By: Blair Stevens, MS, CGC
Genetic testing is increasingly used to help manage, predict, and prevent health concerns, such as cardiomyopathy, epilepsy or birth defects. Conditions like these may be due to changes within our genes called variants that cause the gene to not function properly. A technology called “gene sequencing” is often used to find these changes by reading through the genetic code and looking for variants that might be causing disease. Sequencing tests may involve checking a single gene, a specific list of genes (gene panel), sequencing critical parts of all genes (exome sequencing), or sequencing everything (genome sequencing). Interpreting what these variants mean can be challenging and may result in uncertain results, called variants of uncertain significance (VUS). When a VUS is reported, it means we do not have enough information to know whether the variant will cause the condition associated with the gene or not and that uncertainty can be difficult for some people. The more genes that are evaluated, the more likely it is that we will encounter a VUS. However, a genetic condition could be missed if too few genes are tested.
How do people decide which genetic test is right for them?
Individuals and families considering genetic testing are sometimes given the option of how many genes to include in their genetic testing. For example, hereditary cancer panels may range from as few as two genes to nearly 100 genes. Testing decisions often rely upon personal factors, such as concern level, lived experience, desire for information, and comfort with uncertainty. Genetic counselors are trained experts in risk assessment, genetic testing, and helping families weigh the risks, benefits and limitations of genetic testing.
As a prenatal genetic counselor in a high-risk fetal diagnosis center, I discuss prenatal genetic testing with families whose babies have a birth defect. Understanding the cause of a birth defect can help direct prenatal and postnatal management, in hopes of achieving the best possible outcome. When discussing genetic testing options, some of my patients report their biggest fear is the anxiety of finding something and not knowing what it will mean for their pregnancy management and their child’s future. Others are more worried that missing a diagnosis will result in a worse outcome and will lead to deceptive reassurance during the pregnancy. Both fears involve uncertainty.
Understanding the two types of uncertainty in genetic testing
Uncertainty is a normal part of the human experience, but everyone manages the stress of uncertainty differently. When discussing the nuanced and complex topic of uncertainty in genetic testing, I break it down simply by asking patients which type of uncertainty they are more comfortable with.
Known uncertainty means we found an uncertain result, such as a VUS, and will prepare for the possibility that it is a true positive, knowing that it may not actually cause a genetic condition. This type of uncertainty can cause undue anxiety and potentially unnecessary medical assessments. Uncertain results have been described by some as “toxic knowledge”, meaning overwhelming and distressing information that is not necessarily actionable. However, if someone would prefer to know as much as possible, they may benefit from more comprehensive testing to reduce unknown uncertainty.
Unknown uncertainty means we did not find a genetic explanation for a condition; however, there is a risk that a diagnosis was missed due to not testing all applicable genes. Unknown uncertainty can result in a lack of preparation, delayed diagnosis, and feeling blindsided by a condition in the future. Comprehensive testing may be more harmful than helpful if someone is more comfortable with this type of uncertainty than known uncertainty and they may want to consider a smaller, more targeted panel.
The decision to undergo genetic testing and which type of genetic test to choose is often made during a stressful time, so working through these feelings and exploring your values with a genetic counselor can be extremely helpful. Each family has unique circumstances, and genetic testing should help support your family’s priorities, values and goals.
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