Aortic Dissection Awareness UK

Thank you Stan and Catherine and to Mark for inviting me to speak. I am lucky enough to be the consultant cardiovascular geneticist here at Liverpool Heart and Chest and anyone who's heard me speak before or see me in clinic knows how passionate I am about rare diseases and working with families. So what I thought I'd talk to you about today is who I see and what I can do, what I can offer, how we offer testing and most importantly why I offer testing to families and what I hope will happen next for families and genetics with aortic dissection. So unfortunately this is usually the type of family tree that I see in my clinic at the moment. So the person with the arrow is the person that I will see in my clinic and anybody who's coloured in is somebody in a family who's had an aortic dissection. Anybody with a line through them is somebody who sadly passed away. And this is the type of family tree, this is the type of family that comes to see me in clinic. So after all of these people have already been diagnosed with aortic dissection then somebody makes the connection and says maybe you should go and see a geneticist. And for me this is still too late for me to be seeing these families. So I'd like to talk you through what I'm doing at the moment and what I think we can be doing next. So who do I see? Well I will see anybody who has another member of their family who has an aortic dissection or an aortic dilatation because we know if your aorta is getting bigger then the risk is that it can dissect and I want to see those families and those family members before they have a dissection so we can do something about it. I see anybody who's had a dissection or a dilatation under the age of 50 with no other reason so somebody who doesn't have another explanation for why they've had a dissection I want to see those patients as well and anybody who has a dissection or has a dilatation where somebody is concerned that they might have a different underlying genetic condition I want to see all of those people but I have to start with somebody who has a feature in their aorta so they have a dilatation they have a dissection as much as I am very happy to see family members and that's really what we want, I have to start with DNA testing in somebody who's already got a problem because otherwise it's like me looking for a needle in a haystack when there's no needle. So I need to see the person who's had an aortic problem first of all to start the process of DNA testing. And one of the things I'll talk to families about is how these conditions, how aortic dissection and the genes that cause them are passed on through families and generally what I'll be saying is that there's a 50-50 chance of a parent passing on an altered gene to their children and if you carry an altered gene we know that you are at risk of aortic dissection, aortic dilatation over your lifetime and for me the key point is at risk because if I can detect that you carry an altered gene and you're at risk before something happens and we can do something about it and and that's what I want to do. So I'll talk to families about how if there is one parent who has a DNA change, an altered gene, then each of their children has a 50% chance of also being at risk. Which also means that I can definitively prove that 50% of their children are not at risk and we can safely discharge them from screening and that's what we want to do where we can. Lots of people come to me and talk to me about DNA testing and blood tests but that's not all we do in genetics. We like to examine patients. I always talk and I always say that although we have all these new technology tests actually what a lot of what we do is old-fashioned clinical medicine and we examine patients. So we may examine things that other people haven't examined in our dissection families. Hands and feet, teeth. I'll often get a measuring tape out and measure my patients and if I can find specific clinical features then it can direct me to specific genes. So if I send some of my patients for eye examinations and we can find this specific change known as iris flocculi, I already know that I'm expecting to find a change in the ACTA2 gene because this clinical finding directs me to that gene. And there's lots of other things that I can do that sometimes I can make a spot diagnosis in patients when I examine them. So if I ask patients to open their mouths and the tissue at the back of their mouth, the uvula is split in two like this, I can be fairly sure they've got lower steets and I can tell them that in the clinic there and then. When I examine patients if they're disproportionate then I can often say well I think the most likely diagnosis for you is Marfan syndrome and then this is a patient, a lady who's younger than me, so you can see that she's very very prematurely aged and the diagnosis in this lady was a specific connective tissue disorder, vascular Ehlers-Danlos Syndrome. So just by examining patients and by seeing them in clinic sometimes I can make a diagnosis there and then and give them a huge amount of information and give information for their families. So what do I do? What testing do I offer? Well I usually take a blood sample and we will sequence a number of genes all at the same time. So we will look at genes that cause underlying conditions that predispose to dissection like bleuistetes and other conditions where we know that changes in the genes predispose to dissection but there may not be external clinical clues. I firmly believe that DNA diagnosis gives options and gives information for patients and families. So when we do a test what I say to families is that we want to find something conclusive that's the reason why we're doing it. We want to find something that we know puts people at risk of dissection and that we've seen in other families and that I can be sure about. But I have to be honest and say that at the moment we only find that in about two to three out of ten of our dissection patients. And there is the chance that we may find a DNA change but it's inconclusive. And the problem with genetic testing is that when we sequence genes, when we look at someone's genetic code, there are up to a million DNA changes that we all carry and they're completely harmless they just make us different from one another and sometimes that can make interpreting DNA results difficult because we don't know whether what we