Table 1.
Types of genomic testing and possible outcomes of testing
| Term | Explanation | Additional considerations |
|---|---|---|
| Types of genomic tests | ||
| Whole genome Sequencing (WGS) | WGS utilises next‐generation sequencing (NGS) to sequence the entire genome including the exons, introns and intergenic regions, and even the mitochondrial genome | This has the highest yield, but also generates the most data for analysis. It also allows for accurate copy number (deletion/duplication) analysis. To maximise diagnostic yield and assist interpretation of VUS, a trio WES or WGS is highly recommended and should be considered first rather than singleton testing |
| Whole exome sequencing (WES) | WES utilises NGS to sequence all coding regions of genes. This does not include the intergenic regions or deep introns and may not include the mitochondrial genome |
See above considerations WES sequences only the exons, or protein coding regions of the genome, as well as the immediately adjacent intronic sequence in which variants affecting mRNA splicing may be identified. This includes approximately 50 million base pairs of DNA or ~2.8% of the genome |
| Gene panel | A particular predefined subset of genes is analysed, either in its own genomic test or as a part of WES or WGS | It may be appropriate to only examine the specific genes related to the clinical presentation. For example, in Noonan syndrome, there are approximately 20 causative genes reported to date. Therefore, examination only of those genes that are associated with Noonan syndrome is undertaken |
| Single gene sequencing | Conventional Sanger sequencing of a single gene | When the diagnosis is both clinically and genetically homogenous (e.g. Cystic Fibrosis and the CFTR gene), sequencing the single causative gene may be undertaken. Whilst WES/WGS and tests are covered by the new Medicare item number, to date most single gene tests are non‐rebatable and should be discussed with or referred to the local genetics services |
| Possible outcomes of genomic testing | ||
| Genetic cause identified | A likely pathogenic or known pathogenic variant in a disease gene associated with the subject's phenotype has been found | A genetic cause is identified in 29–57% of cases 7 , 8 and may provide additional information on the patient's condition, family recurrence, and, possibly, management and future prognosis. Additional information may be required to help inform the clinician and family, and local genetics services can assist with this |
| Variant of uncertain significance (VUS) | These are seen in up to 20–25% of cases 28 , 29 and may cause confusion and anxiety. A VUS result may be returned when there is insufficient evidence that an identified variant is the cause of the patient's condition | A VUS should not be used in clinical decision making, and may need further discussion with local genetics services, the laboratory, and even further research and time to clarify. Parental studies may be helpful to determine if a VUS is benign or pathogenic, and this is why doing a trio analysis upfront is so helpful. If the variant is inherited from an unaffected parent it may be considered less likely to be causative. Guidance on setting expectations including possibility of VUS results is provided on the CGE website 30 |
| Incidental finding (IF) | A finding that is unrelated to the initial indication of testing, but is of possible clinical importance. Examples include a cancer predisposition gene, or unrelated genetic condition such as Cystic Fibrosis carrier status. Mathematical modelling estimates their frequency to be 1.5–6.5%, 31 while studies suggest that they are seen in 1–2% of tests conducted internationally 32 , 33 |
The implications associated with finding Ifs may be concerning for the patient or to the parents themselves. However, it is vital to highlight that most diagnostic genomic analysis is patient‐specific and phenotype‐focused, and therefore this approach will largely mitigate the risk. The identification and reporting of Ifs is a controversial area and raises additional issues such as insurance and screening. The Australian approach to Ifs differs from that in the USA where the American College of Medical Genetics recommends screening a certain set of ‘medically actionable’ genes (termed secondary findings) and recommends reporting of all Ifs. 32 Such a practice facilitates surveillance or treatment in a person's lifetime. However, this approach is controversial and currently not standard practice within Australian genomics laboratories |
| Negative result | No causative variant is found. Possible explanations are:
|
Given gene discovery is dynamically occurring, with 300 novel genes identified per year, 34 re‐examination of genomic data in 1–2 years will have increased yield. It is also important to consider additional causes of genetic conditions that will not be diagnosed on standard genomic testing, such as mitochondrial variants, methylation/ epigenetic alterations, deep intronic variants, repeat expansion disorders, and cryptic copy number variants. These can be discussed with local genetics services |