“Unraveling the Genetics of Pulmonary Hypertension” explored the genetic underpinnings of this complex disease. Our panel of experts, including a patient, explored the latest research, information on genetic mutations associated with pulmonary hypertension, and practical guidance on genetic counseling and testing.
Speakers
Prof David Montani, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National French Referral Centre, Hôpital Bicêtre, Le Kremlin-Bicêtre, France Download the slides
Dr Matina Prapa, Consultant in Clinical Genetics, St. George’s Hospital and Royal Brompton Hospital, UK Download the slides
Ms Louise Bouman, Patient, Chair of the Dutch Pulmonary Hypertension Association Stichting Pulmonale Hypertensie, Member of the Board of the Alliance for Pulmonary Hypertension Download the slides
Transcript “UNRAVELING THE GENETICS OF PULMONARY ARTERIAL HYPERTENSION”, JUNE 18, 2024
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ANDREAS REIMAN
Good evening or good morning or good afternoon depending wherever you are looking and watching out for us. I’m Andreas Reimann and I’m happy to moderate this webinar of the Alliance for Pulmonary Hypertension and I’m also very happy to be joined today by a prestigious faculty, which I’m introducing in a minute.
Our subject today is unraveling the genetics of pulmonary hypertension and we will be learning both from a clinicians and geneticist point of view, but also from a patient point of view. You can of course listen, you can ask questions either using your channel, or the chat option in your channel, LinkedIn, YouTube or Instagram. Just write the question and we will come to your question at the end of all presentations. We have three presentations of approximately 15 minutes, 10 to 15 minutes. And after that we still have about 15 minutes to discuss.
Without further ado, I’m very happy to present today’s faculty. Here is already Professor David Montani, he is from the Department of Respiratory and Intensive Care Medicine, from the French Pulmonary Hypertension National Reference Center at the Hôpital Bicêtre. And Louise Bauman, Chair of the pulmonary hypertension association in the Netherlands. And we are still waiting for Dr. Matina Prapa who is a consultant in clinical genetics at St. George’s Hospital and Royal Brompton Hospital in London. David, I think the floor is yours for your presentation and you’re happy to share your slides. Thanks.
PROF. DAVID MONTANI
Thank you very much for this kind introduction and I’m very happy to be here with you and to discuss genetics today.
So we are discussing the genetics of pulmonary hypertension. Clearly I think it’s something very important for the patient but also for the family of patients because it’s probably the only way to go, I will show you at the end that we can probably screen for early pulmonary hypertension and follow patients at risk. And there are a lot of consequences of genetics in pulmonary hypertension.
This is my conflict of interest. I work with most pharmaceutical labs, working in the field of pulmonary vascular disease.
I don’t want to give you a lot of names, of very difficult the names of genes, but 20 years ago we did not know any genes that predisposed to pulmonary arterial hypertension. In the last 20 years we have identified at least 70 genes that are associated with pulmonary arterial hypertension and there are some different kinds of abnormalities that could lead to pulmonary hypertension.
We have some genes from what is called the BMP/TGF-Beta family, a very difficult name, but that means that it’s the gene that controls the proliferation of the vessel cells. And when there are some abnormalities on these genes, you are susceptible to develop pulmonary arterial hypertension. There are also some genes that are involved in channels that control vasoconstriction, vasodilatation, but also proliferation of the pulmonary vascular bed of pulmonary arteries. And when you have a mutation in these genes that would also lead to pulmonary arterial hypertension. And we have some genes that are more complicated that lead to develop motor disorders. That means that the pulmonary vascular bed has an abnormal development but probably was predisposed to pulmonary hypertension, and there are rare genes that are currently on. We try to understand what is the mechanism that leads to pulmonary vascular issues.
So from no genes 20 years ago, we now have more than 70 genes, well-identified and more than this, that are currently studied to understand pulmonary hypertension. The most important gene and the most frequent one, the first gene that has been discovered in pulmonary arterial hypertension, is BMPR2 (Bone Morphogenetic protein receptor type 2). The most frequent gene is BMPR2 and we’ll discuss the gene in the next slide.
What is very important when we discuss genetics is transmission. How we can transmit the risk to a member of the family. And for most, almost all, of the genes involving pulmonary arterial hypertension, we have what is called an “autosomal dominant transmission”. What does it mean? All of us have two copies of all genes, all chromosomes, all genes are with two copies except for chromosome X and hybrid that is for female and male, but all the other genes are in copy by twos, and autosomal dominant transmission what does it mean? It means that when you have one of these two copies abnormal with a mutation, you are at risk of the disease. That means that these patients had one normal gene, blue gene and one abnormal range. So he is at risk to develop pulmonary hypertension. His wife has two normal genes and has no risk. And how does it work for the transmission?
