Rare Genetic Diseases – PediaCast 398

Show Notes


  • Join us for a look at rare genetic diseases. One or another of these conditions affects 30 million Americans, which means taken as a whole, they aren’t really rare! Dan Koboldt (principal investigator with the Institute for Genomic Medicine) and Theresa Mihalik Mosher (genetic counselor) visit the studio as we explore the discovery, investigation, diagnosis and treatment of rare genetic disease. We hope you can tune in!


  • Rare Genetic Diseases


  • Daniel Koboldt
    Principal Investigator
    Institute for Genomic Medicine
    Nationwide Children’s Hospital
  • Theresa Mihalic Mosher
    Genetic Counselor
    Nationwide Children’s Hospital



Announcer 1: This is PediaCast.


Announcer 2: Welcome to PediaCast, a pediatric podcast for parents. And now, direct from the campus of Nationwide Children's, here is your host, Dr. Mike.

Dr. Mike Patrick: Hello everyone, and welcome once again to PediaCast. It is a pediatric podcast for moms and dads. This is Dr. Mike, coming to you from the campus of Nationwide Children's Hospital. We're in Columbus, Ohio.

It's Episode 398 for February 28th 2018. We're calling this one "Rare Genetic Diseases". I want to welcome everyone to the program. So it is the last day of February and you may not realize it but the last day of February each and every year is Rare Disease Day.

And this was news to me, by the way, I had not heard of Rare Disease Day before. It's been around a while. It started back in 2008 so ten years ago. And, the idea was to raise awareness about rare diseases and unique challenges in researching, diagnosing and treating these disorders.

The defect of relatively small number of people which is an important consideration because as you know, one component of healthcare is business. And, when a relatively small number of people are affected by a particular condition, there isn't always the same drive to research, develop, produce and distribute new knowledge and treatment strategies because there isn't gonna be as much demand for that knowledge and the products which is an unfortunate consequence of healthcare delivery system that's eroded in a free economy.


But the good news is it doesn't have to be this way. And in fact in 1983, the United States Congress passed the Orphan Drug Act and we'll talk more about that later in the program. But the Orphan Drug Act of 1983 began to provide incentives for laboratories and companies that explore advanced treatment options for diseases, the impact small numbers of people.

And in the decade prior to 1983, only ten new treatments for diseases came to market. And since 1983, since the Orphan Drug Act was passed, there have been 500 new FDA approved treatments for these disorders. So how many folks are we talking about when we say a disease is "rare"?

Well, it depends on what country you're in. here in the United States, you're talking about diseases that affect less than 200,000 individuals. So that's our definition. But here's the thing, there are 7,000 identified rare diseases which combined, adds up to about 30 million Americans who are affected by one of these diseases or another.

So about 1 in 10 of us have a rare disease. More than half of those affected are children who may not live as long or get to adulthood because of their rare disease. But again, you add up all those small numbers and you actually have a very large number of families who are affected by one rare disease or another.

Not that we need a large number of people to make this an important issue. I'm just making the point that are diseases when taken as a whole aren't really all that rare. And yet, I had not heard of Rare Disease Day and I suspect many of you haven't heard of it either despite its 10-year history every 28th or 29th of February which is appropriate because the last day of February is the only day that varies every 4 years. Making it rare compared to every other month and day of the year.


See what I did there?

So when I heard about Rare Disease Day, and by the way, it was our Genetic Counseling folks who brought this to my attention when they visited the studio back in Episode 393. When they told me about it, I thought, let's raise awareness and do an episode centered on Rare Diseases.

And in particular, we'll talk about rare genetic diseases. So, genetic diseases does make up sort of the bulk of rare diseases. So, we'll cover those and do it the last week of February. Just made sense.

And, here we are ready to talk about it and hopefully, raise awareness. So, that's our plan today. We'll introduce rare diseases, provide some examples, talk about how they're discovered and investigated, and diagnosed, and treated.

We'll provide lots of resources for you. For those who are facing a rare disorder among family and friends, we'll have those in the show notes. And, we'll cover the topic in our usual PediaCast fashion with a couple of terrific studio guests: Dan Koboldt is a principal investigator with the Institute for Genomic Medicine here at Nationwide Children's Hospital. And, Theresa Mihalic Mosher is a genetic counselor at Nationwide Children's.

We'll get to them in a moment. First though, I do wanna remind you if there's a question you have for me; you wanna make a comment, point me in a direction of a news article or journal article, anything that's on your mind, easy to get in touch. Just head over to pediacast.org and click on the contact link.

Also wanna remind you, the information presented in every episode of our program is for general educational purposes only. We do not diagnose medical conditions or formulate treatment plans for specific individuals. If you have a concern about your child's health, be sure to call your doctor and arrange a face-to-face interview and hands-on physical examination.

Also, your use of this audio program is subject to the PediaCast terms of use agreement which you can find at pediacast.org. Let's take a quick break, we'll get our guests settled in to the studio and then we will be back to talk about Rare Genetic Diseases. It's coming up right after this.




Daniel Koboldt is a principal investigator at the Institute for Genomic Medicine at Nationwide Children's Hospital and research assistant professor of Pediatrics at the Ohio State University-College of Medicine. He previously served as a staff scientist for the Genome Institute at Washington University, where he contributed several high-profile projects including the first cancer genome, cancer genome atlas, the 1,000 genomes project and the Alzheimer's disease sequencing project.

He's currently working on the development of tools for the analysis and interpretation of next generation genetic sequencing. And in particular, how these tools can be applied to the study of Rare Genetic Diseases in children.

That's what we're talking about today, "Rare Genetic Diseases". So, let's give a warm PediaCast welcome to Dr. Dan Koboldt. Thanks so much for being here today.

