Reading a Baby's Genes at Birth: What a Large New York Study Learned

How the GUARDIAN study added DNA sequencing to the standard newborn heel-prick test — and what it found in the first 4,000 babies

A major study in New York City tested whether reading a newborn's DNA could catch serious but treatable conditions that today's standard heel-prick test misses. In the first 4,000 babies, most families said yes to taking part, the DNA test worked almost every time, and about 1 in 27 babies had a result worth following up — including 110 babies with treatable conditions that would not have been found by the usual screening. The study shows the approach is possible and that parents welcome it, while also making clear that it is still early, still imperfect, and not yet ready to replace the screening we have.

Why This Question Matters

Almost every baby born in the United States has a few drops of blood taken from the heel a day or two after birth. That blood is tested for a set of rare but serious conditions, and when one is found early, treatment can begin before the baby ever gets sick. This kind of testing began in 1963, when a scientist named Robert Guthrie found a way to detect a condition called phenylketonuria — in which a baby cannot safely process part of normal food — from a dried spot of blood [1][2]. Over the years, states added more conditions to the list, and the results have prevented enormous amounts of suffering.

But the standard test has a built-in limit: it can only find a condition that leaves a chemical clue in the blood. Many serious genetic conditions leave no such clue, so they stay hidden until a child becomes ill. As treatments have improved — including for a muscle disease called spinal muscular atrophy, which was added to New York's screening after a successful pilot [3] — doctors have wondered whether reading a baby's DNA directly could find more of these treatable conditions earlier. The idea has been discussed for twenty years, but testing it properly, in a large and diverse group of families, had not really been done [4].

What the Researchers Did

The study is called GUARDIAN, which stands for Genomic Uniform-screening Against Rare Disease in All Newborns [1]. It offered families at six New York City hospitals an extra, optional DNA test for their newborn, on top of the normal screening. Cleverly, the researchers used the same blood spot already collected for standard screening, so no baby needed an extra needle. The full study plans to include 100,000 babies; this first report describes the first 4,000, enrolled between September 2022 and July 2023.

The DNA test looked at 237 genes linked to 255 conditions, almost all of which begin in early childhood and can be treated or managed. The conditions were sorted into two groups: a set of 156 treatable disorders, offered to everyone, and a second set of 99 conditions involving developmental delay and seizures, which families could choose to include or not. Importantly, this was a screening test, not a final diagnosis. Any "positive" result was double-checked in the laboratory and then confirmed with further medical testing before doctors acted on it [5].

What They Found

Of the families approached, 72% agreed to take part — a high number for a study involving genetics, and a sign that parents were comfortable with the idea [1]. Nine in ten of those families also chose to include the optional group of developmental conditions, suggesting many parents want to know about more than the narrowest list. The DNA test succeeded for 99.6% of babies. Just under 4% of babies (147 out of 3,982) had a positive screening result. Of the results that were reported, about four in five turned out to be true, and 110 of these were conditions that the standard test would have missed entirely.

The single most common finding was G6PD deficiency, found in 92 babies. This is a common inherited condition in which certain foods, infections, or medicines can cause the breakdown of red blood cells, and knowing about it early helps families and doctors avoid those triggers and watch newborn jaundice more carefully. Beyond that, the DNA test found several conditions with immediate, life-changing consequences. One baby boy whose standard immune-system screen looked normal turned out to have a serious immune disorder called severe combined immunodeficiency; because it was caught, he received a bone-marrow transplant at four months of age. Two babies were found to have a heart-rhythm condition called long QT syndrome and were started on protective medication, and in one case the discovery revealed that the baby's mother had the same undiagnosed condition. The test also found early, treatable cases of Wilson disease (a problem with copper build-up) and bone-growth conditions.

It helps to understand what a number like "3.7% screened positive" really means for a family. It does not mean nearly 4 in 100 babies are seriously ill. A positive screen is a flag that says "this is worth a closer look," and in this study about one in five of those flags turned out, after further testing, to be a false alarm. That is why every positive result led to more testing — often including testing the parents — rather than a straight diagnosis. It is also why the researchers were careful to explain results in person, with genetic counselors and specialists present, so that families were not left to interpret a frightening-sounding word on their own. For most families in the study, the DNA test simply confirmed that their baby did not carry any of the conditions on the list, and those results were returned by phone and secure email.