Each parent, mother and father gives one copy of their genes to their children. So in this situation there are four possibilities.
If the father gives the normal gene to his children, these children are unaffected and have no risk of pulmonary arterial hypertension. Of course the mother always gives a normal gene, but for 50% of the cases the father can give abnormal genes that lead to the same situation that he has. And so these children with one abnormal gene and this one and also an abnormal gene are at risk of pulmonary arterial hypertension – that is auto dominant transmission. Only one gene on the two copies leads to risk of pulmonary arterial Hypertension.
This is a family tree and we said that males are square, females are circles and when you have the disease you are in black. So this patient had pulmonary arterial hypertension. One abnormal copy of BMPR2 for example. That means that his father or his mother has probably transmitted this abnormal gene. So one of these either father or the mother is probably at risk of pulmonary arterial hypertension. That means also his brother and sisters could have the same gene from their father and mother. So they’re also at risk of pulmonary arterial hypertension. And as we discussed before, he can transmit one of his mutations to his children. And so they are at risk of pulmonary arterial hypertension.
So when we don’t find a mutation, for example in BMPR2 in a patient, we also have in the family some people who are at risk to develop pulmonary arterial hypertension. So we’ll discuss genetic testing, genetic counseling. But you understand that it’s very important to explain to all these people why it may be of interest to perform testing or to consult if there is dispnea to have a very early diagnosis and not wait for the development of severe pulmonary arterial hypertension before seeing an expert of the field.
So what is BMPR2? BMPR2 basically plays the role of a break on the proliferation of the cells in the pulmonary arteries. When BMPR2 works, you have a break and the proliferation is stopped and you have normal pulmonary arteries. When you have a mutation in BMPR2 you have no break and the proliferation increases and leads to pulmonary arterial hypertension, proliferation of small arteries or cells into small arteries that finally block the blood in the pulmonary arteries. So when you have BMPR2, you are at risk to develop pulmonary arterial hypertension because the break doesn’t work very well.
The second point that is very important and quite common for all genetic forms of pulmonary arterial hypertension is that we discuss that it’s another autosomal dominant transmission. We need to have one abnormal copy to be at risk. There is a female predominance because probably hormonal factors may promote pulmonary arterial hypertension. So there is a female predominance. When you have an abnormal gene of BMPR2, you are more at risk if you are a female than a male. And the last point is that it’s very important to understand “incomplete penetrance”. What does it mean? It means that you cannot have this abnormal gene of BMPR2 mutation and you may never develop the disease if you do have an abnormal gene or a mutation, it doesn’t mean that you will develop pulmonary arterial hypertension. Very important point. Most of the carriers of mutation of predisposing pulmonary hypertension genes will never develop pulmonary arterial Hypertension. And this is an example of the family.
You can see in black people who have pulmonary artery hypertension. But in this family there are a lot of people who carried the mutation but who have not developed pulmonary arterial hypertension. This is very frequent for this thing. It’s probably, as I said, more frequent to develop pulmonary arterial hypertension when you are a female and probably pregnancy may be a risk, hormonal factors may be also a risk as compared to male.
So this is very important: autosomal dominant transmission. You need to have only one copy to be at risk and incomplete penetrance. If you have an abnormal copy, that doesn’t mean that you will develop pulmonary art hypertension. If we test all pulmonary arterial hypertension patients, idiopathic or familial, we find around 20% of patients who carried a BMPR2 mutation. Very important point is that if you test only the patient who had several cases in their family, you lost half of the patients who carried BMPR2 mutation because of the incomplete penetrance. Sometimes there is only one case in the family. That doesn’t mean that it’s not genetic, it means that there are other carriers who have not developed pulmonary arterial hypertension. But in proportion that means if you test only families who had several cases, you lose half of the patients carrying the mutation.
I’s very important for the relatives of these patients, even if there is one case I think we should do genetic testing not only or the patient but also for the relatives to identify the people who are at risk in the family.
Other genes that are more recently discovered that may be important, I will not go further in this, but I will just use some examples. But this is the break. The break doesn’t work and there is proliferation, but there is also now we have identified some genes that are involved in the development of pulmonary vascular beds. And that means that during development there are abnormalities that predisposed when you are children or adults to develop pulmonary arterial hypertension.
Two of them are very important. TBX4 and SOX17, I will be very short on this, but to give you information, TBX4, it’s not the gene of development, are not only limited to the development of pulmonary vascular bed, but TBX4 for example has other consequences. It plays in the development of lower limbs and in the development of lungs. So sometimes we have now identified some patients who have not only isolated pulmonary artery hypertension but also lung disorders and some foot abnormalities or knee abnormalities. And we can notice this kind of gene. It’s very important because we should treat all these bone abnormalities and also treat the lungs, not only the pulmonary hypertension.
