of sudden cardiac death. In this study, we reported two cases of cardiac syncope caused by novel ryanodine receptor 2 mutations associated with catecholaminergic polymorphic ventricular tachycardia and reviewed the related literature.

Case presentations

Case 1

A 9-year-and-11-month-old girl with recurrent episodes of syncope over two years was admitted. Her first episode of syncope occurred at age seven during exertion. Before syncope, she experienced palpitations, sweating, blurred vision, and, subsequently, a transient loss of consciousness lasting for 20–30 seconds. During the attacks, she presented symptoms of pallor and limb stiffness. Over the two years, she experienced nine episodes of syncope during exertion or stress and experienced urinary incontinence three times. Her one front tooth was injured during one episode of syncope. There were no significant abnormalities in previous history, personal history, family history, or physical examination. Tests for myocardial enzymes, echocardiography, a 12-lead electrocardiogram, a 24-h ambulatory electrocardiogram, MRI of the brain, and a 6-h video electroencephalograph demonstrated normal results. An exercise treadmill test was performed. Ventricular bigeminy appeared when the heart rate increased to 164 beats per minute (accounting for 77% of the predicted maximum heart rate) during the first stage of the exercise treadmill test, and the patient experienced blurred vision and palpitation, so the treadmill test was immediately terminated. Subsequently, the patient’s heart rate decreased, ventricular bigeminy disappeared gradually, and the symptoms of blurred vision and palpitation were relieved (Figure 1). The whole-exome gene sequencing was conducted, demonstrating a heterozygous missense mutation in the ryanodine receptor 2 gene (NM-001035.2: c.6938T>G/p. Val2313Gly) located on chromosome 1q43 (Figure 2). This mutation was not present in the blood samples of the patient’s parents, suggesting a novel mutation that was not reported in the Human Gene Mutation Database and is absent from the 1000 Genomes Project (1000g2015aug ALL), the Exome Sequencing Project (ESP6500siv2 ALL), and the dbSNP147 databases. The patient was prescribed propranolol (started at 1 mg/kg/d) twice daily. She didn’t experience episodes of syncope during follow-up for 6 months.

Figure 1.

ECG examination of patient 1 under exercise on a treadmill test. The red arrows show ventricular bigeminy. The black arrow shows the termination of the exercise treadmill test. Ventricular bigeminy appeared when the heart rate increased to 164 beats per minute (bpm) (accounting for 77% of the predicted maximum heart rate) during the first stage of the exercise treadmill test.

An electrocardiogram (ECG) showing ventricular bigeminy during an exercise treadmill test.
Figure 1 Long description

An electrocardiogram (ECG) examination of a patient under exercise on a treadmill test. The ECG shows multiple heartbeats with red arrows indicating ventricular bigeminy, where a premature ventricular contraction follows every normal beat. A black arrow marks the termination of the exercise treadmill test. Ventricular bigeminy appears when the heart rate increases to 164 beats per minute during the first stage of the exercise treadmill test.

Figure 2.

The whole-exome gene sequencing results of patient 1. The black arrow shows the mutant site.

The whole-exome gene sequencing results of patient 1, their father, and their mother, highlighting a mutant site with an arrow.
Figure 2 Long description

The image displays the whole-exome gene sequencing results for patient 1, their father, and their mother. Each sequencing result is presented in three separate panels. The top panel shows the sequencing results for patient 1, with a black arrow pointing to a specific mutant site marked by a red-highlighted 'T' in the sequence. The middle panel shows the sequencing results for the father of patient 1, with the same mutant site highlighted. The bottom panel shows the sequencing results for the mother of patient 1, also highlighting the same mutant site. The sequences are composed of various colored peaks representing different nucleotides: adenine (green), thymine (red), cytosine (blue), and guanine (black).

