Diagnostic Genetic Testing for Arrhythmias: Learning the Most Familiar Gene Mutation Codes

I often wonder if as clinicians, we are thinking globally in our treatment of arrhythmias? Are we treating these as individual problems? Most electrical disturbances for the most part have an underlying cause that has made them surface. At the Cleveland Clinic, we have been changing the way we treat certain arrhythmias with the conventional treatment of these diseases. The word ‘conventional’ is exactly what it means, to do the usual and predictable treatment. But we are not treating a normal or conventional problem anymore. We are learning of arrhythmias that predominantly affected the elderly in a younger population. We need to think a bit more unconventional. We have been successful at identifying disease-causing mutations in affected individuals, which allows us to perform mutation-specific genetic testing of at-risk family members. This includes family members who are clinically asymptomatic and who may have normal electrocardiograms or echocardiograms. Knowing whether at-risk family members harbor the disease-causing mutation can provide information for subsequent medical management and treatment, risk assessments, and prenatal diagnosis in future pregnancies. Below are some of the familiar gene mutation causing diseases that can lead to lethal arrhythmias and can be tested with a simple genetic test. This can be used for the primary prevention of sudden cardiac death, congestive heart failure (CHF), stroke, as well as other CV problems. Prevention is what all clinicians are consequently trying to achieve; if we can prevent a child from undergoing surgery or a severe traumatic experience of inheriting an implanted cardiac device, we have achieved our goal.

