Abstract
A couple is planning to start a family. The husband is 25 years old and Ashkenazi Jewish and has heard he could pass on “Jewish diseases” such as Tay-Sachs 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 carrier screening testing and the new BRCA1/2 test. After receiving the results, the wife is relieved to find out that she tested negative for BRCA1/2. However, they are concerned to learn 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 of these conditions. The husband is also shocked to discover that he has two copies of the ε4 variant in the APOE gene and is now worried about his risk of developing Alzheimer’s disease. They bring the test results to their internist for advice on how to proceed.
Given the rise in public interest in human genetics and precision medicine, direct-to-consumer (DTC) genetic testing continues to grow in popularity, and clinicians should expect patients to present the results of a DTC genetic test, such as the one described in the composite case above, with increasing frequency. DTC genetic tests are advertised and sold directly to the public. In addition to ancestry and non-disease traits (e.g., eye and hair color, preferred wake-up time, cilantro aversion, caffeine consumption, or ability to smell urine odor after eating asparagus), these tests may offer information on risks of developing certain diseases and carrier status for autosomal recessive diseases that have reproductive implications. Pathogenic variants cause disease, and is the preferred term for what are more 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 of testing, or poor insurance coverage, they are not diagnostic and offer information for only 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 giving consumers health information that can be easily interpreted as medical advice (1).
What information do currently available direct-to-consumer genetic tests provide?
DTC companies vary in the services they provide. Some, such as AncestryDNA and National Geographic, provide only genetic ancestry information. Others provide more extensive information but only with the approval of a physician. Genos, for example, offers full-exome sequencing, while Veritas provides detailed genetic health risk information. 23andMe, one of the most prominent DTC companies, is notable for providing genetic health risk information without physician approval or involvement. 23andMe was one of the first DTC companies to offer genetic testing to the general public. Following an investigation by the U.S. Government Accountability Office in 2006, which 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 Food and Drug Administration (FDA) issued a cease-and-desist order in 2013 to 23andMe and several other DTC companies requiring the immediate discontinuation of DTC testing (2). However, by 2015, the FDA partially reversed its position and gave 23andMe approval for its carrier screen for hereditary Bloom syndrome—a rare autosomal recessive disorder characterized by short stature, a wide variety of cancers, and chromosome instability—indicating that 23andMe had provided sufficient evidence that the public was capable of correctly understanding these test results. In April 2017, the FDA authorized 23andMe to market genetic health risk tests for 10 conditions (Parkinson’s disease, late onset Alzheimer’s disease, celiac disease, alpha-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’s disease, late-onset Alzheimer’s disease, alpha-1 antitrypsin deficiency, and hereditary thrombophilia. Over the course of the next year, 23andMe added hereditary hemochromatosis, age-related macular degeneration, celiac disease, and glucose-6-phosphate dehydrogenase deficiency to their reports. In March 2018, the FDA also authorized 23andMe to test for the presence of three specific BRCA1/BRCA2 hereditary breast/ovarian cancer gene pathogenic variants observed largely in individuals of Ashkenazi Jewish descent (4). Although the FDA’s decisions were based on the difference between “genetic health risk” tests (i.e., those providing information as to the genetic risk of developing a disease) and “diagnostic” tests (i.e., those providing information to diagnose a disease once symptoms are present), this distinction is not necessarily understood by the general public (5).
What are the limitations of direct-to-consumer 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 variants included in the test may increase risk, the limited panel of variants tested also typically accounts for only a fraction of the variants contributing to a particular disease, and none of the genes analyzed are comprehensively sequenced or assessed. The predictive value of a positive test for many of the conditions is low because many of the variants tested 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 great for persons of non-European ancestry, because for many conditions screened, the test does not include common variants found in minority populations. On the other hand, for individuals of Ashkenazi Jewish descent, many 23andMe tests are relatively more informative for variants found specifically in that community (6).
How can clinicians help patients understand the meaning and limitations of direct-to-consumer genetic tests?
In its 2017 order to permit 23andMe to offer its genetic health risk DTC testing, the FDA identified three risks relating to the tests and identified certain means of mitigation. The risks included: (1) incorrect understanding by the consumer of the test, (2) incorrect test results (i.e., false positives or false negatives) and (3) incorrect interpretation of test results. The mitigation factors included (a) “limiting statements,” indicating the limitations of the test results, and explanations of how the tests work and how to interpret the results, (b) requirements as to the statistical basis for the accuracy of the information with respect to the variants reported and (c) consumer education (7).