Case 2

A 9-year-and-7-month-old girl was hospitalised for two episodes of syncope over two years. She experienced her first event at age seven when participating in a physical education class. There were no prodromal symptoms, such as palpitations, sweating, blurred vision, etc., before the transient loss of consciousness. No symptoms of pallor, limb stiffness, or urinary incontinence were noted in the patient when she lost consciousness. Five months ago, she experienced the second episode of syncope when she was sitting in the classroom. A 24-h ambulatory electrocardiogram performed at the local hospital revealed sinus bradycardia, with an average heart rate of 64 beats per minute, a maximum heart rate of 127 beats per minute (occurred at 13:04), and a minimum heart rate of 40 beats per minute (occurred at 00:04). A total of 470 beats of ventricular premature from various sources were demonstrated, with 5 episodes of paired ventricular premature, 10 instances of ventricular bigeminy, and 15 episodes of non-sustained polymorphic ventricular tachycardia (the longest time was 27 seconds) (Figure 3). These ventricular premature beats occurred mainly in the daytime during exertion. There were no significant abnormalities in previous, personal, or family history. For physical examination, the patient presented with sinus bradycardia, with a heart rate of 65 beats per minute. Tests for myocardial enzymes, echocardiography, MRI of the brain, and a 6-h video electroencephalograph are normal. The whole-exome gene sequencing suggested a heterozygous missense mutation in the ryanodine receptor 2 gene (NM-001035.2: c.12263A>C/p. His4088Pro) (Figure 4). This mutation was not found in the blood samples of the patient’s parents, indicating a novel mutation. Propranolol (started at 1 mg/kg/d) twice daily was used for treatment, and the patient didn’t experience episodes of syncope during follow-up for 6 months.

Figure 3.

24 h ambulatory ECG examination of patient 2. The red arrow shows ventricular bigeminy and non-sustained polymorphic ventricular tachycardia.

A two line graph showing ventricular bigeminy and non-sustained polymorphic ventricular tachycardia.
Figure 3 Long description

A two line graph displays the results of a 24-hour ambulatory ECG examination. The x-axis represents time in hours, while the y-axis represents heart rate in beats per minute. The first line graph shows regular heartbeats, while the second line graph highlights irregular heartbeats. Red arrows point to specific instances of ventricular bigeminy and non-sustained polymorphic ventricular tachycardia. The graph illustrates the variability and irregularities in the heart rate over the 24-hour period. All values are approximated.

Figure 4.

The whole-exome gene sequencing results of patient 2. The black arrow shows the mutant site.

The whole-exome gene sequencing results of patient 2, father of patient 2, and mother of patient 2.
Figure 4 Long description

The image displays three chromatograms representing the whole-exome gene sequencing results. The top chromatogram is labeled 'Patient 2' and shows a sequence with a highlighted mutation site marked by a black arrow. The middle chromatogram is labeled 'Father of Patient 2' and shows a sequence with a different nucleotide at the same position. The bottom chromatogram is labeled 'Mother of Patient 2' and also shows a sequence with a different nucleotide at the same position. Each chromatogram includes peaks in various colors representing different nucleotides: thymine (red), cytosine (blue), adenine (green), and guanine (black). The sequences are aligned horizontally, and the mutation site is highlighted in red.

Discussion

Catecholaminergic polymorphic ventricular tachycardia is a rare and highly malignant inherited arrhythmia characterised by unexplained syncope and sudden cardiac death induced by exercise or emotional stress mainly in children and teenagers with a normal heart structure and normal resting electrocardiogram. Catecholaminergic polymorphic ventricular tachycardia is one of the leading causes of unexplained sudden death in the population aged 1 to 35 years old. Reference Aggarwal, Stolear and Alam4 It affects approximately 1 in 10,000 to 5,000 individuals Reference Mariani, Pierucci and Fanisio5 and males and females equally. The typical presentation is episodes of syncope induced by exertion or emotional stress. However, syncopal episodes at the initial presentation are often mistaken for vasovagal events or attributed to neurological triggers. A significant proportion of individuals may be incorrectly diagnosed with epilepsy due to seizure-like activity during attacks. Reference Napolitano, Bloise, Monteforte and Priori6

The pathogenesis of catecholaminergic polymorphic ventricular tachycardia is associated with disorders of intracellular calcium-induced calcium release from the sarcoplasmic reticulum during excitation-contraction coupling. Numerous gene mutations have been identified in catecholaminergic polymorphic ventricular tachycardia patients, including ryanodine receptor 2, CASQ2, TRDN, TECRL, KCNJ2, CALM1, CALM2, and CALM3, among which the ryanodine receptor 2 gene mutation is the most commonly identified and recognised as catecholaminergic polymorphic ventricular tachycardia 1. Reference Priori, Napolitano and Tiso7,Reference Priori, Mazzanti, Santiago, Kukavica, Trancuccio and Kovacic8 Ryanodine receptor 2 is located on chromosome 1q43 and encodes the cardiac ryanodine receptor (ryanodine receptor 2 protein), which is mainly found in the sarcoplasmic reticulum of cardiomyocytes and acts as a Ca2+ release channel receptor. Reference Peng, Shen and Wu9 Most ryanodine receptor 2 mutations are autosomal dominant, but a few are autosomal recessive transmissions. Reference Shauer, Shor and Wei10 A total of 96% of ryanodine receptor 2 mutations associated with catecholaminergic polymorphic ventricular tachycardia are missense variants, resulting in a gain-of-function of the ryanodine receptor 2 channel. Diastolic calcium in the sarcoplasmic reticulum excessively accumulates and spontaneously releases into the cytoplasm. Reference Wleklinski, Kannankeril and Knollmann11 This causes delayed after depolarisations and triggered activity via the Na+/Ca2+ exchanger current, leading to malignant ventricular arrhythmias, especially during exertion or emotional stress as catecholamine-mediated beta-adrenergic receptor activation induces calcium releases in the sarcoplasmic reticulum. Reference Cerrone, Napolitano and Priori12

