Paul Wicks  0:03  
Hello, and welcome to today's webinar on international perspectives on genetic testing in ALS. I'm your host for today, Paul wicks. And I'm very pleased to be joined by an esteemed panel, we're very grateful to our hosts, Sano genetics. I'm an advisor to Sano genetics And they've got some amazing tools that really helped to accelerate research and support companies that are trying to do precision recruitment for the increasingly high tech and more targeted trials that we're seeing. So this type of work is really key to accelerating the types of new treatments and cures that patients are really desperate for. So we're very grateful to them for today. So we're just going to start off with just a quick overview of what what we're going to do today. And just to be clear, what we're not going to cover. So I go to lots of ALS talks and webinars where you see pictures of motor neurons and go back to Shaco. And whatever, we're not going to cover that today, we're also not going to go through some of the basics of things to do with ALS, genetics, testing and counselling. Some of the ethical considerations for that. The good news is that the international alliance of ALS and MD associations has done a brilliant series of webinars this team has been involved in to some extent, and you should go and check those out. They're available on the ALS MND Alliance, website, some of them also on YouTube, we for a variety of reasons, we're not going to be talking about specific als trials or specific als treatments on today's call. And we're also not gonna be talking about some of the emotional and sort of sociological aspects of living with familial ALS, if you are affected by ALS, and you have concerns or you want to talk to other people who have been in that same situation, the nonprofit group IMLS runs a support group that's really great meets every Friday does a tonne of work and research and advocacy. So you know, there are things out there to support and to connect you with other people who are who are going through the same thing. So we're probably not going to be touching on any of those issues today, so that we can focus on on the main topic. So just to back up a second, when we talk about genetic ALS, it's important that everybody has in mind the same perspective on just how rare the genetic forms of a rare disease can be. So if you had a big football stadium, like Wembley Stadium with a capacity of something like 100,000 people, in terms of prevalence of people living with a condition like ALS, if you took all the people that were there, only about five of them in this whole stadium might have ALS. And as we know that might present different places might present in the bulbar region might cause issues with walking with breathing, eventually, all regions can be affected. But only one in five of those individuals would have a genetic form. Now I pre apologise for some slips I might make put, you might see familial ALS, genetic ALS, sort of used interchangeably in the literature, I think what I'm hoping to mean, here is someone for whom, if we knew everything, if we had a magic crystal ball, we would probably be able to find that about one in five cases have a genetic link. Now, this one individual here may or may not know that their family member had it in the past, they might not have a complete family history, you know, people may have died of other things, when you start going back and people's genealogy, it's very challenging to, to get a hold of all that. But when we do research studies, this is the number we're starting to look at. It could be as high as one in five with with that form. And the reason that's important, you know, why talk about a rare subset of a very rare group of people? Well, in aggregate, you know, a very large number of people on an annual basis are dying of ALS, something like to take the stadium analogy, again, the capacity of Fenway Park, about 34,000 people a year of dying of ALS, and so 20% of them have a genetic form of the disease, that actually, it's potentially a weak point in the disease itself. Because for the vast majority of people with a sporadic form, we don't really know what's causing the disease. There are lots of theories and there are models. But if we're honest, and we look at the success rate of of trials and therapies that have had historically, I wouldn't say we're at the same level of somewhere like, you know, the the oncology space, or some of the gene therapy, rare disease spaces, we've been able to see really transformational treatments come to play very quickly. So this group could be a real vulnerability. And one of the ways I think about it is, you know, the weak point on a somewhat impenetrable fortress like, like the Death Star here from Star Wars. But if we're able to target this, we're going to need certain things to be true. And if we are going to face als as one species, or united, we need to understand the genetic basis of the disease for all of humanity. And if you take a look at where humanity is concentrated, and against that, you contrast that with Well, where am I fairly confident you could get genetic testing for less than unfortunately, you know, where these arrows show up and again, somewhat subjective, tend to be in those countries that researchers refer to as weird. So Western educated, industrialised rich, democratic countries, to state the obvious that's not necessarily where all of humanity is gathered. So we if we're going to face als as one united species, and we're going to fight it as one disease, we can't just have a very small proportion of the population And with access to genetic testing, otherwise, we're not going to be able to run trials with sufficient number of people. Or if someone's looking at whether or not they should develop therapies in this area versus another condition, they might say, well, it's too spread out. It's, you know, too, too heterogeneous. Another issue is that even in centres and places where we can through specialist centres get genetic testing, there's a lot of variability here. So even making the more green arrows is perhaps not all that accurate, because we have some inconsistency, we have some places where we don't agree. And that's going to be the focus of today's discussion. So there are a couple of references down here, if you want to go into the details a little bit, but when you speak to experts, and obviously when you get 50 experts in a room, you get more than 50 opinions. We don't all agree on how to define genetic, ALS or familial ALS, you know, if your third cousin twice removed, and FTD, does that count, sometimes, if they have a gene test, or didn't have a gene test, you know, does that mean you can have a gene test, various, which tests we check is highly variable. So this is a graph on the right to get the details don't matter. It's a bit of a heat map across different countries, of which of the sort of known als genes are being tested for. If we were all consistent as a practice as a field, this whole tapestry will be read. And so it's more just as the the overall gestalt that we know jeans like sod, one that we've known about since the early 1990s. Yes, most people being tested for those seen on off seven to that probably account for, you know, again, the highest proportion of people with a known gene, probably being tested most places, but again, it's not consistent. And that's a real challenge. There's more technical considerations about how exactly we're gathering what type of samples and we're doing it. And this point about counselling, like I said that the AOS Alliance series was really good at going to details on that. So, you know, until we get some agreement on this, it's going to be challenging to make progress and really attack this weak point that I think we'll see. And it's certainly not not just the four of us who have noticed this, if you look out in the literature, you see editorials, you see commentaries that have been pointing to these inconsistencies for a little while now. And I think you know, where we've seen the most solid sort of call to arms is probably in the ALS MND Alliance actually adding genetic testing to the fundamental rights of people within living with ALS. And so this has gone from perhaps somewhat of a smaller niche space to, you know, with increased interest in in gene therapies really, really come to the fore. And just to say, again, in terms of those variations, if you think of the countries where our speakers today are speaking from the types of variations we're seeing, if somebody like the United States, very research intensive resource rich, a lot of people can't get access to genetic testing without having to pay or, you know, there may be sponsored programmes in place, but not everybody will be eligible. Another issue I think we'll we'll tackle here is, well, what if you don't have a family history of ALS, and in research, we are finding that something like 2% of people without a previous family history, may have a sort of known ALS, associated gene, they're not routinely offered testing, right. And we see this variance across these different countries. And then for those people who you might imagine, would almost all be getting genetic testing someone who, you know, someone's presenting, and they've got suspected als symptoms or diagnosis, and someone like a parent or an aunt or an uncle or grandparents, you know, do they have a family history? Again, it's not consistent, that they're all getting that testing. Another important area that I think is getting more attention recently is Gene carriers. So for people who are, say, children of someone diagnosed with ALS, who may themselves be at something like a 50% risk of inheriting the gene, you know, they may want that knowledge for various reasons. And it may well be that instead of just looking at treatments for people diagnosed with ALS, in the future, we presumably want to prevent als happening. And so if we have gene therapies, we have a research we want to pursue, we can only really do that if we sort of understand who is at risk and and have what so that we can kind of, you know, be talking to future generations of people that were prevented from becoming patients, not just people living with a condition now. Right. So that was a whistle stop over overview of kind of where the situation is. And I want to turn now to Professor Omar, our challenge. Now, Toby first some reflections on that. And just to say, you know, how did we get here? And where are we going?

