Hello and welcome. My name is Dr. Bruce Stambler. I'm a cardiac electrophysiologist at Piedmont Hospital in Atlanta, Georgia. I'm joined by my co-chair and colleague, Dr. Sunit Mittal, who is director of electrophysiology at Valley Health in New Jersey. And I'm also joined by our invited faculty of experts in genetics, cardiology, and electrophysiology. I'd like to welcome everyone to today's educational webinar entitled Advancing Guideline-Directed Care in Hypertrophic Cardiomyopathy. This webinar is sponsored by the Heart Rhythm Society and will focus on the growing role of genetic testing and counseling in clinical management of patients with hypertrophic cardiomyopathy. How genetic testing and counseling fits into a multidisciplinary care of patients and their families, importantly, with hypertrophic cardiomyopathy will be discussed. And finally, we will have a discussion regarding the barriers that are currently present or may be present for genetic testing and counseling and possible solutions we will discuss. We'll start today by talking about the key takeaways from the 2020 AHA-ACC guidelines for the diagnosis and treatment of patients with hypertrophic cardiomyopathy. It's my pleasure to present an expert in this area and a member of the guideline writing committee, Dr. Jose Hoglar, who is professor of internal medicine, UT Southwestern Medical Center, Parkland Health in Dallas, Texas. Jose, take it away. Thank you. Hello, I'm Dr. Jose Hoglar. I'm an electrophysiologist at UT Southwestern Medical Center and Parkland Health Hospital System in Dallas, Texas. I'm going to be talking about the key takeaways or highlights from the clinical guidelines on genetic testing for hypertrophic cardiomyopathy. I have nothing to disclose. So this is a 2020 AHA-ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy. This is a recent published guideline that supersedes the 2014 guideline. You can see that the writing committee was very strong, composed of a number of clinical leaders from across the hypertrophic cardiomyopathy community, all disciplines, including pediatrics, arrhythmias, et cetera. So I'm going to also start by reminding what is the class of recommendation? How do we use those class of recommendations? So usually in guidelines, the class of recommendation, whether you use 1, 2A, 2B, or 3, it's based on the risk versus benefit. The benefit clearly outweighs the risk. Those recommendations usually receive a class 1. When the benefit is still present but less robust, those are 2A. When the benefit is much less or marginal, that would give this a 2B. And there is clear no benefit or harm. We can say a class 3, either no benefit or harm. So with that in mind, let's see what the guidelines said about genetic testing and family screening. And I'm going to go over the main highlights or main points. So really the greatest benefit on genetic testing is for cascade testing of family members. That's the most important consideration. But also the guidelines recommend that other conditions that can mimic hypertrophic cardiomyopathy, the so-called phenocopies, are tested as well because there is a chance, even though small, that some patients do not have HCM but have other conditions. So in that sense, it is important to identify those conditions so the patients can get proper therapy accordingly. And also we make an important recommendation that patients who undergo testing receive pre- and post-genetic counseling by an expert or somebody who is trained in the genetics of cardiovascular disease. That could be a clinician who understands the nuances of genetic testing or could be also a genetic counselor. There's an increased number of genetic counselors being trained across the country and it's important that we give the right information and the right advice to the patients. Also, when we perform genetic testing, it's recommended that the tiered gene tested include those with strong evidence to be disease-causing HCM. And then once you identify those disease-causing genetic mutations, then you can do clinical screening plus genetic testing of family members. And the advantage of that, which we're going to go into in a minute, is that we can then decide whether additional clinical testing is required or not down the road for those family members. Also we made a recommendation for post-mortem genetic testing in order also to facilitate cascade testing of first-degree relatives. There's some patients who sadly die suddenly due to hypertrophic cardiomyopathy and that could still be a consideration post-mortem genetic testing. They're also very important to remember that if during genetic testing mutations that are considered variants of unknown significance that are not just dismissed but these variants get periodic reassessment to see that changes if those become of more significance or not. So genetic testing is not one and done. There's an ongoing process of reviewing and re-evaluating those variants accordingly. And also we made recommendations on preconception and prenatal reproductive and genetic counseling that should be offered. One thing that we cannot do, at least yet, is use genetic testing for re-stratification of sudden cardiac death. There's some evidence that might be something looming in the future but it's not there yet. So the decision on to categorize people into high or low risk of sudden death should be based on clinical information, not on genetic testing alone. So this is my last slide, which is a summary of genetic testing in HCM. So if the proven or the affected individual is tested and this is causing lightly pathogenic or pathogenic variants are identified, then the idea is to test family members. If the family members are positive, then regular follow-up is recommended. But then if the variant is negative and additional clinical information does not reveal any problems, then additional follow-up or genetic testing is not needed anymore. So that's the advantage of doing genetic testing. And as we spoke a little bit already, there's a regular reevaluation of variant reclassification. So some of these variants of unknown significance can be reclassified as likely pathogenic or pathogenic and then it will go into this decision tree. Whereas some actually pathogenic mutations can be reclassified as of unknown