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Genetics and Arrhythmias: Beyond Mendel's Peas
Practical Use For the UK 100,000 Genomes (Presente ...
Practical Use For the UK 100,000 Genomes (Presenter: Elijah Behr, MA, MBBS, MD)
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The next speaker is Dr. Elijah Baer, who comes to us from St. George's in London, U.K., and he's going to talk to us about the practical use for the U.K. 100,000 genomes. Dr. Elijah Baer Okay. Thank you very much, again, for asking me to speak on this particular subject. I'm speaking to you as the co-lead of the arrhythmias subdomain of the Cardiovascular Genome England Clinical Interpretation Partnership of the 100,000 Genomes Project. So that's a mouthful. That's called the GSIP, and that's the research end of the 100,000 Genomes Project, and I'll refer to that later. But I have a sort of – I have the luck in that I email Genome England, and they send me their slide deck. And so some of these slides, if not all of them, are derived from that, with a little bit of my interpretation thrown upon it. And the practical use is a little bit difficult because it's going on at the moment still. It's churning out results at the moment and interpreting and using them for patients as such that I can't give you a great vignette from my own experiences yet to demonstrate the practical use for whole genome sequencing in this particular patient group. Hopefully I'll have that for you next year if you ask me again, but at this point I can't say more. But I'll try and tell you a little bit more about the Genomes Project, the 100,000 Genomes Project, because many of you may not be aware of the background. It was essentially a political decision to have this project, driven by David Cameron, who was responsible for Brexit. But he wasn't aware of that at the time, but he was aware of genetic diseases being an important cause of rare disease in the population because his son died from a rare genetically related epilepsy syndrome in his early teens, was terribly disabled by it. And I think that was what really drove his interest in genomics. This was taken on politically as part of the development of the NHS. After David Cameron left office, the first new sequencing center was established, and more of the strategy behind whole genome sequencing and genomic technologies in the nation as a whole became important parts of our life science strategy in the U.K., including commissioning of a new NHS genomic medicine service that I'll explain to you why that happened in many ways, and completion of the project by the end of last year. The four, in terms of the sequencing at least, the four main aims of the project were to bring benefit to NHS patients, to create an ethical and transparent research program based on consent, to enable a new scientific discovery of medical insights, and to kickstart genomic industry development in the U.K., really focusing on three different areas, rare diseases, which form the majority of the recruitment, certain cancers, and infection response, which has been a much smaller group. Recruitment was undertaken through 13 NHS genomic medicine centers in England initially, and then some of the other nations came on board at a later stage, Scotland, Northern Ireland, and Wales, but with a much smaller recruitment overall. Ninety hospitals in England were responsible, and each of these genomic medicine centers covered a region delivering clinical genetic services to that part of the country. Patients were consented, samples taken, including omic samples from a large proportion, clinical data, basic clinical data inputted, and linkage to secondary longitudinal data, particularly outcome data in the electronic health record. The samples were in a biorepository, underwent sequencing, and went to the Genomics England Informatics Architecture, with anonymized data being made available to the GSIP, the research side of it, and then to industry users as well in the discovery forum. This would help with interpretation of equivocal results, but the results are passed on to clinicians to feed back to patients and then to be used in families. So that's the overall situation. The progress to date, as of the 1st of April 2019, the majority of the patients included have been rare disease patients, and there's 122,000 samples with 106,000 genomes sequenced, the majority being rare disease, as I said, and the analysis and results have been fed back on the majority of those resulting in actionable results, particularly, I think, in the cancer area of 20 to 25 percent in the rare disease section otherwise. And in terms of recruitment, you've seen 85,000 people were reached in this project. Well, actually, just under 5 percent of the U.K. population is at risk of a rare disease. These are, if you add them all together, that's 1,200 disorders, and I don't think that's going to be any different in the U.S. either. Rare diseases, when you add them together, are not that uncommon. And there's a process of standard characterization using the human phenotype ontology classification system, HPO for short, semi-automated analytics through the pipeline resulting in this 20 to 25 percent potential diagnosis of which some can be life-changing, although I can't give you my own experience yet because our results are still churning through in cardiology. We're towards the end of that pipeline at the moment. But you can see cardiovascular disorders here contributed a significant amount, probably the third biggest recruiters, just under 4,000 families participating. This is arrhythmia and cardiomyopathy. I've