Catecholaminergic polymorphic ventricular tachycardia can be diagnosed according to one of the following: (1) in the presence of unexplained exercise-or catecholamine-induced bidirectional or polymorphic ventricular premature beats or (ventricular tachycardia) with normal heart structure and normal rest electrocardiogram; (2) patients who have pathogenic or likely pathogenic heterozygous variants in ryanodine receptor 2, CALM1, CALM2, CALM3, CASQ2, or KCNJ2 or biallelic pathogenic (or likely pathogenic) variants in CASQ2, TECRL, or TRDN; (3) in family members of a catecholaminergic polymorphic ventricular tachycardia index case with a normal heart structure who presents exercise-induced PVCs or bidirectional/polymorphic ventricular tachycardia. Reference Zeppenfeld, Tfelt-Hansen and de Riva13 Our two patients fulfilled the diagnostic criteria. They experienced syncope during exertion or emotional stress, and ventricular bigeminy or polymorphic ventricular tachycardia with various sources was documented. The whole-exome gene sequencing indicated heterozygous missense variants in the ryanodine receptor 2 gene. In case 1, the patient has a nucleotide mutation of the ryanodine receptor 2 gene with c.6938T>G. The sequence falls in exon 46 of ryanodine receptor 2 and changes the encoded amino acid sequence from Val to Gly. In case 2, the patient has a nucleotide mutation of ryanodine receptor 2 gene with c.12263A>C. The sequence falls in exon 90 of ryanodine receptor 2 and changes the amino acid sequence from His to Pro. Until now, no research has demonstrated ryanodine receptor 2 gene mutation with c.6938T>G or c.12263A>C. Based on the clinical manifestations of the two patients, the two novel ryanodine receptor 2 variants were deemed to be potentially pathogenic. Nevertheless, additional functional studies are necessary to validate the pathogenicity.

A previous study reviewed 14 studies about catecholaminergic polymorphic ventricular tachycardia. Reference Abdullah and Ali14 A total of 90 patients aged from 4 weeks to 18 years old were included. The mean age at presentation was 11 ± 4 years old. Forty-six cases were males (51.1%), forty-two were female (46.6%), and 2 were unspecified. A total of 72 patients (80.0%) presented typical episodes of syncope, and 13 patients (14.4%) had the initial presentation of both syncope and seizure. It is worth noting that 4 patients (4.4%) experienced syncopal attacks without exercise or stress-induced events. A total of 3 patients (3.3%) presented with sudden cardiac arrest. In another multicentre study, 95 paediatric patients with catecholaminergic polymorphic ventricular tachycardia were reported. Reference Yan, Tang and Wang15 The mean age of symptom onset was 8.7 ± 3.0 years old, and the mean age of diagnosis was 12.9 ± 6.8 years old. A total of 99.0% of patients were admitted for recurrent syncope induced by exercise or emotional stress. A total of 13 patients (13.7%) encountered cardiac arrest. A total of 16 cases (25.8%) had a family history of possible catecholaminergic polymorphic ventricular tachycardia. A total of 13 patients (13.7%) were misdiagnosed with epilepsy. A total of 79 (83.2%) of these patients received genetic tests, among whom 67 cases (84.8%) had positive results, with 47 cases (70.1%) presenting variants in the ryanodine receptor 2. In the study of a Taiwanese cohort, 40 patients were clinically diagnosed with catecholaminergic polymorphic ventricular tachycardia, among which 29 patients had catecholaminergic polymorphic ventricular tachycardia-related gene mutations with 55% of ryanodine receptor 2 mutations. Exercise-induced syncope and cardiac arrest were more common in East Asian cohorts compared with Caucasian cohorts (79% vs. 59%). Reference Hsu, Wu and Chuang16 In our study, the initial presentation age of the two patients was seven years old, and the diagnostic age was nine years old. They seemed to be diagnosed earlier than those in previous studies as the disease is recognised further. The two patients presented typical episodes of syncope during exertion or emotional stress.

