 Thanks Laura, am I supposed to keep time or is someone else keeping time? Wonderful. Oh fantastic so We had a phone conference about a week ago to discuss some of the potential topics for discussion in your materials There are some draft questions as well for session one and these are some that are a little bit Beyond that we've heard a few times this morning The question raised Whether genotyping should come before the phenotyping whether before patients are seen at a center It would be useful to get Whole exome or whole whole genome sequencing done first prior to their visit. I think that's a Major topic to discuss and may depend very much on what the goals are at the time We've heard that about half of the diagnoses are genetic and we've heard about half of the diagnoses are not based on genetics Even though they're probably all genetic disorders You could you know, that's half full or half empty I guess depending on your perspective I think an overarching question I had as I first got involved in in while learning about the network and And thinking about some of these things is who's the who's the network for is this for patients? Is it for scientists? I think the answer obviously is it's for both, but how do you balance the scientific goals? Which is often discovery almost always with the the needs of the the patients and the and often their local clinicians who are Looking for guidance And then a third one was is really, you know, what it what is the feasibility to having a standard approach to deep? really deep and comprehensive phenotyping across clinical sites across clinical specialties even and And back to this question of whether having certain sites in the network have specific areas of clinical expertise or whether It's best to to really be able to provide a comprehensive evaluation So let me open that up to the discussion, and I can't see everybody's name, so I'm going to point and nod So Sue Berry from Minneapolis So one of the things increasingly in clinical genetics that is emerging is a lot of us are taking the approach of starting out by Looking carefully as much as we're smart enough to do to figure out a handful of specific genes to look at And once we get past those people are saying go screw it Do an exome and so increasingly I think you're going to find that people are going to come to you with exomes completed and possibly negative How are you going to incorporate that data because you're going to need to it'll probably have to be reinterrogated because maybe it wasn't analyzed with the Act well, whatever we call now accuracy that will be required to ultimately define this and how do we how do we Because this what you're going to have is a combination of clinically accessed Standard clinical activity that's going to come to you Before you even see the patient because after we given after we get an exome and we got nothing then we're kind of stymied So what do you think about that guys? Yeah Rachel Ramoni from the coordinating Center So we have even in the early days had an experience of a previous exome Being brought in and those those are re-analyzed typically and in fact in one case They found what they believed to be a an entirely novel diagnosis on the basis of that of that reanalysis But you're gonna have to have a systematic way to do that because increasingly that's something you're gonna get from the beginning Yes, so those typically are being done at the clinical sites And so each site has its own means has its own pipeline So there there will be some variability in how they are analyzed But we hope also that the variability can be leveraged There's even talk in the network of sites taking you know taking an individual Exome or genome and analyzing it through their through their own pipelines if for instance at first it comes up negative at one site So I think You know Clinical utility and clinical exomes are going to focus on known genes and disease variants I think it's and at Baylor we've had the experience where when those exomes are moved to a research setting you increase the yield Not surprisingly, so I think the bottom line is that It's a continuity and a continuous process. There isn't it's not really, you know binary decision and Really at the end of the day my my sense is we should focus on what is most effective and efficient for the patient you know in the optimal world you would have an exome that's done clinically or and then Research interpretation and then you bring the patient in but I just think that you know at the end of the day of Integrating clinical practice into research you have to be practical and it's gonna be context-dependent so as I was sitting and listening to the Discussion and presentation earlier today. I kept thinking is there a difference between unknown diseases and undiagnosed diseases meaning These are entities that that we or certain individuals with specific expertise know Exist and it just takes putting the right information together like the diagnosis as opposed to as we as we well Know the monthly or weekly New disease relevant mutations or new disease relevant genes that are being Described and it seems to me that there might be a difference in how to approach those based on what the what the prior Suspicion is of different entities So Howard Jacob from Hudson alpha, so I want to come back to the question about The exomes and I think one of the challenges you're going to find is it's not so much on the technical side of Sequencing the genome whether it's exome or whole genome or the analysis But it's going to be the comfort level of the physician on being able to make the call So it's the classic end of one and so obviously if the variants been known to cause disease before It's much easier, but I see a huge range in in a physician's Boundaries if you will of well there will they'll make a call some will use model organism databases data some won't some want to have ACMG guidelines before they'll make a call others will go into the research And I think one of the big challenges is more on the clinical side than it is on the technical side of reading the genome and doing the analysis so I think one of the other things that is striking is just how much Pliotropy there is and that there are You know genes that many of us associated with a specific disease where we now know that well, maybe there are 10 or 15 major phenotypes that are different that can result from that and then on the other side of course the heterogeneity and so again it may depend very much on what the what the History is of this individual patient whether the first approach should be more careful