Appelbaum, Paul S.

Chung, Wendy K.

Klitzman, Robert L.

PubMed

Columbia University Academic Commons

Return of Secondary Genomic Findings vs Patient Autonomy:Implications for Medical CareRobert Klitzman, MD,Masters of Bioethics Program, Columbia University, New York, New York, and Division of Law,Ethics, and Psychiatry, Department of Psychiatry, Columbia University, New York, New York.Paul S. Appelbaum, MD, andDivision of Law, Ethics, and Psychiatry, Department of Psychiatry, Columbia University, NewYork, New York.Wendy Chung, MD, PhDDepartment of Pediatrics, Columbia University, New York, New York, and Department ofMedicine, Columbia University, New York, New York.In April 2013, the American College of Medical Genetics (ACMG) recommended thatclinical laboratories conducting whole genome sequencing (WGS) and whole exomesequencing (WES) for specific clinical indications should also analyze and report anymutations identified from a list of 57 genes considered medically actionable, regardless ofwhether patients wish to receive the results.1 These recommendations have sparked a heateddebate with profound implications for countless physicians and their patients.The use of exome sequencing is rapidly increasing in clinical care. Pediatricians are usingthis tool to assist in diagnosing rare conditions. Oncologists are performing genomicanalysis on an increasing number of patients, comparing tumor and normal cells to identifysomatic cell mutations that can guide selection of therapy. In the not-too-distant future, suchsequencing may be incorporated even more commonly into patient care.Yet, in interrogating the genome for mutations causing patients’ disease, laboratoriesgenerate data on other genes unrelated to the indication for testing. With some additionaleffort, laboratories can evaluate genes that confer increased risk for conditions like breastcancer, colon cancer, aortic rupture, and cardiac conditions that can cause sudden death, forwhich preventive interventions are available. The ACMG argues that laboratories have afiduciary duty to seek and return such results for the 57 genes on its list. The guidelinessuggest that the laboratory should report these results to the physician, who can thendetermine whether to convey the results to the patient. However, once such information is inthe medical record, to believe that a physician would or could withhold such informationfrom a patient appears unrealistic.Identification of mutations in these genes2 is not trivial, given the multitude of errors in thescientific literature about the pathogenicity of many genetic variants, the inexact science ofpredicting pathogenicity computationally, and the inability to perform the necessaryfunctional experiments to test for pathogenicity. Until well-curated human mutationdatabases are available, patients may be told about many mutations that, because ofCorresponding Author: Robert Klitzman, MD, Division of Psychiatry, Law, and Ethics, Columbia University, 1051 Riverside Dr,Unit 15, New York, NY 10032 (rlk2@columbia.edu).Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts ofInterest and none were reported.NIH Public AccessAuthor ManuscriptJAMA. Author manuscript; available in PMC 2013 October 20.Published in final edited form as:JAMA. 2013 July 24; 310(4): 369–370. doi:10.1001/jama.2013.41709.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptincomplete penetrance and misclassification of benign variants as mutations, are likelyneither to cause disease nor confer substantial risk when ascertained in the generalpopulation. It is possible that patients with exome sequencing would be identified as havingmutations at a frequency that is much higher than the prevalence of these diseases in thegeneral population. Such erroneous misclassifications could cause anxiety and lead patientsto inappropriately seek expensive medical screening (eg, magnetic resonance imaging andechocardiograms) or unwarranted procedures such as prophylactic mastectomies.Moreover, profound disagreements have arisen over whether mutations in these 57 genesshould be reported to all patients, regardless of patient preferences or age. Critics haveargued3 that patient autonomy should be respected by allowing patients to choose whether toreceive these secondary findings. Whereas proponents claim that the ACMGrecommendations still give patients the choice to undergo exome sequencing or not,opponents counter that patients may need testing for diagnosis and treatment of theirconditions, but simply not wish to be tested for these other conditions. Currently, many well-informed individuals with known family histories of cancer syndromes, such as hereditarybreast and ovarian cancer (BRCA1 and BRCA2) and Li-Fraumeni syndrome (TP53), chooseto forgo or defer genetic testing, given that disease manifestations and timing cannot bepredicted. Additionally, identification of some mutations (eg, hereditary breast and ovariancancer) has led to difficulty obtaining life insurance.4 Furthermore, in some communitiessuch as certain Orthodox Jewish groups, identification of a mutation can severely stigmatizepatients and their families.Additional considerations emerge when the patients are children. For most of the conditionson the list of 57 genes, the mutations are incompletely penetrant and many will not manifestuntil adulthood. Harm may ensue from identifying children as at-risk during formativecritical periods of childhood