Kids' Wellness Matters Podcast Ep. 27: What Every Parent Should Know About Genetic Testing

Genetic screening and testing have advanced greatly over the last few decades. Dr. Mindy Li, a medical geneticist, and Annie McRae, MMS, CGC, PA-C, a physician assistant and genetic counselor from Lurie Children's discuss the evolving nature of genetics, the value of genetic counseling, and the promising future of genetic testing and therapies.

“Our genetic testing just keeps advancing. You look back to the Human Genome Project, which was this massive project, involving five or six countries and $3 billion, and it took over a decade just to map out what we now use essentially as like the reference, letter code for our genetic sequence. That testing can now be done in a really short timeframe. We're talking like hours on prenatal samples in some cases in a pregnant mom.”

- Dr. Mindy Li

"I would say it's almost in a minority of patients who we diagnose that there is a clear family history of that disorder. So, it's certainly not a hindrance if there's not a lot of family history known. Even if there isn't a family history of something, that doesn't mean that the child is not a candidate for a genetics evaluation."

- Anne McRae

Show Notes

• The field of genetics has advanced rapidly with more tools available now than there were decades ago, leading to new developments of treatments.
• All genetic conditions exist on a spectrum but environmental factors, such as parental support and access to developmental services, can lead to an optimization in patient outcomes.
• Some common reasons for genetic consultations for children include neurodevelopmental differences, multiple or highly specific congenital anomalies, hearing loss and growth abnormalities.
• Newborn screening is a public health program that aims to screen for specific diseases, in the newborn period, that can be treated. It includes screenings for hearing, congenital heart disease and oxygen levels.
• Family history is a significant part of genetic screening and can help determine if recessive conditions might be present.
• Social media has proven to be a modern-day support network for families with rare genetic conditions.
• The genetics division Lurie Children’s provides families with a team of deeply knowledgeable clinicians and staff who have expertise in diagnosing rare conditions and who are interested and invested in understanding and creating new treatments and therapies.
• Over-the-counter, direct-to–consumer genetic tests are not recommended to determine health risks or factors. If there is concern and need for genetic testing, medical professionals should be consulted, according to Li and McRae.
• The rapid growth in genetic screening and testing is likely to lead to the general population having access to screening before concerns or symptoms are present, as well as leading to more therapies and treatments for rare diseases.

Transcript

[00:00:00] Dr. Nina Alfieri: Welcome to Kids’ Wellness Matters. I am Dr. Nina Alfieri

[00:00:07] Dr. Rob Sanchez: and I'm Dr. Rob Sanchez. We are both parents and pediatricians at the world renowned, Ann and Robert H. Lurie Children's Hospital of Chicago.

[00:00:15] Dr. Nina Alfieri: On this show, we'll chat with a wide range of experts about caring for children from newborn to young adults because kids' wellness matters.

Rob, this has been one of my most highly anticipated episodes, and I can't wait to hear it. Genetics is one of the most rapidly changing and evolving fields in all of medicine, but what does it mean for parents and families? We're gonna explore that today.

[00:00:50] Dr. Rob Sanchez: I love your enthusiasm for it because one of the things that I love about that too is because of our increased understanding of DNA and how these things work. We're able to do so much, and it's changed so much. Even in just the past few decades, like since we went to medical school, since we were, you know, in training or even beforehand, our understanding of, of these conditions and how DNA and genetics plays a role in our health has just grown exponentially. It's been wild.

[00:01:19] Dr. Nina Alfieri: Yeah, and it's amazing to think about how many benefits there are to having increased access to testing and Just having more technology for genetic testing, but it's really nice to also have a geneticist on our podcast today to help explain the implications of genetic testing because it's a lot more complex than I used to think.

[00:01:38] Dr. Rob Sanchez: We're so happy to have Dr. Mindy Li, an attending physician and medical geneticist, and Annie McRae, a physician assistant in genetics and genomics and certified genetic counselor on the episode today to talk about the advances in the field of genetics and what parents need to know about genetics before and during pregnancy and throughout childhood.

[00:01:56] Nina Alfieri: I'm so excited to learn alongside you what's happening in the field of genetics here at Lurie Children's and beyond.

[00:02:06] Dr. Rob Sanchez: Welcome Dr. Mindy Li and Annie McRae to the show. Welcome y'all. Thank you for joining us.

[00:02:11] Annie McRae, MMS, CGC, PA-C: Thank you very much for having us.

[00:02:13] Dr. Rob Sanchez: We're so glad to have you because this is something that's probably on the minds of a lot of parents. And so right off the jump, Annie I'm gonna ask something to get a sense of what you think is important about this topic. What might be one thing that you would really want parents to walk away knowing after today's episode?

