NANNcast and GeneDx podcast rapid genome sequencing in the NICU

NANNcast Podcast Transcript

The following transcript has been edited lightly for readability while preserving the original discussion.

Sponsored by GeneDx • Speaker: Dr. Linda Genen (CMO)

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This episode of NANNCAST is brought to you by GeneDx. Thank you to GeneDx for supporting neonatal nursing education and helping make conversations like this possible. In the NICU, every hour counts. GeneDx Rapid and Ultra Rapid Genome Sequencing gives care teams genetic answers in as little as 48 hours, helping clinicians move faster, make informed decisions, and deliver family-centered care when families need it most. GeneDx fits the way your team already works. Visit genedx.com to learn how rapid genome sequencing can support earlier answers in your NICU. Hello and welcome to NANNcast. I'm Jill, your host. When a baby is admitted to the NICU, we often move quickly into action, supporting breathing, treating infection, managing prematurity. But what happens when things don't quite add up? When a baby isn't progressing the way we expect and we're left wondering, what are we missing? Today, we're talking about how rapid genome sequencing is changing the way we approach those moments of uncertainty. helping us get earlier answers and make more informed decisions when timing matters most.

I'm really excited to be joined by Dr. Linda Genen, Chief Medical Officer at GeneDx, where she oversees medical and clinical affairs and leads the company's clinical strategy to accelerate adoption of genomic first care across healthcare systems. She works closely with health systems, payers, policymakers, and the broader medical community to integrate genomics into routine care and expand access to earlier, more precise diagnosis. Dr. Genen also brings a unique perspective to this conversation as a neonatologist and healthcare leader, helping bridge the gap between cutting edge genetic technology and real world NICU care. This is such an important conversation as genomic testing becomes more integrated into NICU care, and nurses and APRNs are increasingly part of those discussions with families. As genomic medicine continues to evolve, understanding how rapid genome sequencing can impact care is becoming increasingly important for the entire NICU team. Let's get right into it. Thank you, Linda, for joining us today. To start us off, I love to ground this in what we all are experiencing at the bedside every day.

When you think about the NICU today, where do clinicians most often face uncertainty in understanding what's driving an infant's condition? It's great to be here. Thank you. I think in the NICU, we're typically presented with some obvious conditions initially. So we know the majority of babies who come into the NICU have respiratory distress or issues with their So we think about the NICU as a pie chart. There's large babies, smaller babies. The majority of babies actually 50% are full term coming in with issues such as sepsis, that's infection, difficulty breathing, uh prematurity in the second half of that pie chart, right? The other half of the pie chart is about 25 % of your late preterm infants. So babies who aren't quite fully developed and then your much smaller babies, the extreme preemies. I think about those obvious conditions, and then you think about, what's beyond that? What happens after I've treated that baby with who's struggling to breathe? What's causing that? So it might be infection.

And then I think about some of the things genetically. I'm so focused on that initial condition that I may not right away be looking at what's going on genetically or how that baby's thriving nutritionally, things like that. So it's not always clear on day one, two, or three. Sometimes it takes a little time to determine what is truly the driver of why that baby's with us in the NICU. Yeah, and I think we all seen that. We feel like we have those patients that we're treating what we see. So like you said, respiratory distress or sepsis, but then something just isn't adding up and like what is causing this baby to not respond to the interventions that we're providing this baby? So is there usually a trigger moment or sometime when a clinician starts to realize, okay, there might be something more to this clinical presentation? That's right. So as you think about each condition that we're treating in the NICU, you think, okay, respiratory distress.

Well, maybe it was a baby born by C-section and they've got some retained fluid, so transient to kidney of the newborn. And then... it's been more than two days or it's been more than three days and suddenly they're still having issues breathing, right? And I remember taking care of children with surfactant B deficiency and scratching my head and wondering, why do I have to keep this child on oxygen so much? Why is this child requiring so much support? I had a late preterm infant who required surfactant, right? So to help that baby breathe initially, but then after 24 hours, required surfactant again. It was a constant process. And it took us a while, actually, to say, hmm, maybe we should do a genetic test. Something's not quite right here. We can't keep giving this child surfactant. And when I say a while, I'm talking like two, three weeks, a while, not just a few days. And it wasn't top of mind to right away say we should do a genetic test.

