All right, so we'll go ahead and get started. Our first presenter is Lisa De La Fede Castillo from Northwestern University, and she's going to be starting us off about the title of our session, which is What's New in Postmortem Testing. Okay, well thank you for asking me to speak at this session today. So yes, we are going to dive right in. For those of you who don't know what post-mortem genetic testing is, it's essentially genetic testing of somebody who has died. Recognizing that there's maybe only one pathologist in the room, why do you guys care? So for those of you who are cardiologists, there's always a chance you're going to get that frantic call from hopefully not a family member, but a patient, a neighbor, whoever saying somebody died suddenly and what do I do? So that's why this is important, because this really is real-time information that you can use for your patients and their family members. So I'm going to do who, what, when, where, why, and how of post-mortem genetics. So really a specimen should be saved on anyone who dies under the age of 40, 40 or younger who died suddenly or unexpectedly. So there are national guidelines out from the National Association of Medical Examiners published in 2013 that shows certain circumstances that are suspicious for an underlying genetic etiology. The ones that you guys in the room are going to be most familiar with are people who have cardiomyopathy, aortic dissections, but the ones that are more kind of, I think, more to highlight would be people who drowned, experienced swimmers on a sunny, nice day, really no reason why they should have drowned, that could have been a cardiac event. Same thing with a single motor vehicle accident, they were the driver, sunny, nice day, it wasn't rainy, foggy, snowy, and the car crashed, so was at a cardiac event too. Somebody who had an unexplained seizure and a young person, if there was an unexplained death, and then you do the family history, and they have a family history of an inherited heart disease, cardiomyopathy running in the family. And then really all deaths that are sudden, unexplained, where there's no clear cause of autopsy. Certain triggers that you guys are probably most familiar with being EPs, exercise, emotional stress, acoustic stimuli that go with Long QT, CPVT, Brugada, and really the main thing is to have a really low threshold for saving an appropriate sample. I like this from the guidelines, the foresight to save a sample at autopsy can greatly assist with subsequent genetic testing, which is so true. These are other particular conditions that could actually lead to sudden, unexpected death. We have obvious ones, like we just talked about, cardiomyopathies, aneurysms, but inborn errors of metabolism can also lead to sudden death, chromosomal disorders, thrombophilias, familial hypercholesterolemia, that would obviously, a lot of these would be seen on autopsy, but then you've got the autopsy negative ones, again, are really important for those arrhythmic conditions, sudden, unexplained death in epilepsy, and then sudden, unexplained infant death and death in childhood. So how to do postmortem genetic testing, the most, most, most, most important thing is to save a sample, because the majority of the time, it's not. So purple top EDTA tubes, per my cute little picture here, is the most appropriate, best way to get DNA out of anything. There are some companies now that are taking blood spots. Medical examiners, coroners, they will sometimes save blood spots in people, because it's really easy to save in a file cabinet. One of the things that can sometimes be tough is some labs only take a particular type of filter paper, and the ME might not be using that particular type of filter paper, so sometimes that's come in to be a problem. Newborn screening, also, some states actually save those blood spots for a really long time, and you can go back to a newborn screening office and try and get blood spots from them. Again, filter paper dependent. So a lot of people think, well, we save tissue, this is great. Yes and no. Some labs will or won't extract DNA from tissue. Fresh frozen is the best, or fresh tissue is the best. Filtered fibroblasts, formalin-fixed paraffin is really, really difficult, and of course that's what everybody loves to save, because it can be saved for a long time. There's one lab that is dabbling in this now, we'll see kind of how that data comes out, but there might be finally some hope in that situation. So the main problem is appropriate samples are still not being saved in all jurisdictions on a routine basis in people where it should be saved on. So we are constantly trying to get the word out and have people save samples. So why do post-mortem genetic testing? I mean, the person died, why does it matter? Well, first of all, you really want to try and establish a diagnosis for that decedent, A, to give closure to the family, but then also, even if there is a diagnosis, and in those autopsy negative cases, you can really help to assess risk for at-risk family members and really clarify their risk. So it becomes quite important for those who are still living. So where does it take place? Typically samples are taken at the ME coroner office. Sometimes we can get it through a funeral home, although that's pretty darn difficult. And sometimes if a patient had an arrest, made it to the hospital and they drew blood, I've been able to get blood from a refrigerator at the hospital and try and use that for post-mortem testing. So it's kind of ways to get pretty creative on how to get samples from the decedent. It's typically coordinated by either the ME or coroner. Sometimes a family cardiologist will coordinate it, or EP, and then sometimes, and kind of most often, a genetics professional will actually do it. I listed down here a website for all of our cardiovascular genetic counselors for their locations, so people can have to contact us. So the actual testing takes place at genetic testing labs. There are lots throughout the country, and typically you pick the one that has a panel for the disease that you're trying to test for. It's really company dependent on what the panels look like, and we'll talk more about that, and some of my, some of the other speakers will talk more about that too. Typically it's based on the decedent's autopsy history, their own medical history, family history, all of that kind of comes together to figure out what we're testing for. So when you're working with an ME or coroner, the main thing is the second that somebody tells you, hey, can we do genetics, you got to call the coroner or ME. You got to let them know, hey, I want to save a sample. Ideally that's before the autopsy happens, so they can actually draw the blood. If you don't get to them before the autopsy happens, then on the back end it's really important to call, even when the autopsy's in progress, and say, hey, look, I know we don't know the results yet, but I want to save a sample. Can you put a little flag on the tube so that that doesn't get tossed? You want a big, huge sticker on that saying, please save. So you usually need to wait until the autopsy's actually signed out for them to release any samples unless they're the ones doing, like coordinating the testing. Usually like a written release is required, something