The other example is SOX17, a gene that plays a role to differentiate an artery from a vein. When you have a mutation, the development of the vascularization of the lungs is not totally normal and this abnormal development may predispose to pulmonary hypertension.
You can see here a patient’s lung with some abnormalities on the vein. With Computed Tomography (CT scan) we can identify the patient.
What is important with the discovery of the gene?. We discover that some of the patients who carry abnormalities in the development of genes, SOX17 for example, also have abnormalities because the genes are involved in the development of the heart. So when I began to work on genetics, we considered that we should not test and search for genetic abnormalities in patients who have pulmonary hypertension associated with congenital heart disease. Now we know that some patients with pulmonary hypertension and congenital heart disease also have a genetic or irritable form of pulmonary arterial hypertension. And so we now test the patient with congenital disease and pulmonary arterial hypertension.
This is the example of what we do in France. We consider that we should propose genetic counseling for all pulmonary hypertension patients who are considered to be the first case when there is a family history of pulmonary hypertension, when a patient had pulmonary hypertension associated with congenital disease, and for another rare form of pulmonary hypertension, pulmonary vascular disease. in my center for example, all these patients were offered genetic screening. We are lucky in France there is no cost for the patient and relatives. What we do is called next generation sequencing, but we are able to test all the genes of pulmonary hypertension in one time. So it takes around three to four months to have a result of all the genes I showed you and say whether there is a mutation or not.
What we do after, if we identify in this patient, for example, genetic pulmonary hypertension, we propose genetic counseling. If the patient accepts, we propose testing to this patient and we propose genetic testing to first degree relatives who are at risk. So father and mother, the brother and sisters, and the children even if adults. With this step, if they accept to do the testing, we identify some people who are at risk of pulmonary arterial hypertension. For example, in this family, the father’s brother and one of his sons are at risk of pulmonary arterial hypertension because they carry the same abnormality for example the BMPR2. What is very important for this family also is that, for example, this brother has no mutation, and is not at risk. And so it’s not necessary to test the children because there is no risk for his children to have a mutation.
The mutation does not keep transmitted to his children. So if you know that this brother has no mutation, all his children are safe and at no risk to develop pulmonary arterial hypertension. And we do have step by step for his brother where the mutation we know is at risk and we can test the children to identify who are at risk and propose counseling and testing for this first degree relative. So we do step-by-step first degree by first degree relatives.
What we can propose when we notify an asymptomatic person, someone who carries a mutation, who have no disease but are at risk. That is an incomplete penetrance, meaning that some people will never develop pulmonary hypertension, but some of them are at risk of developing it. So we can propose for adults, for example, in my center, to try to see, to follow the subject at risk to screen for pulmonary hypertension and to diagnose early. It varies, the development of pulmonary hypertension.
This is a program we have developed in France, which can be proposed to all subjects at risk of pulmonary hypertension. We don’t know exactly what is a good delay to see the patient or the subject at risk. But in this program we propose to see the subject at risk of adults who carry a mutation but have no signs, no symptoms, to do a clinical visit, to have a blood sample, to perform exercise testing and to have echocardiography. If there is some abnormality we can go to the right catheterisation to see if there is pulmonary hypertension. The objective of this kind of screening program is clearly to have an early diagnosis and we have been able to demonstrate that this kind of strategy may help to diagnose pulmonary hypertension very early on. And probably, if we are able to detect pulmonary hypertension early in the course, it’s easier to treat.
I have no definite answer about what to do for children who are at risk of pulmonary hypertension. It depends on national ethical laws. For example, in France we cannot propose genetic testing for our children if there is no preventive treatment. And this is exactly the case for pulmonary hypertension. We are not able to have a preventive treatment so we cannot propose genetic testing, but we follow the children and say if there are symptoms that should come very quickly to a pulmonary hypertension center to perform an echography to be sure that there is no pulmonary hypertension.
My last slide is a French family where there are several cases of pulmonary hypertension: the black points are people who carried the BMPR2 mutation.
The young males (at top) carried the mutation and decided not to have children because of the risk of transmission. But, with new techniques and the pre-implantation genetic diagnosis, pre-implantation genetic diagnosis is now possible. What does it mean? We take the ovules, we do in vitro fertilisation (IVF), and we implant only the embryo which does not carry the BMPR2 mutation. With this program, these two males had, each of them two children. So as you can see, there are a lot of consequences of genetic testing and it’s very important to discuss all these points because it opens a lot of questions, a lot of discussions, and a lot of difficulties also.
ANDREAS REIMANN
Thank you very much and I’m happy to report that Dr. Prapa is here. And will be able to present next. Thank you very much for joining and I’ll
DR. MATINA PRAPA
Thank you very much for the kind invitation. I think a lot of the points that I’m going to cover were to some extent covered by Professor David Montani, but I think it would be good to reiterate some of the points and hopefully that will make it very clear for the audience as well what we mean about genetics. So if we go onto my first slide.
