
NEW YORK – A team from Belgium and the UK has shared findings from a prospective, population-based first-tier newborn sequencing (NBS) program known as BabyDetect, centered at a Belgian hospital's maternity ward.
"Results from the BabyDetect project demonstrate the importance of integrating biochemical and genomic methods in NBS programs," co-first and corresponding author Francois Boemer, a biochemical genetics researcher at the University of Liege, and his colleagues wrote in Nature Medicine on Tuesday.
For the ongoing observational study, the team performed targeted deep sequencing on 405 genes on dried blood samples collected from newborns at the public hospital of CHR Citadelle in Liege, focusing on 165 pediatric conditions with available treatment or preventive interventions.
The investigators informed 4,260 families about the project since it began in the fall of 2022, enrolling 3,847 of those families for the current study. Within those families, they found 71 newborns with pathogenic or likely pathogenic variants in the targeted gene set, including variants linked to conditions such as glucose-6-phosphate dehydrogenase (G6PD) deficiency, cystic fibrosis, or hemophilia A.
The team noted that at least 30 of the cases would have been missed with conventional NBS testing, including 10 cases of G6PD deficiency — the most commonly diagnosed condition in the BabyDetect cohort, with 44 positive individuals.
Another 17 newborns were diagnosed with recessive conditions, while nine newborns carried one copy of variants implicated in conditions with dominant inheritance patterns. The remaining case was deemed a false positive after testing on parental DNA demonstrated that risky variants in a gene called AGXT were inherited from an unaffected mother.
Even so, the authors noted that they did not routinely collect parental blood samples because of logistical hurdles such as the need for informed consent and sample storage and tracking and its potential to decrease consent rate; and because samples were useful only if blood could be collected from both patients.
"Addressing this limitation will require future genomic NBS programs to incorporate second-tier tests to ascertain the allelic status of variants (for example, using long-read sequencing technologies)," they suggested.
On the other hand, the investigators found that their variant assessment and interpretation efforts were helped along by data from conventional biochemical assays and confirmatory Sanger sequencing.
"Although genomic NBS has considerable potential, its practical implementation is undeniably complex," the authors wrote, noting that "[b]iochemical and genomic strategies are expected to complement each other in future NBS programs."
Moreover, the authors cautioned that "healthcare systems must prepare to handle the increased demand for genetic counseling and follow-up care that will result from the implementation of genomic NBS."
The Belgian effort is one of many newborn sequencing projects underway internationally, which range from panel sequencing on a select set of genes to whole-genome sequencing on seemingly healthy infants.