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Page 8 of 14 Bros-Facer et al. Rare Dis Orphan Drugs J 2023;2:21 https://dx.doi.org/10.20517/rdodj.2023.26

Disease inclusion, gene lists, and variant types
Two initiatives focus on specific types of conditions: one on metabolic disorders and one on inborn errors
of immunity. The remaining twelve initiatives have developed inclusion criteria for disease selection. Ten
initiatives have ensured that clinical care pathways are available in their country for all diseases on the
screening list, while for the remaining four, care pathways are in place for some, but not for all, diseases to
be screened.

Inclusion criteria applied for disease selection
[25]
Three initiatives will apply the Wilson & Jungner inclusion criteria for NBS , including treatability, disease
onset, disease severity, penetrance, and clinical validity [Supplementary Table 1].

Most initiatives, however, will use a modified version of the criteria to enable a larger number of conditions
to be screened with NGS, hence the need to add “genetic feasibility” (i.e., conditions with a known genetic
biomarker that can be identified by NGS technologies) to the criteria for inclusion. Although all initiatives
will screen for conditions that manifest in early childhood, the specific age of onset might vary. One
initiative has yet to decide the inclusion criteria for their initiative. In addition, three initiatives have chosen
to use two distinct lists for disease inclusion, one for treatable diseases and one for actionable diseases.
Although there is not a universally accepted definition for each of these terms, according to the key
[26]
principles on NBS developed by EURORDIS , treatable conditions refer to conditions where early
identification helps to avoid irreversible health damage. Actionable conditions, which includes treatable
conditions, is a broader term encompassing (1) conditions where early interventions lead to health gain for
the newborn; (2) conditions where early diagnosis prevents the lengthy diagnostic odyssey, and (3)
conditions where parents will have reproductive options during subsequent pregnancies. Several
investigators support the concept of expanding inclusion to diseases affecting young children, but without
an agreed and common definition, the variability in disease selection is likely to be linked to the differences
in the interpretation of treatability and actionability. Furthermore, there are inherent difficulties in clearly
defining what would constitute proof that early intervention leads to improved outcomes.

Based on the agreed selection criteria, the numbers of diseases and genes to be screened vary widely among
the initiatives, ranging from 100 different diseases and genes for one initiative to 300-450 different diseases
and genes for others. One initiative is planning to screen for over 500 genes [Supplementary Figure 1].
There does not seem to be a relationship between the NGS approach and the number of genes to be
included in the screening, although certain NGS tests like WES and WGS will allow easier inclusion of
additional conditions and genes as it is possible to filter post-sequencing for conditions and genes of
interest [Supplementary Figure 1].
[27]
Ten of 14 respondents who have selected WGS and/or WES as the NGS approach(es) have indicated that it
will be possible to add or subtract conditions on the disease list during the duration of their initiatives. All
agree that disease selection should remain flexible in the future.

According to the classification and guidelines from the American College of Medical Genetics and
Genomics (ACMG) , all initiatives plan to screen selectively for pathogenic variants and, to a lesser extent,
[28]
likely pathogenic variants (12 respondents). Regarding the types of variants to be screened for, small
insertions and deletions (indels), single-nucleotide variants (SNVs), and copy-number variants (CNVs) are
at the top of the list, with structural variants (SVs) and short tandem repeats (STRs) included for some
[Supplementary Figure 2].