However, the question remains as to how “protective” these mitigating steps are for the ordinary consumer and how a clinician should advise his/her patient in light of a 23andMe report. We believe that there are several ways in which a clinician can help a patient 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 (i.e., a DTC company) or may be split and performed by two entities (i.e., a DTC company and a third party interpretation company). All data generation that is used clinically should be performed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory, and the laboratory’s certifications can be checked at the Genetic Test Registry (https://www.ncbi.nlm.nih.gov/gtr/.) If any part of the laboratory service or interpretation is not CLIA-certified, the full test and interpretation should be confirmed in a CLIA-certified laboratory that can be identified on the Genetic Test Registry website. Although 23andMe testing is performed 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 test 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 genetic analysis for those genes. The results should be interpreted and delivered by a provider knowledgeable in genetics or a board-certified genetic 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 you are not a practitioner sufficiently knowledgeable about genetics, input from a genetics professional may alleviate the risks of misinterpretation of results, inappropriate choices for disease management or prevention, or inadequate follow up.
More nuanced disclosure. The patient should be told that DTC tests are not diagnostic and provide only limited information on the risk or probability of developing a disease. The medical interpretation of such results is often complex and includes additional patient-specific information such as family and prior medical history and inclusion of other risk factors. This information needs to be incorporated and communicated to the patient in the appropriate context and in an understandable fashion that is culturally and linguistically sensitive.
Information about privacy concerns. To have the genetic testing offered by 23andMe, the consumer is required to agree to a 25-page Terms of Service and a 29-page Privacy Statement. Each of these documents is a legal agreement that permits 23andMe to use various types of personal information, some by virtue of the use of the 23andMe services and some (i.e., identifiable genetic or self-reported information) pursuant to what 23andMe considers to be explicit consent for research. De-identified information has been sold by 23andMe to pharmaceutical companies trying to develop new medical treatments. All of this may leave the typical consumer bewildered. Patients should carefully read the consents they sign and contact the testing laboratory with questions about data privacy. The internist has no responsibility to address the privacy issues of the testing laboratory, and should refer the patient to the testing laboratory.
How should the internist advise the patients in this case?
Given all of this information, what should the internist tell the couple in our case example above? The internist should tell them that the 23andMe test is a targeted only to specific variants and does not screen for all disease-causing variants of either Gaucher disease or cystic fibrosis; thus, the spouse who tested negative for each of these recessive conditions could still be carrying a disease-causing variant. An important factor to consider is the residual risk of being a carrier given the couple’s ancestry (Table 1). Gaucher disease and cystic fibrosis are more common in certain ethnic groups, but disease-causing variants have been found in individuals of all ethnicities (10). As a result, there is a still a small possibility of having a child with Gaucher disease or cystic fibrosis, and additional testing is available if the level of residual risk concerns them. For example, although the husband tested negative for the cystic fibrosis carrier test, 23andMe reports there is a residual risk of 1/390 that somebody of Ashkenazi Jewish ancestry is a carrier for cystic fibrosis even with a negative result (see “Residual Risk by Ethnicity” for cystic fibrosis in Table 1). For Gaucher disease, 23andMe does not provide a residual risk estimate for Latina individuals, so consultation with a genetic professional would be necessary to determine the residual risk of being a carrier. If both the husband and wife are carriers for the same recessive condition, there is a 25% chance of having a child with the condition. They could speak with a genetic counselor about their options for more comprehensive genetic testing, as well as details about Gaucher disease or cystic fibrosis, including the natural history of the conditions, available treatment options such as enzyme-replacement therapy and medication/nutritional support/lung transplant (see “Treatment” for Gaucher disease and cystic fibrosis in Table 1), the efficacy and impact of these treatments, and reproductive options available, including prenatal testing and in vitro fertilization with preimplantation genetic diagnosis, if they are both found to be carriers. A genetic counselor or other qualified provider can also give them additional information, such as that Ashkenazi Jewish individuals who are carriers for Gaucher disease have an increased 7.7% lifetime risk of developing Parkinson’s disease (10).
