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Neurogeneticists Handle the Fallout from Direct-to-Consumer Genetic Tests
Here's Their Advice on How to Counsel Patients

Article In Brief

Neurogeneticists and genetics counselors discuss the misconceptions patients have about results from direct-to-consumer tests and how they address them in practice.

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Wayne W. Grody, MD, PhD, estimates that at least once a week someone contacts the divisions of medical genetics and molecular diagnostics at the UCLA Medical Center after receiving health-related genetic information from a direct-to-consumer (DTC) genetic sequencing company like 23andMe, AncestryDNA, or FamilyTreeDNA.

“They've been given reams and reams of genetic health information, most of which has no clinical relevance whatsoever, but to a layperson, it can look very scary,” said Dr. Grody, director of the UCLA Molecular Diagnostic Laboratories and Clinical Genomics Center and a professor of pathology, human genetics and pediatrics at the Geffen School of Medicine at UCLA. “People freak out, come to us with these printouts, and ask us to explain them.”

The US Food and Drug Administration put a temporary halt to the health information side of 23andMe—probably the most commonly used of the DTC genetic testing outfits—in 2013, charging that the company had failed to provide evidence that their tests were “analytically or clinically validated.”

The company was permitted to relaunch the health information reports in 2015, but only for tests that passed the agency's review. Currently, consumers can receive information about their predisposition to more than a dozen genetically-related conditions, and their carrier status for more than 40 gene variants for recessive health conditions, including familial dysautonomia, Canavan disease, and several types of limb girdle muscular dystrophy.

Two of the neurology-related genetic findings from that list of nine conditions for which 23andMe assesses “health predisposition” involve the relative risk of Alzheimer's disease and Parkinson's disease. 23andMe provides information about an individual's APOE gene variant (associated with relative risk of late-onset Alzheimer's disease) and two genetic variants associated with Parkinson's.

“Most people don't understand the difference between changes in your genetics that are causal for a disease, such as Duchenne muscular dystrophy or cystic fibrosis, and risk-related variants that increase susceptibility,” said Jeffery M. Vance, MD, PhD, professor and founding chair of the Dr. John T. Macdonald Foundation department of human genetics at the University of Miami Miller School of Medicine.

Dr. Vance typically explains the difference to patients using the metaphor of an old-fashioned balance scale, like those held by blind justice in classical paintings. “Let's say you need 100 pounds of causal factors to bring the disease up on the scale. If you have a causal gene for the disease, you could think of that as weighing 105 pounds, and that would bring it up. But these risk factor genes, metaphorically speaking, maybe weigh half a pound or a pound. The variant doesn't mean much by itself. It's a cumulative effect, involving multiple genetic variants plus environmental factors, to make up those 100-plus pounds of weight.”

“Further, we know that different genetic risk factors act differently for individuals of different racial and ethnic ancestries,” he continued. “For instance, APOE4, the strongest risk factor for AD in non-Hispanic whites and Asians, conveys much less risk for AD in individuals with African ancestry. Thus, calculating genetic risk is not necessarily straightforward and should be left to the professional.”

Talking People Off the Ledge

“We do a lot of talking people down off the ledge,” said Tanya Bardakjian, MS, CGC, senior neurogenetic counselor and co-director of the neurogenetics program and Huntington's Disease Center of Excellence at the University of Pennsylvania. “Many of them are people with the APOE4 allele, or people who have a mutation on the GBA gene, a relative risk factor for Parkinson's disease. Getting that genetic information can be very upsetting to people, and we have to explain to them that while they may have a slightly increased risk for these diseases, it's not an absolute risk.”

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“Theyve been given reams and reams of genetic health information, most of which has no clinical relevance whatsoever, but to a layperson, it can look very scary. People freak out, come to us with these printouts, and ask us to explain them.”—DR. WAYNE W. GRODY

The genetic testing companies offer their own explanations and tutorials, but their caveats are not always as prominent or clear as experts would like, and—unlike in an established clinical genetics program—true genetic counseling is not required.