significance or likely benign and then goes into the other decision tree. So that's all I have. Thank you. Thank you, Dr. Hoglar, for that outstanding, concise, and important presentation on the current guidelines for management of hypertrophic cardiomyopathy, focusing on genetic testing and counseling in these patients. Next, we'll have a presentation by Dr. Elizabeth McNally, who's the Director of the Cardiovascular Genetic Center at Northwestern University in Chicago. Dr. McNally. Hello, I'm Elizabeth McNally. I'm from the Blum Cardiovascular Institute and the Center for Genetic Medicine at Northwestern Medicine. And I'm going to talk today about the collaboration between cardiologists and genetic counselors for the care of patients with hypertrophic cardiomyopathy. The learning objectives are to understand the impact of genetic test results on the clinical management of hypertrophic cardiomyopathy, or HCM, and to examine the ways in which genetic counselors and cardiologists can work together in providing care for our patients and their family members. These are my disclosures. Genetic testing in cardiovascular disease is really now being used for a number of different disorders. And by and large, what we use in doing this is gene panel testing, where a number of genes are evaluated at the same time. And the genes are fully sequenced in their coding regions and a little bit of their flanking regions. And the results are interpreted against known panels where people have been found to have mutations. So that's in large databases like ClinVar. And they're interpreted by strict guidelines by the American College of Medical Genetics and Genomics. Most of the time, we apply this for cardiomyopathies. One of the leading indications for genetic testing is, in fact, in the hypertrophic cardiomyopathies. But we also use it in various arrhythmia syndromes and also in neuromuscular disease. So in hypertrophic cardiomyopathy, what we do most of the time is we start with a patient, an index patient in the family who has hypertrophic cardiomyopathy, and then we look at their DNA and conduct the genetic testing, return the results to the patient, and then do cascade testing in family members where there is a positive mutation found. But increasingly, one of the situations we are seeing is individuals who underwent DNA testing, not necessarily in the presence of any disease. And we are seeing this increasingly being offered in the forms of wellness testing. And that's a very different scenario when we go from the DNA back to what is the clinical phenotype. And I'll give you two examples of those. So when I talk about genetic testing, what are we discussing? We're talking about, again, large panels of genes that can cause either cardiomyopathy or arrhythmias. And in fact, many of the testing companies these days offer what is called a combined cardio rhythm panel. So on the right-hand side of these bubbles, you can see many genes that are implicated in arrhythmias. On this left-hand side, you see many genes that are implicated in cardiomyopathies, including genes we know that cause hypertrophic cardiomyopathy, like MYH7 or MYBPC3. But then we have genes in the middle that really can be associated with both types of disorders, cardiomyopathy and arrhythmias. And so that's what's led some people to actually do full panels of all of these genes together. Now, when we do genetic testing, there's a range of results we can get. And most of this has to do with what the frequency of that genetic variant is in the general population. And so variants that are high frequency in the population are considered benign or likely benign. And those results are pretty much never returned on any of our tests. On the other end of the spectrum are variants which are rare in the population and have been previously associated with disease. And these are referred to as likely pathogenic or pathogenic. But in the middle, we have variants of uncertain significance, which are rare in the population, but we simply don't have enough information to know whether they're pathogenic or not. And so these often require some additional work where the counselor and cardiologist can work together. One of the key things we know about hypertrophic cardiomyopathy is that we can largely divide hypertrophic cardiomyopathy into sarcomeric cardiomyopathy, shown here in the red lines, or I'm sorry, shown in the green line, or sarcomere negative, shown in the red lines. And what that means is if you take individuals with hypertrophic cardiomyopathy and you divide those who have sarcomeric gene mutations, they have a very different progression of disease. And so that can be seen here where individuals with sarcomere positive mutations are shown again in the green line, where they're more likely to have heart failure and a bit more likely to have atrial fibrillation in comparison to those who are sarcomere negative. And again, the composite is shown here where you see that their course is quite different. Now, for individuals with variants of uncertain significance, those things we know less about, you can see that they have something of an intermediate phenotype, which means some of those variants of uncertain significance likely do cause disease. So this is just an example of genetic testing. This is an individual who came to our attention because she had hypertrophic cardiomyopathy, as did her brother. And this is her echo. She was about 40 years old at the time. Clear evidence of hypertrophic cardiomyopathy on both her EKG and on her echo. Now, family testing ultimately showed that these three individuals up here in this generation also carry the gene defect, as did two of her children. And so subsequently, these children can be managed with monitoring, while those that are gene negative can be released from having to undergo regular monitoring. And so this is a very important part of testing when there is hypertrophic cardiomyopathy, and again, working with the counselor to offer testing to those other family members. On the other hand, this is an example of an individual who was picked up through what we call that wellness screening. This was actually done as part of a research study through the electronic medical records and genomics group, where we did genetic testing on individuals