Dr. Dan Koboldt: Well, thanks. Glad to be here.

Dr. Mike Patrick: Really appreciate you stopping by. We also have Theresa Mihalic Mosher with us. She is a genetic counselor at Nationwide Children's which means she spends lots of time helping young patients and their families as they're screened, diagnosed and treated for rare genetic disorders. So Theresa, thanks to you too for stopping by today.

Theresa Mihalic Mosher: Hi, thanks for having me.

Dr. Mike Patrick: Really do appreciate it. So Dan, let's start with you. Could you just describe what your role is like here at Nationwide Children's? What is a principal investigator?

Dr. Dan Koboldt: Sure. Well, principal investigator is a research position. And so, my particular area of research aims to uncover the genetic basis of rare diseases and pediatric cancers. And, it also comes with other roles, like I'm part of the leadership committee for the Institute for Genomic Medicine.

And, I also have responsibilities to train our analysts and our post-doctoral fellows and other researchers who are part of the group.

Dr. Mike Patrick: Yeah. So, it goes sort of beyond the research itself but also teaching and then contributing to clinical care through your research is also a big part of this.


Dr. Dan Koboldt: Yes, that's right. We also support the clinical operation because IGM has a clinical testing laboratory as part of the everyday operation. So, we work very closely with them as well.

Dr. Mike Patrick: Yeah. And then, what is a typical day like then? What do you spend most of your time doing?

Dr. Dan Koboldt: Well, no two days are alike, really. I mean, I spend a lot of my time analyzing the sequencing data from our rare disease cases. That's sort of my favorite thing to do in hopes of identifying the underlying cause of disease or the disease genes that are conferring predisposition.

I also do some programming because the volume of sequencing data we're working with usually requires specialized software tools to analyze. And then often, I'm working on a presentation or slides or something for an upcoming meeting or a conference call related to one of our research project. And on top of that, I'm supposed to be doing the primary work of every researcher which is to write papers and apply for grants to get funding.

Dr. Mike Patrick: Yeah, so lots going on, lots of different things. So as you say, each day is a little bit different. And I think that there are a lot of folks out there who may be interested and especially parents who may have kids who are really interested in science and may be interested in becoming a biomedical researcher.

What is that path look like? How do you get from being a graduate of high school to getting where you are and doing what you're doing today?

Dr. Dan Koboldt: Well, the classic path is usually through education. You go to college, and then you go to graduate school for a PhD or to medical school to earn an MD. After that, there's usually post-doctoral training of some kind or a fellowship during which you work under a more-experienced researcher to kind of learn the ropes before you start on your own.


That's the traditional route most people think of to become a professor or a doctor or a research investigator. But there are lots of ways to get into the field of biomedical research. A lot of people who just have a college degree can find entry-level positions in the lab.

For example, we have technicians and research assistants. Another way to get into the field which is how I got in is actually if you learn programming.

Because, that is an increasingly desired and valuable skill in the biomedical research filed because we generate so much data and it requires new programming approaches to sort of sift through it all.

So there are lots of ways to get into it and a lot of people just sort of enter the field because they take an entry-level position and work their way up.

Dr. Mike Patrick: Yeah. And so, when you say programming, of course you're talking about computers, and software.

Dr. Dan Koboldt: Right, software coding.

Dr. Mike Patrick: And I think a lot of times, when folks think of biomedical research, you think of a white lab coat and bench science. But then really, computers are a big part of research in medicine today.

Dr. Dan Koboldt: It's true. I was issued a lab coat but I don't really have a good excuse to wear it very often. So, I spend almost all my time working at a computer. We're in meeting rooms or on conference calls but there are a number of people who work almost exclusively in the lab and almost never get to a computer so.

Dr. Mike Patrick: Yeah, really kinda depends on what your expertise is or what your focus is within the research institute.

Dr. Dan Koboldt: Right, and it depends on what your interests are. So you know, for parents thinking about their children and what sort of careers they might like to have. Some people that really like working on experiments and like being part of a laboratory process would be a good fit for the lab. But, people who are interested in analytical problem solving and things like that would make probably good analysts.

So there are a lot of routes that you can take. But usually, the first step is schooling. Finding the right college education and then maybe talking about a graduate program.


Dr. Mike Patrick: Yeah, absolutely. Theresa, we had a show recently, it's Pediacast Episode 393 where we talked really in-depth about genetic counseling. And, I encourage folks, if you haven't, to listen to that program. Again, 393 and we'll put a link in the show notes for this episode so you can find it easily. But remind us again what the role of a genetic counselor is.

Theresa Mihalic Mosher: Sure, yeah. And I think probably, one of the things that people learned if they listened to that other podcast about genetic counseling is the increasing need and differing roles for genetic counselors as time goes on.

So here at Nationwide Children's, of course, a lot of the genetic counselors who work here are working in a primary clinical role. So working closely with physicians, hoping to try and come up with a diagnosis for patients. And, a lot of that, from a genetic counselor perspective, is facilitating testing.

So, genetic testing and explaining that genetic testing to the families and the patients in a way that they can understand. So we call that, you know, "pre-test counseling" is a big part of what the genetic counselors do, explaining what tests do they wanna do. What can this test tell us? What can't this test tell us which I think is an important piece.

And then involved in the post-test counseling. So particularly if a diagnosis is made, sitting down to explain what that means and offering information, coping, support, resources for those families.

So, that's a pretty traditional role for a genetic counselor. And, a lot of what you'll see going on here. But, we certainly have genetic counselors here who do other roles that are not really traditional or patient facing roles. So, we have genetic counselors in the laboratory and that seems to be an increasing need throughout the country is genetic counselors and these other types of roles.

And, we're seeing some more genetic counselors in clinical research roles which is kinda where I found myself now.

