How is it that we find ourselves surrounded by such complexity? Heh heh, heh Hello, you're listening to DNA today. A genetics podcast and radio show. I'm your host here, Dean. I'm also a certified genetic counselor practicing in the prenatal space. On the show. We explore genetics impact on how through conversations with leaders in the field. These are experts like genetic counselors, researchers, doctors and patient advocates. In this episode. We're exploring the genetics of LS with Mark keel, the chief scientific officer and co founder of the phenomenon. Mark has extensive experience in genome sequencing and clinical data analysis. Thank you so much, Mark for joining me on the show today. Yeah, thank you for having me. Do you work in a lab?

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The link is also available at DNA podcast dot com. I thought we would start the conversation from baseline of just explaining what else is and how it's typically diagnosed for those that may not be as familiar with the disorder. Yeah, sure. It's a great starting questions. So um for those who are unfamiliar, L stands for a maya trophic lateral sclerosis and it's a set of greek words that means a lack of nourishment to the muscle and and that's what you see as a patient or a physician. And then the lateral sclerosis has to do with hardening of the spinal cord, where in the spinal cord that hardening occurs is characteristic of this disease. And when you put all those things together that equates to a motor neuron disorder, which is one of several neurodegenerative disorders like Alzheimer's and Parkinson's. And um ALS is a rare disease. It has a constellation of clinical presenting symptoms that make it a little bit challenging to diagnose.

And so some of the features of the diagnostic approach to the LS include the identity notification of both upper and lower motor neuron disorder components as well as a progression of the disease. And then finally a rule out that any other neurodegenerative or neurological disorders play? So the clinical diagnosis is what has dominated a less diagnostics for many decades and what causes the L. S. Have we figured out this? You know, there's probably multiple different factors when it comes to this. Yeah. So it's it's a bit of a conundrum though. We've made a great deal of progress in the past several decades. So there's a couple of components to the causation of this disease. There's a handful of patients who have a known genetic causation and then there's a handful of patients for whom no genetic cause has been identified and there's an attribution of environmental or lifestyle components to causing LS.

But whether it's genetic or environmental or a combination of of those things, what we do know the path of genetic mechanism of a less is that it culminates on a couple of different features. Bio mechanistic lee things like neuronal excited taxus City. Um uh Renee and protein handling uh challenges as well as oxidative stress and consequences to the glia and neurons in those regions that ail us is affecting. And as you were saying, there's genes that we've identified that can play a role in the development of L. S. Not all patients are going to have a genetic mutation that we're identifying. Which maybe that's changing in the future. How many jeans so far have we identified as playing a role in the development of LS has this list grown in the past 30 years? Yeah that's that's a great question. It's actually been an astounding a series of discoveries over the past 30 years.

Beginning in the mid nineties I believe when the first gene was demonstrated to be associated with A. L. S. And since then um there have been more than three dozen genes that have been associated with a less by mutation by either a single nucleotide change or an indelible or a repeat uh expansion in in one of the genes that's very um well associated with causing A. L. S. But it's important that I classify the types of causes of A. L. S. Into sporadic and familial. And historically those have been operationally defined. Which is to say for familial cases, if a single relative of a patient who's who's presuming to have ALS also has ALs that can constitute a familial case And those comprised 10% of a less patients.

Whereas the other 90% of Ale lost patients who don't have a family member affected by the disease are called sporadic. And of those familial cases There's about 70% of those patients who have a demonstrable genetic mutation that's known to cause LS. However in the sporadic cases there's still a significant fraction of those patients who also are found to have genetic mutations in those same genes that are associated with familial ALs? So the lines are starting to blur as we're learning more and more about the disease as a whole through research and informed by genetic sequence. But also as we're sequencing more and more patients in the clinic, be they familial patients with family members who also have the disease. As well as sequencing sporadic patients for whom no such familial relationship can be found. It also makes me think that people could have a change in one of these genes mutation pathogenic variant whatever we're calling it and not develop A.

