Can DNA Sequencing Improve Newborn Screening?

Source: 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.Investigators from multiple institutions reported on interim findings of a prospective study to assess the feasibility of genome sequencing as an adjunct to traditional newborn screening (NBS) to identify treatable conditions. As part of an ongoing project, parents of newborns receiving care at 6 New York Presbyterian hospitals can provide consent for genomic sequencing in addition to routine NBS. For the genomic sequencing, 237 genes associated with 255 discrete conditions were identified for testing. Of the 255 conditions that were tested for by genomic sequencing, 156 were classified as treatable due to established interventions, and 99 were neurodevelopmental entities associated with seizures that may benefit from early treatment. Some of the conditions screened for with genomic sequencing also are included in routine NBS. The genome sequencing was done using the blood spot from the routine NBS to reduce the burden on study participants. For infants with a positive result on genome sequencing screening, clinical follow-up and testing were done to confirm the test results. The rate of true positives and false positive genomic sequencing screening were determined; the results of some positive screens could not be confirmed due to the age of the infant. Overall, it is planned to enroll 100,000 newborns in the study. The current study included data on participants enrolled in the first year of the project.Data were analyzed on 4,000 newborns who participated in the study. Sequencing was successful in 3,982 (99.6%). Of those with genomic sequencing results, there 147 (3.7%) infants with a positive screen, including 4 who screened positive for 2 conditions. The most frequently positive screen result was for G6PD deficiency, occurring in 92 infants. Overall, the true positive rate was 82.8% (120/145), and the false positive rate was 17.2% (25/145); positive screening results could not be confirmed in 6 newborns. A total of 8 infants were screen positive on both genomic sequencing and traditional NBS (5 with sickle cell disease, 1 with congenital hypothyroidism, and 2 with short-chain acyl-CoA dehydrogenase deficiency). One infant with confirmed severe combined immune deficiency had a positive genomic sequencing screen but was missed by traditional NBS. There were no infants with a positive NBS with a corresponding negative genomic sequencing screen for the same disorder.The authors conclude that the interim results of the study suggest that genomic sequencing screening for a predetermined set of conditions is a feasible adjunct to routine NBS.Dr Beam has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.NBS has been transformative in the field of pediatric medicine, with the detection of serious treatable disorders early in life ultimately changing the quality of life of many infants, children, and families.1 With the expansion of genetic screening in recent decades, researchers have investigated whether NBS can be improved with the addition of genetic sequencing. The GUARDIAN study presented here found that this is a feasible addition to NBS. This is supported by the high number and diversity of individuals that consented to be part of the study.Major questions around this technology include whether genomic sequencing detects disorders not found by traditional biochemical screening or more quickly confirms disorders found by biochemical testing. Several researchers have examined this and found that genomic sequencing has a high specificity (99.7%) and sensitivity (88.8%) for disease detection and confirms up to 88% of metabolic diagnoses in children, demonstrating excellent detection.2,3 In addition, recent study results showed that when used as a first-tier screening test, 59 patients were picked up that traditional biochemical tests did not.4However, practical challenges remain with implementing a widespread genomic screening plan for NBS. These include the long turnaround time of the testing, the need for specialized interpretation, and the associated cost of genetic screening.5-6As costs continue to decline, it remains important to consider how evaluating an entire genome can help with the diagnosis of treatable conditions. As we see the results from the entire 100,000 patients enrolled in the current study, we will begin to understand more of the challenges and how we may be able to overcome them.Genomic screening is a feasible approach to NBS, but challenges remain, including turnaround time, need for specialized analysis, and ensuring adequate understanding of a wide array of racial and ethnic backgrounds.