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Genetic testing for Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (R129)

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is characterised by a reproducible form of polymorphic ventricular tachycardia induced by physical activity, stress, or catecholamine infusion, which can deteriorate into ventricular fibrillation.

Background information

Patients present with recurrent syncope, seizures, or sudden death after physical activity or emotional stress.

Currently there are seven genes on the panel.

CPVT is predominantly caused by autosomal dominant variants in the cardiac ryanodine receptor, RYR2. Missense variants gene account for around 20 percent of cases although a very rare deletion has been identified involving exon 3.

Pathogenic variants in the KCNJ2 gene are can be clinically interpreted as CPVT and individuals typically have a distinctive U–wave morphology on ECG. Pathogenic variants account for the majority of Andersen-Tawil syndrome (ATS) cases. ATS is characterised by periodic paralysis, cardiac arrhythmias, and distinctive facial and skeletal features. This gene is also included on the Long QT gene panel and testing for this gene alone is no longer offered.

Pathogenic variants in the CALM1, CALM2 and CALM3 genes are a very rare cause of CPVT. Individuals typically have severe cardiac arrhythmias which may be diagnosed as CPVT, Long QT Syndrome, or idiopathic ventricular fibrillation (IVF).

Autosomal recessive variants in CASQ2 and TRDN are a very rare cause of CPVT.

Testing strategy

Clinically affected probands:

R129 - Singleton analysis of seven genes. Data from the key coding regions (codons 44 to 466, 2147-2534, and 3778-4959) of the main transcript of RYR2 is always included.

Targeted analysis for known / previously reported familial variants:

Family testing in clinically unaffected family members at risk of inheriting a previously reported familial pathogenic variant (R242)
Diagnostic confirmation in individuals at risk of inheriting a previously reported familial pathogenic variant and clinically suspected of having the familial condition (R240)
Segregation studies in affected family members to aid variant interpretation (R375)
Prenatal diagnosis for families with a pathogenic or likely pathogenic variant identified (R240 and R321 Maternal cell contamination)

Target reporting times

42 calendar days for diagnostic screening of affected individuals
42 calendar days for diagnostic confirmation in individuals at risk of inheriting a previously reported familial pathogenic variant and clinically suspected of having the familial condition (R240)
14 calendar days for presymptomatic testing of clinically unaffected family members at risk of inheriting a previously reported familial pathogenic variant (R242)

Turnaround times for genetic / genomic testing