Toby  9:12  
So thank you very much for that poll. It's a very comprehensive overview. I just wanted to clarify the numbers for familial als testing in the UK, that 20 to 80% is when people don't necessarily know they have a family history. So the because remember, for our system, people come to the primary care physician then go to a secondary care physician, and then it will go to an ALS centre. If they're at an ALS centre, it will be much closer to 100%. But along the earlier parts of that pathway, it will be about 20 to 80% because they weren't necessarily pick up the family history. I think one of the key problems is how do we know when to offer genetic testing, because really, everybody should be offered genetic testing, but there's a number of barriers to achieving that. And probably the biggest one is the time it takes the resource required not to actually take the budget and do the genetic testing. And that was a huge barrier before, but now it costs a few 100 euros to do an entire genome. So that's not the problem. The resource required is actually in the counselling. And the time taken to administer that counselling because you need to spend at least 30 to 60 minutes just explaining the implications of genetic testing, before you can take the blood. And then you'll need some similar length of time to go through the findings afterwards. And they're not always very clear. So I think the counselling aspect is the main issue, because if someone's travelled a long way to see us in a specialist centre, and in the US people can travel three or four hours or more. In the UK very commonly, it's normal to travel one to three hours, I think it's the same in many other countries, they then receive a devastating diagnosis, or they may already know the diagnosis, but have spent a long time discussing clinical trials and things like that. And then we've seen the multidisciplinary team, it's not necessarily somebody that somebody would want to spend another one hour or two hours discussing genetic testing is a lot of burden. So you don't have to make a special trip or offer it remotely. Not everyone has the resource to do that.