Dr. Mike Patrick: Yeah. Tell us more about what your day looks like on a typical day.

Theresa Mihalic Mosher: Sure. So, like Dan said, no two days are the same for sure. You know, I still do some patient care, some patient facing roles in the clinical side. But primarily, I'm working on enrolling patients in this Rare Disease Genomics project that we have in the institute for Genomic Medicine right now.


So, basically that means helping to identify patients that would be a good fit for the program and sitting down with the patients to explain the study. If they're interested enrolling them in the study, so going through consent forms and doing some pre-test counseling. And that setting too, you know, what can we learn from this research project? What might we learn? What might we not learn?

And, what do we get out of it as researchers? What can you get out of it as a patient? And so, having kind of those pre-test, pre-enrolment type of conversations and then also on the back end, you know, talking to the physicians who have enrolled that patient to make sure that they understand where we are in the process and then just wearing a lot of other different hats.

So logistical things, tracking samples, updating databases, and then doing some patient education, working with the team like Dan and others to educate some of the physicians in the hospital about this project and yeah, that's about it. I mean, a lot of different things.

Dr. Mike Patrick: Yeah. You know, as you're talking about this, I'm thinking how difficult it must be to take complex genetic ideas and sort of synthesize those into a form that families really, not just on a superficial level, understand but really feel like they have some ownership in the process and what's going on.

And I think to feel that way, you really have to understand sort of what's under the hood and to take that from complex science to terms they can understand. It must be challenging and rewarding all at the same time.

Theresa Mihalic Mosher: Yeah, it can be a challenge for sure. Trying to assess kinda where people are in their knowledge of genetics. Some people have really read about it before they come in. A lot of patients who are getting enrolled in this rare disease project have kinda been through what we call the diagnostic odyssey.


So, they've been through a lot of other genetic testing that has not provided a diagnosis. So, some of them have a little bit more of a background in what types of testing are available and how genetic testing works. But certainly, kind of, it's a trick of the genetic counselor to try to figure out kinda where they're coming from, what information do they really need to understand and really make an informed decision about, is this the right step for them?

Dr. Dan Koboldt: You know, another role Theresa plays that I'm surprised you didn't mention is genetic counselors are an advocate for the patient. And so, I say this a lot with Theresa, not just sort of updating databases but making sure that patients enrolled in our study get all the way through to the end. That we reach a final conclusion, report the final results back to the clinician. So she's also looking out for the patient that they're involved in the study too.

Dr. Mike Patrick: Yeah, very good point. We're talking about rare genetic diseases today and you've mentioned this a couple of times. What exactly is a rare genetic disease?

Theresa Mihalic Mosher: Yeah. So it kinda depends on what definition you look at. But, so I basically look to see, what does the NIH say is a rare disease? So basically in this country, it's a disease that affects less than 200,000 people. So it's kind of a broad definition. It's not necessarily just a genetic rare disease but about 80% of those are probably, probably have an underlying genetic basis.

Dr. Mike Patrick: Yup and as I was doing some research on this, they were like 7,000 rare diseases currently identified. And, each one of them only affects a small number of people. But there are so many of them that there are a lot of people who actually end up being affected by one rare genetic disease or another.

Dr. Dan Koboldt: It's about 1 in 10.

Dr. Mike Patrick: Yeah, so really pretty common. And so someone that you know, someone in your family, likely has a rare genetic condition.

Theresa Mihalic Mosher: Yeah. And I think a lot of what we see, just in general genetics in the clinic is rare.


And most, everything we see is gonna be rare. Even the most quote, unquote, common conditions that people are referred for. So some examples is Neurofibromatosis Type 1, NF1. That's a condition that has a variety of features. Can put you at risk for benign and other types of tumors. That is, the prevalence of that is 1 in 3000.

So that's pretty rare. It's also considered one of the more common genetic conditions. You know, and we see other things. Chromosome conditions like 22Q deletion syndrome, that's you know, depends on the source you look at but 1 in 4,000. And then we see conditions that are much more rare than that, 1 in 100,000.

Or with new technology, we're finding patients that are one of a handful. And, there's not even a name for it. You know, there's a gene but there's really like a handful of people in the world that have that. So that's obviously a really rare condition.

Dr. Mike Patrick: Yeah. And then once you hit more than 200,000, it does not automatically become, "Oh, this isn't a rare disease anymore." It does seem like that's sort of an arbitrary number. But it just gives you this idea that it's, you know, less than a couple hundred thousand usually.

Theresa Mihalic Mosher: Right.

Dr. Dan Koboldt: And elsewhere, like in Europe because they have different population size. There use a definition of like 1 in 2000 people or if it's more frequent than that then it's not usually considered a rare condition.

Dr. Mike Patrick: So even less. What about, you've mentioned some of the examples. There are things that folks really probably have heard of about before even though they're considered rare. So things for instance like achondroplacia or dwarfism, Duchenne muscular dystrophy, one of the disorders that we talked about recently on this podcast, G6PD deficiency. We talked about that at least it's rare for the United States.

So you can also have disease that maybe in other parts of the world, may be much more common and not considered rare. But in your country maybe it is rare disease. So that was one back in Episode 396 that we talked about Prader-Willi syndrome, Treacher Collin syndrome, things that certainly pediatricians hear about but they're still rare.


And one site that I came across in doing research was the National Organization for Rare Disorders. And, they have a disease database. So if you're interested in any of these diseases that we've mentioned or you know someone who has a rare genetic disease who wanna learn more about it, maybe it affects your family or someone you know, that site has tons of information geared toward not only parents but also providers and researchers, and policy makers.

And for each disease, and there's thousands of them. They have general discussions, signs and symptoms, causes, who's affected? You know, how is it treated? What are some of the investigational therapies? Where can patients and families find support and references?

