 All right. This concept clearance proposes to renew the Centers for Mendelian Genomics Program. The proposed purpose for the renew is to bring the field forward towards the goal of solving all or most of the Mendelian disorders in the foreseeable future by solving as many Mendelian disorders as possible at the founded centers and by enabling and coordinating with the rest over the world. By solving Mendelian disorders, I mean identifying the underlying genomic defects of Mendelian disorders and for the rest of the presentation today I'm going to stick to the term solve. This slide highlights the main achievements made by the three current centers for Mendelian genomics, often referred to as CMGs. These centers have been founded by NHGRI and NHLBI since November 2011. Together they have demonstrated the power of sequencing at scale for solving Mendelian disorders. They have so far discovered soft over 165 Mendelian disorders. In the process of solving Mendelian disorders, they have also made discoveries of phenotype expansions of about 120 Mendelian disorders. By phenotype expansion, I mean the discovery that the phenotypes started and turned out to be underlined by the same genomic defect underlying a previously already solved Mendelian disorder except the phenotypes were not previously observed or documented. Some of these studies have been published in just over 100 publications so far. Along with others, the CMGs have also revealed to a much greater extent than previously anticipated the pleotropy and heterogeneity underlying Mendelian disorders. They have developed methods and tools and data source in the process of solving Mendelian disorders and the effort for disseminating these resources have been ongoing. The progress made by the Mendelian centers and a few other similar efforts and the knowledge and the estimate on the remaining Mendelian disorders to solve have largely informed this concept that I'm presenting today. So how much remaining work lies ahead? This is a summary of current estimates. For about 3,600 Mendelian disorders, there is a known genomic basis. You will notice here that I used the term molecular basis rather than genomic basis and that's because that's the term that OMIM uses and so maybe some of the molecular basis here refer to non-DNA molecular basis but essentially about 3,600 Mendelian disorders have molecular basis and about equal number of Mendelian disorders still remain to be solved. Every year there is still additional number of Mendelian disorders described. In conclusion, much work remains to be done in order to solve all Mendelian disorders. This and the next several slides will present the proposed scope and objectives for the renew. The first objective is to solve 300 also Mendelian disorders in order to learn the approaches and methods and scale and technologies that it will take to solve all Mendelian disorders and the second objective which is as important as the first one if not more to enable others and coordinate with others by developing and disseminate methods and other resources and reach out coordinate with other researchers over the world in order to meet the ultimate goal of solving all or most of the Mendelian disorders. We came up with this production goal of solving 300 also Mendelian disorders based on the NHGRI funding level that I'm going to propose in a few minutes. Also based on the progress that the CMGs have made so far in solving Mendelian disorders also based on the expectation for improvement of efficiency and costs and the anticipation that there will be fewer hanging fruit disorders left to be solved. In other words, the decrease of per-exome cost and the increase of per-disorder cost may cancel out. So these three factors all together led to the estimate of this 300 Mendelian disorders as a production goal. There are two more general goals that we wish that we believe that that we believe solving 300 Mendelian disorders will enable us to still meet. One is to understand the genetic characteristics of Mendelian disorders as a group and the other is to learn what it will take to solve all Mendelian disorders. It is our judgment that 300 represents a significant magnitude in terms of scale and the range of disorders that will allow these two objectives to be met. We are also introducing two new features to the program for the next iteration. One is that when, for example, exome sequencing fails to lead to insight when appropriate whole genome sequencing should be implemented in order to explore the entire genome. And the other change to introduce to the program is to allow a very small percentage of CMG funds to be spent for small scale function assets and this will be a difference to the current program. Of course, we are going to continue to expect follow-up function assets after varying discovery to be largely performed at the collaborators place. And finally, I should mention that this goal is set up based on, as I said, the NHGI funding level that we are going to propose and we are going to seek co-funding from other ICs. Currently NHGLBI puts in $2 million to the program every year and should that amount of money be available or hopefully other sources become available, this goal will go up from $300 million. My estimate is if $2 million become available again from heart and tongue every year, then the goal could raise from solving $300 to $400 million per year through the entire iteration. And then moving on to the next objective for the proposed renew, enabling and coordinating with others. In the process of solving Mendelian disorders, there will be necessary refining and development of approaches and tools and ways to improve efficiency and cost and improved data analysis methods for difficult genomic regions. These methods, we are going to require dissemination of these methods as community resource. In addition, data release is going to be an important feature of the program that we are going to continue to emphasize. And data release will entail DbGaP sequence data release and posting of a course of allele information which would include simple and brief information about the disease names and the location and genomic changes of the course of allele at a public CMG browser and then link to other sites including ClinVar. And also, the CMGs are now coming together to work out issues in the consent process so that data can be pulled together for them to come up with leo counts from the pulled sequence. We anticipate this to be