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#202 Duchenne Muscular Dystrophy with Ann Martin and Madhuri Hegde

by Kira Dineen
September 16th 2022
00:00:00
Description

Learn about a genetic disorder called duchenne muscular dystrophy! We explore the genetics of DMD and treatments available with two experts in the field.

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there's no way I'm the only one that's getting sick of zoom conferences. Um it's great to be able to talk with people from all over the world. But I have to say the in person conference, there's nothing quite like it. So I'm really excited to be going to the Connecticut Janet counselors association's first conference in person. Jackson laboratory is gracious enough that they're gonna be hosting us on friday october 14th and they're in farmington Connecticut. So that's in the middle of Connecticut. Um, I'm honored to be moderating for the roe versus wade panel where we're gonna be discussing the implications for practicing and safe harbor state like Connecticut new york other states around us. Other presentation topics include apologetic risk scores, inclusive practice for L G B T Q I A plus patients building credentialing or packing a lot in. We also built in networking time so that we can meet you chat, get to know each other. So really looking forward to this. There's a link in the show notes to register. Um it's $25 if you're going for no, no see us and then it's 50 if you're going for see us. Um and it's three hours worth of see us.

So pretty decent. I really hope I get to see you there. How is it that we find ourselves surrounded by such complexity, such elegance, the genes of you and me made a the same. Hi you're listening to DNA today a podcast and radio show where we discover new advances in the world of genetics from genetic technology like CRISPR to rare diseases to new research. We have you covered for a decade DNA today has brought you the voices of leaders in genetics. I'm cured. I mean I'm a certified genetic counselor and your host to learn about disorder a genetic disorder called Duchenne muscular dystrophy. I am joined by genetic counselor and martin who serves as the VP community research and genetic services at parent project muscular dystrophy. Our other guest is going to be familiar to loyal DNA Today listeners. She's returning to the show. She's a world renowned geneticist, Dr Madhuri Hegde from Perkinelmer genomics.

She's the senior vice president and chief scientific officer of global lab services at Perkinelmer genomics. She was back on episode 1 77 of DNA today which was really fun episode where we geeked out on the power of whole genome sequencing. So I definitely recommend you go back and listen to that at some point. And speaking of episode recommendations, we also chatted with cure rare diseases. Um Who the guest on the show Rich has a brother that has D. M. D. That was episode 1 56. and links to all of these episodes will be in the show notes which are available at Vienna today dot com. And if you're listening in podcast app usually just swipe right um and you can access that but as I teased earlier we're gonna be exploring Duchenne muscular dystrophy which we're going to call D. M. D. For short. Um I'm particularly interested in the genetic testing aspect and the genetics of it and treatment for D. M. D. But before we get into all of my questions and I'd love to have you start us off with really just defining what D. M. D. Is and what is the average age of onset for symptoms that we see in people that have D.

M. D. Right well Duchenne um like so many genetic disorders is really a devastating diagnosis for families to receive. Um It's characterized by a progressive loss of muscle. Um So that results in deterioration of the skeletal muscle but also the heart and the lungs. Uh Boys are typically diagnosed between 3 to 5 years of age although this still varies considerably even within the United States. Um They usually present with trouble running, trouble climbing stairs, frequent falls, they often have enlarged calf muscles. Um and sometimes even language delays. Um in addition to their gross motor delays. So I would say those are the most common signs. But in terms of progression, Boys with Duchenne usually end up needing a wheelchair for mobility around about 12 years of age.

Sometimes a little later if they're using corticosteroids. Um but many unfortunately die in their teens or twenties from uh cardiac or respiratory failure. And as you said it really is a devastating disorder because right now it's primarily boys that are affected and that boys are passing away in their late 20 or late teens early twenties because of the heart muscles that are affected. Because we're looking at this being a muscular disorder and we have to remember that the heart is made of muscle. Um when we're looking at this disorder um certainly being in the genetics community things maybe more, we would say something as common versus like, you know, I think in the general population would be considered rare. So how frequent is D. M. D. In the population? Right, well in the United States we see about one out of every 5000 boys born um are affected with Duchenne and um like you mentioned, I think the X-linked inheritance means that many more boys are going to be affected than girls.

