Fourteen genetics experts, with the backing of the American College of Medical Genetics and Genomics (ACMG), are proposing a radical shift in how and what
patients learn about what's in their DNA. They argue that anyone whose genome is sequenced for any medical reason should automatically learn whether 57 of
their genes put them at risk of certain cancers, potentially fatal heart conditions, and other serious health problems. The information would be provided
whether patients want it—and often when they're seeking care from a doctor for something else entirely—because, the experts say, knowing the makeup
of this DNA could save an individual's life. The recommendations apply to sequencing children's DNA as well, even if there's no preventive care available
until adulthood. The college's guidelines on a range of
issues are usually written by influential geneticists and physicians and carry significant weight, although they are not binding. Today's report includes
the first recommendations ever given to labs and doctors about how to handle unexpected findings when the genome or its protein-coding "exome" is
The ACMG recommendations, released this morning, come as DNA sequencing is about to take off in doctor's offices and hospitals. Sequencing an entire genome soon won't cost much
more than sequencing a single gene, says Robert Green, a neurologist and medical geneticist at Brigham and Women's Hospital in Boston who co-chaired the
ACMG working group. That means that if a child has an undiagnosed heart disorder that may merit sequencing of a gene, the parents could, for practical and
cost reasons, agree to have their son or daughter's full genome sequenced. "You can't undo the sequence" once you've got it, Green says. "To somehow mask
or ignore it doesn't seem right either."
Under the new recommendations, the parents would learn not only if their child's heart condition is due to a particular gene mutation—they'd also learn
whether she is at high risk of certain breast cancers, colon cancers, cardiomyopathies, aneurysms, and other diseases. (Testing negative for these,
however, would not guarantee that she's in the clear, because not every mutation for a given gene is on the list.) Many of the genetically driven conditions
can strike children, but others rarely show up before adulthood.
Arriving at today's recommendations was an arduous task. Over the
course of a year, a committee led by Green and Leslie Biesecker, chief
of the Genetic
Disease Research Branch at the National Human Genome Research
Institute in Bethesda, Maryland, has been weighing how to handle "incidental
findings" that turn up
when a genome or exome is sequenced for some other medical reason.
The effort is part of a much broader debate that spans research and
clinical care over
which genetic results should be returned—an ethical, legal, and
And the ACMG committee waded right in. Some of those not involved in
it were most startled by the recommendation that patients should have
no choice but to
learn whether they carry dozens of mutations. "[T]he Working Group did
not favor offering the patient a preference as to whether or not to
minimum list of incidental findings described in these
recommendations," the group wrote. The "fiduciary duty to prevent harm
by warning patients and their
families," the authors argued, "supersedes concerns about
autonomy"—the right not to know certain information. Labs, they
suggested, should "seek and
report" mutations in dozens of genes, many of them linked to cancer
syndromes. The doctor who ordered the test would be responsible for
results to patients—something the working group admitted some
physicians might be uncomfortable with, especially if, say, the doctor
is a cardiologist and
the sequencing turns up a cancer gene.
Several experts who did not participate in the report voiced
practical and ethical concerns. "The assumption that it's always benign
to give that
information, and potentially helpful—I don't think that's true,"
said Mark Rothstein, a law professor who studies bioethics and genetics
at the University
of Louisville Brandeis School of Law and School of Medicine in
Kentucky. "Information is often very damaging to people, that's why they
don't want it."
Rothstein notes that patients might begin undergoing "test after
test and worrying themselves sick, and they'll never be affected" by the
The ACMG working group limited its list to genes that carry a high risk of disease—for example, mutations in BRCA1 and BRCA2,
significantly raise the risk of breast and ovarian cancer, and for
which extra screening and prophylactic surgery can reduce risk. But even
genes, the chance of disease varies from individual to individual.
Ashkenazi Jewish women with a family history of breast cancer may have a
disease risk as
high as 90% or more if they carry mutations in BRCA1; another woman
with no family history may have a much lower risk. In some cases, the
highlighted by ACMG are rare and have been studied in just a few
families in which many members have the disease. It's not known how
those risks translate
to someone without any affected family members. The working group
estimates that about 1% of the population would have a positive result
for at least one
of the variants on the list. The list was limited to mutations for
diseases where the chance of getting sick can be mitigated—for example,
screening for those at high risk.
"In many perspectives, they have made an important and brave
contribution," writes Isaac Kohane, a pediatric endocrinologist and chair
of the informatics
program at Boston Children's Hospital, in an e-mail. Still,
while he thinks we have the "sequencing capacity" to deal with the
demands, "[I'm] not
sure we have the cognitive capacity." And our understanding is
constantly changing, even for the diseases and mutations already on the
list. The Working
Group treads carefully here, urging that the list be regularly
revisited and that a voluntary registry be established to follow those
given these findings,
documenting "the benefits, harms and costs that may result."
Many questions remain: Are doctors equipped to return this
information to patients? Can labs handle the additional sequencing? Who
will pay for it? Do
these recommendations establish a new legal benchmark for the
standard of care, something Rothstein thinks is a possibility?
The working group emphasizes that its 30-page document is a
beginning, not an end. "We took so long and worked so hard on this,"
Green says. "We took time
to imagine how the future is going to be different."