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Page 2 of 14 Bros-Facer et al. Rare Dis Orphan Drugs J 2023;2:21 https://dx.doi.org/10.20517/rdodj.2023.26

Conclusion: Here, we provide an overview of NGS-based initiatives in Europe. Importantly, the initiatives described
herein will generate evidence to evaluate the utility and feasibility of NGS approaches to NBS, thereby shortening
the pathway to responsible implementation of NGS in NBS and informing future research efforts.

Keywords: Newborn screening, rare disease, genetic disease, genomic sequencing, genomic screening

INTRODUCTION
NBS is one of modern medicine’s most successful public health initiatives. The identification of life-
threatening or severely debilitating conditions in the newborn period can enable early treatment and
intervention plans.

Traditional NBS with tandem mass spectrometry (MS/MS) has enabled screening programs to effectively
test for dozens of conditions at low cost . However, current NBS with MS/MS is limited to blood- or
[1-3]
urine-based metabolic biomarkers. There are hundreds of early-onset genetic conditions that do not have
discriminating metabolic biomarkers with disease-specific interventions and, as a result, are not yet
systematically screened. Early treatments are available for many conditions (e.g., pyroxidine-dependent
[4]
epilepsy ), but efficacy is limited if initiation of treatment is delayed beyond the first few months of life,
creating a critical need to consider additional NBS approaches.

[5]
Technological advancements in high-throughput NGS have allowed NBS programs to consider expanding
screening to include disorders without readily accessible biochemical biomarkers. In a diagnostic setting,
strong evidence from studies of critically ill infants with signs and symptoms of a possible genetic disorder
has already demonstrated the post-natal utility of genomic sequencing (i.e., whole-genome sequencing) [6-12] .

Further, there are several studies underway that directly investigate the impact of agnostic genetic testing on
newborns. For example, BabySeq is a randomized controlled trial focused on determining the benefits and
risks of newborn genome sequencing. In the BabySeq study, newborn genomic sequencing revealed a risk of
childhood-onset disease in 9.4% of newborns and reported carrier status for recessive diseases in 88%,
noting that none of the disease risks were expected based on the infants’ or family histories nor were they
detectable by traditional NBS assays [8,13,14] . There is an increasing number of resources and databases with
well-curated genes-disease associations and relevant treatment strategies. For instance, in 2021, the Rx-
Genes database became publicly available, including 633 conditions for which treatment is now available .
[15]
A year later, the resource Genome-to-treatment (GTRx) was also made available after a list of 8,889
interventions and over 5,000 publications were reviewed, leading to the retention of 421 disorders for which
[16]
effective treatments are available .

Given the potential of incorporating NGS assays into current NBS programs, numerous large-scale
initiatives have been announced across the globe, including the Genomic Uniform-screening Against Rare
Diseases in All Newborns (GUARDIAN study ), BeginNGS and Early Check in the USA, BabyScreen
[19]
[18]
[17]
[20]
+ in Australia, and Screen4Care , Generation Study [21,22] , Baby Detect and PERIGENOMED in
[23]
Europe . To develop the safest and most efficacious NGS-based NBS, it is important to have knowledge of
[24]
each program’s goals, study design, deliverables, and expected impact on current NBS. Thus, the IRDiRC
sought to gain an understanding of current and planned NBS initiatives including large-scale and pilot
studies by conducting a survey. The specific objectives of this exercise were to gain a better understanding
of the variety of approaches being tested for the expansion of NBS and to raise awareness of the significant
momentum across Europe to evaluate novel technologies for the future benefit of public health programs
such as NBS.