GENETIC SELECTION > INFORMATION > SHEET 5

Testing and screening

In The Gift in 1995, RYAN undergoes voluntary genetic testing. In 2010 JENNIFER comes under pressure from RYAN to undergo a similar test. By 2025 MARK’S contemporaries are subject to a mandatory genetic screening programme at the age of 16. This section provides information about genetic testing and screening and the differences between the two. There is a brief guide to DNA testing and the prenatal tests, amniocentesis and chorionic villus sampling. Case studies of four genetic screening programmes serve to illustrate the later discussion of major issues that result from the ability to carry out a progressively wider range of testing and screening programmes.

Genetic Testing and Genetic Screening

	Annie Kaye

The phrases ‘genetic testing’ and ‘genetic screening’ are sometimes used interchangeably. There is, however, an important difference between testing an individual for a condition that other evidence suggests may be present, and screening all members of a community for a condition where there is no prior evidence of its presence in the individual. In The Gift, RYAN’S sister, ANNIE discovers that she has inherited the disorder, Friedreich’s ataxia. Ryan then requests a DNA test to find out if he too has inherited the disorder or is a carrier.

The Speed of Discovery

Geneticists are discovering the genes responsible for genetic disorders almost weekly. In the recent past, the genes responsible for Duchenne muscular dystrophy, Huntington’s disease and a form of inherited breast cancer have been isolated. The pace of these discoveries will rapidly increase as the Human Genome Project progresses. When the gene responsible for a particular disorder has been pinpointed, the first application of this new knowledge is often the development of a test to identify those individuals who carry a defective version of the gene.

What is Genetic Testing?

In The Gift both RYAN (ANNIE’S brother), and JENNIFER (RYAN’S wife), have DNA tests to discover whether they are carriers of the defective gene for Friedreich’s ataxia. In both instances, the doctor asked them to rinse their mouths out with sterile salt solution and spit back into a bottle. As they washed their mouths out, a few cells from the inner lining of their cheeks were dislodged and deposited in the specimen bottle. Their DNA was then separated from their cells, copied many thousands of times and matched against reference DNA samples containing mutations that cause Friedreich’s ataxia.

There are a number of crucial differences between direct genetic testing by DNA techniques and other forms of medical testing. These are:

• As genes are present in almost all of our cells, samples of any body tissue can be used for testing. Although blood is most commonly used, cells obtained by mouthwash are proving especially suitable for some screening programmes
• As our genes don’t usually change during our lifetime, a DNA test can be performed at any time from conception onwards. As a result of their DNA tests, both JENNIFER and RYAN discovered that they were carriers of the defective Friedreich’s ataxia gene. Had Jennifer already been pregnant at the time of her DNA test, the doctor would have suggested further tests, to ascertain the status of her baby

DNA Markers

DNA diagnosis may be possible even when the particular gene involved in a genetic condition has not been identified. Current tests for the condition in The Gift, Friedreich’s ataxia, examine the chromosomes in detail. Tests can predict whether a disease-causing version of the gene has been inherited by looking at DNA markers that are often inherited at the same time.

Chromosome Tests

Tests can check the number and appearance of the chromosomes. Most human body cells have 23 pairs of chromosomes, but extra or missing chromosomes can be seen in some genetic conditions. Individuals with Down’s syndrome often have an extra copy of chromosome 21 (i.e. three copies rather than two) in their cells. The physical appearance of the chromosomes can also reveal problems. Rearrangements of chromosomes are apparent where a large piece of one chromosome is missing, duplicated or moved to a different chromosome altogether.

How accurate is genetic testing?

DOCTOR FLEMING: The results are only ever percentages. Of course, if you were unfortunate enough to test outright positive, that would be a clear 100% result. But a so-called negative test - that’s not zero, it might be - for example 95% or 99% against developing the disorder. But still you’d have that niggling element of doubt. And who’s to say what an acceptable low risk is? To a clinician a 5% risk is low, acceptable. But to the person being tested…what’s the comfort in a low risk - when you can’t be given an outright ‘no’. Am I making myself clear? After all it’s a complex subject.