The exercise stress test presenting a bidirectional or polymorphic ventricular tachycardia was considered the cornerstone for the diagnosis of catecholaminergic polymorphic ventricular tachycardia in the absence of structural or functional abnormalities. However, the repeatability of ventricular arrhythmia induced by an exercise stress test was moderated. Reference Peltenburg, Pultoo and Tobert17 A negative exercise stress test cannot exclude the diagnosis. Reference Sy, Gollob and Klein18 In symptomatic individuals from families with pathogenic ryanodine receptor 2 mutations, the exercise stress exhibited a sensitivity of 60% and a specificity of 100% for the diagnosis of catecholaminergic polymorphic ventricular tachycardia. Reference Kukavica, Pili and Trancuccio19,Reference Bauce, Rampazzo and Basso20 For asymptomatic relatives of catecholaminergic polymorphic ventricular tachycardia probands carrying mutations in ryanodine receptor 2 or CASQ2, the test yielded a sensitivity of 50% and a specificity of 97%. Reference Henriquez, Hernandez and Mundla21 A 24-h ambulatory electrocardiogram is also important to show the presence of ventricular arrhythmias in children during daily life. Reference Peltenburg, Gibson, Wilde, van der Werf, Clur and Blom22 For our two patients, one underwent an exercise stress test, and one received a 24-h ambulatory electrocardiogram, and the results demonstrated the presence of ventricular bigeminy or non-sustained polymorphic ventricular tachycardia. The whole-exome gene sequencing demonstrated novel variants in ryanodine receptor 2.

For management, recommendations of medication combined with lifestyle, particularly sports restrictions in high-risk patients, are critical to prevent arrhythmic events. A β-blocker is the mainstay of therapy. Reference Baltogiannis, Lysitsas and di Giovanni23 Compared with nonselective β-blockers, β1-selective β-blockers are associated with a remarkably higher risk for arrhythmic events in symptomatic children with catecholaminergic polymorphic ventricular tachycardia. Nadolol, if not available, propranolol is the preferred β-blocker for treating catecholaminergic polymorphic ventricular tachycardia. Reference Peltenburg, Kallas and Bos24 Flecainide directly suppresses sarcoplasmic reticulum calcium release, the cellular mechanism inducing ventricular arrhythmia in catecholaminergic polymorphic ventricular tachycardia. In a multicentre study, catecholaminergic polymorphic ventricular tachycardia patients with maximally tolerated β-blocker treatment continued to receive flecainide. The results demonstrated that flecainide combined with a β-blocker remarkably decreased ventricular arrhythmia during exertion compared with a β-blocker alone. Reference Kannankeril, Moore and Cerrone25 For patients who have no response to optimal medical management or encounter a cardiac arrest before the onset of therapy other than β-blockers or β-blockers in combination with flecainide, an ICD should be implanted. Reference Priori, Wilde and Horie26 However, due to the risk of appropriate and inappropriate shocks of ICD, appropriate device programming may be crucial. A comprehensive assessment of its benefits and risks is required before implantation of ICD. Reference Lamba, Roston and Peltenburg27

Our study has several limitations. First, although we speculate that the de novo mutation is a pathogenic variant, its potential pathogenic mechanism should be investigated. Functional studies are therefore warranted. Additionally, the follow-up duration was relatively short. Long-term follow-up is required to evaluate the prognosis of the two patients. Moreover, a repeated treadmill exercise test should be performed during subsequent follow-ups to assess the therapeutic efficacy.

Conclusions

For recurrent syncope triggered by exertion or emotional stress, the diagnosis of catecholaminergic polymorphic ventricular tachycardia should be considered. The electrocardiogram changes in a stress or provocation test and genetic testing server as a valuable tool for confirming the diagnosis of catecholaminergic polymorphic ventricular tachycardia. Our two patients presented clinical characteristics similar to those of previously reported patients with a ryanodine receptor 2 gene mutation. Two novel ryanodine receptor 2 variants: c.6938T>G/p. Val2313Gly and c.12263A>C/p. His4088Pro may be associated with catecholaminergic polymorphic ventricular tachycardia. β-blockers alone or in combination with flecainide should be administered to reduce exercise-induced ventricular arrhythmias. For those patients who experienced cardiac arrest, an ICD is indicated.

