The Patient Perspective: Diagnostic Exome Sequencing [Profiles in Genetics]


Whole-exome sequencing offers a new level of genetic testing, but the test results require significant time and expertise to interpret. The results can frequently be difficult to communicate, both for technical reasons and because of the impact on the patient and family.

Photo of Teresa Kruisselbrink, C.G.C


Teresa Kruisselbrink, C.G.C., is a Genetic Counselor in the Center for Individualized Medicine at Mayo Clinic in Rochester, Minnesota.


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Hello, I’m Teresa Kruisselbrink, genetic counselor in the Center of Individualized Medicine.

I have no disclosures.

Overview of Whole-Exome Sequencing

The title of my talk, “The patient perspective; diagnostic whole-exome sequencing,” was deliberately chosen to focus on the patient, rather than the technology itself. However, it would be difficult to give such a talk, without at least providing at least some basic background.

Whole-exome sequencing is a very large genetic test that looks at the coding parts of our DNA (those areas of the genetic code that are making something), which encompasses an estimated 20,000 genes.

Historically, technology and cost limited testing to one gene at a time, or over the past few years, panels of genes grouped based on a condition.

However, now, with whole-exome sequencing (WES), we are able test all genes at one time. If you have not seen whole-exome sequencing results, you will get a flavor for them as we move through the talk today.

Which Patients Are Offered WES?

While an incredible advancement in genetic testing, not all patients are offered whole-exome sequencing. So which ones are?

Typically, patients with complex medical issues, often involving multiple organ systems, or unusual presentations of a condition (i.e., very early onset). These patients have already had several other unrevealing genetic tests or they may have multiple conditions that are being considered. In our Department of Clinical Genomics, patients meet with a care team including a geneticist, genomic nurse, and genetic counselor.

Who Are Our Patients?

So who are our patients? They don’t fit one particular mold. Sometimes, they are newborns or children; sometimes, they are entire families. We see adults with lifelong debilitating medical issues and others who had previously been healthy, in which their health has taken a severe downturn.

What Do We Tell Patients before Testing?

What do we tell our patients prior to testing? We explain that the primary purpose for doing the testing is to better understand the patient’s medical issues. We hope to find the answer, but as large as this test is, it can’t detect every possible genetic change. For example, it is designed to find single base-pair changes, but it does not usually detect missing or extra sections of the DNA. It cannot detect if there has been a rearrangement of the genetic material and is not good at detecting repeated areas of the genetic code, such as tri-nucleotide repeats that are seen in a number of neurological conditions like ataxia or Huntington disease.

Impact to the Patient and Family

Unlike other diagnostic testing many people have throughout their life, genetic testing has an impact on both the patient and the family. This is why we talk to the patient about various inheritance patterns as the results may indicate a risk to other family members. We also talk about the various results we may get. We may find the answer; we may find nothing; and we almost always find variants that are not well-described, and we don’t know what they mean. (These are called "variants of unknown significance.")

Unique to whole-exome sequencing is the ability to find genetic variants that are associated with a future risk for a condition the patient is not yet known to have. These are called "secondary" or "incidental findings." These include risks for hereditary cancer syndromes and hereditary structural issues with the heart, such as hypertrophic cardiomyopathy or hereditary heart rhythm issues like long QT. Testing can also reveal if a person is a carrier of a genetic disorder, and some labs also offer some information about drug metabolism; this is called "pharmacogenomics."

Due to the vast nature of this testing, we discuss the psychosocial implications of these results to the patients and their family, as well as privacy concerns such as impact to insurance and identifying family relationships, such as nonpaternity.

Test Logistics

Next, we review the testing logistics with the patients. Again, unique to whole-exome sequencing, the testing is ideally done with the patients and their parent’s samples. We have an extensive medical evaluation to fully describe each patient’s phenotype and family history prior to testing. We explain that results take a long time, often three to four months, and can be expensive, ranging from $7,000 to $12,000. Insurance may cover this, but it is highly dependent on each patient’s plan.

What Do Patients Want?

Now that you have some of the background that we provide to all patients, it’s very important to understand what the patient’s expectations are. Each patient may have different hopes; therefore, we ask each patient, "What are you hoping to learn from this test?"

