13 Mar 2023
Frances Flinter - Council Member and Emeritus Professor of Clinical Genetics at Guy’s & St Thomas NHS Foundation Trust - talks us through some important issues to consider in relation to the introduction of whole genome sequencing of newborn babies.
Children who have rare inherited conditions sometimes go through a protracted 'diagnostic odyssey' before the cause of their illness is identified. 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 missed.
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. Targeted use of genetic testing could also help to guide the choice of treatments and prevent avoidable side effects, such as antibiotic-induced hearing loss in seriously ill babies.
Later this year, the government plans to launch an ambitious screening programme for at least 100,000 newborns in the UK.
It is important that parents who give consent for their babies to become enrolled into this research project also understand the risks.
Parents will be offered the opportunity for their newborn babies to have their whole genome sequenced, alongside the usual neonatal heel prick test which currently tests for nine conditions. The genomic sequence data will be examined for variants in genes that are identified as being ‘actionable’, meaning that intervention in the first 5 years of life would be expected to make a difference to the long-term prognosis. The sequence data will be stored, and used for reference by researchers and also by pharmaceutical companies interested in developing new treatments. It will also be made available to clinicians looking after these individuals when they are older, if they become unwell, to see whether there are benefits to individuals from having their genomic data available to inform future healthcare decisions.
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 of UK Biobank data have revealed some surprising results - apparently healthy adults with genetic alterations that would be expected to have caused serious disease, but yet remain well. We do not understand why this is, but, by implication, not all babies with genetic alterations that we know are linked with genetic disease, will go on to develop symptoms. If different (preferably minimally invasive) tests exist, such as biochemical tests that can help to confirm a genetic condition, then it may be possible to cross-check an abnormal WGS result, but not every potential diagnosis of a genetic condition 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 a gene. It is not difficult to anticipate that there will be a large number of newborns identified by the screening programme as ‘at risk’. With expanded genomic sequencing, an increasing number of individuals will be identified with more than one harmful variant in their genome; but with no clinical evidence to guide the interpretation of WGS results, such scenarios will escalate the level of uncertainty and anxiety for the family. Importantly, harmful genetic variants inherited from an unaffected or mildly affected parent will be of no predictive value, but may induce additional anxiety about the parent’s health as well.
Parents of newborn babies are often exhausted, and being given potentially bad news at such a vulnerable time may affect the process of bonding with their baby. If the baby has a serious illness that warrants early treatment, then the benefit of early diagnosis may outweigh any potential damage to their relationship. Currently, treatments for rare genetic disorders, including gene-based therapies, are not usually considered in pre-symptomatic patients; dealing with uncertainty, or delays while further tests are performed, could well 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 symptoms begin to appear, if at all (see this paper for further exploration).
Most paediatric clinics are already oversubscribed, with long waiting lists, but parents of a newborn who are told that their baby has a serious genetic condition will want to be seen as soon as possible for advice, even if the baby is asymptomatic. There are no guidelines on the best clinical practice for asymptomatic children whose WGS indicates that there may be genetic anomaly present. 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 healthy babies 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 cannot undertake this additional work in the antenatal or neonatal clinics without compromising their other responsibilities. Ideally, a research project that is studying whether, and how, to introduce such a screening programme will also address this issue. In the meantime, it might be better to focus the resources that this research project will use to provide 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 (often many months) are experienced currently. The rapid WGS service has demonstrated that a genetic diagnosis can be established within two weeks, but currently this is available only for acutely ill children, and for those suspected of having a potentially treatable condition. It delivers very successfully for patients for whom a confirmed diagnosis will make a difference. Implementing this model for routine genomic testing in paediatric and genetic clinics 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 health and wellbeing of families.
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.
I agree completely . I have spent four years trying to understand my sons developmental delays and only know have had confirmed he has a very rare genetic condition X linked Raymond type . Although this specific gene may not be tested I believe testing needs to be quicker and more readily available for children’s with delays / illness
Professor Flinter makes very important points. I totally support her views about the difficulties associated with the screening of babies for actionable conditions and the reasons for her concerns.
The programme in my mind still conflates a number of important issues. The first relates to the screening for specific conditions within the existing newborn screening programme. In this context we need to carefully consider whether tandem mass spectrometry (TMS) or WGS is the better technology to use if we are to extend the number of conditions we wish to identify in the newborn period. By 'better' we would include considerations of false positives and negatives as well as costs and other benefits. I am personally (although not an expert) convinced that WGSis the better technology for this purpose.
The second (also related to the screening programme), concerns the choice and numbers of conditions and the criteria to be used to determine what conditions should be added to the existing nine. This is by and large a professional issue and professionals (with lay input) ought to be able to come up with such criteria.
The third is not related to the screening programme as such because the extraction of DNA and the storage of the sequence in one or other file format should be regarded as the production of a resource for future use. This application has little to do with the screening programme as such. it is the word 'sequencing' that may cause confusion since it is possible to sequence without detailed examination and analysis of particular areas of the genome.
I am in principle supportive of so doing and is why I might wish to include WGS as a possible future use of the heel prick. But it should not be conflated as part of the newborn screening programme. Analysis would only occur if and when some symptoms appear which require a diagnosis to be made. Using WGS in this way would obviate the problems of false positives pointed out by Professor Flinter, problems that are very real and give rise to important ethical issues.
The key question to be considered for such use are the costs and benefits of sequence storage in silico for subsequent analysis versus taking blood for DNA as and when required. If investigation shows no benefit to having such a resource then there seems to me little argument for so doing. This is the key to deciding whether or not blood should be taken at the time of the heel prick for this purpose or not.
Dr Ron Zimmern FRCP, FFPHM
Chairman, PHG Foundation, Camrbidge
The implementation of whole genome sequencing would require high literacy of genetic knowledge and extraordinary strong heart of parents. Rather than empowering the parents, in reality, it is forseeable that most of them, especially whose child has been (over)screened positive results, would be left in despair, anxiety, and powerless.