I’m Aware That I’m Rare: Harm Bogaard, MD (450)

phaware global association®
9 min readJan 8, 2024

the phaware® interview

Harm Bogaard, MD, Ph.D., FAHA is a pulmonologist at the Amsterdam UMC. In this episode, he discusses the role of genetic testing in the treatment of patients with pulmonary hypertension at its role in clinical research.

My name is Harm Bogaard. I’m a pulmonologist here in Amsterdam in the Netherlands. I work at the National Expert Center for pulmonary hypertension patients. We have a clinic, obviously, with patients mainly with idiopathic and hereditary PAH. We also have a chronic thromboembolic pulmonary hypertension (CTEPH) program with diagnostics, surgeries, balloon pulmonary angioplasty. In addition to my clinical work, we have a translational lab to find out more about different forms of pulmonary hypertension and its treatment.

Today, I would like to talk about genetic testing that we do in our patients. I think we do it a little bit more frequently than it’s done in the United States. I think it’s an interesting topic for a number of reasons. I think it can help in clinical care of our patients. It can help in making decisions in life about things like having a family, thinking about the chances of your kids, if you already have kids, that they might develop pulmonary hypertension. But I also think that there are important research opportunities by doing more genetic testing and looking more at the genetics of pulmonary hypertension.
There’s a new treatment coming up. You may have heard of it, Sotatercept. It’s really quite a promising development for the treatment of pulmonary hypertension. The reason why we found this drug, why research has been done into this drug, is basically because over the past 20 years, we’ve started to learn more about the genetics of pulmonary hypertension. So also from that perspective, I think it’s really useful to pay some attention to the genetics of pulmonary hypertension.

In patients that we diagnose with pulmonary arterial hypertension when there’s no known association, so there’s no connective tissue disease or there’s no congenital heart disease, there’s no obvious cause for their pulmonary arterial hypertension, we always offer genetic testing. It’s of course not mandatory. Before we do genetic testing, we refer our patients to a clinical geneticists to discuss all the pros and cons of genetic testing, but at least we offer it to all of our patients that could be idiopathic, because there’s no known cause. But if you do the genetic testing and you find the cause, it’s no longer idiopathic, but it’s hereditary PH. I think that the guidelines indicate that you can offer this or that you can suggest this. This is not a mandatory thing. It’s not proven that doing genetic testing will improve outcomes of patients, but still, for a number of reasons, we think it’s useful to offer genetic testing or at least genetic counseling to our patients.

I have to say in the Dutch situation, I think the majority of patients when they are offered genetic testing and after they’ve talked to the clinical geneticists, they do opt for genetic testing. Then on average, maybe one in five, one in six of our patients will show to have a genetic mutation that can be considered the cause of their disease. Of course, there are mental considerations or psychological considerations. Also, a lot of people worry about the legal consequences of genetic testing.

To start with, the psychological aspects. I think a lot of patients who do their research, sooner or later they will stumble upon this issue that the disease might be genetic. This always kind of hangs out there and people are thinking about this and genetic testing in most instances, it will clear the skies because if no genetic mutation is found, of course, then there’s no longer any worry that your children or your siblings might develop the disease.

If you do find the mutation, it can also be helpful because this can increase the alertness, so being alert with your children, for example, if they do develop symptoms, you can be a little bit quicker maybe with finding some medical help and to have an early diagnosis. Knowing that you are at certain risk to develop the disease allows you to diagnose the disease early. We also know now that early diagnosis improves outcomes. Of course also, it has psychological downsides. Not very infrequently, you hear patients that are being diagnosed with hereditary PH who already have children that they feel kind of guilty. It’s strange, because of course it’s none of their fault, but they do feel like, oh, I’ve passed this along to my children and now they may also be at risk of this disease. That can cause some psychological stress for some people. But in most instances I think it gives a better grip, a better handle on the disease and allows you to do something for your children.

Then, there are some other things that you can consider about family planning. You can think about this maybe more carefully. There are things that you can do to minimize the risk of passing on the mutated gene to your offspring. There are possibilities that open up and that you can start to think about. When it comes to the legal issues, it’s of course different in every country. In most European countries, the legal ramifications of knowing that you have a mutation that is a risk factor for pulmonary hypertension is not too much. You can still get a mortgage. You can still buy life insurance. In fact, if you already know that there’s pulmonary hypertension in your family, you would have to say this because this is a potentially genetic disease. It doesn’t change. Only if you test negatively, in fact, you can say this, but if you don’t test, there’s uncertainty. So you still have to indicate this.

But in the Netherlands, the insurance companies, they cannot charge you. If you know you’re a mutation carrier, but you’re healthy, insurance companies cannot charge you more for their insurance fees or whatever, or they cannot give you a higher interest rate for your mortgage just because you carry this mutation. That would not be possible. There’s some exceptions, like super high life insurance. If you want to ensure your life for multiple millions of euros or dollars, then it may have some consequences. But generally, there are no legal consequences of knowing you have a mutation.