As you probably know, pulmonary arterial hypertension is caused by thickening in the small arteries in the lungs due to increased pressure. There are lots of different forms of pulmonary hypertension, e.g. due to left heart disease or to a chronic lung disease. When you have thickening of the vessels, according to the WHO classification, this is pulmonary arterial hypertension Group 1. The other forms don’t really have such a clear underlying genetic cause.
So when we talk about genetics of pulmonary hypertension, we predominantly mean pulmonary arterial hypertension. And this can be idiopathic, which means that we haven’t really uncovered the cause. It can be heritable, which means that there is possibly a family history of pulmonary hypertension, or an unexpected premature death in a relative that sounds suspicious. It sometimes can be associated with other conditions or other exposures, for example, to particular drugs and toxins, or due to chronic heart disease.
What do we mean about genetics? Within our DNA, we have those little tangled sort of bits called chromosomes. And you see in the left hand side of the screen you can order them in size. So chromosome 1 is the longest and then we go all the way down to 22. We have one copy of a chromosome from our mom and one from our dad.
The first 22 pairs are the same in men and women. The last pair is our sex chromosome. So men have an X and a Y and females have two X’s. So in this picture here, which is called the karyotype, you can see the chromosome set of a female because we have two Xs and it is a female with down syndrome because if you have a look at the last row, there is a whole extra copy of chromosome 21.
Now when it comes to genetics of pulmonary hypertension, usually it’s not a chromosome problem, it’s a gene problem and genes are the bits within the chromosomes. And you can see here the double helix of the DNA. And you can think of genes like a series of letters which are DNA courses, the letters A, T, C and G. And what most of the genetic tests do is essentially they read those letters one by one to see if there are any letters missing, any extra letters or any spelling mistakes.
For example, in a position of a letter G, you have an A. And when this happens, we know that sometimes this doesn’t allow the genes to work as they should and therefore they can cause a genetic condition. We know that humans have more than 20,000 genes and they’re spread all across our chromosomes. And like chromosomes, we have most of our genes into copies, one from our mom and one from our dad. And it’s quite important to bear this in mind because when we find a genetic cause for pulmonary hypertension, we always have to think, was this inherited by a parent or is it a new event? Because sometimes spelling mistakes in genes can happen spontaneously out of the blue. Very rarely could still be a chromosome problem and not a gene problem. But this is not the case.
For example, TBX4 syndrome that I’m going to briefly mention and I think Professor Montani also mentioned, sometimes could be due to a chromosome problem and that’s chromosome 17 where the TBX4 gene is and you can have a small missing section that takes out that gene and it can still cause pulmonary hypertension and other problems.
I just want to show you the types of genetic tests that are routinely offered for pulmonary hypertension patients. It used to be a so-called sign year sequencing, which is a single gene test that is very laborious. It used to take a lot of time to complete this test. And what this test did is if you think of genes like books, it opened that book and read the DNA course, all the letters one by one to see if you can find a spelling mistake, a missing paragraph or a few missing words for example.
But this test was quite laborious, it took a long time to complete. Now we have a more sophisticated method which is called “next generation sequencing”, which is mass parallel sequencing and essentially simultaneously looking at a big number of genes. It is much faster and it is also more cost effective. So most of the inhibitors who have genetic testing now do not have a single gene tested. They either have a gene panel, which means that they can have a couple of genes of interest all read at the same time or they can even have the whole entire 20,000 genomes looked at. And then what the people in the lab do is we have all the results. So we have all the series of letters, but then they zoom in and they only look at the genes or books of interest. So we know that pulmonary hypertension is approximately 10 to 20 genes.
So we ask the bio people who are analyzing the results if they can you open those books and read them letter by letter and see exactly if we found a spelling mistake there. There are two types of tests. One is called “whole exome sequencing” and the other one is called “whole genome sequencing”. The whole exome looks at important paragraphs or chapters within the book. Whole genome looks at the entire book. So from a front to back page.
This to show you the gene discovery in pulmonary hypertension over the years. So it was in the year 2000 that the first gene, BMPR2, which is still the most commonly involved gene in pulmonary hypertension, was discovered. And you see since then, with introduction of this new genetic testing method called next generation sequencing, the number of discovered genes has increased exponentially.
But if you see not with the red line but with a gray line that shows the proportion of cases that were explained genetically, we still have a large chunk of them where we don’t know what the underlying genetic cause is. So just because we have discovered lots of genes doesn’t mean that when you do the genetic test you will necessarily find something and there’s probably still a lot more that we need to discover in future. And if we can move on to the next one please.