Most medical genetics programs have a long waiting list for consultations, and little time to spend reinterpreting DTC genetic reports to anxious patients, Dr. Grody said. “We tell them that this is a test we would never order. When we order a genetic test, we do it very carefully, with pre-and post-test genetic conference sessions where everything is explained and interpreted. These results are not clinical results and are not done in CLIA-certified laboratories. Now, if they have a result that appears to be meaningful, like a BRCA gene mutation for breast and ovarian cancer, we will see that patient, counsel them and order the test in a real clinical lab. But for these vague ‘increased risks’ the reports give you, many of which are derived from random journal studies showing some association, there's nothing we can do with that.”

False Reassurance

For Bardakjian, even more concerning than the people who call medical genetics centers, unduly alarmed about DTC genetic test results, are those who may not call because they have been inappropriately reassured by such results.

“Most of these disease-related genes they test for—Parkinson's, Alzheimer's, cholesterol—are relative-risk genes and are making people nervous when they shouldn't be nervous,” she said. “But my biggest concern is not that people are getting information that scares them, but that they are getting results that make them ignore things like a strong family history. For example, if you have a parent who developed Alzheimer's disease at age 40, that's a single-gene mutation and it significantly raises your risk. To date, there are three known genes that cause early-onset Alzheimer's disease. But the direct-to-consumer tests don't include this gene, and if a person gets a clean result from 23andMe, they may think, ‘Oh, I'm not at risk,’ and fail to follow up. But it's not a full sequence. It's like you're canvassing a neighborhood for a lost child and looking only in every fourth house. You're not looking completely and you're missing the highly penetrant genetic risk factors.”

Dr. Vance said he agrees with Bardakjian that it's “likely that age 40 age-at-onset AD is likely to be associated with a Mendelian gene, but it is not an absolute,” Dr. Vance said.

The same point about highly penetrant genetic risks is true of breast cancer. 23andMe tests for only three of more than 1,000 known variants of the BRCA1 and BRCA2 genes associated with increased risk for breast and ovarian cancer; while these variants are the most common ones found in the Ashkenazi Jewish population, they are not the most common BRCA1/2 mutations found in the general population. “People who get a ‘negative’ result from these tests may think they're in the clear, that they have a low relative risk for breast cancer, and this may lead them to ignore more relevant factors such as personal and family history of disease,” said Bardakjian.

In a recent letter to Genetics in Medicine, Fuki Hisama, MD, professor of medicine in the division of medical genetics, adjunct professor of neurology, and medical director of the Adult Genetic Medicine Clinic at the University of Washington School of Medicine, described a case of just such a mismatch between direct-to-consumer genetic testing results and thorough clinical genetic testing in a certified laboratory. Fortunately, in this case the patient had received the comprehensive and accurate results from the Genetic Medicine Clinic first.

“A healthy 47-year-old woman came to the Adult Genetic Medicine Clinic for a family history of two first-degree relatives with breast cancer. Clinical molecular genetic testing identified a heterozygous pathogenic variant in the BRCA2 gene,” Dr. Hisama wrote. “Pre- and post-test genetic counseling allowed her to correctly understand her results, and to implement appropriate medical care. Several siblings who subsequently underwent genetic counseling, also received positive test results, and underwent risk-reducing surgery.”

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“My personal opinion is that if they are running tests for conditions involving Mendelian inheritance, these companies should at least be required to offer some kind of certified genetic counseling, either by phone or online.”—DR. MUSTAFA TEKIN

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“It takes medical knowledge and background to order, interpret, and use these results correctly. My recommendation to fellow clinicians would be not to accept DTC results. If there are reasons for concern with a particular patient, have the tests done in a CLIA-certified lab, and seek a consultation with a genetics professional.”—DR. FUKI HISAMA

A year later, the woman received DTC genetic testing as a gift, and was surprised when the test told her she had a “low risk of breast cancer.” She wrote to Dr. Hisama, “23andme mentions that their test isn't exhaustive of all the BRCA mutation forms, but I feel like this information/disclosure could be easily overlooked/dismissed by the general population. Honestly, if I had done this test (and not spoken with you, etc.), I may have received the results of my 23andme, and thought I was off the hook.”