who were just receiving care in the medical system. And so this individual, 58-year-old male, was found to have a pathogenic gene mutation in MYH7, arginine 870 cis. And looking back in his medical record two years prior, he had actually presented with atrial fibrillation and a stroke, and received thrombolytics, recovered very nicely, and ultimately underwent ablation for his atrial fibrillation. In looking at his echo, he did have some clinical signs of hypertrophic cardiomyopathy by both echo and MRI. And looking at his family history, it was actually quite striking that he did have two individuals in his family, his father and grandmother, that died suddenly of heart attacks. And so now this genetic information can be used in the care of this patient, as well as risk management for his sons. And this, again, represents an important space for collaboration between the genetic counselor and the cardiologist. So what are the ways that the counselor and the cardiologist can collaborate with each other? So a key thing counselors can help do is help cardiologists understand when genetic testing is indicated. We talked about hypertrophic cardiomyopathy today. They also provide pre- and post-test counseling, which can help patients and family members understand what to expect before testing, and then what to do once testing returns. They also help greatly in the interpretation of results. They can help resolve variants of uncertain significance. A lot of times, a result will return as a variant of uncertain significance, and family testing will be encouraged because it's coming close to scoring as a likely pathogenic, and that's a really important part where the counselor can help out. They can help facilitate cascade clinical and genetic testing to ensure that all family members are being properly managed. And most importantly, genetic testing is much more accurately interpreted in the clinical context. And so again, that close relationship between the counselor and cardiologist is really quite important. And so with that, I will thank you for your attention. Well, Elizabeth, thank you for that fabulous presentation. I'm Sunit Mittal from Valley Hospital, and in the next portion of our webinar, we are bringing in key members of the team to talk about the growing role and availability of genetic testing in clinical practice, as well as to discuss the barriers to the routine referral for genetic testing and try to find solutions to overcome these barriers. Today, the moderator for this panel will be Brittany Murray, a genetic counselor at Johns Hopkins University. She'll be joined by Katie Spoonamore from Indiana University, and invited on the panel again will be Jose, Elizabeth, as well as Bruce Dambler. Brittany. Thank you. So thank you all for joining us today. Our panelists represent genetic counseling, cardiology, and electrophysiology. I want to start today's discussion by talking through with each of you actually what you think of the main clinical benefits of incorporating genetic testing and counseling into the daily practice of managing families with HCM. Katie, let's start off with you. Thank you. So I think one of the biggest benefits that I see genetic counseling and testing for families with hypertropic cardiomyopathy is in those situations when we can specifically pinpoint the genetic cause of hypertropic cardiomyopathy where it enables us to do cascade screening and figure out who else in the family is at risk and provide the appropriate preventative care to those individuals. But almost more valuable to that for many individuals is finding out that they don't have the genetic risk factor for hypertropic cardiomyopathy that runs in their family. And it kind of reduces the psychological burden of that for them, as well as the burden of having all the extra healthcare evaluations and screening evaluations for HCM. So I think relieving 50% of at-risk relatives from that burden is one of the biggest benefits. Absolutely, I agree. Dr. McNally, would you have anything else to add there? Yeah, I think pursuing genetic testing is really for two main reasons, right? You want to give a diagnosis to that patient. So first and foremost, patient says, why should I do this? And it's to clarify their diagnosis. We know in hypertrophic cardiomyopathy, there are different kinds of it. We know sarcomere gene mutations have a different progression of disease. And so that's where I think you first and foremost just want to give a diagnosis to that patient. And I think it's very, very helpful lots of times for patients to know this is my diagnosis, this is what I have. And then as we just heard from Katie, the second really important reason is because it's so helpful in the management of patients and patients' family members, I should say, because in the end, the patient does care about their family members. They may know they have some family history of disease. And I find most of the time they're worried that, most people are worried that they got the gene that runs in their family and they're worried that they have the disease. And so it is, again, very gratifying often to be able to tell a family or to be able to tell a parent that their child did inherit it. So that's really an important part of doing this. I might add a comment here. In my own clinical experience, I agree with everything that's been said, but I also have seen patients, especially asymptomatic patients, maybe a primary care doctor heard a murmur, they were sent to a cardiologist for evaluation, and ultimately they were diagnosed with hypertrophic cardiomyopathy and then sent to an electrophysiologist to determine their risk of sudden death and whether they need an ICD. In some of these asymptomatic patients, they may be on the fence about whether they actually need an ICD, even though we may have a very detailed discussion. And I have found that a positive pathogenic mutation finds to be, provides a somewhat compelling diagnosis to the patient whereby they say, you know, I really have this and maybe I should go ahead with the ICD. So it provides ancillary benefit in that regard in the shared decision-making with patients. Brittany, I also wanna add that of course tonight we have the opportunity to speak about genetic testing in the context of hypertrophic