So I mean really, just a thorough site that I think folks would find pretty helpful.

Dr. Dan Koboldt: Yes, that's a great resource.

Theresa Mihalic Mosher: Yeah, and we use that for patients a lot, especially the support resources. I would say that section is really, it's good, patient-friendly information on word. But also, the links out to, you know, if you're looking for a support organization or a foundation. That is actually, that's a great resource which we offer to patients a lot.

Dr. Mike Patrick: And we'll put a link to that site in the show notes for this Episode 398 so folks can find it easily in the show notes. So Dan, how then if a genetic disease is rare, how does it get discovered and then investigated? I mean, how do you find a rare disease?

Dr. Dan Koboldt: Usually, it starts with a patient or a family that comes to medical attention with some apparently inherited condition. Often the cases that we are working on come to attention pretty early because we often see kids with severe birth defects or congenital conditions.

And typically, the clinical team is the front line. They'll refer the patients for lots of testing, molecular testing, lab testing, and other procedures to see if a clinical diagnosis can be obtained and if it can be supported with a molecular diagnosis.


So there is an increasing battery of genetic testing performed as we discover more and more of this rare disease genes that can be used to get a clinical and molecularly confirmed diagnosis. If that does not succeed, which does happens for a good number of patients, they can be referred to a research study if the family is interested.

And so, that is when someone like Theresa will talk to the family about what a research project entails and what the outcome might be. And then, it'll be referred to someone like me, a researcher, and we'll maybe do additional testing, additional sequencing and see if we can find a new disease gene or a new variant that's never been seen before that causes disease.

Dr. Mike Patrick: Yeah. One word I think families hear a lot is genetic sequencing. What exactly is that?

Dr. Dan Koboldt: It, you know, it can mean a lot of different things. I think most testing now uses something called "next generation sequencing" which is a very high throughput assay for generating a lot of sequencing data usually within a week.

So, if you think back to the human genome project, it took about 10 years and cost about 1 to 2 billion dollars depending on how you do the accounting. Now we have this next generation of sequencing instruments that can sequence an entire human genome in a week for around $1200. So the cost have gone down considerably.

With genetic testing and so-called, genetic sequencing, typically clinicians focus on the set of genes that are known to be implicated in human disease. So that's usually about 5,000-6,000 genes that will get the most scrutiny. But usually, we will sequence something called the exome which is all the genes that are known in the genome.

And then, we'll pay most attention to the five thousand or so that are known to be associated with disease.


And, that's just the sequencing. And then, there's an important analysis interpretation component where trained clinical staff members will review the results that come back in sequencing. Review the individual sequence variance and try and assess whether or not these are likely to be causing disease.

Dr. Mike Patrick: Yeah, and when we say sequence, I mean you're really looking at the individual molecules that are in the DNA that then make up what we would consider genes.

Dr. Dan Koboldt: Right. We're taking the patients' blood usually. They can also be the saliva. And then, that would be sent to a lab for extraction where we get their DNA. And then, we do the sequencing on their particular genome. And like I said, sometimes it's really targeted just to look at the genes.

But on the research side, we do something called "whole genome" sequencing which is where we look at all 3.2 billion base pairs in the genome and try to understand what variants might be likely to cause disease.

Theresa Mihalic Mosher: And so if you look at, if you think about whole genome sequencing in your genetic information as a book of information and instructions book, really, the instruments are reading through that book and typing out what is your individual, unique genome sequence.

And then, it's up to people like Dan to kinda sift through that and say which changes in this book are significant spelling errors.

Dr. Mike Patrick: Yeah, and when you think about all the words in that book and then finding that one, you know, word.

Theresa Mihalic Mosher: Oh yeah, it's like a needle in a haystack.

Dr. Mike Patrick: Yeah, so that's one challenge in doing your work. What are some other challenges and barriers that sort of stand in the way to discovery and investigation of rare genetic diseases?

Dr. Dan Koboldt: I think that one of the major challenges we face is uncertainty because we are really good at sequencing genomes. We're really good at finding the genetic variance. It gets a little more difficult when we're trying to determine which ones are likely to have an effect and be causing disease, and which ones are probably neutral.


So every one has somewhere between 4 and 5 million genetic variance compared to anyone else. And so, we're all 99.99% identical but that's still a huge number of differences. And trying to, most of those are probably not going to give you a severe disease.

So we're, usually when we do research sequencing, we're looking for maybe one or two changes out of millions or even thousands, or thousands that once we narrow it down to just ones that are in genes. So it can be a lot of work to sift through that. And, to understand why certain variance cause disease and others that look very similar to them in the same genes don't. That's one of the challenges we're dealing with everyday.

Another challenge is really getting access to the samples, right? I mean we can only work if patients and their families are willing to participate in research. And, with rare diseases like you said, each one might affect 1 out of 5,000, 1 out of 10,000 individuals.

So every patient is extremely viable to research and their willingness to participate is just a huge asset for us.

Dr. Mike Patrick: Yeah. In terms of funding, it would seem the things that we're talking about can get pretty expensive. How does this sort of research get funded?

Dr. Dan Koboldt: However we can. I mean, usually most research, at least in the United States, is grant funded. It's funded by the NIH. So your tax dollars go to work and researchers like myself apply for competitive research grants to get funding for projects. We also happen to work in a children's hospital that provides significant funding for our research.

And, there are private organizations especially patient groups and disease specific organizations that fundraise and provide a significant portion of research funding for researchers like myself. So, we try, we get it however we can. But usually, it's the public that is funding research.

Dr. Mike Patrick: Yeah. And certainly, donations to Nationwide Children's Hospital through our foundation, and a lot of the activities that we have to raise money and to raise awareness does get funneled into research for lots of things including rare genetic diseases.


