Interview | Genetic cardiac conditions may be difficult to diagnose; however, guidelines are actually now recommending broader testing. In recent years, cardiac genetic testing has expanded, exemplified by INVITAE, for example, a company specializing in genetic testing for hereditary disorders. CSWN: Interventions spoke to Colleen Caleshu, ScM, CGC, on methods and controversies of cardiac genetic testing.

CSWN Interventions: Things in the field of genetics are expanding rapidly, aren’t they?

Colleen Caleshu, ScM, CGC: Yes, they really are. We’ve had rapid advances in our understanding of inherited heart conditions, as well as technological advances that have expanded our ability to look at more genes, and look at them faster, and look at them cheaper.

Where are we right now in terms of how many genes we can look at, and how important is this?

We can look at all of the genes, if that is the right thing to do. I think one of the things that is really important, now that we have this really powerful, fast, next-generation sequencing technology, is to be judicious about which genes we need to look at, whom do we look at, and how will it affect the care of the patient and the family—that really gets at how important this is. The fact that multiple cardiology professional societies from around the world are now recommending genetic testing for inherited heart conditions in unexplained, sudden death, really shows you how important it is. The importance comes primarily in the care of the healthy relatives, who are living in uncertainty and don’t know whether or not they could have the familial heart condition.

In the last year, we’ve seen new guidelines on ventricular arrhythmias and prevention of sudden cardiac death; for the first time, the guidelines have incorporated that DNA analysis should be fundamental component of post-mortem assessment in any young, sudden death victim. This is a change.

It is a big change, and it is really great to see for folks like me, who work in centers for inherited cardiovascular disease and who are in the front lines, caring for these families, who have lost a seemingly healthy, young, family member suddenly and traumatically. We see what these families go through, the uncertainty that they deal with, and their intense desire to prevent further sudden deaths in their family. It is great to see professional societies getting behind the need for genetic testing in those families.

Where are we now in terms of who should get tested?

When it comes to sudden death, any young, unexplained sudden death, or it is not always a sudden death that is clearly cardiac. Sometimes it is an unexplained drowning. Sometimes it is an unexplained single vehicle accident in great driving conditions. Or the autopsy shows clear evidence of an inherited heart condition. It is really critical in all of those cases that the right sample be saved for genetic testing. Not all samples are good for DNA. It is so important because sometimes the genetic testing is the only tool that we have to be able to figure out which family members are at risk for sudden cardiac death, and which family members can be reassured about themselves and their children.

In terms of “young,” how is it defined?

It is defined differently by different people in different settings. I think under 40 or 50 years old is a good rule of thumb. Of course, there is a sensitivity and specificity trade off, but if you’re looking at a really thorough, good, cardiac autopsy in which there is no coronary artery disease, there are no signs of cardiomyopathy, and the story fits for a cardiac arrest that someone didn’t survive, even if they are older, the testing is worth doing. In these diseases, we can certainly have sudden death across the life span. It is not only in youth.

It was the company INVITAE that has just recently expanded to another 30 genes. And now there is a total of more than 190 genes that can be analyzed. Should one test all 190? How do you decide what panel?

Deciding what panel, which set of genes, is a really critical part of a cardiovascular genetics evaluation that involves a genetic counselor with expertise in cardiology and a cardiologist with expertise in inherited heart disease. Moreover, it is guided by what we are specifically observing in the whole family, not just the individual. In the case of unexplained sudden death, if the autopsy is normal, the most likely culprit is that it was an inherited arrhythmia, something like Long QT Syndrome, or Brugada syndrome, or CPPT, so we want to include those genes. But many of us will also think about including cardiomyopathy genes. Could this be for somebody who had a hypertrophic cardiomyopathy variant, or an LMNA variant, in which the arrhythmia was the very first presentation of their cardiomyopathic disease with sudden death.

Then in the clinic with living individuals who have inherited heart disease, it is largely guided by what their diagnosis is or, in cases where we are unsure of the diagnosis, what our differential diagnosis is.

Does it also matter depending on heredity in terms of whether they are African American, whether they are European, etc.?

For the most part, no. This issue is true in other genetic conditions. There are many genetic conditions in which certain diseases are more prevalent in certain groups. For example, we see that a little bit in cardiology in familial hypercholesterolemia wherein there are variants that are more common in French Canadians and in South African Jews. In hypertrophic cardiomyopathy there are some variants that are more common in certain European populations, but none of it is any way that would really shift what test you would order. You still want to be looking at the key genes for that disease in that individual.

So where are we in terms of cardiologists actually going to know which patient to send to a geneticist or to say after the fact, “Why aren’t they sending them to me?”

Yes. We’ve actually come a long way in that. There are recommendations now from multiple professional societies that families with inherited heart conditions or unexplained sudden death be seen by an expert center for inherited cardiovascular disease. Genetic counselors and cardiologists specialized in inherited disease are key parts of that center. So it is a recommendation in the heart rhythm society, expert consensus. It is actually a Class One recommendation. So these families really should be referred to people who have that depth of expertise and that is in part because these diseases are rare. They are complex. You have to think about the whole family, not just the individual in front of you. And genetic tests, both selection and interpretation, is a highly specialized skill. Genetic tests aren’t black and white. They are not just clearly abnormal, normal. You really have to be careful in how you interpret the results that you get from a genetic test and how you then apply them to the care of an individual and a family.

You don’t necessarily go out and do all 190 genes at once?

Exactly. The reason why you don’t, in most cases, is because the more genes you add to your panel, your specificity goes down. You’re going to get inconclusive results that you or your lab may interpret inappropriately because it is a hard thing to do. So picking the right panel is really important, and that is a big part of my job as a genetic counselor, whether it is in sudden death or an inherited heart disease.

Keywords: Genetic Testing, Genetic Therapy, Heart Diseases, CardioSource WorldNews Interventions

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