Tim Cottee was busy at work when his smartphone chimed with an alert he'd been anxiously waiting to receive. Weeks earlier, he had sent a sample of his saliva to 23andMe, a California-based company that sells direct-to-consumer (DTC) genetic tests. After the chime sounded on that January day in 2015, the 43-year-old account executive from Winnipeg, Canada, closed his office door for privacy. Filled with a mix of excitement and apprehension, he started clicking through his online health report.
Cottee hoped the DNA analysis would answer a question that had haunted him ever since his mother was diagnosed with Alzheimer's disease at age 58: Was he at high genetic risk for developing the disorder? "I assumed that my mother had a genetic predisposition, because she was diagnosed at such a young age," he says.
After his mother died at age 69 in 2009, another member of Cottee's family was diagnosed with Alzheimer's. "I wondered who would be next," Cottee recalls. After learning that a variant in the apolipoprotein gene called apolipoprotein E4 (APOE4) carries a hereditary risk for Alzheimer's, he decided to get tested for it. "I felt I'd be better off knowing if I had that gene because there might be something I could do about it."
Wider Availability
It's never been easier—or more affordable—for consumers to mine their DNA for hidden health threats, including genes that raise the risk for certain neurologic disorders, such as Alzheimer's disease, Parkinson's disease, and early-onset primary dystonia, a rare condition marked by muscle spasms, shaking, and other involuntary movements.
Genetic tests for neurologic and other diseases used to be available only through medical providers. When the first DTC DNA tests hit the market more than a decade ago, they cost as much as $2,500. Now dozens of companies—including 23andMe, Futura Genetics, and Helix—sell at-home genetic testing kits for $100 to $200, often without any involvement from a physician.
Despite the rise in popularity of these products, the US Centers for Disease Control and Prevention (CDC) advises consumers to "think before you spit," which is usually all that is required for the test. The federal agency recommends carefully weighing the pros and cons, including the possibility of getting incorrect, incomplete, or devastating health information without a medical provider or genetic counselor to explain and interpret the results.
The experts we interviewed echo the cautionary words of the CDC, encouraging those who want to get tested to talk to a medical professional first. Here's what else they shared.
FDA Oversight
In 2017, 23andMe was the first company to receive authorization from the US Food and Drug Administration (FDA) to sell a personal genomic test for disease risk directly to consumers. The test checks for genes linked to increased risk for developing 10 disorders. Three years earlier, the FDA had warned 23andMe to stop selling a similar test until it could prove that its tests were accurate and that consumers could understand the information in its health reports.
After 23andMe provided both unpublished scientific data showing that its tests "correctly and consistently identified variants associated with the 10 indicated conditions or diseases from a saliva sample" and survey results that found that users of the test understood at least 90 percent of the information in their health reports, the FDA changed its stance. It "authorized" the test's sale using a review process reserved for medical devices it deems to have a low to moderate risk for harm, rather than the more rigorous approval process it uses for new drugs.
Erroneous Results
Like all medical tests, DTC genotyping carries a risk for false negative and false positive results. In the case of false negative results, users may be told they don't have a certain mutation when they actually do. With false positive results, they are told they carry a potentially harmful gene when they don't.
That's what happened to Matt Fender, a 33-year-old web developer from New York City. In 2017, he uploaded his raw data from 23andMe into a DNA search engine called Promethease, which combs through the customer's genome for variants that have been discussed in medical studies. (Raw data include a list of every gene that the company's test detected, including some that are not mentioned in the health report the consumer receives.) "After I got a report saying I carried PSEN1 [presenilin PS1], I was shocked and horrified and went through a grieving process. I read that no one survives with PSEN1 and that I'd start losing my memory when I was in my forties or fifties," Fender says.
PSEN1 is one of the three identified genes in which mutations can cause Alzheimer's disease. The mutations tend to cause early-onset Alzheimer's, a relatively rare form of dementia in which symptoms develop before age 65. It accounts for fewer than 5 percent of cases, says Keith N. Fargo, PhD, director of scientific programs and outreach at the Alzheimer's Association. However, many people who develop early-onset Alzheimer's do not have one of these mutations, so just having a family member with early-onset Alzheimer's does not necessarily mean that a genetic mutation is to blame, he adds. "People with the PSEN1 genetic mutation are generally considered 100 percent likely to develop Alzheimer's," Dr. Fargo says. "People considering this testing, which should be done through a genetic counselor or a neurologist, typically have multiple generations of affected family members or many family members who developed Alzheimer's before age 65."