As expected, most patients and families are hoping to find the diagnosis. Our experience thus far has been that we find an answer about 25% to 30% of the time, but this means that 70% to 75% of the time, we don’t. And again, we almost always have some ambiguous results that we can’t yet interpret.

Not surprisingly, the desire for a diagnosis is often driven by a hope for a cure or treatment. And while there are some treatable genetic conditions, many are not. However, understanding the diagnosis may help us in patient management and can at least put closure on knowing what the condition is. Knowing the diagnosis may also help to inform a family of the risks to other family members or future children. When given the choice of how much genetic information patients want to learn, most request all the information.

What Should Patients Expect When Results Are Complete?

Finally, we talk with patients about what they can expect when results are complete.

Given the breadth of the testing, the reports are often multiple pages long.

About 25% to 30% of the time, a pathogenic variant related to phenotype is identified (meaning, we found the answer).

Each patient generally has about 1 to 10 variants of uncertain significance.

And approximately 1% to 3% of patients will have an incidental finding for a future risk.

Almost all patients will have a pharmacogenomic profile that will be important for their physicians in prescribing medications.

Once the medical team receives the results from the laboratory, the additional review of variants often requires a multidisciplinary team and many hours. So, we prepare the patient that even once results are back, the team may need additional time to review the relevance of these findings.

In nearly all cases, a return appointment is necessary to review all of the results with the patient and family.

Patient #1: 8-Year-Old Male

For the remainder of our time, I’d like to present three cases that illustrate the patient experience with whole-exome sequencing. Again, while technical information will be provided, I’d like to focus our attention on the patients themselves and their experience throughout the process.

Our first case is an 8-year-old male and his family who generally accompany him to his appointments. He has a lifelong history of development delays and other features, including a smaller head, skeletal abnormalities, and premature closure of his skull at birth, which was repaired. His sister has many similar features, and both parents have learning disabilities.

Here are some additional photos of him throughout his life.

Previous Testing

Like many of our patients, this patient had numerous studies, including genetic testing, which did not reveal an answer.

We met with the family and reviewed the information about whole-exome sequencing. The family chose to proceed with the test.

Summary of Report

As you can see in the summary, we did not find the absolute answer to his medical issues. There were four variants of unknown significance that are possibilities. We didn’t find any incidental findings, and the family was provided his pharmacogenomic information.

In looking at the variants further, you can see that one was possibly related to craniosynostosis, or the premature closing of his skull, which he inherited from his mother. His father and sister didn’t share the same variant.

There were two variants related to mental retardation: one was inherited from the mom, the other from the dad, and the sister had both. Remember, they all had some level of intellectual disability making it challenging to sort this out.

Finally, a variant was identified in a gene called KCNK9, which is associated with a condition called Birk-Barel mental retardation dysmorphism syndrome. His mother and sister also share this variant.

VUS Related to Phenotype

This slide shows you our patient on the left, and other reported patients on the right. You can see the similarities, particularly with the teeth. Thus, we think we may have a possible diagnosis that may extend to the mother and sister.

Follow-up Visit

We invited the family back for their follow-up visit and discussed the possible diagnosis of Birk-Barel for the patient, mom, and sister. We also reviewed that the other variants may be contributing, but more studies would be needed. We reviewed that if Birk-Barel is indeed the correct diagnosis, the mom would have a 50% chance of passing this on to future children. Additionally, her siblings may also have a 50% risk if this was inherited from one of her parents.

How did the family feel about this potential new diagnosis? It was a mixed reaction. Our patient, the young boy, asked if this would let him get his teeth fixed as he had been teased a lot in school. The parents expressed relief in having a diagnosis for the kids, and the mom found relief in having a potential answer as to why she herself had found learning so difficult throughout her life. However, she was very tearful and sad that she most likely was responsible for passing these issues on to her children. As you might expect, this is not an uncommon set of reactions and emotions as patients process the multiple implications of the test result.

Patient #2: 20-Year-old Male

Patient #2 is a 20-year-old male with lifelong medical complications, including seizures and profound developmental delay and autism. He is nonverbal. He has multiple other systems involved, including optic nerve hypoplasia with diminished vision, brain abnormalities, skeletal issues, and dysmorphism. He has had an extensive metabolic and genetic work-up, which was unrevealing. The family chose to proceed with whole-exome sequencing.