Table 1. Typical 23andMe Results and Suggested Clinician Responses.
| Disease | Reported Results | Clinician Response |
|---|---|---|
| Breast Cancer | “you do not have the three genetic variants we tested; 0 variants detected in the BRCA1 and BRCA2 genes” | • Only 3 out of over 1,000 variants are tested by 23andMe • Many other genes can increase breast cancer risk • Most cases of breast cancer are explained by factors other than these 3 variants • Patient’s family history suggests increased risk of breast cancer regardless of test result |
| Gaucher Disease Type 1 | “you have one of the variants we tested; 1 variant detected in the GBA gene” | • Does not screen for all disease-causing variants • Residual risk of carrying another variant • 25% chance of having child with disease if both parents are carriers • Genetic counselors can advise about increased risk of Parkinson’s disease in carriers |
| Cystic Fibrosis | “you have one of the variants we tested; 1 variant detected in the CFTR gene” | • Does not screen for all disease-causing variants • Residual risk of carrying another variant • 25% chance of having child with disease if both parents are carriers |
| Alzheimer’s Disease | “you have two copies of the ε4 variant we tested; Variant detected in the APOE gene” | • The test result does reflect an increased risk of developing the disease • No proven interventions to eliminate risk • Lifestyle changes may reduce the risk |
The internist should explain to the wife that the 23andMe test includes only 3 common Ashkenazi Jewish pathogenic variants in BRCA1/2 and does not evaluate the genes comprehensively to assess the more than 1,000 other known disease-causing variants in these genes (see “Variants Tested Relative to Total Number of Known Pathogenic Variants”, “Ethnicities at Highest Risk”, and “Pathogenic Variant Detection Sensitivity by Ethnicity” for BRCA1/2 in Table 2). The test also does not include any of the other genes that can increase the risk for hereditary breast cancer such as TP53, PTEN or PALB2 (see “Gene(s) Tested” for BRCA1/2 in Table 2). Since the test is most accurate for Ashkenazi Jews and given her Latina ancestry, the test does not provide much information about whether she carries a pathogenic variant in BRCA1/2. In addition, even for Ashkenazi Jews, the test is positive in only about 10% of those women who develop breast cancer (16). This means that the majority of Ashkenazi Jewish women who develop breast cancer do so for other reasons, including other genetic variants beyond BRCA1/2 and non-genetic factors. Based on her family history, the wife has an increased risk of developing breast cancer, and it is recommended that she meet with a genetic counselor to discuss her breast cancer risk, the risk of carrying a pathogenic variant in one of the hereditary breast cancer genes, and the additional, more comprehensive genetic tests available (17). To manage her risk of developing breast cancer, she has options such as enhanced breast cancer screening, chemoprevention, and risk-reducing surgery (see “Prevention Options” for BRCA1/2 in Table 2).
Table 2: Carrier Status Tests:
The following Table lists 11 of the 43 Carrier Status tests offered by 23andMe, which are those that are currently recommended for screening by the American College of Genetic and Genomics (ACMG). The following are brief descriptions of the information in each column: Gene Tested: the gene tested by 23andMe; Number of Pathogenic Variants Tested and Proportion of Recommended Variants Tested: the total number of pathogenic variants in the gene tested by 23andMe and the number of pathogenic variants tested by 23andMe relative to the total number of pathogenic variants recommended to be tested by either ACMG or the American College of Obstetricians and Gynecologists (ACOG); Ethnicities at Highest Risk: the ethnicities in which the tested pathogenic variants are known to be most frequent; Pathogenic Variant Detection Sensitivity by Ethnicity: the percentage of all pathogenic variant carriers of a given ethnicity that the test is expected to detect given the specific pathogenic variants tested by 23andMe; Residual Risk by Ethnicity: the risk of carrying a pathogenic variant by ethnicity with a negative result from the targeted 23andMe test; Treatment: interventions currently available for treatment or management of the medical condition or disease.