L. S. And we may not see that because they're not coming into the clinic. So you know deciphering all this information of if you have family members that have A. L. S. And you also have it like okay is there a genetic change there? And if you're the only one in your family with that genetic changes a lot of data to sift through and understand the importance and how that all works Because it's not certainly not a straightforward diseases. Other diseases are it's one gene. And if you have a mutation you have that disease. Whereas this is so much more levels to that. I mean you're talking about dozens and dozens of genes that have been identified are all those jeans on a standard genetic testing panel. If someone comes in they have A. L. S. And they're looking to see okay can we find a genetic cause to this? Are they going to be tested for all those genes that have been discovered or is it only a handful at this point? That is a great question. And there's a lot to unpack in that question that you posed the first is sure there's a genotype phoenix tight correlation, there's different levels of expressivity of the disease.

Even if you do have a mutation that your brother has, are you going to develop the same disease historically? It's been challenged by lifespan ban. It's a relatively late onset disease. On average between 45 50. And when average lifespans were much lower, there was a question about whether your family members would have developed a less had they lived long enough and not um passed on from some other cause but with specific relevance to the jeans and the testing. Mhm. Um It's also been challenged by the pace of discovery of causative genes. So that makes it very hard to develop a standard panel when we're learning so much every day that having been said there are codified testing strategies, they typically unfold in a testing algorithm. And the the algorithm usually tests or the most common gene cause which is C nine orf 72.

It's that repeat expansion mechanism that I talked about that includes among the familial cases between 25 45% some of those patients. And so nations when they were trying to inform uh care of the patient and care of the family members would initially just order that one test. And uh oh so the note that testing ordered in the context of a familial case. And so what you described in your question is true testing is easier. It's less algorithmic. So in the past there would be a testing for C nine orf 72 in a subset of patients. And if that were negative there would often be no follow on testing. And that defies our understanding of the genetics of A. L. S. Because there are three dozen other genes that could actually be the cause of the familial case or could be causing sporadic case. And so what we're seeing now is more of a panel approach testing all of those genes up front.

And we're coalescing around an understanding of What should comprise a standard gene panel though. The current panels that are available vary between 20 genes and You know more than the three dozen. So I think for people listening they may have done testing in the past and said okay I've already done the testing. You know I'm done with that and that's really never the case with genetics. I've always checking back with your health care provider and saying are there any updates to the genetic testing? Especially if you didn't find a family mutation or a mutation in that person? So it sounds like that's the case for people that had testing years ago. It's usually I hear about this more in cancer But you know the rules of cancer testing apply here where if you had testing, nothing came back as being found, may be good to revisit, because maybe it was just the one gene, the C9 or 72 that you mentioned. Um now there's just so many genes that we're looking at. Have you heard of patients coming in with family members and saying, you know, I want my sister to be tested, she doesn't have any symptoms, but she just wants to know is there a risk for her?

Because maybe she's a little bit younger and that age of onset um tends to be on the older side, or is this something that we're not doing yet? It's a fantastic question, and it allows me to emphasize that, particularly in the context of a L. S. There's a great deal of self motivation among patients. There's a lot of advocacy coming from the patient's um there become something better educated about the disease and better equipped to exhort their clinicians to perform this kind of testing for them. So, there's a great deal of that groundswell of patient motivation for ales and in particular when we talk about are broadening understanding of the genes that cause this disease. In addition to that, there's a deeper understanding of the variants in known genes. The evidence collected across cohorts of patients who are being sequenced and tested, as well as functional studies that test the mechanism of these individual variants as that information gets published, that contributes to our understanding and ability to diagnose a patient who might otherwise have a variant of uncertain significance.

