Good morning or good afternoon, depending on where you are, and welcome to this edition of the ACMG Genomics Case Conference for Adult Genetics and Genomics. I'm Dr. Matt Taylor. I'm here at the University of Colorado, and I'll be walking you through today's presentation and discussion. We titled this as Mile High Genetics. As many of you know, Denver is a mile high in the sky. And what we're going to talk about today are a few of the cases that we've seen here in Colorado in the Adult Medical Genetics Clinic. We're going to cover some topics, including cardiomyopathies, adult intellectual disability, and breast cancer as well. I'm required to show you a few slides that are mostly disclaimers. This first one is basically to remind you that this is strictly an educational process that we're going through here, and that the ACMG does not necessarily warrant the accuracy and completeness of what is being presented here today. There's a group of dedicated individuals who have been planning and organizing these sessions. They are listed here. I'd like to specifically point out that Shweta Dhar has been very helpful from Baylor in terms of getting our process set up here. And so I certainly appreciate her input, as well as the input of the other members of the organizing committee, and to help you organize this webinar. So here is a picture of the University of Colorado Denver where I operate and play out. I like this picture, because it's actually a beautiful image, and it also implies that the ocean is nearby, which doesn't make any sense, because we're, of course, very far inland. But it is a very nice place to work and operate. And we are the largest academic medical center in the city of Denver. In fact, we're the only academic medical center in the state of Colorado. So 400 or 500 miles in any direction, we represent the major academic center. A couple of our genetic counselors have contributed here. They are not presenting today, but they've certainly been instrumental in getting this set up. There's some disclosures we're required to provide, as well. You can see the disclosure from all of the members of the organizing committee. I have some disclosures, as well, although none of them are particularly relevant to today's discussion. Once more, an official faculty disclosure slide. If you're seeking educational credits for this activity, the American College of Medical Genetics and Genomics is providing that. This designates as one AMA category credit. And there's instructions on the website and at the end of the webinar if you want to seek those credits. If you'd like to ask questions during the webinar, I'm doing this solo at the moment. There should be on your screen, on the left-hand side, a Q&A box. And you should be able to type your question in there. I will probably take questions at the end, depending on the timing of this. So we'll go through four cases today. If you have a particular question on a particular case, it'd be good to start that question with case one or case two or case three, and then list your question. And we'll get to those at the end, assuming we have time. The overall objectives of this webinar series for adult genetics are as follows, to recognize cardinal signs and symptoms relative to adult genetic clinics and diseases, to discuss the relevant diagnostic tools and molecular testing strategies, to recognize some of the challenges and limitations of ordering genetic testing in adults, as well as to explore whole exome sequencing, which most of you in the world of genetics know is certainly a full force come into the clinical arena and is increasingly being used, not just in the pediatric setting, but for adults as well. Specific to this session that we're providing from University of Colorado, we're gonna talk about genetic cardiomyopathy family histories and understand how we use diagnostic testing for those hereditary cardiomyopathies. We're gonna talk a little bit about how we use genotype positivity in a couple of cases to consider how we might actually manage the condition. So using genetics, not just for diagnosis, but also for management. Then we'll move on to a case where we'll look at the advantages of using genetic testing iteratively, meaning that we did one particular test and got some information, but did additional testing as new technology came online and how that altered our diagnostic interpretation of the case. And then our fourth case, if we have time, will be to look at the possibility of exploring variants of uncertain significance in an adult cancer case. The format of this conference, if you participated before, is gonna change a little bit from today. And that's really because we don't see a lot of hereditary cancer in our clinic, and I'll explain that in just a moment. So I'll start by introducing our genetic practice here at the University of Colorado. And instead of doing a single non-cancer case, I'll let you do a couple cases related to cardiomyopathies in the first part of the presentation. And then for the second session, rather than doing two cancer cases, I'll actually show you an additional non-cancer case, as well as one cancer-related case at the end. And then if there's time, we'll do questions and answers at the end. Those of you that like math or were mathletes in college will realize that this in itself adds up to already an hour, and we've already used five minutes of our time. So I'll budget our time accordingly and likely hold those questions till the end. Okay, so that allows us to get started. Let me tell you just a little bit about our adult practice here, since I know all adult clinics are a little bit different around the country. Our program was started back in 2000, and it was started in our Department of Medicine. And it was designed to complement some of the existing infrastructure at our institution. We have a fairly large and typically organized traditional medical genetics and metabolic genetics program that runs out of pediatrics. They do see some adult patients, but largely try to avoid seeing adults, except for those cases of metabolic disease where they need particular nutritional or dietary management that we can't provide on the adult side. Our cancer center has a hereditary cancer clinic that's also been in existence since probably a little bit before 2000. And that's predominantly the reason that we don't see very much hereditary cancer in our adult medical genetics clinic, largely because we try to make sure those cancer cases are seen by the genetic counseling team and oncology team in the cancer center. We have prenatal genetics that sees adults, predominantly women who are pregnant and have ultrasound abnormalities and perhaps need prenatal testing. There's been a neurogenetics presence here that has come and gone over the years, and there's been genetic counseling staff periodically in that operation. Our clinic itself is staffed by one internist geneticist, and that would be me, as well as between