geneIQ – Genetics and Diagnostics

What is newborn screening and why is it important?

Newborn screening (NBS) is a way to detect potentially fatal or disabling conditions. It aims to find these conditions as early as possible after birth. This screening is done before any symptoms are present. An early intervention can prevent disability, neurological damage or even death. Some interventions are dietary, some are medical.

Screening for phenylketonuria (PKU) exemplifies the importance of NBS. PKU is a disease that prevents a breakdown of an amino acid – phenylalanine. Babies are usually screened within 24 to 72 hours of birth. The treatment can be dietary with low protein intake and limiting intake of phenylalanine. Medication can be used additionally to the PKU diet. If the condition is left untreated it can lead to:

• behavioral problems
• seizures
• intellectual and developmental disability

So, what exactly is tested during a newborn screening?

NBS programs around the world vary in what they include. The US program tests:

• hearing
• critical cardiac defects
• a variety of metabolic, hematologic, endocrine, and other inheritable disorders such as:
  • cystic fibrosis
  • congenital hypothyroidism
  • several rare metabolic disorders
  • sickle cell anemia

The exact number of conditions tested varies by state, from 33 to 75. Testing methods also vary, with some performed all at once and others in two stages. Priority is given to the following conditions:

• requiring low screening costs
• not symptomatic at birth
• if untreated will cause serious health problems in childhood
• having effective treatment or management preventing disease development
• with specialists available to diagnose and treat the babies that test positive

In Europe, the number of conditions tested varies widely. Ireland tests for 8, the UK tests for 11, Germany tests for 17, the Netherlands tests for 22, and Italy tests for 49 conditions. Presently, there is a drive to harmonize the testing across Europe. Thus far, there is little agreement as to which conditions should be included in the program.

However, it is important to remember that not all babies in the world have access to newborn screening. Some countries do not offer NBS programs – Honduras, El Salvador and Haiti. In some countries, the access to NBS is difficult due to many remote locations. In others, not all newborns testing positive have access to the available treatments.

Traditional NBS testing involves a heel prick to collect blood for testing. These blood spots can be used not just for traditional tests but also for genetic or genomic testing. In such cases, minimizing need for any extra sample from the newborn.

NBS in genomic era – can we use genomic sequencing for routine newborn screening?

Some countries are struggling to make NBS available to all newborns. Meanwhile, other countries are already looking to the future and are using the power of genomics to expand NBS even further.

Most of the traditional NBS testing is done using mass spectroscopy. There are relatively few molecular tests, with cystic fibrosis being the main example. However, recent advances in high-throughput technologies can change how we screen for diseases and diagnose them. Next-Generation Sequencing (NGS) allows for rapid, screening of entire genomes. With improvements in bioinformatics, and the reduction in costs of sequencing genomes, the use of genomic testing becomes more attractive. It also becomes a real possibility.

Does possible mean genomic NBS testing is ready for the clinic?

This is a difficult question and geneticists, clinicians, bioinformaticians and many other specialists are trying to answer. At the ESHG2025, a survey of participants during the workshop on Genomic newborn screening was conducted and the following word cloud was generated:

The participants clearly agree that using genomic NBS is an opportunity. Some thought it was scary, challenging, and there are uncertainties. Yet, it offers hope for the future. So, where are we with respect to evaluation of whole genome sequencing (WGS) for the purposes of NBS program?

A number of international studies are exploring the use of newborn genome sequencing (NBSeq). The goal is to evaluate performance and economics of the method and expand the disorders for which we can screen. Current gene lists used in the pilot studies are not uniform across the genomic newborn screening programs. This does not come as a surprise considering how different are the standard NBS programs.

In the past, I compared the gene lists from various programs. I have done this while ideating the targets for NBS WGS sequencing controls. It became clear that some programs are testing a wide variety of genes. Other programs include primarily the genes which are well characterized in childhood diseases. To explain it better, it is good to remind ourselves of the principles for screening. These were originally formulated by Wilson and Jungner in their 1968 publication for WHO.

It is important to remind ourselves that screening is not diagnosing. Multiple highly successful diagnostic programs exist using rapid WGS for neonatal cases. In these cases, the clinicians are looking for a variant/s that can explain an existing condition. In a screening program, we will be trying to figure out if a variant/s identified will cause a disease. Since most of the cases will be negative, the specificity of the test is critical. We also need a test that is sensitive so all positive cases will be identified.

While the discussion is ongoing on applicability of the Wilson & Jungner’s principles for genomic screening, there are some points that are important to consider when thinking of panel choice, and genomic testing:

• Weight the harms and benefits of including a condition on the screening list
  • Will the detection of the condition affect clinical management of the patient?
  • Is there a treatment that can cure or manage the condition?
  • How certain are we that the condition will develop?
  • Ethical and legal considerations
  • Equal access to screening, diagnosis and treatment options
• Identification of pathogenic variant/s does not mean a diagnosis.
  • The correlation between them and the health outcomes is sometimes not yet clear.
  • Some variants can cause multiple conditions, while others do not. This variability makes reporting a little tricky. The focus should be only on variants causing a childhood disease.
• Costs and logistics of the delivery of genomic newborn screening are still under investigation

The current newborn research programs around the globe as aiming to address several of the above questions. Besides research programs, there are a few commercial offerings. These are in the US, Spain, Brazil, and Kenya. The research programs vary in size from small (less than 100 samples) to large (100,000 samples). The four biggest programs are: BabySeq (Massachusetts), GUARDIAN (New York), FirstSteps (Greece) and Generation (UK).