[00:02:26] Annie McRae, MMS, CGC, PA-C: One of the biggest changes that's happened of recent, especially in the last decade, is that our testing in this field of genetics has advanced rapidly. There's a lot more tools that are available now than there were 20, 30 plus years ago. Allowing us to lead to developments of treatments and things that were not possible I think many years ago.

 We know genetic testing can be an incredibly powerful tool. I think another thing that I always want families to understand about genetic testing is that it's not always as clear cut as it may be portrayed. It's portrayed as a very black and white positive, negative kind of results and genetic testing interpretation, now with this massive amount of information that we're generating, it can in fact even have kind of a fair bit of subjectivity. So depending on which lab we test for, we may get different interpretations of the exact same results. And there's also some kind of fluidity when it comes to that interpretation too. So things we don't know the significance of today, we expect, you know, to hopefully learn more over time. And then there's things that we think we fully understand today that also may evolve too. So it's kind of a living study. That's why I think ongoing check-ins with a genetics team are really helpful to maintain the most kind of up to date understanding of test results. Because we are just inundated with data and trying our best to comb through it, but our interpretation can't keep up with the technology that's coming out.

[00:03:40] Dr. Rob Sanchez: So important to know that this technology is new, that it's evolving in really important ways. The next point is a big one. How do genetics and environmental factors, also nature versus nurture, work together in shaping a child's health and development?

[00:03:54] Dr. Mindy Li: So in our field, we definitely see the interplay of these two things. Technically when you think about genetic testing, that's running specific tests to look at the simple genetic code that we have. But we now know and we continue learning that just because you actually have a specific test result doesn't necessarily mean that you're going to have, let's say the exact same findings as someone else, who has the exact same test result. We have seen that time and time again with many conditions. And so, we know that there are other types of factors that affect how the genetic instructions work. Environmental factors we think also can play into some of this. This is how you can have a family where something's running in multiple family members, but they don't show all the same findings. So that's one example of how we know those things were kind of interacting. And then also there are some conditions that are really not fully understood. We have identified some factors that are clearly genetic, but there's other cases where we still can't identify the cause and, again, there's likely other factors that are going into it. Things like autism would be a really good example of that. That's one condition where some things are just very clear cut. Okay, this is the genetic cause of it. But there's other cases where you can't find a cause for those things.

[00:05:09] Annie McRae, MMS, CGC, PA-C: Yeah, like you said, almost all genetic conditions exist on a spectrum, and there are certainly as yet unidentified environmental factors or non-genetic factors. There's probably other genetic modifying factors that we don't know how to interpret or test for in the same way. And I think another kind of environmental factor that I always talk about with families, things like parental support, having access to adequate developmental services, for example, can help optimize individuals' outcomes. So, we may have this genetic predisposition for developmental differences over time. But the environment that child's in, the services they have access to, or maybe an understanding of their medical risks that allows us to anticipate or intervene or screen are also environmental factors that can help improve outcomes, although not in the same way as, environmental modifiers that we don't understand as well.

[00:05:59] Dr. Rob Sanchez: I think that totally makes sense and I often will have those kinds of conversations, especially when meeting with families and in my primary care practice, when we have this visit and we're starting to consider maybe some genetics testing. I oftentimes will have that conversation about what role that their environment that they live in and are surrounded by could have an impact, but also just factors relating to genetics and inheritance. Are those the kind of ways that you present it to families that maybe you're meeting for the first time in clinic and just saying yeah, it's a complex component and we try and assess what we can and optimize what we get. Is that kind of how you all approach it when you meet families who have those kinds of questions?

[00:06:34] Annie McRae, MMS, CGC, PA-C: Yeah, and I think we're all pretty transparent too, that we certainly don't have all the answers or, genetic testing is not a crystal ball. And I think being able to leverage that we don't understand everything. Here's some tools that you may have and here's ways that the genetic information can inform or maybe give us some anticipatory guidance. It's definitely a nice conversation that we have with families. Also owing to the big aspect of these diseases that we don't yet understand and hope to, someday.

[00:07:03] Dr. Mindy Li: Yeah, and I would just add too, sometimes, there are diagnoses that, just because you get genetic testing, whether it's positive or negative, would not necessarily take away that clinical diagnosis of what you see. When families come see us in clinic, we are having a big conversation about the testing that's part of the genetic counseling that goes into it, and what a lot of our genetic counselors help with. Annie has some unique background here because she's a genetic counselor as well as a PA. But that's why we try to make sure they understand, sort of the benefits and the limitations of the testing. A common question is, oh, well if we don't find anything, does that mean it's not genetic? And that's not true. Negative testing just essentially means that you were not able to find anything and that's using that test and what it was looking at. There's still a lot that we don't know.