Paul Wicks  11:02  
Yeah, no. And it felt like as I was putting together some of the materials for this, it did feel like a little bit of a lottery as to where you live, you know, like you say, location is a part of this. But what services are available? And I suppose things like digital technology and us getting used to telemedicine during COVID means that I suppose we, as consumers of health, we're not really we're not as concerned with geography, you know, if I can find a specialist over Skype, why wouldn't I, you know, but in the world that many of us live in, especially in the publicly funded health systems, it really is, based on your geography, isn't it?

Toby  11:35  
To a large extent, yes, we are able to offer remote attendances, we do that if people prefer it, actually, in the age group of people who are at risk of ALS. Many people aren't necessarily comfortable with digital technology, or even if they are, they may not be so good when there's a technical problem. And then you're left with making a phone call to do something that actually really needs to be done face to face. So it's not always straightforward.

Unknown Speaker  11:59  
Yeah. And Christiana, you've been doing some some work in Canada, looking at this, this very question of variability. And that was some of your data that we presented there. So can you tell us a little bit about the experience of I guess, trying to upgrade and level set for an entire country? How that's been and where do you see it going?

Christiana  12:15  
Yeah, sure. So for the last two and a half years prior to my current role, I was working on an entire Canadian strategy on improving access to genetic testing for people living with ALS. And I think, you know, there's, there's jokes all the time about how we get free health care in Canada. And it's all beautiful and wonderful with our universal health care system. But how that plays out in reality of how people actually access care is very different. So although our health care system is federally funded, so healthcare comes from the federal government, it is then doled out in a provincial manner. So we have 10 provinces and three territories. And it's up to each of those provinces and territories to decide how healthcare funding is allocated, how resources are utilised. And so what you end up with is 10. In the provinces, at least 10 different mechanisms for accessing genetic testing and counselling. And so it I think, this kind of echoes to how we approach this problem globally, and that there's not going to be one size fits all solution to this. And so it's been very much adapting to what the local provincial infrastructure is, what the gaps are, what we can work with. And having clinicians who are excited and enthusiastic about this really helps. And so getting that conversation going, and I appreciate that we're continuing to move this conversation forward, and webinars such as today, because the more we talk about it, the more we can start to move that needle. But yeah, the experience has been widely variable, and they're still provinces where access is abysmal, despite clinicians wanting to order it for their patients, so

Paul Wicks  13:47  
and has that been a change that you've seen as well, that clinicians wanting to order it? So I mean, I've been in the field for 20 years, and I'm sort of a psychologist, I'm not the main medical field. And thank goodness, I've never had any clinical responsibilities. But I remember many people say, well, what's the point of doing it? If it's not going to change my management, and now we are starting to hear some potential? So have you seen a change, you know, just two and a half, three years, using a change in attitudes?

Christiana  14:09  
I definitely have. Um, so I think I tend to look at my business courses when I when I think about this, and they're early adopters. So there are some clinicians who have been very forward thinking about genetic testing for years. And most of the time, those are the clinicians that have very easy access to it. So I think of our clinic at the neuro where we've been doing genetic testing on everyone since since 2015. But we had a strong support from our geneticists and genetic counsellor unable to access that. Then you have the group of clinicians where it's required a little bit more evidence, and we have more and more of that being put out in the literature in terms of papers calling for improved access and guidelines, etc. But what we're also seeing is the increase in clinical trials that are geared towards genetically targeted therapies. And what is most exciting is it's not just patients who have a clear family history These days, if we look at something like attacks into where they're also including sporadic patients into that trial, that is expanding the scope of why we should be offering genetic testing to an expanded pool of patients. And we recently published some data on that, where we took a pool of patients in our clinic and we started implementing attacks and to patients and all toxin to testing all of the patients that we identified had no, no prior family history of ALS. So that was proof in principle that it was right to implement this at that time, and, and the more trials we have, and the more treatments that we have that are coming along, I think that will feel that fire more and more, but we have to continue to push the conversation in that way.