Distressed by False Positives
Fender has no family history of early-onset Alzheimer's disease. "My doctor referred me to a geneticist for confirmatory testing, but it turned out he didn't see patients under age 50 who had no symptoms or family history. While searching for another medical provider, I ordered a test from Ancestry for a second opinion."
When he uploaded the raw data from Ancestry to Promethease, he was told he did not have the PSEN1 variant. "Naturally, I wanted to believe that Ancestry was right and 23andMe was wrong, but I needed a medical expert to break the tie," says Fender. "After months of awful stress and anxiety, I found a genetics counselor." That counselor, Jill Goldman of the Taub Institute at Columbia University Medical Center in New York City, recommended he get a highly accurate clinical test, which revealed that Fender does not have a disease-causing mutation in the PSEN1 gene.
Misinterpreting Raw Data
A 2018 study published in Genetics in Medicine also raises questions about the accuracy of third-party interpretation services—as well as that of DTC genetic testing companies. Researchers analyzed the raw data of 49 patients who were referred to the Ambry Genetics Corp. laboratory for confirmatory testing by their medical providers. The study found that 40 percent of the variants noted in the raw data were incorrectly reported, and it identified eight cases in which variants in the data were misunderstood by third-party interpretation services.
Harmful or Helpful
"People often assume that knowledge is power—and for some people, these tests offer useful insights about their health. But others feel blindsided when they learn they are at high risk for an incurable disease," says Scott Roberts, PhD, professor of health behavior and health education and director of the Certificate in Public Health Genetics program at the University of Michigan School of Public Health in Ann Arbor.
To find out if consumers are more likely to be helped or harmed by exploring their genetic risks, Dr. Roberts and other researchers recently studied 1,648 people who had undergone DTC testing. More than 93 percent of participants said getting the test was the right decision, and nearly 60 percent reported that the genetic insights they'd gained would influence how they managed their health. Only 2 percent regretted receiving their genetic data, and 1 percent felt they were hurt by it. The findings were published in Public Health Genomics in January 2017.
Inspired to Help
Jessi Keavney says personal genomic testing was the right choice for her, even though she learned that she carries a mutation of the LRRK2 gene linked to a higher risk for Parkinson's disease. "Even though my father has been living with Parkinson's for 17 years and I've seen how it affects him, I wasn't devastated to find out that I was at risk for getting it," says the 41-year-old cost accounting manager from Pendergrass, GA. "Knowing I had the mutation meant my dad must have it too, which unlocked part of the mystery."
It also motivated Keavney to get involved in Parkinson's advocacy and research. "I've volunteered for at least a dozen studies, knowing that one day doctors will be able to prevent this disease," she says. "As a mother of three sons, I'm particularly inspired to help advance science for future generations."
Genes Aren't Destiny
About 15 percent of people with Parkinson's have a family history of the disease—and six variants of the LRRK2 gene rank among the more common genetic causes, says James Beck, PhD, chief scientific officer for the Parkinson's Foundation. He recommends that people who are considering genetic testing consult a neurologist or genetic counselor first. "I've spoken to a number of people who have been tested and have misinterpreted their results. In reality, people with LRRK2 variants have a 30 percent risk for getting the disease-and a 70 percent probability that they won't," he emphasizes. "Another variant, called GBA, increases risk for Parkinson's sixfold, but many people with it will never develop the disease."
Keavney did find her health report easy to understand. "Before your results for the Parkinson's gene are revealed, you are guided through an on-screen tutorial and have to consent to see the results. A year after I found out I had the LRRK2 mutation, I talked to a genetic counselor, and there was nothing she could tell me that I didn't already know."
A Devastating Experience
In 2009, Jamie Tyrone was intrigued when she learned of a research study in which participants received a free DTC genetic test followed by genetic counseling (the study was done to see if test results motivate people to change their health behavior). The 58-year-old retired nurse from San Diego also hoped the testing would solve a medical mystery: "I was having some neurologic symptoms similar to those of multiple sclerosis. I thought the test might help my doctors figure out what was wrong."
