The Generation Study: Which conditions are screened for and why?

Genomic sequencing can be used in different ways.

• Diagnostic testing involves looking at genomic sequencing data to identify variants that would provide a diagnosis. It is driven by the clinical features and symptoms with which a patient presents – for example, finding the cause of intellectual disability and birth defects in a child.
• Predictive testing involves testing for a known disease-causing variant in someone who does not have symptoms, in order to predict future risk of a specific condition – for example, testing someone without cancer whose mother does have cancer and has been found to have a pathogenic BRCA1 variant.
• Carrier testing involves testing for variants that would indicate whether someone is a carrier for an autosomal recessive condition – for example, a couple undergoing testing to determine whether they are carriers for cystic fibrosis in order to understand the chance of their child inheriting it.
• Screening involves testing a population to identify apparently healthy people who may have an increased risk of developing or being a carrier for a particular condition. Follow-up testing is usually needed after a screening result, to confirm or rule out the condition being looked for. Screening can generate false positives (the identification of a condition that is not actually present) and false negatives (failure to detect a condition that is present). There are many screening programmes in the NHS, some of which involve genomic testing.

The Generation Study is an example of screening via whole genome sequencing. It is an opportunity to understand whether we can improve how we diagnose and treat rare conditions, because genome sequencing could identify newborns at risk of hundreds of different conditions using a single test. However, using genome sequencing in this way is new and complex, and this is the first time it is being explored in the NHS on a national scale.

There is much to be learned about the frequency, pathogenicity, penetrance and expressivity of genetic variation, particularly when testing newborns, most of whom will have no medical or family history of a rare condition. This exploration is particularly important in populations that have been under-represented in genomic research (in which data is currently disproportionately represented by individuals with Northern European ancestry).

Although the whole genome is sequenced, it is not analysed it in its entirety. The study is looking for specific types of variant within genes that cause a set list of early-onset and treatable genetic conditions. Think of it as like taking a full body scan, but the radiologist only focuses on looking at certain areas of the body.

This means that the sequencing performed in the Generation Study is not standard-of-care testing, such as the NHS newborn blood spot test or other genomic tests that are conducted via the National Genomic Test Directory (that is, whenever there is a known or suspected history of a genetic condition in a pregnancy or wider family).

There are thousands of conditions that could be detected through whole genome sequencing, but there are ethical, clinical, scientific and operational questions to explore in order to define what should be looked for in newborn babies.

When choosing the conditions that will be looked for in the Generation Study, Genomics England has used an approach that minimises the potential for false positive results. A working group developed four principles, refined through engagement workshops and an online survey with members of the public, people living with rare conditions and healthcare professionals, to guide the selection of conditions and genes.

The four principles are as follows.

• Principle A: There is strong evidence that the genetic variant(s) cause the condition and can be reliably detected. Where appropriate, there is a confirmatory test than can establish whether or not the child has the condition.
• Principle B: A high proportion of individuals who have the genetic variant(s) would be expected to have symptoms that would have a debilitating impact on quality of life if left undiagnosed. The impact on quality of life should consider factors such as the testimony of patients and families affected, and quality-adjusted life year (QALY) measurements where available.
• Principle C: Early or pre-symptomatic intervention for the condition has been shown to lead to substantially improved outcomes in children, compared to intervention after the onset of symptoms. The intervention should normally be initiated in early childhood (by age five) and could either cure, delay or modify the course of the condition.
• Principle D: Conditions screened for are only those for which the interventions are equitably accessible for all. This involves incorporating input from NHS England and other relevant clinical and commissioning bodies.

Genomics England reviewed over 900 genes and associated conditions against these principles using a standard process to collate evidence.

An NHS clinical assurance group was established to give assurance on the availability of interventions and the capacity and capability of NHS services to support participants. Through this, clinical leads from paediatric clinical reference groups, as well as relevant specialists and expert forums, were engaged to review the evidence gathered.

Following the selection process, a list of over 200 conditions, caused by variants in over 400 genes, was established. It includes:

• conditions already tested for in the NHS newborn blood spot test, such as cystic fibrosis and sickle cell disease;
• hormonal conditions that affect growth and development, such as growth hormone deficiencies;
• conditions that affect bleeding and clotting, such as haemophilia and Diamond-Blackfan anaemia;
• immune system conditions that increase someone’s risk of life-threatening infections, such as severe combined immune deficiency;
• metabolic conditions that affect the body’s ability to process certain substances and remove toxins, such as biotinidase deficiency; and
• conditions that can increase the risk of early childhood cancers, such as retinoblastoma.

The list of conditions and genes is expected to change in response to emerging evidence and research. Babies participating in the study will be tested for the conditions listed at the time they joined the study and will not be re-analysed if this list changes.

As well as conditions and genes, the Generation Study limits the genetic variants that are looked for and fed back to participants. It will only look for variants that:

• are pathogenic or likely pathogenic;
• can predict the development of the relevant condition, to the best of available knowledge; and
• can be detected with the genome sequencing technology used in the study.

This means that variants of uncertain significance are not reported.

More information about how results are generated and returned can be found in The Generation Study: What are the different types of result and how are they returned?

• The Generation Study is researching how genome sequencing can be used as a screening tool. It should not replace standard-of-care screening or genomic testing in the NHS.
• The Generation Study sequences the genomes of newborn babies but deliberately limits what it looks for, focusing on select conditions, genes and genetic variants.
• The conditions being tested for usually appear in the first few years of life, can be improved if caught early and have an intervention available through the NHS in England.
• Generation Study screening results are not a diagnosis.

For clinicians

• Genomics Education Programme: CPI: Generation Study: Recruit, enrol and sample
• Genomics Education Programme: CPI: Generation Study: Return results and further care
• Genomics Education Programme: CPI: Generation Study: Sample, sequence and interpret
• Genomics England: Conditions list
• Genomics England: How did the Generation Study decide conditions? (PDF, 11 pages)
• Genomics England: How did the Generation Study decide which conditions to include? (video, 5 minutes 15 seconds)

For clinicians returning results, there are numerous education and training resources. Modules include:

• ‘Key terms and scientific principles’;
• ‘Types of result’; and
• ‘The process of returning the result’.

Please note that some of these resources are hosted on the Generation Study workspace on the NHS Futures platform. If you have not already had an invitation to join, please contact the Genomics England service desk: generationstudy@genomicsengland.co.uk.

Content may evolve over time. Should you have any issues accessing the content, please contact the service desk.

For patients

• Genomics England: The Generation Study
• Genomics England: The Generation Study Participant Information Sheet
• Genomics England: The Generation Study translated participant information