Frequently asked questions for NHS GMC staff

These FAQs are aimed at healthcare professionals who recruit patients in the 100,000 Genomes Project. For general information about the project, please visit our taking part section.

If your question is not answered here, NHS GMC staff can contact the Service Desk via email (link opens in your email application) or on 0808 2819 535.

Recruitment and eligibility

Yes, as long as the proband is eligible in terms of their clinical presentation under one of the existing disease categories and they have not been given a formal molecular diagnosis, the family is eligible. The existing genetic testing result should be entered into the Genetic Tests section of the data capture tool in the usual way.

Yes, deceased probands and relatives are eligible for inclusion in the programme subject to the following conditions:
• A stored DNA sample is available which passes quality control tests
• A relative in a qualifying relationship is available to provide appropriate consent
• The consent obtained from the deceased individual at the time of sampling does not preclude use of the sample for the benefit of family members
• Surviving relatives under the care of the NHS in England will benefit in terms of healthcare or reproductive options if a diagnosis is made.
If the deceased individual had their own NHS number, please use this. If they did not have an NHS number, please use 2222222222 in the NHS number field. Please complete a data form giving details of the cause of death at the time of recruitment.

Yes, fetuses can be recruited as probands or affected relatives if there is sufficient good quality sample available, parents are available for recruitment and consent, and the proband meets a set of eligibility criteria in full, whether as part of a specific fetal category or a disorder which may present antenatally or postnatally. Fetuses should not be recruited where a pregnancy is continuing, because the turn-around time and ease of interpretation of genome sequencing are not yet suitable for use in this sensitive context.
Data entry for fetuses should use the date of delivery in place of the date of birth. Forename should be entered as ‘Fetus of mother’s forename’, for example ‘Fetus of Anna’. The mother’s surname should be used for the surname. The dummy NHS number 333333333 should be used. Please complete a data form giving details of the cause of death at the time of recruitment.

Yes, you can find an Eligibility Change form (and the Disease Nomination form) here. Further instructions can be found with the form. If you would like to discuss a possible change with the science team prior to submitting a form, please put in a service desk request (via email or on 0808 2819 535) including the suggested change and your contact details.

There are over 5 million genetic variants in each individual’s genome and many rare diseases are caused by just one or two of these. Finding the disease-causing variant is often easier if a patient’s genome can be compared with those of their close relatives. For this reason, the majority of patients in the rare disease programme are recruited together with family members ─ a child with a rare disease, for example, with both parents.

Detailed clinical information about participants is also required to make a diagnosis for each family, as interpreting this huge amount of genome data is impossible without the ability to correlate it to the patient’s clinical condition.

Consent and ethics

A participant who has lost mental capacity (to make their own decision about being part of the programme) must be withdrawn from the programme under the terms of the Mental Capacity Act, until and unless an appropriate personal consultee can be found to advise on whether they would have been likely to want to remain in the programme. If a suitable personal consultee can be found by the GMC clinician, the appropriate Personal Consultee Declaration form should be completed and returned to Genomics England via the consent record upload in the data submission tool. Otherwise, a withdrawal form will need to be submitted to Genomics England by the same mechanism.

Please record in the local notes the reason why the participant cannot sign the consent form and record their verbal consent to take part. It is also helpful if the appropriate consent form is completed by the clinician taking consent, and a note is made on the form or with a separate letter to explain why this has been done. The consent form and/or letter of explanation can be uploaded into the consent section of the data capture tool.

Samples

The preference for a sample from a BMT patient is DNA from a stored fibroblast culture, as saliva is likely to have a mixture of donor and recipient genomes, which can cause the sample to fail contamination checks and make the sequence data difficult to interpret. There is more information available in the Sample Handling Guidance. DNA which was stored before the patient had their BMT can also be sent if it passes quality control tests.

Yes, all project staff handling blood samples will follow universal precautions as in NHS laboratories, so samples from patients with infectious diseases can be included in the programme.

