Gene testing will help future treatment

Dr Maite Tome, consultant cardiologist at the Heart Hospital in London, talks about the benefits more gene testing of families will bring to the future diagnosis and treatment of affected families

Cardiomyopathies are heart muscle conditions and most of them have genetic origin. The discovery of the cardiomyopathies and the genetics goes together. The first time cardiomyopathies were described as a new distinctive cardiac pathology date back to the beginning of the last half of the 20th Century. The discovery of the material that transports the genetic information in the cells was made only five decades ago.

The knowledge of both scientific disciplines has changed enormously in the last three decades and it was only in 1989 that the first gene was found in a family with hypertrophic cardiomyopathy (HCM).

During this journey numerous lessons have been learnt and it is a fact that more information needs to be gathered to advance the understanding and treatment of genetically determined conditions.

Genetic information

The genetic information is packed in units called genes. These genes contain the information required to encode proteins which are ultimately the “bricks” that build our bodies. If the information required to encode a protein is altered, then this protein may result in an impaired protein in function or structure. This alteration is known as a mutation.

The cardiomyopathies are the results of these mutations altering the heart muscle composition.The full genetic laws are still to be understood. As it is, we know that for every characteristic we carry two copies of the same gene, one from each parent, and we can carry a mutation. The mutation may not necessarily express the characteristic. The expression of a characteristic resulting from a gene mutation is called penetrance.

It is recognised that in addition to the genetic makeover, (genotype), there are other influences such as life style and environment that will also determine the end product (phenotype). The complexity of genetic jargon has increased and therefore it is important that every patient is offered genetic counselling and appropriate information with regard to genetic testing. This information may need to be updated in the future with new knowledge.

Genetic testing for most cardiomyopathies unfortunately is only available in research units or is dependent on research projects and is, therefore, patchy and not universal. This approach to genetic information is unsatisfactory for the recipients, the patients, the researcher and clinicians.

How is a gene linked to a disease?

This is a lengthy process. It starts with the clinical observation that a specific disease has a strong family association. This is what is called ‘linkage analysis’ and involves investigating large families with at least ten individuals affected by the disease. This allows the geneticist to identify specific patterns of markers and small areas (loci) of the genetic code or genoma where it is most likely that the wrong or altered code might be located. These areas are then read carefully, looking for altered codes. In hypertrophic cardiomyopathy the first gene found was in a gene that encodes a protein of the sarcomere, the muscle unit.

Following this finding, in the last three decades all the genes encoding proteins in the sarcomere have been searched and to date more than 600 mutations have been found in ten different genes. The story behind the finding of the candidate genes in arrhythmogenic right ventricular cardiomyopathy (ARVC) is linked to another clinical observation that started on the Greek island of Naxos.

The first gene causing the disease was found to encode the proteins of the structures that link the cells between each other. This structure is called desmosome. Gigantic advances have been made in the last five years in the discovery of new mutations and genes encoding proteins causing ARVC.

In dilated cardiomyopathy, numerous genes encoding different parts of the cells have been found to be involved; some of the genes encode proteins from the supporting network of the cells, the cytoskeleton, some have been found in the sarcomere, and others in the desmosome. There are still more to be discovered.

How do we know that a new mutation causes disease?

One of the biggest challenges for the researcher is to differentiate a definitive mutation from a benign one, or polymorphism. There are several proofs required and those are based on the before mentioned linkage analysis and the exclusion of the presence of the mutation in healthy people. It is also required that the change in sequence affects an area of the code that is known to be important. One way to ascertain that is to check if the region of the code is also present in other species and is conserved by the evolution of the species.

Some mutations are only private

The information relating the importance of a new mutation is sometimes difficult to ascertain as some mutations are only found in a given family. Others are more common and there is more information available, but in some cases the information is limited to a few individuals.

Genetic testing

If you are asked to give blood for genetic testing it may be for different reasons:

  • To look for a disease causing mutation/mutations. This is the situation in every new family diagnosed with a cardiomyopathy. It can be a lengthy process and it may not find an answer.
  • Predictive testing. Once a disease-causing mutation has been found in a family, predictive testing can be offered to other family members. The results of this test can be:

Negative: the gene cannot be found and therefore the patient is not affected with the condition and further screening in not required.
Positive: the person tested carries the gene. Those who carry a gene can pass on the gene to the next generation and can, at some point during their life, be affected with the condition.

To carry a gene is not the same as suffering the disease

Genetics and the future

There are numerous commercial initiatives looking into genetic testing and certainly for diseases like hypertrophic cardiomyopathy, where so many candidate genes have been found, this is already available in some countries. There is a lot of information about genetics and genetic testing. However, as in many other tests, genetic testing needs to be interpreted within the context of family evaluations and by teams familiar with the cardiomyopathies.

Some patients express their concern with regard to genetic testing and insurance. To date a positive result in gene testing in cardiomyopathy cannot predict if the individual is going to develop the disease, when it is going to develop or what the prognosis is going to be. Therefore for insurance purposes so far, clinical diagnosis prevails along with family history. We should aim to genotype every single family affected with cardiomyopathy in the future and only then will we be able to understand and plan strategies for treatment.