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Hypertrophic cardiomyopathy is a condition which affects the heart muscle and whose main characteristic is a thickening of the heart walls. Cardiomyopathy means a disease of the myocardium (heart muscle) and hypertrophic means an increase in size (thickening). The ways the disease manifest may vary widely between patients.

What are the benefits of discovering the mutation?

Genetic studies allow for the identification of the mutation (genetic alteration) which causes the disease in 50-60% of cases. Depending on the disease, the profitability of the genetic study is higher, as with hypertrophic cardiomyopathy (60%), or lower, as with Brugada Syndrome (20%).

Our bodies are made up of millions of cells. Every cell has a nucleus. Every nucleus has 46 chromosomes. Every chromosome is made up of a long DNA spiral. The DNA spiral is divided into genes. Every gene has the information needed for the production of a protein. Overall humans have 25,000 genes.

A genetic study tries to find where the error or mutation is (as if it were a "typo"). This work can be compared with finding a typo in a word inside a book in a big library. We will first look in the "books" (between 5 and 40) where alterations have been found before. Most times (20-60%) we succeed, but it is possible that after much work we will not find the origin of the problem. The "typo" can be in any other book in the library (25,000 overall).

The performance of genetic studies for these heart diseases is recommended by cardiologists' and geneticists' expert committees and is included in the clinical practice guidelines. The benefit of the genetic study is that it usually allows for the diagnosis of other family members who are carriers of the disease, who must be periodically followed up with in order to detect the development of the disease and to establish a treatment when necessary, and it also allows for proper counseling for those people who wish to have children and are carriers of these defects in genes.

Sometimes, the genetic study may offer prognostic information, although not always. The main value of genetic results is diagnostic.

What does it mean when the genetic study is negative for the index patient in the family?

It is important to understand some concepts first. In every family with an inherited heart disease, there is an index patient, which is the index case, the first patient diagnosed with a particular disease. The genetic study is performed on the index patient. It includes a group of genes, usually between 5 and 40, which are related to the particular disease the patient has. The results of this study on the index patient usually take between 3 and 6 months. The results can be:

Positive, some genetic alterations are found in some of the genes ("books") related to the disease. The error can be known or new.. That is to say, the error has already been found in another person with the same disease (it is known) or on the contrary, it is the first time that it has been found (it is new).
Negative, no alteration has been found in genes related to the disease. Which does not mean that the patient will not suffer from the disease, or that the disease is not genetic, it only means that we have not found the error. It could be in other less well-known genes. New genes associated with inherited heart diseases are identified every year. The list of related genes keeps increasing.

Although sometimes the results of the genetic study provide definitive information (in other words, they are clearly positive or negative) sometimes we find new mutations in associated or non-associated genes, whose significance we do not yet know. We then say that the alteration found is of uncertain significance.

The first time that a genetic error is found, its significance is uncertain, because we are not aware of other cases with the same mutation and we cannot establish for certain that it is the cause of the mutation. In time, and with experience, errors repeat and knowledge is gathered. This leads to the conclusion that the error found is of certain significance, thus confirming or refuting its relation to the disease. That is to say, concluding that the mutation is or is not the cause of the disease.

In our unit, since the year 2003, when we started genetic studies, we have gone through this process on many occasions. Some genetic alterations of uncertain significance have ended up being certain either in one sense or the other.

Does this mean that the results of the genetic study are not definitive in some cases?

Indeed, in up to 50% of cases (this percentage varies depending on the disease) a variant, which we think may be the cause of the disease, is identified. In half of them, there are enough data available to be definitive in the report. In other words, we can assure with high degree of certainty that it is the cause of the disease. In the other half, we believe that it may be the cause but we cannot ascertain it.

In the other 50%, in which the results of the genetic study are negative, we can only say that we have not found any alterations in the genes studied to which the disease could be attributed. In this group, the genetic study should be completed when there are advances in the knowledge of the mechanisms causing these diseases and new genes are found to be involved. This falls into the field of research. The discovery of new genes may take years. Some of our patients have benefited from the results of the ongoing research projects, and our unit has been a pioneer in the identification of new genes and mutations.

