Utility of genetic testing in athletes

Abstract Athletes are some of the fittest members of our society, yet paradoxically carry an increased risk of sudden cardiac death (SCD). The athlete's underlying risk of SCD in sports may be increased due to a number of underlying structural, arrhythmic and inherited cardiac conditions (ICCs). There are also physiological adaptations, which occur in the cardiovascular system in athletes as a result of high‐level athletic activity and may be misinterpreted as pathology. Differentiation of “athlete's heart” from heart disease may be challenging due to the effects of exercise on the electrical and structural cardiac remodeling. Features such as prolongation of the QT interval, left ventricular hypertrophy and cavity dilatation, create significant overlap between physiology and inherited channelopathies and cardiomyopathies. Most inherited cardiac conditions have an underlying genetic basis to disease and genetic testing in an athlete can have diagnostic, prognostic and therapeutic implications, including guiding exercise recommendations. Therefore, genetic testing can be a useful diagnostic tool when used carefully and appropriately by a trained cardio‐genetics expert.


| INTRODUCTION
Despite being some of the fittest individuals in society, athletes paradoxically carry an increased risk of sudden cardiac death (SCD) when compared to sedentary individuals with the same cardiac disease. 1 The prevalence of young sudden cardiac death in the general population is 1.3/100000 individuals aged 1-35 years, while a recent study of screening in young adolescent football players in the UK showed a much higher incidence of SCD of 6.8/100000 in a young athletic population. 2,3 SCD is the most common cause of mortality in an athlete during sports. 4 A number of underlying structural, arrhythmic and inherited cardiac conditions (ICCs) may increase the athlete's risk of SCD in sports. However, there are also physiological adaptations in the athlete, such as prolongation of the QT interval, left ventricular hypertrophy and cavity dilatation that occur as a result of high-level athletic activity and may be misinterpreted as pathology due to the overlap of these changes with inherited cardiomyopathies and channelopathies. 4 When evaluating athletes for potential underlying ICCs, including cardiomyopathies and channelopathies, consideration must be given to the genetic basis of a number of these diseases. 5,6 Genetic studies over the last 30 years have been integral in identifying the gene abnormalities that underpin these diseases. Genetic testing in an athlete can have diagnostic, therapeutic and prognostic value provided that the information is correctly assessed by a cardiogenetics expert in the setting of a specialized multidisciplinary clinic. The yield of genetic testing varies based on the condition for which the athlete is being assessed (from 20%-30% in dilated cardiomyopathy to 70% in long QT syndrome). 5 In addition, most ICCs are inherited in an autosomal dominant manner, meaning that first-degree family members have a 50% chance of also being affected. 7 It is therefore important that before considering genetic testing in any athlete, that the implications, potential challenges and limitations of the testing are understood by the athlete and their club and that they have undergone comprehensive pre-and post-test genetic counseling. 8

| GENETIC BASIS TO CARDIAC DISEASE IN ATHLETES
There are a number of physiological adaptations that occur in the heart as a consequence of regular exercise (>4 hours/week). These adaptations are collectively known as "athlete's heart" and can be considered normal in an athlete, therefore not warranting further investigation. However, differentiation of "athlete's heart" from true underlying heart disease can be challenging for the clinician, as a number of these physiological adaptations such as prolongation of the QT and Brugada syndrome [BrS]). 5,[9][10][11][12] When evaluating an athlete for potential underlying ICC, the genetic basis to these conditions must be carefully considered. 5,6 Molecular studies over the last 30 years have been integral in identifying the particular genetic abnormalities that are the underlying cause of these conditions while rapid technological advances, particularly the advent of next generation sequencing (NGS) technologies, have made genetic testing a readily available tool in the cardiogenetics clinic. Identification of the causative variant allows for predictive (cascade) testing in first-degree family members due to the autosomal dominant inheritance pattern in most ICCs.
Family members who are genotype-positive require ongoing clinical surveillance and management, while those who are genotype-negative can be reassured and released from further clinical surveillance. 7,13 Identification of the causative variant provides benefit to both the athlete under assessment, as well as their family members. Genetic testing has potential utility to assist with diagnosis, prognosis and therapeutics for the athlete, depending on the particular disease in question (Table 1). For some conditions, such as Brugada syndrome, the utility is fairly limited due to the relatively low yield of approximately 20%, whereas in other conditions such as LQTS, the yield can be as high as 70%. In certain situations genetic testing can be used diagnostically to help differentiate between physiology and pathology such as in assessment of the athlete with a prolonged QT interval > 480 ms. 5,14 In addition to defining the underlying disease, offering genetic testing to athletes (when appropriate) may help to inform potential management outcomes for the athlete including exercise recommendations and in guiding prognosis. 5,15 For example in LQTS, different genetic subtypes are often offered differing management strategies, while the overall prognosis and risk of arrhythmic events is known to vary between different LQTS subtypes. 16 In order to improve the yield of genetic testing in an athlete, it is integral to ensure the athlete has undergone a comprehensive clinical evaluation first and that the athlete has a clearly defined phenotype.
It is also relevant whether the athlete has a known family history of disease, as the yield is much higher in those with a family history, that is, a higher pre-test probability. Finally, we would recommend only genes, which have strong supporting evidence to be a cause of the phenotype in question be tested, in order to maximize clinically actionable yield and minimize background noise and variants of uncertain significance (VUS), with pre-and post-test genetic counseling. 5,7 In an athlete, especially a professional athlete, the diagnosis of an underlying ICC has implications for their future sporting career and therefore it is very important the athlete, their family and any other relevant bodies are included in a shared-decision model. 17

