Regular physical activity practice benefits individuals of all ages, sexes and ethnicities.
For athletes, preparticipation evaluation (PPE) is indicated, and can be effective in preventing cardiac SD in that context.
This review describes basic aspects of genetic evaluation, as well as the indications for molecular analysis and their correct clinical interpretation, for practitioners of recreational exercise, amateur sportsmen and high-performance athletes.
One of the major preoccupations in different sports modalities is to establish the risk of SD for each individual and if that modality can increase that risk. There might be a relationship between the sport modality and the cause of SD, which should be taken into consideration on the occasion of screening and prevention. Recent data estimate that among young North-American athletes (<35 years), the incidence of SD would be between 1 and 3 per 100,000 athletes.
Few observational studies are available, most conducted in the USA, Italy, Spain and Denmark.
Thus, for young athletes, screening should focus on identifying inherited heart diseases, such as channelopathies and cardiomyopathies. For older individuals and the general population, however, that assessment should focus on diagnosing CAD.
According to different expert opinions and consensus, genetic evaluation should not be routinely indicated for athletes. Considering that whether electrocardiography should be routinely indicated in PPE is still a matter of discussion, the performance of genetic evaluation should always be very well substantiated for the athlete.
Genetic evaluation is especially indicated on the following two occasions:
positive family history of inherited heart disease (cardiomyopathies, channelopathies, aortopathies) or suspicion of that type of disease (syncope episodes, arrhythmias, cardiac arrest/SD). In such cases, the genetic evaluation should be first performed in the individual or in one of the affected relatives. Once detected the mutation causing the disease, the other family members should be assessed; when the athlete's phenotype strongly indicates the presence of an inherited disease (signs, symptoms and/or tests suggesting specific disease or compatibility with a disease).
Conducting a clinical genetic evaluation should always be the first step before performing a genetic test. That investigation should include the detailed assessment of family antecedents, as well as a complete physical examination. The family history should include the following: age at symptom onset; triggering activities; diagnosed disease; degree of kinship; and number of affected relatives. Building genealogical trees and family pedigree charts (
Thus, the clinician/cardiologist conducting the evaluations should be aware of the signs and symptoms of that group of diseases, and could even refer suspected cases to experts on family heart diseases and/or cardiovascular genetics. Delaying the diagnosis is not wanted, and physical exercise should be avoided in the period. It is worth emphasizing that the evaluation should not be restricted to the one individual diagnosed, but extended to his entire family.
Inherited cardiovascular diseases, such as cardiomyopathies (hypertrophic, dilated, arrhythmogenic, restrictive and non-compacted), channelopathies [long QT syndrome (LQTS), Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT)] and aortopathies (Marfan and Loeys-Dietz syndromes), are a group of entities of high clinical and genetic heterogeneity. Molecular studies performed in different populations have shown that each of those conditions associate with hundreds of different pathogenic mutations.
The European Society of Cardiology (ESC) defines cardiomyopathy as a myocardial disorder with structural and functional abnormalities, in the absence of CAD, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality. Some examples of cardiomyopathies are as follows: HCM; dilated cardiomyopathy (DCM); ARVC; restrictive cardiomyopathy; and non-compacted cardiomyopathy (NCCM). Those cardiomyopathies, except for ARVC, share sarcomeric gene mutations. Different pathogenic mutations in sarcomeric genes, such as MYH7 or MYBPC3, can be associated with several cardiomyopathies (
Non-sarcomeric genes can produce phenocopies. This is the case of the GLA gene, whose mutation causes Fabry's disease. That gene can be associated with HCM development (around 0.5-1% of the cases of HCM are explained by mutations in GLA gene).
The HCM is an autosomal dominant genetic disease. It is relatively common, with prevalence of 1:500 individuals in the general population. According to North-American data, that disease is the most frequent cause of SD in apparently healthy young individuals, especially athletes.
The ARVC is characterized by ventricular myocardial tissue replacement with fibrous and adipose tissue, which has been associated with ventricular arrhythmias. The clinical diagnosis may be complicated, requiring extensive research for confirmation. From the epidemiological viewpoint, its prevalence ranges from 1:5,000 to 1:2,000 individuals.
Channelopathies are a group of diseases sharing some characteristics, such as genetic and clinical heterogeneity. Most of them are explained by changes in the genes that encode myocardial ionic channels. Some channelopathies are as follows: short-QT syndrome, LQTS, BrS and CPVT.
