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TITLE:  Genetic test blunders risk needless abortions
SOURCE: The New Scientist, UK, by David Concar
        http://www.newscientist.com/news/news.jsp?id=ns99993675
DATE:   Apr 30, 2003

------------------ archive: http://www.gene.ch/genet.html ------------------


Genetic test blunders risk needless abortions

Many pregnant women in the US have had risky and unnecessary fetal tests
following genetic screening of themselves and their partners. And some
may have terminated healthy pregnancies after muddles or irregularities
in genetic tests on their fetuses.

This is the warning being issued by medical geneticists who have assessed
the outcomes of some of the tens of thousands of DNA tests carried out
every month in the US as part of the world's largest screening programme
for cystic fibrosis (see Cystic fibrosis: key facts", below).

Some of the companies carrying out the tests blame doctors for
misinterpreting complex results or requesting the wrong tests. But
geneticists say a few companies are at fault too, for failing to stick to
clinical guidelines.

And cystic fibrosis is just the first of many diseases for which genetic
testing is likely to become routine. If mistakes are being made already,
experts warn, what will happen as screening becomes more and more common?
Government regulation of genetic testing in many countries is poor, they say.

 One in four chance

With cystic fibrosis screening, the aim is to discover early in pregnancy
if a woman and her partner carry any of the mutations that cause the
disease. If blood or saliva tests reveal that both are carriers, they
have a one in four chance of having a child with cystic fibrosis. If a
follow-up DNA test on the fetus confirms that it has inherited two
defective copies of the CF gene and will thus get the disease, couples
face a tough decision whether or not to terminate the pregnancy.

Until recently, antenatal clinics in the US offered CF screening only to
couples who already had affected children or family members. Most
countries still offer only this limited screening. But two years ago
doctors' groups recommended that cystic fibrosis screening be offered to
all pregnant women.

The result has been a huge hike in the number of CF tests carried out by
diagnostics labs in the US - and growing concerns about the reliability
and interpretation of some of these tests. "The volume of tests has
exploded, and front-line service providers are having some difficulty
with the hard mutations that are difficult to interpret," says Michael
Watson, executive director of the American College of Medical Genetics (ACMG).

Genetic screening for diseases is far from simple because a mutation in
any of the tens of thousands of DNA letters in and around a gene can
cause a disease. And while one mutation may be harmless, another may be
deadly. As if that were not complex enough, some mutations are dangerous
only if other mutations are present too, which is what has caused the
problems with cystic fibrosis screening.

 900 mutations

Since the CF gene was discovered in 1989, researchers have discovered
more than 900 distinct mutations in the gene or nearby DNA that can cause
some or all of the symptoms of the disease. Routinely screening for every
mutation - most of which are incredibly rare - would be very costly and
time-consuming, so most commercial test kits only look for the 25 to 35
mutations responsible for the overwhelming majority of cases.

One common mutation is called 5T. Though present in as many as one in 20
people, it contributes to cystic fibrosis only if there is a second, much
rarer mutation called R117H in the same gene.

By itself, the 5T mutation does not cause life-threatening illness, and
the consensus among doctors' groups and ethicists is that its presence in
a pregnant woman's DNA does not justify carrying out risky fetal tests
such as amniocentesis or chorionic villi sampling. And no mainstream
group supports terminating a pregnancy if these tests, done for whatever
reason, reveal 5T without R117H.

But according to Watson, there have been both unnecessary fetal tests and
terminations. The extent of the problem is unclear: there are no official
government figures for how many women have been tested for CF mutations
in the US since population screening began in October 2001, or what the
outcome has been in each case.

But at a conference for genetics professionals in March, the ACMG put out
an unprecedented alert on an overhead slide warning delegates that "over
20 prenatal tests were performed with 5T alone and with terminations
occurring". Despite repeated requests, the ACMG did not reveal any more
details of these cases. But Watson told New Scientist that it knows of
"at least 150 prenatals that have been done that perhaps should not have
been done".

 Worrying cases

Other worrying cases have been disclosed by the biggest gene testing
company in the US. In an abstract published at the same conference,
scientists from Quest Diagnostics of California report having so far
received 150 fetal samples for CF testing since October 2001 when
population screening began. Of these, 41 were submitted by clinics after
one parent tested positive for the 5T mutation. None appeared to carry
the accompanying mutation required to put someone with 5T at risk of
having a CF child.

Yet the clinics still decided to screen fetal samples obtained by
amniocentesis. And while many of the women would have had an
amniocentesis for other reasons, in 12 cases the discovery of the 5T
mutation was the sole reason for the procedure, which has a one in 200
risk of triggering miscarriage.

