Hi, you're listening to DNA Today, a multi-award winning podcast and radio show where we discover new advances in the world of genetics. From genetic technology like CRISPR to rare diseases to new research. For over a decade, DNA Today has brought you the voices of leaders in genetics in over 200 episodes. For the past three years, DNA Today has won the People's Choice Best Science in Medicine Podcast Award. I'm Kira Deneen. I'm a certified genetic counselor and your host. Despite incredible advances in genetic testing, many patients with suspected rare diseases still go years without an answer. And this episode explores how whole genome sequencing paired with emerging multi-omic and multimodal technologies is transforming the diagnostic journey, helping clinicians move beyond the limits of single tests to deliver clearer, more actionable answers for patients and families. Joining me in person for this conversation are two experts from Baylor Genetics. We have Dr. Christine Eng, Chief Medical Officer and Chief Quality Officer, and Chris Sands, Chief Growth Officer. So thank you both for coming back on the show so we can dive deeper into the recent announcement from you all at Baylor Genetics about enhanced whole genome sequencing. Thank you so much, Cara. Excited to be here. Thanks. Yeah. So I figure we could kind of start by talking about where the field is at right now. We have, you know, scientific advancements and all of these innovative solutions that move so fast that it's very hard to even keep up in clinic. And my full-time job is doing this podcast and trying to keep up with genetics. I think it'd be helpful to learn more about the state of whole genome sequencing and the role it plays in rare disease diagnosis. Because when I think whole genome sequencing, the first area I think about is rare disease diagnostics, because I would think that's most of what it's being ordered. And certainly in the pediatric setting, I'm thinking, Chris. Yeah. And you're right. And I have to echo what you said. It is such an exciting time in genetics in our field. And looking at the transition from when I don't want to date myself, but getting, when I first started in the field, going from single gene testing to multi-gene panels to then to exome, and now looking at genome as a first-tier test and seeing the adoption rates going from one modality to the other, how quickly it's starting to advance. And here at Baylor, we have made the decision to really focus on utilizing genome as a first-tier test and really promoting to clinicians and educating them on utilizing it as a first-tier diagnostic tool. So setting the stage, too, we have approximately 15 million kiddos that are diagnosed here in the U.S. with a rare disease. And at times, it could take them in the past six, seven years to eventually get that diagnosis. Taking a look at what we're doing from a genome sequencing perspective, saying, hey, how do we shorten that diagnostic odyssey? I know that term is somewhat overused in our field, but it is, I think, very appropriate it to say, how do we take our clinical advancements and put them onto the clinicians and ultimately the patients to say, we can provide you an answer faster to help get you on that path to treatment a little bit sooner? Yeah, it is so important. And I agree with you that term is used a lot of diagnostic odyssey, but there's a reason for that because it is an odyssey and it often does take six, seven years to get to that real diagnosis. And oftentimes there's misdiagnoses along the way too. where you get this diagnosis for a kiddo, and then you kind of learn, wait a minute, this is not right. And hopefully those terms can be retired in the near future, because it's going to just be whole genome sequencing, using so many of these tools that we're going to get into in this episode, so that we can get to that much faster, and that hopefully more and more providers are feeling more comfortable to order whole genome sequencing, because I think that's one of the other barriers. We don't need to convince geneticists and genetic counselors to order whole genome sequencing. Like they're part of our crew. They know what's going on. They know, OK, this is what we need to do. But there's other providers that are not genetic health care providers that I think it is overwhelming to think about. Oh, my gosh, whole genome. That just sounds like, you know, too much. So, Chris, from your experience of working with customers, is this kind of where we're at? Like in terms of like I'm not one of these other specialists. So I'm projecting a little bit in terms of where they might be. Maybe they're further along than I'm giving them credit for. And I think they are. Okay, good. Specifically in the neurology field, we're really starting to see, there are the clinicians that see the patients that have epilepsy or intellectual disability, autism. We're seeing them start to really adopt XOMA genome as a first-tier test. And I think that's really exciting, right? Because I think, you know, when you look at the number of geneticists out there and the number of genetic counselors out there, there's limitations there, right? So now that these pediatric neurologists and developmental pediatricians are seeing these kiddos at a time where that first milestone is potentially missed, what do I do? Do I, again, refer them to a geneticist, or do I do this testing myself to help, again, get that answer as quickly as possible to help