Genetic Sequencing Improves Disease Detection During Newborn Screening

Genetic sequencing in newborns shows promise as a 1^st-tier strategy to detect monogenic diseases, according to study findings published in JAMA Network.

Genomic sequencing-based tests historically have been relegated to use in 2^nd-tier screening. This has been attributed partly to lack of large studies to support use as primary screening tool, and also to concerns about its sensitivity and cost. Whole-exome sequencing in particular remains too expensive for universal screening practice.

For the study, researchers in China tested a combined 1^st-tier strategy using both genomic and biochemical screening. To do so, rather than sequence whole participant exomes, they incorporated a gene panel focused on disease-relevant regions of interest.

Across 8 medical centers throughout China, the team prospectively recruited and screened, in randomized fashion, a total cohort of 29,601 newborns, over nearly a year in 2021. Included infants had blood spot samples collected within 3–7 days of birth, and were without any history of receiving blood transfusion.

The blood samples were analyzed for both genetic and biochemical markers, each at separate laboratories. Of 128 monogenic conditions screened genetically, laboratory tests were also available for 43 of those conditions, including glucose-6-phosphate dehydrogenase (G6PD) deficiency and thyroid function diseases. In babies with a positive genetic test result, the researchers collected follow-up data until diagnoses were confirmed, or until the end of data collection in July, 2022.

Of 797 newborns with a positive screening result who were available for diagnostic follow-up, a diagnosis was confirmed in 402 infants (1.4% of the total). A total of 59 of these positive results were detected through genetic but not biochemical analysis, even though biochemical tests were carried out in 20 of those newborns. The remaining 395 infants with positive genetic screening results were clinically unaffected.

The finding that 59 infants, out of the full cohort of 29,601, had positive screens only through the genomic tests indicated that 1 in 500 newborns (95% CI, 1 in 385-1 in 625) would benefit from 1^st-tier application of genomic screening.

Compared with the genomic panels, biochemical screening for G6PD deficiency, had a higher positive predictive value (PPV; 80.71%; 95% CI, 76.52–84.30 vs 47.61%; 95% CI, 43.90–51.34).

However, the PPV of the genetic tests (70.83%; 95% CI, 50.83–85.08) for amino acid, organic acid, and fatty acid oxidation disorders was markedly higher than that of the biochemical tests (5.29%; 95% CI, 3.49-7.95).

Furthermore, the researchers noted that the genetic tests’ sensitivity of 73.91% and specificity of 99.98%, in detection of those diseases, were roughly comparable with those previously reported for whole-exome sequencing. Highlighting the favorable PPV for many diseases, they suggested that if joint genetic and biochemical tests were adopted broadly, “reducing the number of false positives would, in turn, relieve the stress and anxiety of parents and decrease the number of follow-ups.”

Overall, the researchers acknowledged that “genetic NBS as a first-tier screening test is a promising method to improve the current NBS program.”

The researchers noted study limitations include a lack of a cost-effectiveness analysis, and a study population that may not have fully reflected the diverse demographics of the general Chinese population.