In a typical blood test, results take a few hours or days, since the blood is extracted. This is not the case with genetic studies. The implications of the results of the genetic study sometimes have to be reviewed, taking into account any new findings. There are databases of mutations and there are many research groups that try to explain the effect of genetic errors on cell function. Research studies range from computer simulations to fish or small animal models.

If an error clearly causing the disease is detected in an index patient, what is the next step?

Depending on the error identified, the first thing is to see if having said genetic alteration means a change in the index patient's treatment, something very unusual.

The next step is to confirm whether the immediate family carry the genetic alteration. Technically, verifying whether the immediate family are carriers is very simple and should be fast. We do not perform an extensive genetic study on the family, we just confirm whether they carry the genetic alteration.

If there are other affected members in the family, they usually carry the genetic error. On the other hand, most non-affected members are not carriers. However, there may be carriers of the genetic error who have not developed the disease. For the latter, it is necessary to carry out a regular follow-up, so that we can anticipate the complications in case the disease manifests.

Can the people who do not have the disease and are not carriers stop worrying?

In cases where the genetic error is definitive, that is to say, in cases where we have enough information on which to "blame" the disease, they would be discharged. The patients who do not carry the genetic error are not at risk of developing the disease in the future or passing it on to their children.

Are all the carriers of the genetic defect going to develop the disease sooner or later?

No, between 20 and 30% of the carriers of a genetic mutation that clearly causes the disease identified in other family members will not develop the disease. This percentage is higher for some diseases such as arrhythmogenic cardiomyopathy and Brugada syndrome.

The reason why these people do not develop the disease is unknown. They may have protective genes or there may be unidentified environmental factors that prevent them from developing the disease in spite of carrying the mutation. Despite not developing the disease, they can pass the mutation on to their children, who might develop the disease.

What are the probabilities of passing the disease on to children? Are there any differences between the risk of developing the disease if you are a man or a woman?

In almost every case of inherited heart diseases, the inheritance pattern is autosomal dominant, which means that the disease is passed on from parents to children with a 50% probability. The probability of inheriting the genetic alteration is the same for boys and girls. There are no sex-dependent differences in the probabilities of inheriting the genetic alteration. This is different from the fact that males carrying the genetic alteration usually develop the disease earlier or they may be at a higher risk of having complications when the disease manifests. This is not always the case, but in cardiomyopathies men usually present with a more severe form than women.

Is it possible to avoid the development of the disease in carriers of the genetic defect who do not have the disease yet?

Nowadays, there is no treatment that prevents a carrier of a genetic mutation related to an inherited heart disease from developing the disease. There are many treatments to prevent the complications and reduce the symptoms in patients but we do not have medicines that can prevent the disease from developing.

Different research studies are being performed to try to identify medicines that prevent the development of the disease, but at the moment we are far from having a solution to this problem.

What seems clear is that if the progress of the past few years continues, it is foreseeable that research will provide new treatments for patients with inherited heart diseases within the next 10 years.

Is there something I should avoid in order to prevent the development of the disease? Do diet, tobacco, alcohol, medication or sport affect the development?

In most inherited heart diseases there is very little we can do to prevent those who have the genetic mutation from developing the disease. We do have many effective drugs to control the disease when it manifests, but not to prevent its onset. In any case, it is advisable to have a healthy diet and avoid alcohol abuse. Tobacco is a strong toxin for coronary arteries and one of the main causes of heart attacks. Alcohol, on the other hand, is toxic for the muscles and it causes heart muscle weakness.

Is sport contraindicated for people who have an inherited heart disease?

