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Genetic Testing for Hypertrophic Cardiomyopathy: Special Considerations
Written by Rena Vanzo for use by the Hypertrophic Cardiomyopathy Association
As the world of genetic research continues to advance, information about changes in a person’s DNA can be used for health purposes. For example, researchers have identified mutations (or changes) in several different genes that are known to predispose individuals to (or put individuals at a higher risk of developing) hypertrophic cardiomyopathy (HCM). If a person is known to carry one of these mutations, specific recommendations for his or her medical care, as well as suggestions on diet and exercise, can be given. Genetic testing is the process whereby an individual’s blood is drawn, and his or her genes are analyzed for specific mutations. Genetic testing has both practical and personal benefits; however, the process can be complicated. It may be helpful to meet with a medical geneticist or genetic counselor (1, 2) prior to testing, and those who are considering genetic testing are encouraged to take the following aspects into consideration.
Before genetic testing is carried out, a medical professional should first determine which family member is most appropriate to test. If HCM is thought to run in a family, it is logical to first test the person most likely to carry a mutation (for instance, someone who has symptoms of HCM or has been previously diagnosed with HCM after a clinical evaluation). This is suggested because the testing process may involve a lengthy search (called sequencing) over an entire gene or number of genes. Imagine that a gene is like a book: researchers must read the entire story and look for mutations in each chapter, paragraph, sentence, and word. If a mutation is identified, testing can then be offered to family members who have not been previously diagnosed with HCM. This is because researchers would then know the exact “page and sentence” where the mutation (previously identified in the affected relative) would be found. (For more information on why it is best to begin testing certain family members, see the “Interpretation of Test Results” section below.)
Because it is best to begin testing with certain family members, the process of genetic testing can create tension within families. Two people may have very different opinions about whether or not genetic testing is a good idea. If you believe HCM could run in your family, you are encouraged to discuss the process with your relatives, and also to consider what you would do with the information received through testing. For example: What is most beneficial to your family as a whole? How would you feel and what would you do if the first person tested negative (no mutation was found)? Or if the person tested positive (a mutation was found)? Some families find it helpful to create a plan for each of these scenarios before they proceed with testing.
Postmortem Genetic Testing
In some cases, an individual may suffer an unexpected sudden cardiac arrest (SCA) and be diagnosed with HCM upon autopsy. As these individuals were likely unaware of the diagnosis, they would not have had the opportunity to participate in genetic testing before experiencing SCA. However, there may still be an opportunity to gather genetic information to assist the remaining family members. If a family finds itself in this particular situation, the Hypertrophic Cardiomyopathy Association (3) may be helpful in navigating through the complicated process of contacting the appropriate personnel to procure the deceased’s blood sample and coordinating postmortem genetic testing. Additionally, the HCMA may serve as an educational and supportive resource for the family during difficult times such as these.
Concerns Regarding Discrimination
When deciding whether to proceed with genetic testing, some people hesitate for fear of complications with insurance companies. The Genetic Nondiscrimination Information Act (GINA) is a pending legislation that, when passed, will prohibit employers and insurance companies from bias against individuals based on their genetic test results. GINA has recently passed the House of Representatives, and, as of March 2008, is awaiting reintroduction to the Senate. Ideally, GINA will become federal law in the future; however, many states already uphold similar statutes. For information regarding GINA, as well as the law and genetic testing in your state, visit the links listed in the “References” section below (4, 5).
Cost & Insurance Coverage for Genetic Testing
If a person chooses to proceed with genetic testing, he or she may be concerned with the cost. Currently, testing for the first family member is generally from $3000-$3800. If a mutation is identified, other family members may be offered confirmatory testing at a reduced rate that is around $250. (Remember, this is because researchers would then know exactly where to look for the mutation, rather than searching an entire gene or number of genes.) And, although different individuals have different insurance policies, at least half of those who decide to test will receive some degree of insurance coverage. If you are considering testing, you may want to contact your insurance provider to determine your specific policy’s extent of coverage for genetic testing (and to ensure that genetic testing is notexcluded in your policy). Procedure (CPT) and indication (ICD-9) codes are often helpful in communicating between doctors and insurance companies; these codes should be available through your healthcare provider or the testing laboratory. Furthermore, a medical geneticist or genetic counselor can help determine the most cost-effective testing method (for example, which gene or genes to analyze first), and, in some cases, may write a “letter of medical necessity” that can help acquire insurance coverage.
Interpretation of Test Results
Consultation with a medical geneticist or genetic counselor can help clarify the interpretation of HCM genetic test results. A person can receive a) a positive result, meaning that a mutation was identified, b) a negative result, meaning that a mutation was not identified, or c) a “variant” result, which requires a more thorough explanation.
a) A positive result is generally the most straightforward when reported for a person who has a prior diagnosis of HCM. In this case, researchers have identified a mutation previously proven to predispose to HCM. We can then conclude that the person developed symptoms as a result of carrying that mutation, and would offer testing to appropriate at-risk* family members.
b) A negative result will have different consequences in different circumstances. If a person who does not have a prior diagnosis of HCM is tested after a family member with a prior diagnosis has tested positive, a negative result would be very reassuring. It would indicate that the person did not inherit the family mutation that predisposes to HCM. In this case, that person’s risk for developing HCM would be the same as that of an unrelated person. Additionally, the person who tested negative would not need to continue with his or her clinical evaluations for HCM.
