When you break your arm and get an X-ray, those results are mostly only significant to you – they don’t affect your brother, your sister, your parents or that distant cousin of yours in Alaska. But genetic testing is different, explains Dr. Mark Robson, clinic director of the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center in New York City.
Targeted genetic tests – such as tests for Alzheimer’s disease, Huntington’s disease and certain types of cancer – yield results that can have dramatic and unpredictable consequences for family members. For doctors, deciding whom to test, when to return results and whom those results might impact is perhaps even more complex. With whole genome sequencing, targeted genetic testing and the resulting knowledge of health risks becoming increasingly available, the pressure on doctors to weigh multiple factors and make such life-altering choices is only expected to grow.
“The idea that you’re going to call up somebody over the objections of the patient and say, 'Your sister just had a mutation detected, you need to do X, Y and Z,' is really not viable," Robson says. "Also once you start that, where do you stop? Who are you supposed to call? Sisters? Children? Cousins? Second cousins?”
Making someone aware of their disease risks can help that person take steps to avoid the illness. For example, newborns are screened for a gene mutation that puts them at risk for mental retardation, and an immediate change in diet can prevent the problem. In cases where a disease isn’t preventable or treatable, letting patients know in advance allows them to prepare for an illness.
But there’s a downside as well, Robson says. “If you have information about a risk that you’re communicating to someone who‘s not ready to receive that information because they don’t want to hear it, then you’re actually potentially causing distress," he says. "It’s not necessarily physical harm, but it can be a very real psychological harm.”
About a decade ago, Heidi Rehm, a chief laboratory director at Partners HealthCare Center for Personalized Genetic Medicine and a professor at Harvard Medical School, met what geneticists call an “early adopter”: a woman who had just learned of her risk for cardiomyopathy – a serious heart condition that can lead to sudden death – through genetic testing. After speaking with her doctor, the woman encouraged her entire family to be tested and even collected the samples herself. By increasing the number of family members tested, she could improve the chances that the results were accurate.
“When we find a variant that we don’t fully understand, we’ll often test the other family members who have the disease or don’t have the disease to see if it correlates,” Rehm says. "If it's a disease-causing variant, everyone who has the disease should have it."
What happened next was every geneticist’s nightmare. Rehm ran all of the tests and phoned the family’s doctor, only to learn that none of the family members other than the “early adopter” had consented to be tested. (The woman had written the doctor's name on every form.) So, Rehm phoned and ultimately received consent from the entire family, except one brother. He agreed to be tested but did not want his results back, and told Rehm to give his results to his sister.
But after Rehm's secretary mistakenly mailed all of the reports, the woman's mother waited by her son’s mailbox each day to intercept the letter until it eventually came. Rehm’s office now leaves the responsibility of managing test results primarily to the ordering physician.
But that step alone hasn’t solved all of her problems.
In the late '90s, a 2-year-old child died suddenly of heart failure. Doctors initially believed the cause was a mitochondrial disease – one that's inherited specifically from DNA contained in the mother's ovary. About five years later, an 11-year-old fainted while playing sports and was diagnosed with a genetic heart condition that hardens the organ’s walls and makes pumping blood difficult. Both families contacted the fertility clinic they had used, which discovered that both children were connected to the same sperm donor. The donor was alerted that he was at minimum a carrier for the condition and might be at risk of sudden cardiac death. He had never shown any symptoms of the disease, but was tested and found to have the condition.
Rehm wrote a letter, which was sent by the clinic, to the parents of all the children who were biologically related to the sperm donor. Of the 24 children – two of whom were raised by the donor – nine were found to have the condition, and four never were tested. One couple who chose not to have their two sons tested told Rehm that if one child had the disease and the other didn’t, they worried they might treat the two differently. Rehm was unable to change their minds.
“Short of a report to Child Protective Services, there’s not much that the physician can do other than try to persuade [the parents],” says Dr. Bruce Blumberg, director of graduate medical education for Kaiser Permanente Northern California. Blumberg, who deals with similar ethical quandaries, says he would not have called CPS: “I think the parents probably do have the right to refuse that testing, though I would try to reason with them,” he says.
Even if a medical intervention was available to the parents, Dr. Ellen Wright Clayton – co-founder of the Center for Biomedical Ethics and Society and a professor of law and pediatrics at Vanderbilt University – says she also would not report them to a social services agency.
"I would certainly say that it's not neglectful for parents not to want to know unless there is something really effective that you can do to avoid the risk," she says.
Rehm and Dr. Barry Maron – director of the Hypertrophic Cardiomyopathy Center at the Minneapolis Heart Institute Foundation – thought the case called for more discussion and published an article in the Journal of the American Medical Association in 2009. The San Francisco-based fertility clinic used by the couples now requires all donors to undergo electrocardiogram tests and filters out men with genetic heart problems, The Associated Press reported.
Deciding whether to test someone for a genetic condition and how those results should be returned is difficult at any age, but tests that involve children add another layer of complexity. "Right now there's a major split in the field, because there's been a long-standing consensus that we really ought not to test kids for things that we can't do something about during childhood," Wright Clayton says.
Recommendations from the American Academy of Pediatrics advise doctors in such situations to encourage parents to wait until their children are 18 and can decide for themselves whether or not to be tested. But once an individual's genome has been sequenced – that is, his or entire genetic profile has been mapped – the American College of Medical Genetics and Genomics recommends that in addition to whatever specific condition a doctor is looking for, he or she should report mutations in 56 other genes, regardless of the patient's age.
"There’s always judgment involved in what the relevant aspects of a test result are," Blumberg says. The lab makes the first decision by deciding what information to pass along to the clinician in its report. The clinician applies the next filter in choosing what information is important enough to share with the family, he says.
But whether a doctor is sequencing the entire genome or looking for a mutation on one target gene, there may be some unanticipated results.
“What does a geneticist do when they learn that the father is not the father?” Blumberg asks. He says he typically brings up the possibility in a joking way during the consent process, and mothers who know they have a secret they aren’t prepared to share often find a way for their child not to be tested.
"Sometimes the question is, 'For how long should I hold on to this information?' or, 'Should I hold on to this information permanently?'" Blumberg says.
There are also situations in which a parent will hide a condition from a child. Often this happens with heavily stigmatized diseases such as learning disabilities or sexual development disorders, Blumberg says. When those children become adults and discover their conditions, some are angry at their parents for withholding the information.
Asked whether he worries he may ever have made a mistake in sharing or withholding information, Blumberg answers, "Absolutely, you worry that you made the wrong decision. Sometimes, it comes back to bite you and if you're good, most of the times, it doesn't."
Parents often will disagree about whether a child should be tested. One such case, documented in the journal Pediatrics in 2012, involved a 14-year-old girl whose mother was found to have genetic mutations associated with a risk of breast and ovarian cancer. The girl’s father was in favor of testing, while her mother thought the girl was too young. The genetics test providers consulted with the parents and their daughter. From a medical perspective, if the teenager did have a risk of cancer, no medical intervention – for example, a mastectomy – would be necessary or even available at her age.
Eventually, the girl
was allowed to make the decision herself. She chose to be tested.