The accuracy of the tests depends on the particular genetic condition and the methods available for detecting associated changes in the DNA. Changes in the number of chromosomes are clearly easier to detect than a small part of a chromosome being missing. The accuracy of DNA markers can depend on how close on the chromosome they are to the actual gene of interest. If a number of different markers are used then the overall accuracy of the results will be higher.

Most tests looking at changes in the gene itself are highly accurate but depend on knowledge as to which specific mutation may be responsible for disease in a particular family. Individuals will require information about the accuracy of a DNA test if they are to make informed decisions.

Prenatal tests

There are two sampling methods available to detect harmful genetic conditions in embryos and developing fetuses.

Amniocentesis

Currently the most widely used technique of prenatal diagnosis. It is commonly carried out between 15 and 18 weeks of pregnancy. Ultrasound is used to locate the placenta, and a small quantity of amniotic fluid, which contains cells shed by the developing fetus, is withdrawn through a needle from the amniotic cavity. Cells have to be cultured for two weeks before chromosome examination (for example, to detect Down’s syndrome) or DNA analysis can
take place.

Chorionic villus sampling

Introduced more recently, Chorionic villus sampling is a procedure whereby a small sample of chorionic (placental) tissue, is removed for prenatal diagnosis. Chorionic villus originates from the developing embryo and is removed either by inserting a needle through the abdomen, or by a small 'biopsy forceps' passed through the vagina. Samples can be taken at any time after 10 weeks of pregnancy. Because the cells are derived from the embryo, they nearly always provide a reliable guide to the genetic make-up of the fetus. Early results can be obtained within two days.

What are the advantages and disadvantages of the two prenatal techniques?

With amniocentesis, genetic diagnosis is not usually possible until 16-20 weeks of pregnancy. This time lag can make it even harder for parents considering terminating the pregnancy if the fetus is affected with some severe disabling disorder.

Such late terminations can be physically and emotionally distressing for the mother. Chorionic villus genetic diagnosis on the other hand is usually possible before the 12th week of pregnancy. However, both techniques increase the rate of spontaneous abortion; amniocentesis by about one per cent, and chorionic villus sampling increasing it by about four per cent.

What is screening?

We define genetic screening as a search in the population to identify individuals who may have, or be susceptible to, a serious genetic disease, or who, though not at risk themselves, as gene carriers may be at risk of having children with that genetic disease. While it is individuals who are screened, the results will normally have wider implications. Depending on the nature of the genetic defect that is identified and its pattern of inheritance, siblings and other blood relations, as well as existing and future offspring, may be affected.
Nuffield Council on Bioethics
Genetic Screening Ethical issues

Case Studies of Screening

Case study 1

In the past, screening programmes have led to controversy and the sickle-cell disease programme in the USA is often cited as an example of the problems that may arise. During the 1970s it was possible to identify carriers of this recessive genetic disorder that affects people of African descent. The technologies at the time did not allow prenatal diagnosis, so that no reproductive options were offered where both partners were carriers. Eighteen states passed laws requiring black people to take compulsory testing. There was also a wide misconception that carriers of the sickle-cell gene actually had the disease state. Many carriers themselves thought they had the disease. Carriers found that they were stigmatized and had difficulty in obtaining health insurance and jobs. The programme became political as many black Americans felt that screening was merely a devious way to discourage black people from having children. Although conceived with the best of motives, this programme has proved to be a model of the way in which genetic screening should not be used. It highlighted the need for education, counselling and also raised legal issues. These aspects are now considered to be essential to the success of any genetic screening programme.

Case study 2

Thalassemia is an inherited blood disorder. A screening programme in recent years within London’s Greek-Cypriot community has generally been met with enthusiasm. Health workers recognized the importance of helping carriers to understand the disease and its implications. Very few children are now born with Thalassemia in this community. In Cyprus itself, antenatal screening for Thalassemia has been superseded by premarital screening. The religious authorities had ethical objections to screening during pregnancy on the grounds that it excluded options other than termination of affected pregnancies. The Church in Cyprus now insists on testing as a formal prerequisite to church weddings. The certificate required states merely that partners have been tested and appropriately advised. In this way, confidentiality of the test result is preserved and the couple can exercise informed choices about reproduction.