So we lost time in my humble opinion, trying to help this child when we found out there was surfactant B deficiency and that would have helped that family make a decision about next steps. So we do a lot of, okay, I'm going to treat each symptom and then as the symptoms maybe aren't fully going away, we start scratching our head. So they're also the combination of we're saving babies who are smaller and smaller, right? 22 weeks. 21 weeks, the line has moved quite a bit from when I trained where it was like 26, 24, 25, literally it seems to move every couple of years now. And you're focused on that initial issue. So a preemie will have low tone. You anticipate that that child won't have a lot of strength to them being so small. And then time goes by and you're like, hmm, I'm gaining weight, but I still have low tone. Okay, let me think about other things. Let me think about neurologic issues.

This was a preemie. Maybe there was a brain bleed. So you go down other lines of thought, other differential diagnoses before you get to that key area, which I think are genetics. So we are a little slow or too focused on the symptom, and we don't necessarily always think about that big picture. It takes time to get through that algorithm or stepwise approach. Yeah, I think we're so focused on what's in front of us, what we can easily fix that sometimes, you said, babies that two, three weeks later are still with low tone. Why is that? Or why are we still requiring such high oxygen when we thought this was a TTN picture? So almost that diagnostic uncertainty that we're seeing, I think, is a challenge. We don't have that wait and see, like let's just wait and see mentality in the NICU. I feel like we have to work faster. But then with talking about genetics, like you said, sometimes that takes a while for us to get us there and get us that right diagnosis.

That's right. So that should be on the forefront of clinicians' minds to start thinking after a certain period of time, maybe we need to dig deeper. And I would say I'd like to see us do it as a first line, not to wait. Wouldn't it be great if we knew up front? Think about that. If we knew if we had that answer up front instead of scratching our heads and just, so if you think about the world of medicine, the adult world, we treat a lot of things symptomatically. And we actually do the same thing in the NICU in many situations. We're treating the symptoms without knowing the underlying cause right away. And we say respiratory distress, for example. So we do an x-ray, the x-ray doesn't look beautiful. It's got some haziness. We treat with oxygen, maybe it's surfactant, and we make differential diagnoses. Okay, retain fluid, pneumonia, sepsis, or maybe it's something else. And that genetic thought behind that, respiratory distress comes much later.

So I really think it's very interesting as we look towards moving that genetic algorithm towards the front, we could make a difference in a lot of ways for family members and for us in the NICU as diagnosticians. I think that's a great point to pause for a moment because there are so many terms that get thrown around when we talk about genetics. Can you walk us through the different types of genetic testing that may be available in the NICU today and help us understand when each might be considered? As we get into this conversation, we're going to talk about whole exome sequencing, WES. and whole genome sequencing, WGS. Those are the two types of sequencing that we currently utilize in the NICU. And so you'll hear that as you start reading about this more and more. So whole exome sequencing analyzes only the exome. That's one to 2 % of your DNA that codes for proteins. And because the vast majority of disease- causing genetic disorders occur in these protein-building regions, it's a very effective tool for diagnosis.

And when you look at whole genome sequencing, that's going to give you the entire DNA sequence, right? That will include your protein coding sections, your exome, and the non-coding regions. So it gives you a more comprehensive view of an infant's genetic makeup. And so we can see structural variance as well in non-coding mutations that whole exome sequencing might miss. Both are excellent. And something we should also mention is rapid testing, right? So the ability in the NICU is that we do have rapid sequencing, and that means we can get results much earlier than sometimes takes one to two weeks. We can get it within days. And that is important because then we can make decisions much quicker as to what the next steps are or how parents can be guided into what they may want to choose for treatment going forward. If you think about one of the top reasons babies get admitted to the NICU congenital anomalies is one of the big ones why babies get admitted to the NICU so genetic conditions, about 13 % on average is the leading cause of NICU admissions.

