The Generation Study aims to sequence the genomes of 100,000 newborns, to help understand whether we can improve how we diagnose and treat actionable rare genetic conditions (see BioNews 1172).

This groundbreaking research search study is being run by Genomics England in partnership with the NHS in England and has involved extensive consultation with the public, parents and families affected by rare conditions, as well as healthcare professionals, policymakers and scientists.

The study is in the early stages of launching, initially being rolled out at 13 NHS hospitals in England (see BioNews 1259). Ultimately, the Generation Study will be conducted in approximately 40 NHS Trusts across England.

The study's principal aim is to evaluate the use of whole genome sequencing to screen newborns for genetic changes (variants) associated with more than 200 treatable rare genetic conditions (see BioNews 1210 and 1213). These conditions were selected through a consultation process driven by four key principles:

• Variants that cause the condition must be able to be reliably detected using genome sequencing.
• A high proportion of individuals with those variants should be expected to develop the condition, with a significant impact on quality of life.
• An early or pre-symptomatic intervention is available, that could lead to improved outcomes in children.
• That intervention must be available and accessible through the NHS.

Severe Combined Immunodeficiency (SCID) is an example of a condition included in the initial list. Approximately 14 babies a year are born with SCID, and without treatment usually die within their first year. Babies with SCID are at a greater risk of infections and other life-threatening complications, due to their immune system not working properly. However, if diagnosed early enough, babies can receive a bone marrow transplant which can 'cure' them by replacing their faulty immune system with a healthy one.

Biotinidase deficiency – another condition on the initial list – results in the inability to reuse and recycle biotin, a vitamin that is important for growth and development. Without treatment, children can have delayed development, seizures and problems with hearing and vision. However, if biotinidase deficiency is diagnosed early enough, it can be treated with a simple biotin supplement.

Further to screening for rare conditions, the study will ask all parents for their permission to securely store their baby's genome and health data. This data will only be accessible to approved healthcare researchers and will be deidentified, meaning that the researchers will not know the identity of who gave the blood sample. The data will be stored in Genomics England's National Genomic Research Library, which currently includes data from more than 100,000 consenting individuals.

It is hoped that this data will facilitate evaluation of the study over a long-term period, to understand the impact of any diagnoses made on families and the health service. In addition, having a comprehensive, diverse and longitudinal cohort of genomic and health data – with samples accessible for research – will enable wider exploration for the research and life sciences community, who are investigating questions relating to the effects of genetics on health and the potential to develop interventions and therapeutics, generating insights for wider health benefit.

This leads to the final objective of the study, which is to investigate the possible risks and benefits of storing an individual's genome over their lifetime. This will give researchers the opportunity to look for other health conditions, or to make a diagnosis if the individual develops symptoms of a genetic condition. Expectant parents are invited to sign up during routine checks at participating NHS Trusts, through funded research teams. Like any research, participation is voluntary. Because parents initially consent on behalf of their newborn, when the participating children turn 16, they will be given the opportunity to decide if they wish to continue or withdraw from the study.

It is estimated that only one percent of babies will be suspected as having a rare genetic condition screened for in the Generation Study. Follow-up testing will be carried out by a relevant paediatric specialist team, with expertise in managing that condition. Furthermore, the study will also provide funding for genetic counselling to support families who receive a positive diagnosis, as well as information and links to patient organisations.

Starting with a public dialogue in 2021 on the potential for using genome sequencing in newborns, the study has maintained a clear focus on ethics, engagement and co-design. This included building strong foundations with the NHS, the National Institute for Health and Care Research and the UK National Screening committee to ensure the study has minimal impact on existing services as well as robust evaluation.

The participant journey and materials have been developed using extensive user research with new and expectant parents, as well as healthcare professionals. Collaboration is expected to continue as the study begins its launch, in order to be able to respond to data and insights from the experiences of participants and the NHS.

Ultimately, the Generation Study hopes to do better for the thousands of children born each year with severe, treatable early onset conditions by enabling earlier diagnosis and care. While this comes with clinical, scientific, ethical and operational challenges, the evidence gathered throughout the study will inform future decisions for the benefit of population screening in the health service, and for those families impacted by rare conditions.