Curbside Consultation

Clinical and Personal Utility of Genetic Risk Testing

 

Am Fam Physician. 2018 May 1;97(9):600-602.

Case Scenario

A 65-year-old East Asian woman recently shared with me the results of her 23andMe test, which revealed that she had one copy of the ɛ4 genetic variant, indicating that she has a slightly increased risk of Alzheimer disease. The test instructed her to consider talking to a health care professional if she had any symptoms of Alzheimer disease or any concerns about her test results. The test results showed she was at average risk of other genetic conditions. She is otherwise healthy, takes no medications, has no known family history of Alzheimer disease, and has no chronic conditions. She works full time as a software engineer. She reports misplacing items, such as her car keys or phone, a few times per week, and she is usually able to locate them in 15 to 30 minutes. She asked me whether she should obtain long-term care insurance given her test results.

What is the evidence for APOE genetic predictive testing for late-onset Alzheimer disease? Should these genetic test results be included in my patient's medical record? Is she protected from health or life insurance company rate discrimination? How should I advise her about long-term care insurance?

Commentary

On April 6, 2017, the U.S. Food and Drug Administration (FDA) approved marketing of the 23andMe Personal Genome Service, the first direct-to-consumer genetic test. This test uses genomic DNA collected from mail-in saliva collection kits to provide information on a patient's genetic risk of certain medical diseases or conditions. The diseases and conditions covered by 23andMe that were originally approved by the FDA include alpha1-antitrypsin deficiency, celiac disease, factor XI deficiency, Gaucher disease, glucose-6-phosphate dehydrogenase deficiency, hereditary thrombophilia, Parkinson disease, late-onset Alzheimer disease, primary dystonia, and hereditary hemochromatosis (Table 1). Currently, genetic testing for six of these disorders (alpha1-antitrypsin deficiency, celiac disease, hereditary hemochromatosis, hereditary thrombophilia, late-onset Alzheimer disease, and Parkinson disease) and age-related macular degeneration are offered in the 23andMe genetic health risk report. On March 6, 2018, the FDA approved testing for three mutations in the BRCA1 and BRCA2 genes conferring risk of hereditary breast and ovarian cancers as a separate service. Direct-to-consumer genetic testing for BRCA1/BRCA2 is not included in this discussion because, unlike the other tests mentioned, there is evidence of clinical utility for BRCA1/BRCA2 in patients with high-risk family histories1 and because the complexity of the topic warrants a separate discussion.

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TABLE 1.

Selected Conditions from the 23andMe Personal Genome Service Genetic Health Risk Tests

Disease or conditionEffect on risk phenotypeGenetic variant

Age-related macular degeneration*

Vision loss in older adults

Y402H variant in CFH gene

A69S variant in ARMS2 gene

Alpha1-antitrypsin deficiency*

Increased risk of lung or liver disease

PI*Z variant in SERPINA1 gene

PI*S variant in SERPINA1 gene

Alzheimer disease*

Increased risk of late-onset Alzheimer disease

ɛ4 variant in APOE gene

Celiac disease*

Increased risk of celiac disease

HLA-DQ2.5 haplotype in DQA1*0501 gene

Factor XI deficiency†‡

Increased risk of bleeding following trauma or surgery

F283L variant in F11 gene

E117X variant in F11 gene

IVS14+1G>A variant in F11 gene

Gaucher disease†‡

Increased risk of Gaucher disease symptoms

N370S variant in GBA gene

84GG variant in GBA gene

V394L variant in GBA gene

Glucose-6-phosphate-dehydrogenase deficiency§

Increased risk of anemia

Val68Met variant in G6PD gene

Hereditary hemochromatosis*

Increased risk of hereditary hemochromatosis and iron overload

C282Y variant in HFE gene

H63D variant in HFE gene

Hereditary thrombophilia*

Increased risk of blood clots

Factor V Leiden in the F5 gene

Prothrombin G20210A in the F2 gene

Parkinson disease*†‖

Increased risk of Parkinson disease

G2019S variant in LRRK2 gene

N370S variant in GBA gene

Primary dystonia†‡

Increased risk of early-onset primary dystonia (DYT1/TOR1A-related)

DeltaE302/303 variant in DYT1 gene


*—Most relevant for persons of European descent.