cardiomyopathy, but we should not forget that genetic testing has a more and more important role in the care of our cardiovascular patients. Diagnosing that these mutations in patients, for example, with cardiomyopathies can have a huge implication for how we manage these patients. And so I think in addition to thinking about its role in hypertrophic cardiomyopathy, I want the audience to think about its role in cardiovascular disease. And the more we establish teams of teams and the genetic counselor, an important component of our team, it not only helps our hypertrophic cardiomyopathy patients, but it provides us with the infrastructure to really manage many of the patients in cardiac practice that are gonna be seen today. I just wanna mention one quick thing, which is one of the things we deal with when we take care of families is this discussion around that the genes are actually quite variable in how they express themselves from person to person within a family. And that's a really important part that I think the counselors really can appreciate and bring that into the discussion. So there may be members of the family that really had early onset disease, quite severe cardiomyopathy, and there may be other members of the family that didn't experience that. And so I'm sure the counselors would agree, we've all taken care of relatively young people who have had some severe cardiomyopathy. And when it comes time for them to make a decision about having their own families, that genetic information can again be very powerful in helping them have their own children that maybe don't carry the same genetic mutation through things like pre-implantation genetic diagnosis. Absolutely, it's been more and more helpful in a lot of ways, both with managing all the members of the family. And even just as you mentioned, Dr. Stambler, about motivating individuals who have HCM to make decisions about their healthcare, I found actually just telling family members to be screened for HCM when there's actually a real mutation that you can test for it motivates a lot of family members to get preventative screening as well. So all good thoughts. Jose, did you have any additional thoughts to add or we've all- No, I mean, in clinical practice, the guidelines write about the importance of cascade testing and ruling out other conditions that can mimic hypertrophic cardiomyopathy, but as Sunit mentioned, we don't operate in a vacuum sometimes, there are diseases and there are clinical scenarios that are confusing patients. We're not sure what's going on, the patient in person with heart failure, is it a dilated or hypertensive cardiomyopathy versus hypertrophic cardiomyopathy that has gone undiagnosed but there's a lot of possibilities in terms of genetic testing and clinical scenarios beyond the standard recommendations. Absolutely. Well, thank you all so much for your responses. So the current workflow of genetic testing includes discussing risks and benefits, evaluating and choosing an effective laboratory, collecting and processing samples, pre and post genetic counseling, interpreting and explaining results, and then initiating cascade family in the screening and helping with family communication. All of this has yet to be developed in many clinical cardiology practices in order to effectively incorporate genetic diagnosis and counseling into the practice. What advice do our panelists have for the cardiologist or electrophysiologist who's interested in incorporating genetic testing and counseling into their practice for HCM? Either based on your expertise, your own personal experiences, what advice may you have for this cardiologist or EP who's just getting started? Dr. McNally, can we start with you? Well, I would hope many practices actually start to partner with genetic counselors. I think that's critical, but obviously depends on having a practice of a certain size to keep a counselor busy and active and working. There are some different opportunities now these days presenting themselves with all the telehealth we're doing these days to access counselors who may not be officially part of your practice, but can be somebody who can step in in that virtual way and work with family members. But you're right that a lot of those steps of engaging with the family members and the screening, those are things that your average cardiologist just doesn't have a lot of time to do. And so the partnership with counselors is just a critical part of really making sure that we're not only providing the best care for our patients, but also for their family members. Absolutely. Katie, could you maybe expand a little bit on some of those additional options for accessing a genetic counselor that Dr. McNally referred to? Sure, so as Dr. McNally mentioned and has been mentioned a couple of times so far, it's less common to have a genetic counselor dedicated exclusively to cardiology, certainly less common than there are cardiology practices who will be caring for patients with hypertrophic cardiomyopathy. So I would say a starting point in situations like that would be to reach out to any genetic counselor at your institution, even if they're in a completely different clinical area, because that is a good starting point for seeing if there is someone who may be available or interested or already has some expertise to apply in a part-time role dedicated to cardiology or a way to help connect to other local genetic counseling resources, perhaps at a neighboring institution that you could partner with and maintain local partnerships when possible. Those can be very beneficial for families. Beyond that, there are a lot of emerging telehealth options even in the genetic counseling world specifically and companies that exist that can provide counseling services in collaboration with the cardiology office on an individual patient by patient basis, or even on a contractual basis for all of the patients that come through a cardiology practice with hypertrophic cardiomyopathy, you can set up a workflow with essentially a virtual genetic counselor partner that can be dedicated to your practice. So I think all of those can be really good options and really accessible options, especially thinking about these telehealth companies that often employ genetic counselors licensed everywhere