1. NGS panel - Genetic testing for catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia

March 27, 2017

Clinical features

Catecholamine-induced polymorphic ventricular tachycardia (CPVT) is a pathological disorder triggered by intense physical exercise or acute emotional stress. These conditions could initiate abnormal heartbeat (ventricular tachycardia) which then leads to dizziness, syncope, and in worst cases sudden death due to cardiac arrest.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) should be suspected in individuals who have one or more of the following 1,2:

  • Syncope triggered by acute emotional state or during physical activity/exercise and history of exercise/stress-related palpitations and dizziness
  • Sudden unexpected cardiac death triggered by exercise or acute emotional stress
  • Positive family history of juvenile sudden cardiac death triggered by exercise or acute stress
  • Exercise-induced polymorphic ventricular arrhythmias
  • Some affected patients with CPVT may present with irregular polymorphic ventricular tachycardia (VT)
  • Common findings in CPVT-affected patients are also exercise-induced supraventricular arrhythmias (supraventricular tachycardia and atrial fibrillation)
  • Ventricular fibrillation occurring in the setting of acute stress
  • Most commonly, patients present with the absence of structural cardiac abnormalities.

CPVT is a rare disease with an estimated prevalence of 1:10,000 2. The mean age of onset of CPVT symptoms, in a form of syncopal episode, is at an early age, between seven and twelve years 3. Interestingly, SIDS syndrome (sudden infant death syndrome) has been associated most commonly with pathogenic variants in the gene RYR2 4. Furthermore, a positive family history of sudden death in relatives younger than age 40 year is present in approximately 30% of patients with CPVT 5.

CPVT is a disease with a strong genetic background. The genes CASQ2, RYR2, and KCNJ2 are involved in the control of intracellular calcium fluxes, sarcoplasmic reticulum calcium release, and the cytosolic free Ca+2 concentration. Thus, these genes comprise CENTOGENE´s CPVT panel (see Table 1).

RYR2 pathogenic variants cause about half of all CPVT cases, impairing calcium release from the sarcoplasmic reticulum in conditions of catecholamine activation and thus causing subsequent electrical instability and arrhythmias. Mutations in RYR2 are found in approximately 60% of individuals with a diagnosis of CPVT7. More than 280 RYR2 pathogenic variants have been reported to date, of which 150 were associated with CPVT, while additional variants are associated with Long QT syndrome and other forms of arrhythmias (HGMD® Professional 2016.4).

CASQ2 encodes for the cardiac isoform of calsequestrin, calsequestrin-2, a SR protein functionally and physically related to the ryanodine receptor, with the function of buffering the Ca2+ ions. More than 30 pathogenic variants have been reported in CASQ2 gene, 19 of which are associated with CPVT (mostly missense and splicing mutations and 4 small deletions). All of the reported mutations cause a recessive phenotype with the exception of a missense mutation p.Lys180Arg, which is associated with a dominant CPVT phenotype. The pathophysiology of CASQ2-related CPVT may be related to the loss of calcium buffering capability, and indirect destabilization of the RyR channel opening process.

The third gene included in CENTOGENE´s CPVT panel is KCNJ2, encoding for the Kir2.1 subunit for inward-rectifier potassium channels. 9 The majority of mutations identified in this gene cause Andersen syndrome, an autosomal dominant multisystem channelopathy characterized by ventricular arrhythmias, periodic paralysis, and dysmorphic features. However, some KCNJ2 mutation carriers lack the Andersen syndrome triad of symptoms and they show phenotype of catecholaminergic polymorphic ventricular tachycardia. More than 80 mutations, mostly missense, were reported in the KCNJ2 gene so far.


Overview of the genes in the CENTOGENE´s Catecholaminergic polymorphic ventricular tachycardia panel

Gene OMIM
Locus
Protein % of mutations Allelic disorders
RYR2 180902
1q43
Ryanodine receptor 2 50%-55%2, 3 Ventricular tachycardia,
catecholaminergic polymorphic, 1
Arrhythmogenic right ventricular dysplasia 2
CASQ2 114251
1p13.1
Calsequestrin-2 2%-5% 6, 7 Ventricular tachycardia,
catecholaminergic polymorphic, 2
KCNJ2 600681
17q24.3
Potassium channel Kir2.1 6%, 7% (2/28) 8, 9 Atrial fibrillation, familial, 9
Andersen periodic paralisis syndrome
Short QT syndrome 3

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is treated with beta-blockers as a basic therapy. Non-selective beta-blockers are recommended in all individuals in the absence of contraindications (e.g., asthma). An implantable cardioverter defibrillator (ICD) may be essential for patients with recurrent cardiac arrest while on beta-blocker therapy. Furthermore, left cardiac sympathetic denervation (LCSD) can be considered in those patients who are refractory to other therapies (intolerant to beta-blockers). Clinical trials with human inducible pluripotent stem cells in hereditary cardiac arrhythmias are in progress.

Based on the most recent literature, CENTOGENE experts have designed the Catecholaminergic polymorphic ventricular tachycardia panel which includes the genes: RYR2, CASQ2, and KCNJ2 (Table 1). CENTOGENE offers the Catecholaminergic polymorphic ventricular tachycardia panel, including full gene sequencing and deletion/duplication analysis of selected genes (RYR2, KCNJ2). In addition, any of the genes in the Catecholaminergic polymorphic ventricular tachycardia panel can also be ordered individually, for full gene sequencing and deletion/duplication analysis.


Differential diagnosis

The differential diagnosis of Catecholaminergic polymorphic ventricular tachycardia-related disorders – depending on the major symptoms in the initial case – includes the following diseases6:

  • Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC)
  • Long QT syndrome
  • Short-coupled ventricular tachycardia (SC-torsade de pointes [TdP]) I
  • Andersen-Tawil syndrome (ATS, LQTS type 7)
  • Hypokalemia or hypokalemic periodic paralysis

Testing strategy

CENTOGENE offers advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on the PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and provides sequencing of entire gene at a more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Catecholaminergic polymorphic ventricular tachycardia using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Catecholaminergic polymorphic ventricular tachycardia panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Catecholaminergic polymorphic ventricular tachycardia panel, based on the approval and consent, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.


Referral reasons

The following individuals are candidates for this particular gene testing:

  • Individuals with a family history of disease and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling this disease
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of this gene and related genes should be performed in all individuals suspected for this particular phenotype. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management.

Genetic counseling can provide a patient and/or family with the natural history of the condition, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.


More information on CENTOGENE´s Catecholaminergic polymorphic ventricular tachycardia panel can be found in our genetic test catalogue.