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The State Of: Newborn Sequencing

Newborn sequencing has been a hot topic in the news in recent years. From Guinness World Records to large-scale screening initiatives, scientists across the world have been dedicated to developing rapid methods to diagnose genetic disease in newborns, allowing for timely intervention and treatment.

In this feature, we assess the State Of the newborn sequencing field, and take a look at the past, present and future to give you a comprehensive view of the research landscape.

The past

Newborn screening, the practice of testing newborns for certain genetic, metabolic and congenital disorders shortly after birth, has been in existence since the mid-20th century. Initially, screening focused on detecting conditions like phenylketonuria (PKU) and congenital hypothyroidism (CHT), which, if left untreated, could lead to severe health problems.

By the mid-1960s, PKU testing was ubiquitous across the United Kingdom and the United States, the basis for which was a blood test to check for the presence of phenylalanine hydroxylase. In the 1960s, the UK introduced the use of Guthrie cards, named after newborn screening pioneer Robert Guthrie, which are used to collect drops of blood from an infant’s heel around five days after birth. This new form of dried blood spot screening led to positive results for the UK’s newborn screening programme – by 1974, 98% of infants were tested for PKU, catching most cases early enough for intervention. CHT testing was introduced in the UK in the 1980s.

Later developments in newborn screening programs came in the form of testing for cystic fibrosis and sickle cell disease. Cystic fibrosis testing in particular had been the subject of research since the 1950s, but an effective method had escaped scientists for some time. Throughout the late 20th century, various different tests were trialled globally, and in 2003, Scotland became the first UK nation to introduce cystic fibrosis screening for all newborns, followed by England, Wales and Northern Ireland in 2007 alongside the formal launch of the Newborn Blood Spot Screening Program. In 2015, this was expanded to include additional diseases.

As of 2024, all newborns in the UK are entitled to dried blood spot screening at five days old through the NHS. Nine rare, but serious, conditions are now tested for: sickle cell disease, cystic fibrosis, congenital hypothyroidism, phenylketonuria, medium-chain acyl-CoA dehydrogenase deficiency (MCADD), maple syrup urine disease, isovaleric acidaemia, glutaric aciduria type 1 and homocystinuria. The tests offered in newborn screening programs vary globally and across healthcare providers. If you want to explore the newborn screening landscape internationally, check out our World of Genomics series.

The advent of next generation sequencing sparked new interest in the development of newborn screening programs. As technologies have become more advanced and cost-effective, there has been growing interest in integrating these tools into newborn screening programs globally. Pilot studies and research projects are underway in several countries to explore the feasibility and potential benefits of incorporating genomic sequencing into routine newborn screening practices. In 2022, Genomics England launched the Generation Study in partnership with the NHS, which will see 100,000 newborns have their genomes sequenced by 2025, testing for over 200 conditions. In the US, scientists at Rady Children’s Institute for Genomic Medicine (the institute responsible for the BeginNGS study) obtained the Guinness World Record for the ‘fastest genetic diagnosis’, taking just 19.5 hours to assess the impact of harmful variants in infants.

However, there is still no real consensus on the use of next generation sequencing to diagnose rare disorders in newborns, with some experts suggesting that, despite its diagnostic potential, the process could cause undue stress to parents for relatively little reward. In Australia, this lack of consensus was highlighted in a study published last year, where over 60% of healthcare professionals responded to a survey stating that they did not support the use of genomic sequencing in newborn screening. Despite this, almost 80% of the survey respondents predicted that the technology will be integrated into the screening process by 2026.

It is clear that newborn sequencing has potential, but there are a number of ethical and social challenges to tackle before it can be properly utilised in healthcare services. Not least of these problems is proper education for parents. Questions have been raised as to whether there is a true benefit to the introduction of whole genome sequencing for all newborns, whether this should be limited to exome sequencing, or only provided to those with carrier parents.

The present

Newborn sequencing has been a hot topic in recent years. Let’s take a look at some interesting studies from the last 12 months.

Genomic newborn screening: Are we entering a new era of screening? (Spiekerkoetter et al., 2023.) – This manuscript from 2023 summarises lectures on global newborn screening strategies from a 2022 symposium, discussing the challenges and potential harms weighed up against the benefits of sequencing. It includes perspectives from experts and recommendations for the future.

