SCID newborn screening brings molecular shift to North Carolina

On the wall, just outside the newborn screening lab at the North Carolina State Laboratory of Public Health is a colorful poster with airplanes, teddy bears, and a clothesline. On the clothesline hangs pajamas, overalls, t-shirts, pants, and jumpers, each representing a specific condition identified through newborn screening.

Among the babies saved are those with severe combined immunodeficiency (SCID), a life-threatening primary immunodeficiency. If identified within the first few months of life, though, it can be successfully treated. 

In 2010, the United States Department of Health and Humans Services added SCID to the Recommended Uniform Screening Panel (RUSP) and the North Carolina Newborn Screening Advisory Committee voted to add SCID to the North Carolina Newborn Screening Panel. However, it wasn’t until 2015 that the North Carolina legislature signed a law requiring SCID to be added to the newborn screening panel, and not until April 2017 that North Carolina officially launched newborn screening for SCID.

In a recent SCID Compass Lunch & Learn presentation, “A Look at 4 Years of Universal Screening for SCID in North Carolina,” Scott Shone, PhD, HCLD (ABB), laboratory director at the North Carolina State Laboratory of Public Health, outlined the challenges but also the opportunities that developed while trying to incorporate SCID into the North Carolina Newborn Screening Panel.

Prior to SCID, newborn screening tests typically measured proteins or small molecules, like the sugar galactose — substances that either accumulate or are missing if the baby has a genetic condition. In contrast, molecular diagnostics, like the TREC PCR test for SCID, test DNA itself. 

“There had been small advances in molecular newborn screening, but this was really the first primary, first-tier test that was going to use genetic markers to identify babies at risk,” said Shone. 

Initially, obtaining funding for the program proved challenging. Several requests in the legislature to increase the testing fees failed.

“That is a story well told in many places across the country in the early 2010s where increasing fees was frowned upon, but everyone wanted to expand panels,” said Shone.

Initial funding to implement SCID newborn screening came from external sources, including the Association of Public Health Laboratories (APHL) and the Center for Disease Control (CDC), which provided a grant to RTI International to collaborate with the North Carolina lab, in 2015.

“North Carolina started the race to implementation before, but the pilot began in April 2017. The pilot was designed to help refine the method, define a follow-up algorithm in this state, and assure this system was in place for families who will be at increased risk of immune deficiency,” said Shone.

As North Carolina instituted screening for SCID, the lab decided to alter its testing method from a single TREC PCR reaction to a new test, called multiplex PCR. The multiplex test allows specialists to test for SCID and spinal muscular atrophy (SMA) in a single molecular diagnostic test – but requires specialized equipment and highly trained staff.

The North Carolina lab also had to shift how it processed the dried blood spots collected from newborn babies. Instead of testing the blood on the card directly, as had been done in the past, the lab needed to extract DNA from the blood spots. 

The shift in how the state tested babies led to an examination of how the lab interpreted the results. Premature infants sometimes show up with abnormal SCID tests because their immune systems aren’t fully developed, leading to false positives.The lab decided to move away from using birthweight as a factor in interpretation and instead use gestational age, allowing for more flexibility when it came to collecting data on premature infants. 

“We went to a scenario where even if a result was abnormal, we just requested a repeat until the baby got older and we called this an adjusted gestational age. So, if the baby came out at week 30, we would say in five weeks send us a new sample,” said Shone. “The caveat to that is that if we had no detectable TRECS at all, there was no evidence that this baby had an immune system, we would call that baby out right away.”

Making these changes in gestational age required a whole new data interpretation approach to newborn screening for SCID in North Carolina.

“Instead of doing just this transition to a new method, we completely just blew up our path and realized we were going to have to set all-new cut-offs and we were going to look at our algorithm in general because we learned, as so many states have learned, that these premature babies, and these micro-preemies and these tiny babies who are in the neonatal intensive care unit for extended periods of time cause such havoc on screening for SCID because their little bodies just don’t have a robust white blood cell count to give us that accurate data,” explained Shone.

Finally, a cadre of new staff, such as molecular biologists, needed to be hired to operate the new equipment and perform the tests, and a specialized immunology team had to be hired to interpret the data.

“It was a real paradigm change at the time in the field of newborn screening, including here in North Carolina,” said Shone.

Under the current North Carolina newborn screening process, babies who have an abnormal screen or who are borderline multiple times receive a referral to immunology within 48 hours for clinical evaluation and confirmatory testing.

Immunologists determine the diagnostic results and direct further management, whether it’s more therapeutics or referral for transplant or other diagnostic workups that must be done to move that baby forward in terms of a follow-up pathway, said Shone.

Although implementation was lengthy, North Carolina’s experience with SCID newborn screening has actually positioned the state well to include new recommended molecular tests and as a leader in newborn screening.

Learn more by watching “A Look at 4 Years of Universal Screening for SCID in North Carolina.”