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long-read technologies will be able to do so. Importantly, WES and WGS can miss important genetic
[56]
information, such as pathogenic tandem repeat expansions . gNBS may also have the challenge of
revealing variants of unknown significance (VUS) or unsolicited findings (UFs), although these can be
avoided through a well-defined gene list and careful variant curation, as has occurred in other settings
where genomics has been modelled in a screening setting, such as the Mackenzie’s Mission project for
[57]
reproductive genetic carrier screening (RGCS) .
BUILDING READINESS IN AUSTRALIA FOR THE NEXT GENERATION OF NEWBORN
BLOODSPOT SCREENING MODALITIES
There is a strong consensus that while gNBS is not currently ready for integration into the Australian
healthcare system, it should and could be implemented within the next decade [25,58,59] . Evidently, despite
promising benefits, multiple issues need to be addressed before widescale gNBS can be integrated into
health systems, emphasising the need for more research to fill these knowledge gaps. This includes an
evaluation of its clinical utility and areas where unintended negative consequences may arise for affected
individuals and families, in addition to exploring appropriate consent procedures for an expanded screening
test, and possible storage and reinterrogation of resulting data. A key aspect of the consideration of gNBS is
that it will occur within, or closely alongside, an existing and highly trusted population screening program.
To this end, public acceptance and engagement with gNBS are important considerations within health
system readiness. Structural and other barriers will need to be identified and addressed as research
progresses [60-65] .

gNBS implementation may be guided by a federated approach to the co-development of sequencing
techniques that balance high sensitivity and specificity of conditions, genes, and variants against low false
positive rates . The development of nationally consistent approaches to consent, timing, variant curation,
[66]
security of data storage and privacy is expected to facilitate effective clinical translation. Planning may
safeguard against harm from screening, such as placing families into situations of ongoing uncertainty or
false positive findings.

Clinical impact, consent and condition selection
The potential clinical benefits of gNBS are recognised internationally, with evidence emerging regarding its
ability to facilitate earlier diagnosis of conditions that have no biochemical profile (and thus cannot be
detected by tMS) . Part of the evidence base for gNBS comes from existing initiatives that are evaluating
[52]
the use of genomic sequencing in unwell newborns and in newborns with delayed onset or milder
phenotypes . Balanced against this, gNBS methodology may not be superior in terms of sensitivity or
[67]
specificity for conditions already identified by tMS and included in NBS programs. Additionally, without
careful variant curation (inclusive of variant analysis within Indigenous populations and ethnic subgroups [68]
), it will also yield a greater number of VUS and UFs. This suggests that a complementary approach to the
incorporation of genomics in NBS may be warranted instead of an “either/or” approach [69-71] . Increasing the
complexity of evaluating clinical utility, the paucity of Australia-specific prevalence data for many rare
conditions makes it difficult to ascertain how many children could benefit from a diagnosis through current
or advancing screening techniques .
[72]

These issues surrounding the model of screening with emerging new technologies will also necessitate
appropriate consent procedures, including a move toward an “opt-in” model of gNBS (in addition to
current routine panels based on tMS). Here, it is notable that parents do not always uptake offers of
extensive genetic information. One study of parents of children with congenital hearing loss receiving
clinical exome sequencing revealed one-third of parents elected not to receive additional genetic