Cases in Precision Medicine: When Patients Present With Direct-to-Consumer Genetic Test Results

Abstract

Key Summary Points Direct-to-consumer (DTC) genetic testing is becoming increasingly popular, and clinicians should be prepared to provide guidance to their patients when presented with results from these tests. 23andMe does not perform comprehensive testing of known pathogenic variants and may have limited value and sensitivity for patients who are not of European or Ashkenazi Jewish descent. The positive predictive value of many 23andMe genetic tests is limited because risk is often modified by interacting genes, environment, lifestyle, and family history, which are not included in the risk predictions. Clinicians should refer patients with concerns about genetic test results or genetic concerns not addressed by DTC testing to a genetic counselor or another qualified provider. A couple is planning to start a family. The husband is aged 25 years and Ashkenazi Jewish and has heard that he could pass on Jewish diseases, such as TaySachs disease, to his children. His wife, who is also 25 years old and Latina, is worried because her mother and grandmother both developed breast cancer in their early 40s. They decide to order a 23andMe test after reading about the company s carrier screening test and the new BRCA1/BRCA2 test. After receiving the results, the wife is relieved to learn that she tested negative for BRCA1/BRCA2 (Table 1). However, they are concerned to find that the husband is a carrier for Gaucher disease type 1 and the wife is a carrier for cystic fibrosis, although they know of nobody in their families with either condition. The husband is also shocked to discover that he has 2 copies of the 4 variant in the APOE gene and is now worried about his risk for Alzheimer disease. They take the test results to their internist for advice on how to proceed. Table 1. Typical 23andMe Results and Suggested Clinician Responses Given the rise in public interest in human genetics and precision medicine, direct-to-consumer (DTC) genetic testing is becoming increasingly popular, and clinicians should expect patients to present the results of these tests, such as the one in the composite case just described, more frequently. Direct-to-consumer genetic tests are advertised and sold directly to the public. In addition to ancestry and nondisease traits (such as eye and hair color, preferred wake-up time, aversion to cilantro, caffeine consumption, or ability to smell urine odor after eating asparagus), these tests may offer information on risks for certain diseases, carrier status for autosomal recessive diseases that have reproductive implications, and pathogenic variants (the preferred term for what are colloquially called mutations). Although DTC tests can provide genetic information to a much broader audience than might otherwise be reached because of difficulties accessing clinical genetic testing, high costs, or poor insurance coverage, they are not diagnostic and offer information on a limited number of genes and diseases. In addition, concerns have been raised about the accuracy and technical validity of the analysis underlying the risk profiles given to consumers and the clinical utility of providing consumers with health information that can easily be interpreted as medical advice (1). What Information Do DTC Genetic Tests Provide? Companies vary in the DTC services they provide. Some, such as AncestryDNA and National Geographic, provide only genetic ancestry information. Others provide more extensive information, but only with physician approval. For example, Genos offers full-exome sequencing, whereas Veritas provides detailed genetic health risk information. 23andMe, one of the most prominent DTC companies and one of the first to offer genetic testing to the general public, is notable for providing genetic health risk information without physician approval or involvement. After an investigation by the U.S. Government Accountability Office in 2006 concluded that DTC companies were involved in deceptive advertising and after congressional hearings in 2013 that warned that DTC testing could threaten individual health and safety, the U.S. Food and Drug Administration (FDA) issued a cease-and-desist order in 2013 to 23andMe and several other companies requiring immediate discontinuation of DTC testing (2). However, in 2015, the FDA partially reversed its position and approved 23andMe s carrier screen for hereditary Bloom syndrome (a rare autosomal recessive disorder characterized by short stature, a wide variety of cancer types, and chromosome instability), indicating that 23andMe had provided sufficient evidence that the public was capable of understanding the results. In April 2017, the FDA authorized 23andMe to market genetic health risk tests for 10 conditions (Parkinson disease, late-onset Alzheimer disease, celiac disease, 1-antitrypsin deficiency, early-onset primary dystonia, factor XI deficiency, Gaucher disease type 1, glucose-6-phosphate dehydrogenase