From one genomic diagnosis, researchers discover other treatable health conditions

In 2015, William Bryant got a phone call from his friend, Vincent, about a scientific study that he had joined at the National Institutes of Health (NIH). It was expanding to include more people of color, especially men, and Vincent asked if Bryant would like to participate as well. After some thought, Bryant agreed.

"That small decision turned into the most monumentally important one in my life and that of my family," Bryant said.

Vincent called Bryant about the ClinSeq® study, which looks at the role that genes play in health by sequencing most of a person's genes and searching for variants that could cause health problems.

At the NIH Clinical Center, researchers took a blood sample from Bryant. They also asked him if he would want to know if they found any genomic variants that could affect him or his family. Bryant said yes.

Bryant soon forgot about the study, as the researchers had told him that these types of genomic results take time. In 2018, he received a voicemail that said they had a result from the study.

Despite his initial surprise, Bryant returned the call.

The researchers had discovered that Bryant had a variant in the RET gene, which increased his risk of having a condition called multiple endocrine neoplasia type 2, or MEN2A. People with MEN2A are at risk for several health problems, including up to a 95% chance of thyroid cancer and tumors in the thyroid area. While the tumors are not always cancerous, they can cause painful symptoms and may need to be removed.

Bryant did not know of any personal or family history related to these problems, and the results surprised both him and the study staff, who strongly recommended that Bryant get screened for signs of cancer and be evaluated by an endocrinologist.

Bloodwork and a biopsy confirmed that Bryant had thyroid cancer. Soon after, he scheduled surgery to remove his thyroid. At his early stage of the disease, the removal of the thyroid is usually curative without the patient requiring radiation or chemotherapy.

"It's miraculous that Vincent called me that day. If he had never thought of me, I would have never known," Bryant said. "I'd probably be having symptoms now and be in a terrible shape."

Bryant’s decision didn't just affect himself. His sister and her children decided to go through genomic testing and discovered that they also shared the same RET variant. Armed with the knowledge of the risks posed by the variant, they all chose to have their thyroids removed.

Genome sequencing — the ability to sequence an individual's DNA — is becoming a standard tool to study diseases. In 2019, over 26 million people took direct-to-consumer DNA tests, which speaks to our collective desire to better understand our genomes.

In July 2013, the American College of Medical Genetics and Genomics issued a recommendation that people who have their genomes sequenced in a clinical setting should also have their genomic data screened for variants in 56 genes that can pose health risks. The genes (which includes the RET gene) are associated with increased risks for several life-threatening, but treatable or preventable diseases. The number of genes included in the list increased to 59 in 2016, and clinicians expect that the list will be updated again soon.

When a person comes into the clinic to be tested for a specific condition, any positive result related to that condition is called a primary finding. But when testing reveals information separate from the original condition, it is called a secondary finding. An estimated 1-4% of people receive unexpected health results from genomic tests each year.

Animation of a clinician explaining primary and secondary findings. Credit: Harry Wedel, NHGRI.

Secondary findings are not unique to clinical genomics. People can also receive secondary findings from MRI, radiology and other medical tests.

In the case of genome sequencing, examples of secondary findings can include those related to the BRCA1 and BRCA2 genes, which are associated with breast and ovarian cancer risk, and conditions such as inherited heart rhythm problems. Clinicians share such secondary findings with a person only if the person consents to receiving such information.

Secondary findings are now a component of precision medicine, relying on individual and collective genomic data to make assessments about a person’s health risks. Clinicians can obtain highly accurate findings because of the vast amount of available genome sequence data. Researchers can search this data to improve genomic testing and how they detect people who are at risk of harboring disease-related variants. Specifically, secondary findings provide individuals and families the opportunity to learn about their health risks before they develop a disease.

In 2019, researchers at the National Human Genome Research Institute (NHGRI) started the Genomic Services Research Program, part of what is now NHGRI's Center for Precision Health Research, to further understand and improve the implementation of precision medicine initiatives.

"Secondary findings play a pivotal role in diagnosing diseases, preserving health and saving lives," said Leslie Biesecker, M.D., chief of the NHGRI’s Clinical Genomics Section. "Our research program measures how clinicians communicate these findings and peoples’ reactions so we can identify areas for improvement. The payoff could improve human health by making it commonplace for people to get treatment for diseases before they are sick."

The payoff could improve human health by making it commonplace for people to get treatment for diseases before they are sick.

According to Biesecker, identifying a secondary finding is only the first step. The Genomic Services Research Program studies whether secondary findings have real-life use and value by assessing three key components:

• Whether a person who learns of a secondary finding follows clinicians’ recommendations to evaluate their disease risk.
   
• If the person shares the secondary finding with their family members.
   
• If anyone in their family is diagnosed with a related health problem.
   

Biesecker also emphasized the need for healthcare providers to clearly communicate with patients who receive secondary findings so they understand their treatment options.