This image with the two “pie charts”, as we call them, shows you again the unexplained cases by genetic testing and the different types of genes. And it seems that childhood onset upon pulmonary hypertension is more genetic in a sense. So it’s highly more likely to find something when you run the genetic test as opposed to adult onset pulmonary hypertension where the likelihood of picking up something is much lower, unless there is a positive family history.
Now, which gene should be examined? It’s important to bear in mind that there are two types of genetic tests. It could be a diagnostic test that is done in a diagnostic laboratory or it could be a research test. A research test may include genes that we do not a hundred percent know if there’s a definitive association between the gene of interest and the condition. And what happened is that at the moment there is a consortium, lots of work being done for a lot of different types of rare genetic conditions where we are examining all the genes to see which ones have a definitive association with a particular condition of interest. And for pulmonary hypertension, there was a publication, very recent one, and you can see there was a big number of genes examined and it was only a handful of them, about 10 or 11 where we definitely can say that if you have a fault in one of those genes you are at risk of pulmonary hypertension.
Some of them had a moderate scope, meaning that we’re not as confident, but maybe as more people are tested in the future, this may tilt over the point of saying it’s a definitive association, and some of them had quite limited correlation with pulmonary hypertension. So if you find the gene fault in these genes, you cannot necessarily say to a family, we have discovered why you have pulmonary hypertension, but it’s something that could be of interest in future as more information comes to light.
What are the benefits of genetic testing? Of course, one of it could be the classification of the disease itself and for example, something that was labeled as idiopathic pulmonary hypertension could be so-called PVOD or pulmonary veno-occlusive disease. This is a disease that may not have a good reaction to certain pulmonary hypertension medications and may require to be listed for transplantation. So unless someone has a genetic test, it may not necessarily be picked up. That’s a big benefit of the genetic test itself. Alongside the same line, accurate diagnosis and screening for other features. For example with TBX4 syndrome screening for abnormalities, such a small patella syndrome with other genes could be hereditary hemorrhagic telangiectasia. And of course the number three very important point is family screening. And as Professor Montani probably already has shown you, there is usually a one and two risk for the next generation, because if you recall I said that we have two copies of our genes. Most of these conditions are dominant and dominant means that if you have a fault in one of the two copies of the gene, that is enough to cause the condition. And if you see here you have two chromosomes, one in red, so that’s the faulty gene, let’s assume, and one in green.
So the second chromosome with a normal, non faulty, gene, when we have children we split them in two and we randomly pass one of the two copies to our children. So it’s a 50-50 chance. So you’re going to pass on the red or the green one and that’s where that figure comes from. But it’s worth bearing in mind that we also have the so-called incomplete penetrance and penetrance is the proportion of individuals who carry a gene fault that go on to develop the condition. And it’s not a hundred percent. So we know that one in three carriers only of a gene fault will go to develop disease and the likelihood is higher if you’re a female as opposed to a male. We are not sure why this is the case, but it’s also worth bearing in mind that just because you carry a gene fault doesn’t mean that you’re necessarily going to develop the disease.
This is just to show you an example of a genetic test report from the United Kingdom. So this individual had what we call a “gene panel” and in the middle of the slide you can see a list of genes, the name of the gene, and next to it you will see the percentage. So a hundred percent that says for all of them it means how well we could read those genes, or books. And sometimes the coverage isn’t great because in some of the genes you have repetitive letters written again and again and this can mess up the test. But in this case we can see that we have the number of genes examined and all of them were covered a hundred percent. It’s quite a reliable test. Now if we look at the top of the slide, you see it says the gene, so it’s a faulting gene, BMPR2 and DNA variant. The C dot says 683del. So in position 683 there is a missing letter there and dell means deletion. That missing letter is enough to not allow the gene to work as it should and therefore is causing pulmonary hypertension.
Next to it is the section genomic location. So it tells you in which chromosome that gene is chromosome two and exactly what are the coordinates and “zygosity” means whether you have the fault in both copies of the gene or only one of the two copies. And in this case it is in one copy of the gene and we call that “heterozygous”. If it was in two copies of the gene, we would call that “homozygous”. So this individual has two copies of the BMPR2 gene, but in one of the two he has a fault and we know that that fault is sufficient to not allow that gene to function as it should.
And you see in red classification it says pathogenic, that means it’s a disease causing gene change. Not all gene changes are disease causing and some of them can be normal variation. So it’s important to be quite clear about that as well. And in the bottom it shows you how this result is communicated in the report. So this result confirms clinical diagnosis of familial pulmonary hypertension, and has implications for the rest of the family, who may risk their genetic testing.
I just wanted to show you an example of a family tree. So in the top you see generation one, which is the parents, where the squares are males and circles are females. And when it’s lined across it means the individual has passed away. In the second line you see the affected individual in gray colour. A male who is 45 years old has developed pulmonary hypertension with a BMPR2 associate gene fault.