Data availability statement

All data generated or analysed during this study are included in this published article.

Acknowledgements

We thank the study participants for volunteering to participate in this study.

Author contributions

RZ and CW conceived the research. SW, PL, HC, LL, FL and YW collected and reviewed subjects’ data. RZ drafted the manuscript. All authors contributed to its revision.

Financial support

Natural Science Foundation of Hunan Province (2021JJ70093, 2023JJ30812, 2025JJ81175) and Department of Science and Technology of Hunan Province (2025ZK4179).

Competing interests

None of the authors have any conflicts of interest.

Ethical standard

This study has been approved by the Ethics Committee of The Second Xiangya Hospital, Central South University. The study complies with the Declaration of Helsinki. The informed consent to participate has been obtained from the patients’ parents.

Consent for publication

The informed consent for publication has been obtained from the patients’ parents.

References

Hu, E, Liu, X, Chen, Q, Wang, C. Investigation on the incidence of syncope in children and adolescents aged 2–18 years in Changsha. Front Pediatr 2021; 9: 638394.CrossRefGoogle ScholarPubMed
Wang, C, Liao, Y, Wang, S, et al. Guidelines for the diagnosis and treatment of neurally mediated syncope in children and adolescents (revised 2024). World J Pediatr 2024; 20(10): 983–1002.CrossRefGoogle ScholarPubMed
Schunk, PC, Ruttan, T. Pediatric syncope: high-risk conditions and reasonable approach. Emerg Med Clin North Am 2018; 36(2): 305–321.CrossRefGoogle ScholarPubMed
Aggarwal, A, Stolear, A, Alam, MM, et al. Catecholaminergic polymorphic ventricular tachycardia: clinical characteristics, diagnostic evaluation and therapeutic strategies. J Clin Med 2024; 13(6): 1781.CrossRefGoogle ScholarPubMed
Mariani, MV, Pierucci, N, Fanisio, F, et al. Inherited arrhythmias in the pediatric population: an updated overview. Medicina (Kaunas) 2024; 60(1): 94.CrossRefGoogle ScholarPubMed
Napolitano, C, Bloise, R, Monteforte, N, Priori, SG. Sudden cardiac death and genetic ion channelopathies: long QT, Brugada, short QT, catecholaminergic polymorphic ventricular tachycardia, and idiopathic ventricular fibrillation. Circulation 2012; 125(16): 2027–2034.CrossRefGoogle ScholarPubMed
Priori, SG, Napolitano, C, Tiso, N, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 2001; 103(2): 196–200.CrossRefGoogle ScholarPubMed
Priori, SG, Mazzanti, A, Santiago, DJ, Kukavica, D, Trancuccio, A, Kovacic, JC. Precision medicine in catecholaminergic polymorphic ventricular tachycardia: JACC focus seminar 5/5. J Am Coll Cardiol 2021; 77(20): 2592–2612.CrossRefGoogle ScholarPubMed
Peng, W, Shen, H, Wu, J, et al. Structural basis for the gating mechanism of the type 2 ryanodine receptor RyR2. Science 2016; 354(6310): aah5324.CrossRefGoogle ScholarPubMed
Shauer, A, Shor, O, Wei, J, et al. Novel RyR2 mutation (G3118R) is associated with autosomal recessive ventricular fibrillation and sudden death: clinical, functional, and computational analysis. J Am Heart Assoc 2021; 10(6): e017128.CrossRefGoogle ScholarPubMed
Wleklinski, MJ, Kannankeril, PJ, Knollmann, BC. Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia. J Physiol 2020; 598(14): 2817–2834.CrossRefGoogle ScholarPubMed
Cerrone, M, Napolitano, C, Priori, SG. Catecholaminergic polymorphic ventricular tachycardia: a paradigm to understand mechanisms of arrhythmias associated to impaired Ca(2+) regulation. Heart Rhythm 2009; 6(11): 1652–1659.CrossRefGoogle ScholarPubMed
Zeppenfeld, K, Tfelt-Hansen, J, de Riva, M, et al. ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J 2022; 43(40): 3997–4126.CrossRefGoogle ScholarPubMed
Abdullah, NM, Ali, A. RYR2 receptor gene mutation associated with catecholaminergic polymorphic ventricular tachycardia in children: a case report & literature review. Transl Pediatr 2024; 13(2): 359–369.CrossRefGoogle ScholarPubMed