provide that diagnosis and then put them on the path to treatment? Dr. Ng, you come from the pediatrician world and having that experience, and the AAP guidelines recently kind of updated in terms of what are indications for possibly pediatricians to order genetic testing. So I'm kind of thinking them along with these non-genetic healthcare providers that could be ordering testing. Is that what we're hopefully starting to see? Yeah, I think it was a very important milestone for the AAP guidelines to come out and basically say that for patients who may present at a very young age, perhaps missing their first developmental milestone, that whole genome and whole exome sequencing should be considered. We all know that early intervention with developmental therapy and physical therapy can really make a difference in patients' overall outcome. And so seeing those guidelines that says, you know, don't wait, order these comprehensive tests so that we can arrive at a diagnosis sooner and really attack the problem is really important. And so at Baylor Genetics, we try to make the ordering process and the reporting process as easy and seamless as possible for all providers, not just the ones who may order a genome every day or a few a week but for those who see a patient in their practice and may order it perhaps once a month or so we want to make it as easy as seamless and as informative for both the clinician and the patient as possible. Yeah, that's so important of not just the ordering side, but that report, because as you were alluding to, Dr. Ng, having a report that's understandable by various healthcare providers that may not know, like to us, we're like variant of uncertain significance, VUS. Like we can just say that we all know right now what that means. But you say that to an endocrinologist, they may not know what a VUS is. Understandably, that's not their wheelhouse. So to be able to break that down and have a report that even if we can have, from my perspective, these specialists order whole genome sequencing and get a report and say, okay, I can tell the patients what the results are, but that I can't dive too deep, but now they can be referred to someone. That is going to help so much in terms of how long, going back to what Chris said with the diagnostic odyssey, making whole genome sequencing easier to order for these providers is going to help all of these patients because then they can actually get in and not be on a waiting list to even get the testing done. That's exactly right, Kira. So we want to move the actual testing and the diagnosis so that the answer can be provided earlier. And then the subspecialists step in when it comes time for management and treatment. We all know that making a diagnosis is the first step to having more personalized care and perhaps a therapy. And so it's really important that all rare disease patients get the answer that they deserve. Yeah. You know, the other aspect of it that's that is, you know, been an evolution in the in the space is the pair coverage. Right. So now, you know, having the ability to order this type of testing in an outpatient facility, even by a non-geneticist, where the major payers like UnitedHealthcare and Cigna are now covering whole genome sequencing as that first year diagnostic tool has made a big difference. and has really allowed us to move this process as upstream as possible, to Christine's point, is having that diagnosis and then being referred to that subspecialist. Yeah, the insurance part, unfortunately, is so important that this used to be a test where if you could afford it, you could get it. And now that we have these major, you said United Healthcare and Cigna covering this for certain indications, probably, that is a major milestone. and I hope that more insurance companies can follow suit because then we're taking down another barrier. I feel like we've just kind of been highlighting a barrier and then how we're bringing that down and how specifically Baylor Genetics is. So, Chris, from your perspective, is this insurance part a barrier in terms of the clinicians kind of knowing how to navigate that part? because there's the aspect that the genetic testing laboratory is involved with the insurance companies, but also the clinicians do. Because I did over five years as a prenatal genetic counselor. And so I was talking with the insurance company sometimes. I didn't want to. You know, I'm going to admit that was my least favorite part of the job, just all the paperwork and trying to be like, my patient needs this test. Like, you know, they elected for it and there's a medical need for it. So what are you hearing from your customers in terms of your customers being the clinicians. Yeah, so I mean, it's a great point. And it is the necessary evil to have these conversations. As much as our clinicians don't want to engage, it is a part of the experience that the patient and clinician have. What we try to do at Baylor Genetics is be that silent partner to remove as much of that friction as possible. So we provide them up front, depending on what the insurances are, who covers what and when, and really try to make it as easy as possible. And now with integrating with EHRs and with the portal being, again, more and more intelligent as we get, as more information comes into us, we're allowed to, we then are able to provide that back to the clinician. And again, try to be that advocate for the patient to make sure they get the appropriate