excluded some of the other disorders, congenital disorders, and just to make the slide a bit more intelligible. So you have clearly HCM at the bottom with 1,200 participants and 800 families included, so there will be unaffected individuals or more than one affected individual in the family. The aim was always to try and generate trios, but didn't quite achieve that because most of our disorders are autosomal dominant. They're not straightforward evaluation of trios, other than in the pediatric cardiomyopathy area in particular. DCM coming second and Brigada syndrome being our most commonly recruited arrhythmia phenotype there with just under 200 families. And if we look at what we had to go through, there was an eligibility criterion process. And at the beginning, these eligibility criteria were quite stringent because we wanted to avoid the whole flooding of the system with ungenotyped patients. But then it turned out there was a problem, and I'll show you what happened in a moment. First of all, our clinical features changed. So we went from 2013 guidelines to Shanghai criteria, for example, to try and be a little bit more accurate in how we used that in the drug-induced type 1 pattern. We wanted to exclude non-genetic causes, of course. But the aim of the project was to exclude known genetic causes to begin with and therefore focus on new genes. As we know, in Brigada syndrome, they're not that, you know, the new genes have just been debunked, all 21, 22 of them by ClinGen. So we had a problem from that point of view, and we also had another problem. It actually turned out only a small proportion of Brigada syndrome patients were actually getting genetic testing, partly because of that uncertainty around the genetic result, but also because of widespread inequality of access across the National Health Service. And this is one of those really driving factors for why the 100,000 Genomes Project has become a national service. And I'll show you how that's evolved. So we actually ended up widening the criteria for evaluation for admission towards the end of the project to increase recruitment. So there's a slightly different blend of patients recruited towards the end. And this is the – these are the terminologies that were used from the HPO terminology, and you'll see they're pretty basic. And this is the amount of data that came in, because these were clinicians having to enter data, genetic counselors, fellows, consultants, geneticists, cardiologists having to enter these data into an electronic database held by Genomics England, in addition to their routine clinical work. And so it wasn't really set up to enter detailed clinical data. So limited terminology has been collected, which is a criticism we've made, but we're in the process of delivering methods for harvesting ECG and clinical data for these cases, and they're ongoing in the national service. So in terms of the pipeline for these results, the patient family contributed their DNA. Sequencing would go forward. The VCFs would be annotated. This is an Illumina-developed pipeline with annotation companies providing information on the variants, and the variants are tiered in Tier 1 to Tier 5, and Tier 1 really being your pathogenic-likely pathogenic, and Tier 2 being other findings that are of interest in the cardiac genes, and Tier 3 being those that are really for research, and where the GCIP would step in and say, okay, these might be new genes or new variants of something of new interest. And that clinical assessment and relationship between the GCIP and the clinical output is where we've been trying to work to enhance the results. In terms of reporting back to the NHS, there's a portal that provides information around the family pedigree, about the review of variants, with all the annotation available from that commercial, those different commercial providers, and a report that can be used. And participants are told information about their main condition. That's what they consented for. They also consented for that they could find out about additional, serious, actionable conditions. This is the incidental findings. And if there were parents, whether they're going to be carriers for recessive variants that cause homozygous disease, or at least compound heterozygous disease in their children. And in terms of those additional findings, they were mainly around cancer variants that were clearly highly penetrant, and reliably detected by genomic sequencing, and treatable or preventable. So nobody's going to feed back Huntington's status to anybody. And other conditions were allowed to be added over time as we improved that. And my always thought, well, when are we going to add the PGX variants to these? And PGX is one of the, for pharmacogenomics, is one of the work packages around improving the outcomes from the 100,000 Genomes Project. In terms of what's available in the research environment, if you're a GSIP member, an international participation is very open and welcome. There is a huge amount of data and documentation. All the genomes are there to be analyzed. There are tools for that analysis, and the forum for collaboration. But the collaboration is run through the GSIP because they don't want five different groups doing the same thing with the same data. They don't want waste. They want collaboration. And a utility from everybody's action. And so currently there are about 91,000 genomes in the environment, with primary clinical data for all of those, plus some additional participants, secondary data including hospital episodes, mortality and morbidity outcomes, patient reported outcome