Rare diseases are a group of disorders that are characterised by their relatively low prevalence in the population and are typically defined in the UK as affecting < 1 in 2000 individuals.1 There are approximately 7000 rare disorders, which, when combined, affect around 6% of the population in the Western world.2 About 80% of rare disorders are thought to have a genetic cause.2 If a disorder is caused by a variation in a single gene, the disorder is termed as a monogenic disorder. For only half of the estimated 5000 monogenic disorders, the underlying genes are known.3 The identification of disease-causing variation in the known genes is challenging. Every human individual is believed to have up to 5 million variants compared to the reference genome.4 This variation is responsible for the human diversity, and only a small fraction of variants affects human health.
Variants in genes associated with human health can be benign or pathogenic or be of unknown significance, meaning that the link between genetic variation and clinical phenotype is unknown. For pathogenic variants, the link between genotype and phenotype is known but can be incomplete such that only a proportion of individuals with the pathogenic variation may develop symptoms (incomplete penetrance). These symptoms can further vary in severity even among affected family members (expressivity). This makes it difficult to predict disease even if the underlying genetic cause is well characterised.
Disorders caused by genetic variants can present at any time, from birth [e.g. phenylketonuria (PKU)] to much later in life (e.g. Huntington’s disease). It is estimated that there are about 600 childhood-onset conditions for which there is a potential intervention,4,5 and newborn screening aims to identify the disorders that benefit from pre-symptomatic detection. Early diagnosis enables surveillance and early intervention when available, which can significantly improve outcomes, and it is particularly important in conditions with rapid progression or that cause irreversible damage. Current approaches to screening for rare disorders as part of the UK national newborn blood spot (NBS) screening programme have been successful in both their capacity for detection of infants with rare conditions and in the wide uptake of the screening programme by the public. However, the number of diseases currently screened for in the UK is limited to nine conditions, and screening is based on biochemical markers. In recent years, whole genome sequencing (WGS) as a first-line screening test has emerged as a possible tool for an expansion of the NBS screening programme to identify the genetic disease.
Genetic testing aims to identify gene variants to help confirm or rule out genetic disorders (diagnosis) or establish the likelihood of a person developing and passing on a genetic disorder in the future (screening). Genetic testing can target single variants or single genes either alone or as part of a gene panel, or can consist of whole exome sequencing [WES, looking at all coding portions of the deoxyribonucleic acid (DNA)] and WGS (looking at both coding and non-coding regions of the DNA). WGS can potentially detect every variation in a genome, testing for hundreds of genetic diseases at the same time.
In 2021, Genomics England Limited (GEL) launched its Generation Study using WGS to sequence 100,000 newborns to screen for over 200 rare diseases to test its potential for an expanded UK NBS programme.6 Recruiting of pregnant women began in the first half of 2024. This poses several challenges to the UK National Screening Committee (UK NSC), who advise the four UK governments on screening-related questions, including the addition of new conditions to the NBS screening programme.
No methods exist for the evaluation of hundreds of conditions identified by one test. Multiplex testing has been available for years, and tandem mass spectrometry (MS/MS), currently used in the NBS programme, can detect dozens of statistical abnormalities in the blood spot. The approach to assessing each of the conditions that could be detected on the blood spot has been to look at each condition, in turn allowing a thorough evaluation of the evidence around testing, early treatment and harms and benefits of screening and an assessment of the evidence against the 20 UK NSC screening criteria.7 However, there is pressure to assess all the conditions that might be found with WGS at once, but a condition-by-condition approach for 200 conditions, with many thousands of gene variants, may not be feasible or effective, considering the limited evidence base for rare genetic diseases.