Yan, Y, Tang, L, Wang, X, et al. Clinical and genetic profiles of Chinese pediatric patients with catecholaminergic polymorphic ventricular tachycardia. Orphanet J Rare Dis 2023; 18(1): 380.CrossRefGoogle ScholarPubMed
Hsu, GC, Wu, MH, Chuang, JY, et al. Genetic and clinical characteristics of catecholaminergic polymorphic ventricular tachycardia in a Taiwanese nationwide cohort. J Formos Med Assoc 2025; 124(8): 700–705.CrossRefGoogle Scholar
Peltenburg, PJ, Pultoo, SNJ, Tobert, KE, et al. Repeatability of ventricular arrhythmia characteristics on the exercise-stress test in RYR2-mediated catecholaminergic polymorphic ventricular tachycardia. Europace 2023; 25(2): 619–626.CrossRefGoogle ScholarPubMed
Sy, RW, Gollob, MH, Klein, GJ, et al. Arrhythmia characterization and long-term outcomes in catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm 2011; 8(6): 864–871.CrossRefGoogle ScholarPubMed
Kukavica, D, Pili, G, Trancuccio, A, et al. Prognostic relevance of baseline exercise stress test in RYR2-related CPVT. Europace 2025; 27(2): euae294.CrossRefGoogle ScholarPubMed
Bauce, B, Rampazzo, A, Basso, C, et al. Screening for ryanodine receptor type 2 mutations in families with effort-induced polymorphic ventricular arrhythmias and sudden death: early diagnosis of asymptomatic carriers. J Am Coll Cardiol 2002; 40(2): 341–349.CrossRefGoogle ScholarPubMed
Henriquez, E, Hernandez, EA, Mundla, SR, et al. Catecholaminergic polymorphic ventricular tachycardia and gene therapy: a comprehensive review of the literature. Cureus 2023; 15(10): e47974.Google ScholarPubMed
Peltenburg, PJ, Gibson, H, Wilde, AAM, van der Werf, C, Clur, SB, Blom, NA. Prognosis and clinical management of asymptomatic family members with RYR2-mediated catecholaminergic polymorphic ventricular tachycardia: a review. Cardiol Young 2024; 34(6): 1182–1189.CrossRefGoogle ScholarPubMed
Baltogiannis, GG, Lysitsas, DN, di Giovanni, G, et al. CPVT: arrhythmogenesis, therapeutic management, and future perspectives. A brief review of the literature. Front Cardiovasc Med 2019; 6: 92.CrossRefGoogle ScholarPubMed
Peltenburg, PJ, Kallas, D, Bos, JM, et al. An international multicenter cohort study on beta-blockers for the treatment of symptomatic children with catecholaminergic polymorphic ventricular tachycardia. Circulation 2022; 145(5): 333–344.CrossRefGoogle ScholarPubMed
Kannankeril, PJ, Moore, JP, Cerrone, M, et al. Efficacy of flecainide in the treatment of catecholaminergic polymorphic ventricular tachycardia: a randomized clinical trial. JAMA Cardiol 2017; 2(7): 759–766.CrossRefGoogle ScholarPubMed
Priori, SG, Wilde, AA, Horie, M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: Document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013; 10(12): 1932–1963.CrossRefGoogle ScholarPubMed
Lamba, A, Roston, TM, Peltenburg, PJ, et al. An international multicenter cohort study on implantable cardioverter-defibrillators for the treatment of symptomatic children with catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm 2024; 21(10): 1767–1776.CrossRefGoogle ScholarPubMed
Figure 0

Figure 1. Figure 1 long description.ECG examination of patient 1 under exercise on a treadmill test. The red arrows show ventricular bigeminy. The black arrow shows the termination of the exercise treadmill test. Ventricular bigeminy appeared when the heart rate increased to 164 beats per minute (bpm) (accounting for 77% of the predicted maximum heart rate) during the first stage of the exercise treadmill test.

Figure 1

Figure 2. Figure 2 long description.The whole-exome gene sequencing results of patient 1. The black arrow shows the mutant site.

Figure 2

Figure 3. Figure 3 long description.24 h ambulatory ECG examination of patient 2. The red arrow shows ventricular bigeminy and non-sustained polymorphic ventricular tachycardia.

Figure 3

Figure 4. Figure 4 long description.The whole-exome gene sequencing results of patient 2. The black arrow shows the mutant site.