Things can be further complicated when the DTC genetic testing companies make raw data available to individual purchasers for download. Consumers sometimes then run that data through online third-party interpretation tools like GEDMatch, Promethease, DNA Land, and GeneticGenie.

“I once met with a woman who had a long history of a variety of symptoms, including joint pain and pain in her hands and feet. She did DTC genetic testing, obtained the raw data, and then ran it through one of these programs to interpret it,” said Dr. Hisama.

The program identified a variant in the SCN9A gene; some disease-causing variants in this gene are associated with a rare condition called inherited erythromelalgia. Convinced she had the condition, the woman took the results to her primary care doctor, who entered them in her medical record as a confirmed diagnosis. Finally, she was referred to Dr. Hisama, an expert in inherited erythromelalgia. “I had to disabuse her of the notion that she has the condition; she found a benign variant that doesn't affect anything,” Dr. Hisama said.

Does such DTC testing ever lead to earlier diagnosis or improved management of a genetic condition? In Dr. Grody's experience, only once. He is one of only a handful of experts in a rare auto-inflammatory disorder called familial Mediterranean fever, which is characterized by non-specific symptoms such as fever and abdominal pain, and frequently goes undiagnosed for decades.

“We had two patients self-referred to our clinic within the last two years,” he told Neurology Today. “Each had a sibling who had done testing through 23andMe, and he came back as an unaffected carrier of a variant in the MEFV gene associated with this condition. That clued in the patients who saw me, who had the symptoms, to say maybe this is the cause. But the rare cases in which this testing led to an earlier diagnosis are a drop in the bucket compared to the problems we've encountered.”

Dr. Hisama would like to see such genetic testing only available through a medical professional's office via prescription. “It takes medical knowledge and background to order, interpret, and use these results correctly,” she said. “My recommendation to fellow clinicians would be not to accept DTC results. If there are reasons for concern with a particular patient, have the tests done in a CLIA-certified lab, and seek a consultation with a genetics professional.”

Most medical geneticists who spoke with Neurology Today agreed that the genie of DTC genetic testing is out of the bottle, however, and unlikely to be forced all the way back in.

“My personal opinion is that if they are running tests for conditions involving Mendelian inheritance, these companies should at least be required to offer some kind of certified genetic counseling, either by phone or online,” said Mustafa Tekin, MD, professor and chief of the division of clinical and translational genetics in the Dr. John T. Macdonald Foundation department of human genetics and the John P. Hussman Institute for Human Genomics at the Miller School of Medicine at the University of Miami.

“For the risk alleles, perhaps they could improve matters by providing better and clearer general information on the website. But when it comes to rare diseases and interpretation, they should have some kind of direct counseling.”

A problem that needs to be addressed in the long term, Dr. Vance said, is the fact that most medical schools are not preparing their graduates to deal with patients who come to them with this information.

“We have a program at the University of Miami Miller School of Medicine that offers a concurrent four-year master's degree in genetic medicine along with the MD,” he said. “It will help our graduates interpret genomic sequence data in their own practices, as well as enable them to teach it to other physicians. But ours is probably the only such program in the country. We need to increase the availability of educational mechanisms like this for future physicians, because the data are coming down the pike for these patients. The wave is coming, and we should not turn our backs to it.”

Link Up for More Information

• Schleit J, Naylor LV, Hisama FM. First, do no harm: Direct-to-consumer genetic testing https://www.nature.com/articles/s41436-018-0071-z. Genet Med 2019; 21(2):510–511.