like that, every now and then a court order, but typically not. And if for some reason we can't do genetic testing, try and bank DNA, at least for the family. Now that's, we're in a weird situation where that's a little bit difficult recently, but hopefully that will turn a corner and we can go back to routinely DNA banking on people for family members. So I'm going to quick review kind of some different genetic testing options. More of the people on the panel are going to talk more about this, but there's a few options. Panel-based testing is typically where you've got multiple genes that are pre-selected for a certain disease, and so when you're figuring out what disease you're trying to test for, you'd pick a whole panel that have been already curated. And for instance, if it's a sudden cardiac arrest, we'd be looking at a broad cardiomyopathy arrhythmia panel is usually the best. I try and go the biggest and the broadest because you might just get one shot at it and you want as many genes as you possibly can. Ideally, if you do genetic testing and there's a way to bank that DNA, you try and get the DNA back and save it so that if it comes back negative, you can maybe try again in another however many years. If it was an aortic dissection, you pick like an aortopathy panel. So depending on the diseases you're looking at or the type of panel that you're going to pick, turnaround times typically a few weeks, and just kind of an asterisk if there's any concern for mitochondrial, that's usually a separate test, so you want to kind of ask specifically for that. Exome testing is kind of another tier of testing. That's when you're testing about one to 2% of the entire genome. A medical exome is about 4,000 genes. The main thing is in an exome, you need to actually supply the medical history so that they can pull the genes that they're most interested in for that disease. So without a medical history, it becomes quite difficult to interpret an exome. Sometimes we can do trio exomes. If you've got a young child who's passed, do the two parents. That's kind of more for recessive diseases. Most cardiac indications are dominant, so it may or may not help as much, but turnaround time is definitely getting faster for exomes as well. And then whole genome, you know, you're looking at 3 billion bases that you get back, so you really need to supply medical information because you're not going to get an analysis on 3 billion bases. So medical history is the most important to be able to interpret a genome. Most, you know, some people say, well, you get everything. You're going to find new stuff. Typically, in a clinical genome, you're not going to actually be able to get a new gene back as a positive because it's just they're trying to figure it out, and so nothing's going to be called a positive in that case, so you're kind of still going to get the genes that are already out there, already known, back as positive results. Cost. So this is rapidly evolving, even in the last few months is painful. Panel-based testing is typically more cost efficient, and it usually doesn't matter if you do a huge panel versus a small panel, kind of cost is the same, which is why I always like to go big. Again, there's sometimes self-pay pricing, sometimes you can use insurance, but typically not for decedents. It becomes extremely difficult because a decedent doesn't have insurance. More expensive are exomes and genomes. Those are starting to come down, even in self-pay pricing, and so we've had like a handful of cases where insurance says, yes, I think we will cover because your plan covers the kids, and so the kids are at risk, and they actually think about that. It would be nice if more companies actually thought about that, but typically insurance, we're not going to get to cover for decedents. Barriers, I think I kind of already covered. Really need to make sure that samples are covered, medical history, and then communication to family members about the actual results is the most important thing. Actually communicate those results, and getting the appropriate sample is so valuable. The most important update is, I said in 2013, the National Association of Medical Examiners published the position paper, myself, Heather McLeod, Dr. Lisa Gavin are on a new update for these guidelines that are coming out in probably the fall, hopefully, so that will be super exciting, and then I want to do one quick plug for if you want to learn more about cardiovascular genetic testing, myself at Northwestern University and a couple other people at Northwestern paired up with Jackson Labs, and we created three different educational modules for how to interpret genetic testing in general, red flags for hereditary cardiovascular disease, interpreting positive results, interpreting negative and variants of uncertain significant results. It is CME approved, CNE approved, it's free, it's online, so if you want to learn more, there you have it, and then we also have a cardiogenomics database, and I am done. This is our group of fantastic people at Northwestern, cardiovascular genetics, all trying to do all types of cardiac disease. Thank you, Lisa. I'd like to welcome the second expert, Lisa, to our panel. Dr. Lisa Gavin is a medical examiner at the Clark County Office of the Coroner and Medical Examiner in Las Vegas. She's going to speak to us about post-mortem genetic testing and how it's implemented on autopsy. Thank you. Thank you. Give it a minute to get its display going. Hope you're all hydrating after your partying last night. I was napping. I'm one of those early to bed people. I'm Dr. Lisa Gavin. I'm from the Clark County Office of the Coroner and Medical Examiner in Las Vegas. I have no financial disclosures. Just some general statistics about Clark County from 2024. We have roughly about 2.5 million people in our population estimated, but we have roughly about 45 million visitors that come in per year, viva Las Vegas. In 2024, we had approximately 21,691 deaths. Amongst those, our office was contacted for roughly about 8,700 of those deaths. Amongst those, about 6,000 of them required a death investigation as to determination of whether or not it was our jurisdiction and likewise whether or not we needed to bring an individual in for an examination. It was determined that we brought in roughly a little under 4,000 cases for examination. Of those cases that were brought in, about 147 were children under the age of 18, and of those, about 51 were infants under the age of one year. In the beginning, we were one of the few offices that was doing post-mortem genetic testing in the country. We did ours in the beginning under the SUTI and SDY grant. Within that grant, we could only have cases that the cause of death and manner of death were unknown that we could give to be tested in those cases. Likewise, once a person was identified as being eligible for the testing within the grant, we had to talk to the legal next of kin, which was generally the parents, to be able to request genetic testing. And the only panel we were doing at that time was the cardiomyopathy or the cardiac arrhythmia panel. There were a lot of limitations within the early days, particularly institutional support regarding utilizing post-mortem genetic testing as a tool, a diagnostic tool, in order to determine