Paul Wicks  15:39  
Yeah, absolutely. And, Patrick, I know, you just come back from big genetics conference, I was interested, you know, is this just an ALS problem? Are we are we sort of lagging behind because we're a relatively small area? Or is this something you see in other places, too? Yeah, great

Patrick Short  15:53  
questions. Definitely not just an ALS problem, I think. So breast cancer even being 20 years on to significant scale genetic testing. So it's the same issue. I, I think there's probably two drivers behind the discussion that we're having one is a technological one that Mr. mentioned earlier, which is largely solved, not quite, but we can do whole genome sequencing, pretty soon we'll be able to do long read sequencing at a pretty significant scale. So that means the graph you showed about all the genes becomes an analysis and a genetic counselling, and a people problem, but technologically, we ought to be able to do everything on that list at scale. But I think there's a second one, which is a little bit more challenging, which is who benefits or what is the benefit from doing testing, because depending on the group you speak to, if it's clinicians, then we want to test what's going to deliver clinical benefit. First and foremost, if it's someone running a clinical trial, they're interested in their gene or set of genes, whether or not there's necessarily a clinical benefit, because it hasn't been proven yet. Right? That's the point of the trial. If you ask the people in research, they say test everything, test everyone, because they want to discover the new genes. And I think a lot of the challenge happens when these groups aren't talking to one another because and I think it's being cracked by some of the interesting healthcare and research alliances. So if we look at groups like genomics, England, in the NHS, genome, UK strategy as a whole, I think it's a really interesting application of whole genome sequencing at scale where the data is being used in research, as well as in clinical care. So I'm optimistic. But I think we need to see more of those kind of joined up programmes where the data that's being generated is using first and foremost to make clinical decisions where relevant, but also the data is being piped into research uses. Because then when you spend that it's $200, maybe to sequence a genome, but it's 10 times that to do all the counselling and analytics and support around it. So if you're going to spend that $2,000 all in, let's make sure we get as much benefit out of it as possible.

Paul Wicks  17:51  
Yeah, one of the things I was noticing is in some of the literature there sort of research findings about what types of genes you see in what populations, you know, if someone comes from a European background, or an Asian background or something like that seems like different mix of genes. But I suppose in this increasingly globalised world, just because that's the country they live in, you can't assume that's necessarily where they're from. And it seems like some of the panels we were seeing they were trying to target towards the country they were in, but I don't know, either. Mr. Christiana, how much tailoring Do you really see? So if somebody you know, has been Canada, but you know, ethnic ancestry is from from somewhere else? Is there a different approach? Take, you know, there's a reimbursement only going to cover what say that province expected to find?

Christiana  18:31  
Yeah, so I, we haven't seen any difference in coverage based on ethnicity or race. In Canada, we have different access, depending on what province to different gene panels. So there are some provinces where they have access to a full panel. And if that's appropriate, and the clinician is comfortable ordering that, then then that can be ordered. That's not a problem. Some provinces only have access to a limited panel right now have like, so D one and c nine. And that's where we need to work to kind of fix those gaps if clinicians want to be ordering more than that. But to your point, I think we do need to be mindful that the incidence of certain mutations in ALS will vary globally. And so we need to think about how we make sure that there is broad access to broad panels in a global way to be able to address that. I don't know if Mr. Has any other further thoughts on that? Yeah, it's

Toby  19:19  
very similar in the UK. So we we wouldn't change the panel that's available based on ethnicity, I don't think enough is known about genetics and genomics of ALS, internationally to really make proper informed decisions about that, because, as you said, most of the world, I'm not even sure if you explicitly said this, but most of the research has been done in European derived populations. So we don't really know very much about East Asian populations or sub Saharan African populations or others. So we do need definitely much more information about those. In the UK. If you order a genetics test, and you fulfil the criteria for ALS, you'll order what's called our 58, which is a whole genome sequence, but because that takes some time I've just come back, they initially will screen the C nine or F 72 gene, which is found in 10% of our population. So that's quite high. And that does vary by geography. And they'll also order so D one, because there are gene therapies in trial or in extended access available, so that those two are done very quickly. And then if there's a negative, we get the rest of the panel done, you could argue we should do the rest of the panel anyway, because about 1% of people will have more than one variant more than one gene affected. But those other panels is a whole genome sequence. When it's done, we only get the information back for the ALS panel. And that's about 40 genes. And we've just recently shown that, in fact, if you test those, according to the UK current guidelines, which is that you have to be either have a family history of ALS, or if you don't have a family history of ALS, you have to be younger than 50. It used to be younger than 40. Until about a couple of months ago, if you do that, you miss something like 90 to 95% of people who would have an actionable genetic result, because about 20% of the general als population, regardless of family history will have an actionable genetic result, by actionable, I mean, something that will definitely need proper counselling and discussion because it has implications for the family and will need some kind of approach either a therapy, if it's a sad one based, or trials, if there's some of the other major genes or some other approach like family planning considerations. So it is very important that we do offer genetic testing to everybody. But for the reasons that Patrick and Christian have discussed already, it's very difficult to do that actually, in everybody. In the UK, it also varies by geography. So although officially, those are the rules have to be less than 50. If you don't have a family history, if you speak nicely to the genetic centre, in some centres, some areas, you will be able to get genetic testing on all of your patients regardless. And in other centres that will be impossible. So it even varies within a small geographical region like the UK.

