The questions most frequently asked by patients with Hypertrophic Cardiomyopathy (HCM) during pre- and post-test genetic counseling interviews with the related answers from the team of specialists dedicated to this pathology (cardiologists, geneticists, psychologists, etc.).
1) What can genetic testing for HCM be used for?
The genetic test allows to identify the genetic cause (mutation) of the HCM, helping the cardiologist in the diagnosis; this is particularly important in the case of a differential diagnosis with other forms of hypertrophy such as infiltrative ones (eg Fabry disease or cardiac amyloidosis). However, the most relevant practical impact of the genetic test in HCM is that of being able, once the causative mutation has been identified, to exclude or confirm its presence in family members by means of a cascade screening. Knowing whether or not the mutation that causes HCM in the family has been inherited can be very important. In fact, if the mutation has been inherited, there is an increased risk compared to the general population of developing the disease for which a cardiological visit is recommended; in addition, the subject has a 50% risk of transmitting the mutation for each child. Conversely, if the mutation has not been inherited, the risk of developing the disease is very low, the same as in the general population; in this case the test result can be reassuring and can positively affect the quality of life. Also, the mutation will not appear in subsequent generations.
2) Clinically I was given a dubious diagnosis of HCM. In this case, can the identification of the genetic mutation definitively clarify the diagnosis?
In this case the identification of the genetic mutation is the safest method to confirm the clinical diagnosis. Conversely, if the mutation is not identified this does not mean that it is not HCM, but the situation remains the initial one. In our experience, for example, we have had a case of an athlete with dubious clinical data in which the identification of a mutation described in the MYBPC3 gene allowed the diagnosis to be confirmed.
3) Is the mutation present in my DNA associated with a benign or unfavorable course of the disease?
At the moment it is not possible to associate the course of the pathology with the type of mutation because there is a great intra-individual variability of the phenotype associated with the same mutation. In our experience we have families in which there are subjects with the same mutation (e.g. the proband, the mother and the maternal grandfather) in which the disease has manifested itself in a completely different way, in terms of symptoms, course, age of onset. This variability, also known as incomplete penetrance, can currently be explained by the influence on the genetic mutation of environmental factors (e.g. eating habits, smoking, sporting practice, etc.) and other partly still unknown genetic factors such as modifier genes or polymorphisms. Only large-scale genotype-phenotype correlation studies will be able to give us an answer in the future
4) Will knowledge of the genetic mutation allow me to access targeted pharmacological therapies?
Genetic testing is of little relevance from a medical point of view since there is no preventive therapy, even if there are experimental studies and emerging therapies that open up hope for the future (eg gene therapy). The identification of the genetic mutation can however be of help to the cardiologist for the therapeutic choices.
5) If the mutation is not identified (negative genetic test), does it mean that my cardiomyopathy has no genetic basis?
Genetic testing today involves testing a group of (sarcomeric) genes known to be associated with HCM. It is estimated that this analysis covers about 40/60% of the diagnoses (specificity of the test). If, after completing the gene panel, the mutation is not identified, this means that it could be located in currently unknown genes. For this reason, the relatives of the proband should in any case carry out periodic cardiological check-ups
6) What is the probability of passing the mutation to my children?
The a priori risk that an individual having one of the two parents with HCM is a carrier of the mutation is 50%. The mode of inheritance of HCM is called autosomal dominant; this means that it is sufficient for one of the two parents to have the genetic mutation to transmit it to half of their children and furthermore that the transmission is not linked to the sex of the children but the probability is the same for males and females.
7) Is it possible that a family member who has inherited the mutation never gets sick?
Given the incomplete penetrance of the pathology, and the even intrafamilial variability of the phenotype, the identification of a sarcomeric mutation in a healthy subject cannot be understood as equivalent to the certainty of falling ill. The presence of the mutation must be interpreted as a high probability that hypertrophy will occur, and therefore a high risk of developing the disease. Generally the disease manifests itself within the 4th-5th decade of life; however, there is a percentage of cases where this remains latent even after the age of 60.
8) It seems that I am the only case in my family with HCM; also in this case the cause of the disease is genetic, and if so can I pass the mutation on to my children?