Genomic Sequencing as a First-Tier Screening Test and Outcomes of Newborn Screening (Chen et al., 2023) – This study assessed the benefit of gene panel screening as a first-tier screening tactic in newborns. Using data from almost 30,000 babies, the researchers concluded that gene panel screening is an effective testing method.

Challenges of using whole genome sequencing in population newborn screening (BMJ, 2024) – This analysis piece published in BMJ last month discusses the challenges associated with whole genome sequencing of newborn genomes, and includes expert analysis of the UK Generation Study.

Perception of genomic newborn screening among peripartum mothers (Prosenc et al., 2023) – In this study, over 1,000 Slovenian mothers were surveyed regarding newborn genomic sequencing. Although social and ethical concerns were raised, most parents had positive attitudes and would partake in the process.

Australian Public Perspectives on Genomic Newborn Screening: Risks, Benefits, and Preferences for Implementation (Lynch et al., 2024) – Another global perspective, this recent survey of the Australian public also showed positive attitudes towards the practice of newborn sequencing. The most common benefit highlighted was the ability to quickly diagnose disease and intervene.

Next-generation sequencing based newborn screening and comparative analysis with MS/MS (Shen et al., 2024) – Published in April 2024, this study assessed the accuracy and efficiency of next generation sequencing-based approaches to newborn sequencing compared to more traditional mass spectrometry-based tests. They concluded that NGS techniques broadened the range of diseases that could be detected and was highly accurate.

Prospective cohort study of genomic newborn screening: BabyScreen+ pilot study protocol (Lunke et al., 2024) – This article details the multidisciplinary BabyScreen+ study, a pilot study taking place in Australia to assess the feasibility of introducing genomic sequencing into newborn screening programs. The study will assess not only the scientific aspects of this kind of screening, but also public and professional perspectives.

Determining the characteristics of genetic disorders that predict inclusion in newborn genomic sequencing programs (Minten et al., 2024) – This recent preprint explores the criteria for inclusion of specific genes in newborn sequencing panels across several international pilot studies and programs. The study, which has not yet been peer-reviewed, suggested that a high evidence base and treatment efficacy were the two most important factors for including a gene in a sequencing program.

In the spotlight

BeginNGS – Newborn Genomic Sequencing to End the Diagnostic Odyssey

Based out of Rady Children’s Institute for Genomics Medicine (USA), the BeginNGS program aims to end the diagnostic odyssey for millions of rare disease patients by sequencing the genomes of infants at birth. The program complements current biochemical newborn screening tests, but expands the number of diseases to over 400. The pilot study involves hospitals not only in the US but also abroad, and should a participating infant have a positive result, support via genetic counsellors and other healthcare professionals will be provided.

For more information and to read relevant publications related to the study, check out the BeginNGS website.

The Future

The benefits of newborn sequencing may seem obvious at first glance – with the declining costs of using this technology, a faster and more efficient method to detect rare disease at the earliest opportunity sounds too good to overlook. But despite the efficacy of modern day sequencing techniques, it is yet to formally make its way into the newborn screening repertoire.

Many pilot studies are taking place internationally, and healthcare practitioners predict the integration of the tech into the healthcare sphere in the not-too-distant future, and several of these programs are putting an emphasis on the social and ethical aspects of newborn sequencing. Principally among these concerns is the impact this will have on parents, and their ability to give informed consent to the procedure. Some critics even argue that newborns cannot provide informed consent, and parents may not fully understand the potential implications of genetic testing for their child’s future, for example, if this data could one day be used to solve crimes or for insurance purposes. These concerns play into important discussions around genetic data privacy and discrimination.

Stepping away from the social aspects of newborn sequencing, genetic testing can uncover a wide range of information, which may have uncertain or ambiguous implications. This uncertainty can lead to anxiety and distress for parents, particularly if they receive results indicating that their child has a predisposition to a condition for which there is no cure or effective treatment. Plus, there are additional concerns around ‘overdiagnosis’ and false positives. There is high trust in, and uptake of, newborn screening in the UK as it currently stands, and it is important that the introduction of new technology does not damage this relationship between parents and the health system.

Ultimately, the technology exists to make newborn sequencing a reality, and high-profile studies backed by experts are currently ongoing to ensure that the practice is safe, efficient and ethically sound. The true barrier to the implementation of this technology in the clinic is largely social, and as such, multidisciplinary research will be the key to ensuring the best possible future for all infants and their parents.