[00:07:48] Annie McRae, MMS, CGC, PA-C: Yeah, and I think that kind of circles back to even the first point of an important thing for parents to walk away knowing too, is I think it's our best selected cases are our most comprehensive tests. The estimated yield on the high end is like 40% or so. It can vary, based on a child's symptoms. That means the majority of the time that we do our best test, even in cases we are suspicious about, we still don't find an answer. So that's, again, why the counseling aspect and ongoing follow-up is important.

[00:08:15] Dr. Rob Sanchez: So, what might be some of the most common reasons families would need to begin interaction with the genetic counselor or medical geneticist? This might even happen before pregnancy begins. How do you all approach that?

[00:08:25] Dr. Mindy Li: Because our technology has advanced so much, that does also mean our testing, even prenatally has advanced quite a bit. So, there are things that can screen positive, during a pregnancy that might be a sign that there actually is, let's say maybe an underlying diagnosis there and then that would lead to additional follow-up testing, let's say, to confirm whether that condition is maybe there or not. And so that's why sometimes conversations happen even prenatally with a prenatal counselor. Sometimes if there is an actual diagnosis identified, prenatally and confirmed, sometimes families will also have meetings with, not just prenatal counselors, but also geneticists, let's say, who take care of that specific condition ahead of time. After birth, our conditions are divided into two general buckets. One is more what we call general genetics and one that's called biochemical genetics or metabolic genetics. Metabolic genetics would be, a lot of the conditions that show up on newborn screening, for example, and a lot of those conditions have to do with the way your body basically processes energy. And there's often a problem in the breakdown of those things. That's how you might have contact with a geneticist actually quite early, if a patient flags positive on a newborn screen. There are other cases though, like in the general peds practice, for example, we're setting, probably one of the most common reasons, that we otherwise get referrals in the general genetic space would be, let's say there's concern that a child's having developmental delay, not meeting milestones correctly. Also, if a child's born, let's say, multiple congenital defects, then that could be suggestive of another underlying genetic condition. And honestly, these days, some folks know quite a lot of their own family histories and sometimes families come in and say, we're coming here because we have a family history of this, some very specific condition.

[00:10:04] Annie McRae, MMS, CGC, PA-C: I feel like that's a very good summary. And even with our Lurie Children's genetics team here, we'll sometimes see adults that maybe got a genetic workup like 20 years ago, coming back in because our technology has advanced. But neurodevelopmental differences, people with multiple or maybe highly specific congenital anomalies, hearing loss, growth abnormalities like a child being shorter than normal or having a larger head size than expected. And so really one of the very neat things about genetics is that we end up seeing obscure abnormalities and things from all different body systems. So, we kind of become a little bit of jack of all trades, master of none and can really see increasing numbers of indications too. I feel like from when I first started in genetics till now, we're seeing kids that historically wouldn't have even been sent to genetics. So, it's also an evolving patient population.

[00:10:52] Dr. Rob Sanchez: I can certainly relate being in primary care, kind of having that jack of all trades. Dr. Li, I wanted to focus on newborn screening just a little bit. It's mandatory in all fifty U.S. states. Can you explain newborn screening and what parents need to know about it?

[00:11:05] Dr. Mindy Li: Newborn screening is a public health program that aims to screen for specific diseases, in the newborn period, that can be treated. I mentioned earlier that a lot of these conditions fall in the realm of what we consider those metabolic disorders. Again, rare disorders that have to do with the way your body's processing energy and many of the conditions basically fall in that area. But this also includes other things such as babies now get a hearing screen after birth, and babies now have their oxygen levels checked as well to screen for congenital heart disease. So that counts as well. These were programs that were implemented, to try and catch some of these disorders that we realized if you caught early, and if there was intervention, then you could have better outcomes. It started back in the 1960s with screening for a metabolic condition called PKU or Phenylketonuria. And so that's why actually sometimes some folks still refer to it as the PKU screen, but it screens for many, many, more disorders than just that now. There was a national task force that came together, including geneticists and folks in related fields to put together recommended conditions for these states to determine which conditions are being screened for in each state. So, there's a core set of conditions that they've decided that, okay, this is at least the minimum thing that the state should be screening for. But each state also actually has some individual leeway to add other conditions. And so that's screening for slightly different conditions actually depending on where they're born. And it just kind of depends on their state and what's on the test for their state.

[00:12:36] Annie McRae, MMS, CGC, PA-C: I think what's helpful for parents to also know is, like you mentioned, it is a screening test. So of course, categorizing screening studies is different from diagnostic studies. If you get a phone call about an abnormal newborn screen, it doesn't automatically mean your baby has the diagnosis, but really that they just need further diagnostic workup. And there's, depending on the condition, a high rate of false positive screens as well. Some are definitely more specific than others and that's really why it's so important for specialists with familiarity in interpreting this really early on. And also, why there's kind of, the Illinois Department of Public Health, as I'm sure it happens in many states, kind of designates people who are qualified to kind of do that diagnostic workup once a screen is positive. So, it's a small group of people we're very, intimately knowledgeable about the newborn screen and interpreting it and really able to help gauge the true concern when we make that first phone call to parents.