Dr. Dan Koboldt: Yes.

Dr. Mike Patrick: Yeah. From a clinical standpoint, Theresa, you talked about sort of helping families understand genetic testing. How are rare genetic diseases, how are they diagnosed?

Theresa Mihalic Mosher: Yeah, so there's a couple different approaches and I would venture to say the model is kind of changing as to how we do it over time as our technology improves. So kind of the traditional way would be, you know, you'd go see a geneticist or another specialist and you get an evaluation, and they think of rare condition that fits your symptoms. And, they test you for that either by one single gene. They say, "Let's just test this one gene. I think this is what you have."

Or, a panel of genes that can be associated with some of the features that you're showing. So, based on your symptoms and the way you look, they, you know, what they see on the clinic evaluation that will guide what testing they order.

And so, that's kinda been traditional approach to diagnosing genetic diseases. Kind of the newer approach is you know, you go in, you have an evaluation, we collect all your family history information and just kinda like we normally would.

But if there's not something that immediately stands out or if it's possibly more financially cost effective to order one test like the whole exome sequencing which is a newer test that can look at essentially all of your, the important sections of your genes, the coding regions of your genes. They can look at all of those in one test rather than kind of taking the stepwise approach. You know, one gene and then another gene and then another gene if we don't find something.

So, it's kind of a newer way we're going about. I mean, of course if a patient comes in and we think they are classic for a specific syndrome then we order that test and that's the best way to go.


But a lot of patients are kind of getting this, more bang for your buck type of test, honestly. And we can get more information more quickly.

Dr. Mike Patrick: Yeah. So I mean you could do the entire sequencing of the patient's whole genome if for about the cost that you would get the CT Scan or an MRI, or you know, that kind of thing.

Theresa Mihalic Mosher: Yeah. So in the clinic, it's the whole exome testing, not, most people aren't doing a whole genome sequence on their patients. The exome is just the exons in the genome. So, and that is pretty cost-effective to do. And then, a whole genome is probably coming down the pipelines. You know, in the future, not too far off future for a clinical use too.

Dr. Mike Patrick: Dan, when you mentioned 1200, was that for the exone?

Dr. Dan Koboldt: Yeah, don't quote me on that.

Dr. Mike Patrick: No.

Dr. Dan Koboldt: That's just a reagent cost to do the experiment.

Theresa Mihalic Mosher: Yeah, the actual clinical of a whole exome right now is about $7000.

Dr. Mike Patrick: Okay. Well, that may be a little more than that. A series of MRI's, how's that?

Dr. Dan Koboldt: Right, and then has to account for not just the experimental work but the highly-trained people to have to interpret the data that comes out of that. And, that really is an art form in an increasing area of focus because it takes such a long time and it takes such a certain expertise to be able to distinguish what variants are causing disease. So, that's the analysis component. The clinical interpretation is a big part of the cost of genetic testing.

Dr. Mike Patrick: Yup, and there's a business piece of this as well. And, we talk about patents and as you're coming, as you're figuring out how to do these tests that are also a part of medicine today.

Dr. Dan Koboldt: Right.

Theresa Mihalic Mosher: And certainly, it can add up just doing single gene testing. You know, if every gene costs a thousand dollars or a couple thousand dollars, or you're looking at a panel that costs, you know, $10,000. Sometimes then you're gonna say, "Well, we could do a whole exome. That's more cost effective"

Dr. Mike Patrick: Yeah, absolutely.


So let's say we have a patient. We have done the genetic testing. We have figured out which rare disease that they have. How does that identifying the disease then help us in terms of coming up with a treatment strategy?

Theresa Mihalic Mosher: So if you have a diagnosis, you know, the first thing that your doctor is gonna do or your genetic counselor is gonna do is go look at what other patients with that same condition have had. And, what symptoms have they had, what treatment have they had, and what's worked.

You know, so a lot of times, we sit, tell people we can't go in and fix your individual genes. We can't usually cure things like that. Although, you know, we're getting there, with some conditions.

Dr. Mike Patrick: Sure.

Theresa Mihalic Mosher: But we can at least know what to look for for the future. So if maybe you're at risk for things down the road, we can do some screening. We can send you to appropriate specialists. So if it's a well-described condition, then there's usually guidelines on what kind of management and treatment can be effective.

You know, sometimes we do get these conditions where you're one of a handful. And then we kind of, you're kind of, informing us and we're following you closely. And, we're making some educated guesses on what the best management plan is gonna be for you.

Dr. Mike Patrick: Sure.

Dr. Dan Koboldt: I would say there's also just a value in the knowledge for the patients and their families as to what, what is the cause of this disease. And, what is the inheritance model that this one have, ramifications for when. Your children wanna have children. I mean, this is an important part of the counseling aspect.

Dr. Mike Patrick: Yeah and also, just the natural course of the disease. Once you know what it is, you have a little bit more power in terms of prediction of what things are gonna look like a year from now, 5 years from now, 10 years from now. So folks, you know, have heard of gene therapy. What is gene therapy and how does that relate to this?

Theresa Mihalic Mosher: Yeah, so I'm not an expert on like the exact mechanisms of how gene therapy works. But the goal behind it is to really replace the non-working gene.


So you know, and we've, I think probably heard a lot of people around here have been hearing about that SMA's, spinal muscular atrophy, gene therapy that's going on. Here that's really been promising. And so, that's helpful because they can really target the specific problem there which is the muscle.

And so, you know, you can give the patient the missing gene or the gene that's not really working properly to compensate for.

Dr. Mike Patrick: Yeah, it's interesting stuff and I'm not an expert on it either. But if folks think of it as the DNA is sort of a code that the cells use to make things like proteins and things that the cell is gonna need to work and function properly.