The DNA analysis didn't shed any light on her symptoms. Instead, Tyrone learned that she was at high risk for a different disorder. "I wish I'd been given an opportunity to talk to the genetic counselor before having the test because I was blindsided when I found out I had two copies of the APOE4 gene, the genotype with the greatest risk for Alzheimer's," she says. "If I had talked to a counselor, I could have been prepared for this possibility—or opted not to have the test."
People with one copy of the APOE4 gene have three to four times higher risk than those without the gene for late-onset Alzheimer's, the most common form of the disease. Those with two copies (also known as the 4-4 genotype) are at 15 to 20 times higher risk, according to a 2017 study in Clinical Experimental Psychology. The Alzheimer's Foundation issued a statement in 2018 calling on DTC genetic testing companies to adopt industrywide standards that include easy access and referrals to qualified genetic counselors as part of the testing process.
Informed Decisions
"It is essential that consumers understand [before testing] which genes are included in these tests and that finding out your APOE status can be life-changing," says Lori Frank, PhD, one of the authors of the Alzheimer's Foundation statement. "That way people can make a truly informed decision as to whether they actually want this information. Consumers also need to know that while APOE4 raises risk for Alzheimer's, it doesn't cause the disease. Some people with the 4-4 genotype will never get the disease."
After receiving her test results, Tyrone slipped into a deep depression. "At the time, my father was in the late stages of Alzheimer's, and when I looked into his eyes I saw my destiny," says Tyrone, who spent more than $40,000 on psychotherapy trying to come to terms with her APOE status. "Every time I lost my keys or forgot someone's name, I worried that it might be the start of Alzheimer's. I felt like I was walking around with APOE4-4 tattooed on my forehead and thought about overdosing on pills."
Finding a Silver Lining
Tyrone gradually emerged from her depression and launched a nonprofit organization called Beating Alzheimer's by Embracing Science (BABES), which provides information and resources to others with the APOE4-4 genotype. She has also volunteered for several clinical trials. "Being part of research to find a cure has been one of the most rewarding and meaningful things I've ever done," she says.
No Easy Answers
Genotyping like APOE doesn't always provide definitive answers, says Goldman, the genetic counselor. "You may find it comforting if the test shows you don't have the APOE4 genotype, but you still have a 33 percent risk of developing Alzheimer's if you live past age 85, just like everyone else," she says. "If you're concerned about genetic risk, your family history alone can give you a risk prediction. If you have a parent with Alzheimer's, studies suggest that you are about three times more likely to get it than someone with no close relatives with the disease."
Additionally, DTC tests don't screen for all known genetic variants that may raise the risk for developing a certain disease, says Bruce H. Cohen, MD, FAAN, director of the NeuroDevelopmental Science Center at Akron Children's Hospital in Ohio. "And obviously, these tests don't screen for variants that are still unknown, so even if you don't have any of the mutations included in the test, it's still possible that you could get that disease."
Ripple Effects
Another factor to consider before getting tested is the possible unintended effect on family members, says Dr. Cohen. "If you decide to be tested for a mutation, be careful about sharing that decision and the results with family members and inadvertently revealing information about their health risks," he says. "For example, if you turn out to have the APOE4 genetic variant, your siblings and other close relatives could also be at higher genetic risk for Alzheimer's—and they may not want to know that. You may want to keep the news of your results to yourself or consider how your family members might feel before getting tested."
Beware Discrimination
"Part of my job is to play devil's advocate and make sure people consider all the possible consequences of testing, such as the risk of genetic discrimination," says Amy Shealy, a genetic counselor at the Cleveland Clinic. "A federal law prohibits genetic discrimination by health plans and most employers, but it doesn't cover smaller employers or life, disability, or long-term care insurers, so before being tested for genetic disorders, people may want to obtain or increase this type of insurance coverage, since they may not be able to get it afterwards or may have to pay more for it."
Life-Changing Results
After spending about $200 on the 23andMe test, Tim Cottee steeled himself for the possibility that he might have the APOE4 genotype. "For weeks, I'd run through all sorts of scenarios in my mind, except the one that actually occurred: My report said I did not have the APOE4 gene."