Non-competitive regular sport is beneficial for general health. In arrhythmogenic cardiomyopathy, in catecholaminergic ventricular tachycardia and in long QT syndrome, sport must be restricted because it encourages the development of the disease (in the case of arrhythmogenic cardiomyopathy) and arrhythmic complications (for all three diseases). In dilated cardiomyopathy, hypertrophic cardiomyopathy and Brugada syndrome, non-competitive regular sport does not increase the risk of developing the disease or its complications.

The recommendations for competition athletes and sport professionals shall be made individually. It is hard to say, as a general rule, if they can or cannot go on with their physical activity. It depends not only on the disease but also on its severity.

Should the genetic carriers who have not developed the disease take any precautions regarding sport?

The carriers of a genetic mutation who have already been assessed by a cardiologist and have been told that they have no disease are healthy people. Having a genetic mutation that makes it easier to develop the disease in the future is one thing and being sick is something different. Genetic carriers who have not developed the disease are healthy and do not need any treatment or special precaution. It is however recommended to undergo regular follow-ups (every 1-2 years).

However, medical treatment is indeed recommended to genetic mutation carriers who show no sign of being sick and who have a family history of long QT syndrome and catecholaminergic ventricular tachycardia.

The recommendation to immediate family members of a patient with long QT syndrome or Brugada syndrome is to avoid taking contraindicated drugs that can prolong the QT interval or that disrupt sodium channel function.

Is it possible to prevent passing the genetic alteration on to children?

It is a long process but it is possible. Patients with an inherited heart disease, particularly the carriers of a genetic mutation, can choose not to pass the disease on to their children.

There is a unit at our hospital (Medical Genetics) which will provide you with information and individual counseling about the possibilities and the profitability of these techniques in each case.

What is more important: the performance of tests with a cardiologist or the performance of a genetic study?

It is important to emphasize that a cardiology study is more important than a genetic study. The two techniques are supplementary. Genetic studies such as screening are not recommended to healthy people or family members who have not been assessed by a cardiologist yet.

Regarding this matter, it is important to know that genetic studies are more likely to be conclusive and the genetic information more useful in big families on which a more comprehensive cardiology study is performed and where there are more affected individuals.

Why do genetic studies take so long?

At the moment, the waiting period for cardiology tests (ECG and echocardiogram) at our unit in Virgen de la Arrixaca hospital is between 6 months and 1 year, since several members of the same family have to be assessed.

The genetic study is requested once the family study has been completed and there is confirmation that it is indeed an inherited disease.

For the genetic study it is necessary to obtain a sample of cells from the affected person. The simplest thing is to get a blood sample. No test, even the simplest one, should be performed without the awareness and consent of the interested person, that is to say, the patient or his/her relatives. Therefore, written and signed consent will be requested before performing the blood test.

In cases where no blood sample is available a genetic study cannot be performed. If there is only one person affected in a family and he/she has passed away or it is impossible to perform a blood test, the genetic study cannot be performed.

The Inherited Heart Disease Unit of Virgen de la Arrixaca Hospital has assisted over 2000 families since its beginnings in 2003 (in the last few years 250 new families have been assessed every year). Between 2003 and 2012, the techniques available were very laborious and the genetic studies took a very long time (Sanger sequencing). During the last few years, extraordinary progress has been made in genetic diagnostic techniques (ultrasequencing or massive sequencing) that allow for the testing of many genes in a short period. Although these techniques are available, our unit has a very heavy workload, which has been accumulating over the past 12 years. At the moment, we are making a big effort to complete the genetic studies, which sometimes implies extending the study to multiple genes. Families with several members affected, for whom, in our opinion, the results of the genetic study may imply an adjustment in the treatment, or families in whom the disease is very severe, are logically a priority.

Blood samples are processed and stored at the biobank of IMIB (Institute of Biosanitary Research of Murcia) annexed to Virgen de la Arrixaca Hospital. These samples sometimes have to be stored and sorted by year and the biobank offers the most reliable form of preservation.

Are genetic studies a research topic or are they really of interest for those affected by one of these heart diseases?