| Disease(s) (Reference) | Gene Tested | Number of Pathogenic Variants Tested and Proportion of Recommended Variants Tested | Ethnicities at Highest Risk | Pathogenic Variant Detection Sensitivity by Ethnicity | Residual Risk by Ethnicity | Treatment |
|---|---|---|---|---|---|---|
| Beta Thalassemia and Related Hemoglobinopathies (8, 9) | HBB |
Total: 10 ACOG: Screening is recommended for African, Southeast Asian, Mediterranean, Middle Eastern, and West Indian individuals by complete blood count and hemoglobin electrophoresis before genetic testing. |
Cypriot, Greek, Italian/Sicilian, Sardinian, African, Southeast Asian, Middle Eastern, and West Indian | Sardinian: 97% Cypriot: 90% Italian/Sicilian: 82% Greek: 75% Turkish: 66% Balkan: 41–80% South Asian: 20–70% Southeast Asian: 11–73% North African: 50–61% Middle Eastern: 29–64% |
Sardinian: 1/250 Cypriot: 1/71 Italian/Sicilian: 1/61 Greek: 1/37 Turkish: 1/65 Balkan, South Asian, Southeast Asian, North African, Middle Eastern: Unknown |
Symptom management, blood transfusion, bone marrow transplantation |
| Bloom Syndrome (8, 9) | BLM |
Total: 1 ACMG: 1/1 (for Ashkenazi Jewish) |
Ashkenazi Jewish | Ashkenazi Jewish: 99% | Ashkenazi Jewish: 1/11,000 Other ethnicities: Unknown |
No cure; symptom management to prevent infections/cancer |
| Canavan Disease (8, 9) | ASPA |
Total: 3 ACMG: 2/2 (for Ashkenazi Jewish) |
Ashkenazi Jewish | Ashkenazi Jewish: 98% | Ashkenazi Jewish: 1/2,000 Other ethnicities: Unknown |
No cure; symptom management |
| Cystic Fibrosis (8, 9) | CFTR |
Total: 29 ACMG: 22/23 (for all ethnicities) |
Ashkenazi Jewish, European, Hispanic | Ashkenazi Jewish: 94% European: 89% Latina: 73% African-American: 65% Asian: 55% |
Ashkenazi Jewish: 1/390 European: 1/230 Hispanic: 1/210 African-American: 1/170 Asian: 1/210 Other ethnicities: Unknown |
mutation specific medications, treatment of pulmonary and gastrointestinal symptoms, lung transplant, assisted reproductive technologies (ART) for male infertility |
| Familial Dysautonomia (8, 9) | IKBKAP |
Total: 1 ACMG: 1/2 (Ashkenazi Jewish) |
Ashkenazi Jewish | Ashkenazi Jewish: 99% | Ashkenazi Jewish: 1/2,300 Other ethnicities: Unknown |
No cure; symptom management only |
| Fanconi Anemia Group C (8, 9) | FANCC |
Total: 3 ACMG: 1/1 (for Ashkenazi Jewish) |
Ashkenazi Jewish | Ashkenazi Jewish: 99% | Ashkenazi Jewish: 1/88,000 Other ethnicities: Unknown |
Hematopoietic stem cell transplantation (HSCT) |
| Gaucher Disease Type 1 (8, 9) | GBA |
Total: 3 ACMG: 2/4 (for Ashkenazi Jewish) |
Ashkenazi Jewish | Ashkenazi Jewish: 92% | Ashkenazi Jewish: 1/200 Other ethnicities: Unknown |
Enzyme replacement or substrate reduction therapy (ERT/SRT) for type 1 |
| Mucolipidosis Type IV (8, 9) | MCOLN1 |
Total: 1 ACMG: 1/2 (for Ashkenazi Jewish) |
Ashkenazi Jewish | Ashkenazi Jewish: 77% | Ashkenazi Jewish: 1/550 Other ethnicities: Unknown |
No cure; symptom management only |
| Niemann-Pick Disease Type A (8, 9) | SMPD1 |
Total: 3 ACMG: 3/3 (for Ashkenazi Jewish) |
Ashkenazi Jewish | Ashkenazi Jewish: 97% | Ashkenazi Jewish: 1/3,000 Other ethnicities: Unknown |
No cure; symptom management only |
| Sickle Cell Anemia (8, 9) | HBB |
Total: 1 ACOG: Screening is recommended for African, Southeast Asian, Mediterranean, Middle Eastern, and West Indian individuals by complete blood count and hemoglobin electrophoresis before genetic testing. |
African | All ethnicities: 99% | None | Symptom management, blood transfusion, bone marrow transplantation |
| Tay-Sachs Disease (8, 9) | HEXA |
Total: 4 ACMG: 3/3 (for Ashkenazi Jewish) |
Ashkenazi Jewish, Cajun (French Canadian variants not tested) | Ashkenazi Jewish and Cajun: 99% | Ashkenazi Jewish: 1/2,700 Cajun: 1/29,000,000 French Canadian, other ethnicities: Unknown |
No cure; symptom management only |
The internist should advise the husband that carrying two copies of the ε4 APOE variant increases his risk of developing Alzheimer’s disease, even if he has no known family history of Alzheimer’s disease. The lifetime risk for a male having two copies (i.e., homozygous) for ε4 APOE, regardless of family history, is estimated to be about 51% (see “Penetrance” for Late-onset Alzheimer’s disease in Table 2). Although there are no specific interventions proven to eliminate his risk, there are data that suggest that regular exercise, a healthy diet, and good cardiovascular health may reduce the risk of developing Alzheimer’s disease (see “Prevention” for late-onset Alzheimer’s disease in Table 2). However, at this time the effectiveness of lifestyle modifications in preventing Alzheimer’s disease has not been definitively demonstrated.