What This Means for Families

For today's parents, the most honest takeaway is that this is a promising glimpse of the future, not a change in what happens at the bedside right now. The study proves that adding DNA sequencing to newborn screening can be done at scale, that families across many different backgrounds are willing to take part, and that it can catch treatable conditions earlier than ever [6]. Programs like BabySeq had earlier begun to show what it means to give parents genetic results at birth [5]; GUARDIAN shows it can work for thousands of families at once.

At the same time, the study is careful about what it does not yet show. Because these babies are still very young, researchers cannot yet know how many conditions the test might have missed, or the full emotional effect on families of a worrying result that later turns out to be a false alarm. In this study, 25 results were false positives — including 11 caused by a single misleading genetic pattern that the team stopped reporting once they understood it [1]. This is exactly why a positive screen is a starting point for more testing, not a diagnosis, and why the study surrounded every positive result with genetic counselors, specialists, and a guide to help families find care [7].

There is also an important fairness point. The DNA test needed extra expert review more often for babies whose family backgrounds are underrepresented in genetic databases, simply because those databases contain far more information about people of European ancestry [6]. Making this kind of screening fair for everyone will mean building better genetic reference information for all populations, not just recruiting diverse families into studies [8].

A Brief Look Back, and What Comes Next

It is worth remembering how far this has come. For most of the last sixty years, families whose children had rare genetic conditions often faced a long "diagnostic odyssey" — months or years of tests and uncertainty before anyone could name what was wrong, sometimes after irreversible harm had already been done. The heel-prick test changed that for a specific list of conditions; the hope behind genomic screening is to extend that same early warning to many more treatable diseases before symptoms appear [9].

What researchers are working on next is finishing the larger study of 100,000 babies with long-term follow-up, so they can measure how well the test truly performs and whether early detection actually leads to healthier children [10]. They are also working to agree on which conditions should be included, to speed up results, and to make the test equally accurate for every family. GUARDIAN's message to parents is a hopeful but measured one: reading a baby's genes at birth is now genuinely possible, families are ready for it, and the work ahead is to make it accurate, fair, and truly helpful for every newborn.

References

  1. Ziegler A, Koval-Burt C, Kay DM, et al. Expanded Newborn Screening Using Genome Sequencing for Early Actionable Conditions. JAMA. 2025;333(3):232–240. doi:10.1001/jama.2024.19662 ↩
  2. Guthrie R, Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics. 1963;32:338–343. doi:10.1542/peds.32.3.338 ↩
  3. Kraszewski JN, Kay DM, Stevens CF, et al. Pilot study of population-based newborn screening for spinal muscular atrophy in New York state. Genet Med. 2018;20(6):608–613. doi:10.1038/gim.2017.152 ↩
  4. Stark Z, Scott RH. Genomic newborn screening for rare diseases. Nat Rev Genet. 2023;24(11):755–766. doi:10.1038/s41576-023-00621-w ↩
  5. Holm IA, Agrawal PB, Ceyhan-Birsoy O, et al. The BabySeq project: implementing genomic sequencing in newborns. BMC Pediatr. 2018;18(1):225. doi:10.1186/s12887-018-1200-1 ↩
  6. Ziegler A, Chung WK. Universal newborn screening using genome sequencing: early experience from the GUARDIAN study. Pediatr Res. 2025;97(4):1315–1319. doi:10.1038/s41390-024-03647-w ↩
  7. Bick D, Ahmed A, Deen D, et al. Newborn screening by genomic sequencing: opportunities and challenges. Int J Neonatal Screen. 2022;8(3):40. doi:10.3390/ijns8030040 ↩
  8. Downie L, Halliday J, Lewis S, Amor DJ. Principles of genomic newborn screening programs. JAMA Netw Open. 2021;4(7):e2114336. doi:10.1001/jamanetworkopen.2021.14336 ↩
  9. Kingsmore SF. Dispatches from Biotech beginning BeginNGS: rapid newborn genome sequencing to end the diagnostic and therapeutic odyssey. Am J Med Genet C Semin Med Genet. 2022;190(2):243–256. doi:10.1002/ajmg.c.32005 ↩
  10. Milko LV, O'Daniel JM, DeCristo DM, et al. An age-based framework for evaluating genome-scale sequencing results in newborn screening. J Pediatr. 2019;209:68–76. doi:10.1016/j.jpeds.2018.12.027 ↩