[00:13:28] Dr. Mindy Li: I know in the newborn period there's so much going on, I know it can be really stressful to get this call, it's not necessarily even from their pediatrician, depending on the state that something is off on the screen. But I also want to echo what Annie said, that, in many cases it's actually not positive. It's not truly positive. But, part of the reason why we end up with false positives is that we have to make sure the cutoffs are reasonable enough that we won't miss cases and so that's why there ends up being the ones that kind of fall in there. But some of the ones, for some conditions, for example, you may end up screening positive, but you in fact don't have the condition. But you're actually what we consider even like a carrier for the condition, which means you don't yourself actually have the condition but have some instruction that works. But it's helpful information to kind of know down the line when the child's older. But that's actually how some kids get picked up and it doesn't end up being true. But you know, there are of course cases where it's true and that was the whole goal of this screening, to make sure you don't miss the cases that really be seen.

[00:14:25] Dr. Rob Sanchez: You'd mentioned, having some of these things that they might be carriers for Some of that can be done from things like newborn screens, but also just knowing folks' family history. How important is family history when it comes to potential genetic concerns?

[00:14:37] Dr. Mindy Li: Well, we are genetics, so we definitely are the field that goes into family history, probably in more detail than perhaps other groups in medicine. It's all important to us. It's definitely a really significant piece of evaluations that we do. We always do at least a minimum if we consider a three-generation pedigree, which is where the main patient is at, parents, grandparents and sometimes you can extend further depending on the situation. Every family's different. In terms of, you know, why they're coming in. And, sometimes, there's a lot known about the family history and the child's coming in actually because so and so in the family has this condition or something and it's very laid out and it actually tracks they know a whole lot. And there's other cases though, where we have patients where they're adopted and you really just don't have very much information at all or limited information. We do the best just taking what we can and what the parents and families remember and then we use it to work with that. And sometimes there are very clear patterns and sometimes there's not, for conditions where they can be what we consider recessive conditions. Meaning you have to have two copies of the instructions in your body because everyone gets half from mom, half from dad. You have to have basically two things, both sides not working to cause a problem. But if you only have one change, alluding back to the carrier status we were talking about, you could be walking around and most carriers don't know that they're necessarily carriers for that condition. So that's how in the family history though, when you look at it, you wouldn't expect, let's say multiple family members having that condition. That's very different from some other conditions we have where the medical word is dominant, meaning it is something that can be technically visible. Also, if you lay out that pedigree from generation to generation.

[00:16:16] Annie McRae, MMS, CGC, PA-C: Yeah. And I feel like sometimes there is a misconception that just because there isn't a family history, how can it be genetic? It's not in my family. There is a big difference too between something being genetic and something being inherited. So, there's a large class of genetic conditions that are typically brand-new genetic changes in a baby or what we refer to as de novo. I would say it's almost in a minority of patients who we diagnose that there is a clear family history of that disorder. Either because, like Mindy said, it's kind of inherited in a way that is masked in the family or it's just a brand-new genetic change in that baby. So, it's certainly not a hindrance if there's not a lot of family history known. Even if there isn't a family history of something, that doesn't mean that the child is not a candidate for a genetics evaluation.

[00:17:00] Dr. Rob Sanchez: I'm curious if y'all have any tips, to help parents to start documenting family health history? What are some good ideas of how to go about that?

[00:17:07] Dr. Mindy Li: Yeah, I think it just starts with a conversation with family members. And every family's very different. You know, there are some families that don't necessarily talk about these screens, you know, because you're asking kind of more personal and health questions versus other families. People are just talking about it because let's say there's just something specific running in the family, then you start asking all the questions. So I think the first thing is just, is, almost just to ask yourself, well, have you ever asked your brothers or your mom or dad, or your grandparents actually about their history? That's a good starting point just to say, oh, maybe I should ask. And then certainly when we see families for evaluations it's pretty common where, once you know a child's coming for, whatever reason they're coming in, that also sometimes prompts the question of oh, does anyone else have the same thing?

[00:17:50] Annie McRae, MMS, CGC, PA-C: And I think some of the additional things we kind of ask about or query at least a little bit more closely are maybe just atypical diagnoses in the family. Many people have several, chronic non-genetic conditions, but are there any individuals who just had a very rare, atypical diagnosis or maybe a more common diagnosis like cancer or high cholesterol, but at an atypically young age? Those are additional things that can maybe be a clue for us. And honestly, sometimes we may uncover things when we take a pedigree that have nothing to do with why the child is coming to see us, but that clearly are concerning for an inherited predisposition to a certain risk factor. So sometimes we pivot and certainly address what we're seeing in the family history as well, even if it is a bit disparate for why the child's coming in.