Case study 3

In a recent pilot cystic fibrosis screening in Edinburgh, of the 2207 women invited for carrier screening during pregnancy, 85% accepted it. Only 15% declined to be tested. Of those who declined, over half did so because of opposition to termination of pregnancy. Other reasons given included the partner’s disapproval or non-participation, perceived risk of a cystic fibrosis child being low, the error rate of the test and the generation of unacceptable levels of anxiety.

Case study 4

The gene for the late-onset of Huntington’s disease was identified in 1993 after many years of research. A number of previous surveys had suggested that the majority of individuals would take a predicitive DNA test if one became available. Such tests are now indeed available and are significantly more accurate than previous tests that relied on DNA markers. However, only a small number of people who previously expressed a desire to be tested have now done so. The knowledge of a positive test may well have psychological effects on a person. It is clear that much thought is given before undergoing such a test where no cure is available.

Summary

The ethical and moral questions posed by genetic diagnosis are complex for individuals and society. The choices available to an individual can also be empowering. Some of the most enthusiastic campaigners of genetic testing and screening have been parents who have had an affected child and devoted their lives to caring for the child.

ISSUES SURROUNDING SCREENING AND TESTING

Genetic Counselling

In a recent survey of young people, over three quarters thought that people should be obliged to have counselling before genetic screening.
The new genetics - a debate for young Europeans 1995

Genetic counselling is highly skilled and time consuming; counselling is carried out by specially trained doctors, nurses and other qualified staff.

Information Prior to Screening

The Nuffield Council on Bioethics advised the kind of information required prior to possible screening:

I. The condition to which the genetic disorder may give rise: how serious is it? How variable is it in its effect? What are the therapeutic options?

II. The way in which the disorder is transmitted, i.e. dominant, recessive, sex-linked mechanisms, and the significance of carrier status.

III. The reliability of the screening test, i.e. the typical state of false positives and false negatives, and the probability of the development of a serious genetic disease.

IV. The procedures for informing individuals of results, negatives (normal) as well as positives (abnormal), and what will be done with the samples.

V. Information about the implications of screening positive (abnormal) for their future and existing children, and for other family members.

VI. A warning for pregnant women that genetic screening may reveal unexpected and awkward information, for example about paternity.

Nuffield Council on Bioethics
Genetic Screening Ethical Issues, 1993 4.8

Counselling after screening

Screening for carriers can give people fuller information about their genetic status. Should they test positive, it allows them to make informed choices if and when they make decisions about reproduction. Whereas formal counselling may not be
necessary prior to a genetic test, counselling is regarded as essential should such a test prove positive. In The Gift, RYAN discovers that he is a carrier of the defective gene for Friedreich’s ataxia. In this instance Ryan’s counsellor should have first outlined what it means to be a carrier, emphasizing the fact that being a carrier will have no effect on his health now or in the future, and then gone on to outline his options as regards being a potential parent, i.e. he could use the knowledge to guide his choice of partner and choose to have children only with someone who he knows is not a carrier; or he may choose to have children with someone regardless of their status.

The counsellor might also outline the risk of Ryan choosing a partner who is a carrier. For example, with cystic fibrosis, the most common single defect to afflict northern Europeans, the statistical risk of being a carrier is about 1 in 25. No matter how good the counselling is, it should be emphasized that while the choices that come with that knowledge may be seen as liberating by the majority, for a minority that knowledge may be seen as a burden.

At the point where Ryan discovers his carrier status he hasn’t a girlfriend. The question is what does Ryan do when he meets a potential girlfriend? Does he tell her when he first meets her, if he goes to bed with her or does he tell her at all?

ISSUES SURROUNDING SCREENING AND TESTING
PARENTS’ DILEMMAS

	Jennifer Kaye

JENNIFER: Your father was adamant that we both went for screening before trying for a child. I wanted to let nature take its course, and besides the possibility of anything being wrong seemed so unlikely…

Through DNA tests it is possible to explain the risks of having an affected child to potential parents who are known carriers of a disorder. Counselling can outline the options open to them and should ensure a proper understanding so that they
can make their own informed choices. Depending on the disorder (dominant, recessive or sex-linked) and the pattern of inheritance in the family, several choices are available where potential parent(s) are carriers or themselves affected by a genetic disorder.