the cause of death and manner of death in these sudden and unexpected deaths. Likewise, storage was an issue. In our office, we didn't even have a refrigerator, never mind a freezer, to be able to hold samples in, and that became a major issue in terms of how we were going to be able to afford a refrigerator to be able to put into the office at that time. We were able to get a refrigerator, but then the freezer didn't occur until institutional support shifted its culture. And more recently, now we have a freezer, a negative 80 freezer, that we can actually utilize to retain our samples. So within the 2016 to 2018, there were roughly less than a dozen cases that were on which post-mortem genetic testing was performed that were outside of the SUTI-SDY grant. So now post-mortem genetic testing is being more utilized as a diagnostic tool within our determination of the cause of death and manner of death for our decedents that are applicable within the criteria that we were just speaking about, that Lisa was speaking about previously. And because we're utilizing it as a diagnostic tool within our determination of the cause of death and manner of death, now we're able to do that without necessarily getting permission from the families to be able to do that testing, and it becomes part of our repertoire in terms of our determinations. So because of that and all of those changes that I've mentioned, it's really expanded in terms of the amount of testing that's being done and its utilization within Clark County, so within our office. So as you can see from the bottom up on this particular chart, from 2017 to 2024, there's been an increase in the number of cases on which post-mortem genetic testing was requested. And then amongst those cases, you can see, obviously, we've identified more genes. And that's not necessarily a one-to-one, so to speak. That doesn't mean that of those 69 cases tested last year, that 46 of them had genes identified. It could be that multiple genes were identified within one case. It's just the number of how many genes that we identified overall amongst all of the samples tested. With that information, what do you do? So there's been a big issue with, one, can we get offices to maintain a purple top tube? Great, now we have a purple top tube. Do they even have a place to put it within their office so that it doesn't denature and you'll never get DNA off it? Okay, now we've got a place to put it and we've got a tube. Where are we going to order? And so then how are we going to send off to get that order for post-mortem genetic testing? And what do we order? So now we have more offices that are starting to put out the purple top tube, get an order. But now what the heck do they do with the information that they receive back? And how do they utilize that information? Our office, having done this for almost nearly a decade, has a lot more familiarity in terms of what to utilize that information to do. And some of those cases, but not a large percentage of them, we've used some of that genetic information within death certification. And you could see that represented in the last column here in this particular figure. So obviously the utilization of post-mortem genetic testing in our office has increased substantially over the past decade, roughly about the past decade since we began this process. But how do we do that? What goes into a medical legal death investigation? How do we make the determination of the cause of death, a manner of death, and other contributing conditions that might be related to that individual's demise? Well, it requires a medical legal death investigation. What happened to that individual? What are the circumstances surrounding that death? And in that, we'll need to know things like clinical history or family history, if it's available, and medical records, if they're available to read through and find out some information about that particular decedent. Of course, you go into the autopsy findings and what you're identifying grossly on your examination. And microscopic and histological evaluation may be necessary and is often necessary for these particular types of cases. Ancillary studies are key, and that would be microbiology, toxicology, and now we've incorporated the post-mortem genetic testing into that repertoire for diagnosis. Here's a case example for you of one case in which a post-mortem genetic testing became also cooperative of what the findings were and became part of the cause of death in this particular individual. This is a 12-year-old male. He was last seen alive by his grandfather when he was sitting in his recliner. He had on his headphones and he had on his VR headset, and this was actually his usual sitting spot and likewise his usual sleeping spot, so often the family would have him falling asleep in this particular recliner with his headsets on. In the morning, his mom went to wake him up to go to school, but he was unresponsive. She took off the headphones, she took off the VR set, and he was still unresponsive. She had the grandfather call 911, and she began CPR efforts. However, he was beyond resuscitation. Some recent history, the family had gone to a Golden Knights game, and their transportation service had dropped them off at a nearby hotel on the strip, and consequently, they had to traverse a distance to be able to get to the venue. During that process, they noted that he was lagging behind and wasn't able to keep up with everyone. The family also reported that several of the family members had been feeling congested, they had low-grade fevers, and they were having coughs. They did the viral COVID tests and they were negative at the time, but he reported no symptoms at all. The family said that he was not known to use alcohol, drugs, he didn't use tobacco, vaping, he didn't get into anybody's medications, and then likewise, he had no prescription medications himself. For some history, he was born to a G3P2 mother at 36.1 weeks gestation, and his mom had had preeclampsia during her pregnancy. His newborn screening test results were considered negative normal within normal limits. He had regular pediatric visits within which he had some minor childhood illnesses, and he had no ongoing diagnoses. At autopsy, he was slightly overweight, he was approximately 66 inches in length and approximately 195 pounds, and he had a markedly enlarged heart. For those of you who are not used to seeing kind of gross and histological images, I'm gonna show a couple of them right now, just fair warning to that regard. This is a cross-section of his heart. If you look in this kind of upper left corner as you're looking at the screen, you could see this dark brown-red appearance of the myocardium. The myocardium should be entirely that color throughout, and instead, you can notice that the myocardium is very pale in appearance. Likewise, when you look at the left ventricle, which is on the right side of your screen, you could see that it's extremely thickened. In particular, the septum is quite thickened as well, and portions of the septum are bulging out towards you, which is often seen in sudden cardiac death type findings. Additionally, when you look into the left ventricle, you could see kind of this normal papillary muscle formation. However, when you look towards the anterior portion