Conventional newborn screening panels typically use blood biomarkers to detect for anywhere from 30 to 80 genetic conditions — leaving hundreds of rare but treatable conditions and diseases undetected. Recognizing that whole genome sequencing could provide the more comprehensive screening necessary to give newborns a better chance at early treatment, researchers and physicians at NewYork-Presbyterian and Columbia launched the Genomic Uniform-screening Against Rare Disease in All Newborns (GUARDIAN) study in September 2022.
Babies born at any of NewYork-Presbyterian’s hospitals are offered the opportunity to participate in the GUARDIAN study and receive free screening for over 450 conditions. So far, about 70% of families who were offered the opportunity agreed to participate, allowing more than 10,000 infants to receive this more in-depth genetic testing.
Jordan Orange, M.D., pediatrician-in-chief of NewYork-Presbyterian Morgan Stanley Children's Hospital of Children’s Hospital of New York, and one of the GUARDIAN study’s investigators, discusses the insights it is generating and how the program can serve as a blueprint for a revolutionary approach to newborn screening.
What does today’s genetic testing look like?
Presently, all states have newborn screening tests. Depending upon what state you’re in, there are between 30 and 80 conditions screened for. In New York, for example, the standard newborn screening detects 52 conditions, including cystic fibrosis, severe combined immunodeficiency (SCID), enzyme deficiencies, and many others.
But 30 to 80 conditions represent a very small subset of diseases; there are over 450 treatable genetic conditions that, with appropriate testing, can be diagnosed early in life and have an intervention that could lead to a cure or improve the health of a child.
Through the GUARDIAN study, we set out to screen for as many treatable and curable conditions as possible — many more than standard state screening — to give children the best chance to receive treatment before they become sick.
— Dr. Jordan Orange
What unmet need was the GUARDIAN study designed to address?
While rare, there are many inherited diseases not included in states’ newborn screening programs. Through the GUARDIAN study, we set out to screen for as many treatable and curable conditions as possible — many more than standard state screening — to give children the best chance to receive treatment before they become sick.
When an inherited disease is not diagnosed early, parents often go through a diagnostic odyssey over many years before learning what is causing their child's symptoms. Detecting them early enables doctors to start treatment sooner.
We also know that rare genetic diseases are underdiagnosed in more challenged populations. At NewYork-Presbyterian, we had tremendous participation across upper Manhattan and in other communities we serve. It’s been so meaningful to make a difference so early in these children’s lives, and to help tackle some of what the typical health-access challenges may otherwise interfere with.
What was required to launch the GUARDIAN program from a planning perspective?
We already had the technology; that part was not novel or unique. What was really required was extensive collaboration to assemble such a large-scale initiative to bring this genomic technology potentially to every new life within our system. We had to set up a multidisciplinary team of genetic experts, laboratory staff, and physicians. Genetic counselors were also a big part of it. They are experts who can approach those who have just had a baby to explain what GUARDIAN offers in a way that is meaningful for the parents. They apply their profound expertise to address any questions or concerns a potential participant has and they help parents understand the results. They are the very face of the study to any parents considering it.
What does participation in the study look like?
Participation is simple – anyone giving birth at a NewYork-Presbyterian hospital is eligible to participate. All it requires is the consent of parents and guardians to have their newborn's blood tested for the additional conditions. No extra blood samples are needed; we use the same sample taken for the New York State newborn screening test.
We detected treatable genetic conditions in 120 of the infants; 110 of those cases were not detected through standard newborn screening.
— Dr. Jordan Orange
What are some of the outcomes so far?
We published a paper in the Journal of the American Medical Association in January 2025 reporting on the first 4,000 babies enrolled in the study. At that point, we were screening for 156 early-onset genetic conditions with established interventions, and 99 optional neurodevelopmental disorders associated with seizures.
We detected treatable genetic conditions in 120 of the infants; 110 of those cases were not detected through standard newborn screening. Moreover, most babies who were diagnosed with a condition were associated with a historically marginalized community.
We continue to offer participation in the GUARDIAN study and now screen for more than 450 treatable genetic conditions. But we have a lot of ground to cover before something as comprehensive as the GUARDIAN screening becomes the new norm. We want to make sure the science is as robust and as meaningful as possible.
What hopes do you have for the future of newborn genetic testing?
Medicine as a whole is developing the technology to handle genomic information, to integrate it within electronic health systems, and to provide support for its use in clinical decision-making. I dream for a future where we utilize this technology and science in a way that helps us reduce the suffering caused by these detectable and treatable conditions. How many diagnostic odysseys can be eliminated? How many dollars can be saved by not having a patient go through a series of illnesses and hospitalizations? I don’t know the answers to those questions, but I do know that the results from the GUARDIAN study will help us find out.
Saving Lives, One Screening at a Time
Study investigators describe three rare genetic conditions they detected through the GUARDIAN study that would not have been detected through conventional newborn screening.
Severe Combined Immunodeficiency (SCID)
SCID, which occurs in about 1 in 50,000 children, is often referred to as “bubble boy syndrome” because children born with it lack the ability to produce working T-cells, making them extremely susceptible to infection. The GUARDIAN study found two SCID cases in the first 10,000 newborns screened, both caused by an extremely rare genetic variant. While the form of SCID associated with this mutation is milder than typical SCID, it is still critical to intervene early with a bone marrow transplant.
“Doing the bone marrow transplant within the first three months of life and before an infection happens, leads to a 90%-plus lifetime cure rate, which is incredible,” explains pediatric immunologist Joshua Milner, M.D. “This, to our knowledge, was the first time that a genetic newborn screen was able to identify a treatable immune disorder when the regular screen couldn’t pick it up and where it wasn’t running in the family.”
Wilson’s Disease
Wilson’s disease causes copper to accumulate in the body, resulting in organ damage to the liver, eyes, and brain. By the time it’s detected, typically in the teen years, the liver has been severely injured and a transplant may be necessary. The GUARDIAN study identified four children with genes for Wilson’s disease.
While not everyone with the gene will develop the disease, families can receive education about steps they can take to reduce the need for a liver transplant — such as taking a regular dose of zinc and avoiding high-copper foods such as legumes and chocolate. “There's a lot of benefit to knowing someone has this up front, and possibly giving them some dietary counseling to prevent a rapid accumulation of copper,” says pediatric gastroenterologist Steven Lobritto, M.D.
Long QT Syndrome
This dangerous heart rhythm disorder may be acquired through certain medications or medical conditions, or it may be inherited. The GUARDIAN investigators identified long QT syndrome associated with a mutation in the KCNQ1 gene in one patient. They confirmed it with follow-up EKGs for the child as well as the father, who also tested positive.
Treatment involves beta blockers, the avoidance of certain other medications, and caution with strenuous physical activity. “The fact that we know about it now allows us to put the patient on medication that can significantly minimize the chance of having any arrhythmias going forward,” says pediatric electrophysiologist Eric S. Silver, M.D.