This individual has two children, ages 13 and 8. He has a sister who is 40 and you see the “P” there, that means that his sister is pregnant. He also a brother who is 38 and doesn’t have any children. And if we move on to the next slide,
First of all what we would be inclined to do is identify whether this was inherited by a parent or not. Obviously in this situation we cannot test the father because he’s passed away and it’s very unlikely that we have stored DNA we could test the mother with that would help us, though if the mother is fine at the age of 94, I don’t think that it would really be very informative even if she was found to have the BMPR2 variant or gene fold. The only difference we would make is that if the mother had it, then we would know that there would be a higher risk for this individual’s brother and sister. So for your other two children, even without this information, we would still offer genetic testing in both of his siblings.
Should we test his children? So for the children, the same principle applies to any genetic condition, not just pulmonary hypertension. We have to respect the child’s autonomy, meaning the child’s ability to make decisions for their own selves. And if there is a condition that we wouldn’t offer any screening in childhood, then we always say let’s wait until the children are 16 or older and then we can see them and they can decide for themselves if they want to be tested or not. However, if it’s a high risk situation where we would offer screening to the children, then the parents essentially make the decision on their behalf and we would test them because then we would clarify whether they do need to have an investigation upon hypertension or not. So it really depends on the specific scenario.
How would you manage your sister’s pregnancy? It really depends on how far along she is and how she feels about this particular gene finding. Now that we know what the gene fault is in the family, we wouldn’t do a gene panel test in the system. We would only look for the specific gene change found in her brother, and that would be a very fast test. So we could have results within a matter of weeks and we would be able to tell her if she does carry it or not. Obviously if she doesn’t carry it herself then there’s no risk to the pregnancy, but if she does carry it, then there’s a one in two chance that the baby may have the same gene change as well. Does that mean that the baby will HAVE pulmonary hypertension? Not necessarily. Because remember we talked about penetration, not everyone who carries the gene develops the disease.
So essentially we need to discuss with her how she feels about the pregnancy, depending on local policy. Would this be a condition that would be eligible for termination of pregnancy, or should we just wait and test the baby after birth at some point in life? These are the types of conversations that we would have with her. And does this result inform the brother’s future family planning? Absolutely. And Professor Montani mentioned PGD or “pre implantation genetic diagnosis”, which is where you collect sperm and eggs from both partners. You’ve used them in the lab to create embryos and after a few days you screen those embryos’ DNA to see if they have the BMPR2 gene fault or not. And you only re-implant in mom’s womb the ones that don’t. So that takes away the difficult decision of terminating pregnancy and it’s something that could be considered.
Finally, I wanted to show you an example of another genetic test report, which is the caveat of genetic testing, which is when we do genetic tests, the results are not always black or white. Sometimes we can get a gray result and we call them “variants of certain significance”, VUS. And here you see again a genetic test report, an individual who was found to have a gene called SMAD9 and under DNA variant, you see there was a fault in position 1 66 instead of a letter G, there was a letter C and the patient is heterozygous, meaning that they have one faulty copy and one normal copy. We don’t have enough evidence to say if this is disease causing or not, and therefore we cannot offer testing others for this because it wouldn’t really help us make any decisions and your geneticists would be able to discuss this result further with you.
This is my final slide. So, essentially this is the scale of how confident we are about a disease causing gene change or not. We have a scale from blue, meaning that it’s not disease-causing it’s a normal variation all the way to red, meaning that it is damaging to the gene and disease-causing. And the VUS, the ones that are gray, are right in between in the yellow bit. So you see there is a very wide spectrum being confident from 10% to 90% that this might be disease-causing. And this is the cognitive genetic testing, you don’t always get a straightforward result.
LOUISE BOUMAN
Hello, my name is Louise. I’m 48 years old. I am married. I have two sons of 18 and 16, two dogs and I live in the Netherlands and I was diagnosed with pulmonary hypertension in 2008.
I was pregnant when I was diagnosed. I had a lot of problems, blue nails, blue lips and blue nose, so I thought it would be a good idea to go to a physician. I went to the local hospital and after a lot of examinations they told me there was only one possible diagnosis left and that was pulmonary hypertension. And I was in a very bad condition. I was in functional class IV, I didn’t know it back then, but now I know. And they told me I had to deliver my kid the next day because they wanted to do that even before I went to the expert center for a right heart catheterisation.
So the next day I got contraction inducers and had to deliver my kid in a natural way with 15 liters of oxygen on my nose. And lucky enough, my kid was born healthy and nothing was wrong with him, but I was a wreck afterwards and they brought me to a pulmonary hypertension center the day after and they did a right heart catheterisation and well, I received my current diagnosis, pulmonary arterial hypertension. Well, I think you can imagine how I was after giving birth. I was really without energy, without strength or whatever. And so any physical activities were totally impossible and they immediately started intravenous prostacyclins. So I was tied up to a pump for 24 hours a day.
