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The launch of the Newborn Genomes Programme, a large-scale research programme aiming to explore the use of whole genome sequencing (WGS) to find and treat rare genetic diseases in babies, has been announced.
This Roundup accompanied an SMC Briefing.
Prof Rameen Shakur, Professor of Genomics and Precision Cardiovascular Medicine, Director of Centre for Research Excellence in Precision Health and Translational Medicine, Director of Brighton Integrative Genomics Unit, University of Brighton, said:
“The commitment from government, research, academic and clinical partners in this endeavor will enable the UK to continue to flourish as a global leader in applied genomics for real-world clinical application. We all appreciate how much genomics research can impact our scientific and biological understanding throughout our lives, this will finally be seen more acutely for the betterment in patient and clinical care. This is the future of medicine.”
Prof Emma Baple, Chair, Newborn Genomes Programme Conditions Framework Working Group; Professor of Genomic Medicine, University of Exeter; Consultant in Clinical Genetics, Royal Devon and Exeter Hospital, said:
“The Newborn Genomes Programme is a unique and important research study that will explore the utility and feasibility of using genome sequencing to test newborns for a larger number of childhood-onset rare treatable genetic conditions than would be possible using traditional approaches to newborn screening. If this research shows that babies affected by the rare genetic conditions looked for in the programme could be cured or better managed with an earlier diagnosis, this would be life changing for these children and their families.
“The approach being taken by Genomics England and NHS England to decide which genes and conditions to look for and how to interpret the genomic data has been carefully considered after engagement with clinical and scientific experts, parents, patients and the public. The criteria for making these crucial decisions is both cautious and conservative, in order to make sure that babies and their families receive safe and effective health care.”
Dr Philippa Brice, Deputy Director, PHG Foundation says:
It is great to see fresh investment to help deliver some of the ambitious plans within current genomics strategy, especially the potential to improve rapid, precision cancer diagnosis and to increase the diversity of genomic databases used for ongoing research. At the same time, it is vital that we do not lose sight of the need to support delivery of existing genomic tests in a timely and equitable fashion for the benefit of patients across the country.
Prof Ewan Birney FRS FMedSci, Deputy Director General of EMBL (European Molecular Biology Laboratory) and Joint Director of EMBL-EBI (EMBL’s European Bioinformatics Institute), said:
“Genomics England has moved from the delivery of a specific project, the 100,000 genomes project, to establishing a solid clinical whole genome sequencing service for the NHS, the first at this scale in a large country worldwide.
“This new plan extends this foundation by exploring the impact of general newborn sequencing to catch more rare genetic diseases at birth and provide a backbone for future research into preventive and genome informed studies. Co-designed with the NHS and citizens, this represents another worldwide first. The expansion into more areas of cancer, a complex disease where genomics can make an impact but is challenging in both logistics and analysis, is also welcome.
“The UK has a great research base in genomics and this clinically focused programme helps bring that research to patients and citizens whilst also responsibly creating more data for research in the future.”
Louise Fish, Chief Executive, Genetic Alliance UK, said:
“Families affected by rare conditions will welcome investment in research to explore the effectiveness of using whole genome sequencing to spot rare genetic diseases in newborn babies. However, the UK can’t just invest in genomic research. We also need to see equal investment of time, energy, capacity and cash into NHS clinical genetics services – including the clinical workforce, IT systems and administrative support – if the benefits of this research are going to reach babies and their families in a timely way that helps them to make informed decisions about their treatment and care.
“Some of the hunger for progress in genomic screening from families affected by rare conditions is arising because the UK is not getting full value from its conventional screening programme. For example, the newborn bloodspot ‘heel-prick’ test given to every newborn baby in the UK screens for a maximum of nine conditions – but there are 20 European countries screening for more conditions than the UK, and 13 of those are screening for 20 or more conditions. This technology may not be as innovative or fashionable as whole genome sequencing, but it has just as great an ability to improve the lives of babies and their families where tests are available for a particular rare condition. A great example is Spinal Muscular Atrophy where babies can now be given lifesaving and life-changing medication before symptoms appear and irreversible motor neuron damage is done. But we don’t screen newborns for SMA in the UK, whereas other countries do, and this urgently needs to change.”
Prof Sir Mark Caulfield FMedSci, Vice-Principal for Health for the Faculty of Medicine and Dentistry, Queen Mary University of London, and former Chief Scientist at Genomics England, said:
“I am so delighted to see the announcement of the Newborn Programme led by Genomics England and the NHS, which will test whether reading the whole genome sequence can identify treatable genetic disorders, where an intervention can be made in early life to avoid disability or harm.