phenotyping to guide Evaluation versus a broader brush No, I was going to say just along the same lines that we all we talk a lot about Best practices for this particular point of genotype first versus phenotype first There's certainly no best practices and that might be that could be a goal of the UDN within the UDN I know that there are Widely different approaches some sites do phenotype first We we at UCLA do the exact we do the exact opposite We don't the patients doesn't set foot at UCLA without a genotype with a whole genome or whole exome and That that has been Interpreted maybe on a what you mean Brenda I think by research level it was sort of like lower a little bit the the threshold of potential variants to be Explored to phenotype because we think that one of the practical issues is whether the deep phenotype if it's going to be The same for everyone then of course it doesn't need to be guided by a genotypic investigation But the question is is deep phenotyping for absolutely everything at every single You know organ is it is it practically feasible in in in sort of the real world of of managed care? I'm not sure about that This probably is a bit heretical, but if 75 percent haven't been found when DNA has been done We're all geneticists, so we know this genetic modification, but my question really is aimed at There must be other things like exposures to toxins the natural history Something happened in childhood that is actually what's going on Travel so that you were exposed to bugs and my question is really how much of that kind of data is part of the standard Workup so that if somebody had grown up in Africa you would know it and that would be Directing you to think about their genetic interaction when in the African either environment or Infectious disease So that's a good question, and I think You know certainly we've had some consideration that I think dr. Lee's case of earlier today My view of that as a non-geneticist was boy that was a situation where really the the phenotype in the history really led What what ultimately was a genetic probable answer? There are certainly things that can be sent through the mail. There are certainly things that can be shipped electronically One thing that can't be shipped electronically is the patient and there are some things so as a neurologist I know there are certain things that can be done as physiologic measures that may be Only one or two places in the country have the expertise to do it, but can be the essential diagnostic test To to make a diagnosis or to help interpret genetic testing So so that's the thing that you really can't do is the is the physiology So I'm suggesting though there will be pieces in the history the best source of history is grandma and My guess is grandma doesn't come very often But grandma remembers that something or other happened and I think as we move forward We're going to be really wishing we had more early childhood information or Exposures that that was a really dirty plant in the coming, you know, whatever There is a I was going to say there is a detailed exposure questionnaire as part of the the network Two questions now One is that as people will come with Genomes sometimes they have what looks like it could have be a causative variant But the clinician is really not in a position to explore that further. Is that the kind of case that might well be almost a shortcut to Directing information about About learning about that case And then the second question is how are we or how does how does the network propose to think about? epigenetic variants that will impact phenotype Anyone want to take a stab at addressing those? Well, I can talk about the first case we have seen cases where the diagnosis was already made But the referring physician didn't sort of accept that diagnosis because as you said, there's pleotropy. So specifically A really good gene variant was found and was reported as a variant of unknown significance because even though it was deleterious it was Didn't fit into the clinical phenotype and it turns out that all the clinical phenotypes associated with that gene were loss of function and This was a gain of function or at least, you know, we're pretty sure of that So that'll happen a lot of times and I think those are suitable candidates for us to pursue Because we really can't expect referring physicians around the country to know about those research aspects of it or the you know, the variability of the Potential pleotropy because it hasn't been defined yet As far as the epigenetic stuff someone else can take that Where do the where do the UDP patients come from are most of them? within a convenient drive to a tertiary Or research medical center, or do most of them come from more Rural areas or outlying areas they come from all over the world, but actually if they're in a rural area They're less likely to have had a tertiary care workup Which is required for us to accept the patient, you know having eliminated all the other stuff I would say about a third to Maybe even a half of our patients have been to one of the major medical centers Such as the Mayo Clinic or Hopkins or Cleveland Clinic or Harvard or Stanford, you know One of those Baylor places type places actually probably a half maybe even two-thirds Their comments or our discussion. Yes Good way of tapping in into that population for the future the population that hasn't been assessed at this point So there has to be another pathway Created to give patients the access Sure whose responsibility is that government well Okay, so I'm hired by the government Wendy If what she's sort of talking about is the justice issue in and and this this is There's two elements to this one of those the science which is incredible, but the other one is Access to care which is obviously Skewed in the setting if only half of the diagnoses are coming from genetics What are the other half coming from and do you have a way of knowing which ones are going to be which? So you know who to genotype first and then bring in versus, you know, do the whole work up I just have to say that a half of the diagnoses are not made from genetics It's much more than that What I said was that half of our diagnosis are made without using next-generation sequencing Okay, so a lot of these are like commercial stuff or get an enzyme assay or say things of that sort But I think that probably 90% of our cases are known to be genetic And as you said perhaps 100% of of all cases are genetic By suppose some trauma is not but nonetheless I mean it seems to me if it's 90% plus that are genetic Why wouldn't you get the genetics