Paul Wicks  21:53  
Yeah. And actually, I have to say that, you know, one of my concerns more broadly about this area is, you know, frankly, those people who are more, have more social capital who are more willing to push against the first couple of noes they get are more likely to probably end up with testing. And so you know, by default, that's going to cause drive inequality. You know, if perhaps, if you don't speak English as your first language, or you're not comfortable discussing medical genetics, in your second language, you know, what hope do you really have of pushing through policies like this? And so I think that that we have a risk of just, you know, this being another place where we sort of deeply inequality. So I really do feel like it is a priority area. But I suppose what I'm trying to look for is other disease areas where we saw a step change. I mean, I suppose in places like cystic fibrosis where a particular therapy came along, or was for a particular group, it was pretty, you know, you would have to check to see who was eligible. But is that what we need? Do we need some sort of watershed moment like this? Or do you see the direction of travel coming more into harmonisation? Just as a secular trend, do you think

Christiana  22:51  
so this is something I've thought about a lot, because when I started working on this project in Canada, just a couple years ago, it was it was a little bit more forward thinking than some people were ready for. But I kept bringing up SMA as the example. And it really it took a therapy approved for SMA to really drive forward newborn screening. And if we look at newborn screening, like rates or availability, were, I think three therapies approved now for SMA at this point. And it's still not widespread. So in the US, they've come a long way they have most states will will have newborn screening available at this stage. But in Canada, I think we're there's a programme that's being spearheaded by the Muscular Dystrophy Association of Canada that has really pushed this forward, and several provinces now offer it but there's half the country still doesn't have access to newborn screening. And there's a an initiative in Europe as well. But but many countries are without newborn screening still. And so if we think of spinraza, which was approved in 2016, and then they'll get a couple of years afterwards. And then there's a third therapy whose name is escaping me. We're still not at a state where newborn screening is widespread, and there are therapies on the market and available for people. So we have to push this before something becomes available, while things are still in clinical trials. So that access is there when those people are identified, those people living with ALS who could benefit from these therapies are identified by the time that's available.

Paul Wicks  24:17  
And it's to be clear, it's great that these products come along. And it's great that they do cause those changes. But I guess, you know, what about all the diseases we're not talking about where we could have found some other new technologies. But if we're not even doing relatively consistent testing and disease, we've known about family histories for decades. What chances there for disease X, Y and Zed where we could be brings these these approaches to bear and I suppose that moves more towards either newborn screening. I know the NHS has talked about possibly screening 100,000 individuals or government level citizen genetic projects, you know, so that our future health initiative in the UK we'll be doing gene testing for 5 million people and hopefully that'd be a great resource. But yeah, I

Toby  24:54  
just, oh, can I just speak to that? So there's the problem you have with NP I asked population level screening for something like ALS genes is that you'll get huge numbers of false positives, and therefore, people given unnecessary anxiety in the first round of screening, I can tell people the statistical reasons behind that, outside this. But basically, if you have a relatively rare condition, and then your test must be much, much more accurate than the rarity of that condition. And for ALS, that isn't true for genetics, it's not true. And therefore, you'll end up with something like 20 3050, even for some variants. 80% false positives, you know, so if you actually have a genetic test is positive, you're very actually unlikely to have ALS subsequently, that may sound counterintuitive, but it happens with rare conditions unless the test is really 100% reliable, and genetics is not at that stage. Even a clerical error when it's done at scale, even if it's very rare is enough to disrupt that. So I think we have to look at population based on bias screening carefully in a condition like ALS, for some, for people where there's a pre determined reason they should be tested. For example, if there's a family history, that's a completely different situation and there, then the accuracy is very high. But if you're just talking about generally screening and population with no reason, that's a very different matter.