None of these fetal tests led to terminations, says Charles Strom,
medical director of genetics at Quest Diagnostics. But the fact that they
happened at all, he says, illustrates the confusion over the significance
of the 5T mutation. "This is not a unique situation," Strom told New
Scientist. "I think you can say with some certainty that this is going on
throughout the industry."

Possible explanations, according to Strom, include doctors ordering the
wrong tests, genetic counsellors misinterpreting the parental 5T tests,
or parents getting the right counselling but becoming so anxious that
they request a fetal test anyway.

Strom says that when his company realised there was a problem, it stopped
providing doctors with the results of the 5T part of the company's
standard CF screening test. Doctors who want this information from Quest
must now request it specifically. And when doctors submit fetal samples
solely on the strength of a 5T mutation, Strom says that the company
"does the test and has a genetic counsellor call to make sure the patient
has been correctly counselled".

 Broken guidelines

But others feel such tests should not be done at all. "These couples are
being found with the 5T and no other mutations, and they're getting all
confused and worried," says Wayne Grody, a medical geneticist at the
School of Medicine at the University of California in Los Angeles. "It's
disturbing."

Grody points out that any population screening for the 5T mutation in
pregnant women runs counter to clinical guidelines. Rules drawn up by the
ACMG and the American Academy of Obstetricians and Gynecologists state
that pregnant women should be screened for the 5T mutation only if they
first test positive for the R117H mutation.

"The recommendations as written could not be more explicit on this
point," says Grody. "Why a lab would knowingly violate that, I can't
figure out."

Yet New Scientist's survey of company websites reveals that at least
three companies in the US include 5T in their standard CF test. It is not
clear whether these companies automatically tell doctors and patients
whether the 5T mutation is present or if, like Quest, they withhold the
information unless specifically asked for it.

Either way, as far as Grody is concerned, the companies are breaking the
guidelines, which state that you should not even test for 5T until R117H
is found.

 Raised costs

But following the guidelines to the letter could raise companies' costs.
A big part of the $200 or so they charge for a CF test is the cost of the
test kit. Waiting until someone tests positive for R117H before screening
for the 5T mutation would often mean using up two test kits instead of one.

Another complication is that there is a separate group of patients with a
good reason to know whether they carry the 5T mutation: infertile men.
Men who inherit two copies of the 5T mutation, or one copy plus a CF
mutation, often lack a working vas deferens, the tube that stores and
carries sperm.

If the 5T mutation is found in an infertile man, it tells the urologists
and IVF clinics treating them that there is a good chance that healthy
sperm can be taken directly from the testicle. "It would be unfair to
urologists not to offer a test for 5T," says Strom.

But Strom admits companies currently cannot guarantee that the 5T form of
the CF test that is intended for infertile men will only be used by this
group. And if doctors and prospective parents discover - by deliberately
or accidentally ordering this test during pregnancy - that a male fetus
has the 5T mutation and may grow up to be infertile, they may opt to
terminate the pregnancy.

"They may decide that this may be a child they don't want to bring into
the world," says Strom. "It's not up to us to tell them what reasons
they're allowed to terminate a pregnancy."

And the link with infertility means that companies that test for 5T as
part of CF screening but do not reveal the results risk being sued
decades later when a boy grows up and discovers he is infertile. Quest
has decided to proceed nevertheless but other companies are not prepared
to take the chance.

The US cases also come at a time when countries such as Britain are
considering following the US example and setting up their own national
screening programmes. As yet, the written guidelines covering CF testing
in Britain make no stipulations about when labs should and should not
screen women for the 5T mutation.

Cystic fibrosis: key facts
- About 30,000 Americans, 3000 Canadians and 20,000 Europeans have cystic
fibrosis
- The disease is caused by defects in a gene on chromosome 7 that codes
for the cystic fibrosis transmembrane regulator protein, or CFTR
- CFTR's job is to move chloride ions and water through the membranes of
cells lining the passageways of the body. If it is defective, mucus
accumulates in the intestines and lungs, causing malnutrition, breathing
difficulties and eventually permanent lung damage
- The most common mutation in the CFTR gene accounts for up to 80 per
cent of all cases. People with this classic form of the disease now live
to age 30 or more. But the CFTR gene is very large, and at least 900
mutations can cause the disease. Symptoms vary greatly depending on which
mutations someone inherits
- A child only gets CF if they inherit a defective gene from both
parents. So the first step in testing is to find out if both parents have
a mutated copy: around one in 29 white people carry a single defective gene
- Only if both parents are carriers is the fetus tested to see if it has
inherited two defective genes. But not all CF mutations can be detected
and testing, by amniocentesis or chorionic villi sampling, is risky for
the mother and fetus
- Some parents decide to terminate the pregnancy if tests show the baby
will have cystic fibrosis. But in many cases tests cannot determine how
serious the disease will be