of the cross-section, you can see that there's some finger-like undulations that have occurred in this area. As you look closer into these finger-like undulations, they're not having that normal compaction or normal formation that you would expect to see within an individual who has a normal papillary muscle development. If you take that same section and you kind of flip it upside down, and look at it histologically, you could see again that your loss of the undulations that you would normally expect along that endocardium, particularly with that papillary muscle formation. And then within that, you could see areas of increased fibrosis throughout this particular specimen. As you get closer, you can notice even at this low power that you could see myocyte hypertrophy scattered throughout, and you can see these prominent nuclei associated with those hypertrophied myocytes. And notice that there's not a normal streaming that you would expect to see of the myocardium in this type of cross-section. Instead, you could see a mishmash of directionality for this particular section. Within areas of the heart and the histology, you could see areas of hyper-eosinophilia, which demonstrates that you have early coagulation occurring for those myocytes. They're starting to die. And again, you could see areas of the increased perivascular fibrosis and the myocyte hypertrophy scattered throughout as well along the histological specimen. Here, as you look into another area, you expect to see this kind of nice flow of myocytes throughout, and instead you have these areas of myocyte disarray where they kind of have these V-shaped and Y-shaped areas, which are another signal there's poor compaction and poor formation. Up in this upper corner here, you can see a little bit of the scarring. And in fact, I didn't show a slide of this, but scattered throughout the entire specimen were areas of microinfarction and scarring throughout, demonstrating that he had had other infarctions occur throughout his young lifetime. Of course, other studies were performed and no other histopathological abnormalities were identified within his other tissue. His hemoglobin A1c was with normal. The cultures were non-contributory, and only caffeine was identified on his toxicology. And of course, we get into the post-mortem genetic testing. In this particular case, two heterozygous pathogenic variants were identified within his genetic testing, one of which was associated with the left ventricular non-compaction, and the other was hypertrophic cardiomyopathy, dilated cardiomyopathy. And then the other heterozygous pathogenic gene was a familial hemophagocytic lymphohistiocytosis. There was no evidence of that within the family history and no evidence of that within this particular case. So the death was certified as complications of left ventricular non-compaction cardiomyopathy with a contributing condition of the gene, which was put onto the death certificate, and the manner of death was considered to be natural. Documentation of post-mortem genetic testing results within certification may overall improve death surveillance. It may ensure that we've acquired any additional epidemiological data, and then allow for understanding of mortality patterns across not just areas, but of course the entire United States as well, to document that obviously appropriately and when you have the representation of that, either within the clinical history or within what's been documented at the time of autopsy. All right, thank you very much. I appreciate your attention. Thank you so much. Excuse me, thank you so much, Dr. Gavin. Our next speaker is Rebecca McClellan from Johns Hopkins University, and she's going to be giving us the nuts and bolts of how genetic testing in the post-mortem setting can be implemented in the clinical setting. Well, thank you for the invitation to be here today, and my goal today is to give you really a clinical perspective of how this is incorporated. Dr. Gavin just gave us a lovely presentation sort of from the medical examiner's side in, and so I hope I can share some insights. We've already touched on a lot of this, but, you know, just to kind of briefly review, you know, why we're doing the genetic testing in the post-mortem setting, and always drawing attention to the fact that this does not have 100 percent yield by any means, and that's an important thing, especially when you're setting expectations from a clinical perspective. There are lots of guidelines that tell us we should be doing this, lots of them now, that are outlining it. We have guidelines that are kind of outlining flow from the Lancet Commission, but, you know, there's not a ton that tells us sort of how we actually make that happen, and that's what I'm going to kind of share you with some insights about that. So we've also touched on this briefly already as well, sort of when, and again, usually some of the guidelines say under 50. Many of us will say especially under 40, you know, drawing a little bit of attention down to the, I know we already talked about the unusual situations, but this idea of SUDEP, unexplained seizures, always brings up that sort of chicken and egg situation. Is the arrhythmia causing the seizure? Is the seizure causing the arrhythmia? So in a post-mortem genetic testing setting, if there is sort of a question of that at all, we try to make sure we include the SUDEP genes as well if we can. So really a clinical approach to genetic testing, the referrals are going to come varied just depending on your setting. Sometimes they're going to come from families. Many times they're going to come from outside community, cardiologists. Occasionally, for me, sadly not enough. They come from the medical examiners. In our personal experience, it's often going the other direction where we're hearing from others first, and then we are making contact to the medical examiners teams. For us, the visits are going to be either genetic counseling-only visits. Sometimes they'll be paired with a cardiologist visit depending on sort of how the referral in the family is coming into that situation. If it's a genetic counseling-only visit, we offer in-person or telehealth based on the family's preference. Again, this was mentioned already, but I think it's really important to emphasize because this is what we do in clinical practice too. If it's a recent death, we try to establish contact right away with the next of kin, get consent from the next of kin, and then make contact to the medical examiner's office to let them know we're working with this family. Please hold these samples. Don't get rid of anything. You know, we'll be in touch to figure out and make arrangements. Every state has its own priority list for next of kin, but they generally are going to be spouse-first children to parents, then siblings, unless there's someone legally designated. We try our best, if possible, and again, many of this depends on the timing, to gather and review the autopsy ahead of time. That obviously implies that we're walking into this case down the road a little bit, which can be problematic in its own right, but we have had some cases where the autopsy is actually actively pending as well, so then we don't have that as a resource to guide our side of the decisions. So, our first visit with the family, it