In conclusion, the clinical value of 23andMe testing is currently quite limited because the number of genes and variants included are small and do not provide a comprehensive assessment of risk for most individuals for most conditions. The test result that most commonly has clinical utility is the identification of a pathogenic variant in BRCA1/2 in someone of Ashkenazi Jewish ancestry. However, regardless of ancestry, anyone with an identified pathogenic variant requires management based on National Comprehensive Cancer Network guidelines. However, before acting on a DTC result, patients should have the results confirmed by a clinical diagnostic laboratory and should discuss the results with a knowledgeable medical professional. Clinicians should be prepared to address patients’ concerns about genetic test results. If the volume of patients bringing DTC test results to their internists increases significantly in the future, scalable solutions to educate patients and address common questions will need to be developed by the testing laboratories.
Table 3: Genetic Health Risks:
The following Table lists the 9 diseases included in the Genetic Health Risk test offered by 23andMe. The following are brief descriptions of the information in each column: Gene(s) Tested: the gene(s) tested by 23andMe; Variants Tested Relative to Total Number of Known Pathogenic Variants: the number of variants tested out of the total number of known pathogenic variants in the gene; Ethnicities at Highest Risk: the ethnicities in which the tested pathogenic variants are known to be most frequent; Pathogenic Variant Detection Sensitivity by Ethnicity: the percentage of all carriers of any pathogenic variant in the gene listed of a given ethnicity that the test is expected to detect given the specific pathogenic variants tested by 23andMe. The test may not detect any pathogenic variant carriers among other ethnicities not listed. There may be other genes that cause the disease that are not tested by 23andMe.; Penetrance: the percentage of individuals with a positive test result who will develop the disease at some point in their lifetime (estimates frequently only available for well- studied ethnicities/populations); Prevention Options: interventions currently available to prevent or delay the onset of the disease; Treatment: interventions currently available for treatment or management of the medical condition or disease.
| Disease (Reference) | Gene(s) Tested | Variants Tested Relative to Total Number of Known Pathogenic Variants | Ethnicities at Highest Risk | Pathogenic Variant Detection Sensitivity by Ethnicity (when known) | Penetrance | Prevention Options | Treatment |
|---|---|---|---|---|---|---|---|
| Age-Related Macular Degeneration (8, 11, 12) | CFH, ARMS2 (not tested: at least 34 additional known risk genes) | 2/52 | Caucasian (most common in Caucasians, followed by Hispanic and Asian, least common in African-American) | Uncertain | 0–1 copies: 1.4% 2 copies: 5.2% 3–4 copies: 15.3% |
Smoking Cessation | No cure |
| Alpha-1 Antitrypsin Deficiency (8, 9) | SERPINA1 | 2/>35 | Caucasian | Northern European: 95% | Risk estimates available for Europeans: *MZ genotype: Nonsmokers unlikely to develop chronic obstructive lung disease (COPD), smokers at slightly increased risk, insufficient data for cirrhosis *SZ genotype: 20%–50% lifetime risk of COPD for smokers, insufficient data for cirrhosis *ZZ genotype: >80% COPD, 30–40% cirrhosis after age 50 |
Smoking cessation and limit alcohol | Enzyme replacement, bronchodilators, antibiotics, lung transplant |
| Breast cancer (8, 9) |
BRCA1, BRCA2 (not tested: TP53, PTEN, CDH1, CHEK2, ATM, PALB2, STK11, BLM, WRN, RAD51C, MLH1, MSH2, MSH6, PMS2, EPCAM) |