[00:18:34] Dr. Rob Sanchez: I like to focus on areas where you are able to meet that genetic diagnosis. What are some of the benefits of having a genetic diagnosis for a child and the impact it can have on the family and the child themselves?

[00:18:44] Dr. Mindy Li: One of the more common things we've seen that seems to really help families is that it just provides them with an answer. For some families, they've been searching for a long time, or they've had to see a lot of specialists, and they knew something was sort of off but were never able to find out why. And they say, oh, here it is. That's it. And then, you can sort of stop that workup. And the second part is though, once you name it, once you find out what it's and these days a lot of our conditions, we mostly go off the name of the gene, just because there's so many genes. We have more than 22,000 in our body and we still don't know what all of them do. These days, because of the internet and social media, there are, in most cases, not all, but you know, it's getting there you know, support groups and many rare diseases have foundations already set up by active parents and supporters for those diseases. I think it's really helpful for some families who really are looking for that support as well. Because you deal with a disease, it can be difficult for families feeling like they're the only ones. But when you start seeing that there's like support groups and other researchers out there who are looking at these things and you have a way to connect with other families. It's something that can benefit them. If they want to, you know. We also have families who alternatively, they get a diagnosis, and they don't necessarily want to get super involved with support groups, which is okay as well. Like, everyone has a different level in terms of what they want to know and, do they want to meet other families or not. As we said, I think earlier in the podcast, I think Annie said this, almost every disorder can present a spectrum of it. What applies to their own child may not be the same even if they meet another family who has a child with the same diagnosis. But either way, I think these are some things that can help families once you know what you're looking for, because it's otherwise, you know, you're just kind of clinically monitoring them and not necessarily knowing anything else specifically to look out for.

[00:20:29] Annie McRae, MMS, CGC, PA-C: I kind of joke with families, to your point, Mindy, about like, support organizations. I never thought that in my medical career I'd be talking about or referencing like social media for families to access about their condition. But some of these ultra rare disorders, we're limited to what's published in the literature or what we may have seen. And so, we may say to families, there's 30 published cases of this in the literature. And they're like, oh, well there's 78 kids on the Facebook page. And so sometimes there's even I'll see, you know, a really rare manifestation, like I'm not really seeing this as much in the published cases. And parents say like, five other kids on the Facebook page have that too. It's a really interesting time. Just the absolute interconnectivity of the world as much as it has its downsides allows for connection for these ultra rare families that previously probably were very isolated. And then I think the other thing that having the confirmed diagnosis also allows for is the possibility of research opportunities. So many research studies may require a genetic diagnosis, even if you think you understand the family, you know, of the condition that child has. So, opening the door a little bit to possible research opportunities. And then, like Mindy said, just allowing for improved management, maybe allowing for additional body system monitoring that you weren't looking at or even setting expectations or possibly prognosis.

[00:21:46] Dr. Rob Sanchez: Yhat positive application of the social media sphere, it can be really empowering. And sometimes that leads to really good conversations. Sometimes in the conversations I have, and I imagine it's the same for you, that can lead to making sure that they have appropriate support in school. It can be connecting them with different specialists Especially if certain organ systems are involved? It might lead to future screening testing and things like that. Are those other aspects that you're able to see in working with families once you are able to come to a diagnosis?

[00:22:11] Dr. Mindy Li: Yes, definitely. Aside from just the, you know, medical screening that we think that might be appropriate these days, a lot of our patients are coming to our attention a little bit younger, so they're oftentimes navigating the school system. And, and every school system and the resources available to the families just varies all over the board So when we have patients who have a specific diagnosis we definitely do things like, write support letters to make sure that they can get their IEP or their Individualized Education Program to make sure they have all the resources that they need, on some cases a child let's say is more on the mild, and let say there are some kids who can slip through because they're not moderate or severe. And so then people might say, oh, you don't qualify for X service. When in fact because of the diagnosis, they're still at risk, you know, and adding the extra layer of support for them can help. And it's definitely like a common issue that we see. We tend to follow a lot of these kids a little bit more frequently when they're younger, especially going through these transition stages between school, preschool, kindergarten to elementary age, to make sure that they have all the support and resources that they need as they're navigating these things.

[00:23:15] Annie McRae, MMS, CGC, PA-C: And I think at a family level too, once we confirm a genetic condition in one child, it allows us to much better define the recurrence risk. So, if a family is still considering having more children, or sometimes with older children and adults that we evaluate, their siblings are starting to think about having children and for that family to better understand how this moves through the family, if it does at all. You know, really being able to concretize that information for the family can be really important.