really starts out with gathering information as much as we can, really detailed family history. You know, I spend some careful time, if the family's comfortable, talking through the death, what occurred, both for looking for clues and information that might help us, but also giving them an outlet to share that information, to talk with us about their deceased, to identify people who may be at risk for things like prolonged grief, who were the people to find this person, what family member might have performed CPR on this person. These are all triggers that, you know, we should be keeping in our minds as well as clinicians working with these families. We're then going to be formulating our sort of genetic testing recommendations. Sometimes that is going to be postmortem testing. Honestly, if I have an affected family member that gets identified through my visit with them, I'm going to start there because genetic testing on a postmortem sample, limited resource. If you've got a similarly affected individual in the family, you start there and work backwards, right, to preserve as much of that sample as you possibly can. Again, big part of this is setting expectations, especially making sure the family has an understanding of yield. Often, as Lisa outlined nicely, we're doing many times combined cardiac panels plus minus the SUDEP genes. Some situations we're doing exome or genome sequencing. That's not as easy from a financial standpoint for many families and so, but maybe it'll become hopefully more feasible down the road. We go through the process of the postmortem genetic testing with the family, talking through the steps, giving them an understanding of what's going to happen, how that sample is going to be retrieved and used and handled, talking through those logistics and costs, unfortunately. And also, we are always trying to bring up and mentioning the importance of DNA banking. In our practice, we actually try to simultaneously DNA bank when we retrieve a sample, if we have that possibility. If we have ample access to sample, usually that's kind of your shot, to have ample access to sample. So, we will get as much as we can. We'll bank some and then send some off for genetic testing. It's kind of our personal approach. And then, at that same visit, we're ensuring appropriate cardiac referrals and evaluations going through sort of recommended guidelines for family members that many people, sadly, have not been informed about, providing family letters to help raise awareness among relatives who should be going for screening in that type of situation. And then, on top of all of this, if that wasn't a lot to begin with, emotional support, grief resources, sharing with them about SADS is often a part of my initial conversation, if and when they're ready to kind of connect to other family members. I'll even sometimes offer one-to-one connections if that feels more comfortable for them at the beginning of this process. And so, it's really trying to meet them where they are and what they need. So, what's next after that first visit with the family is we're sort of taking it all in and sort of synthesizing it. We're assessing what available sample is out there and making a decision about what laboratory we're going to use and have the ability to use, based on the different sample requirements, what we have and what we would like to order. At that point, we're retrieving a sample for us at Johns Hopkins that is offered me, cooler in hand, driving across town to the medical examiner's office with a cooler full of dry ice and bringing it back. That's not every clinic, but that's what happens and needs to happen for us. And so, that's what we do. At that point, if DNA banking is available based on sort of sample location and finances, we'll try to make sure we do that. Again, this has already been mentioned that there are some challenges with this right now here in the U.S. There's very limited clinical options. And so, unless you have an internal option at your hospital, really there's basically a lab in Wisconsin that can offer DNA banking right now. And if you happen to live in any one of these states, which I do, they cannot accept samples from you. So, big challenge, hoping it will be resolved, but we don't have a great plan for this yet. So, right now, they're being banked for us under a research protocol at Johns Hopkins and they're being banked internally, but we don't consider that a long-term solution. Throughout this whole thing, communication with the family, I think, is key. I do try to, at that initial visit, try to set what level of communication they prefer. I have some families who want to hear every single step. You've got the sample. It's home. It's back at Hopkins. I've shipped that sample out. And then I have other families who very much don't. They want to just hear when the results are back. So, I try to figure out where they are and, again, how much oversight and information they want. And then, once those results are back, we'll do a post-test genetic counseling session and then arrange for follow-up as appropriate based on the results. So, what are the challenges? And, again, I think you've already heard some of these, but, clinically, they are the big challenges, too. Access to and retention of appropriate samples, especially for old cases. There are different regulations for every state, which I tell you is just maddening for genetic counselors because we don't always work just within our state. And so, sometimes we have a family member that comes to us who lives in Maryland, but the person that died is in Virginia, right? So, there's different regulations all over the place, and families don't always live all in the same state. In Maryland, sadly, samples are only kept for six months. So, we know that clock is ticking. So, as soon as we hear, we're usually on the phone with the medical examiner's office the next day to say, hey, we're working on touch and base with a family. Please hold these. And then we get kind of the consent and keep moving from there. Sadly, our Hopkins pathology team, we've learned the hard way. If you don't notify them sort of at the time, right, of that death, like they are not able to get samples. We've had a few situations, like Lisa said, you can sometimes dig things out of pathology, but they clear freezers and fridges. You know, I think it's every month or every couple of weeks. And so, timing is really critical here. Most genetic testing, I have not had any success getting insurance to cover post-mortem genetic testing. So, you know, we actually present it as self-pay for families, and there can be very significant variability between labs and self-pay rates. And so, that's another thing that needs to, sadly, sometimes factor into the decision of what you can order and what you can send. I think a challenge also is provider time. Genetic counseling visits are billable under the relative and are covered, but these cases require so much time that is not able to be billed because it can't be done on the same day of the visit. You know, that's changed, you know, now that we can bill sort of anything we did on that day of the visit. But I'm not picking up a sample from an ME's freezer on the day that I saw this patient, right? So, it's just a big challenge, and the DNA banking challenge