"Most people seek out genetic testing because they know of a strong family history for a certain disease," said Katie Lewis, Sc.M., CGC, a genetic counselor in the program. "But for those individuals who get these secondary findings, it can be an immense surprise. Our goal is to help individual patients get the care they need and share the result with their families.”

Lewis also adds that there is very little known about the extent to which patients follow through with treatment and the factors that influence their decisions. Understanding what motivates those who do take action and those who do not can help genetic counselors target their efforts to assist an individual with a secondary finding and translate it into improved long-term health.

Amanda Morris gave her father a DNA-testing kit as a birthday gift because she thought it would be a fun way for him to find out his ancestry. Her father took the test, and his results revealed a high percentage of Jewish ancestry.

Surprised by these results, Morris also decided to take an ancestry test, which verified that she was a quarter Jewish. Morris wondered if her results may have potential health risks, so she uploaded them into Promethease, a privately owned website that provides information on diseases associated with genomic variants.

Promethease flagged a variant in the BRCA1 gene from Morris’s genomic data, which could have significant health consequences.

Although websites such as Promethease identify variants associated with health risks, it is not intended to be used in healthcare practices. To confirm the results, Morris sought help from oncologists. They repeated the test, which confirmed the result and told her it put her at an 85% risk of developing breast or ovarian cancer. Morris told her two sisters about her increased risk, and they each took a DNA test. Her younger sister also tested positive for the BRCA1 variant.

Like Bryant, Morris had never suspected that she would be at risk for breast cancer based on her personal and family history. Without the secondary finding, Morris would have had a low chance of knowing about her risks until she or someone in her family developed cancer.

After talking to genetic counselors, both Morris and her sister underwent a preventative double mastectomy. Morris also had her ovaries and fallopian tubes surgically removed. This decision is in line with the National Comprehensive Cancer Network’s 2021 recommendations, which states that women with certain BRCA1 variants should opt to remove their ovaries when they are finished having children. They should also discuss the option for mastectomy with doctors or pursue enhanced breast cancer screening.

Morris reached out to the Genomic Services Research Program after she found the study on the FORCE website, a nonprofit organization that helps individuals and families with breast and ovarian cancer.

Although Morris said she had anxiety associated with the surgeries, she believes that the secondary finding fundamentally changed her life for the better.

"I would do it again. It was the right call — the right decision for me. I wouldn't want to live with a 'what if' in my mind, and now I don't. For that, I will always be grateful," Morris said.

Genomic testing usually leads to three types of discoveries:

• Detect a disease that is actually present but unrecognized.
   
• Predict a future chance of disease.
   
• Change the understanding of a disease that is present but misdiagnosed.
   

Each of the personal stories collected by the Genomic Service Research Program points towards individuals coming to terms with one or all of the outcomes of genomic testing. Those who sought screening, prevention or treatment speak of improved long-term health experiences for themselves and their family members.

However, some researchers and clinicians have expressed that precision medicine requires people to confront health decisions in new and unique ways, which must be reflected in the healthcare system itself.

"It is much easier to suggest surgery or treatment for a disease that one already knows they have," Biesecker said. "Asking individuals to fix something that hasn't shown itself, but most likely could in the future, is tough, and some may say no. But that is why we are taking steps to increase the value of those decisions so that people can become more comfortable making them."

Researchers agree that several stages must occur in tandem for individuals to take action after receiving a secondary finding.

Even before receiving a secondary finding, clinicians must ask the person whether they are willing to learn about a potential genomic risk for a disease based on a concept called the "right to not know." There is also rising support amongst the genomics community to ensure that people have equitable access to genomic findings and treatment so as to not perpetuate existing health disparities.

Because secondary findings are an assessment of risk for a disease and not a disease diagnosis, clinicians must provide options to a person for follow-up tests and also assess the resources they may require to manage the emotional and economic challenges of these results.

“We see people experiencing a lot of surprise when they get their secondary findings. That can shift how they respond for themselves and to their families,” Lewis said. “We need to account for that when counseling these individuals.”

Genetic counselors are largely responsible for such support. They are uniquely trained in both genetics and counseling and can help patients understand their results, cope with feelings of uncertainty and surprise and devise plans to share the result with their family.

In a 2020 statement, the National Society of Genetic Counselors strongly advised people to reach out to a counselor before taking part in any genomic tests, especially those associated with secondary findings. By having discussions about what one can and cannot expect from the tests, individuals are better positioned to make informed decisions about their health. In this way, genetic counselors can use their expertise to help individuals understand and manage their risk for disease.

The Genomic Services Research Program is working on a manuscript that will outline their findings and describe the current landscape of secondary results.

"Many of the clinicians I talk with as part of this project are uncertain about how to optimize care for patients with secondary results.” Lewis said. "We want our findings to help create an evidence-based process that places individual welfare at the center."

The program envisions a future where doctors, genetic counselors and genomic researchers come together to suggest an actionable process for individuals with secondary findings.