And if the genetic code is making a copy of a particular protein or molecule that's maybe not quite right, you know, it's still making it but it's not the right version of it. If you can sort of snip out that code and insert the code for the right molecule, you know, then the right enzyme, protein, whatever gets made.

And then hopefully, as that cell divides and you have more of them, that right code still goes along with the new cells. It's much more complicated than that.

Dr. Dan Koboldt: You're right.

Theresa Mihalic Mosher: And of course, I think the challenge becomes when you have a condition where it's in every cell in your body. Because you know, the genes in every cell are affected. You know, how do you deliver that good gene to every cell?

So it's becoming effective with conditions where they can target specific areas. So when you know the muscles are affected or you know it's a vision problem and the eyes are affected, and you can deliver those quote, unquote, good genes directly to where they need to go then it works.

But when it's widespread it can be a challenge.

Dr. Dan Koboldt: Right, that's great. It's funny you mentioned eyes because it seems like the most early successes we've had in gene therapy have had some certain things in common.


First, it's usually limited to a certain tissue or system that's accessible for therapy. So muscle is one. Some really, trials that have been successful in gene therapy are also for inherited forms of blindness. So that's one thing they have in common is that it's sort of limited to a certain tissue.

Another is the timing. Right, because both of those conditions like inherited blindness and spinal muscular atrophy are conditions where it deteriorates over time. So when the child is born, usually most of their tissue is healthy. And most, their eyes work and their muscles work.

And so that is the intervention window when we can use something like gene therapy to intervene. So in contrast of that, a number of the rare diseases that we see are the result of some genetic defect that happened maybe during development and affected a tissue that was developing.

And there, it's harder to say, "Oh, gene therapy is the answer." because really the change already exerted a defect on the development. And the child or the patient is going to have to deal with the ramifications of that. There's no going back in time.

Dr. Mike Patrick: Yeah, that totally makes sense. And, it shows that there's, it's not a one size fits all sort of approach. I mean there are instances where it's the current production of a protein that you can try to manipulate. And on the other hand, where something happened long ago, yeah, like you say, you can't go back in time.

As we think about the treatment of these and we also sort of mentioned the business of medicine, drug companies want to make a profit. And yeah, there's also the push to have medication treatment for folks who have rare genetic diseases.

And sometimes there can be sort of a barrier there in terms of development of drugs because there's not enough of a demand for those drugs. And so then that's what we would call on "orphan drug", where there's, you know, where there's maybe a lot of money that goes into development and there's not a lot of demand on the other end.


And in fact, this was a pretty big problem in the decade leading up to 1983. There were only 10 products that were developed by the pharmaceutical industry for people with rare diseases. Again, showing there wasn't much demand to sort of stimulate production.

And then, congress enacted the Orphan Drug Act in 1983 which provides incentives for companies to develop treatments for rare diseases. And today, there are nearly 500 FDA approved orphan drugs. So again, it just shows you that the business part of it is big but sometimes it takes government, sort of, coming in and say, "Hey, we need to be fair and you know, help folks who need help."

Dr. Dan Koboldt: It does. And you know, when you mentioned 500 rare diseases that maybe have a treatment now that's out of 7,000 known rare diseases so we still regretfully only have treatments that are approved for like a very small fraction of rare disease patients.

If 1 in 10 people have it, the odds that they have one of those 500 have a therapy are usually pretty low. So that's, orphan drugs are an area where we really hope that there will continue to be development.

I mean those incentives and things are really necessary because if you think about it, it takes 10 years and millions of dollars, sometimes billions of dollars, to get a drug to market from through all the clinical testing, and the marketing, and everything else.

So anyway that we can incentivize companies to do that even if there isn't a huge body of patients who will be buying the drug, I think we should try and pursue.

Dr. Mike Patrick: Yeah and it's not just the development of it. It's also showing that it's safe. That it's not gonna have untoward effects.

Dr. Dan Koboldt: Right.

Dr. Mike Patrick: So all very important things to consider. And, with these orphan drugs too, don't necessarily completely cure or, you know, bring a person to, you know, a hundred percent in terms of treatment.

I mean it may make things easier. It may make them live a little longer but it's not, still gene therapy would, you know, if we can do it would be better.


Theresa Mihalic Mosher: Right. And I think, you know, even for well-described conditions, like a just heard a talk about, I think we both were at that talk about Down Syndrome and kind of the latest, and greatest and what's going on.

So that's a well-described condition but they, still even, you know, for that it's not a high enough demand for some of these companies to, you know, so they're piggybacking on to some other drug trials for other things like Alzheimer's that have bigger population to target.

And so, you know, you hear all these unfortunate stories about these things that seem to have an effect for patients with Down Syndrome but then kinda don't really get picked up and don't go anywhere with the drug company because they don't work for the primary target which is the bigger audience.

Dr. Mike Patrick: Yeah, absolutely.

Dr. Dan Koboldt: Another area that is kind of an active area of research for, especially for targeted therapy is in cancer. And, something like 50% of people with cancer have one of the rare forms which sort of, pancreatic, thyroid, any form of pediatric cancer, any brain cancer.

And so again, that's another area where there's not always a huge patient population that would justify a drug company normally investing under normal conditions to do that. And, genomics has a lot of promise for this area too because we can sequence the DNA of a tumor. We can sequence the healthy DNA from the patient. And, we can do comparison to see what are the genetic changes that maybe are driving the tumor growth.

And, are any of those affecting a gene that we now have a drug that will target? So that's another area where genomics is really helping guide therapy and may have really great potential to help improve the patients.

Dr. Mike Patrick: Yeah. I'm glad you bring that up because one cancer may have a common name but really, the problems that are happening at the genetic level or at the DNA level in the tumor is maybe different from one person with that particular cancer to another.