testing they need without that really abrasive potential out-of-pocket costs. Yeah, I think that's so important. And so as we talk about whole genome sequencing, it's great to hear that these insurance companies are starting to recognize the power of whole genome sequencing and that it really does make sense. Is this quicker, Dr. Ang, in terms of compared to like exome? Because, you know, we were talking about going from like, you know, a gene, multi-gene panels to exome to genome. So has insurance spaces started to learn from that? And like, has it been more expedited with genome? Yeah, I definitely think so. And I think the payers learn from the whole exome experience about the first step towards comprehensive genetic testing and how it can reach answers much sooner and then shorten the diagnostic odyssey, but also save costs. And so I think the momentum has been a bit faster with whole genome sequencing. And I think as we continue to collect clinical utility, it will even advance more. Yeah, we have such a drop in the cost of sequencing that it continues to make more and more sense from a fiscal standpoint to be ordering these tests sooner and sooner and starting to be, you know, this first tier, first line testing. Standard whole genome sequencing is usually short read. So when we're looking at these other tools, there's a way to possibly capture more information to then have more diagnosis because a good chunk, unfortunately, of cases that are ordered with whole genome sequencing don't end up having a diagnosis. So where are we at in terms of comparing this traditional short read whole genome sequencing compared to like all these new tools? Like how is it possibly going to increase the diagnostic rate? In patients who have not had any genetic testing previously, it can approach 50%. And we've seen that in our neonatal intensive care unit patients that undergo whole genome sequencing and they have not really had genetic testing previously, it can fall to a lower number in the 25%, 28%, to 30% range in those patients who have been through what we were talking about, the diagnostic odyssey, starting with chromosomal microarray, panels, exome even, and then going to genome. And we've seen that in the Undiagnosed Diseases Network. They are a network of providers that work with these patients who have had really challenging diagnostic odysseys. The Undiagnosed Disease Network really is a wonderful resource, and it's great that patients do have different resources out there, like UDN, to be able to help them possibly navigate when they've been through multiple genetic tests. How might these newer tools help them maybe that have been on this diagnostic odyssey Because we have quite a few that we dive into now There long read sequencing optical genome mapping or OGM And so explain how these tools are hopefully going to increase that diagnostic yield, particularly for those that have gone through a lot of these tests without an answer. Let's start with RNA-seq, which we introduced in the middle of 2024. So we decided to add targeted RNA-seq because we were encountering variants of unknown significance, particularly around splice sites. And so in order to provide more information for patients, as we discussed, you know, we want our reports to be as conclusive as possible. We decided to add this more functional test so that we could take a look at those splice variants, and then put them through RNA-Seq and determine whether they had a functional impact on the protein. So that's one way that we're able to bring in another technology, in that case an omic technology, to try to clarify our results. We also saw some opportunities in other parts of short read sequencing that can use a little bit of enhancement, a little bit of boost, to give a more precise diagnosis. So in the case of short tandem repeat conditions, and these are not that rare. About 1 in 3,000 individuals have a condition that is caused by a short tandem repeat. We can see evidence of that expansion in the short read, but sometimes we cannot fully interrogate the entire size of it just because it's too big. So we have adopted long read sequencing, to be able to address those short tandem repeats, that we want to make sure we size them correctly. The correct size is really important to give clinicians and patients some idea of the type of phenotype they can expect from that condition. Another example where we saw perhaps a way to boost or enhance our genome was with structural variants, especially those that are complex. This also can be a challenge for short read sequencing to be able to understand the full scope, especially of complex structural variants. And these are variants such as inversions, duplications, and sometimes they're in combination. And we often can't fully understand the scope of it with short read sequencing alone. So we brought in optical genome mapping. This is a different technology from sequencing, kind of gives us a different look at the genome. And we're able, with this technology, to understand especially these complex structural variants and how they are impacting the genome and ultimately the patient. Yeah, I think that's so helpful to be able to have these tools. And from my understanding, it wouldn't be right away that all these tools would be used, but similar to RNA sequencing, like we talked about in a previous episode, we'll link to that in the show notes, your first appearance on the show, that it will be used