two and three genetic counselors, depending on our staffing needs and staffing resources. We operate out of the adult cardiac and vascular center, and that's largely because my home division in our department of medicine is the cardiac and vascular center, and that relates to the genetic research that my laboratory team does, and the fact that there's not a specific genetics division within our department. So there had to be one place for us to operate, and it turns out it's in our cardiac center. That means that we probably see a bias towards cardiac genetics cases over other cases because we're housed in the cardiac center. We have a new personalized medicine center that's been developed, and we're interfacing with that, and we're actively trying to grow. Many of you who are experiencing growing pains of your own realize it's difficult to recruit both adult geneticists, as well as genetic counselors with adult expertise, so we're actively trying to do that. If any of you listening today have interest in talking more about that, I'd be happy to discuss that with you offline. The referrals that we see, we see a fair number of connective tissue conditions. As you might imagine, that's a fairly large part of adult medical genetics practice. Some of the other conditions that we see are cardiac conditions, a couple of which we'll talk about today, a fair share of neurologic conditions, adult intellectual disability, adult intellectual dysmorphic cases. We do manage a number of metabolic diseases, particularly those that are lysosomal storage diseases, and we see a fair number of genetic eye disorders, and many others as well. This is certainly not a complete list. Okay, so that concludes the early introduction part. We're doing pretty well for time, so I'll now dive into the cases, and I'm gonna try to go through four cases, time permitting, and at the end of each case, I'll make a few comments about the case that may stimulate some discussion, and we'll see where that takes us. So the first case we titled, to ICD or not to ICD, that is the question, and this is a hypertrophic cardiomyopathy. So as we move forward through this case, I want you to be thinking about whether or not this patient that we present does or doesn't need an implantable cardiac defibrillator, which is referred to as an ICD, implantable cardiac defibrillator. So the case begins with a couple teenagers who we actually saw a little over a decade ago. They were 13 and 15 at the time. They came to genetics because their mother, who herself was a physician, was concerned about the family history, not her family history, but the father of the children, her husband, concerned about his family history, and I'll show you the pedigree in just a moment. The son was 15, reportedly healthy, but he had some occasional heart palpitations. He had a borderline abnormal EKG, but nothing very specific, and was not receiving any therapy. The daughter was 13 years old at the time. She was very healthy and physically very active, and was actually a gymnast and was quite competitive at the time. Their family history started out looking like this. Fairly benign initially. Here are the two teenagers we're gonna be talking about. This is the father who had actually had hypertrophic cardiomyopathy as a younger man, and actually had been told at the time that it might be genetic, it might be athlete's heart. He wasn't entirely sure, and over time he had started exercising a little bit less. His hypertrophy had reduced, and actually at the end of his story, he was really relatively normally healthy other than some atrial fibrillation. His father had atrial fibrillation, had a diagnosis of hypertrophic cardiomyopathy, but lived actually to the age of 69 and died of a pneumonia, not related to his cardiac disease as far as we knew. But the family history had some other elements in it, and you can see them here and appreciate the dilemma that we see in these families. So we have four siblings here, one who died at age 18 while taking a jog, one who had sudden death at age 23, one who was living at the time at age 48, had pretty severe hypertrophic disease, already had a cardiac defibrillator, and had actually received surgery for her cardiac hypertrophy. And then one other sibling who had a sudden death episode with no prior symptoms at age 18. So a typical family, in some cases, at least a typical dilemma for these hypertrophic cases, one or two individuals where the concern level is low to medium at best, and one or more individuals where the concern level is much higher, and then some at-risk individuals that you don't yet know what you're going to do with. We went ahead and coordinated genetic testing. At the time we did this, genetic testing was only available for a small number of genes. Many of you know now that the genetic panels have several dozen genes on them. The gene mutation we were able to confirm was a mutation in a gene called TNNI3, and we confirmed this in the father and in the living sibling, as well as in two other individuals, because autopsy material would happen to be available at the time. So this was felt to be a pathogenic variant. At the time we used the term mutation, now we would say pathogenic variant. And because this is a dominant condition, it certainly predicts a risk that this could have been passed on to one or both of these siblings. When we did genetic testing, if the animation works here, we were, of course, mostly suspicious of the young boy here with the right bundle branch block, which is an EKG abnormality. But it turned out, my apologies here, there was gonna be some animation here that was going to move this mutation and say this is probably who you thought was gonna be affected. You actually have to imagine that this moves over. It was the perfectly healthy 13-year-old girl who had a normal EKG, a normal cardiac ultrasound, no symptoms at all, was incredibly physically active. The mutation actually should move over to her because she was the one who was carrying this mutation. So we now have time for discussion. We are now looking at a teenager, physically very active, competitive gymnast at the time, normal cardiac studies. So there was no evidence that this young woman had any signs of hypertrophic disease on clinical history or clinical exam. We have a family history with a father who actually has a fairly benign course, a little bit of atrial fibrillation that was really doing quite well from a health standpoint. Contrasting that with the aunts and uncles who had premature or sudden cardiac death and fairly severe disease and a variant that was felt to be pathogenic and a decision to make. And so the decision is whether or not we should implant a defibrillator or whether we should do something else, perhaps follow with serial echocardiograms or something else. So I'm going to be bold here and try to see if we can run this survey. So those of you that are participating should now be able to participate in this survey. This is the one question we're going to ask you during the session. And the question really is, given the information so far about this case, what would you recommend for this asymptomatic girl with this pathogenic variant? And I've given you four options here. If I click run, that should allow you to participate. It looks like I'm getting some answers here, and I'll wait another 30 seconds for you to make your choices. I'll ask you to make your choices in the next five seconds then. We'll go five, four, three, two, and one. I haven't done this before. Let's see what happens if we stop the survey. So I presume that those of you watching can now see the answers here. I will read them for you in case you're not able to see this. So 52% of you playing along today decided that you would do screening by ECHO and EKG for now. 14% voted for some sort of medication therapy like beta blockers. 