And that's in a developed country. So these are children who sometimes you know in advance that there is an issue because of excellent prenatal care or they were able to be diagnosed early. Sometimes you don't. But 13 % is a pretty high number. We always talk about 10 % of babies are born premature in the United States, prematurity being any baby less than 37 weeks. Now think about the genetic conditions as the leading cause of NICU admissions, that's 13%. That's pretty high. And yet, less than 5 % of children who would meet the criteria with a genetic potential diagnosis receive rapid genomic sequencing in the NICU. It's just not adopted across the board. We don't necessarily think about genetic testing in the way that I'd like us to think about it going forward. We do talk about newborn screening. Every baby born in America, NICU or not, so whether your baby goes to the NICU or not, and parents forget about this or don't even know, they get a little heel prick and five dots go on a white paper card, and that goes off to the state lab.

And each state has a different panel of tests for the newborn screen. Now, if we could move that needle and think about genomic testing, you'd get so many more answers much sooner. Yeah, that statistic really stands out that it's such a significant contributor to our NICU population. However, we're not testing early in a lot of cases with the less than 5 % receiving testing. Like we talked earlier, a lot of times we think of genetic testing as almost the last step. And it's sort of a mind shift or a culture shift in NICUs to go from, oh we're going to rule that out later after we've done X, Y, and Z, and then make it more of a first step approach. thinking about it ahead of time. So what are the biggest barriers that you're seeing that are preventing clinicians to think of genetic screening earlier? So I think there's so many answers to this question that are all valid. Obviously, there's variation in care in general.

We know that in America. There's variation in access to care. You'll see that the large academic centers usually have the newest technology that comes across in all areas of medicine, right? Not just in the NICU. And we've certainly seen that where large academic centers, have access to the newest tests, more subspecialists compared to a community or rural-based center. So that's right there is you're setting the stage for, okay, what's available in your area where you've given birth, for example. And the same thing happens in genetics and genetic testing. So there is also a shortage. So we have a physician shortage. We have a nursing shortage, which no one here is unfamiliar with, right? Nursing shortages all over the country. And so we do have a shortage of geneticists and genetic counselors. And they're not necessarily in the NICU, right? How often have you seen geneticists and genetic counselors come into the NICU? It's only after we've asked them to come. So it's not part of their day-to-day routine to do rounds necessarily in a NICU setting.

Maybe in some academic centers, but for the most part, they're not coming through the NICU to engage and interact the neonatologist who's engaging with the maternal fetal specialists, the MFM team, and constantly saying, who have you identified prenatally that we have to be aware of as they identify congenital anomalies in utero, right? And then there's guideline issues. Who should we test and when? So there's a lack of clarity as to how to roll this out and make sure that everyone's following the same standardized. approach, which you know in the NICUs I have to laugh because standardization, even on one guideline, we can't agree on the best feeding guideline now try and get the best guideline for genomic testing. I talked about lack of genetic specialists, but we as neonatologists also are just really learning about genomics. That's another area. So the education for us as providers in the NICU care providers in the NICU. So the nurses, the physicians, we knew about karyotypes years ago.

That's all we had. Then chromosomal microarrays came around and that took some time for adoption. And now we've got whole genome and whole exome sequencing. And you know, we are not very good at necessarily adopting new things across the board. It takes time. So the academic centers get it first and the community and rural hospitals adopted a standard of care later. And then I think the other part is there's lack of awareness actually that this test is covered by insurance. And so that was very interesting to learn over the years how it slowly, and now picking up speed, we have 38 states that cover uh genomic testing for Medicaid. And so that's absolutely amazing, and the majority of commercial insurance. So there's a very big learning curve that we have to climb up a hill essentially to get there. And so that starts with academic centers training neonatal fellows, nurse practitioners, et cetera. So we're getting there. I'd just like to get there a little faster.