And so, treatment's gonna be different and you can base that on what their genetics or what their DNA looks like in those cancer cells.

Dr. Dan Koboldt: Exactly. And, there's even research into trying to boost a patient's immune system to target their specific tumor cells which requires sequencing because we need to know what are the precise changes that make distinct a tumor cell from the normal healthy cells.

And if we can, is there a way to train the immune system of the patient to attack just the tumor cells and eliminate those. And, that's a really promising area.

Dr. Mike Patrick: Yeah and this is all developing so quickly that someone listening to podcast 10 years from now, listens to this episode, things are gonna be different and there's gonna be changes and advances. And so, it's really an exciting time. Really, to be involved in this sort of research and clinical care that you guys are involved with.

Theresa Mihalic Mosher: Yeah, things have been moving fast just since I was in school. You know, whole exome and whole genome sequencing was the wave of the future. And now, we're you know, it's pretty.

Dr. Mike Patrick: The future is here.

Theresa Mihalic Mosher: Yeah, it's pretty daily we're dealing with them.

Dr. Dan Koboldt: If you think about it, the Human Genome Project was completed in 2001. And that was sort of a completion of the first handful of human genomes. And, it took such a long time and super expensive.

And now, hundreds of thousands of genomes have been sequenced. So the pace of technology advancing has been very extreme. And, it's an exciting time to be working in the field but we're also thinking about the next generation.

They will certainly be opportunities for kids that pursue STEM education. And so, we really encourage parents to try and get their kids interested in that sort of stuff cos there will always be jobs in science technology, engineering and math fields.

Dr. Mike Patrick: Yeah, absolutely. As you're counseling families, Theresa, sort of the back into this, once the diagnosis is made, what resources then are available to help families through that?


We talked about one, the National Organization for Rare Diseases, Disorders. What are some other things you recommend and can help patients with?

Theresa Mihalic Mosher: Sure. So if you are diagnosed with something that is a well-described condition, whether it's really rare or not, if there's a lot known about it, usually you can find a foundation or support group, or a group online that provides education and support.

So a lot of, you know, parents have gotten together and they have created groups on a national level. But then, you know, there's usually some state organizations. So you know, I mentioned Down syndrome earlier. Of course, there's a National Down Syndrome Society. But then, each state and most major cities have their own smaller subset of that.

So I encourage people to either look for those foundations or those support groups in your specific diagnosis or ask your doctor or genetic counselor to provide that information for you if it's available.

For conditions where that's not really feasible or for people who don't live in an area where that's, you know, you can get to those support groups easily. There are organizations that are kind of pulling their resources, I would say, to try to kinda help give more information for these really rare conditions where you're one of a handful and we don't know a lot about it.

And kind of creating some algorithms, I guess, I would say, is to how we go about investigating this and how we go about documenting it. So certainly, there's clinicaltrials.gov is a website that if you have a diagnosis, rare or not, you know, you can go there and you can, or your doctor can find out if there are trials going on.

Sometimes there are what we call Natural Histories Studies. So they are just really learning about the condition and documenting over time what the features of that condition are.


And then you know, you have others that are medication or drug trials and other, you know, bone marrow transplants, things to that extreme. So those are options that are available. Of course, there's some bigger websites that you can go to. Gene Reviews is one that is more provider medically oriented but Gene Reviews does have patient support information kinda like NORD does.

They'll link you to some patient support sites. And then if you have a chromosome condition, specifically there's a group called the Unique Chromosome Condition website where you can go and look up more common conditions but also some more rare chromosome deletions or duplications.

And then, we have like Genetic Alliance Global Genes, and these are groups that, like I said, they're kind of trying to pull resources for this really rare conditions. So they're not necessarily specific to one condition.

But if you have a rare condition, they still have resources and support available for you. And I'd really miss if I didn't mention rarediseaseday.org. You know, tomorrow is Rare Disease Day. And they are trying to kind of raise awareness about rare diseases for, you know, just people in the general population. But also to try to affect public policy.

Dr. Mike Patrick: Yeah, absolutely. And, we'll put links to all of those resources in the show notes for this Episode 398 over at pediacast.org. So folks can find them and connect pretty easily. We'll have, again, the link to Rare Disease Day which we talked about in the intro to this program.

And also, that genetic counseling show at PediaCast 393, we'll have a link to that. And then also, National Organization for Rare Disorders and again, tons of information at that site. Not just for patients and families but also providers, patient organizations, industry, researchers, just advocates in general, lots of really targeted information which I thought was great.


And then of course, in-depth educational content for all of those audiences. Practical tips for getting involved. And again, we'll put links to that in the show notes over at pediacast.org.

Theresa, tell us about the clinical genetics program here at Nationwide Children's Hospital. What can folks expect when they see genetics here.

Theresa Mihalic Mosher: Sure. So we have a group of geneticists and genetic counselors. So usually, when you know, we'll get referrals for a variety of things. It's impossible to really say. But we, you know, we get referrals for babies who have birth defects, children who have some developmental concerns.

Sometimes with or without other features like seizures or heart problems, brain changes on imaging. We sometimes see teens or adults. So we do see all the way up through adulthood depending on the features.

And you know, a lot of those are issues maybe that developed later on. So an example is like a connective tissue problem where you have, suddenly having joint problems or joint dislocations.

And we also see babies that are flagged as having an issue on the Ohio Newborn Screen. Or people that just have a family history of a known genetic disease and desire counseling and testing for that.

So quite a wide array of referrals that we get. And usually, you'll see a geneticist and a genetic counselor as part of your visit. And we'll, the genetic counselor will get a detailed medical history. We'll draw out a pretty detailed family history.

The physician will do a detailed examination and really looking for clues. So looking kind of like, we think of them as the Sherlock Holmes of the medical field because you're looking for subtle things that could point you in a direction for testing.

