domingo, 2 de febrero de 2014

JAMA Network | JAMA | Returning Pleiotropic Results From Genetic Testing to Patients and Research Participants

JAMA Network | JAMA | Returning Pleiotropic Results From Genetic Testing to Patients and Research Participants

Returning Pleiotropic Results From Genetic Testing to Patients and Research Participants FREEONLINE FIRST

Jonathan M. Kocarnik, PhD, MPH1,2; Stephanie M. Fullerton, DPhil1,3
JAMA. Published online January 30, 2014. doi:10.1001/jama.2014.369
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Multiple recent guidelines and recommendations, in both the clinical and research realms, call for reporting of genetic information (including incidental information) that is clinically useful to patients and research participants and suggest it is appropriate to withhold information that is inaccurate, not actionable, or could potentially lead to harm.1 Although based on sound ethical principles, including beneficence and respect for persons, these guidelines have largely ignored an important biological phenomenon long-recognized in genetics: pleiotropy, the concept of a single gene or genetic variant affecting multiple phenotypes.2 Variants in some genes have related pleiotropic effects (eg, BRCA1 and BRCA2 mutations increasing susceptibility for multiple cancer types), and variants in other genes affect multiple phenotypes that are less similar (eg, mutations inPAH leading to phenylketonuria, eczema, light pigmentation, and mental retardation). Insofar as current recommendations do not account for pleiotropy, such guidelines are incomplete—and in some cases, contradictory. This could pose important practical problems for clinicians and investigators who may be trying to decide which, if any, genetic results to return to patients or to study participants.
Large numbers of potentially reportable genetic variants are likely to be generated from whole-genome sequencing and related approaches. Most current guidelines attempt to assign these variants to 1 of 3 categories: those that should be returned (results given), those that may be returned (results offered), and those that should not be returned (results withheld). Variants are typically assigned to these categories according to their clinical validity (ie, the validity and strength of the genotype-phenotype association) and clinical utility (ie, whether information about a specific genotype is useful for treatment or prevention of disease). Other criteria can include personal utility or analytic validity. However, all current guidelines appear to apply these criteria with reference to a single genotype-phenotype association, without considering such associations in the context of additional pleiotropic relationships. In some instances, this can lead to conflicting conclusions regarding whether it is appropriate to return a particular genetic result.
One well-known example involves the APOE gene, for which applying current criteria to different phenotypic associations with the same genetic variant (ε4) may lead to recommendations that this information may be returned (due to its implications for cardiovascular disease risk, a potentially actionable phenotype) and, simultaneously, should not be returned (due to its associations with a nonmodifiable risk of developing Alzheimer disease). In the face of such conflicting recommendations, an investigator or clinician must decide whether it is more appropriate to not return any information (avoiding potential harm), return only the clinically useful association (promoting potential benefit), or opt instead for full disclosure of all relevant associations, on the assumption that patients have a right to this information and that the benefits outweigh the potential disadvantages of receiving unwanted or unhelpful information. However, returning only one of several pleiotropic associations will not always be feasible, because a simple web search of the genotype by the patient or participant may readily reveal the other associations. In an era of increasing information availability, media attention, personal health information accessibility, and medical self-management, there is potential for inadvertent psychosocial or physical harm to result from a participant or patient discovering pleiotropic genetic information. This may particularly be the case when ancillary information involves risks for a disease that is more severe, life-threatening, stigmatizing, or less treatable than the initial indication. In addition, such independent discovery of additional pleiotropic associations may occur long after any initial contact with a clinician, researcher, or genetic counselor. Do clinicians or researchers have a responsibility to provide this information to patients or research participants?