done before this funding period ends and to continue through the next iteration, but a better outcome may be that the CMG data and other programs data could be pulled. So the last part of the enabling and coordinating with others are exactly about reaching out to individual investigators. Based on the current CMG's experiences, we anticipate that training of collaborators and other researchers would continue to be necessary in order to equip them with the know-how for sobbing and dealing disorders and the program will continue to participate in the International Rare Diseases Research Consortium. And the last point is a very important point to make. That is, given the rarity of Mendelian disorders, as Rod McGinnis pointed out at the recent July workshop, the goal of solving most or all Mendelian conditions requires unprecedented cooperation and coordination among clinicians and scientists worldwide. We are going to continue to require public posting of the project lists in the CMG pipeline, and we are going to promote matching of samples or candidate genes of the disorders of common interests. So those were the two main objectives and the scope proposed for the program. In terms of relationship to other NIH programs, Adam already touched the anticipated interaction between CDVD and the CMG's, and he will talk about the interactions between these programs with the Genome Sequencing Program Coordinating Center. And the other two programs I list here are the NSGI-funded CSER program and the NIH Undiagnosed Diseases Network. For those of you who are not aware, the current CMGs actually have a coordinating center affiliated to the Mendelian Center at the University of Washington. So a lot of these activities, a lot of the working group activities and steering committee activities and annual meetings and outreach efforts have been coordinated by the CMG Coordinating Center. And the CSER program also has a coordinating center. And these two coordinating centers actually have worked out a communication channel, excuse me, I guess I woke up everyone. And these two coordinating centers have worked out a way of communication so that patients who have not been diagnosed at the CSER sites, particularly those who are suspected of having Mendelian disorders, when appropriately consented, may be passed down to the CMGs to be further studied for discovery. We haven't had a success in this arrangement yet, but we do have our communication established. And the NIH UDN, as you all know, will also discover molecular bases underlying rare disorders. But at least one of the differences is that the CMGs largely study existing samples rather than newly enrolled patients. And one of the goals that the CMG program aims to meet is to lower the undiagnosable diseases and increase the diagnosable diseases over time. Because UDN, even though UDP has been very successful in ongoing, UDN is a relatively newer program, but there have been some initial communications between staff about any potential interactions between the program, between the two programs. And we have a council member here advising UDN, so any advice on any potentially fruitful interactions between these two programs would be appreciated. This slide summarizes the proposed mechanism and funds. Given the scale and complexity of the program, as with the current CMGs, we propose to continue to use a cooperative agreement mechanism. And the program, including the grantees and staff, will regularly seek advice and guidance from an external scientific panel. Both the representative grantees and staff will be required to participate in steering committee and working group activities. And we propose 40 million NHGRI funds for the four-year period, which is at the current level, and $10 million annually. As I mentioned, we will seek co-funding from other NIH institutes. The RFA will fund up to three centers, and it will be open to all participants. So this is the last slide. Just to summarize, I have presented a concept that proposes to fund centers for Mendelian genomics with 40 million total NHGRI funds, aiming to solve 300 or more Mendelian disorders, and to enable and coordinate with others to meet the ultimate goal of solving all or most of the Mendelian disorders in a foreseeable future. That's my entire proposal. Are there any questions? I'll put on my glasses. Yes, Howard. Thank you. You'd mentioned, I think you used the term, low-hanging fruit was already eaten, or you've already, you know, the most available data sets have been started on. Has anyone gone through the OMIM catalog and asked the question how many of the remaining diseases are likely to be, to even have samples or can be assessed? Because it won't be the full number, for sure. That's an excellent question. How hard is the next set going to be, I guess, is what I'm looking at. So my understanding from interacting with the current grantees is that it's going to be a achievable goal to solicit quality samples. I should have mentioned that currently the effort to solicit samples has been at low scale. One of the reasons is because when the current grantees came on board, they brought in samples that they had solicited through years of effort before the inception of the program. The first question you asked was excellent when, in fact, the Coordinating Center at UW just went through the exercise to look over all the listed Mendelian disorders that are included in all the disorders on OMIM together with Ada Hamash, who is the PA of OMIM, and they have identified a set of Mendelian disorders and the PIs who initially published on those disorders, and there has been discussion for the CMGs to reach out to those PIs to see if samples are, some of those samples are actually available. So the current, so the next iteration is going to need to give more funding support for, you know, a higher scale sample solicitation effort. Yes, Jo? Yeah. Howard took part of my question. I was wondering about the bottleneck of this, but also coupled to what other institutes might be interested in partnering based on the samples that are out there, right? So I think you mentioned NHLBI was potentially going to partner again, where they had been an important partner, but I'm wondering if the limitation in finding co-partners is in fact finding diseases associated with those institutes. So if you have a very large set, you can say, okay, we could go this direction, but we'd like to have co-support based on the disease focus of that