23% decided to do something more invasive such as implant a defibrillator. And 8% decided to not offer an opinion, which is perfectly fine. I think if I press the button share now you should be able to see those numbers. So you can see that there's a distribution here. And I'll tell you what we did 10 years ago, and I'll tell you what the outcome was as well in just a moment. So if we move on to the next slide, we were at odds as well at the time as to what to do, and there really wasn't much guidance here. So we actually consulted several cardiologists, and each time I presented this case to a single cardiologist or a group of cardiologists, I would seem to get a somewhat different story or different answer. And so it was largely split on whether or not to implant a healthy individual or not. The family who had been through obviously quite a lot decided that they would implant a defibrillator. This woman did fine for the following 10 years. I'm concerned that the animation I wanted to show is not going to work here. Let's see. It did not. Let me tell you what was going to happen here. The animation would show you that actually she did fine for 10 years, and actually we got an email from the family about a year ago that while jogging as a college student with her boyfriend, she had an episode of sudden cardiac death, and her defibrillator did fire, did save her, and she actually had a positive outcome. Now in terms of whether the right answer was to implant or not, she didn't have symptoms for 10 years, and in fact over those 10 years did develop some hypertrophy, and so one could make the argument that in this particular case, had you waited until she had hypertrophy develop and then implanted a defibrillator, it probably would have saved her as well. Just to round out a discussion of hypertrophic cardiomyopathy, it is a disorder characterized by increased thickening of the wall of the heart without really another external cause such as a valvular problem or hypertension. We think about half or perhaps a little more are dominant, and we can identify about 50%, maybe a little less than that currently with genetic testing. The problem for us is that the condition is actually quite benign. Most people do quite well with a few symptoms, but the complications are grave, and symptoms can be a problem, but arrhythmias and sudden cardiac death are the things we really fear, and there's a lot of variability both within and between families. Even though we're 10 years ahead, the screening of at-risk individuals or individuals who are genotype positive but don't yet have a phenotype, that's been recommended for the last 10 or 15 years, a little bit longer even, but there remains no clear consensus on what we do with the asymptomatic individual who has a positive genotype but at the moment has no clear signs of disease. The limited data so far suggests that these individuals who are asymptomatic have a benign course and might be allowed to be followed clinically. They're often allowed to compete in sports, but we don't know whether there's a subset of these individuals who have a positive gene test but no phenotype who might actually have problems. There are a number of studies that are ongoing to try to address this. One of them is actually ongoing right now. It's called the VANISH trial. There are about a dozen sites around the states and a couple outside the states working on this particular project. If you have any individuals who are genotype positive and have no phenotype or perhaps have a very mild phenotype, again, happy to discuss with you offline because this trial is trying to enroll enough patients to meet its milestones, and it's difficult to find those individuals who are gene positive but don't yet have a significant phenotype. So if you have questions on that case, you're welcome to submit them now. We'll get to them at the end, but let me move on to the second case, which we've titled A Long Came a Spider, and then later, perhaps much later, we had genetic testing. And you can tell I was trying to be creative as we put this together, but this is the last bit of creativity you'll see in this discussion, I promise you. So this is another cardiac case, and this is a 36-year-old gentleman that we saw in the last year who came to us because of his longstanding history of long QT syndrome, inherited arrhythmia syndrome. He was referred to us because his wife was pregnant. They wanted to understand whether their pregnancy was at risk, as well as they wanted to know what their genetic defect might be to see if they were eligible for a research study. The story continues with that he was referred to us because of a pregnancy, and they wanted to know his genotype for research. This family was actually described back in the mid-'70s as a paroxysmal B-fib syndrome family, no genetic studies were done at the time, of course, because of the time period. But at some point, and we don't quite know when, the diagnosis in this family just became long QT syndrome, and all their medical records reflected long QT and not this publication in the literature in 1974. So family members for decades had been screened based on using EKGs and occasionally electrophysiologic studies looking for long QT syndrome. Our patient was generally healthy, as many of these patients are, but he'd had a treadmill test at age 12, which was abnormal. He's 36 now. We don't have the records to review, and for reasons that are not clear to us, because we don't have those records, he was diagnosed with long QT and had carried that diagnosis since the age of 12. A defibrillator had been placed, and he'd had it fire at least three times, once while weightlifting, physical exertion, once while car racing, which could be a combination of physical exertion and or exciting things going on, and at age 19 while he was singing karaoke, which I can imagine was probably more exciting and emotional than physical. We had a little bit of information about his QT interval, which was actually normal as near as we could tell, and we didn't have any clear evidence that he