Study uses genomic screening to look for PI in newborns

A study launched at Columbia University examines the DNA of newborns to look for rare diseases including genes associated with primary immunodeficiency (PI). The GUARDIAN (Genomic Uniform-screening Against Rare Diseases in All Newborns) study uses whole genome sequencing as a newborn screening tool, alongside the traditional blood biomarker screening. By looking at the genome, or DNA, researchers can identify gene variants that can cause PI, allowing many more children to be diagnosed and treated early.

A collaboration between Columbia University Irving Medical Center, New York Presbyterian Hospital, the New York State Department of Health, and genetic testing companies, the study began in September 2022 and published early results in October 2024. Out of the 4,000 newborns enrolled through July 2023, 120 were identified with serious genetic health conditions, most of whom had a deficiency that affects red blood cells and is not tested in traditional newborn screening. In comparison, standard newborn screening identified only 10 infants with serious health conditions. All children identified in the standard newborn screening were also identified by the genetic screening.

One of the babies had a condition that standard newborn screening missed but genomic screening caught—a PI called leaky severe combined immunodeficiency (SCID). Leaky SCID occurs when a person has symptoms similar to typical SCID, but with T cell counts that aren’t low enough to qualify as typical SCID. It’s called “leaky” because some T cells “leak” through, making it difficult to diagnose. The infant was treated with a successful bone marrow transplant (BMT) at age 4.

The GUARDIAN study is ongoing and now has over 12,000 babies enrolled from six hospital locations in New York City. In the published portion of the study, researchers sequenced 156 genes for variants that cause early-onset genetic conditions, some associated with PI, and 99 neurodevelopmental disorders associated with seizures. Researchers have since expanded the number of genes tested to more than 450 with approximately 120 genes that can cause PI. In the expanded portion of the study, which is not yet published, researchers have found several more children with leaky SCID and other cases of PI that are currently being investigated.

Researchers chose genes for the study based on actionable steps like medications or interventions that clinicians can provide to prevent or treat the illness before the age of 5. In addition to SCID, some of the PI genes screened for include those that cause Wiskott-Aldrich syndrome, CHARGE syndrome, IPEX syndrome, hyper IgM syndromes, agammaglobulinemia, complement deficiencies, chronic granulomatous disease (CGD), hyper IgE syndrome, and leukocyte adhesion disorder (LAD).

“We apply the same principles as we do with traditional newborn screening, which is we screen for things that have a very high likelihood of impacting the child early in life and where there is something that could be done about it, and if it were done beforehand, then it would lead to a positive outcome. In fact, there would be a benefit to doing something beforehand rather than waiting for the first symptoms,” said study co-author Dr. Josh Milner, professor of pediatrics and chief of the allergy, immunology, and rheumatology at both New York-Presbyterian/Columbia University Irving Medical Center and New York-Presbyterian Morgan Stanley Children’s Hospital.

For immunologic problems, genetic screening “flips the script,” said Milner. Whereas traditional newborn screening checks for about 60 conditions, genetic screening can look for hundreds of PI types. The frequency of PI is probably a lot higher than the medical community realizes, said Milner.

“There are so many things to do to help babies with immune disorders early in life, before symptoms arise, and there are so many genetic problems of the immune system than can be checked,” said Milner. “In a number of pilot studies to perform genetic newborn screening, one of the largest groups of disorders to be screened is immune disorders. There are not great estimates, unfortunately, of genetic diseases of the immune system because people still don’t even think about it in certain scenarios. Most of these are 1 in 50,000 to 100,000 individually, but collectively we’re talking about probably 1 in 2,000 to 4,000 having one of these conditions.

“Doing the genetic sequencing might justify itself just for the immune problems because, as it is, we already identify maybe 1 in 300 or 400 kids who have something that’s on the newborn screening. And that cost is justified, so for the genetic screening, there’s just an enormous number of what we call ‘actionable immune problems.’”

If clinicians knew that a newborn had CGD or a combined immunodeficiency, for example, they could consider BMT as treatment for the child early in life. In other instances, children with B cell deficiencies could be monitored and treated with immunoglobulin replacement therapy before they develop a severe infection like pneumonia. In still other cases, those children with immune dysregulation could benefit from early BMT or a pathway-specific drug.

The cost to integrate genomic sequencing into newborn screening could be a challenge, admits Milner, as the blood sample test for current newborn screening is about $200 and the cost of genomic screening is on average about $700. Still, the money spent on early diagnosis and subsequent treatment ultimately may be a savings because it reduces costs associated with health complications that occur when a PI goes undiagnosed for years. The list of genes can also be expanded without the cost increasing.

“The nice thing is that you can add as many diseases as you want, and it doesn’t cost any more, whereas if I’m adding a disease to the regular newborn screening, the cost is really quite significant,” said Milner.

The GUARDIAN study doesn’t have a completion date but does have a goal of screening 100,000 babies. Milner said GUARDIAN is one of a small handful of large-scale genomic sequencing newborn screening studies across the globe, pointing to two similar studies in the United Kingdom and Belgium.

“As much as possible, we in the immune system world can really lead on this. It’s striking how people don’t recognize how much can be done for people with immune issues,” said Milner. “As everyone knows, the diagnostic odysseys can be incredibly long. Wouldn’t it be great if you short-circuited that big time? It takes us really advocating for that and for the broad benefit beyond just SCID.”