One of the most exciting aspects of the 100,000 Genomes Project is the fact that there are discoveries and developments just around the corner – this is a rapidly developing and cutting-edge area of medicine. In order to capitalise on these yet-unknown developments, we are examining ways to future-proof our data gathering and make sure we capture as much information relating to people’s genomes as we can. We recognise that these have the potential to add depth to the clinical interpretation of the 100,000 Genomes Project.

‘Omics’ refers to the different technologies used to characterise and quantify pools of biological molecules and to explore their roles, relationships and actions in human cells. This is done by collecting and using, with consent, high quality blood, tissue and other samples. These samples will be used to investigate whether genetic changes in patients are having a measurable effect on a patient’s blood test results, which can be used to help interpret genomic results, or to develop biomarkers to help detect and monitor disease.

Examples of ‘omics’ tests are already in clinical use. Cancers alter how a cell works, which creates new targets for new medicines and treatments. A urine test to detect molecules unique to pre-cancerous colorectal cancer polyps has been developed which is much more sensitive than existing diagnostics for early detection. The 100,000 Genomes Project is investigating whether similar tests can be done using DNA in the bloodstream to carry out an easily accessible ‘liquid biopsy’ to diagnose and monitor cancers.

These additional samples will be stored alongside patients’ genomes. It’s early days but collecting omics today is likely to provide exciting additional insights in the future into diagnosis of rare diseases and cancer that will lead to further developments in personalised medicine.

Yes, as long as each manifest is correct, omics samples do not need to be sent at the same time as the DNA sample for each participant. If a participant has been recruited using DNA only but a subsequent opportunity arises to obtain omics samples, please take the opportunity and submit these samples when they are available.

Data

In order to make sense of the genome data, a detailed set of clinical data needs to be collected about the patient’s condition, symptoms, test results and previous negative genetic tests. For each disease in the programme, a questionnaire asking about the presence or absence of a specified set of Human Phenotype Ontology (HPO) terms is requested from GMC clinicians. HPO terms are standard ways of describing clinical features and symptoms for clinicians.

The initial HPO questionnaires were developed with the assistance of experts in the field, but many contained over 60 HPO terms, the largest being around 120 terms. This meant that they could be time-consuming for clinicians to complete. The questionnaires have now been revised to standardise the use of terms across each model and aim for a size of 20-40 terms. This has improved the quality of the questionnaires and improved the balance between depth of data and usability.

The development of these models is defining a new standardised method of clinical data collection within the NHS. This will be required for the future use of genomic tests in the diagnostic context, but will also have major benefits for future clinical care and research.

Traditionally, clinical information has been: stored on paper or in silo’d electronic health records; recorded in free text; and impossible to analyse at scale or in an anonymised way. The introduction of ontologies into medical records, and the development of standardised disease descriptions, will pave the way for effective rare disease registries in the future, making the most of every available patient cohort for future research.

Results and analysis

No, the clinical and bioinformatics teams at Genomics England will assign appropriate gene panels. The report will show which genes were analysed, and the GMC laboratory will be able to access data on other potentially relevant genes if the genes in the assigned panel(s) are insufficient for the diagnostic analysis.

The early results do not include structural or copy number variants, because these pipelines are still being developed and tested. In future these analyses will be carried out routinely. A retrospective reanalysis will be used to ensure that all participants’ genomes are analysed for structural and copy number variants; the timing of this analysis is not yet known but announcements will be made once this is underway.

Yes, if they meet the eligibility criteria for a rare disorder within the programme they can be recruited. Please select the HPO term ‘Somatic mosaicism – HP:0001442’ in the free HPO entry section of the data entry tool to indicate that you think the patient may have somatic mosaicism. The initial analysis will occur using the standard pipeline; there is currently no facility to accept a second tissue (eg fibroblast cell culture) for sequencing.

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