In LQTS, three most frequent subtypes were identified.
The arrhythmic events associated with the BrS usually occur during fever episodes, use of some medications, sleep or after exercise.
Finally, CPVT is associated with changes in intracellular calcium release from the sarcoplasmic reticulum. It is often expressed during the first decades of life, manifesting as syncope or SD associated with exercise and/or stressful situations. Therefore, international guidelines recommend strict sports restrictions in such cases.
This group of diseases includes a set of inherited connective tissue disorders that predispose to aortic dilations and aneurysms (AA) and/or dissection (AD), with an increased risk for SD during physical activity. Some of those diseases are rare genetic syndromes (Marfan, Loeys-Dietz and vascular type Ehlers-Danlos) and no-syndromic presentations, such as familial thoracic aortic aneurysm disease.
When performing PPE in patients with aortopathies classified as syndromic, the variability or phenotypical overlapping of those diseases should be considered. Identification of some of the following clinical signs in an individual who would apparently have a normal phenotype can contribute to the differential diagnosis:
Phenotypic overlapping can occur in those diseases, as seen with the Loeys-Dietz and Marfan's syndromes. Differentiating between them is important to establish the prognosis and regularity of the clinical-cardiological follow-up. In patients with Marfan's syndrome, it is essential to keep watch on the aortic diameter in relation to the body surface,
In athletes with Marfan's syndrome or other aortopathies, AD or aortic rupture can cause SD. The increase in aortic blood pressure and stress during exercise, in the presence of genetic predisposition, can accelerate aneurysm formation, serving as a trigger for AD/rupture of the aorta or of other arteries. A cohort of individuals admitted with AD to the emergency unit has evidenced that syndromic individuals are at higher risk for recurrence and death as compared to non-syndromic ones.
Currently, with the emergence of NGS, diseases with high clinical and genetic heterogeneity can be studied faster and more accurately. This sequencing technology allows the construction of panels that capture the genes involved in each group of diseases (specific genetic panels for cardiomyopathies, channelopathies or aortopathies). In addition, enlarged panels directed to the study of SD with either structural or non-structural heart disease are useful in this context.
In the presence of evident clinical findings that raise the suspicion of a particular disease, diagnostic genetic testing is usually more likely to confirm it (high pretest likelihood). Regarding the performance of genetic tests in primary cardiomyopathies, using a well-designed panel, mutations can be identified in up to 70% of the cases of HCM, for example. Other genes associated and the pretest likelihood of their identification in cardiomyopathies, channelopathies and aortopathies are shown in
| Cardiomyopathy | Gene (symbol) | Pretest likelihood |
|---|---|---|
| HCM | MYBPC3, MYH7, TNNC1, TNNT2, TNNI3, TPM1, ACTC1, MYL2, MYL3, PRKAG2, LAMP2, GLA, GAA, TTR, PTPN11. | 70% |
| DCM | TTN, ACTC1, BAG3, DES, DMD, DSP, FLNC, LMNA, MYBPC3, MYH7, PKP2, PLN, RBM20, TAZ, TNNC1, TNNT2, TNNI3, TPM1. | 40 - 50% |
| ARVC | DSC2, DSG2, DSP, JUP, PKP2, LMNA, FLNC, TMEM43, PLN. | 50 - 65% |
| NCCM | MYBPC3, MYH7, ACTC1, TAZ, LDB3. | 40 - 50% |
HCM: Hypertrophic cardiomyopathy; DCM: Dilated cardiomyopathy; ARVC: Arrhythmogenic right ventricular cardiomyopathy; NCCM: Non-compacted cardiomyopathy.
| Channelopathy | Gene (symbol) | Pretest likelihood |
|---|---|---|
| LQTS | KCNQ1, KCNH2, SCN5A, KCNJ2, KCNE1, KCNE2, CACNA1C. | 70% |
| SQTS | KCNH2, KCNQ1, KCNJ2 | Unknown |
| BrS | SCN5A, SCN10A | 30% |
| TVPC | RYR2, CASQ2, KCNJ2 | 50 - 60% |
LQTS: Long QT syndrome; SQTS: Short QT syndrome; BrS: Brugada syndrome; CPVT: Catecholaminergic polymorphic ventricular tachycardia.