| INHERITED CARDIAC CONDITIONS AND INDICATIONS FOR GENETIC TESTING IN ATHLETES
While genetic testing can be useful when assessing athletes in selected cases, to differentiate physiological adaptation from underling pathology (or ICC), there are some particular conditions where-by genetic testing has the highest yield and carries the greatest utility.
These are highlighted below, and summarized in Figure 1:

| LONG QT SYNDROME
Long QT syndrome (LQTS) is an inherited channelopathy with an estimated prevalence of 1:2000. 21 LQTS is characterized by the presence of a prolonged QTc after secondary causes for a prolonged QTc such as drugs or electrolyte disturbances have been excluded. 6 LQTS can also be diagnosed in an individual with an LQTS risk score (modified Schwartz score) >3.5 or when an unequivocally pathogenic variant in a LQTS gene is identified on genetic testing. 6,19 In LQTS, proceeding to genetic testing is an integral part of the diagnostic pathway. In an athlete with a repeatedly prolonged QTc > 480 ms,

| ARRHYTHMOGENIC CARDIOMYOPATHY
Arrhythmogenic cardiomyopathy (ACM) is an umbrella term, which encompasses an arrhythmogenic heart muscle disease not due to valvular, ischaemic or hypertensive heart disease. The underlying causes for

ACM include genetic, systemic and inflammatory disorders, however
the key feature is the predominance of arrhythmia in the presentation. 30 The ACM/ARVC has consistently been shown to be an important cause of SCD in athletes due to ventricular arrhythmias provoked by exercise. 32 Additionally, the arrhythmic phenotype has been shown to predate the cardiomyopathy phenotype, with one study showing SCD due to ACM was 16 times more common in athletic individuals compared with nonathletes, often with no prior symptoms. 9 It is important to highlight that many high-level athletes have right ventricular structural changes due to physiological adaptation to exercise.
However, there are some key clinical features, which have been shown to be more commonly associated with underlying ARVC rather than athletic adaptation. These include symptoms (eg, syncope), family history of SCD, high burden of premature ventricular contractions [PVCs (>1000)] or sustained ventricular arrhythmias, abnormal signal-averaged electrocardiogram (SAECG) and abnormal scar on CMR (cardiac magnetic resonance) imaging. 33 Therefore, genetic testing is usually indicated in athletic individuals with a high-index of clinical suspicion for ARVC such as those with right ventricular structural abnormalities and the presence of the other high-risk features listed in Figure 1. In athletes with right ventricular structural change in isolation genetic testing is usually not indicated.
Evidence suggests that athletic individuals with ARVC develop symptoms earlier and have a higher prevalence of ventricular arrhythmias, compared with non-athletes. 34 Even those athletes who are gene carriers with no overt ARVC phenotype (genotype-positive phenotype-negative individuals) have higher disease penetrance with earlier presentation of overt phenotype, more ventricular arrhythmias and more rapid progression to heart failure. 35 Therefore first degree family members of a genotype positive ARVC case should proceed to genetic testing in order to identify those individuals within the family who are genotype-positive who are now recommended to avoid competitive sports as of the most recent guidelines. 36  fore, the use of genetic testing in this group is usually not indicated. 40

| OTHER CONSIDERATIONS
There are often significant ethical and legal factors for any athlete considering genetic testing that must be carefully considered prior to proceeding. The sporting organization may have specific legal requirements and there may be insurance ramifications for the athlete and their club or organization. However, there are potential benefits in identification of a particular genetic result, including initiating life-saving medication such as beta-blockers, which may ultimately facilitate safe "return to play" for the athlete. 17,41 In addition, given the autosomal dominant genetic basis to most cardiomyopathies and channelopathies, there are important implications for first-degree family members of the athlete which also require consideration. Therefore, before any athlete proceeds with genetic testing pre-and post-test genetic counseling by an experienced cardiac genetic counselor is essential ( Figure 2). 7