Overview

The Victorian Clinical Genetics Services (VCGS) offers whole exome sequencing through our Clinical
Exome service.

The Clinical Exome is a powerful tool used to help identify the cause of health and developmental problems. We offer a unique whole exome sequencing service, using the patient's clinical presentation as the tool to drive our analysis pathway.

Our detailed phenotype-based approach provides the most effective and reliable way to identify disease-causing variants

VCGS uses a multidisciplinary team to provide the most comprehensive investigation, interpretation and patient support to help find answers to complex genetic health conditions.

What is this test?

Whole exome sequencing is a tool used to examine specific parts of your genome (known as the exome). Your genome contains your complete set of genetic information (or genes). The genome can be thought of as an instruction manual for how your body functions and your physical characteristics (such as eye colour).

The exome is only a small portion of your genome (about 1%) but changes in your exome can affect your health.

Whole exome sequencing aims to identify changes which are known as 'variants' or 'mutations', that may be responsible for genetic conditions affecting health and development.

The number of variants in any one person's exome is very large (in the thousands). Most variants do not cause health problems, however some are known or highly suspected to affect health. The challenge for health professionals is to know which variants affect health and which do not. VCGS uses a multidisciplinary team of clinical geneticists, specialists, genetic counsellors and clinical scientists to determine the significance of these variants.

The benefits of whole exome sequencing
Whole exome sequencing uses a technology called next generation sequencing or NGS (it may also be called massively parallel sequencing or MPS). Unlike a traditional genetic test that often looks at one specific gene, NGS can test many genes at one time. This is useful when a patient may have a variant or mutation in more than one gene or has a complex clinical presentation.

The Clinical Exome can be performed on either the affected individual only (singleton) or on the affected individual and both his/her parents (trio). Whether a singleton or trio analysis is requested will depend on the level of clinical suspicion and the likelihood of finding an answer using one of these two different approaches.

What conditions does this test look for?

The Clinical Exome analysis is used to investigate any complex health and developmental problem that is suspected to have a genetic cause. In many cases, the clinical exome is used to seek answers for individuals where other testing has failed to determine a cause of their health problems. The Clinical Exome is used by many specialist groups, like neurologists and geneticists, to investigate specific causes of well-known but poorly understood conditions (like brain malformations or rare and complex genetic disorders).

Genetic variants fall into three categories:

  • Pathogenic variants – these are known to cause specific genetic conditions.
  • Benign variants – are unlikely to cause genetic conditions.
  • Variants of unknown significance – there is no clear evidence about whether these are pathogenic or benign. These class of variants often require family studies to help determine their clinical significance.

Refer to the "What do my results mean?" FAQ below or the health professional brochure for a more detailed description of variant classification.

How do I arrange a test?

Clinical Exome testing is coordinated through our clinical genetics service and a request for testing is only accepted from specialist doctors after discussion with our Clinical Exome team. Clinical geneticists can order testing directly by contacting the laboratory: exome@vcgs.org.au

A signed test request form and signed patient consent form is required for testing to proceed.

How does it work?

The Clinical Exome uses a whole exome capture followed by phenotype driven curation to look for any variant/s or mutation/s within genes that are most likely to be associated with a persons health problems. Our multidisciplinary team, which is comprised of clinical geneticists, genetic counsellors, bioinformaticians, scientists who specialise in genomics, and medical specialists, then access all the latest information from the scientific literature and clinical databases to determine which variants might be the cause of an individual’s condition. If no causative or likely causative variant is found within the genes associated with the phenotype provided, there are options of expanding the investigation. This may involve looking at the Mendeliome, which describes the around 4,000 genes that are known to cause a Mendelian disorder/s. Providing a detailed description of the patient's phenotype is an integral component of exome analysis and VCGS has shown that this targeted approach results in consistently high detection rates.

To make requesting a Clinical Exome simpler, VCGS has developed genes lists that include genes known to be associated with particular conditions. More than one gene list may be applied in the case of multiple phenotypes. These pre-curated evidence-based gene lists can also be tailored to the needs of the individual by the addition of extra genes. For clinicians who wish to generate their own gene list, we can provide guidelines to assist in this process. Our pre-curated gene lists are regularly reviewed and updated accordingly. Please contact the Clinical Exome Genetic Counsellor on +61 3 8341 6201 or exome@vcgs.org.au for more information regarding gene lists.

