Sudden cardiac death (SCD) in young and apparently healthy athletes, such as the basketball player Reggie Lewis, raises public awareness that identifying and preventing these unexpected and tragic events is important. SCD accounts for 200,000–250,000 deaths in the United States annually, including 100–150 during competitive sports.1,2 Autopsy studies have demonstrated that the majority (80%) of adult victims who suffer from SCD have coronary artery disease (CAD), 10–15% have dilated or hypertrophic cardiomyopathy, and the remaining have structurally normal hearts, suggesting a primary arrhythmogenic disease as the cause of death.3In the young (<30 years of age), the most common causes of SCD include cardiomyopathies, coronary anomalies, and primary arrhythmogenic diseases — conditions that are often inherited and predispose to malignant ventricular arrhythmias.4 Genetic testing can play an important role in the management of these inherited arrhythmogenic diseases (IAD).5
John (all patient names changed for privacy) battled lightheadedness, dyspnea on exertion, and palpitations for nearly 30 years. At age 53 he was finally diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC), also known as arrhythmogenic right ventricular dysplasia (ARVD), when he underwent cardiac magnetic resonance imaging (MRI) at UT-Southwestern Medical Center in Dallas. Knowing that ARVC is an inherited disorder, he also underwent genetic testing. John was a compound heterozygote (see below), meaning that he inherited one mutation from his father and another from his mother. He insisted that his daughter Karen, age 14 at the time, be tested. In fact, John’s aunt and his sister both died of SCD in their 50s. Karen tested positive for the genetic mutation and had an implantable cardioverter defibrillator (ICD) implanted. The ICD saved Karen’s life during two separate events: once when she experienced syncope due to a ventricular arrhythmia on the volleyball court and the other during her high school prom. In fact, Karen’s cousin Mary, who had been active all of her life, collapsed one day while running on the treadmill. Mary was successfully resuscitated and externally defibrillated after several attempts. She underwent genetic testing and was also found to have the same mutation for ARVC. John’s family now follows in the arrhythmia clinic, as well as the McDermott Center for Human Genetics clinic at UT-Southwestern Medical Center in Dallas. Although the interpretation of the now commercially available genetic testing can be complex, genetic testing in John’s case helped guide therapy and identified family members at risk of SCD.
Approximately 3 billion nucleotide base pairs make up the human genome, with close to 20,000 genes now identified. Nucleotide variations within the genome can serve as genetic markers to localize nearby disease-causing variations. The most common form of genetic variation is a single nucleotide polymorphism (SNP). SNPs are present in 1 in every 1,000 base pairs. Other important types of genetic variation include deletions, duplications, and copy number variations.6The majority of these variations are silent allelic variants that do not alter protein function. However, when differences in a single genetic locus cause a disease state, it is termed a Mendelian genetic disorder. A number of cardiovascular diseases that cause SCD are inherited in a Mendelian manner, usually autosomal dominant. The most common inherited cardiomyopathies predisposing to SCD include ARVC, hypertrophic cardiomyopathy (HCM), and some dilated cardiomyopathies (DCM). The principal channelopathies (resulting from mutation in ion channels) predisposing to SCD include long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT).5
The yield of genetic testing in these disease states is variable and sometimes perplexing because of genetic heterogeneity, incomplete penetrance, and variable expressivity. For example, the yield of mutation-specific genetic testing for LQTS is approximately 75% and for BrS is only 20%.7 Additionally, many disease-causing mutations have yet to be identified. Nonetheless, improvements in both DNA sequence analysis and data analysis methodologies have led to the clinical use of genetic testing in these IADs. Commonly used terms in clinical genetics are listed in Table 1.
Goals of Genetic Testing
Genetic tests should not be used for screening in the general population.7 Additionally, because of the complexity of the disease phenotype and genetic variants, testing should only be done after a full clinical evaluation has been completed. A thorough family history provides an idea of disease penetrance and phenotypic expressivity. Management of IADs should be multidisciplinary, including an electrophysiologist, clinical geneticist, genetic counselor, etc. Before genetic testing is done, patients should be counseled on the benefits, risks, options, and future implications of the test and test results. Therapeutic decisions should not be made solely based on genetic testing.
When an IAD is probable or certain in an index patient based on a comprehensive clinicalevaluation, genetic testing can help confirm the clinical diagnosis and risk stratify the individual and potentially his/her family members. For example, if a causative mutation for a high-yield disease state, i.e. LQTS, is identified in an index patient, a negative genetic test, normal electrocardiogram, and unremarkable history rule out LQTS in his/her family member. Molecular diagnosis via genetic testing has therapeutic implications as well. For instance, beta-blocker therapy is protective in LQT1 (mutation in the KCNQ1 gene) and not as helpful in LQT3 (mutation in the SCN5A gene). As more mutations are characterized, certain genotypes can now be classified as more malignant. Tables 2 and 3 describe when genetic testing should be done, as recommended by HRS/EHRA.
