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

in the USA) have been published recently; however, this evidence is not yet sufficient to put an end to the broad
and animated debate on the use of GS for NBS. Ethical, legal, and social issues still constitute great challenges and
major barriers to wide and uniform adoption of GS in NBS. On the clinical side, a number of issues remain
unaddressed, such as the benefits and limitations of the different approaches (targeted sequencing, GS only versus
GS+standard NBS), the genes/diseases to include and the frequency of incidental findings, identification of carrier
status, and variants of uncertain significance (VUS). Further pilots and consultations with involved stakeholders
will be necessary before GS-based NBS can be accepted and systematically implemented in national healthcare
programs.

Keywords: Newborn screening, genome sequencing, whole exome sequencing, whole genome sequencing

INTRODUCTION
Newborn screening (NBS) programs have been running successfully for more than 50 years since its
introduction in the 1960s. In many countries, the first disorder included in screening programs was
Phenylketonuria (PKU). With the advent of Tandem Mass Spectrometry (MS/MS), the number of
[1]
conditions screened increased to around 50, although with great disparities among countries . The
introduction of MS/MS was therefore a key driver for the expansion of the number of conditions screened,
with an increase in the order of 10 folds. Now, with the costs of genomic sequencing falling quickly and an
ever-increasing capacity of laboratories as more and more are getting equipped with new generation
sequencing instruments, a further scale-up of NBS programs is technically possible, also in the order of 10
[2-6]
folds (from 50 to 500 conditions) . However, it is important to consider that one disease can be linked to
one or more genes, and for each gene, there could be several variants, pathogenic or not. A major limitation
of the GS approach is that several variants cannot be classified either as non-pathogenic or pathogenic and
are actually classified as variants of uncertain/unknown significance (VUS). The specific criteria for
selecting the genes and the conditions to be screened are not yet unanimously accepted, even if there is a
general agreement that only pathogenic or likely-pathogenic variants should be reported and the principles
set by Wilson and Jungner are still basically valid . Moreover, the adoption of Genomic Sequencing (GS),
[7]
meaning whole-exome sequencing (WES) or whole-genome sequencing (WGS), poses a number of clinical,
ethical, and legal questions [8-12] together with organizational and economic challenges [3,13-14] .

This systematic review is part of a feasibility study assessing the introduction of GS for NBS in Lombardy
region (Italy) and is co-funded by the regional government (Regione Lombardia) and Fondazione Telethon.
The study is conducted according to the Responsible Research and Innovation (RRI) principles [15-18] and is
inspired by the EUNetHTA Core Model® [19,20] . RRI principles include, among others, engagement of all
societal actors, gender balance both within the research teams and in the group of consulted stakeholders,
ethics, and governance, with the intent to enable a positive impact of the research on society.

Considering the nine domains of EUNetHTA Core Model®, the purpose of this review is to inform the
activities of the feasibility study in the following domains while addressing relevant and associated issues:

(1) Health Problem and Current Use of the Technology with a special focus on pilot projects that tested GS
for NBS;

(2) Description and technical characteristics of the technology with a focus on the discussion within the
scientific community on the list of genes that should (or should not) be included in the analysis;