Genetic testing and sport: can sudden death be prevented?

Anyone, supporter or not, was shocked by what happened during the Denmark-Finland match of the UEFA EURO 2020. A player from the Danish national team, Christian Eriksen, collapsed due to cardiac arrest. Timely intervention was provided first of all by his teammates and subsequently by the specialized medical team, who, thanks also to the help of the automated external defibrillator (AED), saved his life.

Although this episode had a happy ending, unfortunately there are many cases in which the outcome is fatal.

And therefore the question arises: was it possible to foresee this event? What is the state of the art of sudden death prevention in sport?

And in all this, what is the role of genetics? 

What is the definition of "sudden cardiac death" in sports?

Although there is still no universally accepted definition, "sudden cardiac death, SCD" can be defined as an unexpected death that occurs during or immediately after (1-3h) physical exercise.

A bit of statistics...

Establishing a precise incidence of sudden death events in the general population and among athletes is really difficult, because of the fact that in the literature there are numerous studies with results that have wide variability, ranging from 0.12 events per 100,000 people per year in the general adult population to an incidence of 6.64/100,000 among competitive athletes between 35 and 49 years. This variability is influenced by parameters such as age, sex, ethnicity, the type of sport practiced, but also by statistical biases such as the reference sample, the target population and the definition of the event.

According to a recent internet-based Italian epidemiological research, in 2019 the incidence of SCD was 0.47/100,000 people per year (1/100,000 in competitive athletes and 0.32/100,000 in non-competitive athletes), with the risk increased about 10 times for males compared to females.

Anche i dati sulla sopravvivenza in seguito ad un evento di arresto cardiaco improvviso sono molto variabili con percentuali che vanno da 3.4% a 22%, ma spesso con danni neurologici permanenti e bassa qualità di vita.

Survival data following a sudden cardiac arrest are also highly variable with percentages ranging from 3.4% to 22%, but often with permanent neurological damage and low quality of life.

According to a FIFA epidemiological study conducted between 2014 and 2018, only 23% of soccer athletes who experienced sudden cardiac arrest survived.

But what are the causes of SCD?

SCD can have both cardiac origins due to structural or functional abnormalities of the heart and non-cardiac origins, due to heart malfunctions secondary to another primary cause. Among the most common structural cardiac anomalies there are hypertrophic obstructive cardiomyopathy, dilated cardiomyopathy, left ventricular hypertrophy and coronary artery anomalies. Among the functional cardiac anomalies we distinguish the Brugada syndrome, the congenital or acquired long QT syndrome, ventricular fibrillation and channelopathies. Non-cardiac forms, on the other hand, may be due to cerebral hemorrhages, drug abuse, pulmonary embolism, hyperthermia and rhabdomyolysis.

In athletes with more than 35 years, coronary artery abnormalities (including atherosclerosis) appear to be the leading cause of death, while in athletes under the age of 35, the leading causes of death stem from a hereditary predisposition and are hypertrophic cardiomyopathy, left ventricular hypertrophy and arrhythmogenic right ventricular dysplasia.

Prevention: what is the state of the art?

There are currently several indications for the prevention of sudden death:

  1. The correct execution of the pre-participation cardiovascular screening;
  2. Genetic testing, but only for athletes who belong to high-risk families;
  3. The use of implantable defibrillators in athletes with a diagnosis of malignant arrhythmia;
  4. The reduction of the use of drugs and the correction of the diet;
  5. Avoid extreme efforts;
  6. Early research for risk factors for coronary artery disease;
  7. The presence of a medical team ready to intervene and the external defibrillator (AED).

Certainly, one of the most important steps is cardiovascular screening which includes a first phase of anamnesis to investigate the past and present personal history, family history, the presence of cardiac symptoms and the use of drugs and a second phase that is based on the physical examination of the athlete and which includes several diagnostic tests, including 12-lead electrocardiogram and diagnostic imaging (cardiac ultrasound or magnetic resonance).