measures. There will be some cardiovascular disease linkage there as well, such as the MI database for the country. Clinically interpreted data in QC is there, although it's gradually filtering in. There's an issue of alignment to HRG 37 and 38 that's being addressed, and there's a lot of recalling going on. So there are some delays involved in the system. And I think one of the most important things that are coming out of this is addressing the inequality to access of genetic studies in the National Genomic Medicine Service that is launched earlier this year. There's a national test directory that is being derived from the 100,000 genomes, but allowing for all those genes that they were previously supposed to have been sequenced for, and a restructuring of that addressing concerns around certain genes. So, for example, SCN5A is the only gene that would be thought of as being reportable now for the national information, for the National Genomics Medicine Service, which means that we're only going to have single gene and panels for many of the cardiac disorders, but for some of the pediatric disorders and rare disorders, you'll have whole genome sequencing available and clinical exomes for sudden and expected death in the young as well. So there's been a rationalization of the approach to provide equal access that's all centrally funded. With the NHS leading this and setting up a national laboratory network, there are four cardiac centers providing it across England, and Genomics England, who are responsible for the 100,000 Genomes Project, being responsible for all the genomics knowledge base and the running of national database for genetic, for patients undergoing genetic studies and their genetic results, and providing the whole genome sequencing to support that aspect of it, and supporting the research environment that will continue as it is, but being improved as we've managed to feedback the clunkiness of it. It is pretty clunky, but it will get better. And, of course, there's workforce development, and the one thing I haven't been able to tell you about is there's an enormous education program behind this led by Health Education England that's educating thousands of professionals, allied health professionals and physicians. And the commitment is that there will be half a million whole genomes sequenced in the NHS to deliver genome-suitable sequencing for genome-suitable disorders. So, that's not including, necessarily, those genomic tests that are not whole genome sequencing. And this is the frontage that they're expecting for the genomic health, for the National Genomics Informatics Service, where information will be inputted, and we can get results back through it. It's going to potentially be a national interactive data collection service, a line clinical service, delivery service improvement and audit, and research on a national level. And the latest commitment, would you believe it, is that we'll have 5 million genomes over the next five years, over and above, 4.5 million over and above those 500,000 for the NHS, half a million of those for UK Biobank, and then 4 million for, hopefully, other funded resources. So, you know, let's look for bankrupting Brexit Britain. But hopefully, we'll be able to meet this aspiration, and they're probably going to end up being genomic tests rather than whole genomes, from that point of view. The way forward is equal access and consistent and equitable care for a whole population, with common national standards and protocols, standardized consent to include research, with an approved national directory, with a single UK genomics knowledge base, and a national NHS database with all those results that can be identified data for research and development in the future, and providing new treatments for our patients in the long term. And I think this is where the greatest utility is going to be in the longer term. It's not necessarily the immediate results from the 100,000 genomes. No matter how important it is for those 100,000 individuals and families who participated, it's what it's going to mean for the whole country, and hopefully, it's global impact in the future. Thank you.
Video Summary
Dr. Elijah Baer from St. George's in London discusses the practical use of the UK 100,000 Genomes Project. The project was initiated by former UK Prime Minister David Cameron, who was motivated by his son's rare genetic epilepsy syndrome. The project aims to benefit NHS patients, enable research, and kickstart genomic industry development in the UK. The majority of participants have been rare disease patients, with over 122,000 samples and 106,000 genomes sequenced. Actionable results have been provided for the majority of patients, particularly in the area of cancer. The project is a collaboration between Genomics England and the GSIP, the research arm. The clinical data is collected through NHS genomic medicine centers. The results are then passed on to clinicians for patient feedback and family support. The project has helped address inequality in access to genetic testing and has led to the creation of a national laboratory network and a national genomics medicine service in the UK. The goal is to have 5 million genomes sequenced in the next five years.
Meta Tag
Lecture ID
6688
Location
Room 203
Presenter
Elijah Behr, MA, MBBS, MD
Role
Invited Speaker
Session Date and Time
May 09, 2019 10:30 AM - 12:00 PM
Session Number
S-013
Keywords
UK 100,000 Genomes Project
genomic industry development
rare disease patients
actionable results
national genomics medicine service
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