In about a third of cases, HCM manifests itself "de novo", i.e. for the first time in a member of a family. In this case the cause is always a genetic mutation that has arisen randomly in that subject's DNA. The mode of transmission to the children appears to be the same as that of familial HCM, i.e. autosomal dominant (50% probability of transmission of the mutation).
9) Since I have HCM and know the mutation that caused it, can I have my four-year-old child undergo the genetic test even if he does not currently have any clinical signs of the disease?
In this case there is no indication, since each individual must be free to choose to know or not to know if he has inherited the mutation. We do not deem it reasonable to make a child aware of being at risk of getting sick in the course of life, not knowing how to define the age of onset of the disease or how it will manifest itself, and above all not being able to intervene in any way to prevent the mutation from expressing itself giving the disease. Therefore, in the case of unaffected minors, the genetic test can only be carried out starting from adolescence (from 10-12 years), unless the clinical signs of HCM emerge in the meantime.
10) Now that we know the genetic mutation causing HCM, could we possibly see if this was inherited in any of our children before birth?
This is a very personal matter. Through the techniques of invasive prenatal diagnosis (amniocentesis, villocentesis) it is possible to obtain the DNA of the future unborn child, then proceed with the search for the mutation. In reality we do not deem it appropriate to carry out this type of test since if we identified the presence of the mutation we could not associate it with certainty either the time of the onset of the disease, or the severity, since in the same family we have subjects with the same mutation but with manifestations extremely diverse pathologies.
11) If the genetic test is negative, given that I am currently clinically healthy, can I practice sports with peace of mind? And if it is positive, should I stop?
The negative genetic test, when it agrees with the clinical picture, is certainly a reassuring fact also for the specialist who has to establish sporting suitability. Instead, in the case of a healthy subject but a carrier of the mutation it is important that he carries out repeated checks in order to intervene promptly if and when hypertrophy can occur. Regular physical activity is permitted, while competitive sporting activity may be discouraged if the mutation agrees with a family picture of sudden death.
12) If the test is positive, what effect can it have on the insurance policies I have already taken out?
The genetic data is strictly personal and protected by different regulations from country to country. Even in Italy we have these laws, whereby the patient is not required either in the workplace or following the stipulation of a life insurance policy to declare that he has undergone the genetic test.
13) I learned that genetic testing takes a long time to be performed. But once the mutation has been identified, will it take as long to test my family members?
In the case of screening for HCM causative genes, a very large amount of DNA must be analysed. DNA is a molecule present in the nucleus of our cells and therefore also of cardiac cells which contains the information for the production of proteins. In the case of HCM the proteins produced are those of the sarcomere, i.e. the contractile unit of the heart. The information stored in the DNA is like a collection in a large book and it is the cell's job to read it in order to be able to build the various proteins. Also to carry out the genetic test it is necessary to read and decipher the DNA book in order to identify which is the incorrectly written "word" and on which page it is found. This "word" that is not read well is precisely the mutation that causes HCM.
Reading and deciphering the genetic code, comparable to our alphabet, takes time, as it is necessary to query numerous databases and search the scientific literature for data to support our hypothesis. However, once the mutation has been identified in the patient, only that mutation is sought in the family members, which is why the test takes a few days; in this case we already know the page of the book where the incorrectly written "word" is found.
14) What does it mean if the result of the genetic test is "inconclusive"?
In this case the genetic test has identified a rare variant called VUS (Variant of Uncertain Meaning). Due to their rarity in the population, only a limited amount of information is available for this type of variants. It is important to know that when VUS is identified, the test result is ambiguous and clinically inconclusive. For this reason, a VUS should not be used to establish a genetic diagnosis and guide cascade family screening. Future knowledge or scientific reports could improve our understanding of VUS and help us reevaluate it. The identification of a VUS, even if it represents one of the three possible results of a genetic test (1, positive: pathogenic/possibly pathogenic causal variant; 2, rare VUS; 3, no rare variant identified) can be considered a limitation of the tests genetics.
15) Is it possible that the COVID-19 vaccine caused the appearance of HCM?
The genetic material delivered by mRNA vaccines never enters the nucleus of our cells, where our DNA is stored. Viral vectored COVID-19 vaccines deliver the genetic material to the cell nucleus to enable our cells to build protection against COVID-19. However, the vector virus does not have the machinery needed to integrate its genetic material into our DNA, so it cannot cause HCM.
