Limitations of Genetic Testing

Since the first drafts of the human genome were released at the beginning of this century, our knowledge of the differences between people’s genomes has grown at a remarkable pace. Advances in sequencing technology have been especially dramatic. What once cost millions of dollars can now be done for only a few hundred dollars per genome. As a result, researchers can analyze the genomes of large groups of people, identify genes associated with particular traits or health conditions, and study genetic differences among populations.

These advances also led to the rise of direct-to-consumer genetic testing companies, such as 23andMe. These companies offered testing not only for genealogical purposes but also to identify genetic variants associated with health conditions. While genealogical testing often provides accurate—and sometimes surprising or uncomfortable—information, its novelty has largely worn off. More importantly, the promised health benefits of direct-to-consumer genetic testing have not materialized to the extent many hoped, and several of these companies have struggled or failed as a result.

There are several reasons for this. First, while the cost of DNA sequencing has dropped dramatically, it is still too expensive for most consumer testing. Instead of sequencing an entire genome, these tests look for specific genetic markers that are known to be associated with certain health conditions. This approach is much cheaper, but it only detects common variants and misses many others that may influence health.

Second, relatively few genetic variants cause noticeable but non-lethal effects. Many mutations are either so severe that they prevent survival or so mild that they have no measurable impact. Most common health conditions do not result from a single gene mutation, but from the combined effects of many genes, each contributing only a small amount. For this reason, it is more common to talk about sequence variants than mutations. There is no “ideal” human genome sequence to which all others are compared. Sometimes the variant will inactivate the gene, in which case it can be classified as a mutation or a pathogenic variant. However, even then such mutations often have no effect on the health of the individual due to other compensating factors.

Third, identifying a genetic variant is much easier than predicting what it will actually do. In most cases, a variant changes a protein only slightly. Without extensive—and expensive—testing, it is difficult to know whether that change affects the protein’s function, let alone a person’s health.

Fourth, genetic variants do not act in isolation. Other variations in a person’s genome can influence how strongly a particular variant affects protein function or health.

Finally, it has become increasingly clear that our genes are not our destiny. Genes provide the instructions for making proteins, but how those proteins function is shaped by many factors. This includes what we eat, how much we exercise, and the stresses we experience. Scientists refer to this as epigenetics: changes in gene regulation that occur without altering the DNA sequence itself.

Do these limitations make genetic testing useless? No—but they do mean that we must be cautious about what it can tell us. Genetic counseling is a rapidly developing field that has proven valuable in many medical contexts. It can help guide diagnosis, prognosis, and treatment, especially for people who already have a health condition. In those cases, genetic testing is used as part of a broader medical evaluation.

The situation is more challenging for people who feel healthy but learn they still carry a pathogenic variant. A personal example may help illustrate this scenario.

More than twenty years ago, on the day before her 46th birthday, my sister Wilma died in her sleep. Her death was completely unexpected. She was an active mother of six with no serious health problems, apart from mildly elevated blood pressure. An autopsy did not provide clear answers, and genetic testing was not available at the time. Her family was left grieving and confused.

Years later, another sister, Margaret, was hospitalized with episodes of tachycardia—a dangerously fast heart rhythm. Two of Wilma’s daughters experience similar symptoms. It became clear that this was a hereditary condition, and genetic testing revealed a pathogenic variant in the plakophilin-2 (PKP2) gene. This gene encodes a protein involved in connecting heart muscle cells. When the protein is defective, electrical signaling in the heart can be disrupted, leading to abnormal heart rhythms.

Although variants in many different genes can cause cardiac arrhythmias, the ones in PKP2 are the most common. The particular variant in my family has been studied extensively, especially by Dutch researchers, which makes sense since it originated in the Netherlands. It is inherited in an autosomal dominant pattern, meaning that a person needs only one copy of the altered gene to be at risk, and each child has a 50% chance of inheriting it. However, the trait also shows incomplete penetrance and variable expressivity. In practical terms, this means that not everyone with the variant develops symptoms, and those who do may experience different levels of severity.

Genetic testing confirmed that Wilma and Margaret carried the variant, as did Wilma’s two daughters. This raised difficult questions for the rest of our family. Should all of my siblings, nieces, and nephews be tested as well? For those who test negative, there is reassurance. But what about those who test positive?

Last summer, I learned that I, too, carry this variant. I feel healthy, so what does this information mean for me?

Because this variant does not always cause disease, many uncertainties remain. Will I ever develop symptoms? If I do, how severe will they be? If Wilma had known she carried the pathogenic variant, could anything have been done differently? And should everyone in our family undergo testing?

There are no simple answers. First, we must remember that God may call us home at any time, for reasons far beyond cardiac arrhythmia. Knowing about a pathogenic variant may sharpen our awareness of our mortality, but it should not fundamentally change our perspective on life. Second, testing positive does not guarantee that a condition will develop. Some variants, such as certain breast cancer genes, have very high penetrance, and testing can be lifesaving. That is not the case here. Instead, the goal is to determine whether disease is already present but not yet obvious. On the advice of a genetic counselor, I underwent several tests, including wearing a heart monitor. No abnormalities were detected, and I will continue to be monitored over time.

Even with careful monitoring, uncertainty remains. Our family’s variant is relatively common in people with cardiac arrhythmia, and it has been studied more than many others. Large registries maintained by cardiac centers track people with arrhythmia, as well as family members who do not carry specific variants. In addition, population-wide genetic databases help estimate how common a variant is and how often it leads to disease. Even after reviewing these studies, I still cannot know with certainty whether I will develop arrhythmia, though the risk appears to be well below 50%.

Some people hesitate to pursue genetic testing because of cost or fear that the information could be used against them, for example by insurance companies. To prevent this, laws exist to protect against genetic discrimination, though family medical history can still affect life insurance coverage.

If someone does test positive, what steps can they take? Here, too, uncertainty remains. Meeting with a genetic counselor is an important first step. Medical testing can determine whether the condition is present and guide ongoing monitoring. Beyond that, recommendations are less clear. People with pathogenic cardiac variants are often advised to limit strenuous physical activity to reduce stress on the heart. I have chosen to continue what I was doing earlier, namely exercising regularly, and have not experienced any problems so far. Whether this helps protect my heart or increases future risk is unknown.

My situation is only one example. As genetic testing continues to advance, many people will face similar uncertainties. Each case will involve difficult decisions about health, behavior, and trust. In all of this, we are called to number our days that we may gain a heart of wisdom, and to pray that God will establish the work of our hands (Psalm 90:12, 17).