[00:23:43] Dr. Rob Sanchez: Lurie Children's treats some of the most common genetic diagnoses, but also some of the most rare, can you speak more to that? To be in a place where you can help families who are managing some of the very rare conditions, and the extra support that you can provide in your work in the genetics division over at Lurie Children's.

[00:24:00] Dr. Mindy Li: Yeah, I think families are typically pretty appreciative to meet the least familiar team they may not have seen, 20 of the same diagnosis, but, part of the reason why we go through lots of training to be exposed to as much as we can. I'm like 10 years into practice and there are still genes I have not specifically seen, but there are many diagnoses that even though I may not have seen in person yet, I would recognize them, just based on the way I've learned and what characteristics might show up. I think families are appreciative just to know,  we do our best to support families. And our genetics community is also very small. As in, if someone's written the one paper, you know who is that one person studying this one condition? Personally, just being here at Lure Children's, I had the same experience where, you know, when I was in training, I started studying a rare condition called Trisomy nine mosaicism. And so this is a condition where your body has an extra copy of the ninth chromosome. So when I came to Lurie Children's that was one clinic that I felt was important to try and develop. And so we developed it and it exists now. And that clinic has actually expanded to care for patients with different kinds of variations of the ninth chromosome as well. The condition was rare enough, even rare enough in the genetics world, that there wasn't really a good place for families to go and at least have someone who's a little bit more familiar with these types of changes. And now there is, and I learned along with my families, because you have to see a lot of families to then really actually gain the expertise in it and, so it took, a long time to kind of gain that knowledge. But, even over the next decade, I'm sure I'm going to continue learning even more than I do now. Thanks to the willingness of families who come to the clinic and some even are able to travel and come see us. So that's, I guess, a practical example of how that works sometimes in rare genetics.

[00:25:50] Annie McRae, MMS, CGC, PA-C: I was going to kind of echo them, sometimes learning alongside the families too, because there's kind of a tiers of rarity. There's some conditions that are rare enough, a family's never heard of. Or maybe, other providers haven't heard of it, but we've heard of it. And maybe there's some kind of management guidelines, even if they're not very robust. And then there are the kind ultra rare conditions where there's such limited information and you really have to be invested and find a community of maybe other subspecialists who are also going to be interested and invested and create a specialty team for your family. Really working with not as much information as we would ideally have, but continuing to learn alongside these families. And I think that's one of the wonderful things, being at an institution like Lurie Children's, everyone's at their core, just kind of a nerd that wants to learn about rare things and help families, of course. And so it's the combination of the two and you just have to be invested and interested in things that you care about, which can be uncomfortable as a provider too. But you have this experience to make a difference in caring for these kids.

[00:26:52] Dr. Rob Sanchez: That truly felt so impactful.

Separate, even beyond some of the rare disorders, genetics is really helping us understand some of the more common childhood conditions that can be out there. Things like autism, ADHD, allergies. Can you speak to some of the impacts that work in genetics is affecting on how we understand some of these more common conditions?

[00:27:10] Dr. Mindy Li: Yeah, with every day that passes, we learn more and more about genetic construction or genes that are involved with all of the things you just said. We know genetic changes can happen and maybe increase your risk for some of these things, but in some cases it's not something you can necessarily test for. For example, you know I mentioned earlier we do have some very clear genetic causes of autism. These are genes that have to do with the way the brain functions. And that's why you see the features that can happen in autism. But allergies are a good one. We know that there can be genetic instructions that increase someone's risk but we don't have, like, here is the genetic test. If you have seasonal allergies or any other, severe allergies here and this is what you do. We're not quite there yet. And some of that is because some of the changes you find are more what we consider like risk factors. They're not things that are just very clearly passed on, you know, based on some of those, classic, dominant or recessive inheritance that we were talking about. And so that's why it can make things tricky. But we definitely do know that they are genetic factors that play into a lot of these more common diseases. We even now know, for example, there are genetic changes that can be subtle, to a point where sometimes they may not show in a parent, like the parent carries a gene, but just happens to not show those findings. But then in their child they have some subtle findings and it's not always, let's say like severe developmental delay or something. It could be just some minor learning difficulties, ADHD, things along those realms. And so we're starting to learn a little bit more about those types of genetic risk factors. Some of which we can test for and some of which are not so easy to test for.

[00:28:48] Annie McRae, MMS, CGC, PA-C: Yeah, I would kind of echo that. I think in clinical practice we're kind of identifying rare causes of common things, which just adds to the overall data and helps us understand how multifaceted these apparently common conditions really are. More children are kind of being tested but that data is being generated and there, I think over time we're going to be able to better understand and put together maybe these 10 little risk variants come together in a symphony. And then there's a really increased risk for this common thing. At this point, less commonly observed in clinical practice.