Although this problem of pleiotropy for the return of APOE results has been previously acknowledged,3 increasing evidence of the pervasiveness of pleiotropy suggests that this will not be an isolated example.4 A recent study found that 233 of the 1380 genes in the National Human Genome Research Institute’s Genome-Wide Association Studies catalog (17%) had pleiotropic effects.5 Another study found that 16 of 42 pharmacogenetic genes (38%) gave risk information for diseases other than the pharmacogenetic indication.6 Additionally, several genes appear to be highly pleiotropic: variants in the TERT locus, for example, have been associated with at least 24 different tumor types.7 Moreover, as the identification of pleiotropy requires at least one association to be previously reported, both the number of genes that demonstrate pleiotropic effects, as well as the number of pleiotropic associations for a given gene, can be expected to expand as genetic knowledge increases. Indeed, several studies are actively searching for new pleiotropic relationships with known genetic variants.8 Additionally, efforts to quantify the degree of pleiotropy in animal models suggest that pleiotropy is common in the genome, and that some genes have a large number of pleiotropic effects.2
To demonstrate the relevance of pleiotropy for result return policy, consider the American College of Medical Genetics and Genomics (ACMG) recommended list of 56 genes for which incidental findings should be sought and reported in clinical exome and genome sequencing.9 Using the publicly-accessible Online Mendelian Inheritance in Man resource (, we counted the number of phenotypes (Mendelian Inheritance in Man [MIM] disorders) listed as having a gene-phenotype relationship with each MIM gene listed in the ACMG policy statement.9 Phenotypes without an assigned MIM number were not counted, and multiple phenotypes with the same MIM number were only counted once per gene.
Of the 56 ACMG genes, 43 (77%) had multiple associated phenotypes listed, with an average of 3.5 phenotypes per gene (range, 1-11; eFigure in the Supplement). Thus, while reporting variants in these genes provides information about the 55 actionable phenotypes described in the recommendations,9 these variants also provide information for an additional 116 phenotypic relationships (up to 10 per gene) that are not otherwise mentioned or acknowledged. Together, this example suggests that even stringent attempts to limit disclosure of incidental findings to only a highly scrutinized list are still likely to provide additional pleiotropic information that may not meet the same criteria for reporting to patients or research participants.
The broad pervasiveness of pleiotropy, and evident complications it poses for return decision-making, demands proactive consideration by clinicians, researchers, and policy makers with an interest in ensuring responsible communication of genetic information. Pleiotropy poses important implications for return of result decision making, as well as research oversight and health care management. Specifically, more complete classification schemes that consider pleiotropic associations will be needed to determine which results are appropriate to return to patients and research participants, and under what circumstances. The development of such schemes will likely require further policy discussion about how best to weigh the evidence of pleiotropic associations—including the type and degree of ancillary information implicated—against other criteria such as clinical utility. Ideally, procedures for evidence review and criteria governing return decisions in the presence of pleiotropy would be widely disseminated and discussed. Resources will also need to be devoted to exploring the responsible return of pleiotropic information, including clinician, researcher, patient, and participant understandings of the salience of such information. In addition, informed consent practices may need to be developed that specifically acknowledge pleiotropy and explain the likely conveyance of additional information of unknown significance with potentially any returned genetic result.
Although pleiotropy has been documented by geneticists for more than 100 years, its effect on the return of results from genomic analysis is yet to be recognized. Clinicians and researchers should be aware that additional phenotypes may be associated with any given genetic result returned and that this information is easily accessible. For pleiotropic variants,current guidelines provide incomplete and potentially conflicting guidance on what information should be returned to patients and research participants. These guidelines will likely need to be revised to appropriately address this increasing class of genetic testing results.


Corresponding Author: Jonathan M. Kocarnik, PhD, MPH, Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M4-B402, PO Box 19024, Seattle, WA 98109 (
Published Online: January 30, 2014. doi:10.1001/jama.2014.369.
Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Fullerton reports receiving grant funding from the National Institutes of Health. No other disclosures were reported.
Funding/Support: This work was supported by grants R25CA94880 and T32CA09168 from the National Cancer Institute and grants U01HG006507, U01HG007307, P50HG003374, and U01HG004790 from the National Human Genome Research Institute.
Role of the Sponsor: The sponsors had no role in preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or the authors’ affiliated institutions.
Additional Contributions: We thank Ulrike Peters, PhD, MPH, Carolyn M. Hutter, PhD (both from Fred Hutchinson Cancer Research Center), and Holly Tabor, PhD (University of Washington), for their mentorship contributions. No compensation was received for their contribution.


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