His initial reaction was to get angry with his late mother. "I couldn't help thinking that she brought this disease on herself, because she had led a very unhealthy life. She was overweight, sedentary, ate a poor diet, and didn't manage her diabetes very well," he says. "Then I thought that if her lifestyle was the problem, that was something I can control in my own life. I started exercising more, ate a healthier diet, and lost 30 pounds. Ultimately, I felt learning that I didn't have this gene was empowering because it motivated me to take care of my health."
Testing for Early-Onset Dystonia
A direct-to-consumer test is also available for early-onset dystonia, the type that is most common among people of Ashkenazi Jewish descent, although it may occur in any population. Symptoms of this form of dystonia typically start during childhood, at an average age of 12. The disease seldom develops after age 29. A genetic mutation in the DYT1 gene is the culprit in most cases, according to a 2003 study published in Archives of Neurology.
"Children without symptoms should never have genetic testing to predict their risk for early-onset primary dystonia, even if they have a family history of this condition," says Jill Goldman, a genetic counselor at the Taub Institute at Columbia University Medical Center in New York City. "Children who are symptomatic should be evaluated by a neurologist."
Adults with a family history of early-onset dystonia may wish to be tested for DYT1, "but the testing should be done only after consulting with a genetic counselor to make sure it's appropriate for them," says Goldman. "Only 30 to 40 percent of people who carry the gene go on to develop the disease."
Genetic Tests for Huntington's Disease
The current offering of at-home tests does not provide information about the risk for Huntington's disease. People who have a family history of the disorder who want to know if they have the gene must undergo testing through a health care professional and a genetic counselor.
That is how Kathy and Kelly Gibson learned about their own risk for the disease. In 1986, a mysterious illness killed the Gibsons' father at age 68. Years later, Kelly, who was then in her thirties, began exhibiting some of the same symptoms: problems with balance, shaky hands, and difficulty understanding written instructions, such as a recipe. "We both wondered if she had it, not knowing what 'it' was," says Kathy, now 70, an artist from Berlin, MD.
That's when a relative revealed a family secret: The sisters' father had had Huntington's disease, a fatal genetic condition that causes progressive breakdown of the brain's nerve cells. Symptoms, including personality changes, impaired memory, tremor, and trouble swallowing, typically start between ages 30 and 50. About 30,000 Americans are currently living with Huntington's disease, according to the Huntington's Disease Society of America.
Gene Variant
In 1999, after much thought, Kathy and Kelly decided to be tested for the gene that causes Huntington's disease. Everyone has this gene, but those who get the disease have an expanded form with 40 or more repeats of a certain genetic sequence. Children of a parent with Huntington's disease have a 50 percent chance of inheriting the expanded gene, says Jee Bang, MD, MPH, clinical director of the Huntington's Disease Center of Excellence in Baltimore and assistant professor of neurology and psychiatry at Johns Hopkins School of Medicine. "There's no cure for Huntington's, only symptomatic treatments, but potential disease-modifying therapies are on the horizon and new clinical trials to test them are about to begin," says Dr. Bang.
Testing is available only through medical providers after a rigorous evaluation. "This typically involves a neurologic examination for signs of Huntington's disease, a psychological evaluation, and genetic counseling to provide education about the disease, its inheritance pattern, and possible outcomes of testing," says Dr. Bang. Counseling involves walking patients through a variety of scenarios to help them understand how their test results might affect their life, as results are not as simple as whether or not you have the gene.
"Most people believe only two results are possible from the test: You either have the gene or you don't," says Amy Shealy, MS, a genetic counselor at the Cleveland Clinic. "Actually, there are four possibilities. People with 26 or fewer repeats will not get Huntington's. Those with 27 to 35 repeats will not develop symptoms, but their children might. Some people with 36 to 39 repeats will get Huntington's disease and others won't, so their test won't provide a definite answer. For people with 40 or more repeats, the test can't tell at what age their symptoms will start."
A Fateful Result
Kathy's test results were disclosed to her in person by a genetic counselor. "My sister and I went to the hospital together, and I was ecstatic when I learned that I didn't have the Huntington's gene, until I saw my sister leaving the office of another counselor in tears," recalls Kathy, who became her sister's primary caregiver. Since Kelly's death in 2014, at age 49, Kathy honors her memory by donating a portion of her earnings from her art to the Huntington's Disease Society of America. (Read more about Kathy and Kelly's story.)