deficiency, hereditary hemochromatosis, and hereditary thrombophilia) (3). The following month, 23andMe began offering reports for Parkinson disease, late-onset Alzheimer disease, 1-antitrypsin deficiency, and hereditary thrombophilia. Over the next year, the company added hereditary hemochromatosis, age-related macular degeneration, celiac disease, and glucose-6-phosphate dehydrogenase deficiency to its reports. In March 2018, the FDA authorized 23andMe to test for 3 specific pathogenic variants in the BRCA1/BRCA2 hereditary breast and ovarian cancer genes that are observed largely in persons of Ashkenazi Jewish descent (4). Although the FDA s decisions were based on the difference between genetic health risk tests (those providing information about genetic risk for a disease) and diagnostic tests (those providing information to diagnose a disease once symptoms are present), the general public does not necessarily understand this distinction (5). What Are the Limitations of DTC Genetic Tests? Many of the conditions tested by 23andMe are rare, and the clinical utility of such information for the general public is limited (6). Although the small panel of variants included in the test may increase risk, they typically account for only a fraction of the variants contributing to a particular disease, and none of the genes that are analyzed are comprehensively sequenced or assessed. The predictive value of a positive result for many of the conditions is low because many of the variants are modified by additional factors, such as other interacting genes, environment, and lifestyle. Analysis of a few variants without the context of medical and family history can lead to misinterpretation of test results and inaccurate assessment of disease risk. The likelihood of misinterpretation is particularly high for persons of non-European ancestry because, for many of the conditions screened, the test does not include common variants found in minority populations. However, for persons of Ashkenazi Jewish descent, many 23andMe tests are more informative for variants found specifically in that community (6). How Can Clinicians Help Patients Understand the Meaning and Limitations of DTC Genetic Test Results? In the 2017 order permitting 23andMe to offer its DTC testing for genetic health risk, the FDA identified 3 risks related to the tests and means of mitigating them. The risks included lack of understanding of the test by the consumer, incorrect results (false-positives or false-negatives), and erroneous interpretation of the results. The mitigating factors included limiting statements explaining how the tests work, how to interpret the results, and the limitations of the results; requirements for the statistical basis for the accuracy of the information with respect to the variants reported; and consumer education (7). However, questions remain about how protective these mitigating steps are for the average consumer and how a clinician should advise his or her patient about a 23andMe report. We believe that there are several ways clinicians can help patients understand the meaning and limitations of DTC test results. The following have been suggested by the American College of Medical Genetics and Genomics (1). Appropriate Clinical Data Generation and Analysis Data generation and analysis in genetic testing may be performed by a single entity (a DTC company) or may be split between 2 entities (a DTC company and a third-party interpretation company). All clinical data should be generated and analyzed in a Clinical Laboratory Improvement Amendments (CLIA)certified laboratory (the laboratory s certification can be checked at the Genetic Testing Registry [www.ncbi.nlm.nih.gov/gtr]). If any part of the process does not meet CLIA requirements, the full test and interpretation should be confirmed in a CLIA-certified laboratory. Although 23andMe tests are analyzed at CLIA-certified laboratories, patients may send the data they receive to third-party interpretation companies that provide risk estimates that may not be accurate for clinical diagnostic interpretation. If the 23andMe result is negative but clinical suspicion is high, further testing covering all of the genes and variants associated with the condition of concern may be warranted, with comprehensive analysis for those genes. The results should be interpreted and delivered by a provider who is knowledgeable in genetics or a board-certified genetics professional. Availability of Genetics Expertise A certified medical geneticist or genetic counselor is often helpful in interpreting test results in the context of personal and family history. If the practitioner has insufficient knowledge of genetics, input from a genetics professional may alleviate risks for misinterpretation of results, inappropriate disease management or prevention, or inadequate follow-up. More Nuanced Disclosure The patient should be told that DTC tests are not diagnostic and provide limited information on disease risk. Medical interpretation of res