Population-based, first-tier genomic newborn screening in the maternity ward

Abstract

The rapid development of therapies for severe and rare genetic conditions underlines the need to incorporate first-tier genetic testing into newborn screening (NBS) programs. A workflow was developed to screen newborns for 165 treatable pediatric disorders by deep sequencing of regions of interest in 405 genes. The prospective observational BabyDetect pilot project was launched in September 2022 in a maternity ward of a public hospital in the Liege area, Belgium. In this ongoing observational study, 4,260 families have been informed of the project, and 3,847 consented to participate. To date, 71 disease cases have been identified, 30 of which were not detected by conventional NBS. Glucose-6-phosphate dehydrogenase deficiency was the most frequent disorder detected, with 44 positive individuals. Of the remaining 27 cases, 17 were recessive disorders. We also identified one false-positive case in a newborn in whom two variants in the AGXT gene were identified, which were subsequently shown to be located on the maternal allele. Nine heterozygous variants were identified in genes associated with dominant conditions. Results from the BabyDetect project demonstrate the importance of integrating biochemical and genomic methods in NBS programs. Challenges must be addressed in variant interpretation within a presymptomatic population and in result reporting and diagnostic confirmation.

Fig. 1. List of genes included in the BabyDetect target panel.

Boxed genes were added to version 2.0 of the panel, whereas genes in white font were removed from version 1.0. Genes marked with a superscript letter (^a) are associated with a disorder covered by our conventional NBS.

Fig. 2. Zygosity criteria, based on Mendelian inheritance, for pathogenic (class 5) or likely pathogenic (class 4) variant reporting.

Classes 1, 2 and 3 are benign, likely benign and VUS, respectively. Green indicates negative results. Red indicates samples reviewed manually for the accuracy of variant annotations.

Fig. 3. Variant filtering criteria.

P, pathogenic; LP, likely pathogenic.

Fig. 4. BabyDetect screening and diagnostic flowchart.

The Goldcard is a dedicated golden filter paper card from LaCAR MDx. The BabyDetect timeline represents the theoretical schedule for BabyDetect result availability.