“My team and I designed this programme whilst at Genomics England, having been struck by the number of children in the 100,000 Genomes Project where early diagnosis could have transformed lives. In 2018, Dame Sally Davies (the then CMO) asked me to lead a Genomic Analysis in Children Task and Finish Group. We recommended that every child admitted to ITU without a clear cause should have genomic sequencing (this is now live across England in the NHS via Exeter), and proposed a newborn whole genome sequencing programme. The ambition of the programme as we proposed it is to compare the value of reading a whole genome with the current standard of care in the NHS (screening newborns for nine specific rare but serious conditions with a heel prick).
“The primary goal is to detect a range of disorders where we already have an intervention that could be given at the earliest possible point in life to reduce disability or potentially to avoid harm. It turns out that approximately 1 in 190 births (circa 10 babies born every day in the UK) has one of these problems, and if the intervention is employed, this could be life changing. The majority of these interventions are dietary shifts or vitamin supplements, and only 8% are expensive treatments, e.g. gene therapies or transplantation. The children may not be cured, but the interventions may reduce disability or even allow a normal life, so getting these life changing opportunities to children at the earliest point is so important.
“The secondary goal, based on the 100,000 Genomes Project, is to longitudinally life course these babies to understand if, through research, we can offer other opportunities to prevent or manage problems that may be identified within the genome and might enable us to recall patients for preventive advice or treatment. This is currently being piloted at Barts Health NHS Trust and Queen Mary University of London, and Chelsea and Westminster Hospital NHS Foundation Trust.”
Prof Anneke Lucassen, Professor of Genomic Medicine and Director of the Centre for Personalised Medicine, University of Oxford, said:
“I think there are many questions for this programme to address, and apart from the general “why now?”, when the NHS is on its knees and clearly has other priorities, here are a few more:
“There may be arguments from those saying this programme should take place now that this is a research programme and will therefore not directly impact the NHS. However, it’s hard to imagine offering this sort of screening as a research study and it not impacting on the NHS in terms of follow-up confirmatory and screening appointments at the very least. I would argue that it is no longer possible to separate research from clinical practice as clearly as we may have done in the past, and the consequences for or impact on the NHS should now be an important part of planning medical research in the UK.
“There is already reportedly chaos in the current genomic medicine service in England (as reported by The Times last week), highlighting how the new genomic medicine service is far from the flagship medical service it was advertised as. Adding 100,000 newborns to that system will not help turnaround times for those waiting to end their ‘diagnostic odysseys’.”
Prof Angus Clarke, Clinical Professor, Institute of Cancer & Genetics at Cardiff University, said:
“My list of ‘issues’ with NHS England (NHSE)/Genomics England (GEL)’s policies on the development of whole genome sequencing (WGS) as part of Newborn Screening includes:
1) “The next step being taken by many countries keen to drive forward with newborn screening is: (i) to develop the current tandem mass spectrometry (TMS) to detect more biochemical abnormalities; and (ii) to introduce genetic testing of a panel of genes where TMS will not help but where there is good evidence to believe that early detection of cases can lead to better outcomes for the children.
“The addition of WGS to this seems to be driven not by a wish to make newborn screening better as a screening programme, but to collect more WGS data and develop other uses for this information, primarily in research but perhaps eventually also in terms of holding WGS data as a resource to guide healthcare over a person’s life. The problem with this concept is that the idea has numerous practical and ethical difficulties such as:
a) The tension between allowing access to information as needed and the security of the data;
b) Whether storing WGS data taken today is sensible because of the problems of cost, changing quality standards and changing IT systems over a lifetime when information could instead be interpreted and then destroyed, with the option of a future re-sequencing to contemporary standards and reinterpretation as needed in the future;
c) The need to pass consent to holding and interrogating the sequence data from parent to child over time;
d) The question of secondary uses of the data – searching for evidence of pathogenic variants that are relevant to later-onset conditions not relevant to newborn screening for early childhood disorders – and whether/when/how parents would be given access to this as it could be relevant to them;
e) The overall difficulty of the initial consent, when parents will need to understand a lot of these issues for their initial consent to be valid.
“This debate should be happening openly and publicly, with a decision made after that rather than it being imposed from above, as seems to be habitual for NHSE and GEL policies.