Genetic Influences

Cardiomyopathy is often asymmetrical, meaning that one part of the heart is thicker than the other parts. The condition is usually passed down through families (inherited). It is believed to be a result of several defects with the genes that control heart muscle growth. Younger people are likely to have a more severe form of cardiomyopathy; however, the condition is seen in people of all ages. There are several forms of cardiomyopathy, including dilated cardiomyopathy and hypertrophic cardiomyopathy. Dilated cardiomyopathy is a condition in which the heart becomes weakened and enlarged, and it cannot pump blood efficiently. The decreased heart function can affect the lungs, liver, and other body systems. The genetic mutation codes to test are as follows: LMNA, MYH7, TNNT2, ACTC1, DES, MYBPC3, TPM1, TNNI3, ZASP, TAZ, PLN, TTR, LAMP2, SGCD, MTTL1, MTTQ, MTTH, MTTK, MTTS1, MTTS2, MTND1, MTND5, MTND6. (Table 1.) Hypertrophic cardiomyopathy (HCM) is a condition in which the heart muscle becomes thick. The thickening makes it harder for blood to leave the heart, forcing the heart to work harder to pump blood. HCM is transmitted in an autosomal dominant pattern of inheritance. Therefore, an individual carrying a disease-carrying HCM mutation has a 50% chance of transmitting the mutation to a child, either male or female. Molecular genetic studies have defined HCM as a disease of the sarcomere, the contractile unit within the cardiac myocyte that is comprised of thick and thin filaments. HCM has proved to be a genetically heterogeneous condition, and to date, 17 disease-causing genes and >500 individual mutations have been identified (Table 1). Mutations in these genes have been identified in 40–60% of HCM cases (the majority of which are missense mutations with result in amino acid substitution). Many of these mutations have proved to be unique to individual families. Mutations in b-myosin heavy chain (MYH7) and myosin-building protein C (MYBPC 3) account for the majority of identified mutations. These mutations can be tested by using the gene mutation table (Table 1). Atrial fibrillation (AF) is a common heart rhythm disorder caused by a problem in the conduction of electrical impulses in the upper chambers, or atria, of the heart. In AF, the electrical signals that coordinate the atria of the heart become rapid and disorganized, typically causing the atria to beat faster than 300 beats per minute. (The normal rate when the heart is at rest is about 60 to 80 beats per minute.) When this happens, the atria may contract poorly and no longer effectively force blood into the lower chambers (ventricles). As a result, the flow of blood to the body may be reduced. AF may occur from time to time, or it may be a permanent condition. Scientists have discovered two common genetic variants that increase the risk of AF; near the PITX2 gene on chromosome 4 and in the ZFHX3 gene on chromosome 16. Rare forms of familial atrial fibrillation have been identified due to mutation in the ion channels. Considering that this is a condition that is being seen more and more as a common cause for strokes and CHF among other CV problems, testing the gene mutation might be useful to identify individuals at risk and to institute preventative therapy. A small percentage of all cases of familial atrial fibrillation are associated with changes in the KCNE2, KCNJ2, and KCNQ1 genes. These genes provide instructions for making proteins that act as channels across the cell membrane. These channels transport positively charged atoms (ions) of potassium in and out of cells. In cardiac muscle, the ion channels produced from the KCNE2, KCNJ2, and KCNQ1 genes play critical roles in maintaining the heart’s normal rhythm. Mutations in these genes have been identified in only a few families worldwide. These mutations increase the activity of the channels, which changes the flow of potassium ions between cells. This disruption in ion transport alters the way the heart beats, increasing the risk of syncope, stroke and sudden death. Brugada Syndrome is an inherited arrhythmia that causes the ventricles to beat so fast that they can prevent the blood from circulating efficiently in the body. When this occurs, known as ventricular fibrillation, the individual will faint and could die in a few minutes if the heart is not reset. While this is a disease that usually affects people in their 30s, it has been described as occurring at all ages. Therefore, it is important to screen all members in a family. Not every family member who has the disease will experience arrhythmias. However, we do not yet have the capability to determine who will be affected and who will not. If your patient or any of their family members has had syncopal episodes, this could be related to Brugada syndrome, and our experience indicates that they may be at a higher risk for having them again. The genetic mutation codes to test are CACNA1C, CACNB2, GPD1L, SCN1B, SCN5A. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is characterized by episodic syncope occurring during exercise or acute emotion in individuals without structural cardiac abnormalities. The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic). Spontaneous recovery occurs when these arrhythmias self-terminate. In other instances, ventricular tachycardia may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available. The mean age of onset for CPVT is between seven and nine years; though onset as late as the fourth decade of life has been reported. Genes responsible for CPVT encode for proteins that participate in the trafficking of calcium in and out of the sarcoplasmic reticulum. Genetic mutation codes are CASQ2 and RYR2. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a rare inherited heart-muscle disease that is a cause of sudden cardiac death in young people and athletes. Causative mutations in genes encoding desmosomal proteins have been identified and the disease is nowadays regarded as a genetically determined myocardial dystrophy. The left ventricle is so frequently involved as to support the adoption of the broad term arrhythmogenic cardiomyopathy.¹ Genetic mutation codes are DSC2, DSG2, DSP, JUP, PKP2, RYR2, and TMEM43. Long QT syndrome (LQTS) is an inherited disorder of the heart’s electrical system. LQTS causes a sudden, unexpected, life-threatening type of ventricular tachycardia commonly called torsades de pointes. People who have LQTS are at risk for syncope and sudden death, often at a young age. Most genes that cause long QT encode for proteins that participate in the formation of ion channels in the cell membrane. That is why LQTS is considered a channelopathy. Approximately 10% of LQTS patients in whom a mutation is identified in 1 ion channel gene carry a second mutation in the same gene or in another ion channel gene.² The genetic mutation codes include LQTS, KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, CACNA1C KCNJ2, CAV3, SCN4B, AKAP9, and SNTA1.

Conclusion

Diagnostic genetic testing should be considered for patients who clinically manifest symptoms of any of the forth-mentioned arrhythmias and for patients who are asymptomatic but are within a family with a known mutation. The youngest, 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. If a clinical decision is made to test a patient, keep in mind the financial and societal considerations of this test, which at times may be partially or not covered by insurance. The GINA (The Genetic Information Nondiscrimination Act of 2008) generally will prohibit discrimination in health coverage and employment on the basis of genetic information. Also, if the test should come back positive, the clinician must be prepared to undertake the post-testing follow-up that is needed to provide patients with the best medical outcome.

References

1. Arrhythmogenic Right Ventricular Cardio-myopathy. N Engl J Med 2009;360(26):2784-2786.
2. Tester et al. 2005.

For more information, please visit https://www.nature.com/nm/journal/v11/n12/fig_tab/nm1205-1284_F1.html https://www.med.uc.edu/kranias/Sarcoplasmic_Reticulum.htm https://www.mhhe.com/biosci/esp/2001_gbio/folder_structure/an/m5/s5/index.htm