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Page 6 of 14 Bros-Facer et al. Rare Dis Orphan Drugs J 2023;2:21 https://dx.doi.org/10.20517/rdodj.2023.26

geneticists.

Although not all initiatives have confirmed their plans, eight are presently intending to start providing
information about genetic testing to expectant parents during the third trimester of pregnancy; five
initiatives plan to start providing information earlier in the first or second trimester. Enrollment will start
during the second trimester of pregnancy for one initiative and during the third trimester to after birth for
the others, with the acquisition of informed consent from parents following a similar timeline. For one
initiative involving several sites, the timing of informed consent will vary, offering participating centers the
flexibility to adapt their timing [Figure 3].

Sample type
All initiatives will extract genomic DNA from dried blood spots. Two initiatives will test cord blood for the
NGS analysis, including one that will add a saliva swab to the sample types to be tested. Thirteen initiatives
plan to collect samples upon birth or within 3 days after birth. One initiative focusing solely on the technical
feasibility of using WGS for screening will be collecting samples from children of all ages from a disease-
affected cohort of patients with an already confirmed molecular diagnosis. These patients will be recruited
from the outpatient clinics of the participating University following diagnosis. Another initiative will make
efforts to collect samples in parallel with its national NBS program. For all the others, DBS samples will be
collected independently of the national NBS programs.

Study duration
Five initiatives have a study duration of up to 12 months and five will be carried out over 18 to 24 months.
Two initiatives will last for three years, and one will last for four. For several initiatives, study duration
includes preparation of the sequencing workflow and analytical pipeline as well as recruitment, sequencing,
and analysis. For other initiatives, the project is broken down into phases, with cohorts increasing in size.
One initiative did not provide information related to study duration.

Testing approaches, confirmatory testing, and test validation
The selected NGS approaches vary among the surveyed initiatives [Figure 4].

• Eleven initiatives have selected a single NGS approach for their studies:

1. Six initiatives are using or planning to use only WGS as a first-tier test for NBS, including one that will
also be testing parents using WES to facilitate filtering of variants in selected genes.

2. Three initiatives will be using classical NGS gene panels.

3. Two initiatives will be using WES.

• Two initiatives will use a mix of NGS approaches:

1. One initiative is planning to test and compare WES and WGS.

2. One initiative is comparing WES, WGS, and classical NGS gene panels.