as sort of a reflex. Or like if you don't get, if you don't identify what the genetic change is that's causing the phenotype right away, then you can say, okay, we're going to start using these tools to see if we can dive deeper and uncover that. Am I on the right track with that, Dr. Ang? Yeah, definitely. It's really important for us to use our expertise in a very personalized way with patients. So we have these tools, but we will use them when we feel that there is evidence in the short read to be able to utilize them to their full extent. We've talked about just how important it is to get to the diagnosis. And sometimes there are treatments available and that's wonderful. Hopefully we'll just start having a lot of cures and we can start using that term more often and it will be less of a pipe dream. But even if there aren't treatments, we see that there are other ways that this diagnosis can help and change a person's life. Can you speak to that in terms of just being able to see that impact that it's not for clinicians that are listening or watching that are like, oh, but there's probably not a treatment or like, what's the point of all of this? There is a point. Oh, absolutely. And I could go on several hours on this topic, but actually very early in my career, I was involved not only in a diagnostic lab, but also with clinical trials for enzyme replacement in therapy for a condition called Fabry disease. And so that's where I got my first really exposure to what it means for a rare disease patient to have a potential therapy. So it's so important to make a diagnosis for many, many different reasons. Of course, the end game is for there to be specific therapy for that patient. But without a diagnosis, you're not going to be a candidate for that therapy. So it's diagnosis first. But even if there isn't a therapy, as I mentioned, there are clinical trials all the time. Genetic therapy research is just exploding. And so to be able to know what exactly you have, you and your clinician can monitor clinicaltrials.gov to see if a trial is opening up for your specific condition. Even taking a step backwards, having a diagnosis brings you to the next level of management. You're not spending all of the time figuring out what the problem is, but now you're figuring out how to manage that problem. We know with, especially intellectual disability, starting early with early interventions really helps improve the outcome. And so that's important for all conditions, to know what to expect, to know the things that you can watch out for, to begin proactive intervention in order to improve the outcome. And I think there's something we said, too, about just providing a caregiver or family, the answer why. Why does this happen, right? And what the potential implications are if they are looking to reproduce again. And I think, again, just being able to provide that ability and there are studies that show the impact that just, again, even without treatment, right, just having that answer and how significant and meaningful it is for the families. Yeah, there's certainly when I was in the clinic and seeing patients that had a kiddo with an undiagnosed disorder and they're asking me, like, well, what's the chance that this could happen again if they were to have another full sibling? And to look at them and say, like, we don't know or, you know, we're still trying to figure that out in terms of it's probably if they've gone through genetic testing that was negative and didn't find anything, it's probably random or de novo. But I can't for certain say that until we have the genetic testing to say, OK, this is the condition and we've tested the parents or we learn more about it. Sometimes that appropriate Sometimes that not So it just so important beyond or I would say maybe even if there not a treatment there so much else that goes into it And yeah the early intervention is just so key And just having that information of just an answer that you can start researching, you can start looking. There's now the first paper out about this condition. You know, if it's that early on, if it's, let's say, a nanorare disease that affects less than 20 people in the world that are diagnosed. And this enhanced whole genome sequencing is going to help get more patients diagnosed, and that at the end of the day is really the goal. But it's also important for the extended family. So there are many cases where, you know, we will find that there's an autosomal recessive condition, and then that information can be used definitely for the couple, but it can also be helpful for the extended family. I should also make a point about, you know, we really focus on making the diagnosis. But sometimes a negative whole genome sequencing is important as well. So you can think of it almost as sort of a rule out. And we're seeing that more and more, especially in the NICU, when clinicians are faced with a very complex clinical presentation, that sometimes they're ordering whole genome sequencing just in order to say, okay, this is not genetic, most likely not genetic. And Now we can focus on other causes. Yeah, I'm so glad you mentioned that because we're so focused on like having some answer from this enhanced whole genome sequencing. But yeah, if you also don't get an answer, you're like, well, that rules out a lot. It's still an answer. It's still an answer. Yeah, no, that's true. That is true. It's not a specific genetic change. So the lack of one is an