and available on a really broad schedule, often with the ability to get a patient in within a week or two for a consultation. So I think when we utilize those resources, they really are very accessible options. Yeah, sure. I had a question for Brittany or Katie. Maybe they can educate the audience who may or may not be aware of it. What is the experience, the training, the background of those that are certified as genetic counselors? I think that's important information that at least I wasn't aware of until recently. Sure, absolutely. So genetic counselors are master's level trained clinicians. So we have specific master's degrees in genetic counseling and human genetics programs. So really our bread and butter is expertise in genetics. And then on top of that, we have a lot of didactic work and counseling work in working with these families with these very complicated diagnoses. So I often, when I meet with families and they say, oh, well, I'm not talking to my sister, this or that, I tell them, I work with families, I'm used to this. And so on top of that, then once we graduate from that master's, usually two to three year degree, then we sit for a board examination in genetic counseling. And then on top of that, many of the states, in fact, I think we're up to 36, correct me if I'm wrong, Katie, states will license their genetic counselor on top of that using that board certification. So it is a unique specialty with specific training in interpreting these results within these families. And then on top of that, many genetic counselors will subspecialize like Katie and I have in many years working in cardiology. And I'll just point out that a lot of those companies that have been emerging, these telehealth companies, are employing counselors with specific subspecialty expertise. So there are cardiac genetic counselor experts out there with same week appointments. So it's a much more accessible than it used to be. But thank you for pointing out that really important background. Yeah, Brittany, I just wanted to add, Katie really highlighted very nicely some of the options that are available, but I think it's important for people to think about those in advance. And I don't think it's fair for individual providers all to have to reinvent the wheel. I think it works better if institutions can think about a structure that works for them and then make that scalable across the enterprise. I happen to work at a community hospital and we chose the model of partnering with a neighboring institution that had a very large program that could help us. And then we made all of our faculty aware of that availability and started to really pay dividends in how we approach this entire process. That works a lot better than individuals having to seek out their own system. So I encourage people who may not have an established system yet to work with leadership to find a system that can be scalable across the enterprise. I just wanna follow on that. There's also some position papers in the American Heart Association suggesting that specialized centers are another alternative where patients and families and cardiologists can access testing. And so, for example, you can refer patients to be seen by a cardiologist who's expert in genetics who works with a genetic counselor for consultation to see a patient and family. And then a lot of times those results will return back to the referring cardiologist with not only the full interpretation, but also some of the clinical management around what is really the management of these rare diseases. Certainly the explosion of telehealth after that and during the pandemic has helped us again, experience with those options. Absolutely. Well, thank you. I think to all the panelists for your perspectives today, I mean, I think in summary, we've heard how we identify these barriers to genetic testing. We've heard some ideas about overcoming these barriers. We've certainly discussed the growing role of genetic counseling and ways to access genetic counseling services. And I think that and hope that this will have been of use to our audience. Now, next, we're going to move on to two cases, which I think will illustrate some additional important insights about the management of patients with hypertrophic cardiomyopathy. The first presentation will be given by Bruce Stambler and the second presentation will be given by myself. Bruce. Thank you. Now we'll move on to a case-based discussion whereby we'll highlight some of the key points that we've just gone over by our panelists. Here are my disclosures. So this is a 48-year-old female with hypertrophic cardiomyopathy seen in my clinical practice. She was asymptomatic and is asymptomatic. She exercises regularly and has no limitations. Her echocardiogram shows asymmetric septal hypertrophy with a 16-millimeter septum. Her ejection fraction is 73%. She has an outflow tract gradient, both at rest and exacerbated by Valsalva. A cardiac MRI showed a 17-millimeter septum with a small area of late gadolin enhancement interpretive scar in the basal infraceptal wall, which accounted to 1% of the left ventricular myocardium. Her Holter monitor showed extremely rare PVCs and no non-sustained VT. Notably, her family history was significant for premature death in her mother at age 52 during sleep. And finally, she has a healthy seven-year-old son who plays competitive soccer. So if I can review these questions and then we'll have a discussion about them with our expert panelists. So in this 48-year-old female, are genetic testing and counseling indicated and appropriate in this patient? And will genetic testing have clinical implications regarding her prognosis, risk stratification for sudden cardiac death, and the indication for an ICD? Why don't we start the discussion with those two particular questions, and maybe Jose, what do the guidelines say about these questions that I posed? Yeah, thank you. So yeah, she will be a good candidate for genetic testing. She has a son. So the main important indication is for cascade testing. That's what the guidelines recommend. That's a class one indication. In terms of cascade testing is to test the son to see whether he has a disease or not. There's some other reasons to test as well that we can go over. Whether the decision to implant an