100,000 Genomes Project

Please inform your GP before you move house so that your records can be easily tracked and your results returned as quickly as possible.

Genomics England will always return results to the healthcare professional who asked you to join the Project. If you have moved since joining, that healthcare professional may either arrange to pass the results on to your new specialist, or arrange for you to go back see them again for the results.

All your primary results should have been returned to you by now, via the NHS team who recruited you to the 100,000 Genomes Project.

Genomics England sent all of your initial results back to the NHS clinical genetics labs, with the last ones being sent out during August 2020. The labs are responsible for generating the diagnostic report that is sent to your doctor.

If you haven’t received your initial results, we would recommend that you contact the clinician or department with whom you signed up for the 100,000 Genomes Project, as these are held in your medical record.

If this is unsuccessful, you can get in touch with our Service Desk who will try to guide you to the right contact.

Genomics England works with the NHS to analyse your information and reports it back to your local team. It would not be right for us to cut your doctors out of that conversation, to liaise directly with you. Any findings then need to be assessed by the local hospital laboratory before your doctors can feed back to you.

We do recognise the frustration of those of you who have not yet received a diagnosis, and we are continuing to develop new methods of analysis, to deliver diagnoses to as many people as possible, as quickly as we can.

It’s important to be aware that not everyone in the programme will have a ‘single gene’ genetic diagnosis. There are lots of non-genetic causes of many disorders, which are hard to tell apart from genetic causes. This means that we will not be able to find a diagnosis for some participants.

However, we are still working hard for you, in the following ways:

a) Your de-identified data is being used for research by our approved research partners, and is also being studied by our growing in-house bioinformatics team. These researchers are looking at ways to improve our diagnostic abilities and the way that possible new diagnoses are reported back to you.

If a researcher or a bioinformatician finds a potential diagnosis, this is reviewed by the Genomics England clinical team and sent on to the NHS clinical labs for verification and reporting.

Where a researcher has identified a variant of interest, which is not yet ‘diagnostic-grade’, we get in touch with your doctor so they can investigate further if they think it’s the right thing to do. For example, your doctor may be able to order further tests to help confirm a diagnosis, or the researcher may be able to investigate further in their lab.

b) We are piloting new ways of getting useful diagnostic information from your genomes. These new approaches look beyond the basic structure of the genome, and give an insight into how different parts of a genome actually function within the body, which we hope will give a clearer view of the cause/s of many health conditions.

We are working with several genomics research organisations that may be able to deliver more diagnoses, in new ways:

• we are looking at how the activity of gene variants, rather than just their presence, impacts upon a patient’s condition (known as ‘transcriptomics’)
• we are also studying the proteins that are made by genes – finding out about their quantity, structure, and what jobs they do in the body (known as ‘proteomics’)

We also have an ongoing pilot of new ‘long read’ DNA technology, working with Oxford Nanopore Technologies. The traditional approach to genomic sequencing is to chop the DNA into small strands (‘short reads’) which are recorded by the sequencing machine and then stuck back together. The new ‘long read’ approach means that long strands of DNA are read in one piece. This can make it easier to spot some genomic rearrangements. Hopefully this will give us a clearer picture of the genome and where the problem that’s causing your condition may lie.

All of these projects are at the ‘pilot’ stage at the moment, as we test the effectiveness of these new technologies. So only a relatively small number of your genomes will be looked at initially. Should these technologies prove effective, then we will look use them more widely.

Diagnoses generated from these projects will be returned to the clinical labs for reporting via your clinician – if your genome has been (randomly) selected for the pilot studies. This is new work, and new technology, that will take time to complete. Everyone is learning, so it’s difficult to apply a definite timeline for these results at the moment, but we should know the outcomes of the pilots within the next couple of years.

c) We have also been looking again at patients without a diagnosis, informed by the new discoveries that have been published by scientists around the world since the start of the 100,000 Genomes Project. Our team have returned several hundred new potential diagnoses to your NHS doctors over the last few months. These should be reported back to you by your consultant.