had long QT syndrome, and although he'd been followed for this diagnosis, we were wondering whether this was indeed the correct diagnosis. This slide probably should have been hidden. Let me move on. His family history is interesting. Here is the patient. He had a sibling who, at 27, already had a defibrillator in, had a diagnosis of long QT, and the defibrillator had fired several times. His father had a sudden cardiac death event while playing baseball. He was actually angry at the umpire and was complaining a call, and he had an ICD placed in his 40s. He survived his sudden cardiac death event. It had not fired since. Here's the individual who was startled by a spider at age 12, ran off to tell his friends, and had a sudden death event and could not be resuscitated. Another individual who had multiple syncopal events caused by anger and emotion actually died of another cause. An individual who was a good swimmer but actually drowned, in fact, looked like was having a problem swimming in three feet of water, was pulled out of the water and then drowned on the side of the swimming pool or the riverbank. And then a 17-year-old who was startled by a friend and had a sudden death event and did not recover. So a lot of sudden death, certainly compatible with long QT syndrome, a normal autopsy in a couple of cases. But at least from our reading of the medical records of this gentleman, what was missing was the documentation of actual long QT intervals on electrocardiograms. Here's information from that report back in 1974. This was not our patient. This was one of the other individuals in the family. And there's a rhythm strip here at the bottom with an ugly-looking rhythm. That actually occurred after the patient had had an emotional outburst in the cardiac lab and pushed himself into a fairly abnormal rhythm in front of the cardiologist at the time. And it looks like the version of the slides that got uploaded is going to have a few slides that were supposed to be hidden, so I'm going to just have to skip through those. I apologize for that. Our considerations at the time were that this could be long QT syndrome. After all, the patient was referred to us for that cause. However, as we were taking the family history and the medical history, we really couldn't find evidence of actual QT prolongation. It's possible it was there, and it's possible it was there many years ago and just hadn't been re-documented. But one of the things we do in our adult genetics clinic is we are fairly skeptical of information provided by our patients, not because we don't want to trust our patients and our patients aren't good historians, but in contrast to the pediatric world, we're often dealing with individuals who are trying to give us their medical history over a two-, three-, or four-decade or longer period. And so we need to be careful about the information we receive from our patients. It's a little different from the world of pediatrics. We're often a young pediatric patient. A lot of their medical records can be obtained because most of their medical care has been contained within one particular clinic system. For our patients where they have medical records over years to decades, we're just inherently skeptical, and we certainly record the information patients provide us about themselves and their family. But we do what we can to verify this, and our genetic counselors are very instrumental in getting old records and trying to really see what is truly there. So based on the history, we were starting to suspect this other condition called catecholaminergic polymorphic ventricular tachycardia, another genetic arrhythmia disease, characterized by episodes of passing out, unpleasant and unusual and unsustainable heart rates, and or sudden cardiac death. These are often triggered by physical activity or emotional stress. They begin in childhood, and they have a dominant pattern of inheritance. So we contemplated the Long QT approach, but decided we wanted to make sure that we covered CPVT. We did that testing using a multigene cardiac arrhythmia panel and came up with a pathogenic variant, which had been previously published. Right away, as we reported results to this patient, he asked us about whether or not we could or should test his two children, which are, if I remember correctly, both below the age of 5 or 6. And we could get to that in a question if we need to at some point. Okay, so getting through to the slide I wanted to talk about. From the case discussion here, this was a family that had been followed for four decades. The diagnosis all over this patient's chart and of the other family members was long QT syndrome. And really it was the careful family history in confirming information. And our genetic counselors aren't overly compulsive. I think most genetic counselors are quite compulsive. It's a good skill to have. And they were just very diligent in trying to determine what did we know about the family when we heard that they'd been reported in 1974, we had to dig up that case report, really to try to find out as much as possible what was known about this family and not just take the long QT diagnosis at face value. Because of the phenotype, we were, of course, suspecting CPVT and points of this case to take home were that the molecular analysis confirmed our suspicion, which is always nice to have happen. It removed the long QT diagnosis and noted that that was the incorrect diagnosis. We now have a correct diagnosis. It now allows for molecular screening of at-risk relatives who've not yet had an event. And it allows us to screen them based on not doing silly things such as looking at their QT intervals, which are going to be normal and probably always normal because this is not a long QT syndrome. You may realize also that there are some normal individuals whose QT intervals do vary and do extend into the abnormal range. And so having a correct molecular diagnosis means that we're also not going to misdiagnose some individuals because their QT interval happens to be extended on one day when we check their EKG, we might actually implant defibrillators in patients who don't actually need them. So we can now more accurately cascade screen genetic testing throughout the family, identify who are the mutation carriers, who are not mutation carriers, and then at least have discussions with our cardiology colleagues about how we're going to manage those individuals who have had symptoms and are genotype positive as well as those individuals in these families who have not yet had any symptoms but, of course, are at risk to have symptoms at some point in their life. And because those symptoms can include ventricular tachycardia, fibrillation, and death, have some discussions with those individuals and their parents and family members about how we're going to manage them. So, again, another example where we're using the molecular diagnostics in a cardiac cardiomyopathy situation to make some impact on how