development when identity is significantly shaped by parentalperceptions and attitudes. The new ACMG guidelines contradict the organization’s priorguidelines for genetic testing in children formulated with the American Academy ofPediatrics, which recommended against predictive genetic testing in minors for adult-onsetconditions that are not medically actionable before adulthood.5,6 The earlier guidelinessuggested that children should be allowed to decide for themselves, when they reachadulthood, whether to undergo these tests. Although some have argued that identification ofa child with a mutation will allow cascade genetic testing to identify adult family membersimmediately at risk of disease, it may only be a few years until genomic screening is readilyavailable, allowing these other family members to pursue testing if they desire.In response to these criticisms, proponents of the recommendations7 have argued thatphysicians routinely seek incidental findings in other areas of medicine (eg, finding acardiac abnormality on a chest x-ray ordered to examine possible rib fractures). Opponentshave responded that radiographic analogies are not wholly applicable, because activelyinterrogating additional genes is more analogous to adding an x-ray of the abdomen when achest x-ray was originally ordered.At stake are fundamental differences in ethical views and interpretations—concerning theethical responsibilities of clinicians and laboratories, and of paternalism in the name ofbeneficence vs autonomy. A balance between beneficence and autonomy would seem to beoptimal, but striking such a fine balance may prove difficult. Several laboratories havealready decided not to follow the ACMG recommendations and instead allow patients toopt-in or opt-out of the interrogation of the 57 genes.Given the controversy, it is critical to consider what should be done next. Several stepsappear vital. First, this debate has been occurring without sufficient data. The pathogenicityKlitzman et al. Page 2JAMA. Author manuscript; available in PMC 2013 October 20.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptof rare variants and the prevalence and general population penetrance of true mutations inthese 57 genes should be determined. Patients’ preferences for and responses to thisinformation are currently unknown, but they are actively being sought by researchers andwill probably be elucidated in the next 2 to 3 years. Input from all stake-holders should besought, including patients, patient advocacy groups, and professional organizations such asthe American Society of Clinical Oncology. The ACMG policy has sparked a valuablediscussion, but careful consideration and debate, continued data collection, and curation andrefinement of the classification of genetic variants are all necessary to arrive at the bestpolicy for this important medical tool. Rather than rushing to implement a policy, it seemsmore prudent to continue discussion, research, and analysis and ensure that all theramifications of the policy are considered before laboratories adopt the ACMGrecommendations. While proponents may argue that policy is urgently needed, such short-term benefits are outweighed by the long-range advantages of developing as optimal apolicy as possible.AcknowledgmentsFunding/Support: This research was funded by grants R01 HG006600, R21 HG006596, and P20 HG005535-02from the National Human Genome Research Institute.Role of the Sponsor: The National Human Genome Research Institute had no role in the preparation, review, orapproval of the manuscript; and decision to submit the manuscript for publication.REFERENCES1. Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findingsin clinical exome and genome sequencing. http://www.acmg.net/docs/ACMG_Releases_Highly-Anticipated_Recommendations_on_Incidental_Findings_in_Clinical_Exome_and_Genome_Sequencing.pdf.2. Wheeler DA, Srinivasan M, Egholm M, et al. The complete genome of an individual by massivelyparallel DNA sequencing. Nature. 2008; 452(7189):872–876. [PubMed: 18421352]3. Wolf SM, Annas GJ, Elias S. Patient autonomy and incidental findings in clinical genomics.Science. 2013; 340(6136):1049–1050. [PubMed: 23686341]4. Joly Y, Ngueng Feze I, Simard J. Genetic discrimination and life insurance: a systematic review ofthe evidence. BMC Med. 2013; 11:25. [PubMed: 23369270]5. Committee on Bioethics, Committee on Genetics, American College of Medical Genetics,Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing andscreening of children. Pediatrics. 2013; 131(3):620–622.6. Ross LF, Saal HM, David KL, Anderson RR. American Academy of Pediatrics; American Collegeof Medical Genetics and Genomics. Technical report: ethical and policy issues in genetic testingand screening of children. Genet Med. 2013; 15(3):234–245. [PubMed: 23429433]7. Green RC. ACMG recommendations are a controversial but necessary step towards genomicmedicine. http://www.huffingtonpost.com/robertc-green-md-mph/genetics-incidental-findings_b_3194911.html. Published May 3, 2013.Klitzman et al. Page 3JAMA. Author manuscript; available in PMC 2013 October 20.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript

Return of Secondary Genomic Findings vs Patient Autonomy: Implications for Medical Care

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Return of Secondary Genomic Findings vs Patient Autonomy: Implications for Medical Care

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