Blog16th February 2023
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.
The Newborn Genomes Programme
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.
Next steps
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.
Related projects
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Work programme