Genetic Testing for Inherited Cardiac Disease

By Dr Rohit Khurana

Genetic Testing

Many different types of heart disease can be inherited. Common conditions such as high blood pressure and coronary artery disease blood certainly run in families but likely result from a number of different genetic changes that individually have a subtle effect, but work collectively in a complex manner and influenced by other modifiable risks (including smoking, diabetes, cholesterol metabolism) to cause disease. In these situations, genetic testing is not yet available.

Some other, less common, cardiac conditions are caused by just one or very few genetic changes that have a very strong impact in causing disease. All inherited heart diseases require special attention not only for the individual patient, but also have implications for their family to determine if other relatives are affected – a process called cascade screening.

Genes, comprised of DNA, are the basic units of inheritance. Genes provide the instructions for cells to manufacture proteins, which in turn carry out our physiological functions and define our physical characteristics. Each gene is present in 2 copies, one inherited from each parent. Genetic conditions are caused by a change (or mutation) in one or more genes passed from generation to generation.

To determine if a heart condition runs in the family, it is important to investigate whether your relatives have been diagnosed with any heart problems or died suddenly or unexpectedly. It can be difficult to ascertain because people may not be aware that they have a heart condition because their findings could be very mild or they haven’t consulted a doctor or they haven’t had the appropriate tests performed. The sudden death of a previously healthy young person should be closely examined.

What is genetic testing?

Genetic testing involves taking a sample of a person's DNA to look for mutations that could cause inherited heart disease. The results take a few weeks to become available. It is important to recognize that results cannot predict when the condition will develop or how severe it may be. Inheriting the mutation is also not a guarantee that disease will develop, although it will cause the disease in many people. Furthermore, there are typically no treatments that can prevent or change the course of disease, however we hope that such preventive treatments will be developed in the future. Currently, genetic testing is advised to aid or confirm the diagnosis of a heritable heart disease for which there is a strong index of clinical suspicion and for mutation-specific cascade screening of appropriate relatives.

The results are best understood when the family is evaluated as a unit. This way, both the genetic test results and medical test results in concert provide the most accurate picture of how the disease and the gene mutations may act in that particular family. Such comprehensive information not only helps to identify specific patterns in the family, but also plays an important role in confirming that the gene mutation is truly an accurate marker of the family's heart disease. Genetic testing usually examines a panel of multiple genes known to cause the specific inherited condition of interest, and other conditions that have a similar appearance. The DNA sequence in the patient's DNA is compared to the normal reference sequence. A single change in one gene is sufficient to cause disease. There are three potential test results for the initial person being tested: positive, negative, and inconclusive. Only positive testing results are helpful.

Positive result: Laboratory is confident a gene mutation was identified that can cause the family's heart disease. Family members who carry the same gene mutation are at risk to develop the heart condition and should be followed by a cardiologist. These individuals are also at risk to pass the mutation on to their children and these children should be examined. Relatives who do not have the family's disease-causing gene mutation are very unlikely to develop the family's heart condition and cannot pass the family's mutation on to their children.

Negative result: Laboratory was unable to find a mutation capable of causing disease in any of the genes they evaluated. This result is considered unhelpful because it is still possible that there is genetic cause for a person's heart disease that was simply not detected by the technology used, or is present in a gene that was not evaluated. Genetic testing may be reconsidered in the future if there is new information available about the potential genetic causes of the condition.

Inconclusive result: Laboratory identified a change in a gene, but is uncertain about whether the DNA change is capable of causing a heart condition, modify disease severity, or whether the DNA change they found simply reflects harmless DNA variation that occurs in the general population. This type of inconclusive result is often referred to as a variant of unknown significance, or VUS. A VUS does not provide any additional information for the family. Testing other affected family members may help to better understand the significance of a VUS. If it is present in all other affected family members, as would be expected if it is responsible for causing the family's heart condition, that finding provides additional support that the VUS causes disease. On the other hand, if the VUS is absent from even a single affected relative, it would imply that it is not the cause of the family's heart disease.

Important Caveat about Genetic testing

Our understanding about gene mutations is likely to change over time and test results may be updated.  The ability to distinguish pathogenic mutations from rare, benign, background genetic variants will become more evident. There is a paucity of data from randomized controlled trials (RCTs) designed to determine the clinical utility of high quality gene-testing guided care. Each individual should make a personal decision about whether to pursue genetic testing after counselling on the potential value and limitations of the information.

At Harley Street Heart and Vascular Centre, diagnostic clinical genetic testing is available for the common classes of cardiovascular disease caused by mutations in a single gene:

  • Thoracic aortopathies which include a spectrum of heritable connective tissue disorders - Marfan syndrome (MFS), Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome
  • Cardiomyopathies which are disorders of the heart muscle –hypertrophic (obstructive) cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC), left ventricular non-compaction
  • Cardiac arrhythmias (ion channelopathies) - Long QT syndrome, Short QT syndrome and Brugada syndrome
  • Familial hypercholesterolaemia

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