Whole Genome Sequencing at Birth: Implementing the Generation Study

The Generation Study is a pioneering, large-scale research study currently being rolled-out across England, that aims to sequence the whole genomes of 100,000 newborn babies. This NHS-embedded study, supported by Genomics England, will investigate whether whole genome sequencing (WGS) at birth can improve our ability to diagnose and treat genetic conditions (see BioNews 1172).

The event 'Whole Genome Sequencing at Birth: Implementing the Generation Study' was produced by PET (the Progress Educational Trust) in partnership with Genomics England and its Newborn Genomes Programme. The event explored how the study is being implemented and the benefits and risks that may be involved. It followed a five-part event series discussing the project which was held previously by PET and Genomics England (see BioNews 1126, 1128, 1140, 1141 and 1142).

Sarah Norcross, director of PET, chaired the event and introduced the first speaker Amanda Pichini, clinical director at Genomics England, who is responsible for leading clinical delivery of the Generation Study. She began by addressing why this study is being carried out.

Pichini explained that the 'heel-prick test' has long been the standard test in the UK, performed on five-day-old babies to screen for nine different genetic conditions (see BioNews 1023, 1123 and 1180). However, the scope of such testing is limited, as many genetic conditions are not screened for and the time for diagnosis can be debilitatingly long.

This led to the project's first aim: evaluating the utility and feasibility of screening newborns for a larger number of childhood-onset rare genetic conditions (focusing on those with available intervention) in the NHS using WGS. The data would be deidentified, meaning that the researchers will not know the identity of who gave the blood sample. It will also be screened in order to help achieve aim two: understanding how babies' genomic data could be used for discovery research, focusing on developing new treatments and diagnostics for the NHS. The final aim is to explore the potential risks, benefits, and broader implications of storing a baby's genome over their lifetime.

The study has begun across 13 NHS hospital sites, which are part of ten NHS trusts throughout England (see BioNews 1259 and 1261). Pichini emphasised that birth volumes, diversity and maternity department performance were all factors considered when selecting participating sites to ensure a 'broad spread' across the study. Pichini announced that more than 1000 participants had been recruited to date, and more than 100 samples taken.

The ultimate goal is to sequence 100,000 genomes, with an expectation that one percent of the babies will be diagnosed with one of the 223 genetic conditions that are being screened for, each with an established care pathway (see BioNews 1210 and 1213). Pichini concluded her presentation by stressing that this is a research study, not a replacement for standard care. She clarified that if WGS results are negative, parents should understand that this does not guarantee a 'clean bill of health' for their child.

The second speaker was Phern Adams, the lead research midwife and project manager for the Generation Study at Birmingham Women's and Children's Hospital. As a parent of a child with a rare genetic condition, Adams was able to give a professional and personal perspective on the study and its potential impact on families' lives.

Adams gave an insightful account of how this study is being navigated on the ground. She described efforts to secure staff compliance, including techniques such as lunch-and-learn sessions, Facebook groups and mandatory training for all staff. Adams also explained the study's well-researched approach to participant recruitment: leaflets are distributed early in pregnancy and community midwives discuss the study with expectant mothers at the 16-week visit, with further opportunities at the 20-week scan and at induction of labour. Women can self-refer at any point during pregnancy and many women in Birmingham are making this choice daily, with an overall participation rate of 50 percent. Adams said they are addressing some of the reasons why the other half of parents might choose not to participate.

The third speaker at the event was Dr Chinthika Piyasena, a consultant neonatologist at the Evelina London Neonatal unit at Guy's and St Thomas' Hospital. Dr Piyasena highlighted the established use of rapid WGS as a diagnostic tool for genetic conditions in NHS neonatal units. She explained that it is efficient and cost-effective with results typically returned within two weeks of blood collection, often reducing hospital stay lengths. However, as the Generation Study rolls out, there have already been instances of missed patient recruitment in neonatal units. Sick and premature babies often do not participatel as there is insufficient time for parents to consent before birth.

Dr Piyasena concluded: 'if I were a baby in this study I would feel very privileged to be participating in what is cutting-edge science, and be part of what is truly a landmark birth cohort.'

The final speaker at the event was Dr Robin Lachmann, a consultant in inherited metabolic disease at the Charles Dent Metabolic Unit at the National Hospital for Neurology and Neurosurgery, London. Dr Lachmann opened his presentation with the statement, 'all screening programmes do harm; some do good as well, and, of these, some do more good than harm at reasonable cost'. He provided an evidence-based approach in answering the question: is WGS a suitable tool for newborn screening?

Dr Lachmann explained that genetic variation makes genetic screening challenging, particularly in a group of largely healthy patients, which is the main cohort of the Generation Study. This 'adds an extra level of complexity and difficulty'. Every individual carries multiple genetic variants within each gene, but without an observable phenotype – any signs or symptoms of disease – how do we determine which of these variants might be significant? This uncertainty can lead to possible false positives or false negatives.

Using a previously published study on X-linked adrenoleukodystrophy – a genetic condition that affects the nervous system and adrenal glands – Dr Lachmann demonstrated that biochemical tests can be much more specific and sensitive than WGS. He explained that in some cases, using a biochemical test as a first-line screen, with WGS employed further along the diagnostic pathways, may be more accurate. Dr Lachmann emphasised that WGS in isolation may not be the best means of identifying genetic conditions.

Then there was a range of questions and comments from the audience. Some questions regarded the practicalities of the research, such as how much blood is required from the baby. Adams answered that three millilitres of blood is taken from the umbilical cord. Another question concerned the storage of the genome sequence, as well as ownership and patient access. It was clarified that the parents of the participants own the data until the child turns 16, at which point ownership transfers to the child. If parents request the raw genome sequence, several steps must be followed in the interests of data protection, and they will need to provide storage for the large data file.

There were also questions about the study's impact on a 'resource limited health service' including the extra workload for midwives and how the study's costs compare to newborn screening protocols in other countries. Adams could not praise the midwives enough for their efforts, and explained cord blood collection is already standard practice. Pichini added that health economic analysis is being conducted.

The event was highly informative, offering valuable insights into the project's background and the progress made so far. Public engagement with the Generation Study is clearly strong, making it exciting to follow as the project advances through the implementation phase.

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The next free-to-attend PET event – taking place online on Wednesday 20 November 2024 – will be 10 Years of Womb Transplants: What Have We Learned? What Does the Future Hold?.

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