[00:29:19] Dr. Rob Sanchez: Can you explain a little bit more about what carrier testing is, why it might not be recommended typically? But what might be some certain conditions that might justify for parents to pursue carrier testing for their child?

[00:29:31] Dr. Mindy Li: Carrier testing, as we mentioned a little bit earlier, would be testing for conditions where, basically there's one instruction that's not working well, but the other one is working fine and your body, just needs to have one at least working fine. And then it can otherwise function fine. That's why you may not show symptoms. Basically, this is something that is relevant at the time of, when someone's thinking about family planning, of course, because depending on the carrier status of your partner, then a couple possibly may be at higher risk for having a child with a specific condition depending on their carrier status. Typically, it's not carrier testing in a non-reproductive age group is not typically recommended in the sense that it wouldn't change what you're doing day-to-day management wise for that child because the child doesn't have that condition, if that makes sense. And that's why, for the most part, it's not something that's just done. And also every single person walking around this planet is a carrier at minimum, probably for about three to five recessive diseases. So you can't always find actually what those changes are because our genetic testing is even as advanced as it's now, is still not able to pick up like, all the rare variants that might exist, especially in some individuals who might have a genetic ancestry background that has not just been looked at as much. So, we don't know as much about those changes to carry testing on everybody is not very practical. But you know, many folks, it's certainly recommended for folks when you're getting to that age. You can actually find some of these changes in families, already, honestly, due to things like family history. Let's say, a common example would be the BRCA gene, where, you know, it puts you at higher risk of breast and some other cancers. And if there's just a very strong family history of early onset breast and ovarian cancer, it's possible someone else in the family has had testing and then, that prompts the question within families, to eventually get that done. And these days it's not recommended to do that, certainly for young children. But the conversation does come up if they get to like teenagers. And the other reason too, why you don't just run these tests is that you have to allow that child later to have some autonomy as an adult to decide whether they would want that information.

[00:31:32] Annie McRae, MMS, CGC, PA-C: But we kind of separate the concept of carrier screening as a reproductive risk tool, from presymptomatic genetic testing for adult-onset conditions like the RCA one and two. Which, like Mindy said, individual autonomy is one of the central tenets of genetics. So whenever possible, we like to uphold it. There are cases maybe in older teenagers who can provide assets and, working with our dedicated cancer genetic counselors, can talk through the benefits and limitations of testing. This has definitely evolved with the increased uptake of these very broad genetic tests that we're doing. So now, you know, we test where we're essentially looking at all the genes in the body or at least a portion of all of the genes in the body. And when families consent to this test, they do actually have the option to include some of these adult-onset conditions for the child, even though it's not really the reason they're doing the testing. But I think the rationale with the genetics, kinda medical bodies, when we started testing everything, it's, we're making this data exists. And so the lab may be aware that there is this predisposition that is actionable. And so families really should have the option to opt in, to get that information. So many years ago, the concept of doing presymptomatic, adult onset testing in a child, was just not done. And now it's evolved along with the fact that we're just testing so broadly. But there are medical-legal kinds of implications too, which is why genetic counseling is so important. There's things like, life insurance, disability, long-term care insurance that can discriminate against a healthy person based on a genetic risk factor for disease. It could probably be entirely dedicated podcast to the topic.

[00:33:08] Dr. Rob Sanchez: Annie, you mentioned some of the complications that can come up from other types of testing. And so I want to touch on over the counter genetic tests. Can y'all speak to why it's recommended that parents don't use these to collect genetic information on their children?

[00:33:21] Annie McRae, MMS, CGC, PA-C: Probably another topic there could be a whole podcast about. There are a lot of different versions of direct-to-consumer testing. Many of them are maybe kind of more aptly thought of as almost like, recreational genetic testing. I'll say there's something to be said about the effort behind, like the affordability and the access to these studies. But at the end of the day, if it's a clinical question, it requires clinical testing. There are some types of direct-to-consumer testing that are a little more similar to the clinical testing that we do. May assess for things like the BRCA gene. So cancer predisposition, even those still require clinical validation. There's this large group of these kinds of more wellness ancestry, risk, direct to consumer studies that are not typically FDA reviewed and are giving kind of like correlative estimates of traits and risk. It's actually not uncommon for different labs to generate different disease risks, for multifactorial traits, just depending on what markers they're looking at. So in general, medical bodies really don't advocate for direct-to-consumer testing, but especially in children, we don't want families making health or lifestyle decisions for children based on these results. Again, starting to maybe talk about some of the medical legal implications and really at the end of the day If there's concerns about a child's health or development to the point that testing's being considered they should just see a medical expert.