Here are some pictures just to show how my journey started. In in left upper corner, that’s me and my husband with my tiny little baby, just after giving birth. And I don’t know if you can see it, but I wear a mask with oxygen. I slept a lot with them because that was my one and only activity almost because I couldn’t do a thing in the beginning. I slowly made some progress, I felt better, gained a little bit of quality of life and well you can see that I started to feel better and could give my kids a nice life. The next please,
When I was in the expert center, they did a lot of examinations to find the cause of the pulmonary arterial hypertension, but actually nothing was found. I remember they told me about the possibility of having a gene mutation, but because I already had to process so much devastating information, I wasn’t ready to do anything with the information I got about DNA research. So I just left it aside and I focused on survival, and gaining strength and trying a better quality of life. The first few months I didn’t think of anything else and I think but after four or six months I thought maybe I should to get back to the fact that I might have a gene mutation. And I talked about it with my physician and of course also with my husband and my family.
He actually did not refer me for genetic counseling. So I don’t think they provided it in that expert center, at least that time. But I really wanted to get it done because I worried not only for myself and for my children, but for my brother and his children, and for my mother who also had very big family. If the mutation was found in her family, it would’ve big consequence for the whole family. That’s why I wanted it and did it.
At the center they told me it could take three to six months for the results. So I guess it was an old fashioned method they used back then in 2008. In the meantime I switched to another expert center because I was interested in participating in clinical research and that wasn’t possible in the first one and forgot to ask about the results. When I did we made an appointment with the clinic’s clinical geneticist. My husband and I went there and I got a lot of information about, well actually all the information we heard before from Dr. Montani and Dr. Prapa, and also a lot of information about the chances for my children of developing pulmonary arterial hypertension, but also about health insurance and the ability of getting a mortgage. So very practical information. And also he asked a lot of questions about my family because he wanted to build a family tree like we’ve seen before. So he asked about sudden deaths or people with heart failure or heart diseases and that kind of stuff. And finally I received a family letter. By the way, I have a BMPR2 gene mutation. He told me that, which is the most common one. And he provided me with a family letter for my brother and my parents. And when I left the building, I really felt very sad actually because I felt like I felt a sort of guilt, like I was responsible for maybe giving a lot of worries and problems in my family and it’s a really nasty feeling. But well, I couldn’t do anything about it. So I just told my parents and talked to them and also to my brother and they decided they also wanted to get tested.
So they all got genetic counseling also, and afterwards their blood was drawn, and lucky enough they didn’t have any BMPR2 gene mutation. It went very fast because they already knew what to search for. So it didn’t take six months, but I think around four to six weeks, I don’t remember exactly, but something like that. And so that was already a big weight off my shoulders because now not the total family was involved, but just me and well maybe my kids. And that was another serious thing to think about because they were three and one so very young and what to do about that, that was also a difficult issue.
After many conversations and thinking it over, my husband and I decided we did not want to get our sons tested because well, there’s nothing to do in a preventive way, so you cannot prevent development of pulmonary arterial hypertension in any way. So we thought, well, why should we decide for them? We decided that we wanted them to be able to think about it themselves if they wanted to know. And so that was it for then, until my youngest son got some health issues at I think 12 or 13, something like that. In the Netherlands children ride their bikes to secondary school and my son had a difficulty with the 10 km ride each way and it took a very long time to complete it. So he was always home late and very tired. And that worried us pretty much because we thought, oh no, it can be true.
Our physician immediately arranged an appointment with the paediatric cardiologist who did all kinds of examinations and nothing was wrong. So that was a really big relief. And when we got home, we had a long talk with our boys and I dunno, I think because of this, they thought about it and they really decided together. They wanted to know whether they had the mutation or not. So they were I think 13 and 15. And so they said they wanted to get tested.
Because we were in the lockdown Covid period, the genetic counseling took place digitally. The boys were both very convinced. They wanted to know so their blood was drawn at a local blood lab because we couldn’t go to the hospital. Afterwards we just had to wait. And of course we as parents were pretty nervous because what if one of them has a mutation and what if pulmonary arterial hypertension develops? So you’re constantly worried about that and whenever the data comes closer, when the results come out, it gets worse and worse and it has a very big impact on their lives. So that was a very frightening situation, but it was very strange. We got the results also in a digital way and both boys are not carriers of the BMPR2 gene mutation! This disease started with me, but it also ends with me!
I can’t tell you how relieved we were! You don’t want it for your children! That I am sick and have to deal with this disease is one thing, but your children, you want to have them to be able to do anything they want and to become anything they want. So it was a major relief.