So unusual skin findings, different things about your toes and fingers that maybe in somebody wouldn't notice. But, you know, just subtle things that can maybe put the whole picture together for the geneticist and say, "Oh, maybe we should test for this."

So and then of course we have the conversations about, "Do you think we should do testing? Should we not do testing? Should we kinda take a wait and see approach?" And if we do wanna do testing then there's the conversation about what that would entail.


Dr. Mike Patrick: Yeah. So I mean really, lots of services for a big, diverse population. Lots of different conditions and situations and scenarios, and we'll put a link in the show notes for the Genetics and Metabolic Clinic here at nationwide Children's Hospital as well. So folks can find out more information about that and connect with it pretty easily.

And you see folks, not just here in Central Ohio, right? From all over, who come to see the genetics folks here at Nationwide Children's?

Theresa Mihalic Mosher: Yeah, certainly. We primarily serve Central Ohio, I would say. But we definitely get people coming from, you know, far corners of the country and the world to, you know, see us or seek a second opinion on something. Or they've been through the gamut of testing and they just kinda wanna know, "Is there anything else available?"

Dr. Mike Patrick: Yeah. Well, Dan Koboldt and Theresa Mihalic Mosher, both of you, thanks so much for coming by and especially here as we think about Rare Disease day and just chatting with us and educating all the folks. Really appreciate it.

Theresa Mihalic Mosher: Yeah. Thanks for having us.

Dr. Dan Koboldt: Thanks for having us. This is fun.



Dr. Mike Patrick: We are back with just enough time to say thanks, once again, to all of you for taking time out of your day and making PediaCast a part of it. We really do appreciate that.

Also, thanks to our guests today, Dan Koboldt, principal investigator with the Institute for Genomic Medicine here at Nationwide Children's Hospital. By the way, Dan has a blog called "Kids Genomics". And we forgot to mention that during the actual interview. But I will put a link to it in the show notes over at pediacast.org for this Episode 398, along with all those other terrific links.

So be sure to check that out. Lots of great information for moms and dads, and physicians, investigators, policy makers, you'll find, regardless of sort of what's your role is as we consider Rare Diseases. We have lots of information there for you in the show notes including Dan's blog, Kids Genomics.

Also thanks to Theresa Mihalic Mosher, a genetic counselor here at Nationwide Children's Hospital. Also, really appreciate her stopping by and sharing her expertise with all of us.

Don't forget you can find PediaCast in all sorts of places. We're in iTunes, the Apple podcast app, Google Play, iHeartRadio, Spotify, most mobile podcast apps.

Also have a landing site where you'll find our entire archive of past programs including our show notes, transcripts of the program, our terms of use agreement and of course, that handy contact page for you there as well.

We are also part of the Parents On Demand Network which you'll find at parentsondemand.com. It's a collection of podcast for moms and dads, and that collection includes PediaCast along with many others.

There's also a Parents On Demand Mobile app which you can find in the app store in Google Play. The network's also featured in iTunes so you can subscribe to each show easily.

Another one of the shows in that network that you may be interested in is called the Expectful Podcast. I mentioned one for pregnant moms a few episodes back called "Preggy Pals" which has a lot of great content.


But that particular show is on hiatus so good stuff in the archives though. Nothing new moving forward ay least for the time being. However, if you are expecting a baby or you know someone who is, another pregnancy podcast you may wanna check out is the Expectful Podcast.

Just to give you a little snapshot, some recent episodes include #IHadAMiscarriage Pregnancy Loss and Grief. And that's an interview with a clinical psychologist, Dr. Jessica Zucker, talking about miscarriage and grief.

Another one, Stronger Together, with fertility educator, Jake Anderson. And, fertility, emotional wellbeing and in-vitro fertilization with Dr. Jamie Knopman and Dr. Sheeva Talebian, both who happen to be reproductive endocrinologists.

So not your typical pregnancy podcast in terms of just, not that it's a bad thing, mom, you know, talking about their pregnancies. That's very helpful and resourceful. But this one actually has a lot of interviews with healthcare professionals.

And so, that's why I recommend you to take a look and listen if you are experiencing a pregnancy or you know someone who is. And I'll put a link for you so you can find it easily in the show notes for this Episode 398 over at pediacast.org.

Also don't forget wherever you get your podcast, if you could just take a few seconds and leave a review for Pediacast, always very helpful. I don't know about you but whenever I'm looking for something new, whether it be a podcast, something to watch on TV, a product, a movie to go to, I always look at the reviews.

And so, the more reviews that we have out there, the more helpful it is for other parents who are searching for evidence-based information as they really try to take great care of their families. Also don't forget we're on social media. You can find Facebook on, Facebook, you can find PediaCast on Facebook, Twitter, Google Plus and Pinterest.


And of course, we really appreciate it when you share the show with others, face-to-face. Just let your family, friends, neighbors, co-workers, babysitters, grandparents, you know, anyone who has kids or takes care of kids, please let them know about program.

That includes you child's teacher, and of course his or her pediatric medical provider. And while you have their ear, let them know we have a program for them too. PediaCast CME that stands for Continuing Medical Education.

Similar to this program, we turn up the science a couple notches. And we offer free, you heard me right, free Category I-Continuing Medical Education credit for those who listen. Shows and details are available at the landing site for that show, pediacastcme.org. And that program is also on iTunes, Google Play, iHeartRadio, Spotify, the Apple podcast app, most other mobile podcast apps. Simply search for Pediacast CME.

Thanks again for stopping by and until next time, this is Dr. Mike saying stay safe, stay healthy, and stay involved with your kids. So long, everybody!



Announcer 3: This program is a production of Nationwide Children's. Thanks for listening! We'll see you next time on Pediacast.

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