Frequently asked questions

Exactly how does exome sequencing work?

To understand sequencing, it’s helpful to understand some basic biology.

The cell is the basic building block of all living things. Humans have billions of cells that contain the genetic information for how the body develops, grows and functions.

This genetic information is stored in DNA. The DNA is ‘housed’ in structures called the chromosomes. DNA is made of four chemicals or bases, represented by the letters A, T, C and G (adenine, thymine, cytosine and guanine). These bases form a unique sequence and changes (or variants) to this sequence can cause disease. A person's entire genetic sequence is known as their genome.

Certain parts of the genome are called genes. Humans have around 23,000 genes and they all play a different role in the body (such as determining eye colour or how we break down certain drugs). It can be useful to think of the genome as a book, where each of the chapters represents a chromosome. Sentences in these chapters would be the genes and the letters that make up each word can be considered the DNA bases. In the case of humans, the book has over 3.2 billion letters.

Exome sequencing is a process that ‘reads’ the particular part of genes that are thought to be most important for health. These parts are called exons. These ‘reads’ contain large amounts of genetic sequence information, which would require hundreds of hours for a scientist to analyse manually. Computers are used to quickly identify variants in the genetic information.

This list of variants is then ‘interpreted’ by comparing the results with databases that list variants known or suspected of being associated with genetic conditions. Interpretation is the most complicated and time-consuming component of exome sequencing because it involves input from many health professionals from different specialties to determine the significance of each variant detected.

How much does a clinical exome cost?

Please contact the laboratory for current pricing. Please note, in Australia there is no Medicare rebate or private health coverage for a Clinical Exome but funding may be available through your local genetics service.

What do my results mean?

Once your sample has been tested, a team of experts review any DNA changes or variants found. The team will determine the significance of any variants, using all the available published scientific literature.

Variants fall into a number of categories:

Class 5: Pathogenic Variant:

Pathogenic variants are considered disease-causing

  • At-risk unaffected relatives can be offered predictive gene testing.
  • Other affected relatives can be offered confirmatory testing.
  • Prenatal diagnosis for the pathogenic variant is possible.

Class 4: Likely pathogenic variant:

The level of evidence that likely pathogenic variants are disease-causing is very high.

  • At-risk unaffected relatives can be offered gene testing in conjunction with clinical screening.
  • Other affected relatives can be offered confirmatory testing.
  • The variant may be considered for use in prenatal diagnosis after detailed discussion with a clinical geneticist or genetic counsellor.

Class 3A: Variant(s) of unknown significance with high clinical significance:

VUS with high clinical significance are variants that have evidence to suggest they are pathogenic but there is not enough information to classify them as class 4.

  • Class 3A variants cannot be used for predictive testing or prenatal diagnosis.
  • Co-segregation studies in affected relatives, or testing to determine if the variant is de-novo is strongly recommended as these studies may provide additional evidence to clarify the pathogenicity of class 3A variants.
  • These variants may be re-classified based on new information; for example, family and/or functional studies (if performed).

Class 3B: Variant(s) of unknown significance:

Class 3B VUS are variants for which there is insufficient evidence to classify the variant as either disease causing or likely benign.

  • Class 3B variants cannot be used for predictive testing or prenatal diagnosis.
  • In selected families, co-segregation studies in affected relatives may help to clarify pathogenicity of a class 3 VUS.

Class 3C: Variant(s) of unknown significance with low clinical significance:

Class 3C VUS are variant(s) for which the evidence suggests they are likely to be benign.

  • Class 3C variants cannot be used for predictive testing or prenatal diagnosis.
No variant of significance was found.
  • Reanalysis options may be considered if the family history strongly indicates a genetic cause.

In some cases, patients might receive an ‘incidental finding’. An incidental or secondary finding is one that is not related to your condition and may have been found by chance. To minimise incidental findings, the laboratory specifically excludes sequencing certain genes known to cause adult-onset cancer, cardiac and neurological conditions. Your doctor will discuss any incidental findings with you and refer if necessary.

What happens to my genetic information?

Clinical Exome sequencing generates a large amount of genetic information. Access to and storage of genetic information is strictly governed by national laboratory and health privacy guidelines. You will be required to sign a consent form for exome sequencing which will describe how your information can be used.