The ‘genotype-first’ approach has the potential for harms in the form of overdiagnosis and overmedicalisation, particularly for conditions with pathogenic variants that have low penetrance and for conditions with a high number of variants of unknown significance. The wider psychological and societal impact of genetic testing on such a large scale is also unknown. Most healthy, adult, UK Biobank participants were found to have one or more rare non-synonymous variants when a panel to look at > 500 disease genes was used.8 In healthy adults, these can be assumed to be benign. Similar findings in asymptomatic newborns would be concerning, demonstrating the difficulties in variant interpretation. To assess pathogenicity (e.g. > 99% probability of pathogenicity for pathogenic variants and 90–99% probability of pathogenicity for likely pathogenic variants), variants need to undergo a complex interpretation process, considering the prevalence of the variant, inheritance pattern, variant type and their predicted effects as well as observed gene–disease associations.9 However, not all pathogenic variants cause disease in all individuals who carry the variant. Penetrance is a measurement of the relationship between a genotype and phenotype. For rare diseases, the existing evidence and context for variant interpretation comes mainly from family and clinical studies, which means that penetrance is generally overestimated and the reported pathogenicity does not equate with penetrance.10 Moving to the screening context, knowledge of penetrance of known pathogenic variants in the general population is key for understanding the proportion of newborns who are likely to benefit from detection at screening and those who are likely overdiagnosed.11 An evaluation of WGS for newborn screening should be able to select variants with high penetrance for a low-risk screening programme or identify a variant annotation approach that is effective in filtering out harmless variants. We do not know how informative a review focused on penetrance outcomes in newborn sequencing would be.
A comprehensive health economic evaluation of the impact of screening for 200 conditions simultaneously is unlikely to be feasible, while addressing the question on a condition-by-condition basis is unlikely to be cost-effective. WGS may detect conditions for which high-risk, expensive treatments are available or for which no treatment is available. If more diseases are included in the newborn screening programme, adequately resourced referral pathways must be in place, which will present a challenge for resource allocation in healthcare systems. There is a resource trade-off between the early genetic diagnosis and intervention for less sick or asymptomatic individuals and resource-intensive diagnostic odysseys and later treatment when a rare disease presents symptomatically.12 Typically, an initial step in a cost-effectiveness evaluation is to map out the respective clinical pathways for the intervention and the comparator(s), which is likely to consist of the current clinical practice. Costs and health outcomes are then estimated based on the resources used and outcomes of each pathway. Mapping the full clinical pathways, that is, diagnosis and treatment, for such a wide range of conditions where the patient is asymptomatic, is unlikely to be feasible. A different methodological approach is needed for the economic evaluation screening for potentially hundreds of conditions with a single test.
Finally, the use of WGS for newborn screening presents several ethical challenges. These include consent, data ownership and psychological implications. Since newborns cannot provide consent, the NBS screening programme in the UK relies on obtaining informed consent from parent(s)/guardian(s). However, obtaining fully informed consent for WGS could be challenging and parents may not feel that they can turn down screening.13 As such, seeking consent for WGS, where large panels of conditions are screened for simultaneously, in the same manner may be inappropriate, and there is the question whether repeat consent is required for stored genetic data and whether and when consent should be transferred from the parent to the child. Beyond the consent issues, the possibility of retaining genomic data, linking results to health records and re-evaluating data throughout a person’s life raise important questions about privacy and confidentiality, data ownership and secure data storage.14 This may have psychological implications, and an understanding of how the public and new parents feel about WGS, making decisions about taking part, data security, communication of results, access to treatment and impact on the child and the whole family need to be understood.
We aimed to assess different evidence sources and approaches to evidence synthesis, review methods of costing and collate views of parents with children with rare diseases and expectant parents on the main challenges of WGS to inform an approach to assess WGS for newborn screening in the future. To that effect, we undertook five traditional evidence reviews covering five conditions to establish the evidence base and to provide a reference case for comparison with alternative review approaches. We evaluated the use of the existing resource Clinical Genome Resource (ClinGen) as an evidence source on actionability for the genes associated with the five selected conditions, where ‘actionability’ refers to the level of evidence about pathogenicity, penetrance and expressivity of a genetic variant and the extent to which interventions can be used to mitigate the effect of the disease.15 We undertook a focused review on genomic studies in paediatric screening populations reporting penetrance that may allow the identification of gene variants with high penetrance and expressivity for a screening program that maximises benefits and minimises harms. We conducted a review of economic evaluations of WGS and WES to better understand the methodology employed to date to evaluate these tests. Finally, we explored the patient and public views on questions relating to evaluating and communicating WGS in newborns.