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", page 6). 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 (see Viewpoint, opposite).
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 1 in 4 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.
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 1 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 doesn't 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".
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 1 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".
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.
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 American 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.
A warning that must not be ignored
Kathy Hudson is the director of the Genetics and Public Policy Center in Washington DC
THE numbers and full facts are not yet known, and I can only guess at the confusion and anxiety facing the couples involved in these cases.
But most of us would agree that even one healthy and wanted baby being terminated because of failures in genetic testing is horrifying. We cannot let these disturbing cases be a harbinger of what is to come as screening becomes widespread, and as the number of diseases for which people are screened grows.
If we want to prevent such mistakes being repeated, there is much to do. In the US, there is more government oversight of the colouring used in M&Ms than there is for genetic tests that can have untold physical and emotional consequences, and the same is true in many other countries.
Genetic testing should offer families the chance to get the information they need to guide their healthcare and reproductive decisions. If conducted properly, the tests can do just that. But the current system has two fundamental flaws.
First, the players involved in genetic testing are linked to one another in a one-way pathway. An error or confusion at any step in the process will affect the rest of those in the chain including, most importantly, the patient. There is no reliable system of checks and balances within the system so that errors at one point can be detected and corrected at others.
Secondly, the mechanisms for regulating genetic testing are fragmentary and inadequate. Each government agency involved is only concerned with a single narrow slice of the entire process.
Like similar agencies elsewhere, the US Food and Drug Administration regulates commercially produced test kits as medical devices.
However, many laboratories that perform genetic testing do not use commercial kits but instead develop their own tests. The FDA regulates neither the safety nor the effectiveness of these "home brew" tests, and has so far limited its oversight to a subset of the components laboratories use to generate tests.
In July 2000, a US government advisory committee made several recommendations for increasing government oversight, including that the FDA should regulate all new genetic tests that have moved beyond the research phase. That has not happened.
As for the laboratories that carry out the tests, in 1998 Congress passed the Clinical Laboratory Improvement Amendments and charged the Center for Medicare and Medicaid Services with improving clinical laboratory practice. But the agencies responsible for implementing the amendments have largely stayed out of genetic testing. In May 2000, the Centers for Disease Control acknowledged that improvements were needed in oversight of genetic testing laboratories, but there has been no action since then.
Even if all the various agencies involved meticulously oversaw their particular slice, the problem would still not be resolved because no one would be addressing all parts of the issue. The end result is that the poor patients are left with no assurance that the information they are being given is accurate.
Cystic fibrosis is the first genetic test to be routinely offered to prospective parents in the US, and the cracks in the system are already painfully plain. Reflect on what is likely to happen when the many other genetic tests in the pipeline come through.
We have our canary-in-the-mineshaft warning of the dangers of genetic screening. The physical and emotional stakes, not to mention the legal implications, are too high to ignore it.
New Scientist issue: 3rd May 2003
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