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Genomic technologies in cardiac medicine

In this step, we will hear how genomic technologies have impacted on the diagnosis of inherited cardiac disease
My clinical role at St George’s is as a general geneticist, but I have a special interest in the genetics of inherited cardiac disease. The genetics of inherited cardiac disease includes the cardiomyopathies, the channelopathies, and also the aortopathies. I’m going to concentrate on the channelopathies and the cardiomyopathies as I, personally, do not undertake much of the aortopathy work. The channelopathies and the cardiomyopathies have quite a nonspecific phenotype, and very many diseases appear to be exactly the same. If you take the example of a dilated cardiomyopathy, they can be caused by genetic mutations that we, classically, associated with both hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia.
If you were going to undertake genetic analysis on a gene-by-gene basis, you are going to need to look at a large number of genes before you are going to find your result. And this can take up to a year, and the price is prohibitively expensive. By undertaking large panels of genes all at the same time, you can actually get answers much quicker and much more accurately. They do have their problems, the large gene panels. They are not easy to interpret, but they have radically changed how many genes we can actually look at. And it also has changed the amount of diseases that we can actually diagnose.
When someone dies suddenly, if they’ve never had any symptoms to suggest an underlying diagnosis, you have had no clinical examination to actually direct you towards a clinical diagnosis. The post-mortem may help with this, but it is absolutely essential that the post-mortem has been undertaken by an excellent cardiopathologist. If, though, you still have no idea of the underlying diagnosis, then it is essential to look at a large number of genes as there are known to be a large number of genes that can possibly cause sudden cardiac death.
And it is only at that stage that you can potentially help a family, not only to move on from the tragedy of the death of a relative, but also to help them screen other family members who may be at risk from a similar disaster. We are using a molecular autopsy, and we have examples where it has actually benefited a family. I can think of a particular example with the loss of a three-year-old who died suddenly, and we were able to undertake a molecular autopsy and identify a mutation in the ryanodine 2 receptor which we found had occurred de novo. So no one else within the family actually had this mutation, and therefore no one else was at risk.
And the other children within the family were safe, and we did not need to continue screening. The mother could rest happily at night that her other children were not going to die suddenly. I believe that cardiac genetics will change significantly now that we understand the underlying cause of many of these disorders. If we, first of all, take the hypertrophic cardiomyopathy genes that have been identified to date, many of these are sarcomeric proteins, and there is likely to be generic treatment for those particular disorders. But there are others, such as Fabry’s disease. There is a particular mutation in the Fabry’s gene that can cause a specific hypertrophic cardiomyopathy.
Enzyme replacement therapy with alpha-galactosidase can not only potentially prevent progression of the disease, but there is a potential that you can actually cause regression of the disease. As far as the channelopathies are concerned, specific treatments are slow to becoming available. But there is a huge amount of work on looking at this further. We know that with the channelopathies there are many drugs that you should particularly avoid. And particularly with the potassium channel disorders– with the sodium channel disorders– it is important to avoid things like fevers, and diarrhoea, and vomiting because that can make episodes of collapse much commoner.
I believe very strongly that knowing the underlying cause of a disease will give us therapeutic options that have not been available to date.

Dr Tessa Homfray, Consultant in Clinical Genetics, discusses how genomic technologies have transformed the diagnosis of inherited cardiac disease, how they are transforming available treatment options and the increasing use of molecular cardiac autopsies.

Dr Homfray uses some technical terms in this video. She discusses that genetic conditions can cause a number of the different heart (or cardiac) conditions.

Dr Homfray particularly discusses enlargement of the heart (cardiomyopathy) or disruption of the normal heart rhythm (channelopathies, long QT) which can lead to sudden death from ventricular fibrillation.

Typically, an individual affected with one of these genetic cardiac conditions can appear healthy until they suffer a catastrophic cardiac event. In this tragic eventuality, genetic testing at post mortem (a cardiac autopsy) may provide vital information for the wider family to determine treatment and surveillance of at-risk family members.

Talking point

Can you think of the advantages and disadvantages of a cardiac autopsy?

Would you want to know if you had inherited a genetic predisposition to a heart condition which could result in sudden death?

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The Genomics Era: the Future of Genetics in Medicine

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