we're going to screen and manage these families. Okay. We're now going to switch gears. We're actually doing pretty well for time here. And we're going to talk about an adult that we saw fairly recently who had abnormal chromosomal findings after a workup for mild intellectual disability and some congenital anomalies. So this case is fairly typical for us, a 41-year-old woman who had mild cognitive delay, a unilateral clubbed foot by history, a fused tooth, and a question of immunodeficiency disorder due to a history of recurrent infections. This immunodeficiency disorder had not been confirmed. We saw her back in 2003 when standard chromosome analysis was done. A deletion on chromosome 2 on the Q arm was noted. There was not much information about this deletion at the time. We were able to confirm that there were normal maternal studies, but the paternal studies were not done. So we don't know if this was an inherited deletion or not. And what was known about this region at the time was that there were a couple genes listed here which had been linked previously to dysmorphic features and probably cognitive problems as well as perhaps immune difficulties and immune problems. And this is a fairly typical intellectual disability case for us in the adult genetics clinic. This probably represents about 5% of the patients that we see. And these are individuals who probably have had static cognitive problems their whole lives, may have some other medical issues going on. About a half of them, maybe a little less than a half, have been seen by genetics or at least someone remembers they were seen by genetics back in the day. So perhaps 10, 20, 30 years ago, genetic testing was sometimes done. We often don't have records on that. And for reasons that aren't always clear to us, somebody decides that these patients should get evaluated by genetics again and we see them. Sometimes this is because the patient switches primary care physicians. Sometimes this is because a relative, often a sibling of the patient is getting ready to start a family and wants to know whether there's a genetic diagnosis in their affected sibling. And other times it's for reasons we can't really understand or establish. Oftentimes the history is also challenging because many of these individuals do live in adult care settings. A number of them are no longer connected with their families. And so our ability to get accurate records about prenatal exposures, pregnancy history and childhood history and developmental history is often significantly compromised in these cases. So here is a picture of the patient and she had given permission for us to share a picture. We saw her again just recently. When we updated her history, the recurrent infections, this sort of vague, unverified history from previously, really had resolved and was not considered an active problem. Her health was stable. There were some social and behavioral issues and she was not living independently. She was semi-independent when we initially saw her. But because of some behavioral issues, it was now living independently. And because of some social issues, it was now living in an adult care home. She looked a little older than her stated age. We thought when we evaluated her, she had some dysmorphic features, but nothing that we recognized as a particular syndrome. She had a rash here shown in the picture she provided of her thigh that had been biopsied a couple of times with no particular diagnosis attached to it. So what we decided to do was to see if we could better clarify the region that was deleted and learn anything more about what genes were or were not involved. And we're actually glad we did this. It turned out that the microarray that we used, the SNP microarray, actually changed and redefined the region of loss somewhat and gave us fairly precise coordinates. And that the previous genes that we had hypothesized that might be involved, that had an association with some intellectual disability and dysmorphic features, as well as the other one related to immune problems, those actually turned out to not be in the deleted region. Here's a list of some of the other genes deleted in the region, including collagen 3A1, which is associated with vascular Ehlers-Danlos syndrome. So we have to wonder now if she's haploinsufficient for COL 3A1, whether or not she might be at risk for vascular complications. So it gave us new information. It's hard to know how much of this information is actionable, obviously, in these patients. And again, I apologize for we have the version uploaded with some information that we didn't need to share. These were hidden slides. Here's the information that we are happy to share, was that from this case, the original genes of interest actually became less interesting because they were not in the deleted region. And we have new coordinates. At this point in time, it was nice to see her back after 10 years because there are now about 50 cases described in the literature with recurrent deletions in this region. There are some common features of which she had several of these, including some intellectual problems, behavioral problems, perhaps some psychiatric issues as well, some dysmorphic features. We queried her very carefully about bruising and hypersensibility over the phone and queried her caregivers. And at the moment, she does not report any of these problems. There are distal deletions, which have a bit more cognitive issues, and her proximal deletion with some milder features. So we were able to give a little bit of, if you will, prognostic information to the caregivers, although fundamentally the utility of that information is somewhat limited because, of course, we're providing information about this individual might have mild intellectual disability while she's already in her 40s. I think we understand her cognitive state. So certainly this doesn't provide very usable information for families here. However, the implications of losing COL3A1 are of interest. The patient, again, has no findings by history, and we didn't notice anything on the original exam. Of course, we weren't clued into this particular question at the time we saw her. So we'll be seeing her back in clinic. We'll be taking some additional history and looking to see whether other features of the syndrome show up in her, as well as paying attention to the COL3A1 question. And we're having some discussions internally about whether or not we should consider doing skin biopsy analysis in her to see whether she provides a skin biopsy finding that would be consistent with vascular Ehlers-Danlos syndrome. We did note that she looked a little older than her stated age, but beyond that, an idea of a vascular form of Ehlers-Danlos syndrome really did not come up at the time. And this case provides a little bit of time for us to reflect that the microdeletion syndromes are something that we've really seen in the world of adult and pediatric genetics really mushroom and explode