Disclosure of Incidental Genomic Findings Involving Children

Are We Making Progress?

Janet K Williams; Martha Driessnack; Sandra Daack-Hirsch; Nancy Downing; Christian Simon


Personalized Medicine. 2013;10(6):519-521. 

"The decision to disclose clinical or research incidental findings involving children may be best made by involving parents, children when appropriate and healthcare professionals, including researchers, clinicians and institutional review boards, in order to arrive at a decision that is logical to all parties."

The current shift in healthcare delivery from a provider-centered to a patient-centered model focuses on increasing patient-oriented healthcare and research.[1] Concurrent with this shift is the increasing use of next-generation sequencing (NGS), a method that analyzes an individual's genome that is used to establish a diagnosis, seek answers to research questions involving genetics and potentially improve public health through population-based genomic screening. NGS produces large amounts of personal genome data, not all of which currently are interpretable. Genomic information is one component of what is now termed 'precision medicine'; the tailoring of medical treatment to an individual's characteristics.[2] The use of NGS requires consideration of how resultant findings fit within the context of patient-centered care. Additional considerations are needed when the person is a child.

Consequences of a child's NGS findings potentially span the child's lifetime, with many findings being difficult to interpret immediately. There are several types of findings. While some NGS findings have immediate relevance for the child's health, the clinical significance of other findings may only become apparent over time. In addition, significance of still other findings will be difficult to predict, and some will need to be interpreted with other biological, family and environment risk-exposure information. While researchers and clinicians highlight challenges of NGS, the participative component of disclosure decisions for children remains primarily in the shadows. Although one option is to discuss disclosure issues with the child and parents prior to genetic testing,[3] there are multiple reasons why this option may not be used. Another consideration is what is best for the child.[4] A third approach is contained in a recent statement by the American College of Medical Genetics and Genomics (ACMG), which recommends that laboratories should seek and report mutations specified by the ACMG, and that clinicians have a duty to report these incidental findings (IFs) for both adults and children. The report and the criticisms it has drawn bring this topic into sharper focus.[101–103] However, guidelines on genetic testing provide little evidence of contributions from multiple stakeholders.[5] In our recent study that focused on the challenges inherent in the discovery of IFs, we cast a wide net to capture the perspectives of multiple stakeholders. Of particular note were responses when the individual with the IF was a child, due to the perception by the public of parents as information gatekeepers,[6] confirming gaps between priorities held by the public and those of genetic specialists, researchers and institutional review board (IRB) chairs. An IRB is a committee charged with reviewing, approving and monitoring research involving humans.

The ACMG's guidelines on reporting of IFs as part of clinical sequencing recommend that a targeted list of IFs be reported to the parents and child when appropriate, regardless of age of the patient. This recommendation makes sense in light of the ACMG's proposed list of conditions. These conditions are largely inherited in an autosomal dominant (or semi-dominant) pattern, thus potentially having implications for the parents and other family members. The current US healthcare system uses cascade screening, which relies on family members to prompt their genetically at-risk family members to have genetic testing; therefore, the need for parents to know about these IFs is integral to cascade screening. We also found that members of the lay public focused on the need to disclose IFs to parents because of their understanding of their child's readiness to know. Involving parents in the disclosure decision would, in part, heed the words of the lay public, who ask healthcare professionals to "lay it on the table"[6] prior to the time of disclosure. There seems to be consensus building for the involvement of parents in disclosure IFs in their children, albeit for different reasons.

What is concerning about the ACMG's recommendations is that families, children and their parents are put into a situation that forces them to accept a test only if they are willing to hear about all the disorders listed in the ACMG guidelines. It is clear that the public wants to have a choice about disclosure of such information when it is not asked for and a role in how genetic information is managed.[7–9]

It is interesting that the ACMG guidelines state that the analysis of IFs does not need to be technically equivalent to that used to examine the gene of primary concern. If these regions of the genome are going to be targeted for analysis, why not impose the same rigor as the primary targeted gene? This recommendation invites confusion over results, which can further complicate clinicians' interactions with families and among family members about the potential health significance of the reported finding.

Genetic IFs as described in the ACMG guidelines differ from other medical situations where IFs are possible because, in these guidelines, the genomic regions are purposefully sequenced and interpreted, making it less clear if the findings are actually incidental in NGS analysis. A separate element to consider is how stakeholders define an IF. Regardless of how carefully a clinician or researcher defines IFs to parents prior to testing, parents may consider some or all findings to be incidental to the reason for the test if they are not emotionally prepared to hear the results.[7] The need for a partnership model for NGS testing may occur in both research and clinical settings. This is apparent in a recent case in which a child underwent NGS in a research study with an n = 1.[10,11] Identification of a causative mutation enabled the child to be treated and provided data on this mutation for genomic scientists to consider. The trend toward rapid translational science and health learning systems[12] suggests that scientific and clinical use of NGS will overlap and become difficult to disentangle. Current guidelines for genomic research[13,14] stress respect for autonomy and informed (or parental) consent, while those for clinical care[15,102] make a case for disclosure of certain results without consent for disclosure.

Parents of children undergoing NGS may be in for an uncertain and confusing time if the current trend towards separate guidelines in research and clinical care continues. This trend will likely lead to time-consuming and difficult-to-understand decision-making to determine whether candidates for NGS need to be consented to the disclosure of results based on whether they are a patient/patient's surrogate or a research participant at a given moment, a distinction relying on increasingly technical and elusive criteria. In general, our analyses suggest that members of the public see distinctions between genomic research and clinical care as arbitrary and irrelevant; what matters to them is access to the information so they can choose how to act on it.[7] In other words, the lay public appears to have embraced the participative component of patient-centered healthcare and research. Healthcare record systems will need to allow open access and communication among multiple stakeholders. This will require electronic medical records that accommodate large quantities of information and are interactive with clinicians, patients and perhaps researchers.

The decision to disclose clinical or research IFs involving children may be best made by involving parents, children when appropriate and healthcare professionals, including researchers, clinicians and IRBs, in order to arrive at a decision that is logical to all parties. Research-based evidence suggests that parents want to be part of the decision process about what, how and when information regarding their children will be disclosed to them, and how they and the child can access it as new information becomes available.[6,7] Healthcare providers expect to use their professional judgment in reaching a decision about what, when, where and how a child's IFs will be disclosed, noting that circumstances surrounding the child, family and the test may make it difficult for parents to benefit from a 'one-size-fits-all' disclosure protocol.[16]

Opening the communication and information for all stakeholders will require new ways of thinking. Thomas Edison is quoted as saying: "The value of an idea lies in the using of it".[104] The questions we raise in this editorial regarding disclosure of genomic IFs involving children include: what ideas about IFs discovered through NGS are being used, which ideas appear to lie dormant and undervalued and what ideas could inform the larger context so that what we do going forward reflects all stakeholders?