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How important is the family study?
What are the benefits of discovering the mutation?
Why do genetic studies take so long?
Is it possible to establish in which cases a genetic study is beneficial?
Introduction
Some heart diseases have a predominant family component. In other words, they are inherited diseases in which one or several genetic alterations enable the development of the disease throughout the lifetime.
Genetic alterations, also called mutations, affect the production of certain proteins which are important for heart muscle fiber contraction, for cell structure maintenance or for transmission of the electrical current that coordinates heart function. One type of protein or another is altered depending on the disease. For example, in cardiomyopathies (both hypertrophic and dilated) the problem is usually in the proteins that make up muscle fiber, in arrhythmogenic cardiomyopathy the proteins of cell unions are affected, in contrast, channelopathies (Brugada syndrome, long QT syndrome, etc.) affect some proteins that are like "pores" or "channels" through which molecules with electrical charge pass (sodium, potassium or calcium).
Below, you will find information that we hope will help you understand the need of a family study and the complexity of a genetic study in some cases.
How important is the family study?
The family study is very important in order to identify people in the family who might be at risk of developing, or who have developed, the disease. These people could benefit from an effective treatment to prevent the complications that may arise and improve their quality of life by reducing the symptoms, if they have any. Usually, the family study entails the performance of two non-aggressive tests, such as an electrocardiogram (ECG) and an echocardiogram. Depending on the disease and on the results of the ECG and the echocardiogram, other well-tolerated tests are requested, such as a stress test.
The family study in these cases is recommended by every national and international organization (it is included in the clinical practice guidelines). It is recommended to every immediate relative of an affected person, in other words, parents, siblings and children. The disease does not always present with the same severity or at the same age in every member of a family. Although there are no fixed rules, most cardiomyopathies appear from adolescence on, while channelopathies are usually diagnosed as early as childhood. Therefore, in some cases it is necessary that children be seen by a pediatric cardiologist.
It is important to have an overall view of the family when dealing with these diseases, since the way they manifest in some family members may influence the treatment of other family members. The elderly have had more time to develop the disease. The objective of the study is to prevent complications and to improve quality of life.
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%). The results of the genetic study can be difficult to construe as we will see later. With technological development and our increasing knowledge of these diseases, new genes and mutations are reported every year. For this reason, in cases where a mutation is not identified in the first study, it is possible to do a broader study some years later.
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 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.
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 consent 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 healthcare 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 non-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 of 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/