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example, while preparing this manuscript, a rapid evidence review on the implementation of large-scale
[44]
genomic screening was published by Alarcón Garavito et al. .
Moreover, the decision to focus exclusively on NBS programs using WES or WGS forces to neglect some
works on disease-specific genetic screening that could provide some additional evidence, especially on
topics such as acceptability by the parents and management of incidental findings and VUS.

Finally, for this work, only peer-reviewed articles were taken into consideration. This could have limited the
identification of relevant information, especially on governance and legal aspects that could have been
included in grey literature, such as project public deliverables, reports, and policy guidelines.

CONCLUSIONS
Although there is a broad and animated debate on the use of GS for NBS, there is still little real-world
evidence available from a few pilot projects (namely BabySeq and NC-Nexus, both carried out in the USA).
Other pilot projects have been recently launched in Europe and the UK and more evidence will become
available in the coming years. Despite a consensus in the literature on the key principles that should guide
the use of GS in NBS, many important issues are still to be adequately addressed and solved.

All authors agree that NBS should include only actionable genes, but the definition of actionable is still a
matter of debate, as well as the criteria and ideal frequency of updates of the list of genes-diseases to be
screened for. Currently, informed consent from the parents seems to be the preferred approach, but there is
still an open discussion on how to manage incidental findings or information on the status of the carrier.

Ethical, legal, social, and budgetary issues still constitute great challenges and major barriers to the wide,
equitable, and uniform adoption of GS in NBS. When looking at these aspects, it is important to also
consider the other side of the coin, i.e., the burden that inherently accompanies a family who did not get the
chance of an early diagnosis or the management of critically ill patients in NICUs. Early diagnosis could also
generate cost savings for the healthcare systems as it allows them to prevent severe symptoms that may
require frequent hospitalizations. These savings could at least partially balance the additional costs
generated by GS-NBS, which, according to the majority of authors, should not substitute the current NBS
programs but run in parallel as additional screening. Unfortunately, it was not possible to find any
published studies with information on cost-effectiveness and the estimation of potential savings of
healthcare resources by using GS in NBS.

The management of genomic data of newborns for secondary use (e.g., for research purposes) should be
balanced with the right of children to an “open future” and to autonomously make decisions on the use of
their own genomic profile. As shown by this literature review, no easy or straightforward solutions have
emerged so far. Moreover, a one-size-fits-all approach will probably never work, as GS-based NBS should
take into consideration the specific value and ethical frame of the community where it is deployed. Ten
years ago, 50% of the surveyed experts of the ACMG expected GS to be implemented in the NBS everyday
practice. Evidently, we are not there yet. Further pilots and consultations with the stakeholders will be
necessary before GS-based NBS programs can be widely implemented.

DECLARATIONS
Acknowledgments
The authors would like to thank Virginie Bros-Facer, David Pearce, and Daniel Scherman for their precious
support. Special thanks also to Maria Iascone for the valuable suggestions.