Patrick Short  26:13  
I was going to say from I spent about five years working on a very long tail of ultra rare disorders as part of the deciphering developmental disorders project, which is a big exome. At the time exome sequencing, I think they're going back to add additional omics data to it but about 10,000 families in the UK with a child has a developmental disorder of unknown origin. But But presumed to be genetic. And one of the biggest, I think surprises out of that study was the long tail of ultra rare diseases that are uncovered through large scale and not not unbiased to Mrs. Point the child was presenting with a severe and significant developmental disorder. And we saw great progress in that field over the space of about a decade from low double digits to single digit diagnostic rates to now most of the labs are getting in the 40 to 50% diagnostic yield for knowing the cause. And this is due to the discovery of hundreds of literally hundreds of novel disease genes in this space. And it has led to new therapies in some cases, but it's a very long road. But I think we have to start with the diagnostic platform. And then once you've got that up and running, that really lays the foundation for trial recruitment, new therapies, but until you've really got a solid diagnostic platform, it's really hard to, to do everything else. Because Because parents families are in the dark as to actually what the what the cause is underlying their condition.

Paul Wicks  27:37  
So far, what I'm getting from this as I should teach my kids, so they want to be genetic counsellors when they grow up, because it's gonna be a growth area. Great. I want to handle some some questions coming in on the chat and on the q&a. So I guess there's a question for anyone who wants to put their hands up. But someone's asked, Could you speak to the companies who are doing genetic testing and ownership of data? And I think this is particularly referring to the US. So I had mentioned earlier, some people would have to pay quite high out of pocket cost because of insurance. And that's obviously financially very disturbing. I've heard numbers like six to $8,000 out of pocket, there are some testing probe programmes available that are sponsored by companies looking to sort of, you know, enrol people in trials. But I guess the question is, you know, what are some of the the pros and cons of each of those approaches? And I guess, you know, the US is not a socialist utopia, like the UK and Canada. How do we make sure that people's data is being put to put to the best uses and you know, we're not inflicting financial harm on people, but also not risking their data going to places they're not happy with?

Christiana  28:30  
Yeah, so there's, there's a lot of really good discussion about sponsor testing programmes, and they do have their pros and their cons and how data is handled. And what companies can do with that data is is definitely one of the hot topics. I see a lot of benefit in sponsored testing programmes from the sense of a being able being able to provide access to genetic testing in the short term, but always with the mindset that we need to work on the underlying issues of providing access through means outside of a sponsor testing programme, to be there to catch the system when that programme leaves. So we did have a sponsored testing programme provided by an vitae in Canada, which was missing C nine, so it was not a great fit. But then that was pulled away with like a week's notice from us. We were very fortunate that I own us and prevention genetics are now offering us sponsored testing programme in Canada and I believe the US as well, where we can now fill that gap again, and clinicians are very much of the mindset that will use this temporarily but we want to work towards a more long term solution. But But with those programmes, yes, there the data is owned by the company and those that are sponsoring the programme and how that data is used is definitely concerns. I'm not fully aware of data privacy rules and regulations in the US so I can't really speak to that fully. But there are some other options that could be available for people living with ALS. In the US most genetic testing companies will have a private pay option. or when an individual does not have insurance coverage, or it is not covered through other means. And that is at a lower cost than what it would be charged to for insurance companies, or through health care systems. So I know people living with ALS in Canada who have gone through this, and the it isn't out of pocket cost. But the private, the private pay option is less than what like a hospital where I worked would pay for the test as well. So companies do recognise that. So that could be something else to look into. Not sure if I fully addressed that question or not, or anyone else wants to pick up? Well, there.