in the last several years. This is largely due to the advances in sequencing technology, or rather microarray technology, that's allowed us to define a number of these deletions and microdeletion syndromes. In the world of adult genetics, we struggle from time to time because oftentimes there's not very much information available on these syndromes. And the information that is available is often available largely from pediatric cases. And so most of these literature cases described really occur in pediatric patients. So natural history, long-term history, and whether new complications develop are often lacking in a number of these patients that we see. And that adds to the challenge of providing results to patients and counseling patients and families about those particular findings. Okay. The last case, and I see that we're actually doing quite well for time, so if you're thinking of questions, we'll be able to get to those at the end, is our attempt at a cancer case. And I have to acknowledge again that at the beginning of this webinar I mentioned that we really steer away from cancer in most cases in our adult genetic clinic largely because when our clinic was established, there was already a very robust hereditary cancer program for adults in place, and we saw no need to replicate, duplicate, or compete with that on any level. And in fact, when we see patients that come onto our schedule for a cancer indication, if we can intercept those patients before they actually show up for clinic, we often try to refer them on to the hereditary cancer clinic. Similarly, if that cancer clinic sees a patient and it turns out to be a non-cancer case or another problem shows up, they often refer the patients on to us. So we do try to partition those activities just for the sake of efficiency. The nice thing about our hereditary cancer clinic is that it's staffed by an oncologist, and that oncologist has, of course, a knowledge set about oncology that I don't particularly have. So patients in that clinic get excellent genetic counseling as well as the opportunity to talk to an oncologist about their case and some of the treatment things that have happened. So that works out very well. So this, of course, is a bit of a stretch for us to get to breast cancer. And this is a case we actually saw yesterday, so this was prepared at the last moment. I certainly hope we have the right slides here to go through it, but we'll see. So here is the story as it was presented to us before the clinic visit. A 51-year-old woman who was actually seen by a local cancer genetics group, not actually our group here, but another local group in town, because of a personal history and a family history of cancer. And that personal history included breast cancer at age 51 with a malignant phyllodes tumor, which had sarcomatous stromal overgrowth features. So I'm not a cancer person, but I know enough to know that that's not a very common breast cancer. And in fact, this is a fairly unusual breast cancer. And offhand, before we saw the patient, I really didn't have any idea about the heritability risks in these particular tumors and whether they were genetically driven or not. So that was something that we were obviously going to look into. Additional history that the outside group collected, and I'll show you a pedigree in just a moment, was that a breast biopsy had been done, several breast biopsies actually starting in her 20s confirming fibroadenomas. And she actually had had surgical excisions of some of these fibroadenomas, including one in the breast at age 45, and actually had been told for most of her life, don't worry, your breasts have fibroadenomas, they're not malignant, you know, don't worry about it, and we'll just keep doing regular breast cancer screening. She also had some other biopsy-proven fibroadenomas, one from her neck, one from her wrist, and one from behind the knee. And then around the age of 50, 51, one of these fibroadenomas, or at least in the region of one of the previous fibroadenomas, it continued to grow, and she had biopsy confirming this tumor, and then ultimately had surgery to remove the tumor. So although she'd been told for years, none of these are cancerous, in her mind, one of these had potentially converted into a cancer. She was also seen by the hereditary cancer folks because of a family history of alleged and reported premenopausal breast cancer. So a pretty appropriate cancer referral, at least on the surface. So here's our patient, age 51, breast cancer, multiple fibroadenomas, and I'll draw your attention to the other information that was present in the family. There was breast cancer that was premenopausal, this says in her 30s or 40s, felt to be premenopausal breast cancer. Another breast cancer over here, Nonschodchian's lymphoma in her father. So there was certainly some breast cancer here. There was also breast fibroadenomas present in her sister as well. So this, on the surface, looks like a fairly straightforward hereditary cancer case with an early breast cancer, complicated a little bit by this unusual histology on her breast cancer. But the plot thickens, and I'll show you how it thickens as we move forward here. So genetic testing was done using a standard, I guess standard these days in the world of cancer genetics, 23-gene cancer panel, and it was essentially negative other than a variant in the neurofibromatosis type 1 gene where there was a variant of uncertain significance listed here for you. This variant was present in the exact databases. The clinical, ClinVar listed this in their database as having uncertain significance. And it was predicted to be pathogenic by two in silico programs and benign by one other. But it was classified by that laboratory as a variant of uncertain significance. The group provided negative results to the patient and then asked the patient about any skin findings just to kind of close the loop, I suppose, on this NF variant. And the patient reported a couple things that were of interest. She reported inguinal and axillary freckling. She reported she had dark macules on her skin. And she reported her son had some macules and her son also had an optic glioma. And all these things should clue you into the idea potentially of this could be neurofibromatosis, making us wonder whether this VUS is really a VUS or not. If we go back to her family history, I'll also note that here's her son who was noted in their family history as having an optic glioma. So the cancer team had answered or at least tried to answer the cancer question, had not come up with a hereditary cancer variant that was clear for her unusual neoplasm, but was now posed with asking the question of, well, could this be a case of neurofibromatosis based on the history she's reporting about her skin and her son's skin? And could that neurofibromatosis variant be real? And could it be telling us that the tumor she had, the breast cancer, is somewhat driven by NF and not your typical BRCA1 