Genetic Evaluation of Athletes With Cardiovascular Disease: Incorporating a Genetic Counselor on Your Team

Apr 30, 2019   |  Christina Rigelsky, MS, CGC; Kenneth G. Zahka, MD, FACC

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Identification of genetic forms of cardiovascular diseases, including channelopathies, cardiomyopathies, and aortopathies, are an important component of a sports cardiology practice. The potential for sudden cardiac death has made these diseases the centerpiece of screening at all levels of organized sports participation. The recognition and diagnosis of the genetic forms of cardiovascular disease which may impact sports participation may be challenging. The awareness of the role of cardiac clinical findings and imaging modalities is well established. For the sports cardiologist, the role of a detailed family history and non-cardiac clinical findings is evolving. Collaboration with cardiovascular genetic counselors can provide the bridge between the cardiac and non-cardiac assessment as well as a clear and effective approach to genetic testing.

Over the past 10 years genetic testing for cardiovascular disease has become more widely utilized. Multiple publications have illustrated the complexity of genetic testing in cardiovascular diseases and the role of genetic counselors.1-3 Genetic testing is not more challenging when considering its role in the evaluation of an athlete; however, there may be higher stakes with multiple interested parties. To clinicians unfamiliar with genetic testing there is an appeal to utilize genetic testing to confirm or rule out a specific hereditary condition, but in reality genetic testing is not so straightforward. Like most of the clinical tools familiar to cardiologists there are nuances in the interpretation of genetic testing that requires specific training and experience. In this article we will focus on the role of genetic testing and genetic counseling in the evaluation of athletes for genetic cardiovascular disease. Guidelines from European and American groups on genetic testing in cardiomyopathies, hereditary arrhythmias, and aortopathies will be highlighted to help inform the role of genetic testing.

Guidelines for Cardiomyopathies

European and American guidelines (ACC/AHA, HRS/EHRA and ESC) support the role of genetic testing for hypertrophic cardiomyopathy to aide in the evaluation of at-risk family members and in atypical cases. The 2014 ESC and 2011 HRS/EHRA guidelines suggest that genetic testing in borderline cases should only be done in the setting of expert centers.4-6 HRS/EHRA recommend genetic testing for dilated cardiomyopathy with conduction disease or family history of sudden cardiac death or in familial dilated cardiomyopathy to aide in family screening.4 HRS/EHRA suggests the possible utility of genetic testing for arrhythmogenic cardiomyopathies in the setting of a clinical diagnosis or possible arrhythmogenic right ventricular cardiomyopathy.4,7

Guidelines for Hereditary Arrhythmias

HRS/EHRA recommend genetic testing for Long QT syndrome (LQTS) when the diagnosis is clinically suspected or there is unexplained QT prolongation (QTc ≥ 500 ms postpuberty, QTc ≥ 480 ms postpuberty). Genetic testing for LQTS may be considered with unexplained QT prolongation (QTc ≥ 460 ms postpuberty, QTc ≥ 480 ms). HRS/EHRA recommend genetic testing for catecholaminergic polymorphic ventricular tachycardia (CPVT) when there is clinical suspicion. HRS/EHRA indicates genetic testing for Brugada syndrome can be useful when there is clinical suspicion.4

Guidelines for Aortopathies

European, Canadian, and American guidelines have been developed for genetic aortopathy as well. ACCF/AHA indicated it is reasonable to offer genetic testing for a patient with familial thoracic aortic aneurysms and dissections or when there are features suggestive of other genes (i.e., findings associated with Loeys-Dietz syndrome).8 CCS recommends clinical evaluation and genetic testing when Marfan syndrome is a suspected diagnosis.9 ACCF/AHA and ESC recommend referral to a geneticist when a familial aortopathy is suspected.8

Guidelines for Genetic Counseling

European and American groups also recommend genetic counseling as part of the genetic testing process.4-6 Cardiovascular genetic counselors are healthcare providers that work with cardiologists, electrophysiologists, and surgeons to provide genetic services to their patients. Genetic counselors have advanced training in genetics and can translate that information to patients in understandable ways. Genetic counselors also are skilled in taking multi-generation family histories that can aide in identifying other at-risk relatives or more fully understanding the genetic risk in the family and help to identify the best person in the family to test.1

How the Guidelines Inform Genetic Testing in Athletes

When a definitive diagnosis of a genetic condition such as hypertrophic cardiomyopathy or Marfan syndrome is made based on clinical findings, the role of genetic testing is primarily to help identify at-risk family members or to inform reproductive choices. In borderline cases, such as tall, thin athlete with long arms and above average aortic dimensions or an athlete who presents with lightheadedness and is found to have hyperdynamic left ventricular outflow tract obstruction at maximal exertion, is genetic testing appropriate? A case can be made for genetic testing in both of these scenarios but it is important to consider the potential for possible uncertainty that may result. In the past, some of this uncertainty has come from differences in the nomenclature between labs and the evolving experience in the meaning of mutations. This has improved since the ACMG/APA guideline publication for variant classification.10 These guidelines have helped unify genetic test results across genetic testing labs; however, interpretation remains dependent on clinical interpretation and assessing all available information.11 In general, genetic test results are usually reported in the following ways:

  • Pathogenic variant – Reaches high threshold for evidence supporting causal role in disease presentation. Useful for testing other family members to determine risk of developing disease.
  • Likely pathogenic variant – Some supporting evidence for its role in development of disease but lacks more convincing evidence to increase to level of pathogenic variant. In some cases, testing of family members may be appropriate. No case is the same and needs to be reviewed in the context of what is known about the variant and the patient's and families' clinical characteristics to determine if further genetic testing is warranted in a family to help clarify pathogenicity or to aid in risk assessment.
  • Variant of unknown significance – These are typically rare findings or maybe they have never been seen before in population-based databases. There may be some computational algorithms that support pathogenicity but overall there is not enough data to determine if it causes disease or not.
  • Likely benign variant – Variants in this category may occur at a frequency that is more common than expected for the condition, lack segregation in affected family members and likely have never been reported as causing disease.
  • Benign variant – Variants in this category are usually seen at a relatively high frequency in the general population (>5%).