that we've already talked about. I'd like to close just with a brief case of why this matters, and this is a case that I've been involved with, and I haven't quite figured out who my counterpart is. There's another counselor somewhere out here in California who's seen a piece of this family. So, if it's familiar to any of you, let me know. It starts with a 31-year-old who passed away suddenly in 2019, previously healthy, no medical issues, completely normal autopsy. A couple, no one at that time, sadly, suggested family evaluations or genetic testing evaluations after her death. A couple years later, her father had a cardiac arrest at 66. The only medical history that is known is sort of a recent diagnosis of AFib for him. So, it's the same thing at that time. No one really, at least what I've been told, no one recommended any cardiac evaluations or any genetic testing in the family. What happened is not long after that, father had his arrest, as the partner of this sister here, let me find my little pointer, the partner of this woman suggests like, hey, this is kind of weird that both your sister died suddenly and your father had a cardiac arrest. Maybe you want to find genetic testing or look into this. So, she goes to her primary care doctor and he ordered genetic testing. That genetic testing identified a pathogenic truncation in KCNQ1 and she went on to get cardiac evaluations that did confirm that she has evidence of long QT syndrome. First step, as most of us would do, is probably go back to that father that had the cardiac arrest. He was negative, not what any of us expected, right? So, this is where our team comes into play. Couple months down the road here, summer of 23, this woman, the mother of these two girls, woman presents after her own brother had had a cardiac arrest. Now, he had his own genetic testing out here in California somewhere where they did a big panel, very appropriately, even though he was 69 at the time, but given the family history, he had genetic testing sent as well and was found to have the same KCNQ1 variant. So now, by proxy from the family testing, we know that she has it as well, but for emotional reasons, she presented to our team, not only for cardiac evaluations, but wanted to have her own genetic testing done, and we were able to confirm the presence of the variant. She presented alongside her sister at the time for cardiac evaluations and testing as well, and now a few years into this, this is now where this family stands. Our nuclear family is here in the red box. This woman had seven siblings. Here's the brother who had had his own cardiac arrest at 69. This is a sister that died at 54, suddenly, possibly, in arrhythmia, a little unclear, said there was an enlarged heart on autopsy, which wouldn't really go along with this. She had a history of cervical cancer and chemotherapy treatment a year prior, so a little uncertain if this was part of it or not, but what you can see here is that there are many people in this very extended family that have gone through genetic testing, been found to have the pathogenic variant. You know, what draws my attention with this case every time I present it is that the genetic testing in this family was sadly initiated by a family member, and that just shouldn't happen, right? It just should not happen, and that occurred after another cardiac arrest had occurred, right? Now, ultimately, right, that father, we don't quite know why he had his cardiac arrest, but six years later, about, we've got 11 people and counting who have Long QT syndrome. We still have a couple of loose ends here of people in the family that haven't necessarily been tested or wanted to be tested, and we don't know the exact cause of the cardiac arrest in the father, and honestly, probably the most meaningful diagnosis in this family is I was able to help them retrieve sample from an ME in Michigan, and we were able to confirm that the deceased actually had a positive for the variant as well, so thank you very much. That was fantastic. Thank you so much. I'd like to welcome Heather McLeod. She's coming to us from the Data Coordinating Center for the SUID and SDY case registry, and she's gonna talk about what's next, how post-mortem genetic testing is being implemented in public health. Thank you, Heather. Good morning. Thank you all for coming. I'm so excited to see you here Sunday morning. Let me pull this up. It took mine a minute. Awesome. So I helped put together this session and you have the true champions here of this work. People that are leading the way in making this happen. And I want to give you some information on what's next and from where I sit where we should go. So my objectives are to summarize where and how post-mortem genetic testing is being done. We've already heard from Dr. Gavin and some of our genetic counseling colleagues but there's a couple other medical examiners that are implementing this on a systematic basis. I also want to talk about why it is important to public health and how we can use this information that we're gathering from this testing for future preventative efforts. I typically save this slide for the end but it has been a really rough year to be federally funded. So I want to acknowledge that the work that I do is fully funded by the NIH and the CDC and if I say anything weird it's on me and not a reflection of the federal government. So I work on the sudden unexpected infant death and sudden death in the young case registry. This is a multi-government, multi-state, multi-jurisdiction project trying to better understand the number of cases of sudden unexpected death in children in the United States, understand the causes and risk factors, and use this information to inform strategies to prevent future deaths. So we have both a public health surveillance part of the project so we know in funded jurisdictions what the population is and then we know we get reported all of the deaths. So we have both the numerator and the denominator so that we can give true incidence numbers. This is something that has been missing in the past in this field. We also offer a research component in the states that are funded for component B or SUID and SDY. We're implementing the 2013 name recommendations of collecting biospecimens at autopsy and attempting consent for DNA banking and research. We no longer attempt consent for diagnostic post-mortem genetic testing that is up to the purview of the medical examiner during their investigation. So this is our current map of what it looks like. We're covering 40% of the sudden unexpected infant deaths through our registry work. The sites that are dark blue are the sites that are doing both SUID, the under one cases, and then the cases up to the age of the limit of child death review in this state, typically age 18. So these are the sites that are doing surveillance and collecting biospecimens. There's currently 12 states and or jurisdictions funded to do the registry work. This is what a sudden death looks like just from a more basic perspective and it could even be like the family perspective. The sudden death occurs on the one side. Dr. Gavin's doing the autopsy, collecting samples, running all the ancillary testing. On the family side they're notified. Typically if it's an infant they're with the child but it might be