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Page 4 of 15 Pintos-Morell et al. Rare Dis Orphan Drugs J 2024;3:12 https://dx.doi.org/10.20517/rdodj.2023.52

even in a well-defined context of conditions selected for the screening, there is the possibility of identifying
incidental findings, late-onset conditions, and non-treatable diseases, thereby affecting individuals’
autonomy in deciding whether to be informed or in self-determining their future life. In addition, the
ownership, custody, and protection of genetic data are still a matter of controversy. Altogether, it raises
ethical questions that are difficult to address . All these and other open questions must be carefully
[8]
pondered before national genomic screening programs are implemented. The most prudent approach to
implement, particularly when considering cost containment while evaluating analytical and clinical validity,
is using targeted gene panels that screen for treatable conditions [36,37] .

This report presents an analysis of the present situation of NBS for IMDs in parts of Europe, including a
potential set of treatable IMDs not screened today for the reasons described before. Moreover, this report
describes the various NGS approaches, such as targeted gene panels, whole-exome sequencing (WES), and
whole-genome sequencing (WGS) with virtual panels, the challenges of including such methods in NBS,
and the possible solutions. For practical reasons, we consider WES and WGS, such as “genome sequencing
with short reads” (GS), because the concerns regarding these two comprehensive techniques are, to a large
degree, similar.

The current situation with conventional biomarker-based NBS (BIO-NBS)
NBS is a public health program that includes a multidisciplinary organization responsible for overseeing the
entire screening process, from taking the sample to diagnostic confirmation and referral to appropriate
clinical care pathways, improving the quality of the total process based on short and long-term data.
Together, this requires a tuned coordination of a flexible and sustainable entire NBS system.

Table 1 lists the conditions included in the conventional NBS programs of three European countries, Spain,
Netherlands, and Italy, based on the authors’ expertise. As anticipated, the emerging panorama is
exceptionally heterogeneous for the list of diseases tested and for technical aspects, such as timing of blood
sampling, quantity of blood, and cut-offs used. For example, the age at which the sample is taken may
influence the cut-off levels used to classify a sample as abnormal .
[18]
The purpose of Table 1 is to provide an inventory of IMDs that have at least one informative biomarker to
be screened in a population program. Most of these diseases are concurrently screened using tandem MS,
referred to as expanded newborn screening. The informative biomarkers commonly used for each disease,
along with the second-tier tests that are useful to improve the specificity of the initial screening and the
appropriate confirmation methods, are extensively described in the literature and clinical guidelines .
[26]
In Spain, the official recommendation is to obtain the DBS sample at 24-72 h of life and transport the
sample to the NBS laboratory at 3-4 days; the lab result should be ready in < 4 days, so the result of a first
sample should be optimally ready in < 10 days after the obtention of the DBS sample, and < 20 days in case
of inconclusive results and a second sample is needed for verification .
[20]
In Netherlands, the time of blood sampling varies from 72 to 168 h after birth, usually after 96 h in
combination with the hearing test. Samples are afterward dispatched via regular post to 5 NBS laboratories.
For most IMDs, except MMA, PA, MPS1, and ALD, the sample from the child should arrive at the
metabolic clinic by day 10 at most.

In Italy, DBS samples are collected at 48-72 h of life and sent to the regional NBS laboratory for the first-tier
test via a dedicated transport service that ensures delivery of the samples within 24/48 h of collection and,