Ventricular Tachycardia, Catecholaminergic Polymorphic, 3

A number sign (#) is used with this entry because of evidence that catecholaminergic polymorphic ventricular tachycardia-3 (CPVT3) is caused by homozygous mutation in the TECRL gene (617242) on chromosome 4q13.


Catecholaminergic polymorphic ventricular tachycardia-3 (CPVT3) is characterized by overlapping features of long QT syndrome (see 192500) and CPVT. Affected individuals exhibit adrenergic ventricular tachycardia associated with a high prevalence of cardiac arrest and sudden cardiac death, with recurrent atrial tachycardia sometimes triggering the ventricular arrhythmias. In addition, affected individuals have a normal or mildly prolonged QTc on baseline electrocardiography, with a paradoxical QT increase during adrenergic simulation (summary by Devalla et al., 2016).

For a general phenotypic description and a discussion of genetic heterogeneity of CPVT, see 604772.

Clinical Features

Bhuiyan et al. (2007) studied a large consanguineous family of Sudanese origin in which 3 sibs died suddenly during physical activity. The first death occurred in a 10-year-old girl who died while playing in a fun park; no evaluation was performed. The second death involved her younger brother, who collapsed at 12 years of age while skating; during resuscitation he was noted to have several episodes of ventricular tachycardia. Electrocardiography (ECG) revealed a mildly prolonged QTc (450 to 490 ms) and premature ventricular contractions (PVCs) with a right bundle branch block (RBBB) morphology and superior axis, indicating a left ventricular origin. ECG showed no structural cardiac anomaly. He remained in a vegetative state until his death from pneumonia 2 years later. The third sib was a younger sister who underwent palliative surgery for tetralogy of Fallot in infancy, at which time ECG revealed a QTc of 440 ms; ECG at 14 months of age showed QTc of 480 to 490 ms. After corrective cardiac surgery at 3 years of age, ECG showed RBBB with QRS duration of 110 ms and QTc of 470 to 490 ms (uncorrected for widened QRS complex). She collapsed and died while playing sports at 8 years of age. A 7-year-old male cousin, also born of consanguineous parents, was the only surviving patient. ECG after a syncopal episode while playing outdoors showed borderline prolonged QTc of 480 ms; echocardiogram was normal. Exercise stress testing revealed isolated PVCs at a heart rate of 144 bpm, with couplets appearing at a heart rate of 170 bpm after exercising for 6 minutes, at which time the test was terminated. He was put on a beta-blocker and restricted from exercise and was still alive at follow-up 18 months later. The parents were all asymptomatic, and the parents of the surviving patient had normal ECGs; 3 asymptomatic sibs of the deceased sibs had no PVCs on 24-hour ECG monitoring.

Devalla et al. (2016) studied 2 unrelated French Canadian women who were successfully rescuscitated from cardiac arrest. The first presented with ventricular fibrillation and cardiac arrest while walking at age 22 years, without prior history of syncope or documented arrhythmia. Coronary angiography, echocardiography, and invasive electrophysiologic (EP) testing were normal. Resting ECG showed a normal QT interval, but isoproterenol infusion resulted in QT prolongation. During follow-up the patient had recurrent episodes of exercise- or emotion-induced atrial and ventricular arrhythmias, resulting in multiple shocks from an implantable cardioverter-defibrillator (ICD). In addition, significant repolarization abnormalities with QT prolongation (QTc range, 451-494 ms) were occasionally seen on resting ECGs, and the patient was given a diagnosis of long QT syndrome (LQTS). Family history was negative for sudden cardiac death except for a paternal cousin who died suddenly at age 34 years; no details were available. The second French Canadian woman presented at age 18 with numerous syncopal episodes triggered by emotional stress and documentation of nonsustained ventricular tachycardia (VT) during exercise stress testing. Despite beta-blocker therapy, she experienced aborted cardiac arrest at age 31 years. QTc at rest was 437 ms with repolarization abnormalities. Isoproterenol infusion induced sustained polymorphic VT, and epinephrine challenge resulted in a 57-ms paradoxical QT prolongation with ventricular bigeminy, suggesting a low repolarization reserve consistent with LQTS. During follow-up, the patient had multiple episodes of adrenergic atrial and ventricular arrhythmias, provoked by either exercise or emotion, resulting in numerous ICD shocks. EP mapping revealed an extensive low-voltage area along the interatrial septum, as well as multiple foci of atrial tachycardia that were successfully ablated. Family history was negative for arrhythmias, and the proband's 2 sons were asymptomatic with normal baseline ECGs and 24-hour Holter monitoring. In addition, her father was asymptomatic, with a normal ECG and negative epinephrine test. Devalla et al. (2016) also restudied the consanguineous Sudanese family originally reported by Bhuiyan et al. (2007), noting that 7 of 13 children had experienced exertion-induced arrhythmias and/or sudden cardiac death in early childhood; 5 of the 7 children had undergone a fatal arrhythmic episode.


In a large consanguineous family of Sudanese origin with a history of sudden death following exercise, negative for mutation in 11 genes involved in cardiac electric impulse propagation, including RYR2 (180902) and CASQ2 (114251), Bhuiyan et al. (2007) performed whole genome scanning and identified a homozygous region on chromosome 7p22-p14 that was shared by the 2 deceased sibs from whom DNA was available and their affected cousin. Mapping with additional markers revealed a 25-Mb interval flanked by D7S526 distally and D7S481 proximally that showed complete cosegregation with disease. A maximum multipoint lod score of 3.17 was obtained with marker D7S493. No significant sequence alterations were detected in coding exons or exon-intron boundaries of screened candidate genes in that region.

Devalla et al. (2016) restudied the Sudanese family originally reported by Bhuiyan et al. (2007) and noted that reanalysis with inclusion of a young family member who was only later identified as affected indicated that the consensus homozygous locus in all affected individuals was on chromosome 4.

Molecular Genetics

In a consanguineous Sudanese family with CPVT and QT prolongation, previously studied by Bhuiyan et al. (2007), Devalla et al. (2016) performed whole-exome sequencing and identified homozygosity for a splice site mutation in the TECRL gene (617242.0001) that segregated fully with disease in the family. By whole-exome sequencing in 2 unrelated French Canadian women with CPVT and prolongation of the QT interval, who were negative for mutation in the 5 genes most commonly associated with LQT, they identified homozygosity for the same missense mutation in TECRL (R196Q; 617242.0002).