I know you talked about access and workflow. We all know that that's where things really break down. If you don't have access to it or a good workflow. But then we also talked about how difficult it is to get something standardized because if there's no clear process, it just doesn't happen. Do you know of any centers that are doing things right and are having success with this? What are they doing that are making success? Yes. So there are some hospitals that are doing this as standard of care in their day-to-day care, right? And there's two approaches. There's an inclusion or exclusion criteria approach. Inclusion criteria would be, I'm going to test children who meet certain categories, such as a metabolic crisis, right? We all remember those lovely things we had to learn back in physiology, which I really don't love that much. But all the metabolic pathways, those inborn errors of metabolism, those are very challenging. And those are the ones that would meet the criteria for this.

Other things, so any cardiac symptoms of unknown origin, if you don't know, depending upon mom's prenatal care, right? There might be information that you're not aware of. And then things such as growth issues. So a child who's not gaining weight appropriately, failure to thrive situations. Things I didn't really think about, quite honestly. Even for me, I've learned. I wasn't taught that you should do genetic testing necessarily and failure to thrive. So constantly learning as we... learn about what are their conditions. So that's an inclusion criteria. You've identified certain things that are not quite clear. Seizures, right, is another one. Exclusion criteria, that's actually used pretty exclusively in non-birthing sites. So NICUs that get transfers in, right? You don't necessarily know what the prenatal diagnosis is. By using the exclusion, you're getting rid of some of the main NICU admission diagnoses. So prematurity, a child who's born premature may not be tested. What's interesting is child is premature, their phenotypic presentation hasn't shown up yet. And so that child matures and you start to see some indications that would maybe be appropriate for genetic testing.

And so the exclusion criteria meaning you're going to test the majority of children who come in. Some units. tests only when certain phenotypic presentations arise, and some only when other avenues are exhausted. So it's really quite a range and not surprising. We're not standardized yet. I'd really like to see this future where we do have exome and genome sequencing standardized in the NICU. The variability in who's included and who's getting tested is really striking because like you said, there are those babies that stand out and have those features that you're, oh, we should definitely send genetic testing, but then there's others that don't get diagnosed early because they might not be presenting that way. How does earlier access to genomic insights actually change our management of these babies? So as we talked about before, right, sometimes we're so focused on treating that symptom and we're not seeing the bigger picture. So by having that earlier access to genomic insights, now I know what I'm dealing with.

So I've got diagnostic clarity in very complex or in involving clinical presentations. So it directly gives me information about my next steps as the clinician and then the overall care planning. It enables me to have more confident decision making when timing is critical. And it also helps reduce prolonged diagnostic workups. So unnecessary procedures, right? Going down a path that might not be where I need to go. Now I know where to focus. Could mean I'm changing the treatment as well in a quicker manner that's going to help that child long term. I love that, the confidence in decision making, because that's true. It's now we have armed ourselves with more information and we can actually change what we're doing instead of sometimes just keep trying, keep trying, see if this works, see if that works. But now we have that information and we can really change the trajectory of this patient and the family. That's right. So what does the data show about how often genomic testing actually impacts care?

So actually there's a recent study that showed that rapid genome sequencing changed clinical management up to 87 % of infants in a level 4 NICU. Now that sounds crazy, right? But keep in mind level 4 NICU, you've got your sickest children, most acute children, higher percentage of congenital anomalies. So this is a very select group to begin with. And that's very important because we don't want to think that every single baby is born with a congenital anomaly or genetic syndrome. However, in a focused targeted group, it really changed management up to 87%, which is really impressive. That earlier diagnosis also is associated with shorter NICU stays. And what do we want? We want our babies to go home with their parents. And so by diagnosing earlier, the NICU length of stay was able to be decreased as high as 20 days. It can reduce unnecessary testing. Healthcare utilization is a problem in America have the worst, second worst actually, maternal infant outcomes in a developed country and we spend the most actually in healthcare.