2) “It is planned that the WGS aspects of newborn screening (NS) will be for treatable, or at least ‘actionable’, conditions, but what does that mean? I have the sense that NHSE/GEL may well stretch the idea of an ‘actionable’ disease to include ones that no parents would accept, once many of them have seen how the early diagnosis doesn’t help their child in any substantial way. It is too easy to include the offer of being recruited into a clinical trial or a natural history study, or being able to offer prenatal diagnosis in a future pregnancy, as “actionability”. But none of these interventions are likely to give access to treatments that have been established as safe and effective. All those types of actionability may be a good idea, and I would support offering this type of screening to parents, but only as part of a research programme where there was a real focus on ensuring that parents understood what was and what was not being made available.
3) “Unfortunately, the pilot programme of NS by WGS that is being launched is a pilot for the lab aspects and the bioinformatics; it is not in any sense a pilot of how the programme would operate if it came in as standard across the NHS. To me, this is a mistake as we need to see how parents and infants would be recruited and supported once this is running as a regular programme not as a pilot. There needs to be a pilot of how it would really work, without all the recruitment and consent work being delivered by specific research staff as proposed in the current launch – unless that level of staffing and support was going to extend across the whole NHS and carry on indefinitely. (And there would then be questions of whether this was the top priority for the NHS when it is facing so many other problems).
4) “There needs to be more recognition of the extra work that this project will land on the NHS. In the interval between the molecular diagnosis being passed to parents and the child developing problems that lead to paediatric referral, there would usually be little or no care provided to the family beyond what is very normal/usual for any family with a small infant. Once a child has been flagged as having a genetic condition, however, the parents are likely to need a lot of support that would not usually be needed while they wait for the child to develop problems (except for those uncommon conditions where there is a safe and effective treatment that can be started before the onset of symptoms). This need for support will be extra, above and beyond the usual demands on the NHS. We may be able to cope during the pilot phase with 100,000 infants being screened in this way, but could not possibly cope if this was happening nationwide.
5) “To place such extra demands on the NHS just now, when the NHS is failing more and more blatantly to cope with the demands it already faces, would be clearly unprofessional and wrong. We have the NHS operating on ~90% of staff required, with less than that in some relevant groups such as midwives (~80%), health visitors (~60%) and GPs (<90%), who would be essential for a proper consent process and for post-diagnosis support of families.
6) “The advantage of an early diagnosis for conditions that in the past have faced long delays in diagnosis is a major benefit of genome-based genetic investigations, even where no treatment is available. An explanation for serious problems can itself be very helpful and even therapeutic in an emotional sense. This achievement of diagnoses for children (and indeed adults) with serious problems has been a great advance. However, the screening of healthy newborn infants for gene variants that it might prove helpful to know about is bound to flag up lots of variants in infants who will develop problems years into the future or perhaps never at all. This is imposing a different type of diagnostic odyssey to replace the one we have been dealing with until now. This is the lengthy, distressing and (I would expect in many cases) hugely expensive search for a disease phenotype that may or may not ever appear. These will be “patients in waiting”, (as Stefan Timmermans has termed it) and will suffer the psychological sequelae of intense medicalisation, as well as being subjected to lots of investigations and monitoring, and with consequences for the parents such as the imposition of much anxiety and sadness that they may well resent.
7) “And finally, I should remind everyone that WGS can never replace the metabolic aspects of NS for two reasons: because the commonest diagnosis is congenital hypothyroidism, which is not a (simple) genetic condition; and because the metabolic evidence can be generated much more rapidly than the interpretation of the genome and is much stronger evidence for a diagnosable disease than is the WGS data because the metabolic measurements on TMS are part of the phenotype.”
Prof Frances Flinter, Emeritus Professor of Clinical Genetics, Guy’s & St Thomas’ NHS Foundation Trust, and Member of the Nuffield Council on Bioethics, said:
“Using whole genome sequencing to screen newborn babies is a step into the unknown. Getting the balance of benefit and harm right will be crucial. The potential benefits are early diagnosis and treatment for more babies with genetic conditions. The potential harms are false or uncertain results, unnecessary anxiety for parents, and a lack of good follow-up care for babies with a positive screening result.
“Ensuring that parents can make informed choices about whether they want their baby to have this kind of testing, and what happens to the genomic data collected, will be vital. Currently, tests offered as part of screening programmes are often seen by parents as routine or automatic.