We intend to revisit everybody’s data at least once using the latest information and diagnostic tools in search of an answer for you. There are also thousands of researchers around the world, led by doctors across the UK, who are now working in our database on specific areas of medicine – they may also find answers for you in the future. If they do, we will tell your local doctors. As with all research findings, these then need to be assessed by the local hospital laboratory before your doctors can return any findings.

At the moment, around 20%–25% of participants are receiving an initial diagnosis (1 in 4, or 1 or 5 of families). We will continue to research the 75%–80% of participants who receive an initial result in which no diagnosis has been found (a ‘negative result’). For some people, this is because the gene which has caused their disorder has not yet been discovered. For some people, it may be because the type of genetic variant causing their disorder is complex, or because there is more than one gene causing the problem, and more work needs to be done to find them.

Compared to standard NHS genetic tests, we’ve already been able to find answers for more people. For example, we have used whole genome sequencing to find a diagnosis for nearly 40% of children who are on this Project because of an intellectual disability, compared to an average diagnosis rate of 18% for those using microarray testing in the past. And we will continue to get better at finding answers for you, as technology improves and we all learn more about what different parts of your genome really do.

Like the main results analysis, additional findings analysis starts with your genome data being run through a central analysis ‘pipeline’ at Genomics England.

The results are then returned to the NHS Genomic Medicine Centre where you joined the Project. The clinical scientists in the NHS laboratories then assess the results before they are returned to you, to make sure the result is ready to be used in planning your treatment.

Additional findings have not been processed in family groups, so your family’s results may not all come back at the same time.

This process started in Summer 2021, and genomes have been passing through the pipeline in batches since then.

The Additional Findings team at Genomics England have now run over 90% of patients who asked for this analysis through the pipeline. These results are now with the NHS who are in the process of reviewing the results and passing them back to patients. As with all analyses using large datasets, the final stage of the process involves working through the extra-complex situations e.g. where there are issues with data format. This means that the last stages of the process may take a bit longer and need some extra work from the Genomics England team. However, we are expecting that the last people’s genomes will run through the pipeline in Summer 2022.

We apologise that this is later than originally expected, due to the impact of COVID-19 delaying our work. If you don’t hear anything by the end of the year, please contact the Genomics England Service Desk to ask for advice.

The more clinical information we receive from your clinical team, the better chance we will have of finding answers about your condition. Genomics England makes available the initial analysis data (called ‘tiered variants’) from your genome to your clinical team so they can also review the data themselves if they want to.

The Project is sequencing the whole genome of every participant – this lays it all down on file for future reference. So far our analysis of this data has been focusing on your genes – the more than 20,000 bits of the genome that play an active role in making your body do what it does. We use very sophisticated ‘gene panels’ to compare your genes against the ones that we know are associated with certain medical conditions. Beyond the genes, we have also begun to analyse other variants – this expands how much of your genome that we look at. In the very near future, we will also be able to use new technology to look at more bits between your genes, which will help us to find more answers for you.

When you join this Project, your blood sample is sent to Genomics England alongside information about your clinical features, coded in something called HPO terms (HPO stands for Human Phenotype Ontology – this uses standard terms to describe humans all over the world, so we can compare you and your genome more accurately against other people).

This information is submitted by the clinical team (doctor, nurse or genetic counsellor) who recruited you onto the Project. It gives us clues about which genes to look at first. We also look at your NHS health records for more clues, and these are updated on our system regularly – so if you have developed new symptoms since you signed up for the Project, we should be able to consider them too.

We are keeping all the panels up-to-date used in both the 100,000 Genomes Project and for the NHS Genomic Medicine Service.

PanelApp is being used as the tool to store and collect information about genes and panels for the NHS Genomic Medicine Service (GMS), as well as for continuing analysis in the 100,000 Genomes Project. Some panels being used for the NHS GMS are the same as those used for genome interpretation for participants of the project. Others have been developed afresh for the NHS GMS. This is because the range of disorders which will be available to test in the NHS (outlined in the Test Directory) isn’t quite the same as the disorders that were investigated in the project.