And I think yeah it's certainly good to know that that inheritance pattern is that um only females can be a carrier of D. M. D. Um So that's certainly something that comes up a lot in my work as being a prenatal genetic counselor. Um Why is it important for people to be offered carrier screening before they're trying to conceive? Because I'm gonna go on my soapbox for a little bit um you know, coming from the prenatal perspective, but why is that important? Instead of just saying oh everybody should just do it during pregnancy? Well, gosh, I mean I feel like the early years, you know the more options you're going to have. So I know is genetic counselors, we always like to say that knowledge is power. So um we really encourage families whenever there is a diagnosis of Duchenne and you know, please talk with their relatives especially their female relatives and make sure that they're being offered genetic counseling and genetic testing because um like I said earlier, you know, the more options you're going to have.

And I think another important part of that is when we're looking at carrier screening. Most of the time when someone comes back as a carrier, they probably don't have symptoms themselves but D. M. D. Is an exception to that rule. Um So what type of symptoms can a carrier of D. M. D. Have themselves even though they don't have the full disorder? Right, well we know that women who are found to be carriers are at risk for cardiac complications. That's by far the most serious complication and that would be dilated cardiomyopathy. Um so all female carriers are now recommended to see a cardiologist um starting at approximately 18 years of age and then routine follow up really based on that baseline exam. Um Some female carriers can have neuro muscular symptoms such as cramping or muscle pain weakness. Um And then of course there are the rare females who actually have more classic signs of Duchenne and they have been called in the past manifesting carriers or the true manifesting carriers.

Um I think we're trying to use newer terminology and call them females with destroyed Ganapathy but they're often still called manifesting carriers. Yeah I think that's good for people to realize that they should be starting to meet with a cardiologist. And most people when they get carrier screening, usually they're over 18. So basically if you end up learning that your carrier of D. M. D. You're probably over 18 so it's good to book an appointment with a cardiologist as soon as possible. You know it seems like at that point. Um I mean with the increasing adoption of expanded carrier screening and prenatal genetic screening and testing with Amniocentesis and CVS are we starting to see a shift where people are diagnosed earlier as we said, most people that have it are our boys and usually symptoms would have their onset at like 3-5 years old. But with all of this carrier screening and prenatal screening our people more often diagnosed when they're asymptomatic before symptoms even start. Yeah I mean we have definitely seen a huge increase at P.

P. M. D. In terms of the number of women the number of women reaching out who um you know have no family history of Duchenne or Becker but then they're diagnosed as a carrier through the expanded carrier screen that's being offered at most O. B. G. Y. N. Offices now. Um So this can certainly be a really challenging situation as you know as a prenatal counselor yourself. Um So you know it's especially challenging when we're identifying some in frame deletions and duplications that maybe have not been reported before in the literature. That makes the genetic counseling really difficult. Um And we've actually worked with several families now where we've um done familial testing and found that there are adult males in the family who carry that in frame variant but are apparently asymptomatic. So which is surprising. Very surprising. It's definitely um I've been very eye opening and learning that the more we know, the more we don't know.

So yes, that's the theme of this show, I think. Yes, for sure. Support for DNA today comes from the people for the ethical treatment of animals also known as Peta whose scientists have developed the research modernization deal a strategy to phase out ineffective experiments on animals with high tech state of the art research. Peter has collected an abundance of evidence demonstrating that the use of animals and biomedical research hinder scientific progress and puts patients at risk learn more at P E. T A dot org slash new deal. Again, that's Peta dot org slash new deal. Have you heard of track gene track jane is a clinical genetic software solution used by over 1000 genetic experts around the world. You can customize the front page. So it's streamlined to your specific workflow. The intuitive patient information entry page makes data entry efficient and user friendly pedigrees are also easy to draw and document. Here's another vital feature. It supports H. L. Seven integration to be used with other clinical genetic software databases and hospital information systems.

So you can build custom reports with the simple drag and drop report builder. This has an interface with data visualization tools such as those from Microsoft to make it easy workflow and there's more features on the way all designed with us. Mind as the genetics expert. Track gene has an experienced team has been working in the clinical genetic industry. Forget this over 15 years. You can request a demo for free go to Track Gene dot com. Again that's T R. A. K. Gene. So track without the sea dot com. Stay tuned for upcoming episodes of DNA today where we're gonna be chatting with Track Gene and so as an is bringing up you know the genetics of D. M. D. This is you know interesting and I'm also thinking about you know as we were talking about like carrier screening like more people are finding out at that point. Um Dr Hector when we had you on back on episode 1 77? We talked a little bit about newborn screening and how Perkinelmer is really a leader in this field. Do we see D. M. D.