The or apprised of the newly published information, a clinician can be the better able they will be to provide an accurate diagnosis to their patients. If you have patients with Prader Willi syndrome, please let them know about a new clinical study. Looking for participants across the United States. Harmony Biosciences will be studying the safety and impact of an investigational medicine. The study will focus on excessive daytime sleepiness, cognition and behavioral function in people with Prader Willi syndrome. The study participation is four months long and consist of five visits. If you're patient at your visits, you will participate in sleep tests and have general check ins on how you're feeling. You'll also need to keep a sleep diary for the first two weeks in a closing diary. Once you start treatment, if you're a caregiver, you'll attend all visits with the patient and help provide information to the trial researchers, There are 13 trial sites in the United States and Harmony Biosciences will reimburse patients to travel to their closest site, refer yourself a patient or a loved one to the study by visiting the link in the show notes, which is also available at DNA podcast dot com.

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Again, that's thermo Fisher dot com slash aspire hyphen DNA today. For 500 bonus points. See the show notes for terms and conditions and that link if someone is deciding. Okay, I don't know if I want to do the genetic testing and they're kind of in limbo with that decision. Is there risk numbers that say a genetic counselor, their healthcare provider can offer them in terms of, okay this family member has a L. S. Has been diagnosed. Maybe they don't have their genetic test report with them for that relative. What is the range and risk that we would give like a first degree relative? So a sibling, a parent, a child of someone that has a L. S. Because I'm imagining this isn't just one number like we have with other men. DeLeon disorders. We're talking about single genes. Yeah, I'll hasten to add that. I'm not a clinician though. I was trained as a medical doctor. I am a pathologist in my specialty and now I'm a data doctor. But the question that you raise is a good one and you can take it in two ways.

In one way before you've been tested, if there's not not knowledge of a causative genetic variant, we can go from uh the empirical evidence to say if we have an isolated patient with a. L. S. What statistically are the chances that their sibling is also going to have a less if they're younger or if they may be priests symptomatic and statistically there's an order of magnitude increased risk above baseline considering that Ailes has such a constellation of causes including environmental and lifestyle. However, if you do know that there is a genetic component either because it was diagnosed or because there's a very strong, highly penetrate family history that risk goes way above the order of magnitude risk. You know, the baseline is two out of every 100,000 cases in the United States um individuals rather than cases.

Um It increases by 10 fold if you have a sibling with A L. S. But it it goes Who's up to 50% if you have a first degree relative who has a LS with a known genetic cause that's a dominant mechanism. Um They're taking into account issues of express embody and um background genomics that may help contribute or help mitigate the development of the disease. But again, we're talking about very significant numbers and that's where the patient empowerment comes into play, where this now becomes a known genetic disease and all of those relevant genetic counseling tenants uh come to bear when you're talking not just about the program, not just about the patient who was initially diagnosed, but about all of their family members. One of the one of the coolest things that I learned when I was going through my training was that genetic counselors don't just treat a single patient, They treat the whole family. And in this case, that's very true. And what we're seeing in neurology which historically has has not had many genetic aspects to its clinical care is a need for that now for diseases like a L.

S. That are demonstratively genetic. Yeah, I think that's very well said. And just that, as you know, me coming from the genetic counseling perspective I don't work with LS patients I'm in prenatal but often times we're starting with one patient and that leads us to meet a lot of family members and doing a lot of testing. Um So it's important for people to understand that genetic counselors can help you understand all of this and if you have a genetic test report, that's the best thing to bring to appointments. I'm always reminding patients that if you bring a test report, we're able to help you so much more. The other part with genetic testing is that I'm wondering if it can change a person's treatment plan. So if you're able to find, okay, there's a genetic mutation in this specific gene. Is that going to change the type of treatment they're having as opposed to you have a L. S. This is the standard treatment we're giving everybody with A L. S. That is excellent and very appropriate given some recent developments in a less treatment.

Um It's important to note that especially in neurology there was a reluctance to perform any genetic testing when it wouldn't inform care. It's it's important to know what the cause of the disease is, if it informs its diagnosis, if know that knowledge informs prognosis and if it informs treatment approaches and previously there was no knowledge of the genetics of a L. S associated with any of those things. But what we're learning more and more is that there is in fact a genetic association with different prognosis and now there's things that we can do from a treatment perspective depending on which mutations in which genes the LS patient has. So in particular um there are two compounds that are anti sense Olivo nucleotide compounds. I hope I'm not mispronouncing them to jefferson specifically targets g mutations in the sod one gene Which is I think 20% of familial patients.