institute. So if you had that population early, you could potentially interact with ICs in a way that says these are the diseases that we're looking to go after. Yeah, that's, yes. Versus the other way around of saying, well, we got this great program and we're working on diseases, something that would directly interest them. Is that possible? I think that's possible, Jo. Just a few words about the current collaboration with Heart and Lung. So the contribution of their dollars represent about 16% of the total funding level. And what Heart and Lung has been doing is to publish XO1s to solicit samples that represent Heart, Lung, or Blood phenotypes. And the XO1 mechanism has not brought in enough samples to consume 60% of their funds, but has had some success. And what we ask the grantees to do is to purposely choose Heart, Lung, or Blood samples in the samples they already have and also pay attention when they go out and solicit samples to be sure that they will feed the pipeline, 16% of the pipeline that can give, that can lead to discoveries. And there have been some good publications coming out of the joint effort. So I think looking into the samples, the grantees will already have and the grantees might already have and the network they have already built. And there could be something presentable to other potentially interested ICs. Okay. I have Carol, then Dan, then Bob, and then Val, and then mine, so Carol. So in looking at the current centers, there seems to be a distinction between solved and completely solved. Yes. So I'm wondering if you, and just for my own education, can you clarify on what the distinction between those two things are? What do you mean when you say solved and what's the difference between solved and completely solved? Okay. First of all, given where we see the advantages of the central efforts are, we have required that they focus their effort on discovery of the quote-unquote causal variance which I'll define for you in a minute. And then we are going to continue to urge the grantees to rely on their collaborators to perform function assets which will help validate the discovered causal or underlying variance if that's a better term. So in order to be able to call completion of, you know, to call when it's, when would be a good time to, you know, complete a project, the CMGs have defined that a variant that they have discovered to associate with the disorder understudy has to be discovered in at least two other families. So that's their definition of project completed and disease solved. I don't know that, you know, there will be absolute proof of causality. And the other layer to this question is that there are some dealing disorders that can be actually explained by the discovered underlying genomic defect. And because of genetic heterogeneity, you know, the underlying genomic defects cannot explain every individual that suffers from the same syndrome, modifiers and also, and heterogeneity. Okay, Dan. Carol asked sort of much of my question. So again, I'm going to focus on words. I think solved is the wrong word because I think of some cardiovascular guy and I think of hypertrophic cardiomyopathy or long QT syndrome, you know, from one level those are solved. And another level 20 years later, they're still not solved. There's still people out there. There's still other genes that remain to be discovered. There are compound heterozygates, there are modifiers. So at what point do you stop working on those and let the community do those? So I think solved is, again, sort of not quite the right word and I understand the appeal of using it. But the other question I had was this, I think the function is underplayed and really very vaguely described in this document. I mean, it's just there's just a, you know, somebody will do function and there's even the term small amount of function or something. And at some point, function becomes important because otherwise you really have no confidence that the variant does anything. And the third point that I wanted to make was that maybe the reason NHLBI has been interested is because they're these high profile, not so rare diseases, it turns out, but we didn't know that when we started. But I'm sure that the I Institute and the Kidney Institute, you know, and neurological guys, all those people might be equally interested and have investigators have family. Can I can I follow up on that though? Are these centers the right place to approach function? Well, that's a great question. But I think that that you can't have your cake and eat it too. You can't say a little bit of function is what we want. We either do function or we don't. So, you know, what we have considered again and again is that function assays for Mendelian disorders and actually will be all sorts. You know, so it will be very hard to scale. And also, we, you know, consider a lot about what the available funds can do most effectively. Well, let me take my answer back a little bit and say that, you know, 20 years later, most of the variants that cause hypertrophic cardiomyopathy don't have we don't understand it to this day. And so that you can have a you can set an army of people to work on function and still not get to an answer. So I but I think that that this sort of lip service to function maybe is is the wrong way to spin it. That say maybe maybe we should say function is not part of this. I take variant and then and then let somebody else prove it. I don't know. Maybe and maybe at the end of the day, you've put more time into it than I have and you probably phrased it right. I don't we probably don't want to spend too much time on this. I have a feeling function sneak in here because many of the grantees have trouble publishing these manuscripts without some aspect of function in it. That's that's part of that. That's actually the main reason when a collaborator does not have the capacity or expertise to do some function assays. Then we are thinking about allowing the grantees to perform a few in order to publish. OK, we have Bob and then Val, Lon and Howard. So I had a couple of points. One was that there's a lot of Mendelian disease discovery going on through commercial laboratories that are doing whole exomes. And I'm wondering what efforts are made to try to capture that information because I mean, if you just look at one large but currently unnamed clinical laboratory, they have, quote, solved 500 disorders that they have studied in the last couple of years. And that's