I wanted to give you some take home messages because if you are diagnosed with idiopathic pulmonary arterial hypertension and it might be a long time ago and you never thought about genetic counseling, please ask for it. And that doesn’t mean you have to choose immediately if you want your DNA to be tested, but just listen to this person and let them tell you about the chances and everything around it because the rules and things are different in each country.
Talk to your friends and your family about the pros and cons and talk to your physician because he/she can provide you with a lot of information. Talk to the genetic counseling people and take your time to decide and don’t ever rush. If you have any doubts, just ask more questions. These were the most important things I wanted to tell you. So I hope you enjoyed listening and if you have any questions, please ask them now.
ANDREAS REIMAN
Thank you so much Louise, for sharing with us. You were very open and it was very helpful to have all the details. Thanks very much. We are running time but we can take two questions if that’s okay to you, Dr. Montani. Question from Dora.
I had a double lung transplant due to idiopathic pulmonary hypertension; a few years later I had symptoms and was diagnosed with pulmonary hypertension. Can it be because i have the gene mutation? In case of a second lung transplant could the same happen?
PROF. DAVID MONTANI
Thank you for the question. Of course, it’s very difficult to have a definite answer to this kind of question, but what we know is that it was not described, but various recurrences of pulmonary hypertension in patients carrying mutations in pulmonary hypertension predisposing genes. But of course transplantation is a very difficult procedure and sometimes there are other reasons that lead to pulmonary hypertension in this kind of patient. And usually it’s not a recurrence of the initial disease, but it’s rather a complication of the transplantation and it can be cured but with a difficult, different mechanism. We changed the lungs so it should not carry the genetic mutation.
DR. MARTINA PRAPA
I just want to say yes, the same as Prof. Montani. Transplantation is like a form of a gene therapy because if there was a genetic mutation, it wouldn’t be expressed in the new transplanted lung and therefore we wouldn’t expect it to reoccur if that’s the case. So the same applies with heart conditions. For example, when you have a heart transplant, you wouldn’t expect someone even if they have a mutation, to develop the condition again.
ANDREAS REIMANN
Thanks very much. So we have another question from Alena: what recommendations do you have to detect early signs of the disease if a genetic disposition of BMPR2 mutation is detected, specifically when the heterozygous pathogenic variant is identified?
PROF. DAVID MONTANI
What is very difficult is that there is no clear recommendation for children. For adults we all agree that we should propose a screening program for people who carry a mutation and are at risk of pulmonary hypertension. For children, it is more debatable to know to decide if we can test all children at risk or only various symptoms. It depends on ethical laws in each country. For example, in France, I cannot test asymptomatic children because we have no preventive treatment and we can only propose echocardiography and regular echocardiography until the age of 18. And at this stage the subject can decide to do or not genetic testing. Of course, if there are various symptoms, we can do genetic testing and it could be helpful because if you have dyspnea for example, it can avoid invasive procedures. Dyspnea is usually the first sign of pulmonary hypertension, but it could be asthma too. And the most frequent cause is not pulmonary hypertension, unfortunately, it’s asthma or something that is easy to treat.
DR MATINA PRAPA
Thank you. I’m not a pulmonologist, so I don’t have much to add, but I agree. If you have breathlessness, that’s a red flag to think about genetic testing. I really enjoyed Louise’s talk and thank you so much for your heartfelt presentations. You got such nice results. I found it quite interesting for your children that you went back and forth and then they themselves wanted to be tested. So it is, always, we treat each family in a unique way and we’re very much led by the children’s and the parents’ wishes. So we may test children even in the absence of symptoms, if parents, for example, are kept up at night thinking about it or we just wait and watch and if there are symptoms, then we test or we revisit when they’re 16. So there’s no right or wrong answer there when it comes, when to test genetically.
ANDREAS REIMANN
Thanks very much. Very appropriate. If you have the last workflow for this session, if you could share, you made a very strong point for improving on genetic testing and for encouraging parents and patients to ask for genetic testing. What can patient organizations like yours do for this?
LOUISE BOUMAN
Well, at least they can provide information on their websites. I suppose not only about genetic counseling, but also about this form of pulmonary arterial hypertension, because there’s not a lot of information you can find easily or it’s very difficult and it’s also difficult information. So what you can find, you can’t read as a normal person. Doctors can read it easily, but for most patients it’s like going crazy when you read it because you can’t understand a word of it. So it’s very important that there’s more information on the websites.
ANDREAS REIMANN
Yeah, and that’s, thanks very much. That’s why it is so important to have the knowledge sharing platform and this webinar is adding to that knowledge sharing. Thanks for joining us this afternoon, and I think it was worthwhile to run overtime. It was so rich and so important. I’d like to be available soon on the website. I’d like to invite you to our next webinar on September the 17th on clinical trials. Thanks very much and have a great evening.