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Page 10 of 15 Magnifico et al. Rare Dis Orphan Drugs J 2023;2:16 https://dx.doi.org/10.20517/rdodj.2023.17

included in the newborn genomic sequencing report with definitive or strong evidence to cause a highly
penetrant childhood-onset disorder; category B: genes included in the newborn genomic sequencing report
based on actionability during childhood; category C: genes that did not meet criteria to be returned in the
[6]
newborn genomic sequencing report .

A comparison between the NC NEXUS age-based framework and the BabySeq categorization approach
revealed differences in the methods used to define each category. The NC NEXUS age-based
semiquantitative metric includes several components to achieve actionability score criteria, whereas the
BabySeq criteria differ between each of the three categories. BabySeq category A is focused on clear evidence
of gene-disease relationship without actionability considerations. Category B includes potential
actionability. Category C includes low penetrance, insufficient evidence or late-onset conditions, and non-
invasive intervention in childhood. A solution proposed was to report actionable genomic information at
the corresponding age-appropriate stage (e.g., infancy, childhood, adult) to overcome any potential social,
[5]
ethical, or psychological issue related to non-actionability conditions .

Societal
Incorporating WGS/WES into population-wide NBS programs triggers significant ethical and policy
concerns, as it implies the generation of incidental health information of known and unknown clinical
[36]
significance for millions of infants annually . When implementing a new technology in a state-run
program, it is particularly important to reach clarity in the evaluation of benefits and limitations. This is
notably valid when the technology is GS, as test results present a heterogeneous, complex, and unsure
nature .
[33]

Conventional (biochemical-based) NBS is considered a standard of care and is often a mandatory, state-
supported activity, e.g., in Canada and the US, where parental consent is typically implied [40,41] . Introducing
NGS technologies could dramatically change the context, shifting the balance between clinical benefits and
risks and raising new questions that could threaten the universality and moral authority of NBS. GS
technology has raised fundamental challenges to the traditional ways genomic information is
communicated. If GS was to be incorporated into standard NBS practice, clinicians, public health officials,
and other stakeholders would need to agree on the type of information that they should seek and
[31]
communicate to parents .
Ulm et al. in 2015 surveyed members of the American College of Medical Genetics and Genomics (ACMG)
[32]
to gather genetic professionals’ opinions regarding the use of WGS in NBS . Starting from the premise that
86% of the respondents believe WGS should not be included in NBS yet, many critical challenges were
identified, such as the introduction of pre- and post-counseling, the interpretation of results, and follow-up
access. Informed consent should be required from parents to enable them to decide which information to
receive but with the confidence of knowing that laws and policies are being implemented to protect against
[32]
discrimination and privacy . It is interesting to notice that at the time the participants filled out the survey
(November-December 2012), 28% believed WGS would have been implemented in 5 years (by 2017) and
23% in 6-10 years (by 2018-2022).

Informed consent and return of results
Given the nature of NBS, for which the primary beneficiary is the newborn, parents have a substantial role
in the process. Joseph et al. conducted four focus groups with socioeconomically and ethnically diverse
pregnant women to examine their views and perspectives regarding the potential application of WGS to
NBS. For many women, knowledge and information are fundamental tools to have a sense of control over