When we reanalyse the whole genome of participants we add new panels to the reanalysis if there have been major changes in your condition. Even if we use the same panels, they will have been updated if there are newly discovered genes. We now have a field called ‘Panel type’ on each panel page within PanelApp, which indicates what the gene panel is for. Panels with ‘GMS…’ in this field will be used for a clinical indication in the NHS Genomic Medicine Service, while panels with ‘Rare Disease 100K’ or ‘Cancer Germline 100k’ are for project participants. Some panels will have both, for example the intellectual disability panel.

The curation team at Genomics England is continuing to support updates to panels for the NHS GMS and in the project. The aim is to use the same expertise and evidence to keep them all updated together. External reviews help with this effort – we encourage experts to add new publications or new genes to panels, and the curation team review the ‘Activity’ page for new reviews each week. You can view the Activity page to see changes we are making.

Genome reanalysis may happen for a number of reasons. Sometimes a researcher or the Genomics England bioinformatics team will find a new diagnosis while analysing particular groups of genomes. Sometimes a person’s medical condition may change and their doctor may want to take another look at their genome data with the new information.

Genomics England is aiming to reanalyse everyone’s genome data once we have returned everyone’s initial result to the NHS. This will mean all participants benefit from the learning that has taken place during the project. At the moment we are still working on getting a preliminary result back to everyone, so the timing of reanalysis for any particular patient is not yet possible to predict.

We recommend seeking clinical advice if your circumstances change, as full evaluation is sensible at this stage. There may be additional investigations that need to be carried out, based upon your new circumstances – and this would enable an updated review. We recommend either directly contacting the original clinical team or hospital department where you were seen, to seek up-to-date advice, or contacting your GP to request a referral to your local Clinical Genetics Department. This is because any review of your genome data will only be helpful if it is combined with a wider review of your condition.

‘Exome sequencing’ or ‘panel testing’ are different ways to ask similar questions of the genome. There can be times when a different test could be helpful, but usually if a genomic analysis has been done already, the chance of finding a new answer with a different test will be low.

All genomic tests (genome, exome or large panel tests) generate raw data which shows where your genome sequence is different from the ‘average’ genome. We all have about 5 million of these genetic variants, and most have little or no impact on our health. The key process in making sense of the data is to filter down from the 5 million to a handful which can be assessed by an NHS scientist.

It is important here to note the difference between a technology (the method) used for a genomic test, and an analysis, or question that is being answered.

Genome, exome or panel tests are different technologies which can be used to generate a list of genetic variants. A whole genome sequence generates a much bigger list of variants than an exome, which generates a much bigger list than a panel test, but none of those technologies on their own can provide useful information for healthcare until the data is filtered and analysed.

There are several key pieces of information which help us do that filtering, and these pieces of information are essentially the same in all genomic analyses, whether from a genome, an exome or a large panel test.

One key fact is how commonly each variant has been seen in other people, as common variants are unlikely to cause a rare disease. Another key fact is linking what is already known about each patient’s clinical condition, and what is already known about the effect of a gene on our health. Highlighting variants which affect the genes which are known to cause the relevant health condition is one way to make this connection. This is called a ‘virtual panel’ analysis, and was used in the 100,000 Genomes Project.

Therefore, there is often little difference in immediate outcomes between a genome, exome or panel test, because very similar filtering steps are used for each of these. What you do get with a genome is a larger body of raw data, much of which isn’t interpretable diagnostically today, but which is already generating new insights into tomorrow’s diagnoses. Because of the set-up of the project and the links with the NHS, when new insights are made, there is a system for returning these diagnoses to your doctors, as above. It is difficult to predict how this will affect each individual participant, because we don’t know whether you have a single genetic diagnosis, or whether your diagnosis is currently detectable and interpretable, or will become detectable and interpretable in the near or more distant future, but Genomics England, researchers and the NHS are all involved in the process of ensuring that when new advances are made using your data, you are able to make use of those advances if relevant for your individual condition.

Genomics England owns the data after it has been donated by participants with their generous consent to its use for research purposes.

But in the sense that participants can withdraw their consent to use of their data at any time, it belongs to the participants.

You can withdraw from the 100,000 Genomes Project at any time, for yourself, your child, or someone you are a consultee for. Please download the appropriate form below, which you should return to the clinical team of the person who is being withdrawn.

Find withdrawal forms on our Participant resources page.

More guidance on withdrawal can be found on each form.