On newborn screening or is this too hard because onsets later? Like how does that work? Not yet. Not yet. I like that answer. You know significant effort from many advocacy groups really led by P. P. M. D. And in a lot of physicians and so a lot of activity around that to get D. M. D. Included in the rust panel. Unfortunately it is not that easy either. You know, one of the criteria for newborn screening is that there has to be an effective intervention. Um and that's been challenging. Right? I mean, if you look at the list of disorders that are included in the Rust Panel, I mean you've got 60 fibrosis there and it has always been there. Um but edition is right now not on rust and there is significant activity going on around that. But having said that what Perkinelmer did a couple of years ago was take a little bit of a proactive step in uh you know, getting into the direction of newborn screening.

So Perkinelmer has a C. K. Mm as a approved FDA approved for new bonds. So that as it could be easily put into any laboratory which is doing the state labs which are doing on newborn screening, it just goes on the same instrument which is used for the FDA approved other assays. So in terms of readiness for newborn screening as an essay is it? S a available. Yes. So but ck mm is not the primary biomarker for decision. That's something to be remembered. I mean there's so much debate around several things for dilution. Right? It's not the primary biomarker. The second thing is that the, you know, the affected gender is males. And and and I have been on several meetings and committees where this discussion comes up should the testing be limited to two gender, two males only. But that is not the principle of newborns training.

That would be a whole another level to it. Like we don't stratify in that way. No but also manifesting carriers unknown. So there's no reason to limit it. And then you know follow up testing is very important. So if C. K. Is high then it needs to be sort of go to tier two which is a molecular confirmatory testing. And fortunately in the molecular world, things have evolved significantly like what we talked about on our episode of whole genome sequencing that we have come such a long way. I mean I remember my PhD most of my PhD was on D. M. D. And you know we were doing the 32 plaques pcr for 32 exons to look for deletions and duplications had to be done by sudden lot and we have come from that today too. You can look at deletions, duplications and point mutations in one single asset. So things that we and you know I remember talking about the cost of the assay at one point and things have come a long way since then.

Also that the cost of the essay itself has also reduced significantly. So in terms of the testing I think we are there. Right CK mm is FDA approved to be done for newborn screening and then follow up testing for molecular to identifying the precise molecular event and that is a very important step because now many startup farmer companies are jumping in into rare diseases. Unfortunately there's a huge interest in D. M. D. There are different strategies that are being designed right now to address different types of mutations. And there's a whole list of pharma companies right now which are interested in addition, largely due to the efforts of P P. M. D. Um so we are getting closer to that point. But I think the next step really is that early diagnosis step right where we either get it in the oven screening or make sure that in the pediatric evaluation the baby, well check visits that it's included that this this is an important disorder to be included in that early check sort of process.

Especially in the first two years of the first three years when the baby goes to the pediatrician. Yeah, that makes sense. So in terms of workflow, more population based screening for infants with the biomarkers you were talking about. And then if something comes up with that biomarker screening, then dive into the molecular genetics. Am I getting that right? Because I mean, D. M. D. Is the largest known human gene, which I think was one of like the quiz questions that like sGC for for one of the companies, maybe it was one of you guys, I would think. but there's 79 exxons and 2300 killer bases. So it's massive. This is a huge huge gene. So it makes sense that the genetic testing is really complicated. And as dr Hector was saying like you did your thesis on this like you're doing you know back for PhD like having to do multiple different types of assays to be looking at one to get information on one gene. Yeah so you know it's really interesting so if someone, so you know we were talking about it from like a population screening standpoint let's hone in a little bit more on if we're suspicious that a child has D.

M. D. Either because we found out that the egg donor or the biological mother is a carrier of DND where we're like okay now we know there's a 50% chance or for some reason there's some other suspicion. Maybe their male cousin has D. M. D. Something like that. What is the first genetic test they should order at that point when we're talking about a certain person that were suspicious for. I mean I still think initially the you know I guess it really depends on the setting but typically the first test ordered is the C. K. Test because it's such a quick and simple test and inexpensive um And you know the C. K. Is always dramatically elevated and boys with Duchenne and even Becker um you know in some cases where there's a known family history I think obviously and especially if the genetic variant is known. We could do um familial mutation testing just to look for that specific variant. But I'd say most of the time we're ordering the next gen sequencing panel um you know through perkinelmer which you know really identifies as Mcgury said all of the deletions duplications and and the smaller um copy number variants.

