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Page 8 of 15 Magnifico et al. Rare Dis Orphan Drugs J 2023;2:16 https://dx.doi.org/10.20517/rdodj.2023.17

[28]
variants in a single newborn .

Regarding the yield of the GS approach compared to standard NBS methods, the BabySeq project’s results
[29]
were discordant compared with conventional NBS and NBS plus WES : 84% of newborns were NBS and
WES negative; 1/159 infants were positive for the same disorder by both approaches; 9/159 infants were
NBS positive and WES negative. Among the latter, 7 were reported as false positives after subsequent
analysis. 15/159 infants were WES positive and NBS negative, indicating the risk of genetic conditions not
detectable through the conventional NBS approach . However, the BabySeq project results demonstrated
[29]
the efficacy of newborn GS in detecting risk and carrier status for a wide range of disorders that cannot be
detected by current NBS assays .
[28]

The North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) project
(ClinicalTrials.gov Identifier: NCT02826694) was concluded in 2020 and examined the use of WES for NBS
versus the conventional NBS approach. 106 infants were enrolled, including two cohorts: 61 healthy infants
whose parents were approached for participation in the study prenatally and 45 ill infants affected by inborn
errors of metabolism (17) and hearing loss (28), already detected by conventional NBS methods. Trio
analysis was not performed. However, a follow-up parental sequencing has been performed in cases for
which compound heterozygosity was suspected.

In the NC NEXUS project, WES correctly identified 88% of the cases with already diagnosed metabolic
disorders and only 18% with already diagnosed hearing loss. Moreover, actionable findings that would not
have been revealed by conventional NBS were revealed in four newborns. Some parents were selected to
receive additional information about childhood-onset conditions with low or no clinical actionability,
clinically actionable adult-onset conditions, and carrier status for autosomal-recessive conditions . Carrier
[27]
findings in newborns whose parents requested this information were detected with an average of 1.8 per
infant (with a maximum of 7 variants).

Clinical actionability was detected using the age-based semiquantitative metric .
[5]

(1) Conditions were categorized into four categories:

(2) Pediatric conditions with high medical actionability;

(3) pediatric conditions with low or no medical actionability;

(4) adult conditions with high medical actionability;

(5) adult conditions with low or no medical actionability.

According to these criteria, 755 gene-disease pairs were categorized (the list of 755 genes from Milko et al.
(2019) has been included [Supplementary List 2] . An abnormal or positive screen GS-NBS result related to
[5]
high medical actionability conditions was reported by observing likely pathogenic and/or pathogenic
variants in genes associated with pediatric conditions. A normal or negative GS-NBS result was defined by
the absence of likely pathogenic or pathogenic variants. Positive results were associated with the presence of
likely pathogenic or pathogenic variants found in gene(s) reported in the metabolic or hearing loss
diagnostic list. Inconclusive results included, for example, a single heterozygous variant found in a gene
associated with an autosomal-recessive condition and/or variants of uncertain significance (VUS) in genes