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In That Case
Paul H. Mason
Centre for Values, Ethics and the Law in Medicine, University of Sydney
Department of Anthropology, Macquarie University
Woolcock Institute of Medical Research, University of Sydney
Jordan, an absent-minded, mid-forties paramedic with two children, places an online order for a personal genomic test for health and ancestry from an overseas company. After receiving the test kit and following the instructions, Jordan sends back the required biological sample. Eight weeks later, Jordan receives an e-mail detailing how to access the results through a private portal on a public online website. Jordan is eager to read the results and opens the link.
Several of the personal genomic test results catch Jordan by surprise. More than 75 per cent of Jordan’s genetic inheritance is European, which was expected given that Jordan’s paternal grandparents were French and Italian. However, just under 25 per cent of Jordan’s genetic inheritance is determined to be East Asian, and more specifically Japanese. Jordan’s mother, who had always been told that she was Dutch, was born just after the Second World War in Southeast Asia. Sadly, Jordan’s maternal grandmother died during childbirth, and Jordan’s mother died young from complications associated with diabetes.
Nothing immediately alarming is revealed in regards to Jordan’s health. However, Jordan is found to carry the ε2/ε3 variant of the APOE gene associated with Alzheimer’s disease. According to the personal genomic testing company, ε3 is the most common variant of the APOE gene with a frequency of 11 per cent in European populations and 8 per cent in East Asian populations. The APOE gene comes in three main variants: ε2, ε3, and ε4. The website states that African Americans and East Asians have higher odds of developing Alzheimer’s disease if they carry variants of these genes, but Jordan does not know what that means for someone of a European and East Asian background. Jordan is partly comforted, however, by the information that she is not found to carry the ε4 variant of APOE, which is the gene associated with the highest risk for Alzheimer’s disease.
Despite what appears to be clear and reassuring information, Jordan becomes concerned. Experience working with patients with Alzheimer’s disease makes Jordan acutely aware of the tragic future that can lie ahead with regards to such a diagnosis. Jordan asks colleagues for advice, but none of them can provide clarification about the risk factors for developing Alzheimer’s disease. Some of Jordan’s colleagues raise concerns about trusting the personal genomic test results and suggest another test from a different company.
Jordan orders a second test—this time a special blood test with a greater menu of variants at three times the cost of the first. The sample is collected in a pathology clinic in the city and then sent to a laboratory overseas for processing. Three months later, Jordan returns to the clinic to obtain the results. The two-page report finds that Jordan carries a heterozygous PSEN1 gene variant, c.236C>T (p.Ala79Val), a variant classified as “pathogenic for Alzheimer’s disease.” Heterozygous variants of “unknown clinical significance” also were detected in the PSEN2 gene, c.983A>T (p.Tyr328Phe), and the SPG11 gene, c.6878G>A (p.Arg2293GIn). The second page of the report includes an interpretation of these results indicating that early-onset familial Alzheimer’s disease has been associated with mutations in three genes: Aβ amyloid precursor protein (APP) located at chromosome 21q21.3, presenilin 1 (PSEN1) located at chromosome 14q24.3, and presenilin 2 (PSEN2) located at chromosome 1q42.13. According to the report, mutations in the PSEN1 gene account for up to 70 per cent of early-onset Alzheimer’s disease cases, and mutations in the PSEN2 gene account for less than 5 per cent. The SPG11 gene has not been reported to be associated with Alzheimer’s disease but is reported to be associated with amyotrophic lateral sclerosis 5, Charcot-Marie-Tooth disease, and spastic paraplegia 11 in an autosomal recessive manner. The report states that approximately 1 per cent to 6 per cent of all Alzheimer’s disease is early-onset (age < 60–65 years), and approximately 60 per cent is familial, with 13 per cent appearing to be inherited in an autosomal dominant manner. Jordan, however, does not know how to relate this information to the current results.
Jordan reads widely about Alzheimer’s but is overwhelmed with sources and material that go off in numerous directions about lifestyle, nutritional, stress, microbial, and even fungal components of the disease. Jordan learns about an international research consortium that is conducting a large drug trial of people who are at genetic risk of Alzheimer’s disease but who do not currently exhibit any symptoms. Jordan is unsure about whether to become involved. She also considers registering for brain bank donation but puts off making a decision for a later date.
In addition to the questions raised about Jordan’s family tree, Jordan is left with even more questions about Alzheimer’s disease and healthy ageing. Furthermore, as a parent, Jordan is unsure whether to share these results. The second report states that “offspring have an estimated fifty per cent chance of inheriting the reported pathogenic variant, PSEN1.” What will it mean for children to learn about their genetic inheritance and potential future health? Should they also undertake a genomic test to determine if they carry variants of APP, PSEN1, and PSEN2? What measures can Jordan take to ensure longevity and quality of life? On the flip side, what burden of proof and veracity of data should be required of a determined association before the association is allowed to worry the general public through testing? Finally, Jordan no longer wants either overseas company to retain this genetic information and wants them to destroy the samples and corresponding data, but she is uncertain how to ensure that this wish is respected. What began as a personal curiosity in health and ancestry ended up raising questions about family genealogy, healthy ageing and genomic risk, test validity, data sharing, research database security, and familial testing, among other concerns, and Jordan is not clear where to start.
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