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Page 12 of 15 Pintos-Morell et al. Rare Dis Orphan Drugs J 2024;3:12 https://dx.doi.org/10.20517/rdodj.2023.52

proven efficacy may still bring eventual benefits for patients and their families, for example, decreasing the
time to diagnosis and avoiding disease complications. On the other hand, identifying newborns and infants
bearing a late-onset condition and predicting a probable later disease manifestation may cause parental
anxiety and stigmatize the affected child, but in spite of that, genetic information may help make decisions
for the future. The balance between possible future benefits and the psychological hurdle is difficult to
[48]
achieve .
Another aspect to consider is that currently, the interpretation of genetic variants is supported by the deep
phenotyping of patients, which is necessary before performing the test, and through reverse phenotyping
after the completion of the genomic test, which helps to evaluate the clinical significance of the variants.
This essential exchange process between clinic and laboratory, along with the simultaneous analysis of
[49]
parents (trio), helps to reduce the uncertainties of genomic results (class 3 variant or VUS) . The lack of
phenotype in asymptomatic newborns (screening context) makes this exchange process between laboratory
and clinic impossible, allowing for reporting only variants with a high probability of pathogenicity (class 4
and 5), increasing the possibility of false negatives in genomic screening. The database will need to be filled
with class 4 and 5 variants, but class 3 (VUS) can also be used if they are being controlled with biomarkers
(if possible), to help to know whether it can be judged as a class 4 or 5 variant in the future.

This would possibly create confusion even among expert operators in the field, but we want to emphasize
the critical importance of careful variant curation, ensuring that only combinations of biallelic variants that
are known to be associated with early-onset disease are reported, and that communicating uncertainties or
making predictions of a remote future is not necessarily beneficial.

The use of genomic techniques in this target population brings up unprecedented ethical, psychological, and
social issues in the field of screening. All these and other open questions must be carefully considered before
national genomic screening programs are implemented [30,39,50] .

CONCLUSIONS
Recommendations include assessing the accuracy and predictive capacity of gNBS, by cautiously
implementing gNBS with a focus on treatable disorders, utilizing second-tier analyses or biomarkers to
refine diagnosis and treatment decisions, and establishing protocols for the close monitoring of conditions
with uncertain prognostic implications.

A prudent approach would be to start gNBS by including only a combination of (likely) pathogenic DNA
variants associated with an established list of treatable disorders. With this approach, some patients will be
missed, but it will limit many false positives. Along the way, we will learn how to reclassify the variants from
the missed patients who will manifest these disorders.

The evaluation of early-initiated therapies is imperative for determining treatment efficacy, aligning with
the criterion of treatability in NBS inclusion criteria. Indeed, one of the classical criteria for including a
condition in the NBS is its present treatability, if possible, with strong evidence, to significantly improve the
natural history of the disease for most of the patients bearing such genetic variants.

For those conditions with an expected late-onset manifestation or genetic variants without a precise
prediction of the disease evolution, we need to carefully discuss whether these should be included and, if
included, protocols for a close follow-up of these newborns must be established with the objective of not
missing the possibility of initiating a specific treatment before the appearance of irreversible organ/system
damage.