Alternatively, if a person who has a prior diagnosis of HCM is tested, a negative result could have two meanings:
1) This person’s symptoms are not related to a genetic predisposition, and other family members are not at risk of inheriting a gene that predisposes them to HCM, or
2) The person’s symptoms are related to a genetic predisposition, but the causative mutation was not identified. This could occur because of the following circumstances:
i) The laboratory’s testing method was not capable of identifying the individual’s specific mutation.
ii) The gene containing the mutation was not analyzed. Researchers may begin analyzing those genes most commonly associated with HCM; thus, a mutation in a less commonly associated gene would go unnoticed. (Remember, Genetics Specialists may help determine which gene or genes are most likely to be mutated for a particular individual.)
iii) There may be other, currently unidentified genes that are related to HCM; until these genes are identified and until mutations within them are proven to predispose to HCM, analysis of those genes will not be possible.
In summary, it is important to recognize that a negative result does not exclude a genetic cause for a patient who has symptoms and/or a prior diagnosis of HCM (6).
c) A variant result is reported when a gene change has been identified, but that specific gene change has not been consistently shown to predispose to HCM. For example, if a person who has a prior diagnosis of HCM is tested, we would be uncertain as to whether or not the variant contributed to the diagnosis. In other words, the variant could be either a predisposing mutation or a polymorphism. A polymorphism is an alteration from the normal gene sequence that is found in a certain percentage of healthy individuals; polymorphisms do not usually interfere with one’s expected growth and development. In order to determine whether a variant is a predisposing mutation or a polymorphism, additional family members (both with and without a prior diagnosis of HCM) may be offered genetic testing. If family members with a prior diagnosis tend not to have the variant, and if family members without a prior diagnosis tend to have the same variant, the variant is more likely a polymorphism. With information gathered over time and across different families, researchers may be able to reclassify variants as either predisposing mutations or polymorphisms. It is important to keep in mind, however, that mutations may cause different symptoms in different families. If testing does not begin for a family member with symptoms and/or a prior diagnosis of HCM, researchers may have more difficulty gathering information about whether a variant is more likely a predisposing mutation or a polymorphism.
If you are considering genetic testing and would like to clarify or discuss these issues with a Genetics Specialist, you may refer to one of two links listed in the “References” section below (1, 2). Alternatively, you may choose to share this information with your cardiologist and ask for his or her opinion on testing and/or referral to a Genetics Specialist.
Receiving a Positive Result
If a person who has a prior diagnosis of HCM receives a positive result, he or she should continue with regular treatments, recommendations, and clinical evaluations as planned. Additionally, he or she is encouraged to meet with a Genetics Specialist to review the 50% chance that at-risk family members have the same mutation; those family members should also undergo a clinical evaluation (which usually includes a physical examination, electro- and echocardiogram) with a cardiologist every 12 to 24 months from the ages of 12 to 22 years and every five years thereafter (6). Additionally, these evaluations may be considered for at-risk children, particularly if there is a family history of sudden cardiac arrest (see the “Post-test Implications” listed below) or if that child is a competitive athlete (7).
If a person who does not have a prior diagnosis of HCM receives a positive confirmatory result, regular screening and clinical evaluations take on a much greater significance. This is because that individual is no longer considered an at-risk relative with a 50% chance of carrying a gene that predisposes to HCM; rather, he or she is a confirmed carrier of a gene that predisposes to HCM. Thus, that individual is encouraged to undergo clinical evaluations with a cardiologist and also to meet with a Genetics Specialist to discuss the 50% chance for at-risk family members to also be confirmed as carriers.
Although a positive result may be most easily interpreted, it is important to keep in mind that it may raise more questions than answers. If a person with a prior diagnosis of HCM tests positive, we are unable to predict if and when he or she will experience further complications. If a person who has no symptoms or diagnosis of HCM tests positive for the family mutation, we cannot definitively predict if he or she will go on to develop HCM**. And furthermore, if that person does go on to develop HCM, we could not predict the stage of life at which it would occur or what particular symptoms he or she would express. For example, would it be shortness of breath and chest pain as a young adult, or more serious complications in the fourth or fifth decade of life? Unfortunately, the world of genetic research is currently unable provide these predictions for each specific mutation. Also, symptoms are variable, which means that they may be different for people with the exact same mutation—sometimes even among those people within the same family!
Remember, if a person carries a mutation that predisposes him or her to HCM, there is a 50% chance that each of his or her children has inherited (or will inherit, if the diagnosis is made before that person has children) that mutation. Even though we have no control over which genes we pass to our children, strong emotions—including anger, anxiety, fear, and even guilt—have been associated with this possibility. There is some debate within the medical profession regarding the age at which genetic testing is appropriate (8, 9, 10). And, if testing is discouraged until a child reaches a certain age or maturity level, it may be difficult for parents to wait with uncertainty until that time.