The only program embarking now on a large-scale implementation is the UK NBS genomic screening. The NHS plans to sequence 100,000 babies over the next 10 years. So, the short answer to the question if genomic NBS is ready for the clinical implementation today is – “No”.

That said, we should be monitoring the developments closely as global efforts are converging. The large studies like the one in the UK will reveal tool readiness for data management. Are we capable of interpreting the data in timely fashion? Can the results be conveyed clearly back to the patients and clinicians?

How do the NBS genome panels compare to each other?

I already hinted that the panels chosen by the various NBSeq programs are quite different. In fact, the more of them you compare the harder it is to find a common set. The 2024 paper by Downie et al, indicated that only 55 genes were in common (<5%) between seven different programs. The comparison between three US gene lists (T. Minten et al.) (BeginNGS, Early Check and GUARDIAN) showed only 72 genes in common!

What causes the differences, and can we have a universal panel? The selections were based on:

• clinical validity of the gene, is this gene causing the disease we want to detect?
• treatability or actionability – can a positive result lead to a meaningful prevention? Can it help in disease-risk mitigation? In some cases, can the disease be cured?
• technical aspects – mapping and variant detection issues. A reliable variant identification is essential for a successful NBSeq and some regions in the genome make that process difficult.

The development of a completely universal panel for NBSeq is probably unlikely. I expect there to be some regional differences. Hopefully, there will be a core set of genes. And all programs can agree on their inclusion in local NBSeq panels.

Testing technology is improving. Similarly, treatments for diseases once thought to be incurable are advancing. These diseases include cystic fibrosis or spinal muscular atrophy. The issue is that not all forms of the disease can be cured just yet. Treatments are not necessarily globally approved. Additionally, the costs of the therapy are not making it accessible to all. This equitable access not just to testing but also to treatment is also an important aspect for NBS programs.

Summary. What is the bottom line of this discussion?

Are you planning to have a baby? Will the newborn genomic screening be something available for you? If it is available, would you opt-in? What do you need to know?

• The current technology enables genomic newborn screening
• Economical, ethical, legal, and medical aspects of the proposed NBSeq are being assessed globally. As a result, NBSeq can be unavailable in your region just yet. If you are interested, check with your doctor
• What conditions will be screened for and what results are returned back to you? Who will be in charge of the data?
• Are there legal protections against discrimination if a condition is detected?
• What will be the next steps if a screen is positive?
• Can a positive result be missed?
• Each country’s screening program will be unique, so understand how it works in your country

The best option is to discuss it with your family doctor. If they are not familiar with the options, ask for a referral to someone who can explain the genomic newborn screening. This explanation should relate to your situation and location. Make sure that the informed consent you will be signing is truly informed and you feel comfortable with the process.

Resources and Further reading:

1. Newborn Screening in Your State | Newborn Screening, accessed 03 July 2025
2. Newborn Screening Tests | Children’s Hospital of Philadelphia, accessed 03 July 2025
3. New cystic fibrosis guideline aims to make newborn screening more equitable, accessed 03 July 2025
4. Newborn screening – EURORDIS-Rare Diseases Europe, accessed 03 July 2025
5. T. Minten et al. (2024) Data-driven consideration of genetic disorders for global genomic newborn screening programs, medRxiv [Preprint] 2025 Mar 25:2024.03.24.24304797. doi: 10.1101/2024.03.24.24304797, accessed 04 July 2025
6. Screening programmes: a short guide, WHO 2020 9789289054782-eng.pdf
7. J. Wilson and G Jungner Principles and practice of screening for disease (1968) WHO_PHP_34.pdf
8. A. Anderman et al (2008) Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years 07-050112.pdf, Bulletin of the World Health Organization | April 2008, 86 (4)
9. L. Downie et al. (2024) Gene selection for genomic newborn screening: Moving toward consensus? Genetics in Medicine, Volume 26, Issue 5, May 2024, 101077
10. S. Gillner et al (2024) The modernisation of newborn screening as a pan-European challenge – An international delphi study. Health policy 149 (2024) 105162
11. The BabySeq Project – Genomes to People, accessed 04 July 2024
12. S. Rankin et al (2025) The UK National screening committee, the newborn genomes programme, and the ethical conundrum for UK newborn screening | Community Genet (2025). https://doi.org/10.1007/s12687-025-00788-1
13. NHS plans to DNA test all babies in England to assess disease risk, BBC, accessed 04 July 2025