So by doing the test early, we've actually shown that you can decrease the overall cost of care up to $15,786. It's a pretty exact number. And so really genetic testing done early supports more efficient use of resources and earlier intervention and gets the baby home sooner with their families. Those are incredible outcomes and data that are so meaningful, not just clinically, but for the families and the systems themselves to be able to decrease that length of stay. Everybody wants to save money. We've saved cost. And just to be able to have better clinical management for these babies. So now we know how implementing genomic testing can vastly affect our care at the bedside. Let's talk about the bedside team. What role do NICU nurses and APRNs play in recognizing when testing may be appropriate? So the NICU nurse is literally by the infant's bedside throughout their shift, right? They are the advocate for their patient who really can't advocate for themselves. And so they really get to know their patients and they can identify nuances that I might not pay as much attention to because I don't have the luxury of time because I'm bouncing around from bed to bed.

And honestly, we know, I'll speak for myself, I won't speak for my entire practice, but we as a neonatologist, I know NICU nurses run the show in the NICU. And if a nurse says to me, Linda, I'm concerned, here's what I'm seeing, I'm 100 % gonna listen because they really do see the significant changes that I might not pick up on. And so they're advocating on behalf of that little tiny baby and it's great to see the nurses advocate for that earlier testing, which is why I'm so glad we're having this conversation to help educate more and more nurses about exome and genome sequencing. I think that if nurses feel empowered and they have that knowledge, they'll speak up and they'll advocate for their baby in rounds or whenever where they see something's not quite right because they are, like you said, we spend the most time with these babies. And we also spend a lot of time with the families and the families could say, hey, I've noticed something doesn't seem right.

And it's in those communications that we can really. target stuff. But I think, like you said, it's really important that nurses feel empowered to speak up and really advocate, especially when something doesn't seem to align clinically. And this is uh a great conversation to be having to give nurses that knowledge about genomic testing, because maybe that's not something that's in the system that they work at or something that's not talked about often, because maybe it's just something that's not in their workflow, like we talked about earlier. 100%. Yeah, we cannot survive without our nurses at all. And also, too, like we talk about families and the impact that genomic testing can have on families, too, because, again, it's the shorter length of stay. They'll have quicker answers if they're feeling uncertain about a clinical picture of their baby. Why isn't my baby getting better? Oh, well, we sent some genetics. This is what came up, and now we can target that really tailor that plan of care towards your baby.

And hopefully that will help decrease any kind of uncertainty or mistrust that they're having with the team. Yeah, I couldn't agree more. It's very, very true. We're talking about how nurses can use their voice at the bedside. But what are some guidelines that they could discuss recommending when it comes to genomic sequencing? So, know, in medicine, nothing happens without a guideline in place for the most part really, especially when we're dealing with little tiny babies, we've definitely taken things from adult literature over the years, how we use antibiotics, things like that. So having guidelines is extremely important for that standardized care. So we have actually several different societies and American academies and colleges that have recommended this and I'll quickly do a rundown. And it does really speak to the fact that there's been a lot of research over the last decades plus, the last really 15 plus years on exome and genome sequencing. So there's the American College of Medical Genetics and Genomics, that's known as the ACMG, and they recommend genome or exome as first line tests for developmental delay, intellectual disability, and congenital anomalies.

Then there's the National Society of Genetic Counselors, the NSGC. Also recommending genome and exome as first-line tests for all individuals with unexplained epilepsy. And that's been endorsed by the American Epilepsy Society, the AES. So we're at three different academies or societies at this point. The International Precision Child Health Partnership recommends also exome or genome as first-line tests for NICU patients with unexplained hypotonia. So it's not a guideline, but that's a recommendation that's specific for NICU babies. And then this past May, May of 2025, the American Academy of Pediatrics, the AAP, which we really look towards as neonatologists and NICU nurses, recommends ordering exome and genome as first line tests for children with global developmental delays and intellectual disabilities. And so while this does focus on a older population, it does reinforce the need for the standardization of care with exome and genome, and epilepsy is part of that as well. It's really interesting to see how these guidelines are finally now catching up with what we are seeing clinically at the bedside, and I hope that this would be expanded more.