found is something conclusive that puts patients at risk or whether we've just found a harmless DNA change. And in about six seven out of ten patients after the dissection or dilatation we might not find any DNA changes and that doesn't mean that what they have isn't genetic it just means our technology isn't perfect. And when we get a DNA diagnosis and something that's conclusive it gives a wealth of information. So it may give options to the patient and the family, it may give information to the surgical team so we know how the tissues behave in low estates and we know that if patients who have vascular illness down loss syndrome for example go to surgery then their tissues are much more difficult for the surgeons to handle so we can give more information and what we really want is to offer testing to relatives. So once we have a conclusive DNA diagnosis in that first person in a family I can then say right any of your close relatives can be offered a DNA test and in about four to six weeks I can tell whether or not they are at risk of dissection or dilatation over their lifetime. So what happens then? Then I would like to see any close family members and they come into genetics and they see us and they have the relative luxury still of an hour long consultation with our genetic nurses, with our genetic counsellors and they discuss the pros and cons of testing and there are things that we get asked quite commonly when we're talking about DNA testing. So we talk to them about how likely they are to inherit the DNA change from their parent or relative. We talk a lot about psychological implications, so the psychological implications of knowing that you carry an altered gene and are at risk of a dissection. Often people ask me about insurance and actually the short answer is there's no insurance implications because you don't have to declare a test, a predictive genetic test like this. And we also briefly talk to them about what their options might be after they have a genetic test which is a bad news result and puts them at risk. We also obviously talk to them about a good news result and the fact that we can say that they can be safely discharged from any additional screening and they're not at increased risk. If we have a DNA diagnosis we may be able to put in place aortic surveillance and that's what we really want to do to protect family members. If we've got a DNA diagnosis we can often personalize their aortic surveillance so we can decide which part of the aorta they need to have imaged. Is it just the top part of the aorta? Is it all of their blood vessels from their brain to their legs? How often do they need to have it? Is this something that we need to do every year or can we wait till five yearly intervals? And we can also liaise with cardiologists and the surgeons to decide the best way to look at the aorta. So is it with the echo, the ultrasound scan, do we need a CT or do we need some of the more high-resolution imaging like MRI scans? And we can also decide when we need to start this screening. So for some of our families we start surveillance in childhood because we know that there's a period of risk and we can decide when we can be reassured that their aorta is normal and they can stop this extra screening. So the DNA diagnosis gives us lots of information about the aorta and about screening but it may also direct us to other bits of the body that we need to put surveillance in place for as well. So if I see a patient who's had an aortic dissection and it turns out that they've got an underlying diagnosis of a condition like Marfan, I know that their children need to have detailed eye examinations all throughout childhood. In Lois Deet syndrome if we make a diagnosis of that in a family then I will offer specific x-rays of the neck and talk to families about their increased risk of other health problems that other health professionals may not be aware of such as migraine and very rare bowel problems that often go under diagnosed in Lois Deet. And in other conditions like vascular Ehlers-Danlos syndrome we can use specific preventative measures so really aggressive blood pressure management to keep their blood pressure as low as possible and sometimes things like restricting them from exercise so restricting them from contact sport even when their aorta is still normal to prevent them having a dissection. So lots of information from the DNA results. And more and more I'm talking to families about reproductive options so if you carry an altered gene and you've not yet had your children you may want to know what your risk of passing the altered gene to your children is and some families not all but some families will come to me and ask about IVF type techniques something known as pre-implantation genetic diagnosis. So if I have a patient a family member who carries an altered gene and is at risk they may choose to go through this IVF type procedure to only select embryos that don't carry the altered gene so that to the absolute best of our technological ability they know that their children will not be at increased risk of dissection and dilatation over their lifetime. And I'll also talk to patients and families about when we can test their children so when is the earliest time that we would test a child to see if they carry an altered gene, how we talk to children, what we say to children explain to them and what screening we would put in place to keep them safe. So lots of options for not just the generation that I see but future generations as well. Unfortunately we don't always get a conclusive genetic result that can give all these options and we still have a large percentage of our families after a dissection who don't have a DNA diagnosis either because we've found no altered genes or because we've got something inconclusive. If I have a family like in the family tree I showed you at the very beginning where there are lots and lots of people who've sadly already had a dissection we may be able to track a DNA change through that family to convince us that it's what's causing the dissections in that family and if everybody who's had a dissection carries the same DNA change then that convinces us that it's a bit more their evidence is more conclusive that it puts people at risk. But not all families are we able to offer that, some because there's never been a DNA change found or some because sadly everyone who's had a dissection has already passed