| Genetic aortopathies | Gene (symbol) | Pretest likelihood |
|---|---|---|
| Marfan’s syndrome | FBN1 | ~70 - 93% |
| Loeys-Dietz syndrome | TGFBR2, TGFBR1, SMAD3, TGFB2, TGFB. | ~70 - 95% |
| Vascular-type Ehlers-Danlos syndrome | COL3A1 | >95% |
| Familial thoracic aortic disease | ACTA2, TGFBR2, TGFBR1, MYH11, SMAD3, MYLK, FBN1 | ~17 - 20% |
Proper interpretation of the results of a genetic test is essential not only to establish the correct diagnosis, but also to properly guide athletes and their families. Therefore, careful assessment of the pathogenesis of a variant (
| Classification of the variant | Classification criteria | Clinical usefulness |
|---|---|---|
| Pathogenic | Not identified in the general population; variant widely described in the literature, with cosegregation demonstrated and strong evidence of genotype-phenotype association. Deleterious functional studies. | - Predictive clinical value. |
| Very likely pathogenic | Not identified in the general population; likely cosegregation of the variant in at least one family, truncating-type or in frame ins/del mutation in genes described with genotype-phenotype association that explains the patient’s disease. Deleterious functional study. | - Predictive clinical value. |
| Likely pathogenic | Absent truncating-type or in frame ins/del mutation or identified in the general population with very low allele frequency (<0.01%); intronic variant that affects splicing. Genotype-phenotype association documented in at least two individuals. | - No predictive clinical value. |
| Uncertain clinical significance | Variant with contradictory information on its pathogenesis, does not meet the criteria to be included in another category of the classification. | - No predictive clinical value. |
| Likely non pathogenic or benign | Allele frequency of the variant in control populations is higher than expected for the pathology. Absence of cosegregation. Missense variant in one gene, where only radical mutations are considered pathogenic. Benign functional study. | - No predictive clinical value. |
| Non pathogenic or benign | High frequency in the control population or previously described as benign. Absence of cosegregation. Benign functional study. | - Benign variant. |
PGD: Pre-implantation Genetic Diagnosis.
It is consensus that, in case of uncertainty about the pathogenesis of the mutation (uncertain clinical significance), it should be used for neither disease diagnosis nor familial screening (no clinical predictive value). In addition, some cases are of difficult solution, even after proper identification of the pathogenic variants. International guidelines disagree about athletes who are clinically healthy or not affected (negative phenotype), but carry the pathogenic variant (positive genotype). Considering the early diagnosis in athletes with positive genotype and negative phenotype, the North-American guidelines are much more liberal, and often do not disqualify those athletes for competitive sports. The ESC guideline, however, is much more restrictive.
The presence of a genetic mutation in an athlete does not mean the athlete will develop the disease, but increases his susceptibility to develop it. Sometimes, not all carriers of a mutation develop the disease (incomplete penetrance). Some mutations require additional environmental (sports, hypertension) or genetic factors (presence of other mutations in the same or other genes). In the following situations an athlete can test positive for a genetic study:
- The athlete clearly has a familial heart disease (cardiomyopathy, channelopathy or aortopathy). The presence of a positive genetic test will confirm the diagnosis and help in screening the athlete's family. - There is a previous diagnostic suspicion that the athlete has a family heart disease. A positive genetic test might help in establishing the definitive diagnosis and identifying whether the mutation is pathogenic, very likely pathogenic, or likely pathogenic. - The athlete has no clinical manifestation of the disease, but an affected first- or second-degree relative. A positive genetic test in the family's index-case will confirm or discard that variant in the athlete.
Absence of a genetic variant does not rule out the disease in the athlete. In the following situations an athlete can test negative for a genetic study:
- The athlete clearly has a familial heart disease. In the presence of a negative genetic test, other genes that have not been described may be involved. In this case, the percentage of positivity (yield) of currently available genetic studies (in the presence of disease), which vary according to different pathologies ( - There is a previous diagnostic suspicion that the athlete has a family heart disease. A negative genetic test confirms the absence of disease in this individual, although a follow-up is recommended, at least annually, if there is a borderline change in previous diagnostic tests. - The athlete has no clinical manifestation of the disease, but an affected first- or second-degree relative. A negative genetic test in the family's index-case will not allow proper familial screening. Thus, predisposition to develop the disease can be neither confirmed nor ruled out. In this case, follow-up is recommended, at least annually, especially if there is a borderline change in previous diagnostic tests.