*Note that Cardiology Genetics – has a mandatory statement of informed consent. It is attached as a third page to the above.
Catecholaminergic Polymorphic Ventricular Tachycardia and its Genetics
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially fatal cardiac arrhythmia in individuals with a structurally normal heart. The disorder is characterized by syncope, typically beginning in the first decade of life, which may be triggered by physical activity or intense emotion. In patients with CPVT, stress-induced releases of catecholamines cause a dysfunction of calcium-ion channel in myocytes. The ion channel dysfunction induces ventricular arrhythmias, which can lead to syncope or sudden cardiac death. Spontaneous recovery from the arrhythmia is possible, but the ventricular tachycardia can progress to ventricular fibrillation and sudden death.
CPVT is most commonly an autosomal dominant genetic disorder with mutations affecting calcium regulation within the heart. A less frequent autosomal recessive disorder is clinically identical. Almost 30% of patients with CPVT have a relative who died suddenly prior to age 40 (Priori et al 2002). CPVT affects men and women equally. The incidence of CPVT within the population is not precisely known, but is estimated to be 1:10,000 (Liu et al. 2008).
In many cases, the first clinical manifestation of CPVT is syncope triggered by acute emotional or physical stress. The average age of symptom onset is between 7 and 9 years (Priori et al. 2002; Leenhardt et al. 1995), but a wide range of ages has been observed. The diagnosis of CPVT is often not obvious because resting electrocardiograms (ECGs) appear normal. The CPVT diagnosis is frequently missed unless an exercise stress test or Holter is performed to document ventricular arrhythmias. Symptoms of CPVT, which may occur without warning, include heart palpitations, dizziness and syncope occurring during physical activity or acute emotion. The distinguishing characteristic of CPVT is an alternating QRS axis morphology with rotation of 180° on a beat-to-beat basis (Liu et al. 2008). Bidirectional ventricular tachycardia is typical of CPVT, but is present in less than half of cases. When the typical bidirectional VT is not observed, progressive worsening of arrhythmias with increasing exercise workload may help establish the diagnosis (See Figure 1). In some cases, sudden death can be the first symptom. Approximately 30% of probands present with a family history of stress-related syncope, seizure, or sudden death; therefore, a detailed family history may help establishing the proper diagnosis.
Figure 1. (Right) Exercise stress test in a patient with polymorphic VT and RyR2 mutation. Ventricular arrhythmias are observed with a progressive worsening during exercise. Typical bidirectional VT develops after 1 minute of exercise with a sinus heart rate of approximately 120 beats per minute. Arrhythmias rapidly recede during recovery. (Image from Liu et al. 2008)
||Potassium channel, inwardly rectifying subfamily J member 2
||Ryanodine receptor 2
Genetics of CPVT
Mutations in at least two genes have been associated with CPVT—RYR2, which codes for the cardiac ryanodine receptor channel, and CASQ2, which encodes calsequestrin, a calcium buffering protein in the sarcoplasmic reticulum (SR) (Priori et al. 2002). Mutations in these two genes account for 51%-56% CPVT cases. The majority of identifiable mutations occur in the RYR2 gene, which is inherited in an autosomal dominant manner. Each child of an individual with autosomal-dominant RYR2 associated CPVT has a 50% chance of inheriting the mutation. De novo mutations have been observed and may account for half of autosomal dominant CPVT, likely due to the high rate of premature death (Napolitano et al 2009). Less frequent are mutations in the CASQ2 gene, an autosomal recessive genetic disorder. Parents of an affected child are unaffected carriers, while full-siblings of the proband have a 25% chance to also have CPVT.
Genetic testing for CPVT and its utility
Diagnostic genetic testing can be considered for patients who clinically manifest with symptoms of CPVT and for patients who are asymptomatic but are within a family with a known mutation. Testing should be performed first on the family member who is symptomatic, i.e. has clinical manifestations of CPVT. Preferably, the youngest of most severely affected family member should be tested first. The three possible outcomes of genetic testing are: positive, negative, and variant of unknown clinical significance (VOUS). Identification of a mutation in the family can lead to genetic identification of at risk family members who are clinically asymptomatic and who may have normal ECGs. Family members who test positive for the familial mutation should have regular cardiac evaluations. Alternatively, a negative genetic test result for the familial mutation would obviate the need for repeated follow-up examinations. Genetic testing can be used for prenatal diagnosis. All patients who undergo genetic testing should receive pre-test and post-test genetic counseling to understand the implications of testing.
Resources for Patients
- GeneDx cardiology page
- Gene Reviews, a database of genetic diseases: www.geneclinics.org
- National Society of Genetic Counselors, to help you find a counselor near you: www.nsgc.org
- Sudden Arrhythmia Death Syndrome (SADS), a patient support organization: www.sads.org
- Cardiac Arrhythmias Research and Education Foundation (C.A.R.E.), a patient support organization: www.longqt.org
- The Canadian Sudden Arrhythmia Death Syndromes (SADS) Foundation, a patient support organization in Canada: www.sads.ca
- Sudden Cardiac Arrest Association, a patient support organization: www.suddencardiacarrest.org
- GeneReviews. NCBI/NIH. Initial posting 2004, last update 2009.
- Liu N, Ruan Y, Priori SG. Catecholaminergic Polymorphic Ventricular Tachycardia. Progress in Cardiovascular Diseases. 51(1); 2008. 23-30 PMID: 18634915
- Leenhardt A, Lucet V, Denjoy I et al. Catecholaminergic polymorphic ventricular tachycardia in children: a seven-year follow-up of 21 patients. Circulation 91: 1512-1519. 1995. PMID: 7867192
- Priori SG, Napolitano C, Memmi M et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 106; 69-74. 2002. PMID: 12093772