Italy is one of the few countries that recommends this screening to all competitive athletes, and its long experience has shown efficacy in identifying potentially life-threatening cardiovascular diseases.

And what role does genetics play?

As previously mentioned, genetic testing is recommended in athletes in whom mild cardiac anomalies are identified, or who have a positive family history. But what are we talking about?

There are forms of hereditary cardiomyopathies that result from mutations in specific genes that code for functional or structural proteins of the heart. Some of these cardiomyopathies such as dilated or hypertrophic cardiomyopathies generally have an autosomal dominant inheritance, while long QT syndrome, short QT syndrome and catecholaminergic polymorphic ventricular tachycardia can have autosomal dominant, recessive, X-linked, and in some cases mitochondrial inheritance.

The main problem with this type of disease is that in addition to being characterized by genotypic variability (many genes associated with these conditions are known), they are characterized by phenotypic variability and often the dominant forms have incomplete penetrance. On the other hand, however, these are very subtle pathologies, which often manifest themselves primarily with sudden death and for which the diagnosis arrives always too late.

So, if genetic testing is able to reveal some of these not yet manifest diseases and prevent sudden death, why is it not used for wide-range screening, especially among athletes?

Although genetic testing has strong potential in preventing these diseases, it is still very little used in clinical practice.

Primarily due to technical limitations, given that there are few laboratories capable of performing a complete analysis of all the genes involved and providing useful results.

The second problem is that unfortunately in many patients the causative mutation is not identified (low mutational detection rate) and inconclusive results can be harmful from an ethical point of view and would make it difficult for the physician receiving to interpret the results. And then we must not in any way underestimate the presence of variants of uncertain significance, namely those rare variants for which neither pathogenicity nor non-pathogenicity has been definitively demonstrated.

Then there is a bioethical problem: is it right to limit the life and freedom of an athlete who does not show symptoms?

Infine c’è un problema di costi: non solo per quanto riguarda l’accesso al test genetico, che negli ultimi anni si è ridotto notevolmente, ma anche per il follow-up diagnostico a cui dovrebbe essere sottoposto un individuo e/o i suoi familiari, con oneri non indifferenti per il sistema sanitario nazionale.

Finally, there is a cost problem: not only with regard to access to the genetic test, which has been significantly reduced in recent years, but also for the diagnostic follow-up to which an individual and/or his family members should be subjected, with considerable burdens for the national health system.

And what do you think? Could the application of genetic testing as part of the prevention of sudden death be a good strategy or are the risks greater than the benefits?

Our opinion?

According to Breda Genetics, genetic testing for sudden death should be recommended at least to all competitive athletes, only after extensive genetic counseling in which, in addition to collecting the patient's anamnestic data, are explained the technical limitations of the analysis, the possibility of not find any mutation and the possibility of encountering a variant of uncertain significance, with its interpretation.

Breda Genetics rapidly offers the analysis of all genes associated with sudden death in its whole-exome sequencing based-panel:

Pan143 - Sudden death (ABCC9, ACTN2, AKAP9, ANK2, CACNA1C, CACNA2D1, CACNB2, CALM1, CALM2, CALM3, CASQ2, CAVIN1, CAV3, CSRP3, CTNNA3, DES, DPP6, DSC2, DSG2, DSP, DTNA, FBN1, FGF12, GJA5, GPD1L, HCN4, JPH2, JUP, KCNA5, KCND2, KCND3, KCNE1, KCNE2, KCNE3, KCNE5, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNQ1, KLHL24, LAMP2, LDB3, LMNA, LRP6, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, NEXN, NPPA, NUP155, PKP2, PLN, PRKAG2, RANGRF, RBM20, RYR2, SCN10A, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SCN10A, SEMA3A, SLMAP, SNTA1, TANGO2, TECRL, TCAP, TGFB3, TGFBR2, TMEM43, TNNC1, TNNI3, TNNT2, TPM1, TRDN, TRPM4, TTN, VCL)

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Posted in Academia, Last Update, Medical Genetics.

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