So that is really the best test to or again like science has come a long way. And today we can also take and do the testing on multiple sample types. Right? So dry blood spot, cars, saliva or a whole blood sample many pediatric cases at times it's difficult to collect whole blood. Um So you know there are different options available now to do the test. And what I mean is you can do on the same blood spot the C. K. S. A. And the same spot can be used for the molecular testing. And the reason I mention this is that you do not want to lose a child to follow up right um You want to make sure that the testing gets completed and by that I mean that if the C. K. Is high you know the next step Molecular confirmation occurs and you know I think and I have been through many situations where you know over the past 20 years. You know sometimes you see this depends on where the test is getting done right.

People live in different geographical zones and maybe, you know, the access to testing is to just limited to doing deletions and duplications only. So if that is negative, you want to make sure that the testing is completed. Look at the point mutations as well. You know what we have at. Perkinelmer is just one single assay. And that was really my intention. That I did not, you know, knowing the going, having gone through this exercise of, you know, lost to follow up the physician doesn't know what to do next. Having that one single asset which catches everything was very important. But the options are many now and I think this is really important to remember that making sure that the testing gets completed. F CK is high is very important. I think also important is to point out that we've really worked hard to reduce any barriers to genetic testing. Um that was the whole point of P P. M. D. We launched the decode Duchenne genetic testing program, which is a free testing program that we actually run with Perkinelmer genomics.

Um but we started the program back in 2013. Um, and it's really been a phenomenal program and just a great example of how, You know, it's industry sponsored, but it's industry working with an advocacy organization and working with a laboratory to truly benefit the community because we've been able to provide free testing to over 2000 individuals at this point. And we do not only diagnostic testing, but also free carrier testing, which has been huge for, for women. That that is huge because some of these programs that I hear about, which it's such a beautiful combination of like nonprofits and industry working together to get people this, you know, no cost genetic testing. Um, but usually, you know, some of my questions are like, oh, well, do you offer carrier screening then? They're like, oh, we don't offer that part. So it's really cool. You guys are extending that part of it as well because a lot of people are looking at future pregnancies Or their siblings are like other people in the family that are certainly having a chance to also be a carrier or be affected.

So it's really cool to hear. And I didn't realize to be honest how long to code Duchenne has been going on. So you guys are going on 10 years next year. I know big anniversary coming up. Yeah, yeah, definitely. I feel like we should record this next year except I want to get this message out to people right. Um, and I think something else I want to pull out of what we've been talking about is once you get to the point where you're doing genetic testing, you know, if the biomarker levels are high, um, you know, it's important to make sure you're right, you're ordering the right genetic testing. So in like, you know dr Hector, why is it important to include the deletion duplication analysis. Like there's all these different aspects of the genetic testing. It's not just oh sequences we don't see any variants or mutations. It's it's more than that. So the d. m. d. gene is a unique gene in the human genome not just by size but also the types of mutations you see. So most of the genes, what we see about 80% of the events are point mutations and about 20% are deletion duplication.

D. M. D. is unique right in that sense that you're now flipping that where deletions and duplications are about 60% delusions, 5% duplications and 35% point mutations. So traditionally the approach was because deletions and duplications could not be detected when you're doing sequencing. The traditional approach was to do a multiplex pcr run it on the jail. And if the exons don't amplify or you don't see a band you got a deletion there. Right, duplication was a little harder and that's why sudden plotting was done. And then if that is negative then you go into Sanger sequencing. So now you're on step three. Exactly wow all for one look analyzing one gene correct. That's a lot And you know in that process I mean we have been through many many cases now where you know sample comes and you see that this was done and that was done and even in deletion duplication, it was complicated, not all 79 exhaust.