• To have children without making use of the results of any genetic tests
• Adoption of a child
• To use sperm or eggs donated by someone who is not a carrier
• To use prenatal screening but have a termination if the baby tests positive

Whatever the option available, a counsellor must remain sensitive to a couple’s moral, religious and cultural beliefs. Their decisions and privacy should always be respected and potential parents should be allowed to make a free choice.

PREDICTIVE TESTS

A diagnosis in the case of some disorders can be made many years before any symptoms show. An example is Huntington’s disease, a serious brain disease caused by a single dominant defective gene. Symptoms of Huntington’s disease commonly first appear in individuals between 40 and 50 years of age. DNA tests are now available that can identify individuals who will develop symptoms and these tests can also be carried out prenatally. Given that a cure may be found during the lifetime of a potential Huntington’s disease sufferer the decisions to test a fetus and how to act on the results are likely to be even more difficult for the parents. Symptoms of Friedreich’s ataxia usually occur during adolescence and presently there is no cure. The rights of a minor to know their own status are currently the centre of some debate. There are arguments for and against being screened for a disease that only becomes apparent years later.

• Would you want to know in your adolescence the probable cause and date of your death ?
• What about the emotional and psychological stresses that could accompany that knowledge ?
• What implications might a positive result have on employment, insurance and mortgages ?

  What about the case of a family whose father had died of cancer at the age of 50, before exhibiting the symptoms of progressive degeneration of the brain resulting from the Huntington’s disease gene he carried. His children carried on, unaware they had a 50% risk of developing the disease, went on to higher education and fulfilling careers. The question is would they have done so, had they known their risk status through a predictive test, say one by their father’s employer?

Sue Watkins of the Huntington’s Disease Association addressing a meeting by the Genetic Interest Group

There is nothing that can currently be done to delay, prevent or treat Huntington’s disease. This is not true of some other late onset dominant disorders such as Familial Hypercholesterol or polygenic disorders such as coronary heart disease. Tests for such disorders raise the possibility of treatments that might reduce the risk of becoming ill. If you can be shown to be genetically likely to develop heart disease, you may be able to reduce the risk by stopping smoking or improving your diet. By not taking such a genetic test you might denying yourself the opportunity of a treatment that could prolong your life.

A useful analogy to consider - in paving the way for and informing the complex debate that society will be faced within the near future - is that of the HIV disease. It is not a genetic disorder but is the only comparable contemporary disease here where an individual who feels perfectly healthy is likely to be told years in advance - as a result of testing - that they may die of an incurable disease.

Current research suggests that half of all people infected by HIV will develop AIDS within ten years, and the rest in more than ten years after the infection. The history of HIV and AIDS to date, has highlighted issues such as voluntary/
compulsory testing, confidentiality, employment, insurance, individual rights, discrimination and prejudice.

FUTURE THERAPY

The identification of a gene responsible for a disorder is likely to lead to a DNA test being available. The development of effective therapies may take much longer. However progress for some diseases is being made. Gene therapy trials that attempt to treat cystic fibrosis are just one example of a number underway in the UK and elsewhere. The outcome of such developing research and how long it may take to find a cure is unknown.

Molecular biology has, in an astonishingly brief space of time, been able to pinpoint the sources of much of mankind’s misery (at least those associated with single gene mutations), but it has yet to find the means to put them right. We know the causes, but cannot yet neutralise them. That means we are in an interim phase in modern genetics. We can spot the dangers, but we generally remain powerless to neutralise them, other than by carrying out termination. However that situation is already changing. The first tentative steps to remedying these problems, with the creation of new drugs and genetic therapy, are already being taken.

The Book of Man, Walter Bodmer and Robin McKie

ECONOMICS OF SCREENING

The screening programme for cystic fibrosis in Edinburgh cost £80,000 funded through the Cystic Fibrosis Trust. Of the 1882 women who agreed to be screened, four identified carriers were found to have partners who were also carriers. Of these, only one mother was shown to have an affected fetus and the couple decided to have this pregnancy terminated.