“There is general agreement that we should use WGS to look for specific diseases – rather than as a fishing exercise – and that we should only look for serious, childhood conditions for which an intervention is indicated at a young age. But there are difficult questions about how to interpret these criteria, which those designing this research programme will have to grapple with.
“We must not race to use this technology before both the science and ethics are ready. This research programme could provide new and important evidence on both. We just hope the question of whether we should be doing this at all is still open.”
Prof Frances Flinter has provided the following extended, alternative comment to provide further background and context for journalists covering this story
“Children who have rare inherited conditions sometimes go through a protracted ‘diagnostic odyssey’ before the cause of their illness becomes apparent. This can be distressing for their parents, expensive for the NHS and, in some situations, may mean that opportunities for early intervention with effective therapies may be delayed. Current newborn screening in the UK involves Tandem Mass Spectrometry (TMS) to screen for just nine conditions – fewer than in many other countries. The analysis done by TMS could easily be extended to include a number of other inherited conditions, but not all genetic diseases are detectable in this way. The ambition to achieve early, and in some cases pre-symptomatic diagnosis of a wider range of conditions, is understandable; it will undoubtedly benefit some children and may even save lives. It is important, however, that parents who give consent for their newborn babies to become enrolled into this research project also understand the risks.
“Our ability to understand the implications of rare genetic variants identified by Whole Genome Sequencing (WGS) may be limited in children who are currently asymptomatic. Other large studies have revealed some surprising results – apparently healthy adults may have genetic alterations that would be expected to have caused serious disease, and yet they remain healthy. We do not understand why this is, but, by implication, not all babies with apparently pathogenic genetic alterations will go on to develop a genetic disease. If different (preferably minimally invasive) tests exist, such as biochemical tests, then it may be possible to check the validity of an abnormal WGS result, but not every potential diagnosis can be confirmed in this way. The risk of a false positive result cannot be completely eliminated, and it may be years before this becomes apparent.
“Each healthy human genome contains 100-300 severe gene changes* of which up to 50 may affect both copies of the gene (bi-allelic). It is, therefore, not difficult to anticipate the number of newborn babies the screening programme will identify as being ‘at risk’. With expanded genomic sequencing, an increasing number of individuals will be identified with more than one harmful variant in their genome; with no clinical evidence to guide result interpretation, such scenarios will escalate the level of clinical uncertainty and anxiety for the family. Importantly, harmful variants inherited from an unaffected or mildly affected parent will be of no prognostic value, but will induce additional anxiety about the parent’s health as well. *(nonsense Single Nucleotide Variants (SNVs), gene deletions and other Loss-of-Function (LOF) variants)
“Parents of newborn babies are often exhausted, and being given potentially bad news at such a vulnerable time is likely to impact the process of bonding with their newborn baby. If the baby has a serious illness that warrants early treatment, then the benefit of early diagnosis may outweigh any damage to their relationship. Currently, treatments for rare genetic disorders, including gene-based therapies, are not considered in pre-symptomatic patients; but dealing with results of uncertain significance, or delays while confirmatory tests are performed could be distressing. For a significant number of conditions, no disease marker is available, meaning that there may be many years of uncertainty and worry until the clinical features present, if at all.
“Most paediatric clinics are already oversubscribed, with long waiting lists, but parents of a neonate who are told that their baby has a serious genetic condition will want to be seen soon for advice, even if the baby is asymptomatic. There are no guidelines on the best clinical practice for asymptomatic children who test positive following WGS. Adding these babies to the waiting list may compromise the time and resources available to children who are already ill. Indeed, paediatricians may decline referrals from screen-positive referrals until the baby develops symptoms, in order to protect the limited time and resources that they have for children who are already under their care, leaving the parents of neonates who test positive in limbo.
“Enabling NHS staff to discuss all these scenarios with new parents will take time, and require training. It is clear that in the current climate, NHS staff could not undertake this additional work in the antenatal or neonatal clinics. Ideally, a research project that is studying whether, and how, to introduce such a screening programme would also address this issue. In the meantime, it might be better to focus the resources that this research project will use on providing an efficient WGS service for symptomatic, undiagnosed children, together with timely validation of potentially abnormal results, as this is an area of clinical service in which lengthy delays are experienced currently. The rapid WGS service has demonstrated that a genetic diagnosis can be established within two weeks. Currently this is available only for acutely ill children, and for those suspected of having a potentially treatable condition even though they may not be acutely unwell at the time of testing; it delivers very successfully for patients for whom a confirmed diagnosis will make a difference. Implementing this model for routine genomic testing would improve the efficiency of the service for all patients being investigated for a possible genetic disorder, and could shorten the diagnostic journey for many, while avoiding over-medicalisation of the care of some healthy babies, and protecting the mental well-being of families.”