Paul Wicks  30:35  
There's another question in the comments about you know, whether or not the US healthcare covers the cost of ALS, genetic testing? I mean, I think the answer is it varies dramatically. Right. So people could be under different health systems, if they've served in the military and fit the right criteria. They could be under the VA, obviously have employer based insurance, there's there's Medicare, there's all different sorts of situations. And I mean, this is part of the problem that we're talking about. Right that it is inconsistent. You know, I think there is, I think there's a flowchart somewhere on one of the FTD portals and of course, we've seen on Oh, seven, two, having overlaps between ALS and FTD. Somebody FTD community are our potential allies in this to that, you know, they kind of have a flowchart of well, you know, you could try this, you could try this the sponsor testing, there's research platforms, whatever. But But as you say, Christiana, they vary in which genes are covered. Exactly. So it's tricky to navigate. Unfortunately, there was another question here about Yeah, about access to therapy. So I guess this comes down to timing, right. So so let's say somebody is got a new onset of ALS symptoms, they are in that diagnostic process. And there's a delay because it's difficult to get, like you said, I'm healthy genetic counselling, the genetic testing, if therapies come online, or have trials come online, and presumably we only have a window, right with time is neuron. And and I don't know if there's a risk that if we don't get some of these railway lines greased a little bit better, people might miss useful therapeutic windows. Is that sort of in the minds of clinicians and researchers at the moment?

Toby  32:02  
Absolutely. I think that's the key issue, we have to be able to get these answers very quickly. That's why, as I said, for us, they screen C nine and so D one, separately from the rest of the panel, so we get an answer quickly. But that that then just pushes the block back to how quickly can we do the genetic counselling and without the resource that is delayed, sometimes by months. So that, for me, the biggest way we the easiest way we can grease these wheels or get the lines on crust or whatever the the analogy we're using was, would be to have some system where we can guarantee very prompt access to genetic counselling, which could be delivered remotely, it doesn't have to be at the visit. And that might be an easier way to do it. Because then you could have for each country, just a small group of counsellors could, you know, you can refer to them, they can arrange an appointment with the person affected and their family at their convenience and then deliver the counselling. And then you can just be informed, yes, that person's had counselling, the test can now be sent off. There are lots of simple, relatively simple solutions, relatively low cost solutions, but they do require something done centrally. And so all we can really do is try and influence the people in charge of the health systems in each country. Because I think it's going to be difficult to do this internationally. The only other way to do it would be to come together as a group and lobby for it internationally. But actually, we could then if we were going to do that get other diseases on board, because we'd be a much louder voice. Because there are probably other conditions in which early treatment matters. We know that's actually true for SMA. And that's why they've got the newborn screening is probably true for other conditions to

Paul Wicks  33:37  
and lots of what I've read and heard about about the counselling genetic counselling protocols are say based on Huntington's, which you know, clearly life changing impact for families, but equally relatively small numbers of people. And so taking more conservative approach and putting lots of checks in there like psychiatric counselling, and you know, multiple sessions, I guess can be resourced. Probably, again, not ideal. But I guess the reality is, if if we start doing this across multiple conditions, it wouldn't matter if you could double the number of counsellors overnight or triple this is becomes a scale problem. And obviously, we don't want people to have a poor experience. We don't want people to be suddenly shocked by information, but But it sounds like we really have to rethink this if we're going to have any chance of succeeding. Yeah,

Toby  34:17  
I'm in the UK, for example, used to have genetic counsellors specifically for ALS. So in the past, if we saw somebody with familial ALS, we could deliver the counselling ourselves if we were trained or we could refer them to the genetic Council counsellor service and they will deliver it. Now, all neurologists are expected to deliver the genetic counselling that's actually true across all of medical specialities. So they've moved the burden of genetic counselling from the genetic counsellors who only do very complex counselling now, to the general practitioner, the general not really practitioner but general physician within their speciality. And not everybody is comfortable with doing that. Not everybody is trained to do that very easily. And it's actually quite difficult to navigate how do you fill in the correct forms and you know, it's not like ordering food blood count or a normal blood test that we would do you just tick a box. It's actually a much more complex process. So all of those things are barriers.

Paul Wicks  35:07  
And I suppose, you know, a lot of a lot of people have quite a rapidly progressive form. So if someone's coming to you, and their biggest issue is mobility, or their biggest issue was conversation about, you know, because trust me of ventilation, I guess one has to prioritise that time, right. So between time Yeah, and

Toby  35:23  
as you know, there's usually at least, on average, a year's diagnostic delay, so that already one year into the disease. So we do need some system to pick people up earlier.

Paul Wicks  35:32  
Yeah. A question here about so I mentioned earlier, the overlap between ALS and FTD, particular 59? Or some two? Do you think there are any issues around consensus that we need to be aware of? So you know, as we go looking back through people's family histories, or we start looking at carriers, you know, are there safeguards we need in place to ensure that, you know, first of all, everyone's been treated with respect, you know, many of the cognitive impairments that we've seen a very mild issue with executive function, they certainly don't necessarily impact on people's ability to make really important decisions. But yeah, can you just comment a little bit about, you know, what impact is the fact that this is not just ALS, potentially, it's FTD, as well, how on how we approach these topics?