If, however, there is a circumstance where the benefits of the genetic testing outweigh the risks, medical professionals may determine that testing a child is justified. This is especially true if strategies to help prevent symptoms exist. For example, researchers are gathering information about mutations that may be more likely to predispose an individual to sudden cardiac arrest (11, 12). And, families who have already lost someone to this devastating symptom are more likely than a family without SCA to experience it a second time. Studies have also suggested that implantable cardioverter-defibrillators (ICDs) can prevent SCA (13, 14, 15). So, if a child is at risk for SCA, as determined by the type of mutation in the family and a family history of SCA, steps could be taken to potentially reduce that individual’s risk, including genetic testing and use of an ICD.
Because of these complexities associated with genetic testing, careful consideration should be taken before a person chooses whether to proceed. People who choose to test may do so because they find comfort in having answers; they can focus on one particular result and what it means for them personally, as well as for their family. People who choose not to test may make that decision because they do not feel overly burdened by the unknown. They may find comfort in reserving the option to test for the future, especially if they are unsure about how they would use the test results at the present time. And furthermore, after learning this information, one can never reverse the decision to test if they find that results were not helpful or were burdensome.
The results that are revealed through genetic testing may be very personal. If you are considering testing, it may be important to think about whether or not your self-concept or world views would change after finding out that you are “negative” or “positive.” Would you be comfortable sharing this information with anyone else? Would you want to tell friends or co-workers? Would it affect your daily lifestyle? Are there any important decisions that you would make differently based on this information? And if so, would that decision be for the best?
Regardless of the result a person receives, the emotional and psychological reactions that follow genetic testing can be both delicate and complex. It may be helpful to share your thoughts on genetic testing with other family members. And, as previously mentioned, contacting a Genetics Specialist prior to making your decision is also recommended. He or she can be helpful as you choose whether genetic testing is the best option for yourself and your family!
*At-risk family members are the first-degree relatives—parents, children, and brothers and sisters—of someone who has a prior diagnosis and/or experiences symptoms of HCM.
**HCM is described as an autosomal dominant condition with reduced penetrance. This means that only one mutation is necessary to lead to the symptoms of HCM, but some individuals who have a predisposing mutation will never develop those symptoms.
- The National Society for Genetic Counselors. The “Quick links—Find a Counselor” tab on the left hand panel can provide you with counselor contact information: www.nsgc.org
- The American Board of Genetic Counseling. This page provides links to accredited genetic counseling programs where personnel may be reached for information regarding appointments:www.abgc.net/english/view.asp?x=1643
- The Hypertrophic Cardiomyopathy Association (HCMA) can be contacted via telephone at (973) 983-7429, email at email@example.com or website at www.4hcm.org
- Genetic Information Nondiscrimination Act of 2007. This page describes the act’s progression through legislative process: http://www.genome.gov/24519851
- National Conference of State Legislatures. This page provides links to citations in most states regarding the law and genetic testing: www.ncsl.org/programs/health/genetics/ndishlth.htm
- Ho CY and Seidman CE. A contemporary approach to hypertrophic cardiomyopathy (2006).Circulation 113: e858-e862.
- Maron BJ. Hypertrophic cardiomyopathy and other causes of sudden cardiac death in young competitive athletes, with considerations for preparticipation screening and criteria for disqualification (2007). Cardiology Clinics 25(3): 399-414.
- The American Society of Human Genetics (ASHG) and American College of Medical Genetics (ACMG) policy paper regarding the ethical, legal, and psychosocial implications of genetic testing in children and adolescents can be accessed at http://www.ashg.org/genetics/ashg/pubs/policy/pol-13.htm
- Richards FH. Maturity of judgement in decision making for predictive testing for nontreatable adult-onset neurogenetic conditions: a case against predictive testing of minors (2006). Clinical Genetics70(5): 396-401.
- Duncan RE et al. An international survey of predictive genetic testing in children for adult onset conditions (2005). Genetics in Medicine: the official journal of the American College of Medical Genetics 7(6): 390-396.
- Moolman JC et al. Sudden Death due to Troponin T Mutations (1997). Journal of the American College of Cardiology 29(3): 549-555.
- Piva e Mattos. Sudden death risk stratification in hypertrophic cardiomyopathy: genetic and clinical bases (2006). Arq Bras de Cardio 87: 351-359.
- Woo A et al. Determinants of implantable defibrillator discharges in high-risk patients with hypertrophic cardiomyopathy (2007). Heart (British Cardiac Society) 93(9): 1044-1045.
- Maron BJ et al. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy (2007). JAMA 298(4): 405-412.
- Nishimura RA et al. Hypertrophic cardiomyopathy, sudden death, and implantable cardiac defibrillators: how low the bar (2007). JAMA 298(4): 452-454.
Rena Vanzo has a Bachelor of Science in Psychology from the University of Wisconsin-Madison. She is currently a graduate student in the Indiana University Genetic Counseling Program, and will graduate in May 2008 with a Master of Science in Medical Genetics. She wrote this article in order to highlight some important considerations that may be overlooked during the process of genetic testing, particularly when testing for hypertrophic cardiomyopathy. She plans to continue to focus on education during her career as a genetic counselor.