notification of the family. We think all families deserve bereavement support and it's something that we've tried to implement at our sites because nobody saw this coming. These are sudden unexpected deaths. We are working to incorporate collection of family history information. We were all trained to ask a million questions and we have narrowed it down to, is there a family history of sudden death less than 50? If yes, who? Is there a family history of cardiac disease? If yes, who and what? That is what can be captured at the time of the death investigation. You can't do typically a three generation pedigree in a family who's just lost their child. In our sites samples are stored and something we're really trying to do is figure out what was the cause of this death. Becky brought up prolonged grief and I tend to see that more in families that the case remains unexplained. So the current state of postmortem diagnostic genetic testing from where we sit I know it's changing on the clinical side but what our medical examiner offices are reporting it's about $250 to $500 a panel. We ask for the self pay price. There's a number of companies doing this testing and typically the results are available in three to four weeks to the medical examiner. Major barriers still exist to ordering testing, to cost and interpretation as other speakers have shared. We have some basic understanding of the yield of postmortem genetic testing but I will point out these are convenient studies. So these were families that referred a case to a researcher, testing was done. So we estimate 15 to 35 percent of cases have cardiac pathogenic variant, 10 to 20 percent of sudden unexplained death and epilepsy has a genetic component. But know that those are families that figured out how to get their sample to a researcher or a lab. And so in the end those numbers might be lower from a public health surveillance aspect but we can't only look in the same places. We know cardiac causes and epilepsy causes sudden death but there are other things that we should be looking at that we don't yet know. So this is just a brief update on the 211 genomes that have gone through the research process at the Seward and SDY registry. Our original cohort was deeply biased towards infants. The median age was four months. There were more males than females. What's great about the registry is that it is genetically diverse in terms of ancestry. If you look at a lot of the convenience studies they are very biased to the Caucasian population which is not representative of the U.S. population. What we found was a lower yield. Six percent of cases had a pathogenic variant identified, 12 variants. So we did see two variants in one cases and 11 decedents. And we saw a lot of TTR variants so amyloidosis which has a later onset. We'll talk more about that. Something that we thought was very interesting about this work was in the cases under the age of one we saw a greater burden of epilepsy variants and in the cases over one we saw a greater burden of cardiac variants. And I think that's really really important as we implement post-mortem genetic testing. You can't only look at the cardiac causes. So this gives us some framework for ordering post-mortem genetic testing. We want folks to be doing both cardiac and epilepsy. And I want to share where our registry sites are, which ones have implemented this systematically. So this was a collaborative effort with Clark County with Dr. Gavin and Candice Caterer, their office champion. Roy Hoffman at the Philadelphia Medical Examiner's Office. Allison Garbarini at the South Carolina Charleston County Office. And Laura Knight, the medical examiner in Reno, Nevada. I'm just going to give you a chart of kind of what folks are doing right now. Most of these offices are doing panel-based testing. Dr. Gavin's team has gotten very expert and so they are deciding the panel based on what they find at autopsy and the circumstances. Many are doing testing just a cardiac panel with the 10 SUDEP genes added on. Charleston County has moved to doing a full cardiac panel and an epilepsy panel, a full epilepsy panel. And of course they've already gotten a hit on one of the epilepsy genes that's not in the 10 SUDEP genes that are added on. And then in Washoe County, they moved to doing an exome. There's a company offering an exome called Newberg. It's $325. I've done a positive and negative control through that lab and at this point I don't recommend it. So don't look at that and think, yes, this is the one. I found their process confusing. I couldn't tell if they were doing a targeted exome or a full exome. So there's work to be done there. I want to keep moving. I only have a minute. We have a number of sites that are working towards implementing this and there's many other non-registry sites working on implementing this. You need to know what state and county you're in. Is it a medical examiner's office? Is it a coroner system? Do they have funding? I sit in many talks at this meeting where they say medical examiners should be offering this testing and they're totally publicly funded. So we need to look at the circumstances. In Indiana coroners are elected every two years. They're not doing the autopsies but they are in charge of how the money is spent. So let me just keep going. My plea to you and I'm gonna go a couple seconds over time is that we use this information to inform newborn screening. Ninety-eight percent of infants in the United States are born in a hospital. Barely any of the families opt out of newborn screening. We could know this information early on and prevent some of these deaths instead of waiting. It is a much more regulated system than the medical examiner and coroner system. And I just have a graphic of like wouldn't it be so much better if we are doing the testing at the time of birth instead of the testing at the time of death. Thank you. Thank you so much to all of our brilliant speakers. We do have time for questions so if folks want to come up to the microphone or put it into the app using the QR code on the screen. I will. Oh we have somebody coming up already. I'll hold mine in case my question is the same as your question. Hello good morning. Thank you everyone for the presentations. I have a quick question regarding genetic testing in like light of that we have a lot of movement in genetics and there are obviously new findings new evidence coming through. You mentioned something about storage and there's quite time limited storage. How do you see re-evaluating samples like as you know sometimes reclassifications of the U.S. comes through. Do you have the possibilities to then reassess old samples where you might have not found something previously but now with new evidence maybe there would be something. Is there a possibility for that. I'll take it. Can you hear me. This is working. I think what's great about how genetic testing is being done right now is the data is there. And so the labs are in charge of the re-analysis. If say nothing was identified and five years later you want to retest the same case that would rely on the DNA having been banked. The samples are not going to be left at the medical examiner's office in that time frame. But if say the family had an exome or a genome that information is stored at the lab and could be