When a child or adult has unexplained health problems, families go through several consultations, scans, blood tests, and genetic tests without getting a clear diagnosis. This can be  difficult when symptoms involve multiple parts of the body or when doctors suspect a rare genetic condition. In such situations, whole exome sequencing (WES) may be considered. This test analyses the exome, which consists of the protein-coding regions of genes, allowing many genes to be examined at the same time. This broad approach can help identify genetic variants that may explain a person’s clinical features and contribute to reaching a genetic diagnosis..

Key Takeaways

• Whole exome sequencing (WES) examines the protein-coding regions of many genes to identify genetic variants that explain certain health conditions.
• WES is considered when symptoms remain unexplained, multiple body systems are affected, or a rare genetic condition is suspected.
• Previous inconclusive genetic testing is also a reason to consider WES when the clinical suspicion of a genetic condition remains.
• Family-based testing, including testing the affected person and both biological parents, can help doctors interpret genetic variants and understand inheritance patterns.
• WES results require clinical interpretation because finding a genetic variant does not always mean it is responsible for a person’s condition.

What Is Whole Exome Sequencing?

To understand whole exome sequencing, it is important to understand the terms genome, genes, and exons.

The genome is the complete set of DNA in a person. Genes are segments of DNA that contain instructions for making proteins or producing functional RNA and help direct many biological processes. Many genes contain exons, which are the portions that remain in the mature RNA and, in protein-coding genes, contain the sequences that contribute to making proteins. The collection of exons from across the genome is known as the exome. Whole exome sequencing analyses these protein-coding regions across many genes at the same time. 

The exome represents only about 1-2% of the human genome, but many known disease causing genetic variants are located in these regions. WES examines these regions across many genes simultaneously. 

How Is Whole Exome Sequencing Different From Other Genetic Tests?

Genetic testing can differ from examining a single gene to analyzing a much larger portion of DNA.

• A single-gene test looks for changes in one particular gene when a specific condition is suspected.
• A gene panel examines a selected group of genes associated with a particular disease or group of symptoms.
• Whole exome sequencing examines the protein-coding regions of many genes at the same time. It may be considered when several different genes could potentially explain a person’s symptoms or when the underlying genetic cause is not clear.

The most appropriate test depends on the person’s symptoms, medical and family history, and the types of genetic changes that need to be investigated. 

When Is Whole Exome Sequencing Recommended?

Whole exome sequencing is considered when a genetic condition is suspected but the specific cause is unclear:

• Unexplained symptoms: When developmental delay, intellectual disability, congenital abnormalities, seizures, or other significant features remain unexplained after initial clinical evaluation.
• Multiple body systems affected: When a person has a combination of neurological, developmental, skeletal, metabolic, or other systemic symptoms that cannot be linked to a single condition.
• Previous genetic tests were inconclusive: When targeted genetic testing or a gene panel has not identified the cause. 

How Does Whole Exome Sequencing Work?

Step 1: Clinical Evaluation

A doctor reviews the person’s symptoms, medical history, family history, and previous test results.

Step 2: DNA Collection

A DNA sample is usually collected from blood. Depending on the test and laboratory, a saliva or other suitable sample may also be used.

Step 3: DNA Sequencing

The laboratory extracts DNA from the sample and sequences the protein-coding regions of many genes that make up the exome.

Step 4: Data Analysis

Computational tools identify variants across the genes in the sequence. Depending on the testing strategy, the analysis may focus on genes known to be associated with the person’s symptoms or may examine data across the exome.

Step 5: Clinical Interpretation

The identified variants are assessed alongside the person’s symptoms, family history, and other medical information. This final step is important because finding a genetic variant does not mean that the variant caused the person’s condition.

When Does a Family Need Whole Exome Sequencing?

Whole exome sequencing is not required for every person with a possible genetic condition. It may be considered when a person has unexplained clinical features, a suspected genetic disorder, or a combination of features that could have several possible genetic causes. In some cases, testing the affected person alongside both parents can make the results easier to interpret.

The value of whole exome sequencing depends on asking the right clinical question and interpreting the results in the context of the individual and their family. A genetic counselor or a doctor can help determine whether the test is appropriate and explain what the results mean. 

Conclusion

Whole exome sequencing can be valuable when doctors suspect a genetic condition but do not know which gene is responsible. By examining the protein-coding regions of many genes at the same time, WES can help identify genetic variants that may explain unexplained clinical features and contribute to reaching a diagnosis.

However, identifying a variant is only one part of the process. Its significance needs to be interpreted in the context of the person’s clinical and family history to understand whether it may explain the condition and how the finding could inform care.

If unexplained health concerns have raised the possibility of a genetic condition, Whole Exome Sequencing with Whole Exome Sequencing test with LifeCell Diagnostics can be considered as part of a discussion with your doctor or genetic counsellor about the right testing approach.

FAQs

1. What is whole exome sequencing?

Whole exome sequencing (WES) is a genetic test that analyzes the protein-coding regions, called exons, across many genes. It can help identify genetic changes that are associated with unexplained genetic conditions. 

2. When is whole exome sequencing recommended?

Whole exome sequencing is recommended when a genetic condition is suspected but the specific cause is unclear, multiple body systems are affected, or previous genetic tests have not provided an answer.

3. Does whole exome sequencing test the entire family?

WES can be performed for one individual or together with biological parents. Testing the affected person and both parents can help doctors interpret genetic variants and understand how they were inherited. 

4. What can whole exome sequencing detect?

Whole exome sequencing can identify genetic variants in protein-coding regions of genes that cause certain genetic conditions.