What Do My Whole Exome Sequencing Results Mean?

Whole exome sequencing (WES) is a genetic test that analyzes the protein-coding regions of your DNA, known as exons. Since these regions contain the instructions for building proteins, a WES report can provide significant information about your health. This article explains what the test examines, the different categories of results, and potential next steps.

What Whole Exome Sequencing Examines

Whole exome sequencing focuses on the exome, which represents all the protein-coding regions (exons) in your DNA. While exons make up only about 1-2% of your entire genome, they contain up to 85% of the genetic variations known to cause human diseases. This concentration makes the exome an efficient area to search for the genetic cause of a person’s symptoms or medical condition.

WES is often used when a specific genetic disorder is suspected but other, more targeted genetic tests have not provided a diagnosis. This targeted analysis distinguishes WES from whole genome sequencing (WGS), which sequences a person’s entire genome, including both the coding exons and the non-coding introns. The results are generated by comparing a patient’s exome sequence to a reference sequence to spot medically significant differences.

Understanding Different WES Result Categories

After your exome is sequenced, any identified genetic variants are classified based on the likelihood that they are related to a medical condition. This classification process provides a clear interpretation of each variant’s potential impact on your health.

A “pathogenic” variant means there is strong scientific evidence to show that the specific change in your DNA is known to cause disease. Similarly, a “likely pathogenic” variant indicates there is a very high likelihood that the variant is disease-causing. These findings can often lead to a formal diagnosis.

Conversely, “benign” and “likely benign” variants are genetic changes not believed to cause any health problems. A benign variant is a common variation not associated with disease, while a likely benign finding means the variant is highly unlikely to be disease-related.

A more ambiguous finding is a “variant of uncertain significance,” or VUS. A VUS is a genetic change whose connection to disease is not currently understood because there is not enough evidence to classify it as either pathogenic or benign.

Navigating Variants of Uncertain Significance (VUS)

A VUS result occurs when there is insufficient or conflicting scientific evidence to determine a variant’s effect on health. It may be a very rare change that has not been studied, or the existing research may not be conclusive. Everyone has these types of variants in their DNA; the challenge is determining which, if any, are related to the medical reason for testing.

The classification of a VUS is not permanent. As scientific knowledge grows, a VUS may be reclassified to pathogenic or benign based on new research or family studies. For this reason, a VUS is not typically used to make a diagnosis or guide immediate medical treatment.

Living with this uncertainty can be challenging, and discussing the implications with a genetic counselor is an important step. They can help you understand the specific details of the VUS found in your exome and what it might mean for your health in the long term.

What to Do After Receiving Your WES Results

If a pathogenic or likely pathogenic variant is identified, it may confirm a suspected diagnosis. This information can be used to guide medical management, inform treatment options, and predict the course of the condition. It also has implications for family members, who may then choose to undergo testing for the specific variant, a process known as cascade testing.

If your report includes a VUS, the primary recommendation is to discuss it with a genetic counselor. They can explain the current evidence and discuss potential next steps, which might include testing other family members to see if the variant tracks with the medical condition. Periodic review of the VUS classification is also recommended.

A “negative” or “uninformative” result means that no pathogenic variants or VUSs related to your symptoms were found. This does not rule out a genetic cause for your condition. The variant may be in a non-coding region of your DNA not analyzed by WES, or it could be a type of mutation that WES technology cannot detect. In this situation, your doctor may suggest re-analyzing the data in the future or considering other forms of genetic testing.

Incidental and Secondary Genetic Findings

During WES, the analysis may uncover genetic information that is unrelated to the primary reason for the test. These are known as incidental or secondary findings. An incidental finding is a variant discovered unexpectedly, while a secondary finding refers to a specific set of medically actionable genes that a laboratory may intentionally analyze with your prior consent.

Before undergoing WES, you are counseled about the possibility of receiving these types of findings and have the choice to opt in or out. The American College of Medical Genetics and Genomics (ACMG) maintains a list of genes associated with preventable or treatable conditions that should be reported as secondary findings. These conditions often include predispositions to certain cancers or heart disorders.

The purpose of reporting secondary findings is to provide you with potentially life-saving health information. For example, finding a variant that increases the risk for a condition could lead to increased screening or preventive measures. Deciding whether to receive this information is a personal choice and an important part of the consent process.