away and it's just not possible for us to track DNA changes. So where there are families who don't have DNA diagnosis and I know already that there are a few people in the room who have heard about 100,000 and some people who are already involved, we are able to offer those families the 100,000 Genomes Project. So this has been a project that we've been running here at Liverpool Heart and Chest. It's organised by the Department of Health for the last couple of years. And the aim of this is, instead of sequencing the nine or ten genes that I can routinely offer on the NHS, we sequence people's entire genetic code, so all 30,000 pairs of genes. So it's a huge step up and hopefully with this new technology we'll be able to find DNA changes and bring with it all those options from a DNA diagnosis for our families who don't yet have that through routine NHS testing. So this is one of my families and this is where I think we should be focusing in terms of genetics and dissection because I think there is a hugely powerful influence of genetics to change from doing genetics after somebody has had a dissection to preventing it from happening in those families where we can. So this is one of my families. So this lady here had a dissection and sadly died in her 40s, swiftly followed by her sister who had had a dissection and died in her late thirties. This lady had two daughters who thankfully were sent to genetics when they were in their late childhood years. They were seen in childhood, they were given a genetic diagnosis and they had lifelong aortic monitoring. So they underwent yearly aortic scans to monitor the size of their aorta so that if there was any widening any dilatation something could be put in place for them and they would have early elective surgery. They've both been through pregnancies and they've both delivered in hospitals where there is expert surgical cover because we know that ladies with aortic problems going through a pregnancy are at even higher risk and thankfully both of these ladies have been through and had three successful pregnancies. This lady had a daughter and we did a genetic blood test in childhood and she has the same condition. She has Marfan syndrome, she is at risk of aortic dissection but she's under the paediatric cardiologist at Alder Hey. She'll be transferred here when she reaches adult life and her aorta will be monitored for as long as she is alive and if anything develops early treatment will be instituted. This lady went on and had another daughter who had a genetic blood test in childhood and thankfully does not have the same condition and she can be safely discharged and we can tell her that she is not at increased risk of having a dissection. This lady her sister went on and had a little boy and what we did with him because we knew the family they're in close contact with us in genetics is that we made sure that we took a sample of this little boy's blood as soon as he was born. So we took blood from his umbilical cord when he was a few hours old so he didn't even have to undergo a blood test with a needle because we just simply scoop it out of the umbilical cord and we DNA tested him and he has the DNA change he has the altered gene but we knew that when he was four weeks old. So he went straight into aortic surveillance and again will be under that for his entirety of his life and the idea is that we will keep him safe and if there is any hint that his aorta is misbehaving something will be done about it before he dissects and this I think is the future of genetics if we can pick up these families and decide who is at risk and do something about it for them that's where the power of genetics comes into play. So what's next? More DNA testing. So if I've only got 10 genes that I can offer you on the NHS now, in a couple of years I will be routinely offering you the option to sequence your whole genetic code. That's no good if I am sitting in my clinic and I know that you've got a DNA change but I've never seen it before. I need to be able to communicate with my genetics colleagues, with my aortic colleagues, not just in the UK but around the world, so we need to share data, we need to share our families, we need to compare our patients and DNA results so we can actually use them for the benefit of patients. We need to understand what the aortic dissection genes do, so it's all well and good reading the DNA code and looking at the changes in it, but we need to really understand what that gene means. So now we're getting better at so-called omics technologies. So when a gene is transcribed, it's made into a protein. So we have a transcriptome and a proteome, and we can study those to see what happens to the proteins in the body and the aorta and learn more about them. And we can then learn what happens when those proteins and substances are metabolized, the so-called metabolome. And that's going to be the next step in really truly understanding what these genes do, when they work, and what they do when they go wrong. And we also need to look into better preventative treatments, so blood pressure management, lipids, timing of surgeries for specific genetic conditions, better ways to image. So lots of things in terms of the next steps for genetics. So I think in terms of a summary from me, what I would like in terms of genetics and dissection is that we move away as far as possible from picking up families after lots and lots of people have sadly already had a dissection to try and pick out those people who we can predict are at risk, prevent them from having any more problems, personalise their treatment and prepare them for the future, whatever that might be for them, career options, reproductive options, anything that they need in terms of psychological preparation from genetics. Because we want to keep relatives safe and healthy and enhance their survival. And I know from my experience of seeing lots of families after an aortic dissection that if we can find a DNA diagnosis, children, grandchildren, other family members see that DNA diagnosis as a silver lining. They see it as options and opportunities for themselves to be healthy. So this is what I would really like. I would really like to come back and talk to you in 10 years' time and give a talk called The Importance of Genetic Testing Before Aortic Dissection. So thank you for inviting me, and I'm happy to answer any questions over lunch. Thank you. Applause. End