Whole genome or whole exome sequencing tests are used to look for a genetic cause in newborns and children who have global developmental delay, intellectual disability or congenital anomalies –changes that are present from birth – when the cause is not apparent from the clinical findings or other testing. DNA sequencing is also used for the diagnosis of childhood cancer.

What is being tested?

Whole genome testing looks at DNA, reading the entire genetic code of a patient to try and determine if there are variants in genes which could be responsible for their clinical condition. Whole exome sequencing is sometimes performed instead which only looks at the code which contains the genes, and does not look at the so called, non-coding sequence.

How is it used?

Whole genome/exome testing allows us to look for changes in the genetic code which could explain the patient’s symptoms.  It does not require us to know in advance which genes to look for as all genes are sequenced (or read).

The results for each letter in the genome are compared to a reference sequence and any variations are identified. 

When is it requested?

When an infant is found to have moderate to severe developmental delay, intellectual disability, or dysmorphic facial appearance and one or more major structural congenital anomalies and the cause is not apparent from the clinical findings or microarray testing. 

What does the result mean?

We compare each letter in the genome with the reference sequence.  For all of us there are many thousands of differences between our sequence and the reference, these so called “variants” are for the most part of no consequence and are called benign. 

Sometimes a variant is found in a gene which is known to produce a damaging effect and these are called pathogenic variants.  Finding such a variant will usually be sufficient for the patient to be given a diagnosis and for information on the likely recurrence in other children to be given to the family.

Sometimes a variant is found which looks as though it is damaging but is not known to cause the clinical features in the patient.  These are reported as probably pathogenic since we know that other variants in that gene do cause symptoms so it is likely any damage to the gene could produce the symptoms.

Sometimes variants are found, the significance of which we don’t know. These are called “variants of uncertain significance” or VUS.  As our knowledge increases some of these VUS will become obviously benign as they are found in healthy individuals, or clearly pathogenic as other patients with the same clinical features are also found to have the same variant.

If we find a VUS in the child it may be helpful to see if the same variant is present in either parent, so called “Trio studies”.  If a healthy parent also has the VUS it is unlikely to be the cause of the child’s problems.  If neither parent has the VUS then it is a new (or de-novo) mutation in the child and could be the cause.

Even looking at all the letters in all the genes may not give an answer.  The test is most useful for what we call “monogenic conditions” or problems caused by just one gene.  However, for some children with these features it is not one single gene involved or may not be genetic in origin.

Common questions

• How long does the testing take?

Generally, a result is available within two months.

• How much does it cost?

In Australia, from May 2020 the Medicare schedule will rebate whole genome or whole exome testing in a child under 10 who has dysmorphic facial appearance and one or more major structural congenital anomalies; or intellectual disability or global developmental delay of at least moderate severity to be determined by a specialist paediatrician.  The test can only be ordered by a clinical geneticist or consultant physician practicising as a specialist paediatrician, following consultation with a clinical geneticist.