ICD or not, that will not be recommended yet. I know there's just a lot of research maybe in the future, but for now, the decisions to implant an ICD will be based on clinical grounds, not on the results of genetic testing. Thank you so much, Jose. So Brittany, what would be the role of genetic counseling in this family? And what would be the benefits of genetic counseling? Yeah, sure. So one of the things that we often talk about is that this woman, not only would she be interested in learning more about testing and what test results may have implications for her and her care, but something we often think about, sounds like her son is a big part of her decision-making in this case. So we've talked about the implications for her son, the pros and cons of testing. Many patients have a lot of questions about insurance discrimination, which there's a lot of misinformation out there about that. But then also it's so important to identify those who are at risk of developing disease early. So there's a lot of benefits of getting her son tested and identified if he's at risk, or 50-50 potentially that he's not at risk at all and he doesn't need to be monitored. So a big piece of counseling that we would talk about with a woman like this is for her children. So Katie, should we include a genetic counselor before or after we pursue genetic testing and the results are back, or maybe both, before and after? What do you have to say? I think all of those are great options. I think genetic counselors can be worked into the collaborative care for patients with hypertrophic cardiomyopathy in a variety of ways, and it may look different from one practice to another. I think it's best from a teamwork perspective and a relationship with the patient perspective to have a pre-test conversation, to go through some of those things ahead of time, like Brittany mentioned, pros and cons of testing, any concerns about insurance discrimination before they've embarked on that process, and also to kind of understand what to expect with the testing, and then when we have results, going through how we apply that to not just the patient's care, which is often primarily discussed with the cardiologist, but also how that changes our plan for providing preventative care for family members. So any of the panelists maybe can answer this one for me. What if a practice doesn't have a genetic counselor directly available to their clinical practice? What options do cardiologists, electrophysiologists have to provide what it sounds like would be appropriate genetic counseling for this family? Yeah, well, I guess I just want to come back and say, the other, there are multiple reasons to pursue genetic testing in this patient. One is because we know there's a clear difference between sarcomere negative patients and sarcomere positive hypertrophic patients. So those who are sarcomere positive have a greater risk for atrial fibrillation, and in general, have a faster progression of disease compared to those who are sarcomere negative. So strictly from a clinical management standpoint, it gives you more information. The other really important part is to recognize that in and among those sarcomere negative patients, so you've done the test and it is in a sarcomere gene, you may find patients who have Febrez and Pompei and things like that, that can masquerade as appearing like sarcomeric hypertrophic cardiomyopathy. And it's really important not to miss those diagnoses because one, they're treatable, and two, they have different genetics in some cases in terms of how they're passed on. And so those risks have to be managed again for family members, as well as your patient. But I agree, it's hard. There aren't enough genetic counselors. We need more of them. It is possible for a clinician to order a test. They are the ordering clinician. And a lot of times the results come back and do have a very clear cut indication. So if you're not in a position where you don't have a counselor, a lot of times where there are limited supply of counselors, we can use them after the test, just if the result is confusing and also for post-test counseling. I mean, it's ideal to have pre-test counseling and post-test counseling, but we know sometimes that just isn't possible. Very good. There was some excellent points, which you highlighted both you and Jose in your excellent presentation. So getting to the child here, this seven-year-old healthy young boy who plays soccer, at what age should routine screening for hypertrophic cardiomyopathy begin in asymptomatic children with a first degree relative with hypertrophic cardiomyopathy? Well, I'll jump on that. So, I mean, he's seven, I guess now, or some young age. If you choose to do genetics in the child and the child does not carry the family mutation, it's been resolved. The child doesn't have hypertrophic cardiomyopathy and doesn't have the 50% risk that's in the family. And as geneticists and cardiologists, that's our favorite answer when we get that answer. So that's what we hope to find is the answer. But for the 50% of offspring that are going to carry that mutation, first and foremost, then the child has to have an echocardiogram. And if they are genotype positive, meaning they carry the gene, but they are phenotype negative, meaning their heart looks completely normal, there is no need to restrict that child at that point in time. And so all the genetic testing does is it helps guide which children have to be followed and seen regularly by a pediatric cardiologist. I see. And at what age would you recommend screening of a child? What age do we start that? Let's say the child is genotype positive. Usually we like to do a baseline screening just to know things look okay. And then pretty typically it's every year, every other year, especially as the child is going through puberty and going through growth spurts. And some parents, if their children are really active in sports, certainly want to participate in that a little bit more, you know, yearly, I would say. Bruce, I wonder if I could ask a question in the final couple of minutes we have. Going back to the sudden death question, I think you mentioned the patient's mom died without a defined etiology at age 52. This patient's 48. We often get the patients, you know, coming at this stage