A Paediatrician's Guide to Ordering Whole Exome Sequencing (WES) Under Medicare

Introduction to WES in Paediatric Care

Whole Exome Sequencing (WES) is a powerful diagnostic tool used to identify the genetic cause of an individual's health condition. While the human genome consists of both coding regions (exons, ~2%) and non-coding regions (introns, ~98%), genomic sequencing of the exome can detect up to 40% of causal gene variants responsible for single-gene disorders.

WES can be performed on an individual (singleton testing) or, ideally, in combination with both biological parents (trio testing) to yield the highest diagnostic accuracy.

Medicare Criteria (Items 73358-73363)

To be eligible for the Medicare rebate, the child must meet strict clinical criteria. Testing is indicated if the child is aged 10 years or younger, is strongly suspected of having a single-gene disorder, and presents with:

• Global developmental delay OR intellectual disability of at least moderate severity. AND/OR
• Dysmorphic facial features AND the presence of at least one major structural congenital anomaly.

Prerequisite Testing: Before ordering WES, the child must have had a non-informative chromosome microarray (CMA) test (Medicare item 73292). Additionally, negative Fragile X testing and urine metabolic screening are highly desirable prior to proceeding with WES.

The Ordering Pathway: Consultation and Consent

Ordering WES requires careful multidisciplinary coordination and thorough informed consent.

1. Clinical Genetics Consultation

A clinical geneticist must be consulted regarding the test indications before proceeding. Clinical genetics services in each Local Health District (LHD) facilitate this process differently. Genetic counsellor support may also be available depending on regional staffing resources.

2. Obtaining Informed Consent

NSW Health requires a standard consent form for both the parents and the child. For a trio exome test, three separate consent forms are required. When completing the form, clinicians must select 'Diagnostic Testing' in the 'Type of Genetic Test' section.

Consent discussions must cover the potential limitations and outcomes of testing, including:

• Identification of a cause: Finding a pathogenic/likely pathogenic variant.PDF
• Uninformative results: Failure to identify a genetic cause, noting that this does not completely exclude a genetic diagnosis.PDF
• Variants of Uncertain Significance (VUS): Unclear results that may require testing of other family members or future review.PDF
• Incidental Findings: The rare possibility (<1%) of discovering gene changes unrelated to the child's primary condition but with implications for future health.PDF

Clinicians must also discuss data storage, the potential impact on relatives, the implications for insurance, and the possibility of unexpected family relationships (such as non-paternity revealed during trio testing).

Sample Collection and Data Re-analysis

Ideally, 2-5 ml EDTA blood samples are required from both parents and the child. Stored DNA from previous diagnostic tests can also be utilized, and some laboratories will accept saliva samples.

Genetics is a rapidly evolving field. If the initial test is non-informative, reanalysis of the genomic data can be requested under Medicare twice for an individual up to 16 years old (provided it is at least 18 months after the initial test). This ensures patients benefit from new gene discoveries.