or BRCA2 genes? So this was an interesting case for us. And we'll tell you what happened next when we saw the patient just yesterday. So she provided some permission for us to take some pictures. So we were all keyed up and turned on, ready to diagnose neurofibromatosis. But histories are only as good as you think they are. And they do evolve. And they do change. So we confirmed her history of breast cancer. We then talked to her for a bit about these fibroadenomas. And she actually had been biopsied at least six times, had been told she had multiple fibroadenomas in her breasts as well as on other parts of her body, and really knew that she had fibroadenomas from a fairly young age. Her skin history, when we asked targeted NF questions, and it turns out that we have genetic counselors who see a lot of NF, was actually underwhelming. We thought it was going to be crisp and clean. But it wasn't. So she did not have a clear history of capillary macules. And her freckling history was not compelling. It was fairly warm and dendry yesterday. So she was wearing a sundress. And so we actually could see, you know, two-thirds of her skin exposed anyway during the interview portion of our visit. And she certainly didn't look like someone with NF just sitting there. When we had her changed into a gown, got our Woods lamp out and looked at her, she did not have clear capillary macules. She reported some pigmentary changes that you may be able to appreciate here on her ankle, her foot's down here. This is the upper part of her calf. But this was not really a capillary macule. It certainly didn't appear to be one under a Woods lamp. Here was a hyperpigmented lesion that was small, not really meeting the size criteria, and not really looking like a calf ALA under our exam. She had some lumps and bumps, but those were hard and firm. There's one that's outlined right here. Didn't really feel like a neurofibroma. And she was pretty convinced it was another one of her fibroadenomas. So really, a physical exam that was not going the direction we thought it was going to be. And we put on our thinking cap because we knew we were going to have to think a little bit here. When we talked to her about her family history, it turns out her son has a spot on his optic nerve that is not a cancer, and it's just affecting his vision a little bit. And she would not endorse that this was actually an optic glioma. And it just affects his vision. She then told us her sister had fibroadenomas, and another sister had a daughter who has a pituitary problem, possibly a pituitary tumor. And when we pressed her on her grandmother's history, and let me go back to our family history here. When we press her on her grandmother's history here, the premenopausal breast cancer, her thought was, well, this happened a long time ago. And back then, they just took off the breasts if there were lumps and bumps there. And she's not even sure and could not confirm that cancer was found. And she actually said, we asked her, could it be possible that this was for fibrofolliculomas or, excuse me, for fibroadenomas. She said, yeah, it probably could have been, because I don't know if it was ever confirmed to be cancer. And this is not to say at all that the family history that our cancer colleagues took was inaccurate. They took a fairly standard cancer history, and this is probably what she told them. Our suspicion is a little bit that she probably had a little bit more time to think about her family history, asked a few more questions of her mother, and got some more information, and was a little bit more prepared to give that second family history when we saw her, and we got some different information. I won't claim the patient was a meticulous historian and had all of this documented, but she had clearly done some thinking about this. And we think that some of this evolution, if you will, of her family history was just that we were asking those questions again. And as we were now a bit more confused about, well, this isn't clearly cancer, not clearly NF, we started to ask some more pointed questions. It's also relevant to notice the fibroadenomas in the sister and this pituitary problem, which sounded like a tumor, but it was a little unclear if that was a tumor. And that's relevant, because as we concluded our thought on this case, this is where we were yesterday late morning, I guess. We weren't convinced this was a hereditary cancer syndrome, because the family history of true cancer became less impressive, and we knew that the current gene testing panel was negative. So we didn't have a good explanation for why she had her unusual breast cancer at the age of about 50. We were walking pretty far away from neurofibromatosis. Her exam wasn't compelling. Her history wasn't compelling. Her son's lesion, we don't know what to make of that. We're going to have her ophthalmologist share records with us. We're going to go ahead and do ophthalmology on the patient anyway, just because of this possibility that her son, who we have not evaluated, does have a true optical illness and does have true capillaries. But I suspect that her ophthalmology exam for Lisch nodules and other neurofibromatosis findings will probably be normal. We started a discussion about her cancer. So these tumors tend to not spread as I understand them. The recommendation is she might need chemotherapy, excuse me, might need radiotherapy, not chemotherapy. Obviously, if she has true neurofibromatosis, we might have some concerns about applying radiotherapy to some individual who presumably is radiation sensitive at baseline because of NF. However, if this is not the correct diagnosis, then of course radiation could be recommended with the standard risks. As we looked at these multiple fibroadenomas in multiple relatives, at least the patient, at least her sister, maybe also the grandmother perhaps, and this pituitary problem in the niece, we started to wonder if we were looking at a prolactin receptor gene mutation. This is a disorder that is quite rare. It's been described only in the last several years. And these individuals who have mutations in this receptor gene can sometimes have hyperprolactinemia, not typically associated with pituitary adenomas. So we have to find out whether the relative has just hyperprolactin levels or actually has a pituitary adenoma. And it's associated with multiple fibroadenomas, typically of the breast, but elsewhere also. There are some other considerations as well that seem less likely at the time. So I will tell you what our plan is, and then we'll see if there are any questions because we have about 12 minutes left. So our plan as of yesterday was to get some records on the son to find out whether he has signs of neurofibromatosis. And we're actually exploring whether or not we'll proceed ahead with testing this patient. If we can confirm that this is the cause of her fibroadenomas and there's really no concern for NF, then I think that will allow