of their lives, very worried, you know, about the issue of sudden death. Obviously we have the patient phenotype. We know very little about the mother. I just wonder if I could ask Jose again, you know, in terms of the sudden death issue, could you remind the audience, you know, where family history of this type, you know, factors into your own clinical decision-making? Yeah, and that's one of the guidelines also discuss the risk factors. Like I mentioned, you make the decision to implant an ICD based on clinical risk factors. And one of them is family history of sudden cardiac death, but it has to be unexplained death at a young age, meaning under the age of 50, 55. So this person will be a high risk. Of course, genetic testing like Dr. McNeely mentioned will help you sort out other things or other possible etiologies, phenocopies of hypertrophic cardiomyopathy. But certainly the most important risk factor are those who have already suffered a cardiac arrest. Those have been defined as very high risk patients, but also a family history of sudden death is an important risk factor. So if this person happens to have hypertrophic cardiomyopathy and other conditions are excluded, she will be a candidate for an ICD. Excellent. Well, thank you very much, panelists. I think we had a robust discussion with highlighted many of the points we've already made. Well, Bruce, thanks very much for that excellent case presentation. And then it's my privilege now to share another case for my clinical practice and try to see what the panelists would do in this particular case. Here are my disclosures. So the patient is a 55-year-old Indian female who at age 48 noticed shortness of breath and arm pain during her evening walks while living in Melbourne, Australia. She was diagnosed with hypertrophic cardiomyopathy. Her family history is largely unremarkable. At the age of 53, she moved to the United States where she was evaluated at an HCM center. An MRI was performed and this showed asymmetric left ventricular hypertrophy with maximal end-diastolic septal thickness of 23 millimeters. There was evidence of systolic anterior motion of the mitral valve, but no late gadolinium enhancement. An echocardiogram in 2020 showed severe biatrial enlargement, moderate to severe mitral regurgitation, moderate tricuspid regurgitation with moderate pulmonary hypertension and an apical form of asymmetric septal hypertrophy. She was begun on treatment with verapamil 40 milligrams twice daily. She came to my attention when an ambulatory external ECG monitor demonstrated the presence of persistent atrial fibrillation as well as a nine beat run of non-sustained ventricular tachycardia. Not surprisingly, she was quite symptomatic in the persistent atrial fibrillation and we cardioverted her to sinus rhythm. And of course, she'd been on therapeutic anticoagulation for some time. The ECG shown here, a somewhat interesting ECG, sinus bradycardia, a relatively short PR interval and deep asymmetric T wave inversions in the anterior lateral leads. So for the panel this evening, I'm going to pose three separate questions. The first is, again, is genetic testing indicated? Two, how do we interpret genetic tests in populations with limited control data? In this case, as I mentioned, this was a female of Indian descent. And third, what is the importance of identifying conditions that can mimic hypertrophic cardiomyopathy? As Dr. McNally mentioned earlier, there are several conditions that can be mimickers of hypertrophic cardiomyopathy and how important and how frequently can we actually expect to find these? So before I go on with the case, let's address these. And maybe again, I can start with Brittany and ask, is genetic testing indicated in such a patient? Well, exactly. I think that just even in your explanation, you pointed out several reasons why genetic testing may be indicated. Absolutely, for this woman, for the management of her HCM, as we've discussed in some earlier, that this could be important. But then also because she has some quirks about her diagnosis and her clinical presentation, to catch those mimics, which may have major other treatment paths or other things that should be factored into their management, genetic testing can be a really important part of that. So I would say, yes, genetic testing is indicated for this woman if she chose to proceed with it. If I may comment on that also, to answer your question, the mimickers is about 1% or so. So it's rare, but it's a very important situation because you can make a diagnosis and provide the right therapy to the patient. So it's only 1%, but it's a very important 1% in that sense. So I think that what we've heard consistently today is the need for genetic testing, but we rarely see that being done in clinical practice. When we've looked at our own data, probably no more than 20% of eligible patients are ever referred for genetic testing. I wonder, Katie, if you could maybe hypothesize what have traditionally been the barriers and what are we doing these days or what resources are available to really make this more of a ubiquitous portion of the patient's evaluation pathway? That's a great question. I think the most common perceived barrier that I have encountered is the idea that the genetic testing costs an exorbitant amount of money, is not going to be covered by insurance and is going to be either not doable for that reason or result in some large financial burden on the patient that is somehow unknown and unable to really mitigate. And I would say that there was a time where that was sometimes the case, absolutely, but that in the last several years that has really changed dramatically and that the cost and accessibility of genetic testing itself has dropped dramatically. Insurance coverage has improved and there are a fair number of other programs available to reduce the out-of-pocket costs for those who do not have insurance coverage or who have insurance that has genetic testing exclusions or something like that. So although genetic testing truly is very accessible for anyone for whom it is indicated now based on the guidelines, it is still a major perception out there that that's not the case. So I think that that limits referral in a lot of cases. And I also think kind of a lack of understanding