I don’t know what the cost is in the US, obviously, but the costs have really come down for all these genetic tests. What is usually done, it’s not like a whole genome sequencing, but it’s a focus panel of somewhere between 10 and 20 genes. It varies a little bit hospital by hospital which genes are being tested, but it’s a limited panel of genes that may be involved in development of pulmonary hypertension that will be tested. So it’s not a super expensive test, but still, I know that in the US in general, it’s not reimbursed.

In the clinical management of a patient, knowing that there is a mutation, it gives some information, for example, in prognosis. In general, hereditary PH in all the cohorts, it tended to be a little bit more aggressive than other forms of idiopathic PH. That gives you more reason to be quite aggressive with upfront treatment. So upfront triple therapy is something that is considered really early on in a patient with a mutation. In fact, the data showed that if you do this, so if you find a mutation and you decide to give fairly aggressive upfront triple therapy, prognosis becomes actually really good.

In some of those patients, maybe a choice would’ve been made by giving just oral combination therapy. But now by knowing that there is a genetic cause of the disease, treatment may be escalated earlier on and this could improve outcomes. But I think a lot of the ramifications for genetic testing are not just for the individual but also for the family members. That’s actually where a lot of the consequences also are. So being informed about your own genetic cause of your disease allows you to alert your family members, children, siblings, to make them think about doing genetic testing as well so that they are better informed about the potential risk that they are at to develop pulmonary hypertension. They can consider this, they can consider genetic testing, and if a mutation is found, they can be surveyed and more closely, which I’m convinced really helps them. It has happened too often also in our practice that you see a sibling of a patient with pulmonary arterial hypertension that you treated maybe 10 years ago and unfortunately passed away. Then, this sibling comes in also at a very late stage of the disease and it feels like such a missed opportunity. If you would’ve known that this sibling had the same mutation, you probably would’ve made an early diagnosis and could have done a lot for this sibling in this case.

But coming back to a patient who already has pulmonary hypertension in whom you detect a mutation, there are some consequences to clinical management in terms of being maybe a little bit more upfront with combination therapies. Where it also informs is I think particularly in young patients in family planning. This is something that people do consider, like could I pass along the mutation to my children? You can think about this. If you want, there are techniques to avoid passing on the gene to your offspring. That’s also something that you can consider then. That’s of course both for male and female patients.

We’ve done some research into this also and how people like this best. These things are slow. You do genetic testing and it takes a couple of months before you get the result back, so it’s all quite slow. But if you do get the positive result back, you do have a genetic mutation, we used to give just a letter on paper to this patient. We will tell him or her, like you can distribute this to your children, your siblings, your cousins. This created actually quite a bit of barriers. Some people obviously wanted this, but for a lot of other people also, this created some hurdles. So what we do right now, if we identify a new patient with PH and with a mutation, we just offer a Zoom session or Teams, like just a kitchen table session.

We tell this patient, invite everybody you want in your family, send them the link or invite them over to your home, and I will be online and they can ask all the questions that they have. We do it in a more personal way, but then by Zoom or by Teams. This works actually quite well, because you can directly answer all the questions that they have. It doesn’t mean that everybody wants testing, of course, because there are pros and cons. But I think in terms of giving information, it really helps them.

We have a research program, unaffected mutation carriers. So all the relatives that we do detect a mutation in, we offer them to come in every year and to do mainly a baseline. We do a CT scan and an MRI. They come in every year and we do an echo and an exercise test and we take blood samples. The whole idea is obviously to identify the development of pulmonary hypertension really early on, which happens. In this program, we do detect pulmonary hypertension early. I think we’ve helped quite a few people by doing this. But there’s also an interesting scientific aspect of this because we collect blood samples from all these individuals. In those individuals that do develop pulmonary hypertension, we have historical blood samples or imaging or whatever kind of biomarker we took. Of course, it’s unfortunate because they developed the disease, but if we gather more and more data, that could help us to identify an early marker of the disease.

Right now, we diagnose the disease because patients basically develop heart failure because that’s why you get symptoms, not because your pulmonary vessels become sick, but because your heart is not able to cope with it any longer. But it’s quite likely that your pulmonary vascular diseases happens much earlier than heart failure. We hope by having this program that ultimately, we will be able to maybe identify a blood biomarker that could become an early a test for early diagnosis of pulmonary hypertension. That’s of course something that everybody would really like to have, to have a simple blood test that enables early diagnosis. That’s also an interesting aspect of following these unaffected mutation carriers. We do this collaboratively with a cohort in France and a cohort in Germany and the UK. All these countries, they do genetic testing. So together, we follow quite a few unaffected mutation carriers now. Hopefully in the next couple of years we will be able to identify some useful biomarkers.

I’m Harm Bogaard, and I’m aware that my patients are rare.

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