Prof Peter Braude, Emeritus Professor of Obstetrics and Gynaecology, King’s College London, and immediate past chair of the Royal College of Obstetricians and Gynaecologists (RCOG) genomics taskforce, said:
“This is an exciting and ambitious programme with noble aims and the prospect of revolutionising early diagnosis of genetic diseases.
“However, there are several ethical and practical issues which will affect families and NHS maternity services that should be addressed publicly before being we are carried away in the excitement. I outline just two here.
“This test will involve three sets of genomic data for each couple – the neonate, father, and mother. Although only the child’s DNA will be analysed initially, if a suspicious anomaly is found, both parent’s DNA will have to be examined to see if this is a new significant mutation or whether it has been inherited from one (or both) parents. Such testing is not innocuous; it has potential medical implications for the parents, and their extended family – which they did not sign up for. It could also reveal the unlikely but possible finding of non-paternity. Thus, implications counselling is of profound importance before neonatal whole genome sequencing (WGS) is contemplated1. This should best be undertaken during the pregnancy when there will be time for the facts to be assimilated and questions asked, not left until after delivery, a highly emotional time when it might be rushed, and implications not fully assimilated.
“Information of this import will need to be given by a trained professional in the antenatal period, probably in the antenatal clinic – with the father also present for completeness of information and appropriate consent. Although research fellows/assistants might be able to undertake this in the project evaluation phase, eventually it will fall upon midwives (already in short supply and over-stretched), or genetic counsellors of which there are far too few. The impact on service will be profound both in terms of cost and staffing and should be appropriately addressed during the study and not underestimated2.
“A serious and not infrequent finding is the uninterpretable result – a VUS (variant of uncertain significance) or a mutation with unclear medical implications – especially if one parent has it and seems entirely well. At best this may require follow up of the child throughout their life, even where no pathology (illness) has been identified, or more likely a lifetime of anxiety if little is known about the implications of the particular variant. Although anxiety may decrease (or indeed increase) as genetic knowledge accumulates, this adverse effect needs to be balanced against the advantages of a known and treatable cause – of which there may be relatively few3.”
Sarah Norcross, Director, PET (Progress Educational Trust), said:
“Research commissioned by PET this year – conducted by Ipsos – shows that a majority of the UK public (53%) supports the idea of whole genome sequencing at birth, and just 10% of the UK public is opposed to the idea.
“These are promising circumstances in which to launch the Newborn Genomes Programme research pilot. However, a number of practical and ethical challenges were raised at a series of lively public debates on newborn sequencing that PET produced recently, in partnership with Genomics England.
“These ranged from concerns about pressure on the health service – in particular midwives – to a desire for reassurance on questions of data security. The research pilot must be sensitive to these challenges and proceed with caution, in order to retain and build on existing public support.”
Prof Steve Jones, Emeritus Professor of Human Genetics, University College London (UCL), said:
“I am by no means against this, but one should get it into context. Nearly all mortality before the age of sixty is due to smoking, deprivation, accident, disease, suicide and the like; for most people, genetics does not raise its ugly head until much later in life, when there is a real heritability of life expectancy, which goes up with age. Of course, there are relatively rare single-gene conditions that manifest themselves much younger – Hb S (sickle cell disease), cystic fibrosis (CF) and many more – and it will certainly be worthwhile to diagnose these as early as possible in the hope of treating these, although at the moment, for most, not in curing (of course, things may improve fast, and there are signs that progress is being made in that direction). It is well worth doing, but one should be careful about raising expectations too high.”
Declared interests
Prof Ewan Birney: “I am a non-executive director of Genomics England.”
Prof Sir Mark Caulfield was the Chief Scientist for Genomics England from 2013 – July 2021.
Prof Frances Flinter: “In addition to being a member of the Nuffield Council on Bioethics, I am a member of the Genomics England Newborn Screening Ethics Working Group, which provides advice to the research team leading this project.”
Sarah Norcross is the director of PET, a charity which improves choices for people affected by infertility and genetic conditions.
For all other experts, no reply to our request for DOIs was received.