Likely Causative

As you can see with this patient, a likely causative variant was identified. The variant was a new mutation in the patient (also referred to as "de novo") and is associated with Bosch-Boonstra Schaaf optic atrophy.

At the time of our patient’s report, a paper was published with 20 new cases of this condition. There is good phenotypic overlap with our patient.

Follow-up Visit

We invited the family members back to provide them the results. We felt very confident that we had arrived at the diagnosis. This was a new mutation, so other family members were not at risk. There are no other reported findings that would increase genetic risk for the patient. We were able to find a support group of individuals with family members with this condition, and the author of the aforementioned paper welcomed direct contact from the family. As providers, we had felt like we had found the Holy Grail.

How do you think the family felt with receiving this information? The first question the family had was whether the testing had included metabolomics, which it hadn’t. While they hadn’t expected a cure, they had really hoped that there would be some information learned that would help even with some of the day-to-day struggles. Unfortunately with this condition, there were not.

This case highlights the importance of understanding and honoring a patient’s and family's expectations.

Patient #3: 17-Year-Old Female

Our final case is a 17-year-old female who had an unremarkable childhood. In her teens, she developed a complex sleeping disorder and began having cognitive issues impacting school. She developed postural orthostatic tachycardia (also known as POTS), headaches, hyperflexibility, bone pain, and had some abnormal lab tests. Interestingly, she developed an altered sense of taste, smell, and texture. She notes unpleasant smells that are not obvious to others, which rendered her unable to eat. She described to us that certain foods tasted like dirt. The family chose to undergo whole-exome sequencing to determine if there was anything genetic causing this unusual clinical history.

Pathogenic Variants in Disease Genes Related to Clinical Phenotype

Unfortunately, there were no pathogenic variants identified to explain her medical issues.

Medically Actionable Pathogenic Variants in Disease Genes Unrelated to the Clinical Phenotype

However, we did identify a significant medically actionable secondary finding in a gene called KCNQ1 that is associated with a heart arrhythmia called long QT. This can be a dangerous condition that can lead to sudden cardiac arrest.

Follow-up Visit

We invited the patient and her mother back for follow-up and explained the results. We did not have a diagnosis or any additional leads to the follow-up. We identified that she was a possible carrier for a condition called Wilson disease. Of more immediate concern due to the secondary finding, our recommendation was an immediate referral to our long QT specialist to include genetic testing for the parents and brother as well as discussion regarding reproductive risks.

How do you think the patient might respond to this information? Her response was, "I don’t care." We were unable to diagnosis her medical issues prohibiting her from eating, and she felt like she was slowly starving and that a cardiac risk was not of concern to her, perhaps even a blessing. We talked extensively through these concerns. After visits with other specialists, we were able to address her nutritional needs by her attaining a g-tube, particularly as dehydration and malnutrition can exacerbate long QT issues.

Patient Reaction to Results

These cases highlight that even though patients have the testing for similar reasons, each patient’s reaction to a given result is unique.

When a diagnosis is made, patients can feel a wide range of emotions including relief, shock, and disappointment. Many immediately start thinking about the future, what can be done next, how they will communicate this to family members, and who else they can connect with for ongoing support.

When a diagnosis is not made, patients can again feel disappointed, and they can be left with ongoing uncertainly about variants of unknown significance that were found, and wondering whether or not we will learn more information in the future. They may wonder if the condition is genetic at all, and should they consider having other children without knowing if there is a chance this could happen again? They may also feel relief that nothing bad was identified, providing some reassurance that perhaps the condition isn’t genetic. Unfortunately, there are times we simply don’t have the answers for these patients.

Take-Home Messages

I hope the examples provided in our brief time together have highlighted the unique genetic counseling challenges of working with families undergoing WHOLE-EXOME SEQUENCING testing. The interpretation of the findings and communication of the results to the family take a lot of time and involvement from a multidisciplinary team. And, finally, our patients' motivations and reactions are unique to their stories and may be very different than our own.


Finally, I would like to acknowledge Mayo Clinic’s Center for Individualized Medicine, whose purpose is to bring genomic advances to patients, and the Department of Clinical Genomics, where our team of medical geneticists, genetic counselors, and genomic nurses care for our patients with genetic-based medical issues such as those seen today.

All future genetic testing topics will be housed within our Hot Topics program moving forward.


MML Education

This post was developed by our Education and Technical Publications Team.