It started with 16 then 32 and so you know, it has been an evolution of processes but with next generation sequencing becoming available now you can detect deletions and duplications with point mutations in one single acid. I think the next step of what we took at perkin Elmer was and just given my own interest in neuro muscular disorders. And duchin specifically was given the size of the gene, right? You got a 2.3 mega bass gene, you're looking at, what I decided to do was to develop an essay which sequences the entire genomic sequence of the D. M. D. Gene. So we are talking of literally a D. M. D. Genome if we can say that, I think we can because it is exactly it. And uh the idea really was to fold about 2% of the mutations are in the entrance deep in tronic.

Um and those cannot be detected if you're just sequencing the exons and the flanking boundaries And then I think from my perspective and my team's perspective at perkinelmer, you know, being that sort of leader in newborn screening and making sure that not just identifying the child but sort of taking that next step is to getting answers right, what can be done next. And we have all heard about crisper cast nine But for CRISPR Cas nine. The main important thing is they need to know where to put that are any guide that means they need to know. So if it is a deletion they need to know what is a break point of the deletion and those break points are in the entrance. So now if you're not sequencing, so now you're introducing step four, probably then after testing if the child is eligible for let's say eggs on 51 crisper cast nine approach.

Now you need to know where the break points are and you need to do another round of sequencing. So this one single assay now is helping you capture everything all types of mutations down to the deep end chronic mutations but also knowing where the precise breakpoint is. And that information then we can give to the pharma company which is developing the essay to know where to actually design the therapeutic target too. So again you have come a lot a long way in technology and fortunately we are at a place where we can actually facilitate this. Yeah and it's I think with crisper there's so much potential there and DMG would certainly be a candidate for that. As long as we give. Like I think about it like CRISPR is like a car we need to give it a gPS coordinates to say you're going exactly to this spot on the gene because D. M. D. Is like a huge continent. It's just like all right you got to give a specific address so we can get there and know exactly what to fix. Um So that's really interesting that, you know, you just have this one essay, one test that can cover all of these angles that we've been talking about.

And as you said, I mean the point of doing the testing is not only to have an answer and a diagnosis but to say, okay now how do we treat this person? And you know, I have to say one medication that I've been following is Spin raza. I mean this has been a game changer for people with spinal muscular atrophy and you know, this is groundbreaking. I mean I was in grad school when this, you know, was was coming out. So a few years ago and I mean I'm still amazed by it. I think this is really a landmark in terms of gene therapy and and looking at treatments, it's for a muscular condition. So is there any current treatments and approaches that are using information from Spin raza? I'm just thinking like they're both muscular conditions. Is there anything in common that we can use or is it just too different? You know, there's certainly a lot of interest and excitement around gene therapy and Duchenne right now, we have several actively recruiting clinical trials. Um so and they're showing a lot of promise.

So um of course they're still in trials. So, you know, nothing has been FDA approved yet. Um But there's definitely, you know, a lot of excitement focused around gene therapy, but also a lot of hurdles, I mean we know there are immune response issues, there's the whole question of the, you know, duration of the effect. Um and whether or not we could ever re dosed these boys who do receive the gene therapy. So there's there's a lot of hurdles we have to work through with gene therapy, but um I think it's definitely an exciting time in Duchenne. Um you know, we're fortunate in the douche in space if we can say that, but I feel like we're fortunate in that we have so many researchers and so many industries who are interested in Duchin and focused on Duchin and they're all targeting it from a different angle. I mean, so there's those who are looking to restore or replace dystrophin, but then there's a lot of companies who are looking at other effects like how can we target inflammation or fibrosis or improve muscle growth or you know restore the cell's energy.

And um so I think tackling it from all these different angles is so important because in the end, I think we all believe there's not gonna be one magic cure for Duchenne, it's going to be more of a combination approach. Um and I'll just add to that. I think, you know, one thing is about basically understanding the differences in the genetics of both disorders. Um and both disorders have their own unique situation. So D. M. B. A. Large gene multiple mutation events. Each event a deletion approach is going to be different from a duplication approach to a point mutation approach. Now you flip that over to S. M. A. And you have to unique situations here. There's only one real mutation event which is eggs on seven homocide deletion. That makes it way simpler. And everybody could have the same treatment. So 95% of the kids are going to have the same event.