answer. And Chris, from your experience of just working with so many of these clinicians as your customers, is there anything that you want them to know about this new enhanced whole genome sequencing? I mean, we've talked about that the ordering side doesn't change. We've talked about how the report is really helpful of like the language that's used and having it be very useful for people that aren't necessarily trained in genetics. Is there anything else that you want to make sure that people understand about the process or that's helpful? I think the biggest thing is that, you know, again, the process is the burden is on us, right? And I think that's the one thing. We want to make the process for the clinician as seamless as possible. So that's where, at Baylor Genetics, we decided that their traditional ordering pathways for genome sequencing is not going to change, right? So we are going to kind of take a look and use our expertise to when these, you know, to utilize these enhancements and those additional technologies to provide that answer. And again, we understand that speed is important, so we're not going to sacrifice speed. And we also know that that cost is also something to consider. So there's not going to be any undue or additional cost for these enhancements as well. That's a really good point because I didn't ask about that in terms of with all these new tools, it's not considered like with other reflex testing, you'd be like charged for the next. But with this, it's really it's all under the umbrella of whole genome sequencing. You're just really taking advantage of these new tools. And from the billing perspective, it's also not different. Exactly right. Our goal was to continue these providers on that same traditional pathway to not interrupt what their traditional office workflows are when ordering this type of testing. Yeah, and to add value to our clinical genome by bringing in these new technologies that are going to personalize it. So it's not going to be for all patients. But when we suspect something from the short read, we will then bring on these other tools to help us elucidate it. I just have to say, this is just a little mind-blowing to be sitting here and talking about all these tools used with whole genome sequencing. I'm like, you know, this show started in 2012 and like thinking about, you know, we were all in the field that, I mean, I was in high school starting the show, but so I was like trying to get in the field. But it is just remarkable that we've gone from, okay, yep, you figuring out what gene we're ordering to panels, to exome, to now, like genome is becoming standard to order and it's feasible to actually order this. And, you know, it's just sometimes it's just like overwhelming in a fun way to think about how far genetics has come and just what labs like Baylor Genetics are able to offer. It's a little pinch me, right, of just where we're at. Yeah. And we're not going to stop here. Exactly. Things are going to continue. And we also have to remember that, you know, patients who have had a genome maybe or an exome a few years ago, you know, there are all these new modalities. So maybe it's not just test once and that's all, but to continue to think about those patients who will remain undiagnosed, which of the new tools can be brought in to help those patients? Yeah. Clinicians that are listening and watching, I think that's really important to know that if you've had a negative whole genome sequencing a few years ago, it might be time to reorder that knowing that these tools are available to aid with a more comprehensive view of all the genetic information, at least what we're looking at through genome. There is no test that tests for everything in genetics. That would make our job far too easy. Yeah, maybe not necessarily reorder, but also, you know, let's not forget about reanalysis. Reanalysis. That's the term I should have used. Thank you. Yes. So maybe it's not about reordering the genome, but it's about reanalyzing that genome and seeing if there are patients who remained undiagnosed from their first genome, taking a look at that data again and seeing whether a new disease gene has been discovered or perhaps that patient might be a candidate for one of these new technologies. Thank you, Dr. Ng and Chris, for coming on and explaining all of these new technologies surrounding enhanced genome sequencing. I'm really excited for how this is really going to shift diagnostics. And it's just such a great time to be in genetics, as it has been for many years. But we just keep pushing the needle. So thank you both so much for coming on the show. Yeah, thank you for giving us the opportunity. Yeah, we really appreciate your time. And thank you so much for having us. that's a wrap on this episode of DNA today to keep exploring the world of genetics and genomics with us head to dnatoday.com for hundreds of episodes show notes and resources from our archive dating back to 2012 DNA today is part of gene pool media the science podcast network to check out more of our episodes visit gene pool media.com for questions guest pitches or sponsorship inquiries, email info at dnatoday.com. And if you enjoyed this episode, a rating or review on Apple Podcasts or Spotify helps more people find the show. Thanks for joining us. I'm Keira Dineen, and I'll be back next week to continue discovering new advances in the world of genetics. We're all made of DNA We're all made of the same care
