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Ji et al. Rare Dis Orphan Drugs J 2023;2:26 https://dx.doi.org/10.20517/rdodj.2023.30 Page 9 of 19

Figure 2. Integrated newborn bloodspot screening processes in Australia [7,44] . *In addition to dried blood spots (DBSs) collected from its
own state, the Queensland (QLD) laboratory also receives cards from Katherine, Northern Territory (NT), and towns in NT north of
Katherine. Similarly, the South Australian (SA) laboratory receives DBS cards from SA as well as Tasmania and towns south of Katherine
[1]
in NT. **As per the Human Genetics Society of Australasia (HGSA)’s definitions and categorisation of conditions . NBS: newborn
bloodspot screening; DBS: dried bloodspot; SCID: severe combined immunodeficiency; SMA: spinal muscular atrophy: CF: cystic fibrosis:
MCADD: medium-chain acyl-CoA dehydrogenase deficiency. This figure was created using https://www.biorender.com/.

In 2021, there was a targeted call for applications within a specified stream of the Genomics Health Futures
Mission of the Medical Research Futures Fund looking ahead to the possible incorporation of gNBS. This
called for projects to develop new models of NBS that incorporated genomics, either as a first-line test or a
complement to existing biochemical screening . Five projects, which engage through the Genomic
[50]
Screening Consortium for Australian Newborns (GenSCAN) , have been funded under this call and are
[51]
now underway. These are exploring the feasibility, scalability, and cost-effectiveness of gNBS, as well as its
ethical, legal, and social aspects- including acceptability for Australia’s Indigenous populations and those
from culturally, ethnically, and linguistically diverse groups. Scientific aspects being studied include the
validity and utility of newborn genome sequencing, the use of epigenomics to identify newborns at risk of
imprinting disorders, and metabolomic profiling on DBS to stratify newborns at risk of metabolic
conditions into further screening opportunities. The projects are also considering which conditions to
screen for, including how this can reflect condition prevalence in diverse populations and draw on
appropriate genomic datasets for variant calling and interpretation.

The impetus for these projects has come in part from the significant increase in the use of genomic
sequencing, including WES and WGS, in clinical practice and translational research. This, in turn, has been
driven by a decline in sequencing costs and improved time to results [52,53] . Such testing has become the
diagnostic standard of care for children with a suspected monogenic condition, demonstrating diagnostic
[54]
yields of up to 50% in some Mendelian cohorts . In Australia, WES is approved and reimbursed for
diagnostic investigation of children with moderate to severe intellectual disability, and there is evidence of
[55]
effectiveness in the acute care setting . While WES identifies variants in the protein-coding areas and
intronic regulatory sequences of the nuclear genome, WGS has the added benefit of detecting structural
rearrangements, copy number variants, non-coding regions, and mitochondrial DNA. Currently used
short-read technologies cannot detect disorders of methylation (which cause imprinting syndromes), but