[00:34:37] Dr. Mindy Li: Yeah, I would agree with that. You know, I think, finding out ancestry is very different, yes, compared to some of the other tests where they're talking about this is your risk for X, Y, Z. I think families should be careful when they utilize those types of tests, especially if there isn't access to genetic counselors or clinical individuals who can help interpret some of those things. It's very different, if you're testing for, you know, do you like asparagus versus like, are you at higher risk for cancer, you know? But, in general, I think care should just be taken for sure with those kinds of things, especially for minors.

[00:35:10] Dr. Rob Sanchez: Oh, for sure. I've commonly heard how you taste cilantro. But you're absolutely right. We kind of sometimes deal with genetic testing and things that can probably realistically happen is that there can be cases of, misattributed paternity, or kind of other questions about family relationships. How do you handle those cases and have those conversations with family members?

[00:35:29] Dr. Mindy Li: The way we handle it is, just providing some appropriate counseling, both before the visit and then if something actually happens in the testing reviewing the information after. So, as part of, you know, reviewing testing, especially some of the bigger, broader testing that we're doing these days, that looks more broadly at most of the genetic information. And a lot of those tests are being done as with, let's say parental samples if they're available. So it's like the child and the parents as part of the long consent. We do that because of information involving multiple members of the family. There can be a risk of confirming that the parents are not fully the parents, and so they do receive that information before those bigger tests are done. When you see results like that come back, we go back to the family members to let them know what it is. You know, this is obviously a very delicate topic. So you kind of have to gauge the social situation and the family set up.

[00:36:17] Annie McRae, MMS, CGC, PA-C: Yeah, it really underscores why pre-test, counseling and consent are such a huge part of the testing process. We certainly have had families where we talk through all those risks and then they decide they're not comfortable with them and then maybe don't pursue the testing or, parents don't submit samples. One of our genetic counselors, Andrea Paris, spearheaded a project and presented at the American College of Medical Genetics meeting last year on a designated kind of protocol that Lurie Children’s has in place regarding misattributed paternity specifically. The genetic counseling team worked with our ethics team just to give additional guidance because it can be really tricky and, not the purpose of the testing, to uncover all of this additional stress on a family that probably already has a lot of stressors. If they're having a child getting extensive genetic testing.

[00:37:02] Dr. Rob Sanchez: it's great to hear that there's dedication to making that protocol or organized approach that you can handle those cases in a really equitable and professional manner. So important. The genetics team at Lurie Children's, I know y'all stay current with all the latest developments, could y'all speak to what are some exciting things in the pipeline that might be available for our patients?

[00:37:20] Dr. Mindy Li: Yeah, I think, probably the biggest thing is that our genetic testing just keeps advancing. You look back to the Human Genome Project, which was this massive project, involving five or six countries and $3 billion, and it took over a decade just to map out what we now use essentially as like the reference, letter code for our genetic sequence. That testing can now just be done, in a really short timeframe. We're talking like hours, on prenatal samples in some cases in a pregnant mom. I mean, and that's how much it has changed. Now we're not doing that level of testing, unlike everybody, of course. I bring that up because I think as the time continues on, as that test gets better and we learn more about the information you get back from that and the cost continues to come down. I think that level of testing at some point will actually get into more of the general screening for, what you would consider maybe healthy populations or, you know, extending outside beyond patients who are coming for a specific reason, like, a specific symptom or something that brings them to our team.

[00:38:21] Annie McRae, MMS, CGC, PA-C: I think something that's also been really exciting to see is diagnosing more. Learning more about the pathophysiology or kind of what is happening at the level of the cell that's abnormal or causing the condition of these very rare disorders. We've been better able to kind of create broader categories of individually rare diseases. And then we look at what's happening at the level of the cell and allow us to maybe pull treatments from similar disease groups. So we've had several instances of repurposing medications that were not created for our patients, but that are able to target the same pathway as the conditions. So there's certain cancer medications, that if we dose them differently or repurpose them, we can actually treat patients with conditions that involve that same pathway. Allows us to offer more from actual therapy. A lot of management of that general genetic category is supportive and so to actually start to have interventions and therapies, is really exciting and I think speaks to the fact that we have a lot to look forward to.

[00:39:19] Dr. Rob Sanchez: Thank you for sharing so much of your expertise and insights. Truly it's great. to Know you're working with us here at Lurie Children's. Thank you so much for joining us today, on our episode. and thank you again for the work that you do.

[00:39:31] Annie McRae, MMS, CGC, PA-C: Thank you guys so much

[00:39:34] Dr. Rob Sanchez: Thanks for listening to Kids Wellness Matters.

[00:39:39] Dr. Nina Alfieri: For more information on this episode and all things kids wellness, please visit luriechildrens.org.