already greater than the 300 that you've proposed. So there's a lot of sequencing going on. It's not being paid for by NIH, and we should get that information in. The second question I wanted to ask about is whether there should be any increased attention to picking appropriate populations that have a lot of first cousin marriages, et cetera, that would help with finding rare Mendelian disorders. And the third thing I wanted to raise to you is about the function question. I mean, whenever I have found anything in a Mendelian disorder, that's a genetic variation. The first thing I do is I go and look at the literature and I find the world's expert on the function of that protein. And I don't care where that person is and the likelihood that they're going to be in my institution or even in my lab is vanishingly small to zero. And so maybe you should consider some kind of supplement that would allow people to, excuse me, that would allow people to reach out and have a small amount of funding through a supplement mechanism to try to work up the function in the hands of the people best suited to do that function. Yeah, so all excellent points. To your first point, and it's actually good news to it's always good news to learn about other ongoing efforts that scale in for the ultimate goal. And that that is precisely why the program is going to continue to push for sharing and for disorder list. OK, Val. Well, much of my comment was already said, but it's picked up on the low hanging fruit thing, too. And now going for the high hanging fruit seems to me that means smaller families, fewer cases, less well-defined phenotypes, greater heterogeneity, which all leads to more mistakes or more false positives. And so thus I was going to comment on the function part. My comment a little different is I think that means that there does need to be a more strict criteria of what actually solve means. And and that may indeed mean a function. I like Bob's comment about, yeah, where do you go to get the function? And it probably is to the experts somewhere else. But I would agree then that a supplementary proposal thank you would be a good idea. Thank you. I take all of your comments about the importance of doing functional assets to at least to a certain extent validate the variant discovery. I wanted to point out that so far the CMGs have been doing quite well to rely on their collaborators to perform function assets. But but they they have run into cases from time to time when the sample providers don't have the expertise and capacity to do functional analysis. And that's when it becomes helpful to go out to the right expertise who actually didn't provide samples. So I understand your comments and thank you for the advice. I want to go back to Bob about the second point you raised. And we have one and among the three current centers, we have one center and who has done a lot of sequencing of our consanguine families. And that has actually turned out to be quite productive. Yeah, in identifying very extreme phenotypes. It's just I'm wondering whether we could do more to reach out to the populations in the countries where these samples exist and these families exist and have a quid pro quo of of helping them understand and deal with the problem and also contributing to the research and making sure that those populations in those countries don't feel like they are being exploited, but instead are partners in an important discovery. Thank you. So there's a common theme coming out here, so I'll be brief on mine because I think Bob and Dan and others have stated it. I'm really excited about this, actually. I think this is great. I think it will work and I think it will work at scale. And it comes back to that that question then if it works at scale and you have 300 all of a sudden diseases out there and you take the patient perspective, apart from validation, which we can get through, there's nothing that can do about it. And so so I think we owe it to ourselves to have some statement of what the follow up is of the initial discovery here and not just not just leave it behind. If it's a supplement, great, if but we have to have some stance, it seems to me and not just leave it hanging because because it will work and it will work for a lot of new diseases. Can I just press you? What do you have in mind? Well, I mean, so so you've I mean, it takes us back to Huntington's or something, right, where we know the defect, but we can't do anything about it. And so it is exactly what Bob was saying. Can we find some mechanism not just to validate the defect itself or the causal variant, but to begin to understand what it's doing? And only then do we start talking about solving it to me. But is that going to be a practical thing for NHGRI to do? I think I don't know that NHGRI. I think we need a stance on it right out of this. What what are the steps? Are we going to facilitate ICs coming in? Are we going to provide potential supplements? I don't know what that solution is, but I don't I don't think you can just leave it hanging personally. I think something has to come out of this. Howard, you had your hand up. I don't know if the point already got made or you wanted to I just want to say that I think on the function side, it's yeah, I think on the function side, we just want to give these guys some latitude. And so whether they're coming in on a supplement or they want to come in on as you some of their own resources, I think we got to give them a little bit of latitude. They're not asking for a huge amount on this. So I'm supportive of that side of it. I do want to be careful on it and come back to the whole utility side. There's a whole series of issues around that. And so just making a diagnosis for some families is really a lot. And so I just think we want to be careful on how far we want to push that with within this institute relative to the other ICs. I guess one other quick comment about this issue about who does functional studies is that in general, what I found is that if you pick the right collaborator, it actually will not require a lot of money because they've already got everything set up and know exactly what to do. In fact, that's a biomarker for being the right person to have chosen. Maybe not sufficient, but at least necessary. All right. So no further comments. Can I have a motion to accept the concept as per. Okay, can I have a second? All in favor, please keep your hands up. Okay. Any opposed? Abstentions. Thank you.