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Magnifico et al. Rare Dis Orphan Drugs J 2023;2:16  https://dx.doi.org/10.20517/rdodj.2023.17  Page 7 of 15

               (5) Guidelines for informed consent on genomic testing, sample uses (e.g., research studies) and storage
               need to be developed and widely shared within the appropriate workforce;

               The European initiative EuroGentest was established by the European Commission to promote accurate
               and high-quality genetic diagnostics across Europe, and it was integrated as a working group with the
               European Society of Human Genetics (ESHG), with whom in 2016 they published the guidelines for
               diagnostic applications of Next Generation Sequencing (NGS) for rare genetic diseases, consisting of 38
               statements with a particular focus on WES and sequencing on selected genes identifying  small germline
               variants (Single Nucleotide Variants (SNVs) and insertions/deletions). In 2021, an update of EuroGentest
               guidelines for NGS has been published, including five additional statements (a total of 44 statements) by the
               Solve-RD, a Horizon2020-funded project, born with the aim of finding a diagnosis for a large number of
                                          [22]
               rare diseases (www.solve-rd.eu) .
               GS-based NBS pilot projects
               The implementation of GS in newborns triggered great interest in the setting of explorative pilot projects to
               assess medical, economic, ethical, and social impact in the healthcare system and among the general
               population.


               The BabySeq project (ClinicalTrials.gov Identifier: NCT02422511) is a randomized trial on newborns with
               the aim to assess the impact of genomic sequencing in the newborn period to screen healthy infants for
               current and future health risks and provides data about the feasibility, risks, benefits, and costs of the
               integration of exome sequencing in the clinical care of newborns. The BabySeq2 Project (ClinicalTrials.gov
               Identifier: NCT05161169) is currently in the recruitment phase and aims to expand and improve the results
               obtained in the first study. Results reported for the BabySeq project were obtained by the clinical trial on
               159 children from the well-baby nursery at Brigham and Women’s Hospital (127 healthy newborns) and
               from the neonatal and pediatric intensive care units at Boston Children’s Hospital in Massachusetts General
                                      [28]
               Hospital (32 ill newborns) . 1,514 genes [Supplementary List 1] were curated and classified into three
               categories (A, B, or C). Category A includes genes with definitive or strong evidence to cause a highly
               penetrant childhood-onset disorder; Category B includes genes based on actionability during childhood;
               Category C includes genes that did not meet criteria to be returned in the newborn genome sequencing
                    [6]
               report . A table including an example of genes from category A from Ceyhan-Birsoy et al. (2017) has been
                       [28]
               appended  [Supplementary Table 1].
               After testing, a newborn genomic sequencing report is generated, including information on pathogenic and
               likely pathogenic variants, monogenic disease variants, recessive carrier variants for childhood-onset or
               actionable conditions, and pharmacogenomic variants. The analysis also contains information on variants
               of uncertain/unknown significance (VUS) indications. However, only a randomized group of families
               received newborn GS reports and the results obtained from the study were disclosed to the newborn’s
               parents during an in-person consultation by a genetic counselor and physician. The reports are available in
               both hospitals and online through a GeneInsight Clinic instance .
                                                                     [14]

               In the BabySeq project, WES analysis uncovered the risk of childhood-onset diseases in 15/159 (9,4%) of
               newborns, and none of these was expected based on the clinical histories of babies and their parents. Only
               parents of 85/159 newborns accepted to receive information on adult-onset actionable conditions, and in 3/
               85 cases a risk was identified. 88% of newborns were carriers of recessive disease and 5% were carriers of
               pharmacogenomics variants. Among the newborns with carrier-status variants, 8 of 140 (6%) also had VUS
               in one of the reported carrier genes. The number of carrier-status variants ranged from one to seven
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