Toby  36:09  
I mean, I think, as clinicians, we always assess whether the person we're speaking to has capacity to make the decision that we're giving them. And if someone clearly has a frank dementia and wouldn't have capacity, sometimes even somebody with quite avert dementia will still have capacity to make the decision. But if they clearly don't, then we have to work around that in some way. Otherwise, we, of course, part of the counselling process is to make sure somebody has fully informed consent. That's really what the counselling is about. It's about getting fully informed consent and the consent, the information is about what do you do? If you get a positive test? What will you do? Will you tell your family, if you're not going to tell the family members? Should you be having the test done? So what are the implications of telling family members? There's lots of other things to consider than just having a blood test. It's not that simple. So all of those things are about consent. And even the interpretation of a negative test. What does that really mean? And actually, the big block now that's that's becoming a real problem for us, is what are called the variants of uncertain significance, the vos for us, those are variants which may not have been described before, but they're in an ALS gene, for example. Are they relevant to that person's ALS? Or is it just a coincidence that it's there. And there's no easy way to predict if a variant is relevant, if it's been seen in many people and goes down a family? And you can see yes, that's clearly an ALS variant. That's easy. But if it doesn't, that makes it a much more difficult problem. So there are ways to try and address that. And one of them is the Clint Gen panels, which are internationally convened panels that have a system of rules where we will convene, we meet every two weeks or so there's gene curation, expert panels, G set, those look at deciding the evidence that a particular gene is relevant in, for example, ALS or not. And then there are variant curation expert panels where within a particular gene, you decide which of the variants for which there is proper evidence that are relevant to that disease within the variants that are definitely benign. And then which ones are the variants of uncertain significance? Where do we get that extra evidence from? Because you need that to be able to give the counselling with the result to the person who's had the

Paul Wicks  38:10  
test? And then presumably, you know, where we've banked samples and new information arises, it means we can go back to people and say, hey, the landscape has changed. We have new information for you.

Patrick Short  38:20  
Yes. Okay. But What's tricky about that, and I think MRA is a really important example here about the complexity of counselling. And there are a number of groups talking about newborn screening and the complexity of pretest counselling. And that kind of approach blows up to an even more significant level, how do you in an hour or in half an hour explain all of the different potential outcomes, positive and negative. I've been in this field for more than a decade, and I learned a new, interesting, rare but potential outcome where if the child comes up with a rare bracket, two homozygous so they need a bone marrow transplant. That also means both parents are braca, two positive. So both parents have now learned they're at high risk of breast cancer. So from a newborn screen, you can end up with the whole family receiving news they weren't expecting. So I think it's a big challenge for us as a field of how do we, on the one hand, we have this known, limiting reactant of good genetic counsellors or neurologists time or skill, Dr. Time to do this. But on the other hand, we have an increasing complexity of potential outcomes, and how do we square those two, while still getting testing to everybody who needs it?

Christiana  39:29  
Yeah, that's a great point and really speaks to the importance of genetic counselling when you're offering genetic testing. And I think one of the things that we do have going for us in this capacity is that the field of genetic counselling, we're very early adopters for telemedicine and so pulling some of those resources into remote visits, for example, and putting more complex cases with a genetic counsellor. Mr. Mentioned that not all clinicians are willing to to provide the genetic counselling themselves, some are and so, you know, can we balance resources in those cases where neurologists can provide, let's say, say pretest counselling and a genetic counsellor can pick up the post test counselling. So it's really looking at what kind of alternative service delivery models are available to help fill some of these gaps. And then to your point, Patrick, really, for those complex cases, and the evolving complexity, involving the specialists who can help address those cases will be key. That's great.

Paul Wicks  40:29  
Well, so you know, I feel like we've just scratched the surface, really. And we could certainly delve deeper on this. But, you know, we're going to we're going to finish up, they're incredibly inspired by all the progress that I suspect this group is going to make in the years to come. And clearly, it seems like you know, we're not the only one with this challenge. So we can benefit from the progress made from other technologies, other conditions, and my hope is in you know, five or 10 years time, if we redraw those maps, you know, we'll be a united front against ALS. So, thank you so much to Patrick to Christiana to AMA for their time for their thought for all the work they've done throughout their careers. And thank you all for joining us today.

Transcribed by https://otter.ai