After the end of the project, the Health Authority decided to continue the screening. The current cost to the National Health Service for treating someone who has cystic fibrosis is around £10,000 a year. Life expectancy is at least 20 years, and with the expected advances in medical care in the future it is likely to be between 30 and 40 years, so the average cost of caring for a cystic fibrosis sufferer will certainly exceed £200,000. In the above example, it could be argued that screening is an economical benefit to society. There are, however, inherent dangers in this argument… The public health definition of ‘success’ or failure of a programme may be in danger of turning on too narrow a calculation of costs and benefits. Benefits must not be calculated purely in financial terms of preventing the birth of individuals who may have higher than average health care needs and costs. The benefits should be seen as enabling individuals to take account of the information for their own lives and empowering prospective parents to make informed choices about having children.
Nuffield Council on Bioethics
Genetic Screening Ethical Issues

Economics will continue to be a deciding factor in both the future development of screening programmes and the likely conflict of interests between individuals and the population at large.

SCREENING, TESTING AND THE LAW

	Ryan and Annie Kaye

RYAN: The reason why I want to be tested is so I can plan my future. I’m taking exams at the moment and I might go to college. Also I want to be able to work even if I am going to have the disorder. I need to be able to make an informed choice as to a career and life plan that will take account of my capabilities and needs for the future.

ANNIE: But think about the consequences for your future, Mr Kaye, of a positive result. There is no cure, as you know, and a positive result - evidence of testing - in your medical records can be a black mark on your future - things like applying for mortgages, driving licences, insurance policies.

The gift of our expanding genetic knowledge brings the possibility of both prevention of inherited genetic disorders and of new treatments. Yet it also raises difficult ethical and legal issues. Independent and Parliamentary reports have
identified several topics which need addressing:

VOLUNTARY OR COMPULSORY SCREENING

MARK: And what happens when you are sixteen - at schools all over Eurasia.... gene profiling. Everyone else at college is going through gene profiling, seeing the college medics.

To date in the UK all screening programmes for inherited genetic disorders have been voluntary. Some countries like China have opted for compulsory screening of certain inherited conditions.

Adequately informed consent should be a requirement for all genetic screening programmes. The voluntary nature of the screening process must be emphasised.
Nuffield Council on Bioethics,
Genetic Screening Ethical Issues, 1993

In the future society, portrayed in The Gift, all young people undertake genetic screening at the age of 16. This presumably resulted from the completion of the Human Genome Project and the resolution of the ethical, legal and moral debates we are currently involved in. However, it is, of course, just one possible scenario.

Employment

Genetic tests are not currently required as a prerequisite by employers, although employers may take into account existing information such as medical records. No legislation currently controls the use of genetic data by employers.

Insurance

While British insurance companies currently do not require any genetic tests as a prerequisite for obtaining insurance this could change as more genetic tests become available. In the Summer of 1995, Parliament asked insurance companies
to develop their own code of practice for dealing with the use of genetic information in insurance. They have been asked to do so within 12 months and legislation regulating the use of genetic information after this period remains a possibility.

Confidentiality

Genetic tests raise issues about an individual’s right to privacy and the confidentiality of personal medical information. The recent Select Committee report on Human Genetics recommends that misuse of genetic information should be a criminal and civil offence. As mentioned before, the results of genetic tests often have implications for other family members. While most individuals will be prepared to communicate such important information to other members of their family, there have been instances when an individual decides not to. Arguments have been made that there may be legitimate exceptions to personal privacy.
In such exceptional circumstances the individual’s desire for confidentiality may be overridden. The decision can only be made case by case.
Nuffield Council on Bioethics
Genetic Screening Ethical Issues

SUMMARY

New knowledge about human genetics, and the links between genetic inheritance and susceptibility to disease, have important ethical implications. Medical scientists can now identify the presence of abnormal genes by simple tests that are easy to administer. But what uses might be made of this knowledge? Who should share it? What are the implications for people identified as having an abnormal gene or genes? For their families, for society?