her to explore whether or not she should receive radiation therapy or not for her breast cancer. We might also then be able to diagnose other people in the family and let them know whether they're at risk for fibroadenomas or potentially for cancers. It's going to be hard to figure out whether that grandmother really had a premenopausal breast cancer at age 30 or just had fibroadenomas and had mastectomy surgery for that. So that will probably remain an open question for this family. OK. So that actually gets us through on schedule almost with approximately 10 minutes left. I saw that a few of you made comments earlier that the sound was out, but that has been resolved. If there are those of you that would like to ask any questions now, we're happy to field some of those. If you don't have any questions, that's absolutely fine. I'll let you know that there is a recording of this seminar that can be viewed online by going to this website in a couple of weeks. And please, if you are asked to do an evaluation of this, if you could do the evaluation at the end of the webcast, I'd be appreciated. So we have a question here coming at this point. And the question is a good one. This is referring to case four. What if the son's clinical presentation suggests NF1? So that's a great question. And we sidestepped that one yesterday. She was describing the dark patches on his skin and wasn't doing a job, a very good job of them, in terms of describing them as capillary macules. So it sounds like he might be a somewhat freckly guy. But we're going to ask her to send some pictures of his skin findings. He's an adult. I don't think he lives in Denver, but we're certainly willing to see him or have him be seen. And I'm going to be very curious as to whether or not he has an optic glioma, perhaps one that was detected after it had stopped growing and they decided not to enucleate his eye. We'd be also curious if he has other findings of NF. Hard to know. And oftentimes, the person you want to see is not the person that's in the room in front of you. So if it turns out that he has NF, we will have to tackle that when we come up with that. In spite of that, even if he had confirmed neurofibromatosis, based on our exam yesterday of the patient, she did not have any other criteria. So she would still fall short of being diagnosed with NF even if he had a confirmed case. But that would certainly complicate the case a little bit and make us a little bit less comfortable moving on. And we might have to contemplate the possibility of somatic mosaicism in the mother, I suppose. So great question. Perhaps if we do another webinar next year, we might get to that point and give you folks follow-up. Question from the same person about penetrance. I'm guessing you're talking about penetrance of NF1, perhaps, if we're still referring to case four. So penetrance in NF is believed to be quite high. Obviously, mosaic cases complicate that a little bit. This son is now an adult, and so we would expect, if he inherited a typical NF1 mutation, that he would clearly be showing signs of it by now. Again, if he does have signs and symptoms of NF that are causing us to pause more and shift again in this particular case that has had already a couple twists and turns, we'll have to decide if there are other experts that we'll reach out to in NF to perhaps weigh in on that. So a good question. Again, this was a case that we just saw yesterday. It's not fully resolved. But we were certainly looking long and hard for NF yesterday, both in the history and on the exam. And I have to tell you, it was pretty underwhelming yesterday. But again, we'll see whether anything comes up to shift this down the road. Let me see if there are any other questions. Someone's asking about any linkage needs to be done for this family. Could be two different but linked involved genes potentially in this family. I don't know, I think if this is still a family of four, I don't know that we have enough individuals living and available to perform linkage. I suppose it's something that could be done. At the moment, I guess the question would be, what would we be linking it to? Given that from a cancer standpoint, we certainly have done a fairly, or the cancer clinic did a fairly comprehensive assessment of what known cancer genes are out there. We're a little underwhelmed as to whether this is a hereditary cancer family at this point. Doing a little bit of research into the malignant phalloides tumor that she had, I didn't find very much about linking that to particular germline mutations. So we're going to focus on her fibroadenomas and this question of NF as we move forward. We'll potentially send the patient back to the hereditary cancer clinic if we get more cancer history that may be relevant for them. Case four, someone is asking who or what decides whether we move from panel-based to exome-based sequencing. I think at the moment, for this particular case, from a cancer standpoint, as I mentioned, we were a little underwhelmed as to whether or not this would be worth pursuing further from a cancer standpoint because we had essentially one postmenopausal typical age onset breast cancer, one alleged premature premenopausal breast cancer, which on further questioning sounded like the certainty it was cancer was much, much less than originally thought, and then the patient's unusual cancer tumor history. So I don't know offhand whether there's value there in expanding beyond a cancer gene panel. In terms of the rest of her phenotype approach, our set point yesterday was thinking that this fibroadenoma familial syndrome might be explaining her presentation, and there is testing for that, and we will genotype her for that specifically. Assuming we can comfortably exclude neurofibromatosis, I don't think we're going to go any further with that. Obviously, if her phenotype or the family phenotype remains unclear or controversial or uncertain, we'll have to explore whether or not we want to go bigger and broader. So far, we've mostly done exome sequencing in those intellectual disability complex genetic cases where we haven't had a diagnosis in mind. Excuse me. So when we have one or two things on our differential, so far, our practice has been to pursue those, check those boxes off first, and then if we're still left with nothing, decide whether exome would be helpful or not, and I just can't answer yet whether we'll get there in this case or not, but certainly a good question. All right, I think that was our last question. I'll remain online for another four minutes in case others have questions. Thank you again for participating. This is obviously a fairly new enterprise we have. Please provide us feedback because we certainly value your feedback, and thanks for participating.

ACMG Genomics Case Conference

University of Colorado

hypertrophic cardiomyopathy

TNNI3 gene

long QT syndrome

CPVT gene

chromosome 2 deletion

microarray testing

neurofibromatosis type 1 gene