So a significant number of patients and then JC Fusin targets the variants in the phosgene, which I think accounts for maybe five or 10% of familial patients. And there's newer compounds that vary in Phase one trials. Those farmers who are in Phase three trials and showing very promising results that that target mutations in the C. Nine orf 72 gene that repeat expansion that we talked about That comprises a significant number of familial cases though those are in Phase one trials. The results are preliminary to Jefferson and Jason Houston are showing a great deal of promise and necessitating in my view, sequencing for all patients, whether their familial or sporadic because that will inform care it will be for a minority of those patients. But for those patients there's a great deal of promise that these interventions will will prolong on and improve the quality of life for those patients and as we've seen for other genetic disorders when medication is developed specifically for certain pathogenic variants in certain genes.

So it's like, okay you have a very in a certain gene. And so we're going to prescribe this medication then other genes follow suit. So as you're saying, it's not just those specific genes, they'll probably be others in the future. And especially if you're hitting ones that a good chunk of LS patients have, then you're able to provide personalized medicine was really what we're talking about here to those patients with specific drugs to target that. We've seen this in with people with cystic fibrosis. We did a whole series on that of just the different drugs designed for mutations in different genes and really lining those up. Um and a lot of this for a L. S. I was really intrigued to learn more about with your comprehensive genomic landscape for a. L. S. Report, where you get into a lot of this information and it's really well written. I have to say it just like reading through the report. Um what are some of the key findings from this that you were surprised by the big takeaway messages from, you know what the company found. Yeah, sure. Uh all praise for the writing goes to uh my team members, Lauren chung in particular was spearheading a lot of this uh investigation and the report writing.

Um I'll back up and describe what our approach, which was what it means to say, a comprehensive genomic landscape. So the genomic non specializes in genetic and genomic evidence coming from the empirical literature over the many decades of scientific and clinical inquiry and for any disease, not just A. L. S. And for any gene, not just the three dozen or so genes we've been talking about. We have a great understanding of where those genes and diseases are described in the empirical literature and what variants are described and in which patients and what are all of the attendant clinical and bio mechanistic descriptions of those genes and variants and proteins and patients and their diseases. And so particularly for A. L. S. What we're talking about when we say a comprehensive genomic landscape, that means every single variant ever published in any one of those 36 genes which numbers over 20,000 7000 of which were known to be associated with A.

L. S. We know every one of the papers that describes all of those variants and we have clinically assessed that evidence for action ability, pathogenic and likely pathogenic variants based on defined clinical grade criteria. We have that great compendium of information from all of those genes and from all of those patients in all of those references. And we've annotated that data around things like age of onset, the rate of progression of the disease characterized. And you teach to those individual patients and the relative prevalence of those g mutations across erratic and familial cases. This isn't. And so some of the findings that with our that there is a demonstrable association with patients who have g mutations in certain genes with earlier ages of onset and with more aggressive progression of disease. And some of that had been known before, but not in this grand view, very detailed, very exhaustive, comprehensive approach as a as a case in point.

Um, there are certain mutations within a gene that confer a more aggressive disease and earlier age of onset, whereas other mutations in that same gene don't confer as aggressive disease. And so when you think about the depth of that analysis, amortized across all of those references and all of those patients and all of those genes, what we're able to do is see patterns emerge to lend better and more clarity to the path of genetic mechanism of disease as well as the clinical presentation of behavior of those patients. And it's all summarized in this one report, which it sounds like it would be hundreds of pages long and it's not, it's it's so greatly just packaged to understand and see, as you said, that the age of onset can depend on which gene is involved and going deeper, as you said, that's just what the genetic changes within the gene can also make a difference.