A major component of genetic counseling in the post-genomic era is interpretation and education surrounding genetic testing results. The educational component is essential to set realistic expectations from the patients, their families, and their clinicians. There is a wide breadth of testing available from single site testing for a known family mutation, to single gene testing to disease specific gene panels, to whole exome or genome sequencing. The genetic counselor is also in the best position to navigate the various insurance benefits and commercial testing laboratories to provide the best test while trying to minimize the patient's out of pocket expense. For those individuals who have had testing in the past it is important to stay in contact with a genetic counselor for ongoing review of result interpretation and ensure that the testing appropriately addressed the patient's phenotype, to update the interpretation of any identified variants and consider additional testing as new testing becomes available if no mutation was identified.

We have, in general, favored a disease or clinical problem panel approach to testing. In this setting, the athlete and all interested parties must be aware that a negative result cannot rule out a genetic cause and that a variant of unknown significance does not confirm a diagnosis. The potential that either a negative result or a variant of unknown significance might not direct a different path for medical management must be considered when considering genetic testing as a component of the diagnostic tools used to evaluate the athlete.

A positive genetic test confirming the presence of a genetic cardiovascular condition requires both follow-up for counseling of first degree relatives and recommendations for long term follow-up of the affected individuals. While for some conditions, particularly Marfan syndrome, this may lead to exclusion from competitive sports, there remains a role for the sports cardiology team in designing patient-specific guidelines for recreational activities. While, in general, the diagnosis of hypertrophic cardiomyopathy has been a contraindication to competitive sports, the 2015 guidelines do offer some flexibility for participation of asymptomatic individuals and they as well will benefit from counseling for recreational activities.

The approach to individuals who are clearly phenotype negative but who have a positive family history with or without a known gene is evolving. Typically, these individuals can be followed clinically with the presumption that they are normal. For those with a known family mutation, some will decline genetic testing because of concern that a positive test will impact sports participation. Prospective studies will help clarify the risk of sports participation on the progression of disease or sudden death in genotype negative-phenotype positive individuals.

For individuals with borderline phenotype and negative genetic testing and a noncontributory family history, we recommend screening parents or siblings for the same phenotype. If first degree relatives do not have obvious disease, we tend to permit sports participation but stress the importance of regular follow-up to ensure that the athlete's phenotype does not evolve into overt disease.

We have found that embedding cardiovascular genetic counselors into the sports cardiology program, in much the way nutrition and exercise physiology has been included, offers the best format for the counselors and the cardiologists to share and understand their individual expertise.

Resources:

References

  1. Arscott P, Caleshu C, Kotzer K, et al. A case for inclusion of genetic counselors in cardiac care. Cardiol Rev 2016;24:49-55.
  2. Ackerman, MJ. Genetic purgatory and the cardiac channelopathies: exposing the variants of uncertain/unknown significance issue. Heart Rhythm 2015;12:2325-31.
  3. Golbus JR, Puckelwartz MJ, Fahrenbach JP, Dellefave-Castillo LM, Wolfgeher D, McNally EM. Population-based variation in cardiomyopathy genes. Ciric Cardiovasc Genet 2012;5:391-9.
  4. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm 2011;8:1308-39.
  5. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;58:e212-60.
  6. Elliot PM, Anastasakis A, Borger MA, et al. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:2733-79.
  7. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation 2010;121:1533-41.
  8. Hiratzka LF, Bakris GL, Beckman JA, et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. J Am Coll Cardiol 2010;55:e27-129.
  9. Boodhwani M, Andelfinger G, Leipsic J, et al. Canadian Cardiovascular Society position statement on the management of thoracic aortic disease. Can J Cardiol 2014;30:577-89.
  10. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-24.
  11. Caleshu C, Ashley EA. Taming the genome: towards better genetic test interpretation. Genome Med 2016;8:70.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Congenital Heart Disease and Pediatric Cardiology, Heart Failure and Cardiomyopathies, Sports and Exercise Cardiology, Vascular Medicine, Implantable Devices, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and CHD and Pediatrics, Cardiac Surgery and Heart Failure, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Sports and Exercise and Congenital Heart Disease and Pediatric Cardiology

Keywords: Sports, Athletes, Cardiomyopathy, Dilated, Conduct Disorder, Brugada Syndrome, Genetic Counseling, Loeys-Dietz Syndrome, Marfan Syndrome, Health Expenditures, Arrhythmogenic Right Ventricular Dysplasia, Tachycardia, Ventricular, Aortic Aneurysm, Thoracic, Arrhythmias, Cardiac, Genetic Testing, Long QT Syndrome, Cardiomyopathy, Hypertrophic, Risk Assessment, Genomics, Phenotype


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