5% do have a point mutation. So you need to sequence the gene. But then the other thing which has sort of worked for sme is S. Mm two gene. The gene event there's only one single nucleotide which different shares sm. N. One from S. Mm two in exon seven. Which is the advantage uh that has been sort of afforded to develop the therapeutics for sme right. But the approach is different here because you've got one event, you got this studio gene, you got S. Mm two. And people have Now we report not just S. M. N. One copy number but we also report S mm two copy number. Because that is an important um note that pharmaceutical companies need for the therapeutic strategy. So I think there are different disorders but there's a lot of learning from it that how to it's not about just developing a therapeutic approach but what comes with its a full programmatic approach.

Right? The way newborn screening is a program, it's not a test, it's the same thing, what it what comes with sort of identifying and then making sure the treatment is given and then what and just mentioned, you know, the all the other effects have we assist. Um you know, it's an inflammation and what else could be going on in the functional genomics? Part of it becomes very important. How are you going to look for gene expression and what is the functional aspect of it? Seeing gene expression doesn't mean a functional effect that the boys already is actually walking. So there are so many different events that need to be tracked post sort of developing a therapeutic approach and for people to keep up with this. I think it's very challenging. It's challenging for me as a provider. Um but luckily P p M D has a great resource, parent project. M D dot org. And can you tell us a little bit about as we wrap up the guides that you provide, especially for caregivers of newly diagnosed kids.

Yeah, well, like you said, we we do have a great website. I mean we have a ton of just wonderful information on our website there, There's so much, but it's amazing. It's amazing that it can also be overwhelming, especially for the newly diagnosed families. So we actually have a newly diagnosed section. Um it's under the about Duchenne tab of our website. So hopefully the newly diagnosed families find that um I think it's really nice. It actually starts with a note from Pat furlong, who is the founder of P. P. M. D. Many, many years ago, she's still our leader. She actually had two sons with Duchenne. Um So I think the note is just very personal, very touching. But the other thing we really try to focus on in the newly diagnosed section is um to take it slow that you know this is really overwhelming and I think the most important thing to do initially is just adjust to your child's diagnosis but also work to get them into a neuro muscular care center that's really focused on Duchenne.

Like we have several um P. P. M. D. Certified Duchenne Care Center. So we always encourage families to try to get to one of those centers. I think that's the most important thing to do initially. And then as you settle more into the diagnosis then you can you know tackle learning more about all of the research opportunities or um possibly connecting with other families or getting involved in P. P. M. D. Events. Um the options are endless but um I think it's most important for families to really just take it at their own pace and do what feels um what feels best for them and then we just always want to make sure people know that we have a great staff here at P. P. M. D. And we're always available to help families. Um Every step away along that journey. Well I think that's beautifully said and it's just such a great home base for people to go to. Especially the parents and caregivers to learn more and also have that sense of community. I think that's really important from you know, interviewing patient advocates over the years on this show.

Um But thank you so much. I'm shocked the episodes already over because I think we can all talk about this for so long. Um But thank you Dr Hector, thank you anne for coming on and just sharing all of this experience with us. Um And we're definitely gonna link to everything we talked about in the show notes that's all available at DNA today dot com. So you don't have to remember everything. You can just go there and find the episode. Um So thanks everybody for listening and thank you and doctor for coming on. Thank you. Track jean has designed a genetic electronic health record. Here's what it features pedigrees, demographic data, genetics, information risk tools and sophisticated reporting all within a clinician designed workflow. It integrates with other clinical genetic software databases and hospital information systems. To maintain accurate patient records. Go check it out at T. R. A. K. Gene dot com. Again that's track gene without the C. Dot com and keep your eye out for a full episode, interviews with track Gene coming soon to DNA today. This is a shocking statistic.

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N. A podcast dot com. Where you can also stream all episodes of the show. We encourage your questions, comments, guest pitches and ideas, Send them all into info at D. N. A podcast dot com. Search DNA today on twitter instagram youtube facebook so you can connect with us there and a favor. Please rate and review the podcast on apple Spotify or wherever you listen. This truly helps us climb the charts and allow more genetic nerds like yourself to find the show Today is hosted and produced by myself here Deneen, Our social media lead is Corinne Merlino. Our video lead is Amanda, and really thanks for listening and join us next time to discover new advances in the world of genetics. We're all made of the same.

#202 Duchenne Muscular Dystrophy with Ann Martin and Madhuri Hegde
#202 Duchenne Muscular Dystrophy with Ann Martin and Madhuri Hegde
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