Other uses of genetic testing include molecular autopsy and prenatal diagnosis.5,8 When SCD occurs, especially in the young, and the anatomical autopsy is inconclusive, blood and frozen tissue samples of the heart from the victim can be tested for IAD. If a genetic test is positive, family screening is advised. The decision of individuals with an autosomal dominant IAD to conceive a child should involve consultation with a genetic counselor. One option is the use of in vitro fertilization with testing of the embryo for the specific mutation before being implanted in the mother.8 Ethical considerations, especially for couples requesting a prenatal diagnosis through amniocentesis to contemplate the termination of a pregnancy for a gene mutation, may apply in these situations.8
Complexities of Genetic Testing – Using ARVC as an Example
ARVC is caused by a disruption between cell-cell adhesions in the heart, specifically of the desmosomal proteins. The disorder classically affects the right ventricle, though the left ventricle may also be affected, and is characterized by fatty infiltration of the myocardium, leading to ventricular arrhythmias and SCD in young patients (ages <35). Patients often present with arrhythmia, rather than heart failure. As stated above, ARVC is typically transmitted as an autosomal dominant trait, but incomplete penetrance and variable expressivity may obscure Mendelian inheritance patterns.7
Prior to genetic testing, clinical suspicion based on the task force criteria9 and a thorough familyhistory of ARVC and SCD should be obtained. If a clinical diagnosis is uncertain, some suggest that the patient be referred to a high-volume center that specializes in the treatment of the particular disease.7 It must be emphasized that only about 30–50% of patients with ARVC have an abnormal gene that has been identified as causative. This means that other patients may have genetic mutations that have not yet been found. The most common causative gene for ARVC is plakophilin 2. This genetic abnormality may require a second mutation in that gene or in another desmosomal gene (desmoglein 2, desmoplakin, desmocollin 2, etc.) to render the disease phenotype. Therefore, an individual who has a mutation for ARVC inherits the risk of having the disease but may not manifest the disease phenotype. Our patient, John, as discussed above, is a compound heterozygote for ARVC; he inherited a mutation from his mother and another from his father in the same gene. In general, those with two mutations tend to have severe signs and symptoms of the disease.
Once a genetic defect is identified in the proband/index patient, mutation-specific testing is recommended to determine the risk of first-degree relatives (parents, siblings, offspring).5,7,8The discovery of the same gene defect in a family member indicates that they are at risk for developing ARVC. The family member should be monitored for the development of ARVC by electrocardiogram, echocardiogram, Holter monitor, or possibly a cardiac MRI. If no genetic defect is found in the family member, he/she likely will not have the disease. However, the proband may have an unidentified mutation that may be present in the family member, which could confound the clinical management/risk stratification.8 First-degree relatives in this situation may still warrant periodic screening for the disease. Some suggest consideration of testing at a research laboratory to characterize potential previously unidentified mutations.7
Genetic testing has been made commercially available and is paid for by most insurance companies. It is a useful tool to help confirm and risk stratify the clinical diagnosis of IADs. Furthermore, it can help identify family members at risk for SCD. Interpretation of genetic testing results for IADs requires specialized knowledge for the reasons stated above. At UT-Southwestern Medical Center in Dallas, patients with suspected IADs are referred to the clinical genetics clinic. They are seen by geneticists and genetic counselors to discuss the appropriateness and implications of genetic testing. Genetic laboratories used include GeneDx (www.genedx.com) and AMBRY Genetics (www.ambrygen.com). Typically a sample (2–5 mL) of whole blood in EDTA is sent for next-generation sequencing, which offers several multi-gene testing panels. They consist of a 12-gene LQTS panel, a 9-gene BrS panel, a 29-gene arrhythmia panel, or a “Pan Cardio Panel” of 79 genes that incorporates genes implicated in IDAs/SCD. Once a mutation (or mutations) has been identified, mutation-specific testing is offered to the first-degree relatives. Each family member is seen in separate clinic visits for pretest counseling. Tests take about 6-8 weeks to complete. Post-testing counseling is done to discuss the test results, especially important for both positive and inconclusive tests (variants of uncertain significance).
Disclosures: Dr. Lo has no conflicts of interest to report. Dr. Wu reports grants/grants pending to his institution from Medtronic, as well as travel/accommodations expenses covered or reimbursed by St. Jude Medical.
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- Chugh SS. Early identification of risk factors for sudden cardiac death. Nat Rev Cardiol. 2010;7(6):318-326.
- Adabag AS, Luepker RV, Roger VL, Gersh BJ. Sudden cardiac death: epidemiology and risk factors. Nat Rev Cardiol. 2010;7(4):216-225.
- Shen WK, Edwards WD, Hammill SC, Bailey KR, Ballard DJ, Gersh BJ. Sudden unexpected nontraumatic death in 54 young adults: a 30-year population-based study.Am J Cardiol. 1995;76(3):148-152.
- Mazzanti A, O’Rourke S, Kanthan A, Priori S. Genetic testing for inherited arrhythmic conditions. Cardiac Rhythm Management: A CardioSource Clinical Community. Published March 29, 2013. Available online at http://cardiosource.org/crm/learn-from-the-experts/2013/03/genetic-testing-for-inherited-arrhythmic-conditions.aspx. Accessed April 22, 2013.
- Ho E, Bhindi R, Ashley EA, Figtree GA. Genetic analysis in cardiovascular disease: a clinical perspective. Cardiol Rev. 2011;19(2):81-89.
- Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. 2011;8(8):1308-1339.
- Marcus FI, Edson S, Towbin JA. Genetics of Arrhythmogenic Right Ventricular Cardiomyopathy: A Practical Guide for Physicians. J Am Coll Cardiol. 2013 Mar 13. pii: S0735-1097(13)01004-8. doi: 10.1016/j.jacc.2013.01.073. [Epub ahead of print]
- Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J.2010;31(7):806-814.