The Inherited Heart Disease Unit of University Hospital Virgen de la Arrixaca has been accredited by the Spanish Health Ministry as a national reference unit for the diagnosis and treatment of said diseases (CSUR - reference centers, services and units - unit 2013). For that accreditation, it was necessary to prove a specific level of experience and collaboration between different units such as Cardiology, Pediatric Cardiology, Medical Genetics, Heart Surgery and Anatomical Pathology. The unit also counts on the participation of the Legal Medicine Institute of Murcia and the Sport Cardiology Unit of the University of Murcia. The accreditation process entailed an audit.

During the assessment process for the accreditation as a reference unit, patients' care, research, training and teaching were assessed. The aim of the unit is to offer all of the available diagnostic methods, including the performance of genetic tests.

It is important to stress that our unit has an important research element, aimed at solving problems raised by patients on issues that are at the moment not very well-known but very novel. All the research projects performed at the unit have been presented and passed by the ethics and research committee of Virgen de la Arrixaca University Hospital. The participants of these projects are duly informed and must give their consent. The clinical data are used exclusively by the personnel of the unit and the patients remain at all times anonymous and confidential.

The samples are gathered at the biobank, since it is the center that offers the best guarantees for the samples' safety at the moment. The authorization form, filled out at the time of the extraction of the blood sample, includes the will of the patient for their samples to be used exclusively for health care purposes (only for their own benefit) or for research studies.

Is it possible to establish in which cases a genetic study is beneficial?

Before specifying for whom and under which conditions the genetic study is beneficial, it is important to understand some concepts. In every family with an inherited heart disease, there is an index patient, which is the index case, the first patient diagnosed with a particular disease. Then the cardiac study is performed on the immediate family, which reveals which family members are affected and which are not (affected relatives and on-affected relatives).

A genetic study is not usually necessary to diagnose the index patient. Most cardiomyopathies and channelopathies are diagnosed by means of an ECG and an echocardiogram. A genetic study is recommended to establish the type of long QT in the homonymous syndrome and is one the diagnostic criteria in arrhythmogenic cardiomyopathy.

The genetic study may result in a treatment modification for the index patient in some cases (in limited cases when dealing with long QT syndrome). There are some mutations considered low-risk whereas others are considered high-risk regarding complications. In other words, some (few) genetic alterations provide us with important prognostic information for the patient.

The truth is that the results of the genetic study are rarely useful for diagnosis (because it has already been established with the usual tests) and only on rare occasions do they result in the cardiologist changing his treatment.

The benefits of genetic studies are not for index patients, for whom diagnosis and treatment is usually clear, but for the family members who take part in the study. Nowadays, a genetic study in all inherited heart diseases is useful for the diagnosis of carriers at risk within the family of a patient.

How can I apply for assessment by the Inherited Heart Disease Unit? How can I contact the Unit if I have questions?

For adult patients, the simplest thing is to go to the Inherited Heart Disease Unit at the General Hospital (3rd floor, cardiology, Monday or Tuesday morning) and make an appointment. For children, the appointment has to be requested in the Pediatric Cardiology Service (ground floor of the new Maternity building). You can also contact us via email: cardiopatias.familiares.sms@carm.es.

Apart from the information we can give you at the hospital, we provide some links below where you will find information and other links to patients' associations where you can seek personal support. The diagnostic process of one of these diseases is sometimes associated with a level of uncertainty, which we try to reduce, but sometimes the help of other professionals and patients' associations is needed.

We are sorry for the delays in the performance of the family and genetic studies. We are implementing some changes at the moment to try to speed up the process and reduce the waiting period that depends on our unit's operation.

For more information on hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy and Brugada syndrome in Spanish, you can visit www.murciasalud.es/miocardiopatias.

For more information on cardiomyopathies in general (in English) you can visit the leading international association for these diseases: www.cardiomyopathy.org

To contact associations in our region: www.d-corazon.org.

Other related associations: http://www.todocorazondemurcia.com/

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