re-analyzed. Okay thank you. And then to Dr. Gavin just a quick question. You mentioned you have 45 million visitors compared to local population of 2.3. I presume you have lots of international visitors. How do you handle that cases where the person is not locally and how do you coordinate with the family who lives abroad. We've had that issue with actually a couple cases and one of mine that occurred many years ago. We were unable to do testing and we couldn't get familial related pieces of data if you will or even samples sent over. So we weren't able to correlate for that family and we had a visitor that was in a competition locally who had a sudden cardiac death during the competition or shortly thereafter. We were obviously able to get samples from that particular individual but then we couldn't do anything afterwards with that piece of information and we searched far and wide to try to get that to happen. But through the different grants that we were doing and the like we weren't able to get funding to make it happen. So we've run into that now. I think it would be a little bit easier for us to be able to deal with something like that assuming we can get samples that would be sustainable over long distances to be able to utilize them. And of course referring the families and be able to have that communication between the United States and wherever they are and hopefully they have a receptive person or clinician in that environment to hear that information and help the family along. Thank you. Got a couple of questions online. Dr. Gavin another one for you. Do you include postmortem genetic testing in cases where a cardiomyopathy for example appears to be incidentally seen and not the primary cause of death. It depends on the circumstances surrounding the death itself. So if we have individuals that are more related to an overdose or some type of situation that has a clear and definitive result found with drug paraphernalia for example and then they have elevated levels of those particular drugs within their system. We're less likely to use our funding to be able to do genetic testing in those types of cases. It's more of the cases where you especially amongst the younger individuals where you're kind of looking at what are the possibilities within the context of this case. And then utilizing the genetic testing tool within that context. Thank you. And then Becky and Lisa you both touched on this and just wanted to see if they can help the person who can release the sample for testing. Is it the coroner medical examiner? Is it the family member? And how much is this a local issue or state issue? In our office it's the medical examiner that decides to utilize the sample for testing. And so we as using it as a diagnostic tool we can use it as we would doing a blood sample for toxicology testing. In our office we can utilize that. Okay we're going to do genetic testing. So it becomes at our order rather than the consultation or at the will of the legal next of kin which we were subject to in the early portion of our testing under the grants. And then clinically it is going to be kind of the opposite. You're going to need to figure out who that legal next of kin is. You know and based on that family situation and get consent from them and then take that to the medical examiner. So that's part of what we need to kind of put in place before we can retrieve those samples to send off for clinical testing. Last official question. This was a terrific session. Thank you all for being part of it. Tying together a little data from a couple of the talks for 15 years we've had this paradigm of patients get where decedents get referred to the medical examiner's office. There's an autopsy there's toxicology and then there's genetic testing. But Dr. Gavin made a good point which is there's often an inciting illness that triggers these deaths. And in the SDY database we actually saw that there were cases that had been signed out as pneumonia or signed out as as asthma. Would any of you on the panel. Is that testing in the right place. Does it belong at the end of that series of decision makings or given as Dr. Gavin's data showed at this talk that about 18 percent of deaths end up down that pathway to autopsy. Are we in the right place. Should it be higher in that chain somewhere. I'm not sure it's worth the discussion at this forum all the way for newborn testing but in the postmortem setting is there are we in the right place of that chain. Some of our offices send everything off at the same time. They're just they're like this meets criteria for a young sudden death. And when they're sending off the samples for talks they're sending off the samples for genetic testing. I don't know how you guys are doing it in our office particularly amongst the children. That'll be done simultaneously. And then in terms of the older individuals depending upon the circumstances surrounding the scene we'll make the decision as to whether or not it's sent off simultaneously. So you can have it very fluid where you have multiple prongs going out on your medical legal death investigation. So you may be sending a sample for toxicology you may be putting in histology slides and then likewise you may be doing postmortem genetic testing. You may also be doing culture. So you may send out all of those tests at once and then wait for the return of information to be able to culminate into your cause of death in your manner. I wonder if sometimes if we're missing important data from status asthmatic us. Why do some people die with status asthmatic us and some people recover if you have underlying a V.C. and then you have status asthmatic us. Is that the reason you have lethal status asthmatic us. So I wonder sometimes if this excluding everything else first means that there's a block of people that we're missing their underlying genetic rationale and of course then the questions for their family members. So I wonder if it's sometimes if it should be even higher on that chain. Yeah I mean I would absolutely agree that if we had every ME coroner office doing what you guys are doing I think we'd get that data right. But the problem is is that most offices don't have the funding for it. They don't have the means to get it accomplished and so it ends up being after because that's just where it has lied for so long. And if we can actually get it where it's easy to order it's easy cost wise it's right and then it would be all at once and then we'd get all that data. But we need it to be at that level where it's easy. I agree that we are certainly the folks to advocate for that work at our local and county levels but also at our state and federal levels. And I think one thing we've seen throughout this meeting is the conversation of the interplay of cardiac genetics with environments such as myocarditis which is a super hot topic right now. So I am very excited to be able to work with all of you and to continue this work into the future. So this is the official end of the session but we will certainly be happy to hang out for a bit and answer any additional questions. Thanks you all for attending.

postmortem genetic testing

unexplained deaths

sudden deaths

genetic disorders

family health

specimen collection

public health

newborn screening

cardiomyopathy

preventive healthcare