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Barwell et al. J Transl Genet Genom 2018;2:13. I https://doi.org/10.20517/jtgg.2018.17 Page 3 of 10

Figure 1. Predicted change in patient pathway. Clinical pathway model for diagnostic genetic testing and cascading of results to relatives
in 2018 and proposed changes in the genomics medicine era

Referrals of qualifying patients are sent by clinicians to one of thirteen genomic medicine centres across the
country where samples are collected. For all patients this involves a whole blood sample, but for cancer pa-
tients, an additional requirement is a fresh frozen sample from the tumour, to provide a contrasting genome
to the germline. Tissue samples must yield high quality DNA, as formalin-fixed paraffin-embedded samples
rarely provide high quality DNA for sequencing. These must be processed within 24 h to avoid denaturation
of the DNA.

After storage and checks at the UK Biocentre, samples are sent to a NHS genomic sequencing centre for se-
[3]
quencing and tier analysis using a crowd-sourced database called PanelApp . This database lists genes that
are potentially involved in each rare disease studied by the project. Experts worldwide can add to this list of
genes and review the degree of evidence supporting their involvement in these conditions. The evidence for
each gene is ranked with a traffic light system from green (meaning high diagnostic-grade level of evidence
that the gene is involved) to red (low evidence). This provides a global consensus, which helps to standardise
the genes tested for each disease. After an expert panel from GE has evaluated the gene panel, it can be used
to interpret genomes from the project. The number of genes added to these panels is expected to increase as
researchers learn from the data collected by the 100,000 Genomes Project. The analysis sorts results into five
categories: nonsense or frameshift in known genes, missense in known genes, frameshift in suspected genes,