first and to lead lead your phenotype? And if I might answer the reason is that some of our patients who come to us at the NIH We don't get any genetics on because they don't They don't have objective findings. We sometimes make mistakes like that. Not very often anymore but or sometimes we can look at the patient and do a phenotype and Foon phenotypic analysis and make the diagnosis without any genetics at all and that means that we're wasting Exomes and genomes beforehand which subsequently have a responsibility associated with them, you know Incidental secondary findings getting back to the patient. Tell me what the results were etc. And And so it creates an additional burden. So I would I believe that really our phenotyping should dictate and guide our Genotype analysis rather than having our genotype analysis of basically guide a phenotype And why would you alter your phenotype? Incredibly much Because when you do an examination of a patient and have all your consultants around It's important to find out things and ask the same questions of one patient that you would of another You know not completely but to be thorough enough to look for things that you might not have thought of Based upon a genotype But just to push a bit more I mean if you figured out either the cost the time or the burden on the family to do this very wide Phenotyping and what the yield is have you done that type of analysis to know that versus taking a very targeted approach Which might be even deeper in a specific dimension if you were guided by the genes No, that type of analysis. We haven't spent the time on I Would just follow up on the last comment though. I think in terms of You know the long-term goals and the data generated by the UDN Identifying a gene before a patient scene is very satisfying from the standpoint of the family You don't have to travel etc. But in terms of generating deep phenotype data and linking that to genetic data linking that to other data and and Expanding the ongoing development of the Bioinformatic tools for future, you know, you lose that if you don't do the process And just back to the idea of plyotropy to or off-target effects that you know having the genotype alone may tell you very little about what is causing disability or what you know, what symptoms are Worth focusing on treating as opposed to you know, you have a ABC XYZ 3 2 Which means almost nothing to the patients and so it's in the that Conversation based on the phenotype. I think the very often is the most useful information for for the patients Yeah, I'm gonna take a stab at your question about epigenetics Okay, I definitely believe that I think whether there's data or not We all believe that epigenetics will explain a component of the missing heritability that we see and I think that the UDN is a perfect Venue to begin to explore this return of clinical application because you have deep phenotyping information We have deep genomic information and so I mean for example, I mentioned we're doing RNA seek part of the reason for that is You know to ask the question Globally in blood, do you see evidence of altered expression in the transcriptome which you could relate back to Not just a primary genomic defect if you had a gene candidate that was expressed But really also in fact an epigenetic alteration if you didn't have a structural or you know a mutation So I do think this is exactly a question that we need to be tackling in the future because that's the next stage of clinical diagnosis Time for one more. Yeah, I wanted to get back at the earlier question about diversity in UDN and so So one way to do that. I think and what the model we have trying to follow in Tennessee Is actually provide phone directed consultation. So because of The way we have advertised UDN services in Tennessee We will occasionally get physicians calling us from rural communities who Have a patient and they want to know Based on the presentation The patient may have or has whether that patient is suitable for UDN and we can Give them a good idea about our advice about hey, this is what you have to do You're close to Memphis go to and we have contacts you can go and talk to this physician And this is the pathway to starting a sort of baseline work up So I think that is probably one of the ways that we can Help a lot more patients and the follow-up to that is that we All sites or the one the sites that are going to be doing this They need to have a metric and record this because I think this is an important point that not only that UDN saw X number of patients in their site, but they actually helped guide Through a physician or a subspecialist in another medical center Care that actually helped that patient Okay, so our time is up. Let me just take a couple of minutes to to summarize I'll leave I'll leave this up. I think Certainly this issue of genotype first versus Phenotyping first probably there is no right answer And I think depending on who's doing it one approach may be more efficient the other But I think that is something for for discussion going forward. I think that the the main Importance I think of of having a network like this is is to make sure that all of that information is captured So that as was mentioned, you know, if you have a genotypic answer before you see the patient that may minimize the amount of Useful phenotypic information that is that is gotten but certainly Other ideas, you know for future and for areas of emphasis, I do think certainly ways of looking at Environmental early early life history elements and potential interactions Will be Important and then the last question on the slide I think is still one that that we didn't discuss very much But one going forward the question will be should there be a reasonably at least a kind of a minimum core Dataset that should be obtained for paces with certain types of complaints across the network so that if you are seen at a UDN site Should it be you know really expected you will get a completely different kind of evaluation depending what sites you go To perhaps based on what their expertise is or should this be something where there needs to be some At least minimum level of uniformity of what type of phenotypic data are collected and in what way they're collected But I think that's that's a very good. I think future question Thanks John So we now have a break scheduled for 15 minutes for those of you who are seeking caffeine There is a snack shop off the lobby that probably will be able to provide some for you And we are due back at 10 20 and then we will have questions 2 3 and 4 before we break for lunch. Thanks everyone