Newborn screening is transforming, as advances in genomic sequencing pave the way for earlier, more accurate diagnoses of rare diseases.
With healthcare systems under pressure to improve patient outcomes while managing costs, the integration of whole genome sequencing (WGS) into newborn screening programmes is emerging as an opportunity for early identification and disease prevention.
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Children are born every day with genetic conditions that go undetected for years – sometimes never receiving a diagnosis at all. For those affected, the journey to an answer is often long and uncertain, delaying treatment and increasing the risk of irreversible complications.
Now, several studies around the world are investigating whether sequencing newborns at birth could help close the diagnostic gap. Two major studies leading the charge are the Generation study in England and the GUARDIAN study at Mount Sinai in New York, US. Both studies aim to sequence the genomes of 100,000 newborns, integrating genomic data into healthcare. The Generation study, led by Genomics England in partnership with the NHS, focuses on over 200 treatable conditions where early diagnosis could significantly impact health outcomes. The GUARDIAN study screens for around 250 conditions, including ultra-rare disorders that may not yet have established treatments.
As technology advances, Swaroop Aradhya, Illumina’s global head of medical and clinical affairs, says that WGS is poised to become the dominant method for newborn screening in the not-too-distant future.
“We expect WGS to become standard, especially in nationalised healthcare settings,” explains Aradhya.
The case for WGS
A May 2024 survey from Eurodis found that the average time from symptom onset to a confirmed rare disease diagnosis is nearly five years. The survey, which included 13,300 responses from 104 countries, found that many families received multiple misdiagnoses and extensive medical consultations before reaching a definitive answer.
Michelle Werner, CEO of Alltrna, says her family underwent a decade-long struggle to obtain a diagnosis for her son, who was ultimately diagnosed with Duchenne muscular dystrophy (DMD) at ten years old – far later than the typical diagnosis window of three to five years.
At six months old, her son was missing gross motor milestones but was misdiagnosed with hypotonia and given extensive physical and occupational therapy designed to build muscle.
“Building muscle is not what you want to do with DMD because that accelerates the breakdown of muscle and makes the situation worse,” Werner explained.
By the time he was correctly diagnosed, he was too old for clinical trials for experimental treatments that may have helped. Werner believes that newborn screening could have spared years of incorrect treatment and provided access to potential therapies.
“If we had newborn screening at the time my son was born, we would have known right away that he had DMD. Instead, we didn’t have that diagnosis.”
Efforts to close the diagnostic gap
Early data from the GUARDIAN study is promising. Among the first 4,000 newborns enrolled, genome sequencing identified 120 babies (3%) with serious health conditions, only ten of whom were detected through standard newborn screening.
For one child, the identification of a rare gene variant causing a severe immunodeficiency disorder—missed by traditional screening—resulted in a life-saving bone marrow transplant.
Wendy Chung, clinical and molecular geneticist at Boston Children’s Hospital and principal investigator of the GUARDIAN study, emphasises that while some rare diseases now have innovative treatments, others benefit from simple, life-changing interventions like dietary changes or vitamin supplements.
David Bick, principal clinician for the newborn genomes programme at Genomics England, echoes this sentiment. He highlights biotinidase deficiency, an inherited disorder in which the body is unable to recycle the vitamin biotin. The rare disorder causes rashes, seizures, and hypotonia, and is treated with biotin vitamin tablets.
“You can go down to the health food store and pick up a little thing of biotin tablets for almost nothing. The treatment is incredibly effective…if you give them oral biotin every day, they will never have a symptom their entire life, ever,” explains Bick.
Advances in technology
Traditional screening methods rely on biochemical tests, such as tandem mass spectrometry, which detect metabolic imbalances in a newborn’s blood sample. However, this method can miss genetic disorders without clear biochemical markers, leaving many rare diseases undiagnosed until symptoms emerge – often when treatment options are limited.
WGS examines all the genes in an individual’s genome, allowing for the detection of a wider range of genetic conditions. This approach can uncover genetic mutations associated with rare diseases, some of which may not have visible symptoms at birth or have no established biochemical markers.
Aradhya explains that WGS is becoming increasingly accessible and cost-effective, positioning it to potentially become the standard platform for genomic analysis shortly. However, while the price has decreased significantly, WGS is still more expensive than traditional screening methods. This can be a barrier to widespread implementation, especially in resource-limited settings.
There are also ethical and logistical questions surrounding parental consent, data storage, and incidental findings – cases where a child’s genome reveals risk factors for conditions that may not manifest until adulthood. Bick says there must be a cautious, transparent approach when enrolling families into these types of studies.
The cost-benefit of expanding newborn screening
Newborn screening, particularly when expanded to include WGS, presents a complex cost-benefit analysis. While the initial costs of implementing comprehensive screening programmes can be high, the long-term benefits often outweigh these expenses.
The GUARDIAN study incurs higher upfront costs compared to traditional methods, according to Chung. However, this approach offers flexibility, allowing new treatments to be added easily as treatments become available. This flexibility could reduce long-term expenses by avoiding the need to develop and validate multiple individual tests.
“You’re paying more of that cost upfront, but you’re actually – over what could be the lifetime of this new platform – really minimising the cost downstream,” notes Chung.
Early diagnosis through newborn screening can prevent irreversible damage and save lives, ultimately leading to significant cost savings over a patient’s lifetime. Bick explains that the Generation study is closely examining the economic impact of expanded screening. They are collecting data on screening costs, potential savings from early interventions, and comparing outcomes to traditional diagnostic methods. This analysis will help the NHS make informed decisions about scaling up genomic screening.
UK versus US healthcare systems
The UK and US are taking different approaches to newborn screening, influenced by their respective healthcare systems. The UK’s study is integrated into the NHS, aligning with the existing newborn screening programme and exploring the long-term use of genomic data. In contrast, the US study is hospital-led, focusing on expanding diagnostic capabilities and refining WGS in clinical settings.
The UK currently screens for nine conditions while the US screens for around 35, with some states testing for up to 50. The decentralised nature of US screening programs can lead to variations in both the conditions tested and how they’re implemented while the UK’s centralised NHS system allows for a more uniform approach.
“The CDC [Centers for Disease Control] has been trying to think about how to move the individual newborn screening programmes in each state into this genomic era,” explains Bick.
“One thing that’s working in everybody’s favour is that the cost of sequencing is dropping very rapidly, but you still have the issue where you have to analyse the variants, the DNA changes, and you want to try and find the kids who need a treatment and not bother the parents of the ones who don’t need a treatment.”
The future of newborn screening
The adoption of WGS in newborn screening is still in its early stages, but the technology is rapidly advancing. Beyond newborn screening, genomic data collected at birth could have long-term benefits, contributing to a better understanding of rare diseases and supporting the development of new treatments.
“Most importantly, we want the researchers and the drug companies to make treatments for conditions that don’t currently have a treatment,” concludes Bick.
“We want to work with the drug companies. We want to work with researchers around the world to use our data to move the ball forward on that.”