3/>1000 | Ashkenazi Jewish although observed in all ethnicities | >95% among Ashkenazi Jews | BRCA1 female (by age 70): 45%–85% breast, 39%–46% ovarian BRCA2 female (by age 70): 45%–85% breast, 10%–27% ovarian BRCA2 male (lifetime): 7%–8% Breast |
Increased screening, chemoprevention, prophylactic Surgery | Surgery, chemotherapy |
| Celiac Disease (8, 9) | HLA-DQA1, HLA-DQB1 (not tested: 39 other genetic risk loci that contribute only ~5% of the genetic risk for celiac disease) | 2/2 | Caucasian (rarely diagnosed in those of sub-Saharan African descent) | 100% | 1 or more copies of HLADQ2.5 or HLA-DQ8 haplotypes: ~3% | Gluten-free diet | Gluten-free diet |
| G6PD Deficiency (8, 13) | G6PD | 1/>160 | African (variants common to Italian, Mediterranean, and Middle Eastern ethnicities not tested) | African descent: 90% | Penetrance dependent on the exposure to triggering medication. Males: ~71% (Xlinked) Females 2 copies: ~48% Females 1 copy: ~7.5% |
Avoidance of triggers (fava beans, certain drugs) | Elimination of triggers, blood transfusions |
| Hereditary Hemochromatosis (HFE-Related) (8, 9) | HFE | 2/~28 | Caucasian (these variants are most common in Northern Europeans, but also found in Hispanics, African-Americans, and Asians) | Caucasian: 91% | Males 2 copies C282Y: 24–36% Females 2 copies of C282Y: 4–14% Males 1 copy C282Y 1copy H63D: 3% Females 1 copy C282Y 1 copy H63D: 2% Other genotypes: Not likely at Risk |
Phlebotomy | Phlebotomy |
| Hereditary Thrombophilia (Prothrombin-Related and Factor V Leiden Thrombophilia) (8, 9) | F2, F5 | 2/2 | Caucasian (both variants most common in Europeans, extremely rare in African and Asian populations) | Caucasian: >95% | 1 copy F5: 2/1000 2 copies F5: 15/1000 (1- year risk of blood clot) |
Avoid estrogen-containing contraception and hormone replacement therapy | May include Anticoagulation |
| Late-Onset Alzheimer’s Disease (8, 9, 14) |
APOE (Not tested: APP, PSEN1, PSEN2) |
1/1 (for Late-Onset Alzheimer’s) | All ethnicities | All ethnicities: 100% | Males 1 copy ε4: 20–23% Females 1 copy ε4: 27–30% Males 2 copies ε4: 51% Females 2 copies ε4: 60% (lifetime risk) |
Healthy diet, exercise, and improved cardiovascular health | No specific treatment, supportive care |
| Parkinson’s Disease (8, 9, 15) |
LRRK2, GBA (Not tested: SNCA, VPS35, PRKN/PARK 2, PINK1, PARK7, ATP13A2, FBX07, SLC6A3, TAF1) |
2/at least 28 | Caucasian, Ashkenazi Jewish, North African Berber | Caucasian: 100% for GBA Uncertain for LRRK2. |
1 copy G2019S: 24–91% 2 copies N370S: 9.1%% 1 copy N370S: 5.9%% |
None | Dopaminergic Therapy |
Key Points Table.
Key Points
Direct-to-consumer genetic testing is becoming increasingly popular, and clinicians should be prepared to provide guidance to their patients when presented with such genetic test results.
23andMe does not perform comprehensive testing of known pathogenic genetic variants and may be of limited value and sensitivity for patients who are not of European or Ashkenazi Jewish background.
The positive predictive value of many 23andMe genetic tests alone is limited because risk is often modified by interacting genes, environment, lifestyle, and family history that are not included with the risk predictions.
Clinicians should refer patients with concerns about genetic test results or genetic concerns not addressed by the direct-to-consumer testing to a genetic counselor or other qualified provider.
Acknowledgements:
This publication was supported by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), through Grant Number UL1TR001873. KK was additionally supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) through the Kidney Precision Medicine Project (KPMP), grant number UG3DK114926. Both KK and WKC were supported by the National Human Genome Research Institute (NHGRI), grant number U01HG008680. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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