of if and how it would make a difference in a patient's care. I think the people who understand and have experienced perhaps the 1% of a mimicker showing up in their clinic unexpectedly or the true power of being able to test at-risk relatives when the identified genetic cause is found in a family and we can use it for cascade screening, those people refer quite regularly and many, many, many patients do get this on a regular basis. But for those who don't really understand or for patients who don't understand why this is gonna make a difference, that's a barrier for referral or for showing up with the referral in place. Another issue I'd like you to address for the audience is there was a time when you would order genetic testing and it would take a very long time to get genetic testing back. And clinicians were very concerned about that because they felt they needed to make decisions on patients clinically sooner. And often the test just went and you never heard anything back. I know that that's also changed. Could you provide the audience with some assessment as we head into 2022? What is the typical turnaround for a genetic test? That's a good question as well. It has definitely gotten much, much faster. Sometimes I get the results faster than I'm ready for them. But often, probably I would say around three to five weeks to be safe, but we often get results in two. Yeah. Elizabeth, if I can ask you, obviously life is easy when a test is positive or pathologic and negative, as you mentioned. But one of the things that I think confuses a lot of clinicians is that when it comes to genetic testing, there's often a variant of unknown significance for a variety of reasons. Often, as I mentioned, the population hasn't been well studied. What would be your general comments about that and how important it is then to work with genetic counselors to properly interpret the data for a patient? Well, that's definitely improving day by day as we talk. So in the case you mentioned was a woman of South Asian ancestry, and we now know our databases that we have access to have thousands and thousands of people of South Asian ancestry. Now, admittedly, that's still a small number considering how many South Asians there are in the world, but it is absolutely improving day by day. It is true that some groups are more likely to get a result that is called this variant of uncertain significance than some other groups, but again, that's improving pretty regularly. The other thing to recognize is, especially for hypertrophic cardiomyopathy, there are some genes, the two main genes that lead to hypertrophic cardiomyopathy are actually the easiest genes that we have to interpret genetic testing on. And so we're much less likely to get variants of uncertain significance in those genes compared to some of the other genes that we do testing for. And in fact, we're now using domain knowledge, so where the change falls within the gene can be used to help interpret that result. And so again, it's getting better day by day. Most of the companies will also do reinterpretation. So if something comes up and you're not quite sure, it's very reasonable to go back to the company a year later and say, has anything been updated? Do we have any new information? But the other place where the counselor and the cardiologist can really work together is in testing other family members. So we know this is a familial disease. And so the recommendation is if you find an individual with hypertrophic cardiomyopathy, their first degree relatives should undergo screening for hypertrophic cardiomyopathy. So if you find other individuals in the family that have findings on ECHO that look a little bit suggestive or they have hypertrophic cardiomyopathy, then you can test that variant of uncertain significance in those family members. And a lot of times actually improve the data so that you yourself, along with the counselor, can help interpret that result. And you can even report it back to the company. And sometimes you can change the interpretation yourselves just by working together with the family and the counselor. Tony, if I may comment also real quick, the guidelines also will evolve and it takes time for the clinical community to incorporate guidelines, to adopt those into daily practice. It takes some time, but the guidelines are making a very hard effort. The genetic chapter, the recommendation on genetic testing in these guidelines is very robust. They talk about every detail, what to do with the results. They talk about the variance of a non-significance, what's positive, what's negative. They provide a very good framework for clinicians on how to approach this genetic testing in this disease. So it just being an evolution, but I think we're there now. Okay. Well, in the interest of time, let me just take the audience through what we found in this patient. So interestingly, the genetic testing demonstrated a variant of uncertain significance in the GLA gene, which is associated with X-linked Fabry disease. The cardiac MRI was repeated. She had severe biatrial enlargement, asymmetric hypertrophy, mid distal cavitory obstruction and systole, and patchy myocardial enhancement in multiple segments. This prompted additional diagnostic testing, which was then confirmatory of Fabry's disease. And she's been started on enzyme replacement therapy. And I think it's a wonderful case to highlight the importance of looking for mimickers and making the correct diagnosis in this patient. So I want to really thank the panel for their invaluable input. So in summary this evening, we've learned about the need to recall the guidelines for executing the best care for patients being diagnosed with hypertrophic cardiomyopathy. We've learned how genetic testing is growing more and more in clinical practice. And we've also learned how to overcome some of the barriers for referral for genetic testing, and hopefully have provided you with some possible solutions. Want to thank everyone for the time and attention. And I thank all the panelists for participating this evening. ♪♪

genetic testing

counseling

hypertrophic cardiomyopathy

cascade testing

personalized treatment

barriers to genetic testing

telehealth options

interpretation of genetic tests

clinical implications of genetic testing