Whole Exome Sequencing: The incredible advantage of a single test
Oct 30, 2018

Whole exome sequencing (WES) is a single, comprehensive test which examines the genetic information contained in all of our 20,000 genes for changes that may cause hereditary disease.

When should you consider WES for your patient?

“Patients with early onset, multiorgan involvement are more likely to have a genetic cause for their symptoms and therefore are more likely to receive a diagnosis through WES,” said Kim Gall, Clinical Liaison at Blueprint Genetics.

WES is best suited to patients with:

1) A complex, non-specific genetic condition with multiple differential diagnoses

Selecting a single gene test or a panel for patients with complicated or non-specific presentations can be difficult. In these cases, WES, ideally with a genotype first approach, is an optimal diagnostic tool.

“A genotype first approach means that we look at of all the genes with likely disease causing variants in them to see if the gene offers an explanation for part, or all, of the patient’s phenotype. In contrast, a phenotype first approach refers to pre-selecting a limited set of genes for review, based on the patient’s phenotype,” Kim Gall explained.

A genotype first approach improves the interpretation team’s ability to find variants in patients with atypical presentations and has the potential to diagnose more than one condition. It can also identify novel genes where a disease association has not yet been described.

“When the differential diagnosis is broad and the conditions have significant genetic heterogeneity, WES is often more cost effective and efficient in making a diagnosis. If WES is ordered early in the diagnostic testing process, it can significantly reduce the time from presentation to diagnosis,” Gall concluded.

2) A severe presentation in the neonatal or childhood period

Critical illness in neonates and children are challenging on many levels.  The patient’s young age and serious nature of the disease may limit the clinician’s ability to completely phenotype the infant or child, and the characteristic symptoms may not be present or may be difficult to assess.

“In these cases, genetic testing can be life-saving. Making a genetic diagnosis allows for care to be provided based not only on current symptoms, but also in anticipation of known complications of the disorder. This has the potential to spare the individual (and the health care system) from additional, costly tests and, at times, invasive procedures,” Gall said.

3) A complicated medical history and previous inconclusive genetic testing

Patients with rare disease often experience a never ending diagnostic odyssey, seeing several  specialists and enduring multiple tests and procedures without ever obtaining a diagnosis.

“If the patient’s previous genetic testing (for example, a panel or single gene test) is inconclusive or if it does not explain all of their features, expanding the testing to include WES may provide the diagnosis. Our current technology utilizes a flexible platform that makes the analysis, reintepretation, reflexing or expanding of the data set relatively straightforward. This flexibility of testing options should have great clinical impact”, Gall says.

In order to maximize the diagnostic yield, it is essential to provide thorough clinical information as a diagnostic exome only reports variants related to the patient’s current phenotype. Many  believe that a diagnostic WES will reveal all genetic issues a patient may face, both now and in the future.  However, the purpose of a diagnostic exome is to provide an answer for the symptoms the patient is experiencing currently, not to be a crystal ball for possible future risks.

“The laboratory geneticist is trying to find the 1 or 2 harmful genetic variants that explain the patient’s phenotype out of an average of 20,000-35,000 variants. For the interpretation process to be timely and successful, providing detailed clinical information about the patient is extremely important.”

When disease causing variants are identified in unexpected genes, detailed clinical information allows the laboratory geneticist to dig deep into the atypical presentations and focuses the interpretation process.

“Too little clinical information may result in more VUS (Variants of Uncertain Significance) being reported,” Gall underlined.

WES is also more likely to provide a diagnosis when parents provide samples along with the patient. This may be referred to as an exome trio and at Blueprint Genetics is called Whole Exome Family Plus. A trio exome allows the lab to immediately determine if a variant is de novo (not inherited from either parent), whether a novel variant in gene causing an autosomal dominant disorder is inherited from an unaffected parent, and whether two variants in a gene causing an autosomal recessive disorder are in cis or trans (both variants in the same copy of the gene or one in each gene).

“This information allows the lab to classify the variants correctly in the most time efficient way possible and eliminates the need to do family member testing to clarify the role of VUSs,” Gall said.

In short:

When to consider a panel:

  • Your patient has a known or suspected clinical diagnosis


  • The causative genes are well-described and available on the panel of your choosing.
    All of our panels can be customized to add up to 20 desired genes and remove any number of genes

Read more:

When to consider single gene testing: 

  • Your patient has a genetic condition that is very likely caused by a single gene
  • You want to do carrier testing

Read more:



Last modified: October 29, 2020