Do you think there's going to be NICU-specific guidelines in the future? Yes, I absolutely do see a future with NICU guidelines as part of our standard everyday care. We've got studies coming out, SeqFirst out of Seattle Children's, for example. There's some really pivotal large consortiums as well. So I wholeheartedly believe that it's just a matter of time over the next couple years where we're going to have a genome-first care that will happen in practice. So genomic testing will happen earlier on in the diagnostic workup not as a last resort. We're going to move away from the sequential testing approach that causes a delay in answers, As opposed to doing a karyotype and then a microarray and then maybe a muscle biopsy for fibroblasts, things that we used to do years ago. Let's focus on doing the exome and genome upfront and then making sure that we educate everyone so that people feel comfortable with any new approach that we have. So I think with genomic first care, that's really going to require a cultural shift in how we approach diagnosis in the NICU.

But what does it take to successfully integrate this into NICU workflows? It takes an amazing team. This is definitely a team. Think about any protocol you've put in place, right, in the NICUs you've worked in. It does take that understanding of what is the stepwise approach. So as you think about this first in education, right, why are we doing this? And why is this important to me as a clinician and to your patient? So that's the first thing is that initial buy-in, because we all have seen what happens when something new comes into the NICU and there isn't that initial buy-in and you've got these factions who are some people are pro and some people are not so pro. It's that same, the concept of change transformation happens in the NICU with great regularity. Someone wants to change the oxygen requirements. Okay, we're going to have higher SATs, lower SATs. Let's figure out that protocol. Same concept here. So we have to have that protocol clearly identified.

So clear guidance on who to test and when. You do need access to testing. So the ordering system has to be easy. We don't want to add more pain and stress. We all love that EHR so much. And we want to make sure it's very easy to order and that people understand what they're ordering for which situation. That alignment on workflow is extremely important, not just in the NICU, but also with your lab department, which means you want a trusted lab that's providing that expert interpretation. And then the clinical support to help guide patient care, right? I remember when I first started doing HULT. genome sequencing and I got a very big report and I didn't know what to do with it. I didn't understand it all that well. So having that next step of, okay, I'm not a geneticist, what do I do next? That's important to know who your resources are, where you can get guidance on the next step. And then that family-centered care, that conversation is very important for the nurses and the NICU teams.

So what's one thing a NICU could do today to start moving this forward? So I think the first thing is to let's take on the test, right? Let's get a workflow in place and ensure that people are aligned and that we do have it available because we know there are issues with access to care, right? And we don't think about it as much in the NICU as I think we should. But having that consistent and equitable access for testing is very important for the right patients in the right setting. And that earlier diagnosis is going to help the day-to- day care decisions that are so important. So the first thing is really what we're doing now. This conversation we're having and then people who listen maybe go back to their NICUs and say, have we talked about this? Are we gonna consider genomic testing, should we start learning about this? Because I do think that's one of the biggest barriers is the awareness that the test exists and that it's covered by insurance and that there's support for people who utilize the test.

So that greater alignment across care teams is very important as we roll this out in every single NICU everywhere. So looking ahead, where do you see genomic testing going in neonatal care? My dream? My dream is that genomic testing is standard of care, that every newborn actually gets a genome as opposed to our limited newborn screening approach. So instead of having different state approaches with a panel, unfortunately, I do know people who went through the standard newborn screen, it did not pick up a disease that that child ended up having. And if only they had had that identification early on, it would have made a significant difference in their child's life and in their life overall. So I really believe in exome and genome sequencing as being newborn screening. That's my dream. At a minimum, I would ask all of the neonatologists and NICU nurses and nurse practitioners and PAs to use genomic testing as a first-line approach to any baby they see could benefit from this.

Thank you, Linda, for joining us today. This has been such an insightful conversation, and you've really armed nurses with so much knowledge so that they can bring this to the bedside and hopefully make your dream a reality. But I think the biggest takeaway from today's episode that just having these early answers can change everything. It can change how we communicate, how we care for the baby. and how we can support our babies in the NICU. So thank you so much for joining us today. I'd like to thank GeneDx for sponsoring today's episode and supporting this important conversation about the growing role of genomics in neonatal care. Make sure you never miss an episode of NANNcast by subscribing now. This podcast is made possible by listeners like you. Thanks for your support and letting us into your ears. Have a great day.

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