†—Most relevant for persons of Ashkenazi Jewish descent.

‡—Test cleared by the U.S. Food and Drug Administration on April 6, 2017, but not included in the 23andMe genetic health risk profile as of March 9, 2018.

§—Most relevant for persons of African descent.

‖—Most relevant for persons of North African Berber descent.

TABLE 1.

Selected Conditions from the 23andMe Personal Genome Service Genetic Health Risk Tests

Disease or conditionEffect on risk phenotypeGenetic variant

Age-related macular degeneration*

Vision loss in older adults

Y402H variant in CFH gene

A69S variant in ARMS2 gene

Alpha1-antitrypsin deficiency*

Increased risk of lung or liver disease

PI*Z variant in SERPINA1 gene

PI*S variant in SERPINA1 gene

Address correspondence to Sean P. David, MD, SM, DPhil, at spdavid@stanford.edu. Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.

References

show all references

1. National Academies of Sciences, Engineering, and Medicine. Committee on the Evidence Base for Genetic Testing. An Evidence Framework for Genetic Testing. Washington, DC: National Academies Press; 2017....

2. Genin E, Hannequin D, Wallon D, et al. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry. 2011;16(9):903–907.

3. Letenneur L, Gilleron V, Commenges D, Helmer C, Orgogozo JM, Dartigues JF. Are sex and educational level independent predictors of dementia and Alzheimer's disease? Incidence data from the PAQUID project. J Neurol Neurosurg Psychiatry. 1999;66(2):177–183.

4. Lambert JC, Ibrahim-Verbaas CA, Harold D, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013;45(12):1452–1458.

5. Leusink M, Onland-Moret NC, de Bakker PI, de Boer A, Maitland-van der Zee AH. Seventeen years of statin pharmacogenetics: a systematic review. Pharmacogenomics. 2016;17(2):163–180.

6. Teutsch SM, Bradley LA, Palomaki GE, et al. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative: methods of the EGAPP Working Group. Genet Med. 2009;11(1):3–14.

7. Broadstock M, Michie S, Marteau T. Psychological consequences of predictive genetic testing: a systematic review. Eur J Hum Genet. 2000;8(10):731–738.

8. Zintzaras E, Kitsios GD, Triposkiadis F, Lau J, Raman G. APOE gene polymorphisms and response to statin therapy. Pharmacogenomics J. 2009;9(4):248–257.

9. Hudson KL, Holohan MK, Collins FS. Keeping pace with the times—the Genetic Information Nondiscrimination Act of 2008. N Engl J Med. 2008;358(25):2661–2663.

10. Green RC, Lautenbach D, McGuire AL. GINA, genetic discrimination, and genomic medicine. N Engl J Med. 2015;372(5):397–399.

11. Christensen KD, Roberts JS, Zikmund-Fisher BJ, et al.; REVEAL Study Group. Associations between self-referral and health behavior responses to genetic risk information. Genome Med. 2015;7(1):10.

12. Taylor DH Jr, Cook-Deegan RM, Hiraki S, Roberts JS, Blazer DG, Green RC. Genetic testing for Alzheimer's and long-term care insurance. Health Aff (Millwood). 2010;29(1):102–108.

Case scenarios are written to express typical situations that family physicians may encounter; authors remain anonymous. Materials are edited to retain confidentiality.

This series is coordinated by Caroline Wellbery, MD, Associate Deputy Editor.

A collection of Curbside Consultation published in AFP is available at https://www.aafp.org/afp/curbside.

Please send scenarios to Caroline Wellbery, MD, at afpjournal@aafp.org. Materials are edited to retain confidentiality.

 

 

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