Um that was really intriguing to me that it's not just okay, what gene is that, okay, this one is involved with earlier onset or this one makes it more aggressive. Um, but you know, going into the fine details of the spelling of the gene and where that mistake is and what it is to lead to that. Do you see this information being used to help with clinical trials and figuring out how to group people and helping with some of this drug development and trying it with subsets of people that have a mutation in this gene and maybe looking at even like they have a certain mutation and then trying that. Um do you see this being a way that the information is going to be used in the future? Yeah. It's a great question. In fact it is being applied to clinical trials for A. L. S. As I suggested before. Phenomenon works with all manner of genetic disease, not just a rare disease, not just neurodegenerative disease, but also cancer and other forms of mono genetic disease. Um In specifically related to LS.

And the data that we put together in this comprehensive report, all of that detailed information that was summarized in the report. The detailed per variant level information of across those thousands of genetic variants is applicable to clinical trial design, defining inclusion or exclusion criteria based on the evidence that's been assembled um Enrolling patients into trials for some of these targeted compounds. For instance, based on the evidence that's accumulated in this comprehensive report to ensure that the most appropriate patients and the maximum number of those appropriate patients are able to be enrolled in these trials to ensure the success of the trial Right patients with the right treatment as necessitated by these precision therapies but also not leaving anybody out if there is enough evidence to indicate that they're likely to respond. And so you you know very well about the variant of uncertain significance.

Challenge the big hump of variants in the in the bell curve where the majority of variance across any gene fall into that category. Our goal with this approach was to flatten that hump as much as we can based on the evidence, still ensuring the utmost accuracy of that interpretation. But just ensuring that we don't miss any of that evidence. Because manually identifying that information just such a challenge phenomenons automated approach ensures that the utmost sensitivity of finding that evidence and bringing it to bear for clinical purposes. And that's really useful for health care providers to have access to as well because if they have a patient that has that the U. S. As we're saying very unknown significance. Looking at that and saying okay it's been a few years. I've been seeing this patient. Let me see if there's any updates with that And that could provide more information at that point. Yeah that's exactly right. And we're seeing that in all manner of disease as next generation sequencing. I'm dating myself have been uh it's been around for a long time but I remember.

Yeah. Um Not being a thing in the clinic. I remember when we were doing Sanger sequencing and looking at these single mutations. Well now we have the ability to sequence across the entire genome and for about the same and cost as a simple variant analysis. And what we're what we're seeing is that is true in the clinic as much as it is true in the research realm and that great burden of new information that's being uh published year over year, sometimes month over month or week by week is accumulating and informing the interpretation of all these other variants. And so there's a great need to stay on top of that information as a patient, as a clinician, as a researcher. And that's one of the things that the comprehensive landscapes that we produce are able to provide because they're kept up to date on a week. Quarterly or yearly basis is needed. That's fantastic because it just takes so much time to sift through all this data. So for people to be able to access already funneled information is fantastic.

And people can check out phenomenons comprehensive genomic landscape for a. L. S. Report by going to the show notes for this episode. We're gonna have a direct link to it. And also in the blog post for this episode available at DNA podcast dot com. Thank you so much. Mark for coming on the show and just sharing all of this and exploring all the details with this because I am not as familiar with A. L. S. And I learned so much in this episode. Um, so I just really want to thank you for bringing your expertise on the show and for everything that you guys do to help bring more information to the public to be able to help understand LS and so many more disorders. That phenomenon is able to provide that extra information. My pleasure. Thank you. Thank you for having me. You guys can check out DNA today on twitter, instagram youtube facebook and connect with us. There any questions for myself or Mark. You can send into info at DNA podcast dot com and we would love if you could rate and review the show on Apple. That is really how we're able to get new listeners and new sponsors to attract us.

So please take a moment rating and review on Apple. It will take you approximately 60 seconds. So please do that. Thanks for listening. Everybody join us next time to learn discover new advances in the world of genetics and DNA were all made to be in a