Where does DNA testing fit into newborn screening? In order to answer this question, it is important to examine some of the difficulties faced by current newborn screening programs.

Historically, newborn screening has been performed by biochemical analysis. Certain analytes (chemicals or substances) in the body are analyzed and measured to determine if the correct amount is present. If an abnormal amount is detected, a newborn screen is considered positive and follow-up testing is required to confirm the initial findings. Although this sounds simple, it is actually a very complicated process. Each newborn screening lab must determine its own cutoffs (what’s considered normal) for its specific population and must constantly assess whether these cutoffs are accurate. Each lab also runs multiple analyses or tests on each newborn screening sample. The first screen for phenylketonuria (PKU) was a bacterial inhibition assay to detect excess phenylalanine in diapers. Over time, new testing methodologies were developed and as more tests became available; more diseases and more analytes were added to newborn screening panels, thus increasing test complexity. Alongside these complexities, there are also biological and environmental factors that can complicate results and test interpretation. Newborn screening analyte cutoffs are usually set for healthy full-term babies and question remains about the effectiveness of these cutoffs for premature or very sick infants. Additionally, some infants receive treatments – TPN and steroid treatments – that may interfere with their newborn screening results. The delicate specimen collection methods may also lead to inaccurate results; a potential difficultly when gathering a specimen for a newborn.  All of this can lead to false-positive newborn screens and more importantly, false-negatives in which abnormalities are not recognized but can be life threatening. 1 All in all, current newborn screening practices in the U.S., while effective, are incredibly complex.

DNA sequencing of the specific genes associated with the conditions newborn screening tests for provides an advantage over the current system. DNA is a stable molecule that is independent of some of the biological concerns that analyte testing faces – the DNA of a premature infant is as testable as the DNA from a full-term infant. DNA does not fluctuate with sample collection methods, as might be seen in biochemical testing. DNA is also unaffected by  treatment status – neither TPN nor steroid treatment will cause changes in the individual’s DNA.  DNA sequencing is a testing methodology that allows for multiple different disorders to be tested at the same time, easing the difficulties and cost of performing sequential tests for multiple conditions.2 Additionally, new disorders can be added with relatively little expense. Interpretation of DNA variants can be cumbersome, but with the continued growth and development of national databases such as ClinVar and EXac, this will become easier over time.

So how does next generation sequencing of DNA fit with current newborn screening practices?  Can and should it replace newborn screening by traditional biochemical testing? Should it be used a confirmatory test, or a supplementary to state newborn screening? The answers depend on where you are standing.

In the United States, every state has its own newborn screening program. This is both a benefit and a challenge. The benefit is that state newborn screening programs provide more than just a newborn screening test. State programs provide newborn screening testing, education and coordinated care at the local level. The drawback is that each program has its own panel of disorders, its own cutoffs, and its own set of rules and regulations. While the trend over the past few years has been to move to screening for a more uniform set of disorders 3; there is still a long way to go. Infants in different states are still screened for different disorders. Some states differ by over 20 total screened conditions meaning that a child’s birth location will impact its accessibility to robust newborn screening.  Currently, DNA sequencing is used only as a second tier test for certain diseases (cystic fibrosis) or as a confirmatory test for a positive newborn screen, which is a costly and limited use of this technology.  The use of DNA gene sequencing in newborn screening is likely to grow as cost savings make the technology more available to newborn screening labs. However, it is unlikely that every state will develop its own DNA lab which may lead to further inequities. Next generation DNA sequencing has the potential to help in cases of borderline abnormal results, preterm or medically complicated newborns, and as a confirmation test to positive newborn screening results.

Newborn screening in the global environment is very diverse. Some countries have adequate newborn screening programs, some offer limited newborn screening panels, and others have no newborn screening at all. In countries that lack comprehensive newborn screening programs or offer limited newborn screening panels, using DNA sequencing of specific genes related to newborn screening as the first line newborn screen has distinct advantages. The testing is independent of cut-offs, is relatively inexpensive, works well in full-term and pre-term infants and the technique of DNA sequencing is independent of environmental and biological constraints. Turnaround time is short and the test results are reliable. Offering newborn screening via DNA sequencing of gene panels is the optimum choice for infants in these countries.


The continued integration and expansion of DNA testing in newborn screening programs will provide better, faster, more impactful newborn screening options worldwide.