Ethics, Gene Sequencing and Incidental Findings

As whole genome and exome sequencing rises in popularity, clinicians must know how to handle potentially life-saving incidental finding. But what information should be shared, and with whom?

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Imagine this scenario: a young boy with autism undergoes whole exome sequencing in order to identify possible gene mutations that may be linked to the cognitive disorder. In the process, the geneticist identifies an HPC1 gene mutation, which indicates risk for developing prostate cancer later in life but is unrelated to autism, the clinical indication for the test in the first place. What should the geneticist and referring physician do with this result? Is it a violation of the child's autonomy to share this information with the boy's parents, or a service that could prompt his father to get sequenced himself and mitigate his own risk?

What about a woman who has a genetic test to determine her risk for developing breast cancer, which runs in her family, and the results reveal a high likelihood for developing heart disease? Should she be informed even though it's separate from the condition she's being tested for, and her consent regarding secondary findings has not been sought?

These are examples of the ethical questions surrounding the reporting of incidental findings, defined as findings secondary to or unrelated to the clinical indication for the test performed.

It's likely that whole genome and exome sequencing will become more common as costs come down and availability increases over time. How to manage incidental findings in a way that prioritizes patients' best interests while respecting their autonomy, therefore, will become more important as well.

The lack of uniform guidelines led the American College of Medical Genetics and Genomics to produce "Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing".1
"The process got started about two years ago, when we started to set guidelines for how genome sequencing should be used in clinical practice," said Leslie Biesecker, MD, chief of the genetic disease research branch of the National Human Genome Research Institute and corresponding author of the report. "That led to a discussion of incidental findings, which couldn't be adequately addressed in our initial discussions. So a separate working group was set up."

At the core of the group's recommendations is a minimum list of about 25 conditions that geneticists should always report on, regardless of patient preferences. While some will interpret this stance as a violation of patient autonomy, the working group felt that because the list is "weighted toward conditions where prevalence may be high and intervention may be possible," the duty to prevent harm overrides patient preference. Additionally, "we believe it will be impractical for those preferences to be truly informed when sequencing scales up," said Sarah Kalia, certified genetic counselor at Brigham and Women's Hospital and a member of the working group.

The same emphasis on preventing harm also guides recommendations concerning adult-onset disorders found in children. In predictive genetic testing for healthy people, the standard is not to test children for adult-onset conditions. Doing so compromises children's right to decide if they want to know that information. "That decision should be made as an adult," Kalia said. However, the situation changes when sequencing is done to look for a specific condition in a child who is already sick, and a separate, adult-onset illness shows up as a secondary result. Especially when that finding is highly pathogenic but highly preventable, it could have serious implications for relatives.
In this case, "there is someone who stands to be harmed greatly by not divulging this information. If a predisposition for a cancer is found, for example, one of [the child's] parents could be at a very high risk for a highly lethal but preventable disorder," said James Evans, MD, PhD, clinical professor of genetics and medicine at UNC School of Medicine. "This also subjects the child to harm by placing their parent in danger." Kalia also highlighted that there is little data to support the idea that knowing about high risk for a debilitating disorder could cause psychological harm to a patient who may have preferred not to know.

Until now, physicians have handled incidental findings on a case-by-case basis, in a "process of shared decision-making" between clinician and patient. Given the "minimum list" recommendation, patients should be fully informed during pre-test counseling what kinds of results they could receive. If they are uncomfortable with potential findings, they may reconsider having their genome or exome sequenced at all.

"It would be irresponsible not to tell patients abut incidental findings that could potentially be life-saving," Evans said, "It's the clinician's obligation to report things that they're worried could cause harm, and then it's a collaborative process to decide how to proceed."

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The minimum list also "needs to be short and have a very high bar, including severe disease, high probability of harm, and well-established preventative modality," Evans said. Indeed, the ACMG's report states specific criteria disorders must meet to be included on the list, including proven available preventative or treatment options and pathogenic qualities that may remain asymptomatic for long periods of time.

Biesecker added that "the word recommendation means exactly what it's defined to mean." In other words, the ACMG guidelines are not requirements or mandates, and every physician must decide if he or she will follow a recommendation for a given patient. "However," Biesecker added, "we feel it's good practice, if you're not going to follow recommendations, to document why."

While the ACMG's recommendations are a "fantastic starting point," according to Howard Jacob, PhD, professor of molecular genetics at the Medical College of Wisconsin, they are only the first steps into a long journey of developing protocols for this emerging technology. "The College is developing a process for carrying this forward," said Biesecker. "Petitioning to add or take away disorders on the minimum list... we want that process to evolve in a deliberate way over time."

As that process unfolds, more research needs to be done to determine the implications of returning incidental findings: what they mean for patient outcomes, healthcare utilization and insurance issues, for example. As the field of genetic sequencing expands, we can expect bodies like the ACMG to become more involved in tackling these complicated questions.

Katie Siegel is on staff at ADVANCE. Contact: ksiegel@advanceweb.com.


1. Biesecker, Leslie; Robert Green, Sarah Kalia et al. "ACMG Recommendations or Reporting of Incidental Findings in Clinical Exome and Genome Sequencing." American College of Medical Genetics and Genomics. March, 2013. Retrieved from: http://www.acmg.net/docs/ACMG_Releases_Highly-Anticipated_Recommendations_on_Incidental_Findings_in_Clinical_Exome_and_Genome_Sequencing.pdf

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